Docstoc

The Neuropsychology of mental illness

Document Sample
The Neuropsychology of mental illness Powered By Docstoc
					This page intentionally left blank
The Neuropsychology of
Mental Illness
The Neuropsychology of
Mental Illness
Edited by
Stephen J. Wood
Melbourne Neuropsychiatry Centre and ORYGEN Research Centre, Departments of Psychiatry and Psychology,
The University of Melbourne, Australia

Nicholas B. Allen
Melbourne Neuropsychiatry Centre and ORYGEN Research Centre, Departments of Psychiatry and Psychology,
The University of Melbourne, Australia

Christos Pantelis
Melbourne Neuropsychiatry Centre and ORYGEN Research Centre, Departments of Psychiatry and Psychology,
The University of Melbourne, Australia
CAMBRIDGE UNIVERSITY PRESS
Cambridge, New York, Melbourne, Madrid, Cape Town, Singapore,
São Paulo, Delhi, Dubai, Tokyo

Cambridge University Press
The Edinburgh Building, Cambridge CB2 8RU, UK

Published in the United States of America by Cambridge University Press, New York

www.cambridge.org
Information on this title: www.cambridge.org/9780521862899
© Cambridge University Press 2009


This publication is in copyright. Subject to statutory exception and to the
provision of relevant collective licensing agreements, no reproduction of any part
may take place without the written permission of Cambridge University Press.
First published in print format 2009

ISBN-13    978-0-511-64162-6       eBook (NetLibrary)

ISBN-13    978-0-521-86289-9       Hardback



Cambridge University Press has no responsibility for the persistence or accuracy
of urls for external or third-party internet websites referred to in this publication,
and does not guarantee that any content on such websites is, or will remain,
accurate or appropriate.

Every effort has been made in preparing this publication to provide accurate and
up-to-date information which is in accord with accepted standards and practice at
the time of publication. Although case histories are drawn from actual cases, every
effort has been made to disguise the identities of the individuals involved.
Nevertheless, the authors, editors and publishers can make no warranties that the
information contained herein is totally free from error, not least because clinical
standards are constantly changing through research and regulation. The authors,
editors and publishers therefore disclaim all liability for direct or consequential
damages resulting from the use of material contained in this publication. Readers
are strongly advised to pay careful attention to information provided by the
manufacturer of any drugs or equipment that they plan to use.
To our wives for all their support
Amanda, Sabura and Kimberley
Contents
    Foreword ix
    Preface xiii
    List of contributors   xv



    Section 1 – Neuropsychological                   8   The neural basis of attention 105
                                                         Susan M. Ravizza, George R. Mangun
    processes                                            and Cameron S. Carter
1   Developmental neuropsychology:                   9   The role of executive functions in
    normative trajectories and risk for                  psychiatric disorders 117
    psychiatric illness 4                                Renée Testa and Christos Pantelis
    Marisa M. Silveri and Deborah A.
                                                     10 Decision-making 138
    Yurgelun-Todd
                                                        Luke Clark and Trevor W. Robbins
2   Processes and mechanisms in
                                                     11 The neuropsychology of social cognition:
    neuropsychiatry: sensory-perceptual    15
                                                        implications for psychiatric disorders 157
    Ester Klimkeit and John L. Bradshaw
                                                        Tamara A. Russell and Melissa J. Green
3   Processes and mechanisms in
    neuropsychiatry: motor-executive
    processes 25
                                                         Section 2 – The importance of
    Nicole Rinehart, Phyllis Chua                        methods
    and John L. Bradshaw                             12 Psychiatric diagnoses: purposes, limitations
4   The neurobiology of the emotion                     and an alternative approach 178
    response: perception, experience                    Henry J. Jackson and Patrick D. McGorry
    and regulation 37                                13 Neuropsychological methods in mental
    Sarah Whittle, Murat Yücel                          disorders research: illustrations from
    and Nicholas B. Allen                               methamphetamine dependence 194
5   Frontal asymmetry in emotion, personality           Steven Paul Woods, Jennifer E. Iudicello, J. Cobb
    and psychopathology: methodological issues          Scott and Igor Grant
    in electrocortical and hemodynamic               14 The study of emotion and the interaction
    neuroimaging 49                                     between emotion and cognition:
    John D. Herrington, Nancy S. Koven, Wendy           methodological perspectives 206
    Heller, Gregory A. Miller and Jack B. Nitschke      Kimberley R. Savage, Nathan A. Gates, Aleksey
6   Behavioral and electrophysiological                 Dumer, Stephanie Assuras, Michelle M. Halfacre
    approaches to understanding language                and Joan C. Borod
    dysfunction in neuropsychiatric disorders:       15 Using neurophysiological techniques
    insights from the study of schizophrenia 67         to study auditory hallucinations
    Gina R. Kuperberg, Tali Ditman, Donna               in schizophrenia 221
    A. Kreher and Terry E. Goldberg                     Judith M. Ford and Daniel H. Mathalon
7   Associative memory 96                            16 Neuroimaging 233
    Marc L. Seal and Anthony P. Weiss                   Paolo Fusar-Poli and Philip McGuire                 vii
         Contents



       17 Psychopharmacological modeling                       Section 4 – Integration and synthesis:
          of psychiatric illness 252
          Garry D. Honey                                       are mental illnesses disorders of
       18 Cognitive phenomics 271                              consciousness? A trialogue between
          Robert M. Bilder, Russell A. Poldrack, D. Stott      neuroscientific, philosophical and
          Parker, Steven Paul Reise, J. David Jentsch,
          Tyrone Cannon, Edythe London, Fred W. Sabb,          psychiatric perspectives
          Lara Foland-Ross, Angela Rizk-Jackson, Donald     27 Mental illness and the consciousness
          Kalar, Nik Brown, Audrey Carstensen and              thesis 390
          Nelson Freimer                                       G. Lynn Stephens and George Graham
                                                            28 A non-reductive physicalist account
           Section 3 – The neuropsychology of                  of affective consciousness 399
                                                               Jaak Panksepp
           psychiatric disorders
                                                            29 Consciousness of oneself and others
       19 Neuropsychology of ADHD and other
                                                               in relation to mental disorders 408
          disorders of childhood 285
                                                               Kai Vogeley and Albert Newen
          Eve M. Valera, Ariel Brown
          and Larry J. Seidman                              30 Trialogue: commentaries on “Are mental
                                                               illnesses disorders of consciousness?”
       20 A multidimensional neurobehavioral model
                                                               Comments on Panksepp and on Vogeley &
          of personality disorders 300
                                                               Newen 414
          Richard A. Depue
                                                               G. Lynn Stephens and George Graham
       21 Neuropsychology in eating disorders      316
                                                               Affective consciousness and the psychiatric
          Laura Southgate, Kate Tchanturia
                                                               comfort zones of experienced life 416
          and Janet Treasure
                                                               Jaak Panksepp
       22 Neurobiological and neuropsychological
                                                               The definition and the constitution of mental
          pathways into substance abuse
                                                               disorders and the role of neural
          and addictive behavior 326
                                                               dysfunctions 420
          Murat Yücel, Dan I. Lubman, Nadia Solowij
                                                               Kai Vogeley and Albert Newen
          and Warrick J. Brewer
                                                               Response to commentaries 423
       23 Neuropsychology of obsessive-compulsive
          disorder 342                                         G. Lynn Stephens and George Graham
          Thilo Deckersbach, Cary R. Savage                    Understanding affects: toward a neurobiology
          and Scott L. Rauch                                   of primary process mentalities 425
       24 Neuropsychological investigation in                  Jaak Panksepp
          mood disorders 353                                   Replies to comments by Jaak Panksepp and
          Paul Keedwell, Simon A. Surguladze                   by G. Lynn Stephens & George Graham 427
          and Mary Philips                                     Kai Vogeley and Albert Newen
       25 Manic distractibility and processing
          efficiency in bipolar disorder 365
          David E. Fleck, Paula K. Shear and Stephen
          M. Strakowski                                        Index   430
       26 Schizophrenia 378                                    The color plates are to be found between pages
          Renée Testa, Stephen J. Wood                         388 and 389.
viii
          and Christos Pantelis
Foreword



It is just over 30 years since the publication of the     even to increase, the distances by insisting on the
influential article by psychiatrist George Engel          “independence” of their own field.
(Engel, G. (1977). The need for a new medical model:          The primary importance of the feeling of unity of
a challenge for biomedicine. Science, 196, 129–136).      individuals is the recurrent motif of this comprehen-
The paper was a significant attempt to bridge the gap     sive handbook. This unity is achieved by an ongoing
between psychiatrists and other medical colleagues to     interaction between individuals and the environment,
enable “psychiatry to become better integrated with       as a whirling dance of the self with the rest of the
medical practice.” The result was what has become         world, which includes paradoxically the very self.
known as the “biopsychosocial model,” almost uni-             The simple conceptual framework of the experiential–
versally accepted as a way to treat human individuals     existential loop that I discuss below may be helpful in
simultaneously as biological organisms, as psycholo-      providing the means to weave elements for such unity
gical beings with subjective feelings and also as         within the extensive collection of diverse articles. This
members of diverse social groups. Despite this serious    framework is based on our evolutionary past, and is
attempt to find a unitary home for the previously         consistent with much of the available scientific literature.
disassembled humans, the model paradoxically retained         The evolution of the brain probably started from a
an even sharper separation between the biology, the       primordial set of functional loops made of (1) sensory
psychology and the social issues of “mental” diseases.    neurons, which encode changes of various physical
The idea that humans exist in two separate worlds,        energies into neural signals, (2) integrating neurons
the “physical” and the “mental” still hovers over much    and (3) motor neurons that transform neural activity
of modern medicine and popular philosophy. The            into mechanical energy. Survival required this pri-
spectre of the proverbial Cartesian dualism of a res      mordial sensorimotor loop to be dynamically adapted
extensa, the world of matter, and the res cogitans, the   to the imperatives of detecting, evaluating and selecting
world of the mind, still lives on.                        amongst the actions to ensure food, water, shelter and
    This encyclopedic volume represents a significant     defense, and reproduction. The already complex loop
contribution to the process of bridging this gap by       for immediate actions and reactions, limited neverthe-
bringing together workers in many diverse areas, all      less the primordial horizon of existence to the present.
focusing on the disturbances of mental life, whether      Evolution has been accompanied by the appearance of
caused by genetic, biological or life experiences. The    increasingly longer, superimposed neural loops that
very title “neuropsychology,” linking the “mental” to     form our brain. With the increased complexity of such
the “neuro,” reflects a precise philosophical choice of   a hierarchical neural system, organisms like us, in
accepting that the mental world is founded solidly on     addition to living in the present, acquired the ability
the neural circuits of the brain. With this aim the       to project their fictitious experiences both in the past,
editors provide a remarkable resource of modern           as memory and in the future, as expectations and
advances in the field. Yet, reading together the many     imagination. Indirect experiences of the past and the
in-depth chapters paradoxically reinforces the feeling    future could be successfully integrated with the imme-
that the desired unity is still somewhat out of reach.    diate experiences of the present. Horizons of existence
Nevertheless this volume will enable readers and the      beyond the present thereby become unlimited.
authors themselves to compare notes and decide                At every new level of superimposed neural
whether to accelerate the process of unification under    loops, corresponding to broader horizons, adaptive
a broad neuroscientific perspective or to retain, or      processes are still required for detection, evaluation
                                                                                                                         ix
       Foreword



    and decision for action. At the higher levels neural              For example, perception disorders, thought dis-
    circuits for perception, emotions and decision-               orders and disorders of executive function may
    making become the corresponding loops for survival            simply represent disturbances of the higher levels of
    in the extended horizons.                                     the experiential–existential loop, which still requires
        Increased awareness of the environment, of one’s          detection, evaluation and action selection.
    body and of one’s intentions via the internal “corol-             The terms appearing across this volume such as
    lary discharges,” evolved in parallel. Awareness of           “underlie,” “cause,” “entail,” “mechanisms,” used to
    other similar beings also developed in parallel, with         refer to the relationship between states of the brain
    “mirror neuron systems” playing critical roles.               and states of mind, reflect the philosophical uncer-
    Humans are the result of the evolutionary accretion           tainties about the nature of such a relationship. Des-
    of these superimposed loops adapted to extend “hori-          pite serious attempts of philosophers to live with
    zons” in time and space and yet also adapted to the           the consequences of the Cartesian dualism, the mind
    present. The unified self is the result of a crafted          irreducible to the biology of the brain, most contribu-
    construction that goes on throughout life.                    tors of this handbook provide convincing evidence
        The balance between “voluntary” top-down influ-           that mental states are always accompanied by more
    ences, interacting with internal standards based on           or less subtle bodily states and vice versa. Hence, the
    prior experiences, and sensory-driven bottom-up               sensible search for new markers, signs and symptoms
    influences reflect the need to apportion actions to           of mental disorders.
    the present or delaying many for the future. This                 What about principles of intervention for mental
    perhaps is the origin of the sense of freedom.                disorders? There is an apparent incompatibility
        The task to maintain an integrated unity in the           between the choice of intervening either on the fun-
    face of many choices for action available within the          damental biological pathology of the brain or on the
    extended horizon is an ongoing challenge for each             life experiences and human interactions that appear
    person. It is not surprising that such a delicate             to have generated the disorders. This alternative has
    dynamic balance to avoid any mismatch between                 divided generations of professionals involved in
    what is experienced subjectively and what is “out             mental and neurological disorders. Yet the framework
    there” is not always achieved. Indeed, new emerging           of multiple levels of existential loops may help to
    levels that are usually acquired originally with aware-       overcome the apparent incompatibility of views. A
    ness, become more automatic, moving below the                 pharmacological agent or a genetic disorder affecting
    horizon of consciousness and are thus not easily cor-         some aspect of synaptic transmission are bound to
    rected. The gradual automatization of the lower loops         have effects on the state of the entire system of super-
    probably generates the inner feeling that top-down            imposed loops. Similarly, words (psychological ther-
    “voluntary” influences are effortful, while bottom-up         apies) will modify the state of higher loops, and thus
    influences are effortless. Was this the origin of the clash   the synaptic transmission in these. This reciprocal
    between will and flesh? Between spirit and matter?            interdependence of the biological on the psycho-
        The increased dependence from frontal lobe cir-           logical (and social) is the unavoidable consequence
    cuits for delaying and inhibiting actions are revealed        of the functional architecture of the hierarchical
    in the very syndromes of frontal disinhibition and            system of existential loops.
    various types of acquired sociopathy, perhaps evolu-              The brain, core of such loops, is a single biological
    tionary prices to pay for the flexibility of goal-directed    organ evolved for the adaptation of bodily functions,
    behaviour in an ever-changing environment.                    social interactions and awareness of the world and the
        Many of the difficulties confronting neuropsycho-         self (consciousness).
    logy in deciding what are the more fundamental levels             The editors should be commended for providing
    of interplay of the organisms with the world can be           a path for the difficult, but not impossible, process
    brought back to the complexity of multiple superim-           of bringing human existence under a single
    posed loops. The concepts of bottom-up and top-               perspective.
    down within these loops begin to make sense of
    otherwise incomprehensible observations in clinical                                             Marcello Costa, FAA
x   and experimental neuropsychology.                                                       Professor of Neurophysiology
                                                                                                   Foreword



Marcello Costa, is a Fellow of the Australian Academy     of the Australian Neuroscience Society, becoming its
of Science (FAA) and Professor of Neurophysiology         President for a term in the 1990s. He has increasingly
at Flinders University in Adelaide, South Australia.      become interested in the broader issues of how to
He was educated in Argentina and Italy where he           navigate across the many neural domains, while
obtained his medical degree before moving to Australia.   maintaining scientific rigor and without trivializing
He has been involved in research and teaching neuro-      the problems inherent in such cross-disciplinary
science for over 40 years. He was one of the founders     dialogue.




                                                                                                                   xi
Preface



A neuropsychological approach to understanding            diagnosis. In the second section various experts sum-
various mental disorders has flourished over the last     marize and critique the methodological approaches
two decades, and particularly over the decade or so       used in the study of neuropsychological processes
since the publication of a book on the neuropsycho-       within mental illness, and discuss future directions
logy of schizophrenia by one of us (Pantelis et al.,      and innovations, including the use of sophisticated
1996). Since then, the field has evolved and matured      analysis methods to complement traditional
tremendously, with an exponential rise in the number      approaches in order to address unique questions.
of publications in this area. While the largest body of   Section 3 covers each of the major disorders, and is
work has been in schizophrenia, the methods and           particularly interesting in providing a “state of the art”
approaches of neuropsychology have begun to inform        summary of neuropsychological findings for each con-
our understanding of all psychiatric disorders. Neuro-    dition. The final section considers whether the neuro-
psychology has been of particular importance in           psychology of consciousness is an appropriate
helping to unravel the mechanisms underlying brain        integrative rubric under which to conceptualize these
function, and has helped us to understand the impact      disorders, and represents a “trialogue” between neuro-
of treatments on various abilities and their relevance    scientists, psychiatrists and philosophers. This section
to functional outcome in psychiatric disorders.           is unique in that the contributors of each chapter offer
Indeed, our motivation to produce this book evolved       a commentary on the other chapters on this theme.
from our growing interest in a neuropsychological             We hope that this book will be valuable to all who
approach across such disorders, and to inform the         are interested in studying the healthy as well as the
interface of neuropsychology with other neurobio-         disordered brain, not only those from the fields of
logical approaches, such as neuroimaging and genet-       psychology, neuroscience, psychiatry and philosophy,
ics. We have brought together some of the world’s         but also all who have an interest in understanding
leading experts in the field to discuss approaches,       how our brains work.
conditions and future directions.                             The editors thank all the authors who have con-
    The book is divided into a number of sections,        tributed to this volume. Special thanks to Renée Testa
including an introductory section that lays out the       for helping with proofing the various chapters, and to
rationale for examining neuropsychological processes      Barbara Stachlewski for her assistance in the final
within clinical disorders. The study of these processes   stages of the book.
provides a complementary approach to diagnostically
oriented approaches to neuropsychological dysfunc-        Reference
tion. Given that dysfunction in some processes is         Pantelis, C., Nelson, H. E. & Barnes, T. R. E. (1996).
common across disorders, this approach has the              Schizophrenia: A Neuropsychological Perspective.
potential to offer new insights into etiology and           London: John Wiley.




                                                                                                                       xiii
Contributors



Nicholas B. Allen                                    Ariel Brown
ORYGEN Youth Health Research Centre and              Clinical and Research Programs in Pediatric
Department of Psychology                             Psychopharmacology and Adult ADHD
University of Melbourne                              Massachusetts General Hospital
Parkville, VIC, Australia                            Boston, MA, USA

Stephanie Assuras                                    Nik Brown
Department of Psychology                             Department of Computer Science
Queens College and The Graduate Center               University of Calfornia at Los Angeles
of the City University of New York                   Los Angeles, CA, USA
Flushing, NY, USA
                                                     Tyrone Cannon
Robert M. Bilder                                     Jane and Terry Semel Institute for Neuroscience and
Jane and Terry Semel Institute for Neuroscience      Human Behavior
                                                     Department of Psychology
and Human Behavior, Lynda and Stewart
                                                     David Geffen School of Medicine at UCLA
Resnick Neuropsychiatric Hospital
                                                     Los Angeles, CA, USA
David Geffen School of Medicine at UCLA
Los Angeles, CA, USA
                                                     Audrey Carstensen
                                                     Brain Research Institute
Joan C. Borod
                                                     David Geffen School of Medicine at UCLA
Department of Psychology                             Los Angeles, CA, USA
Queens College and The Graduate Center of the City
University of New York                               Cameron S. Carter
Flushing, NY, USA, & Department of Neurology
                                                     Departments of Psychiatry and Psychology
Mount Sinai School of Medicine
                                                     University of California, Davis
New York, NY, USA
                                                     UC Davis Imaging Research Center
                                                     Sacramento, CA, USA
John L. Bradshaw
School of Psychology Psychiatry and Psychological    Luke Clark
Medicine                                             Department of Experimental Psychology
Monash University                                    University of Cambridge
Clayton, VIC                                         Cambridge, UK
Australia
                                                     Phyllis Chua
Warrick J. Brewer                                    School of Psychology, Psychiatry and Psychological
ORYGEN Youth Health Research Centre                  Medicine
The University of Melbourne                          Monash University
Parkville, VIC                                       Clayton, VIC                                          xv
Australia                                            Australia
        List of contributors



      Thilo Deckersbach                                     De Crespigny Park
      Department of Psychiatry                              London, UK
      Massachusetts General Hospital/Harvard Medical
      School                                                Nathan A. Gates
      Charlestown, MA, USA                                  Department of Psychology
                                                            Queens College and The Graduate Center of the City
      Richard A. Depue                                      University of New York
      Laboratory of Neurobiology of Personality             Flushing, NY, USA
      Department of Human Development                       Terry E. Goldberg
      Cornell University
                                                            Psychiatry Research
      Ithaca, NY, USA
                                                            Zucker Hillside Hospital
      Tali Ditman                                           Glen Oaks, NY
      Department of Psychology,                             Albert Einstein College of Medicine
      Tufts University &                                    New York City, NY, USA
      Department of Psychiatry                              George Graham
      Massachusetts General Hospital                        Department of Philosophy
      Boston, MA, USA                                       Georgia State University
      Aleksey Dumer                                         Atlanta, GA, USA
      Department of Psychology                              Igor Grant
      Queens College and The Graduate Center of the City    Department of Psychiatry
      University of New York                                University of California, San Diego
      Flushing, NY, USA                                     La Jolla, CA, USA
      David E. Fleck                                        Melissa J. Green
      Department of Psychiatry                              School of Psychiatry
      University of Cincinnati                              University of New South Wales & Black Dog Institute
      Cincinnati, OH, USA                                   Prince of Wales Hospital
                                                            Randwick, NSW
      Lara Foland-Ross
                                                            Australia
      Laboratory of Neuroimaging
      Brain Research Institute                              Michelle M. Halfacre
      David Geffen School of Medicine at UCLA               Department of Psychology
      Los Angeles, CA, USA                                  Queens College and The Graduate Center of the City
                                                            University of New York
      Judith M. Ford
                                                            Flushing, NY, USA
      Department of Psychiatry
      University of California, San Francisco               Wendy Heller
      San Francisco, CA, USA                                Psychology Department and Beckman Insititute for
                                                            Advance Science and Technology
      Nelson Freimer                                        University of Illinois at Urbana-Champaign
      Center for Neurobehavioral Genetics                   Champaign, IL, USA
      Jane and Terry Semel Institute for Neuroscience and
      Human Behavior                                        John D. Herrington
      David Geffen School of Medicine at UCLA               University of Illinois at Urbana-Champaign
      Los Angeles, CA, USA                                  Urbana, IL, USA

      Paolo Fusar-Poli                                      Garry D. Honey
xvi   Neuroimaging Section                                  University of Cambridge
      King’s College London Institute of Psychiatry         Department of Psychiatry
                                                                                  List of contributors



Brain Mapping Unit                                 Tufts University
Cambridge, UK                                      Boston, MA, USA

Jennifer E. Iudicello                              Edythe London
Joint Doctoral Program in Clinical Psychology      Jane and Terry Semel Institute for Neuroscience and
San Diego State University                         Human Behavior
University of California, San Diego                Department of Pharmacology
San Diego, CA, USA                                 David Geffen School of Medicine at UCLA
                                                   Los Angeles, CA, USA
Henry J. Jackson
                                                   Dan I. Lubman
Department of Psychology
                                                   ORYGEN Research Centre
University of Melbourne
                                                   The University of Melbourne
Parkville, VIC
                                                   Parkville, VIC
Australia
                                                   Australia
J. David Jentsch                                   Daniel H. Mathalon
Department of Psychology                           Department of Psychiatry
University of California, Los Angeles              University of California, San Francisco
Los Angeles, CA, USA                               San Francisco, CA, USA
Donald Kalar                                       Patrick D. McGorry
Department of Psychology                           ORYGEN Research Centre
David Geffen School of Medicine at UCLA            The University of Melbourne
Los Angeles, CA, USA                               Parkville, VIC
                                                   Australia
Paul Keedwell
Department of Psychological Medicine               Philip McGuire
Cardiff University Hospital                        Neuroimaging Section
Cardiff, Wales, UK                                 King’s College London Institute of Psychiatry
                                                   De Crespigny Park
Ester Klimkeit
                                                   London, UK
Monash University Centre for Developmental
Psychiatry and Psychology                          George R. Mangun
Monash Medical Centre                              Center for Mind and Brain
Clayton, VIC                                       Departments of Psychology and Neurology
Australia                                          University of California, Davis
                                                   Davis, CA USA
Nancy S. Koven
Department of Psychology                           Gregory A. Miller
Bates College                                      University of Illinois at Urbana-Champaign
Lewiston, ME, USA                                  Urbana, IL, USA
Donna A. Kreher                                    Albert Newen
Department of Psychology                           Department of Philosophy
Tufts University                                   University of Tuebingen
Medford, MA, USA                                   Germany

Gina R. Kuperberg                                  Jack B. Nitschke
Department of Psychiatry, Mass. General Hospital   Departments of Psychiatry and Psychology
and Athinoula A. Martinos Center of Biomedical     University of Wisconsin at Madison                    xvii
Imaging, & Department of Psychology,               Madison, WI, USA
          List of contributors



        Jaak Panksepp                                           Trevor W. Robbins
        Department of VCAPP                                     Department of Experimental Psychology
        College of Veterinary Medicine                          University of Cambridge
        Washington State University                             Cambridge, UK
        Pullman, WA, USA
                                                                Tamara A. Russell
        Christos Pantelis                                       Macquarie Centre for Cognitive Science
        Melbourne Neuropsychiatry Centre                        Macquarie University
        The University of Melbourne & Melbourne Health          North Ryde, NSW
        National Neuroscience Facility (NNF)                    Australia
        Carlton South, VIC
        Australia                                               Fred W. Sabb
                                                                Jane and Terry Semel Institute for Neuroscience and
        Mary Philips                                            Human Behavior
        Director of Functional Neuroimaging Program             Department of Psychology
        Department of Clinical Psychiatry                       David Geffen School of Medicine at UCLA
        Western Psychiatric Institute                           Los Angeles, CA, USA
        University of Pittsburgh Medical Centre
        Pittsburgh, PA, USA                                     Cary R. Savage
                                                                Hoglund Brain Imaging Center
        Russell A. Poldrack                                     Department of Psychiatry and Behavioral Sciences
        Departments of Psychology and Psychiatry &              Kansas University Medical Center
        Biobehavioral Sciences UCLA                             Kansas City, KS, USA
        Los Angeles, CA, USA
                                                                Kimberley R. Savage
        Scott L. Rauch                                          Department of Psychology
        Psychiatry for Neuroscience Research                    Queens College and The Graduate Center of the City
        Massachusetts General Hospital/Harvard Medical School   University of New York
        Charlestown, MA, USA                                    Flushing, NY, USA
        Susan M. Ravizza                                        J. Cobb Scott
        Department of Psychology                                Joint Doctoral Program in Clinical Psychology
        Michigan State University                               San Diego State University
        East Lansing, MI, USA                                   University of California, San Diego
                                                                San Diego, CA, USA
        Steven Paul Reise
        Department of Psychology                                Marc L. Seal
        Franz Hall, UCLA                                        Melbourne Neuropsychiatry Centre
        Los Angeles, CA, USA                                    The University of Melbourne & Melbourne Health
                                                                National Neuroscience Facility (NNF)
        Nicole Rinehart                                         Carlton South, VIC, Australia
        Center for Developmental Psychology and Psychiatry
        School of Psychology Psychiatry and Psychological       Larry J. Seidman
        Medicine                                                Harvard Medical School Departments of
        Monash University                                       Psychiatry at Beth Israel Deaconess Medical
        Nottinghill, VIC                                        Center and Massachusetts General Hospital
        Australia                                               Boston, MA, USA
        Angela Rizk-Jackson                                     Paula K. Shear
        Brain Research Institute                                Department of Psychology
xviii   David Geffen School of Medicine at UCLA                 University of Cincinnati
        Los Angeles, CA, USA                                    Cincinnati, OH, USA
                                                                                 List of contributors



Marisa M. Silveri                                 National Neuroscience Facility
Cognitive Neuroimaging Laboratory                 Carlton South, VIC
McLean Brain Imaging Center                       Australia, and
Belmont, MA, USA                                  Monash University
                                                  School of Psychology, Psychiatry and
Nadia Solowij                                     Psychological Medicine
School of Psychology                              Clayton, VIC, Australia
University of Wollongong                          Sunshine Hospital
Wollongong, NSW, Australia and,                   St Albans, VIC, Australia
Schizophrenia Research Institute
Sydney, NSW, Australia                            Janet Treasure
                                                  Department of Academic Psychiatry
Laura Southgate                                   Guy’s Hospital
Section of Eating Disorders                       King’s College London Institute of Psychiatry
Psychological Medicine                            London, UK
King’s College London Institute of Psychiatry
De Crespigny Park
                                                  Eve M. Valera
London, UK
                                                  Clinical and Research Programs in Pediatric
G. Lynn Stephens                                  Psychopharmacology and in Psychiatric
Department of Philosophy                          Neuroscience
University of Alabama at Birmingham               Department of Psychiatry
Birmingham, AL, US                                Massachusetts General Hospital\Harvard Medical
                                                  School
D. Stott Parker                                   Charlestown, MA, USA
Department of Computer Science
University of Calfornia at Los Angeles            Kai Vogeley
Los Angeles, CA, USA                              Department of Psychiatry
                                                  University of Cologne
Stephen M. Strakowski                             Cologne, Germany
Department of Psychiatry
Center for Imaging Research                       Anthony P. Weiss
University of Cincinnati College of Medicine      Department of Psychiatry
Cincinnati, OH, USA                               Massachusetts General Hospital and Harvard Medical
                                                  School
Simon A. Surguladze                               Boston, MA, USA
Division of Psychological Medicine & Psychiatry
King’s College London Institute of Psychiatry
De Crespigny Park                                 Sarah Whittle
London, UK                                        ORYGEN Research Centre & Melbourne
                                                  Neuropsychiatry Centre
Kate Tchanturia                                   The University of Melbourne
Section of Eating Disorders                       VIC, Australia
Psychological Medicine
King’s College London Institute of Psychiatry     Stephen J. Wood
London, UK                                        Melbourne Neuropsychiatry Centre
                                                  The University of Melbourne & Melbourne Health
René Testa                                        National Neuroscience Facility (NNF)
Melbourne Neuropsychiatry Centre                  Carlton South, VIC                                    xix
University of Melbourne and Melbourne Health      Australia
       List of contributors



     Steven Paul Woods                     The University of Melbourne and Melbourne Health
     Department of Psychiatry              Parkville, VIC
     University of California, San Diego   Australia
     La Jolla, CA, USA
                                           Deborah A. Yurgelun-Todd
     Murat Yücel                           Brain Institute
     ORYGEN Research Centre & Melbourne    University of Utah
     Neuropsychiatry Centre                Salt Lake City, UT, USA




xx
Section   Neuropsychological processes

    1
          Why examine neuropsychological processes in mental illness?
          In the first section of this volume we have included a series of chapters that examine the neuropsycho-
          logical mechanisms that underlie a range of basic psychological processes with relevance to understand-
          ing mental illness. There are a number of reasons for beginning the volume in this way. First, many
          neuropsychological processes are more amenable to objective measurement than the core symptoms of
          mental disorder (which often rely on self report for their “gold-standard” measurement through
          diagnostic interviews – see Jackson and McGorry, Chapter 12, this volume). As such, neuropsycho-
          logical evaluation of basic psychological functions may ultimately be used to aid diagnosis, especially in
          cases where self report is impaired.
              Furthermore, although still far from complete, the brain bases for many neuropsychological
          functions have been established to some degree. In contrast, our understanding of the neural correlates
          of psychiatric symptoms is much more hazy. Studying neuropsychological processes may help our
          understanding of which brain regions are involved, and when they first show dysfunction. Consistent
          with this is the observation that although genetic risk factors for mental illness are well established
          (McGuffin et al., 2002), many scientists conjecture that the relationship between genetic vulnerability
          and disease phenotypes will be clarified if intermediate phenotypes or endophenotypes are also included
          in models (Beauchaine et al., 2008; Meyer-Lindberg & Weinberger, 2006). Because these intermediate
          markers fall along the causal chain between the distal genotype and disease they are likely to be more
          strongly associated with both the disease phenotype and the genotype than these latter variables will be
          with each other (Gottesman & Gould, 2003). As such, the examination of intermediate phenotypes and
          endophenotypes can be critical in both identifying the specific alleles associated with risk for psycho-
          pathology, and also in developing a mechanistic understanding of the particular neurobiological and
          behavioral expressions of the genotype that are proximally involved in the transition for risk to
          disorder. The neuropsychological processes examined here constitute an important set of such potential
          intermediate phenotypes (Abbott, 2008).
              Furthermore, although the diagnostic system treats disorders as categorical entities, most disorders
          do not satisfy strict taxometric criteria for classes (Haslam, 2003). In other words, in many cases we are
          imposing a categorical distinction where none exists in nature. Associated with this issue are the facts
          that comorbidity between diagnoses is common (Jacobi et al., 2004; Kessler et al., 2005), and that
          similar symptoms are often observed across different disorders (Krueger, 1999). Examining basic
          neuropsychological process in mental disorder may therefore help to clarify the nature of the distinction
          between disordered and non-disordered states in a more principled way, and also may help to explain
          the patterns of comorbidity between diagnostic entities.
              Finally, many analyses of the definition of mental disorder have emphasized that understanding the
          nature of disordered psychological and neuropsychological function is critical to the distinction
          between disordered and non-disordered states. For example Wakefield’s “Harmful Dysfunction”
          analysis of mental disorder (Wakefield, 1999) proposes that mental disorder must have two properties.
          “Harmful” refers to the fact that the features of the disorder cause significant harm to a person under
                                                                                                                          1
          present cultural circumstances. This first criterion is therefore partially defined by the current social and
    Section 1: Neuropsychological processes



                    cultural context. However, in order to qualify as a true mental disorder the condition must also result from
                    the inability of some internal mental mechanism to perform its “natural function.” In this context “natural
                    function” is defined as the ability of that mechanism to perform the task for which the mechanism was
                    “designed” by evolution. In other words, one strong implication of this analysis is that one must begin with
                    an understanding of the natural (or evolutionarily designated) neuropsychological functions of the
                    brain, before neuropsychological dysfunction (and therefore mental disorder itself ), can be defined.
                         With these considerations in mind, we felt that it was appropriate to begin the volume by surveying
                    the neuropsychology of a range of basic process that are implicated in mental disorder. The section
                    begins with a chapter by Silveri and Yurgelun-Todd on the role of developmental processes. They
                    conclude that neuropsychological evaluation of children and adolescents can reveal important changes
                    in cognitive function that may relate to later onset of psychopathology, and note the important role that
                    risk status and age must have in interpreting such evaluations. They note the importance of differenti-
                    ating between the normal trajectory of cognitive development, delayed achievement of developmental
                    milestones and cognitive deficits associated with risk for psychiatric illness.
                         This chapter is followed by contributions addressing sensory and perceptual processes (by Klimkeit
                    and Bradshaw). They note that while anomalies of perceptual processes are good models that partly
                    explain higher-level neuropsychiatric dysfunction, the link between perception and action will ulti-
                    mately be critical to our understanding of the neuropsychological basis of psychiatric disorder.
                    Accordingly, motor executive processes are reviewed by Rinehart, Chua and Bradshaw. The potential
                    etiological relevance of neuromotor dysfunction has long been noted in a number of psychiatric
                    disorders, especially autism and schizophrenia. However, developments in our understanding of the
                    connectivity between the prefrontal cortex, basal ganglia and cerebellum has resulted in renewed
                    interest in the application of neuromotor assessment in psychiatry. Rinehart and colleagues particularly
                    note advances in our understanding of higher-order awareness and control of “action,” mirror neurons,
                    the concept of affordances, utilization behavior and extreme neurological motor conditions such as the
                    anarchic hand, and explore what these findings may have to offer our understanding of mental illness.
                         Whittle, Yücel and Allen provide an overview of neurobiological models of emotion, with an
                    emphasis on the specific neuropsychological systems involved in the perception of emotional stimuli,
                    the experience of emotion, and its regulation. Herrington, Koven, Heller, Miller and Nitschke then
                    examine the links between emotion, personality and psychopathology, with a specific emphasis on the
                    role of asymmetry of brain function in these processes. They note the benefit of integrating multiple
                    theoretical perspectives from personality psychology with theories regarding the frontal lateralization
                    of emotion. They conclude that determining which psychological construct best explains lateralization
                    in the frontal lobes may depend on which area of the frontal cortex is being examined. They suggest that
                    hemodynamic imaging will be an invaluable tool for addressing these questions, and explore the
                    appropriate data analytic techniques.
                         The role of language is explored by Kuperberg, Ditman, Kreher and Goldberg, and they show how
                    paradigms at various levels of language including words, sentences, and discourse, can be used to study
                    neuropsychiatric disorders. They provide a broad theoretical framework to help understand the
                    relationships between these levels of dysfunction and to help guide future theoretically motivated
                    studies of language, particularly in schizophrenia. Seal and Weiss examine associative memory and
                    note several challenges exist for associative memory research in mental illness. One is to make more
                    extensive use of memory research in the neuropsychology of non-psychotic disorder such as depression
                    and obsessive-compulsive disorder. Increasing the sensitivity and specificity of associative memory
                    tasks to both cognitive processes and brain regions is also an important challenge. They also note that
                    exploring the molecular and genetic mechanisms that underlie memory dysfunction in mental illness is
                    a critical priority for future research.
                         Attentional control and selection is addressed by Ravizza, Mangun and Carter. They note that the
2                   ability to control attention involves the interaction of specific cortical and subcortical neural networks
                    influencing multiple stages of information processing. They conclude that to elucidate the neural
                                                          Section 1: Neuropsychological processes



mechanisms of attention, and its abnormalities in mental illness, it is essential to investigate and
characterize attentional processes at a variety of levels of information processing. Likewise, Testa and
Pantelis note that although the evidence of a fractionated executive system in mental illness is strong,
the use of different executive tests to assess unique cognitive functions is an important challenge for
future research in the area.
    Clark and Robbins then explore the neuropsychology of decision-making, particularly implicating
prefrontal cortical pathology in the decision-making deficits observed in mental illness. Once again,
they note that developing assessment methods that isolate the various subcomponents of these
neuropsychological functions is a significant challenge, albeit one upon which significant progress is
being made. Finally, Russell and Green examine the neuropsychology of social cognition. Given the
prominence of social dysfunction in those suffering from mental illness, understanding the neural
networks subserving social cognition may prove to be particularly important for identifying the
neuropathology of major psychiatric disorders, and is likely to be pertinent to the formulation of effective
treatments for social cognitive disturbances in these individuals. They also address the critical question of
domain specificity with respect to social cognitive processes and conclude that while neuropsychological
studies suggest that social cognition cannot be fully accounted for by domain-general processes (such as
attention, memory or executive function), this does not warrant an overarching conclusion that social
cognition is completely independent of domain-specific processes.
    In sum, this collection of chapters provides the reader with a series of up-to-date reviews of the
neuropsychology of basic psychological functions as they pertain to mental illness. Critically, they also
clearly lay out the future research agenda that must be addressed in order for examination of these
processes to continue to advance our understanding of mental illness.

References
Abbott, A. (2008). The brains of the family. Nature, 454, 154–157.
Beauchaine, T. P., Hinshaw, S. P. & Gatzke-Kopp, L. (2008). Genetic and environmental influences
   on behavior. In T. P. Beauchaine & S. P. Hinshaw (Eds.), Child and Adolescent Psychopathology
   (pp. 58–90). Hoboken, NJ: John Wiley & Sons.
Gottesman, I. I. & Gould, T. D. (2003). The endophenotype concept in psychiatry: etymology and
  strategic intentions. American Journal of Psychiatry, 160, 636–645.
Haslam, N. (2003). Categorical versus dimensional models of mental disorder: the taxometric evidence.
  Australian and New Zealand Journal of Psychiatry, 37(6), 696–704.
Jacobi, F., Wittchen, H. U., HöLting, C. et al. (2004). Prevalence, co-morbidity and correlates of mental
   disorders in the general population: results from the German Health Interview and Examination
   Survey (GHS). Psychological Medicine, 34(4), 597–611.
Kessler, R. C., Berglund, P., Demler, O. et al. (2005). Lifetime prevalence and age-of-onset distributions
  of DSM–IV disorders in the National Comorbidity Survey Replication. Archives of General
  Psychiatry, 62(6), 593.
Krueger, R. F. (1999). The structure of common mental disorders. Archives of General Psychiatry,
  56(10), 929–931.
McGuffin, P., Owen, M. J. & Gottesman, II. (2002). Psychiatric Genetics and Genomics. New York, NY:
  Oxford University Press.
Meyer-Lindenberg, A. & Weinberger, D. R. (2006). Intermediate phenotypes and genetic mechanisms
  of psychiatric disorders. Nature Review Neuroscience, 7(10), 818–827.
Wakefield, J. C. (1999). Evolutionary versus prototype analyses of the concept of disorder. Journal of
  Abnormal Psychology, 108(3), 374–399.


                                                                                                                3
        Chapter




                1
                         Developmental neuropsychology:
                         normative trajectories and risk
                         for psychiatric illness
                         Marisa M. Silveri and Deborah A. Yurgelun-Todd


    Introduction                                                   permit the rapid improvements in cognitive abilities
                                                                   observed from infancy through late adolescence.
    Examination of neuropsychological functioning, both                 To date a large body of research has focused not
    in healthy populations and in individuals with brain           only on structural brain development, but also on the
    injury, has provided important information with re-            maturation of individual neuropsychological domains
    gard to lateralization of cognitive function, sex differ-      and the process by which these domains become
    ences in neuropsychological performance, functional            integrated during development (Webb et al., 2001).
    differences associated with disconnection syndromes,           It is known that both genetic and experiential factors
    and cognitive capacity at various developmental stages.        play a role in how brain networks develop (Nelson,
    Studies of neuropsychological performance conducted            2000; Williamson et al., 2003). Furthermore, brain
    at different maturational levels have helped identify          maturation and cognitive function have been shown
    abnormalities associated with childhood disorders,             to be sensitive to the timing of both toxic exposure
    including chromosomal and genetic disorders, struc-            and environmental experience (see Knudsen, 2004;
    tural abnormalities, prematurity and low birth weight,         Thompson & O’Quinn, 1979). This dynamic process
    infections, toxic damage, nutritional disorders, anoxic        of brain maturation therefore raises special challenges
    disorders, traumatic brain injury, focal neurological          for the neuropsychological evaluation of children and
    disorders, convulsive disorders, hemispherectomy               adolescents.
    and other effects of surgical manipulations (Spreen
    et al., 1995b). The utility of neuropsychological assess-
    ment in children and adolescents with neuropatho-
    logic conditions is not only to provide information            Neuropsychological domains
    regarding their progress in achieving normative devel-         Neuropsychological assessment is aimed at measuring
    opmental milestones but also to provide a framework            cognitive-intellectual ability. Cognition is the process
    for the identification of brain dysfunction and for the        of knowing or thinking, and in childhood age-related
    development of remediation strategies.                         changes in cognition occur, including quantitative
        Significant development of the central and periph-         increments in cognitive ability. Early researchers con-
    eral nervous systems occurs throughout early life,             sidered cognitive processing capacity as a unitary
    with major alterations being observed from infancy             measure, however this approach proved limited,
    to adolescence (for review, see Huttenlocher, 1994).           since deficits may be found in a specific cognitive
    These rapidly evolving systems include the sensory             area while performance in other cognitive functional
    systems (auditory, visual, chemical senses, somes-             areas remains essentially intact (Lezak, 1995). This led
    thetic), motor systems (pyramidal and extrapyrami-             clinicians and researchers to focus on the assessment
    dal) and integrative higher-order systems (association         of separate functional domains. In general, these
    areas, reticular formation and brainstem chemical              domains include attention, memory, executive func-
    pathways, language areas) (Spreen et al., 1995a). Both         tion, language, visuospatial function, and processing
    structural and functional changes in these systems             speed, which are described in greater detail below.



4   The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by
    Cambridge University Press. # Cambridge University Press 2009.
                                                                     Chapter 1: Developmental neuropsychology



Attention                                                    lobe during rotational tests, and that subjects with
Attention encompasses a number of functions, includ-         lesions in their right parietal lobe perform worse on
ing four different commonly reported components:             mental rotation tasks than both normal controls and
divided attention, the ability to perform two tasks          subjects with lesions in their left parietal lobe
simultaneously; sustained attention, the ability to          (Ditunno & Mann, 1990; Papanicolaou et al., 1987).
maintain attention over an extended time; selective
attention, the ability to filter out irrelevant informa-
                                                             Language
tion to focus on the task attention; and attentional         Language processes can be divided into three catego-
switching, the ability to switch between attention sets.     ries, including expressive speech, object naming and
Attentional capacity can vary significantly depending        language comprehension. Studies involving the elec-
on mood state and level of arousal, as well as matu-         trical stimulation of the brain have implicated three
rational level. The neural substrate for attention is        main cortical areas of interest regarding language
thought to lie within a complex set of networks includ-      processes: the anterior language area (Broca’s area),
ing the frontal cortex, the posterior parietal cortex and    the posterior language area (Wernicke’s area), and
the reticular formation (Stuss & Benson, 1984).              the supplementary language area (the supplementary
                                                             motor area) (Penfield & Jasper, 1954; Penfield &
                                                             Perot, 1963; Penfield & Roberts, 1959). Broca’s area
Memory
                                                             in the inferior frontal gyrus is largely responsible
Memory is an active process that records information         for language processing and speech production, and
from the past so that it may be used in the present. It      Wernicke’s area in the superior temporal gyrus is
involves a number of processes including encoding,           important for speech comprehension (Lezak, 1995).
storage and retrieval. Memory deficits are most often        These processes are lateralized to the left hemisphere
due to retrieval and encoding problems rather than           in most individuals. The posterior-inferior temporal
limitations in storage capacity. Anatomical regions          gyrus has been identified as the “naming center”
implicated in memory involve multiple bilateral              of the brain, and is important for object naming
brain regions, with the hippocampus and the frontal          (Penfield & Roberts, 1959).
lobes being particularly important. Working memory
involves short-term maintenance, sorting and manipu-         Speed of processing
lation of new and retrieved information; and is often        Speed of processing typically measures the required
considered a component of the attentional domain.            time to complete a specific cognitive task (Reitan &
Brain regions important for working memory include           Wolfson, 1985; Smith, 1991). Multiple brain regions
the prefrontal cortex and the inferior parietal lobule       are involved in this function, although white matter
(Goethals et al., 2002), as well as the visual association   integrity is thought to be particularly important, since
area, the inferior temporal cortices and portions of the     the size of axons and the thickness of myelin are
cerebellum (Berman et al., 1995).                            predictors of speed of processing (Gao et al., 1999).
                                                             Changes in white matter that are associated with a
Visuospatial function                                        reduction in processing speed may also affect per-
Visuospatial function encompasses the ability to visu-       formance in other cognitive domains, such as atten-
alize objects in space. Tasks that measure visuospatial      tion and working memory.
function include tests of mental rotation and spatial
localization, both of which require intact parietal          Executive function
lobes, particularly in the right hemisphere (Benton,         Executive functions include a broad range of pro-
1985; Heilman & Van Den Abell, 1980). The visual             cesses involved in implementing goal-oriented behav-
features of an object are processed via a pathway from       ior. These processes include inhibitory function,
the occipital to the temporal cortex, called the ventral     mental flexibility and planning. These behaviors are
stream, and the spatial locations are processed via a        dependent on multiple cortical networks including
pathway from the occipital to the parietal cortex,           prefrontal areas and posterior association areas,
called the dorsal stream (Ungerleider & Mishkin,             particularly the dorsolateral prefrontal cortex.
1982). Studies have shown that cerebral blood flow           Spontaneous flexibility in particular is reliant on        5
increases are significantly higher in the right parietal     the frontal cortex, whereas reactive flexibility
       Section 1: Neuropsychological processes



    requires intact cortical-striatal interconnections           scale study to measure information processing, as
    (Eslinger & Grattan, 1993).                                  indexed by habituation to novel stimuli, in children
        Age-related increases in cognitive capacity are          examined at 4, 6, 18, 24 and 49 months of age.
    thought to reflect brain maturational changes. During        Habituation efficiency observed at 4 months was
    childhood and adolescence these neurobiological              shown to predict performance observed on the
    changes are paralleled by greater functional capacity,       Denver Developmental Screening Test (6 months),
    as well as more efficient synchronization of function        the Mental Development Scale (18 months), the
    between individual cognitive domains. Neuropsycho-           British English MacArthur Communicative Develop-
    logical measures can provide estimates of overall            mental Inventory (24 months) and the Wechsler
    intellectual ability and can assist in the identification    Preschool and Primary Scale of Intelligence Revised
    of deficits within functional domains. It is this            (49 months). The authors concluded that subtle
    approach that has provided the greatest insights             differences during the development of a cascade of
    into the neuropsychological changes associated with          age-appropriate achievements could influence later
    psychiatric disorders.                                       academic success.
                                                                     Significant improvements in cognitive processing
    Considerations in the assessment                             speed and intellectual functioning have been shown to
                                                                 continue into childhood and adolescence, with the
    of children                                                  most dramatic improvements occurring in the devel-
    It is important that appropriately designed neuro-           opment of executive functions including abstract
    psychological tests are used to evaluate children.           thought, organization, decision-making and plan-
    Often, adult tests are modified for use with younger         ning, and response inhibition (Anderson, 2001;
    populations; however, these may not provide an               Klenberg et al., 2001; Rosso et al., 2004; Williams
    accurate functional assessment, because children and         et al., 1999). Recent neuroimaging studies have pro-
    adolescents may not have fully developed the skills          vided evidence for changes in brain structure and
    required. Further, tests designed to assess specific         function being commensurate with improvements
    adult abilities may not accurately reflect the same          in cognitive abilities. For instance, rapid brain re-
    cognitive features in children. Age-appropriate tests        organization has been shown to include changes in
    are clearly required to accurately assess the cognitive      white and gray matter, each of which undergo distinct
    skills of children and adolescents, in order to consider     developmental patterns, with white matter increasing
    the varying abilities associated with different develop-     (reflecting myelination) and gray matter decreasing
    mental stages.                                               (reflecting synaptic pruning). There is a growing body
        There are additional challenges involved in pedi-        of evidence demonstrating significant relationships
    atric neuropsychological assessments, including the          between brain structure and function with cognitive
    need to be aware of and account for several factors          processing speed and performance (Casey et al., 1997;
    that can affect the test performance of children in          Reiss et al., 1996; Sowell et al., 2001; Yurgelun-Todd
    different age groups. These include attentional ca-          et al., 2002). Age-related improvements in higher-
    pacity, including distractibility, as well as the level of   order cognitive domains, including executive func-
    social skill of the child. Issues related to mood, includ-   tions, are thought to be related not only to a marked
    ing stress and anxiety, are also important consider-         re-organization of the frontal lobe (Giedd et al., 1999;
    ations when interpreting performance data, given             Pfefferbaum et al., 1994; Sowell et al., 1999, 2001), but
    the fear associated with separation from a parental          also to improved functional white matter connectivity
    figure, new locations and/or testing situations.             within and between brain regions during adolescence
                                                                 (Giedd et al., 1999; Pfefferbaum et al., 1994).
    Developmental neuropsychology                                    In summary, rapid improvements in cognitive
                                                                 function are observed from infancy through adoles-
    milestones                                                   cence, as well as into adulthood. Neuropsychological
    Cognition during infancy is largely observed as infor-       assessment of a variety of cognitive domains show
    mation processing. These maturing processes include          distinct developmental patterns, with the develop-
6   the development of attention, learning and inhibitory        ment of information processing occurring very early
    function. Bornstein et al. (2006) conducted a large-         in life and more complex, higher-order cognitive
                                                                    Chapter 1: Developmental neuropsychology



abilities, such as abstraction capacity and planning,       groups in these studies varied, but included cohorts
that come online during adolescence and into adult-         of children of psychiatrically healthy parents, children
hood. Thus, examination of normative developmental          of parents with depressive disorder, children of
patterns of cognitive function, as well as delays or        parents with a physical illness, and less frequently,
impairments in cognition, provide an informative            children of parents with manic-depression illness, or
framework for understanding and identifying indi-           bipolar disorder.
vidual profiles of cognitive performance deficits later         Several large-scale cohort studies also have been
in life. In addition, alterations in cognitive abilities    conducted. These studies have typically followed
observed in the first decades of life may reflect risk      thousands of participants from childhood into adult-
factors for the later onset of psychiatric illness.         hood. Individuals are examined on clinical and
                                                            cognitive measures at specified intervals, with the
Neuropsychological deficits: risk                           objective of identifying variables that may predict
                                                            later onset of psychosis. As with the high-risk studies,
for psychiatric illness                                     the majority of the cohort studies have been con-
As indicated earlier, studying neuropsychological           ducted to examine adult onset of schizophrenia (for
performance in children serves as a valuable strategy       review see Jones & Tarrant, 2000). These studies
for identifying potential risk factors associated with      include, but are not limited to, the British 1946 birth
the development of psychiatric illness. Over the past       cohort (Jones et al., 1994; Jones & Done, 1997), the
50 years, a number of studies have been conducted to        British 1958 National Child Development Study
examine neuropsychological performance in children,         (Done et al., 1994; Jones & Done, 1997), the North
with the goal of identifying areas of cognitive function    Finland 1966 birth cohort (Isohanni et al., 1997;
that might be associated with onset of psychiatric          Rantakallio, 1988), the 1949–1950 Swedish Conscript
illness. In general, three types of research studies have   Study (David et al., 1997; Malmberg et al., 1998) and
been reported: (1) genetic high risk for psychiatric        the Israeli Conscript Study (Davidson et al., 1999).
illness in children of one or both parents with a           While these studies have focused on identifying
psychiatric disorder; (2) large-scale longitudinal          risk factors associated with schizophrenia, additional
examination of population birth cohorts; (3) short-         data have been reported for risk for affective and
term longitudinal examination of male conscripts;           bipolar disorders (Done et al., 1994; Isohanni et al.,
and (4) follow-back studies of pre-illness levels of        1997; Jones et al., 1994; Rantakallio, 1988; van Os
cognitive functioning in adults inflicted with a psy-       et al., 1997).
chiatric illness. Results from genetic high risk and            It has been suggested that the paucity of develop-
population birth cohort and conscript studies will be       mental investigations focusing on risk factors for
briefly examined and discussed to highlight the             bipolar illness is due to difficulty with diagnostic
approaches used in earlier investigations.                  classification and limited numbers of patients with
    The majority of the genetic high-risk studies con-      first-onset bipolar disorder within samples ideal for
ducted during the last 50 years examined children of        cohort studies. Thus, most cohort studies utilize a
parents with schizophrenia (for review, see Niemi           general affective disorder category. Furthermore, it
et al., 2003). Sixteen high-risk studies were conducted     is possible that cognitive risk factors for some forms
between 1952 and 1994, requiring that at least one          of bipolar illness, which may have an earlier age of
parent (predominantly the mother) meet criteria             onset than schizophrenia, are difficult to detect against
for schizophrenia (Niemi et al., 2003). There have          a background of rapidly changing cognitive abilities
been a significant number of additional investigations      observed during the first two decades of life. The results
conducted since 1994, which have examined children          of genetic high risk and population cohort studies
and adolescents who are the offspring of schizo-            are discussed below, as they relate to the manifesta-
phrenic parents (e.g. see Byrne et al., 1999; Cornblatt     tion of schizophrenia, bipolar disorder and depression.
et al., 1999; Cornblatt & Keilp, 1994; Davalos et al.,      Although not a topic reviewed in this chapter, a
2004; Goldstein et al., 2000; Sorensen et al., 2006),       number of investigations have also found abnormalities
although only one recent high-risk study examined           in social and emotional functioning during childhood
cognitive performance in offspring of bipolar parents       and adolescence to be associated with heightened risk        7
(McDonough-Ryan et al., 2002). The comparison               for the development of schizophrenia (e.g. Done et al.,
       Section 1: Neuropsychological processes



    1994) and affective disorders (Dworkin et al., 1991,         their later manifestation of schizophrenia (Cannon
    1994; Gotlib et al., 2005).                                  et al., 2002; Davidson et al., 1999; Jones et al., 1994;
                                                                 Jones & Done, 1997).
                                                                     Cohort studies, given their longitudinal nature,
    Schizophrenia                                                are particularly well suited to characterize develop-
    Risk for schizophrenia has been studied extensively          mental neuropsychology milestones and the role of
    in children of parents with schizophrenia, with such         such development on the risk for future psychopath-
    studies examining a wide range of clinical, experi-          ology. For instance, subjects in the British 1946 birth
    mental and cognitive measures.                               cohort were examined prospectively at 11 time points
        Genetic high-risk studies have documented ab-            prior to age 16 (Wadsworth, 1987). Thirty cases of
    normalities in intelligence quotient (IQ), attention,        schizophrenia were diagnosed from this birth cohort,
    executive functioning and verbal memory in high-risk         with these subjects demonstrating later attainment of
    children relative to psychiatrically healthy children        developmental milestones during the course of the
    or children at risk for affective disorder, although         study (Jones et al., 1994; Jones & Done, 1997). Sub-
    study findings have been inconsistent. For instance,         jects from the British 1958 National Child Develop-
    a number of studies have documented lower intelli-           ment Study were examined at birth, 7, 11, 16 and 23
    gence quotient (IQ) in high-risk children relative to        years. Twenty-nine subjects from this cohort were
    healthy comparison children (Byrne et al., 1999;             later diagnosed with schizophrenia. Manifestation of
    Goldstein et al., 2000; Goodman, 1987; Neale et al.,         schizophrenia was associated with pre-schizophrenic
    1984; Rieder et al., 1977), while other studies have         reductions in verbal and performance IQ, delayed
    failed to find such differences (Klein & Salzman, 1984;      advancement in mathematics and reading, and lower
    Lifshitz et al., 1985; Mednick & Schulsinger, 1968;          levels of general knowledge (Done et al., 1994; Jones
    Sameroff et al., 1984; Sohlberg, 1985; Worland &             & Done, 1997). Children and adolescents were exam-
    Hesselbrock, 1980; Worland et al., 1982, 1984).              ined from ages 7–12 and again in mid-adulthood in
    Impairments in attention observed in high-risk               the New York High-Risk Project. Verbal memory
    children relative to comparison children have been           deficits, gross motor abnormalities and deficits in
    observed on some (Cornblatt et al., 1999; Cornblatt &        attention observed early in life predicted 83%, 75%
    Keilp, 1994; Erlenmeyer-Kimling & Cornblatt, 1992;           and 58%, respectively, of adult cases of schizophrenia
    Erlenmeyer-Kimling et al., 2000; Mirsky, 1988;               from this sample (Erlenmeyer-Kimling et al., 2000).
    Nuechterlein, 1984; Schreiber et al., 1992; Weintraub,           Conscript studies may provide more limited
    1987) but not all neuropsychological measures of             information with regard to cognitive risk for psychi-
    attention (Driscoll, 1984). Furthermore, there is evi-       atric illness, as individuals who are conscripts are
    dence that high-risk children demonstrate abnormal-          typically males aged 18 or older that are involuntarily
    ities in other functional domains including working          enrolled in military service (i.e. “drafted”). Data from
    memory (Davalos et al., 2004), executive functioning         conscript studies have likewise found significant rela-
    (Byrne et al., 1999), math and spelling (Ayalon &            tionships between low IQ and manifestation of
    Merom, 1985; Mirsky, 1988), verbal skills (Davalos           schizophrenia (David et al., 1997; Davidson et al.,
    et al., 2004; Weintraub, 1987), verbal memory                1999; Malmberg et al., 1998). Although these studies
    (Erlenmeyer-Kimling et al., 2000) and perceptual             similarly offer a longitudinal perspective, changes
    motor speed (Mirsky, 1988; Sorensen et al., 2006).           observed during a younger course of cognitive devel-
        Cohort and conscript studies examining risk for          opment may be more informative. For instance, in
    the development of schizophrenia have likewise               the 1949–1950 Swedish Conscript Study, males were
    reported evidence for attenuated levels of IQ during         examined at age 18 and again up to 13 years after the
    development, which was associated with later devel-          initial assessment (David et al., 1997; Malmberg et al.,
    opment of schizophrenia (Cannon et al., 2002; David          1998). In the Israeli Conscript Study, males were first
    et al., 1997; Done et al., 1994; Jones et al., 1994; Jones   examined at age 16 or 17 and then re-examined
    & Done, 1997; Malmberg et al., 1998). Deficits in            between 4 and 10 years after initial assessment
    verbal and non-verbal abilities, as well as mathemat-        (Davidson et al., 1999). Cohort studies, given the
8   ical skills and organizational abilities have also been      younger age period and more repetitive assessments,
    reported in cohorts of children examined prior to            may therefore be more sensitive in characterizing
                                                                    Chapter 1: Developmental neuropsychology



developmental abnormalities associated with risk for            There is evidence for a relative impairment on
psychiatric illness. Nevertheless, findings from con-       measures of performance ability (PIQ) versus verbal
script studies suggest that estimates of less efficient     abilities (VIQ) in high-risk children compared with
intellectual functioning were associated with a broad       psychiatrically healthy controls (Decina et al., 1983;
category of psychotic disorders. It is important to         Kestenbaum, 1979; McDonough-Ryan et al., 2002).
note, however, that high-risk studies typically have        However, not all high-risk studies have found this
documented more marked abnormalities across a               deficit; Worland & Hesselbrock (1980) reported that
greater number of cognitive domains (as opposed to          VIQ, PIQ and general IQ did not differ between the
IQ alone) than cohort and conscript studies, under-         offspring of manic depressives and non-psychiatric
scoring the influential roles of both genetics and          control children. Interestingly, of the 6 offspring of
environmental factors on manifestation of psychiatric       parents with manic depression and the 17 offspring
illness.                                                    of parents with unipolar depression, the offspring of
    In summary, high-risk, cohort and conscript stud-       manic-depressive parents demonstrated lower VIQ
ies of children have indicated that attenuated matu-        than offspring of parents with unipolar depression.
rational increases in IQ as well as deficits in several     There was also evidence from a high-risk sample
cognitive domains may be associated with later devel-       of delayed achievement of cognitive milestones in
opment of the disorder. Diminished psychomotor              individuals from the North Finland 1966 birth cohort,
function, delayed achievement of developmental              however, no distinction was found between subjects
milestones, and attention deficits are all cognitive        who developed either schizophrenia or bipolar illness
domain abnormalities that have been associated with         (Isohanni et al., 1997; Rantakallio, 1988). There have
increased risk of developing schizophrenia.                 also been no significant differences in overall IQ
                                                            found between children of bipolar parents and chil-
                                                            dren of non-psychiatric parents (Grigoroiu-Serbanescu
Bipolar and depressive illness                              et al., 1989; Todd et al., 1994).
The majority of studies of individuals at risk for              Surprisingly, there also are limited high-risk inves-
bipolar disorder have been conducted during adult-          tigations that specifically focus on the role of neuro-
hood rather than during childhood or adolescence            psychological deficits associated with major depressive
(Ferrier et al., 2004; Gourovitch et al., 1999; Keri        disorder. Often, children of parents with depression
et al., 2001; Zalla et al., 2004). Cognitive changes have   are included as comparison subjects in studies exam-
not been consistently reported in adult high-risk popu-     ining children of parents with schizophrenia and bipo-
lations (Kremen et al., 1998), as several adult studies     lar disorder. To this end, the majority of studies that
have documented cognitive deficits in psychiatrically       have included children with high-risk for depression
healthy relatives of people with schizophrenia but          have failed to find consistent cognitive impairments
not in relatives of bipolar patients (Clark et al.,         relative to healthy controls and offspring of parents
2005; Gilvarry et al., 2000; MacQueen et al., 2004;         with other psychopathologies. For instance, two stud-
Schubert & McNeil, 2005). However, a number of              ies failed to find differences in IQ between groups of
studies examining neuropsychological functions in           children at risk for depression as compared with chil-
adult unaffected relatives of bipolar patients have         dren of psychiatrically healthy parents (Pellegrini et al.,
reported poorer performances (Gourovitch et al.,            1986; Weissman et al., 1987). Furthermore, in the 1946
1999; Sobczak et al., 2003; Zalla et al., 2004). These      National Survey of Health and Development cohort
investigators suggest that deficits in verbal memory,       study, although subtle decrements in educational test
attention and psychomotor function may be associ-           scores were associated with onset of affective disorder
ated with risk for bipolar disorder. There is a paucity,    during adulthood, more pervasive cognitive abnor-
however, of child and adolescent genetic high-risk          malities were only observed when the onset of affective
(Decina et al., 1983; Kestenbaum, 1979; McDonough-          disorder occurred during childhood (van Os et al.,
Ryan et al., 2002; Worland & Hesselbrock, 1980) or          1997). Similarly, only small differences on educational
cohort studies (Isohanni et al., 1997; Rantakallio,         tests were found in prodromal children, whereas more
1969), and there are no conscript studies that are          marked deficits were observed in pre-schizophrenic
aimed at examining developmental cognitive deficits         children from the 1958 National Child Development             9
associated with bipolar illness.                            Study (Done et al., 1994; Jones & Done, 1997).
       Section 1: Neuropsychological processes



         In summary, there are relatively few developmental    cognitive tasks are complex or effortful. For instance,
     cognitive data that suggest risk for acquiring bipolar    test performance on measures of executive function
     disorder. Reduced performance IQ compared with            and attentional capacity would be expected to differ
     verbal IQ has been associated with increased risk for     between children and older adolescents, given the
     bipolar disorder, as well as delayed achievement of       significant maturation of the frontal cortex during
     developmental milestones in children prior to the         this age period. Therefore it is essential to differen-
     appearance of both schizophrenia and bipolar dis-         tiate between the normal trajectory of cognitive
     order. Evidence for cognitive impairments associated      development, delayed achievement of developmental
     with risk for development of major depressive dis-        milestones and cognitive deficits associated with risk
     order tends to be more subtle, and appears limited to     for psychiatric illness. In summary, the study of
     small differences on educational tests, as compared       cognitive processes provides empirical research find-
     with the more pronounced deficits observed for            ings that complement diagnostic evaluation. Previous
     verbal memory, attention, estimated intellectual ca-      investigations have identified deficits in a number
     pacity (IQ) and other complex cognitive deficits          of functional domains including attention, verbal
     observed in children at risk for schizophrenia and        memory and estimated level of intellectual function-
     bipolar illness.                                          ing that may predict the onset of psychiatric illness.
                                                               Future studies should characterize the normative tra-
                                                               jectory of neuropsychological function and the neuro-
     Conclusion                                                biological correlates associated with compensatory
     Neuropsychological evaluation of children and ado-        mechanisms that would in turn improve early diag-
     lescents can reveal important changes in cognitive        nosis and treatment approaches.
     function that may relate to later onset of psychopath-
     ology. There are several limitations that should be
     considered when identifying these deficits as potential   Acknowledgments
     risk factors for the later manifestation of psychiatric   This work was supported by K01 AA014651 (MMS)
     illness. First, data collected from children at high      and R01 MH069840 (DYT).
     risk should be interpreted cautiously, as there can
     be increased incidence of prodromal symptoms and
     presence of other psychopathological traits that could    References
     contribute to the observed neuropsychological profile.    Anderson, V. (2001). Assessing executive functions in
     In addition, children at high risk for psychosis may be     children: biological, psychological, and developmental
     exposed to a greater number of environmental stress-        considerations. Pediatric Rehabilitation, 4(3), 119–136.
     ors as a result of being reared in a household with one   Ayalon, M. & Merom, H. (1985). The teacher interview.
     or two parents with a diagnosable psychiatric condi-        Schizophrenia Bulletin, 11(1), 117–120.
     tion. Importantly, the age of assessment must be          Benton, A. (1985). Some problems associated with
     considered when examining the neuropsychological            neuropsychological assessment. Bulletin on Clinical
     functioning of children, given that multiple and rapid      Neuroscience, 50, 11–15.
     changes in cognitive abilities are occurring during       Berman, K. F., Ostrem, J. L., Randolph, C. et al. (1995).
     childhood and adolescence.                                   Physiological activation of a cortical network during
         Cognitive impairments observed in both high-risk         performance of the Wisconsin Card Sorting Test: a
     and cohort studies do not consistently predict psychi-       positron emission tomography study. Neuropsychologia,
                                                                  33(8), 1027–1046.
     atric illness, as a large number of subjects who have
     measurable deficits during development (even in the       Bornstein, M. H., Hahn, C. S., Bell, C. et al. (2006). Stability
                                                                 in cognition across early childhood. A developmental
     high-risk group) do not go on to develop schizophre-
                                                                 cascade. Psychological Science, 17(2), 151–158.
     nia or other psychiatric illnesses. It is important to
                                                               Byrne, M., Hodges, A., Grant, E., Owens, D. C. & Johnstone,
     consider then, the presence of adaptive or compen-
                                                                  E. C. (1999). Neuropsychological assessment of young
     satory strategies that may help overcome cognitive           people at high genetic risk for developing schizophrenia
     vulnerabilities associated with risk for psychiatric         compared with controls: preliminary findings of the
10   illness. In younger children, it may be particularly         Edinburgh High Risk Study (EHRS). Psychological
     difficult to identify neuropsychological deficits when       Medicine, 29(5), 1161–1173.
                                                                           Chapter 1: Developmental neuropsychology



Cannon, M., Caspi, A., Moffitt, T. E. et al. (2002). Evidence        symptoms: a longitudinal study of children and
  for early-childhood, pan-developmental impairment                  adolescents at risk for schizophrenia and affective
  specific to schizophreniform disorder: results from a              disorder. American Journal of Psychiatry, 148(9),
  longitudinal birth cohort. Archives of General Psychiatry,         1182–1188.
  59(5), 449–456.                                                 Dworkin, R. H., Lewis, J. A., Cornblatt, B. A. &
Casey, B. J., Trainor, R., Giedd, J. et al. (1997). The role of     Erlenmeyer-Kimling, L. (1994). Social competence
  the anterior cingulate in automatic and controlled                deficits in adolescents at risk for schizophrenia. Journal
  processes: a developmental neuroanatomical study.                 of Nervous and Mental Diseases, 182(2), 103–108.
  Developmental Psychobiology, 30(1), 61–69.                      Erlenmeyer-Kimling, L. & Cornblatt, B. A. (1992).
Clark, L., Kempton, M. J., Scarna, A., Grasby, P. M. &               A summary of attentional findings in the New York
   Goodwin, G. M. (2005). Sustained attention-deficit                High-Risk Project. Journal of Psychiatric Research, 26(4),
   confirmed in euthymic bipolar disorder but not in first-          405–426.
   degree relatives of bipolar patients or euthymic unipolar      Erlenmeyer-Kimling, L., Rock, D., Roberts, S. A. (2000).
   depression. Biological Psychiatry, 57(2), 183–187.                Attention, memory, and motor skills as childhood
Cornblatt, B., Obuchowski, M., Roberts, S., Pollack, S. &            predictors of schizophrenia-related psychoses: the New
  Erlenmeyer-Kimling, L. (1999). Cognitive and                       York High-Risk Project. American Journal of Psychiatry,
  behavioral precursors of schizophrenia. Development                157(9), 1416–1422.
  and Psychopathology, 11(3), 487–508.                            Eslinger, P. J. & Grattan, L. M. (1993). Frontal lobe and
Cornblatt, B. A. & Keilp, J. G. (1994). Impaired attention,          frontal-striatal substrates for different forms of human
  genetics, and the pathophysiology of schizophrenia.                cognitive flexibility. Neuropsychologia, 31(1), 17–28.
  Schizophrenia Bulletin, 20(1), 31–46.                           Ferrier, I. N., Chowdhury, R., Thompson, J. M., Watson, S.
Davalos, D. B., Compagnon, N., Heinlein, S. & Ross, R. G.            & Young, A. H. (2004). Neurocognitive function in
  (2004). Neuropsychological deficits in children                    unaffected first-degree relatives of patients with bipolar
  associated with increased familial risk for schizophrenia.         disorder: a preliminary report. Bipolar Disorder, 6(4),
  Schizophrenia Research, 67(2–3), 123–130.                          319–322.
David, A. S., Malmberg, A., Brandt, L., Allebeck, P. &            Gao, W. Q., Shinsky, N., Ingle, G. et al. (1999). IGF-I
  Lewis, G. (1997). IQ and risk for schizophrenia: a                deficient mice show reduced peripheral nerve
  population-based cohort study. Psychological Medicine,            conduction velocities and decreased axonal diameters
  27(6), 1311–1323.                                                 and respond to exogenous IGF-I treatment. Journal of
Davidson, M., Reichenberg, A., Rabinowitz, J., Weiser, M.,          Neurobiology, 39(1), 142–152.
  Kaplan, Z. & Mark, M. (1999). Behavioral and                    Giedd, J. N., Blumenthal, J., Jeffries, N. O. et al. (1999).
  intellectual markers for schizophrenia in apparently               Brain development during childhood and adolescence:
  healthy male adolescents. American Journal of                      a longitudinal MRI study. Nature Neuroscience, 2(10),
  Psychiatry, 156(9), 1328–1335.                                     861–863.
Decina, P., Kestenbaum, C. J., Farber, S. et al. (1983).          Gilvarry, C., Takei, N., Russell, A. et al. (2000). Premorbid
  Clinical and psychological assessment of children of               IQ in patients with functional psychosis and their first-
  bipolar probands. American Journal of Psychiatry, 140              degree relatives. Schizophrenia Research, 41(3), 417–429.
  (5), 548–553.                                                   Goethals, I., Audenaert, K., Jacobs, F. et al. (2002). Toward
Ditunno, P. L. & Mann, V. A. (1990). Right hemisphere               clinical application of neuropsychological activation
   specialization for mental rotation in normals and brain          probes with SPECT: a spatial working memory task.
   damaged subjects. Cortex, 26(2), 177–188.                        Journal of Nuclear Medicine, 43(11), 1426–1431.
Done, D. J., Crow, T. J., Johnstone, E. C. & Sacker, A. (1994).   Goldstein, J. M., Seidman, L. J., Buka, S. L. et al. (2000).
  Childhood antecedents of schizophrenia and affective              Impact of genetic vulnerability and hypoxia on overall
  illness: social adjustment at ages 7 and 11. British              intelligence by age 7 in offspring at high risk for
  Medical Journal 309(6956), 699–703.                               schizophrenia compared with affective psychoses.
Driscoll, R. (1984). Intentional and incidental learning in         Schizophrenia Bulletin, 26(2), 323–334.
   children vulnerable to psychopathology. In N. F. Anthony,      Goodman, S. H. (1987). Emory University Project on
   E. J. Anthony, L. C. Wynne & J. E. Rolf (Eds.), Children         Children of Disturbed Parents. Schizophrenia Bulletin,
   at Risk for Schizophrenia: A Longitudinal Perspective            13(3), 411–423.
   (pp. 320–326). New York, NY: Cambridge University Press.       Gotlib, I. H., Traill, S. K., Montoya, R. L., Joormann, J. &
Dworkin, R. H., Bernstein, G., Kaplansky, L. M. et al.              Chang, K. (2005). Attention and memory biases in the
  (1991). Social competence and positive and negative               offspring of parents with bipolar disorder: indications       11
        Section 1: Neuropsychological processes



        from a pilot study. Journal of Child Psychology and           Klenberg, L., Korkman, M. & Lahti-Nuuttila, P. (2001).
        Psychiatry, 46(1), 84–93.                                        Differential development of attention and executive
     Gourovitch, M. L., Torrey, E. F., Gold, J. M. et al. (1999).        functions in 3- to 12-year-old Finnish children.
       Neuropsychological performance of monozygotic twins               Development and Neuropsychology, 20(1), 407–428.
       discordant for bipolar disorder. Biological Psychiatry,        Knudsen, E. I. (2004). Sensitive periods in the development
       45(5), 639–646.                                                  of the brain and behavior. Journal of Cognitive
                                                                        Neuroscience, 16(8), 1412–1425.
     Grigoroiu-Serbanescu, M., Christodorescu, D., Jipescu, I.
        et al. (1989). Psychopathology in children aged 10–17 of      Kremen, W. S., Faraone, S. V., Seidman, L. J., Pepple, J. R. &
        bipolar parents: psychopathology rate and correlates of          Tsuang, M. T. (1998). Neuropsychological risk indicators
        the severity of the psychopathology. Journal of Affective        for schizophrenia: a preliminary study of female relatives
        Disorders, 16(2–3), 167–179.                                     of schizophrenic and bipolar probands. Psychiatry
                                                                         Research, 79(3), 227–240.
     Heilman, K. M. & Van Den Abell, T. (1980). Right
       hemisphere dominance for attention: the mechanism              Lezak, M. D. (1995). Neuropsychological Assessment
       underlying hemispheric asymmetries of inattention                 (3rd edn.). New York, NY: Oxford University Press.
       (neglect). Neurology, 30(3), 327–330.                          Lifshitz, M., Kugelmass, S. & Karov, M. (1985).
     Huttenlocher, P. R. (1994). Synaptogenesis in human                 Perceptual-motor and memory performance of high-risk
       cerebral cortex. In G. Dawson & K. W. Fischer (Eds.),             children. Schizophrenia Bulletin, 11(1), 74–84.
       Human Behavior and the Developing Brain (pp. 137–152).         MacQueen, G. M., Grof, P., Alda, M., Marriott, M., Young,
       New York, NY: Guilford Press.                                    L. T. & Duffy, A. (2004). A pilot study of visual backward
     Isohanni, M., Makikyro, T., Moring, J. et al. (1997).              masking performance among affected versus unaffected
        A comparison of clinical and research DSM-III-R                 offspring of parents with bipolar disorder. Bipolar
        diagnoses of schizophrenia in a Finnish national birth          Disorder, 6(5), 374–378.
        cohort. Clinical and research diagnoses of schizophrenia.     Malmberg, A., Lewis, G., David, A. & Allebeck, P. (1998).
        Society of Psychiatry and Psychiatric Epidemiology, 32(5),      Premorbid adjustment and personality in people with
        303–308.                                                        schizophrenia. British Journal of Psychiatry, 172,
     Jones, P., Rodgers, B., Murray, R. & Marmot, M. (1994).            308–313.
        Child development risk factors for adult schizophrenia        McDonough-Ryan, P., DelBello, M., Shear, P. K. et al.
        in the British 1946 birth cohort. Lancet, 344(8934),            (2002). Academic and cognitive abilities in children of
        1398–1402.                                                      parents with bipolar disorder: a test of the nonverbal
     Jones, P. B. & Done, D. J. (1997). From birth to onset: a          learning disability model. Journal of Clinical and
        developmental perspective of schizophrenia in two               Experimental Neuropsychology, 24(3), 280–285.
        national birth cohorts. In M. S. Keshavan & R. M. Murray      Mednick, S. A. & Schulsinger, F. (1968). Some premorbid
        (Eds.), Neurodevelopment and Adult Psychopathology              characteristics related to breakdown in children with
        (pp. 119–136). New York, NY: Cambridge University               schizophrenic mothers. In D. Rosenthal & S. S. Kety
        Press.                                                          (Eds.), Transmission of Schizophrenia (pp. 267–292).
     Jones, P. B. & Tarrant, C. J. (2000). Developmental                Oxford, UK: Pergamon Press.
        precursors and biological markers for schizophrenia and       Mirsky, A. F. (1988). The Israeli high-risk study. In Relatives
        affective disorders: specificity and public health              at Risk for Mental Disorders (Dunner, D. L. &
        implications. European Archives in Psychiatry and               Gershon, E. S., eds). New York, NY: Raven Press.
        Clinical Neuroscience, 250(6), 286–291.
                                                                      Neale, J. M., Winters, K. C. & Weintraub, S. (1984).
     Keri, S., Kelemen, O., Benedek, G. & Janka, Z. (2001).             Information processing deficits in children at high-risk
       Different trait markers for schizophrenia and bipolar            for schizophrenia. In Children at Risk for Schizophrenia:
       disorder: a neurocognitive approach. Psychological               A Longitudinal Perspective (Watt, N. F., Anthony, E. J.,
       Medicine, 31(5), 915–922.                                        Wynne, L. C. & Rolf, J. E., eds), pp. 264–277. New York,
     Kestenbaum, C. J. (1979). Children at risk for manic-              NY: Cambridge University Press.
       depressive illness: possible predictors. American Journal      Nelson, C. A. (2000). Neural plasticity and human
       of Psychiatry, 136(9), 1206–1208.                                development: the role of early experience in sculpting
     Klein, R. H. & Salzman, L. F. (1984). Response-contingent          memory systems. Developmental Science, 3, 115–130.
        learning in children at-risk. In N. F. Watt, E. J. Anthony,   Niemi, L. T., Suvisaari, J. M., Tuulio-Henriksson, A. &
        L. C. Wynne & J. E. Rolf (Eds.), Children at Risk for            Lonnqvist, J. K. (2003). Childhood developmental
        Schizophrenia: A Longitudinal Perspective (pp. 371–375).         abnormalities in schizophrenia: evidence from high-risk
12      New York, NY: Cambridge University Press.                        studies. Schizophrenia Research, 60(2–3), 239–258.
                                                                         Chapter 1: Developmental neuropsychology



Nuechterlein, K. (1984). Sustained attention among                 (Eds.), Children at Risk for Schizophrenia: A Longitudinal
  children vulnerable to adult schizophrenia and among             Perspective (pp. 482–513). New York, NY: Cambridge
  hyperactive children. In N. F. Watt, E. J. Anthony, L. C.        University Press.
  Wynne & J. E. Rolf (Eds.), Children at Risk for               Schreiber, H., Stolz-Born, G., Heinrich, H., Kornhuber,
  Schizophrenia: A Longitudinal Perspective (pp. 304–312).         H. H. & Born, J. (1992). Attention, cognition, and motor
  New York, NY: Cambridge University Press.                        perseveration in adolescents at genetic risk for
Papanicolaou, A. C., Deutsch, G., Bourbon, W. T. et al.            schizophrenia and control subjects. Psychiatry Research,
   (1987). Convergent evoked potential and cerebral blood          44(2), 125–140.
   flow evidence of task-specific hemispheric differences.      Schubert, E. W. & McNeil, T. F. (2005). Neuropsychological
   Electroencephalography and Clinical Neurophysiology,            impairment and its neurological correlates in adult
   66(6), 515–520.                                                 offspring with heightened risk for schizophrenia and
Pellegrini, D., Kosisky, S., Nackman, D. et al. (1986).            affective psychosis. American Journal of Psychiatry,
   Personal and social resources in children of patients           162(4), 758–766.
   with bipolar affective disorder and children of normal       Smith, A. (1991). Symbol Digit Modalities Test. Los Angeles,
   control subjects. American Journal of Psychiatry, 143(7),      CA: Western Psychological Services.
   856–861.
                                                                Sobczak, S., Honig, A., Schmitt, J. A. & Riedel, W. J.
Penfield, W. & Jasper, H. (1954). Epilepsy and the                 (2003). Pronounced cognitive deficits following an
   Functional Anatomy of the Human Brain. Boston, MA:              intravenous L-tryptophan challenge in first-degree
   Little Brown.                                                   relatives of bipolar patients compared to healthy
Penfield, W. & Perot, P. (1963). The brain’s record of             controls. Neuropsychopharmacology, 28(4), 711–719.
   auditory and visual experience. A final summary and          Sohlberg, S. C. (1985). Personality and neuropsychological
   discussion. Brain, 86, 595–696.                                 performance of high-risk children. Schizophrenia
Penfield, W. & Roberts, L. (1959). Speech and Brain                Bulletin, 11(1), 48–60.
   Mechanisms. New York, NY: Oxford University Press.           Sorensen, H. J., Mortensen, E. L., Parnas, J. & Mednick, S. A.
Pfefferbaum, A., Mathalon, D. H., Sullivan, E. V. et al.           (2006). Premorbid neurocognitive functioning in
   (1994). A quantitative magnetic resonance imaging               schizophrenia spectrum disorder. Schizophrenia Bulletin,
   study of changes in brain morphology from infancy to            32(3), 578–583.
   late adulthood. Archives of Neurology, 51(9), 874–887.       Sowell, E. R., Delis, D., Stiles, J. & Jernigan, T. L. (2001).
Rantakallio, P. (1969). Groups at risk in low birth weight        Improved memory functioning and frontal lobe
  infants and perinatal mortality. Acta Paediatrica               maturation between childhood and adolescence: a
  Scandinavica, 193(Suppl.), 1.                                   structural MRI study. Journal of the International
Rantakallio, P. (1988). The longitudinal study of the             Neuropsychology Society, 7(3), 312–322.
  northern Finland birth cohort of 1966. Paediatric and         Sowell, E. R., Thompson, P. M., Holmes, C. J.,
  Perinatal Epidemiology, 2(1), 59–88.                            Jernigan, T. L. & Toga, A. W. (1999). In vivo
Reiss, A. L., Abrams, M. T., Singer, H. S., Ross, J. L. &         evidence for post-adolescent brain maturation in
   Denckla, M. B. (1996). Brain development, gender and           frontal and striatal regions. Nature Neuroscience, 2(10),
   IQ in children. A volumetric imaging study. Brain, 119         859–861.
   (Pt 5), 1763–1774.                                           Spreen, O., Risser, A. H. & Edgell, D. (eds) (1995a).
Reitan, R. M. & Wolfson, D. (1985). The Halstead-Reitan            Development of functional systems. In Developmental
   Neuropsychological Test Battery. Tucson, AZ:                    Neuropsychology, pp. 37–56. Oxford, UK: Oxford
   Neuropsychology Press.                                          University Press.
Rieder, R. O., Broman, S. H. & Rosenthal, D. (1977). The        Spreen, O., Risser, A. H. & Edgell, D. (1995b).
   offspring of schizophrenics. II. Perinatal factors and IQ.      Developmental Neuropsychology. Oxford, UK: Oxford
   Archives of General Psychiatry, 34(7), 789–799.                 University Press.
Rosso, I. M., Young, A. D., Femia, L. A. & Yurgelun-Todd,       Stuss, D. T. & Benson, D. F. (1984). Neuropsychological
  D. A. (2004). Cognitive and emotional components of              studies of the frontal lobes. Psychology Bulletin, 95(1),
  frontal lobe functioning in childhood and adolescence.           3–28.
  Annals of the New York Academy of Science, 1021,              Thompson, O’Quinn (1979). Developmental Disabilities:
  355–362.                                                        Etiologies, Manifestations, Diagnoses, and Treatments.
Sameroff, A., Barocas, R. & Seifer, R. (1984). The early          New York, NY: Oxford University Press.
  development of children born to mentally ill women.           Todd, R. D., Reich, W. & Reich, T. (1994). Prevalence of
  In N. F. Watt, E. J. Anthony, L. C. Wynne & J. E. Rolf          affective disorder in the child and adolescent offspring of    13
        Section 1: Neuropsychological processes



        a single kindred: a pilot study. Journal of the American           across the life span. Developmental Psychology, 35(1),
        Academy of Child and Adolescent Psychiatry, 33(2),                 205–213.
        198–207.                                                        Williamson, D. E., Coleman, K., Bacanu, S. A. et al. (2003).
     Ungerleider, L. G. & Mishkin, M. (1982). Two cortical visual         Heritability of fearful-anxious endophenotypes in infant
       systems. In D. J. Ingle, M. A. Goodale & R. J. W.                  rhesus macaques: a preliminary report. Biological
       Mansfield (Eds.), Analysis of Visual Behavior.                     Psychiatry, 53(4), 284–291.
       Cambridge, MA: MIT Press.                                        Worland, J. & Hesselbrock, V. (1980). The intelligence of
     van Os, J., Jones, P., Lewis, G., Wadsworth, M. & Murray, R.         children and their parents with schizophrenia and
        (1997). Developmental precursors of affective illness in a        affective illness. Journal of Child Psychology and
        general population birth cohort. Archives of General              Psychiatry, 21(3), 191–201.
        Psychiatry, 54(7), 625–631.                                     Worland, J., Janes, C. L., Anthony, E. J., McGinnis, M. &
     Wadsworth, M. E. (1987). Follow-up of the first national             Cass, L. (1984). St. Louis Risk Research Project:
       birth cohort: findings from the Medical Research                   comprehensive progress report of experimental studies.
       Council National Survey of Health and Development.                 In N. F. Watt, E. J. Anthony, L. C. Wynne & J. E. Rolf
       Paediatric and Perinatal Epidemiology, 1(1), 95–117.               (Eds.), Children At Risk for Schizophrenia:
                                                                          A Longitudinal Perspective (pp. 105–147). New York,
     Webb, S. J., Monk, C. S. & Nelson, C. A. (2001).                     NY: Cambridge University Press.
       Mechanisms of postnatal neurobiological development:
       implications for human development. Developmental                Worland, J., Weeks, D. G., Weiner, S. M. & Schechtman, J.
       Neuropsychology, 19(2), 147–171.                                   (1982). Longitudinal, prospective evaluations of
                                                                          intelligence in children at risk. Schizophrenia Bulletin,
     Weintraub, S. (1987). Risk factors in schizophrenia: the             8(1), 135–141.
       Stony Brook High-Risk Project. Schizophrenia Bulletin,
       13(3), 439–450.                                                  Yurgelun-Todd, D. A., Killgore, W. D. & Young, A. D.
                                                                          (2002). Sex differences in cerebral tissue volume and
     Weissman, M. M., Wickramaratne, P., Warner, V. et al.                cognitive performance during adolescence. Psychology
       (1987). Assessing psychiatric disorders in children.               Report, 91(3), 743–757.
       Discrepancies between mothers’ and children’s reports.
                                                                        Zalla, T., Joyce, C., Szoke, A., Schurhoff, F. et al. (2004).
       Archives of General Psychiatry, 44(8), 747–753.
                                                                           Executive dysfunctions as potential markers of familial
     Williams, B. R., Ponesse, J. S., Schachar, R. J., Logan, G. D. &      vulnerability to bipolar disorder and schizophrenia.
       Tannock, R. (1999). Development of inhibitory control               Psychiatry Research, 121(3), 207–217.




14
    Chapter




           2
                     Processes and mechanisms in
                     neuropsychiatry: sensory-perceptual
                     Ester Klimkeit and John L. Bradshaw



Despite there being only few simple and purely sen-            intra-modal form of synesthesia, in which a stimulus
sory (or even perceptual) disturbances per se in psy-          evokes an additional, unusual response within the
chiatric disorders, sensory-perceptual abnormalities           same modality. For instance, an individual “sees”
may help us better understand their neurobiological            vivid colours when looking at certain digits, letters
underpinnings. Sensory-perceptual distortions are also         or words; these synesthetic colors may appear “out in
observed in neurological conditions such as neglect,           space” or merely in their “mind’s eye.” However, in
neuropsychiatric conditions such as disorders of mis-          some rare individuals, stimulation in one sensory
identification (e.g. Frégoli syndrome), and in non-            modality results in a vivid involuntary sensory expe-
neurological, non-psychiatric populations including            rience in another (Rich, 2004; Rich & Mattingley,
phantom limb phenomenon and synesthesia. The                   2002), where, for example, some synesthetes will “see”
two different medical fields, psychiatry and neurol-           colors when they hear particular sounds, whereas
ogy, often adopt different explanations for these sen-         others have specific taste sensations when they read
sory disturbances, where the psychiatrist will often           certain words. These experiences are unusual, as
assume the absence of organic causes, whilst the neu-          whilst it is common for a perfume or a tune to
rologist will take the opposite view. This occurs even         suddenly and powerfully evoke vivid associations or
though both fields may merely be encountering dif-             images, usually we do not literally “see red” when
ferent aspects of disorders of the same brain systems.         hearing a gratuitous insult, or “feel blue” when things
For example, the neurological basis of prosopagnosia           go badly wrong.
likely mirrors the underlying processes (or deficits)              The relationship for an individual between the
in the psychiatric disorders of Capgras and Frégoli            stimulus and synesthetic experience is highly consis-
syndromes, while the complex visual hallucinations             tent over time, and has usually been present since
observed in the ictal phenomena of temporal lobe               early childhood; affected individuals are usually sur-
epilepsy and the thought disturbance of schizophrenia          prised to learn that others do not share these experi-
may be comparable and therefore amenable to similar            ences. While the prevalence of synesthesia has been
treatment (Starr & Sporty, 1994). In this chapter we           estimated variously as between 1 in 2000 and 1 in
will bridge the traditional divide between psychiatry          25 000, our own Australian data (Rich et al., 2005)
and neurology, and outline our understanding of                provide estimates of around 1 in 1150 for females and
some selected instances of anomalous sensory pro-              1 in 7150 for males, with a strong familial component.
cesses in these often difficult-to-differentiate neuro-            Synesthetes cannot generally suppress their expe-
psychiatric conditions.                                        riences voluntarily, and conscious identification of
                                                               a letter or digit seems necessary to elicit a synesthetic
                                                               color (Mattingley et al., 2001). In respect of this lack
Synesthesia                                                    of voluntary control and the necessity of awareness
Synesthesia offers insight into anomalous perceptual           of the inducing stimulus, synesthesia may provide
processes, which are not dysfunctional or detrimental          a model for some forms of induced hallucinatory
to daily living. This condition commonly involves an           states in psychopathology. Two broad and different


The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by          15
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



     explanations for synesthesia have been proposed:            sensations may occur for a number of reasons,
     synesthesia is mediated by either normal neural and         including physical loss of a limb, deafferentation,
     cognitive architecture or by special neuroanatomical        sensory root loss or spinal injury. In the case of an
     and/or neurophysiological mechanisms that are only          amputee, even though he or she knows that the limb
     present in synesthetes (Rich & Mattingley, 2002). Rich      is missing, the phantom experience may be so power-
     et al. (2005) found that in a subset of 150 lexical-color   ful and compelling that he or she may be tempted to
     synesthetes, for whom letters, digits and words induce      use, rely or even stand on the missing limb. Parietal
     color experiences, there was a striking consistency         damage can induce experiences of supernumerary
     in the colors induced by certain letters and digits.        limbs, such as a ghost arm or a third arm perceived
     Thus “R” frequently elicited red; “Y,” yellow; and          to emerge from the chest. More unusual phantom
     “D,” brown. Given that a similar, but less consistent,      phenomena have been reported following removal of
     association was identified in a non-synesthetic control     a breast, penis, eye, bladder or rectum. Such phantom
     group, it suggests that early learning experiences may      sensations may be painful or characterized by func-
     be involved in determining these sensory perceptual         tional sensations, e.g. of urination or erection after
     experiences that are common to all individuals. These       penis removal. Phantom limbs occur less commonly
     learning experiences, particularly for synesthetes, may     in instances of congenital limb deficiency (aplasia)
     determine particular patterns of lexical-color associ-      or early limb loss (in 20%; Melzack et al., 1997).
     ations that could generalize to other words or infor-       While phantom limbs are typically experienced soon
     mation sequences (e.g. days of the week, number and         after limb loss, they may develop many years
     letter sequences).                                          later; they may be transient, fade gradually or persist
         If anomalous neural architecture occurs in synes-       permanently.
     thesia, it may take the form of additional synaptic             In instances where the phantom is perceived as
     connections between brain regions responsible for           fixed, it may be possible to reinstate voluntary
     processing auditory and color perception, or may            phantom movement by providing false and illusory
     even stem from inadequate neural pruning (apo-              visual feedback (via mirrors) of a moving limb cor-
     ptosis). A small PET study of response to auditory          responding in shape, size and spatial position to the
     words has shown that color-word synesthetes, like           phantom (Frith et al., 2000). The reafference theory
     non-synesthetes, show activation of areas concerned         (see the following chapter) offers one explanation as
     with language and visual feature integration including      to why this may occur. It proposes that the mirror-
     the perisylvian regions, as well as the posterior tem-      derived visual feedback allows the reafference predic-
     poral cortex and parieto-occipital junction (Paulesu        tors to be updated; consequently the efference copies
     et al., 1995).                                              produced in parallel with the motor commands bring
         Synesthesia provides an opportunity for investi-        about changes in the predicted position of the missing
     gating variable interconnections between different          limb that correspond to what the patient observes in
     sensory systems, and the most significant advances          the mirror. Thus the individual, while neurologically
     towards a biological and cognitive model of synes-          intact and retaining full insight into the situation,
     thesia will probably emerge through future functional       experiences powerful illusory perceptions.
     imaging and transcranial magnetic stimulation studies.          Older theories propose that phantom sensations
                                                                 result from impulses generated in the stump; however
                                                                 this explanation was inadequate, as it did not explain
     Phantom limbs                                               aplasic phantom limbs. More recently, disturbances
     Up to 98% of amputees may report phantom limbs              have been invoked in the body schema (an internal,
     following limb loss or deafferentation (Giummarra           dynamic representation of the body’s spatial proper-
     et al., 2007); often the experience is of phantom pain,     ties), or in the body’s structural description (a topo-
     though each amputee experiences a unique combi-             logical map of body part locations). Re-organization
     nation of spontaneous and evoked phantom sensa-             of the somatosensory homunculus occurs after ampu-
     tions. While phantom phenomena do not represent a           tation and is strongly correlated with phantom limb
     psychopathological condition per se, the condition          pain (Knecht et al., 1998). Internal representations of
16   may provide a good model with which more complex            the body appear to be stored in the parietal cortex
     hallucinatory experiences can be compared. Phantom          where there is multimodal convergence of visual,
                                                       Chapter 2: Processes and mechanisms in neuropsychiatry



vestibular, proprioceptive and efference copy inputs       synesthete (Blakemore et al., 2005). This “mirrored-
(Ventre-Dominey et al., 2003). The neuromatrix con-        touch” synesthetic experience was assessed by fMRI.
cept (Melzack, 1990) extends these ideas, as an innate,    Results indicated higher somatosensory cortex and
genetically determined representation of the body in       left premotor cortex activation in the synesthete, and
the parietal lobe that is continuously modified by         activation in the anterior insula cortex not seen in
sensorimotor and emotional experience throughout           controls, during the observation of touch. The
the lifespan. Phantom limb perception is seen to           authors interpreted these findings as evidence for an
derive from excessive neuromatrix activity, despite        overactive mirror system for touch. A link between
an absence of somatosensory input following ampu-          phantom limb and unilateral neglect phenomena is
tation. This consequently leads to a wide range of         suggested by the report that vestibular caloric stimu-
sensations from excruciating pain to orgasm. The           lation (which laterally biases attention) provoked
neuromatrix concept can also accommodate the rarer         temporary perception of a normal phantom limb in
phantom experiences, usually also free of pain, with       a substantial group of amputees who previously did
congenital limb loss or aplasia. It is also compatible     not experience phantoms (André et al., 2001). In
with the high incidence of referred sensations from        others who currently experienced deformed or pain-
the mouth/face region to the phantom hand/arm              ful phantom limbs, caloric stimulation led to tempo-
(Ramachandran & Blakeslee, 1998), given the strong         rary replacement of the abnormal phantom with a
functional connectivity between the adjacent cortical      non-painful normal phantom. This evidence suggests
representations of the hand and face regions.              that vestibular bias can trigger reconstruction of the
    Phantom phenomena are regarded as a more               global body schema.
complex perceptual disturbance than synesthesia,
and may also throw light upon body integrity identity
disorder. The latter is characterized by a desire, often   “Missing” and supernumerary limbs
beginning in childhood or adolescence, to amputate         After peripheral deafferentation, a patient may
a healthy limb (First, 2005). Most cases desire ampu-      develop a “phantom” even though the deafferented
tation (apotemnophilia) of a lower limb to “restore        limb is still there. A phantom may be contained
my true identity or optimal shape.” When sexual            within the space occupied by the real limb, or sepa-
arousal is associated with the condition, some indi-       rated from it in space and be regarded as supernumer-
viduals report being attracted to other amputees           ary (Kew et al., 1997). In other cases, patients do not
(acrotomophilia). It is possible that, during an emo-      develop phantoms, but become unaware of the limb
tional state, patterns of neural activity from sensory     unless it is continually present in vision; otherwise it
input from the genitals and lower limbs (that are          seemingly fades from consciousness, presumably due
represented closely adjacent in the cortical homuncu-      to the absence of sensory information or feedback
lus) reinforce a desire to amputate the lower limbs        from the limb. Hemianesthesia after right inferior
(Kell et al., 2005).                                       parietal damage can result in similar problems (see
    Phantom limb phenomena also have links with            Frith et al., 2000, for a review). Patients can only initiate
conditions such as synesthesia and unilateral neglect      simple movements in the absence of continuing visual
(discussed later in this chapter), and also with the       feedback, to provide information about limb position
concept of mirror neurons. Mirror neurons, discussed       prior to, during and after movement.
in detail in the following chapter, refer to neurons           McGonigle et al. (2002) report the case of a stroke
observed to “fire” during the observation of actions       patient (right frontomesial lesion) who sporadically
performed by others. These are active during action        experienced a supernumerary “ghost” left arm, which
preparation and in initiation and communication,           occupied the position the real left arm had occupied
and may also play a role in the phantom phenom-            around a minute earlier. Frith et al. (2000) review
enon. The activity of mirror neurons may indeed            other instances of apparent supernumerary limbs,
reinforce the internal representation of a limb within     noting that the estimated position of a limb involves
the body schema, even when the limb has failed to          the integration of information from motor com-
develop (Brugger et al., 2000). A link with synesthesia    mands (in moving a limb to new target positions)
comes from the report that visual perception of touch      and sensory feedback (relating to old and new posi-             17
elicited conscious tactile experiences in a female         tions attained). Failure to integrate these two sources
        Section 1: Neuropsychological processes



     of information (e.g. because of defective sensory           space (scene-based neglect). It may also be limited to
     feedback) could lead to the experience of a super-          near (peripersonal) space, or to far (extracorporeal)
     numerary limb. Conversely, additional failure to            space. Neglect may be transiently corrected, alleviated
     receive signals indicating absence of intended              or compensated for by a variety of vestibular maneu-
     movement in an already paralyzed limb may lead              vers. These may include caloric irrigation of the
     to the false belief that the limb can be, and indeed        auditory meatus on one side (cold water to the con-
     has successfully been, moved. Even normal healthy           tralateral or warm to the ipsilateral ear), or rapid
     individuals may falsely believe that they have moved a      rotation on, for example, an office chair, so as to effect
     limb when they have not (Ramachandran & Blakeslee,          apparent attentional redirection (see Buxbaum, 2006
     1998). Imaging studies would be helpful in under-           for a review).
     standing how these phenomena occur.                             Unattended material, of which the patient is
                                                                 apparently unaware, may still bias how the individual
                                                                 is perceiving or interpreting material that he/she are
     Unilateral (hemispatial) neglect                            aware of, or attending to. Therefore, it is apparent
     Right parietal or parieto-frontal damage may result         that the material in the neglected side is still available
     in the patient’s apparent unawareness or inability to       for sophisticated preattentive or implicit processing,
     acknowledge the existence of objects or events in           even though it is below the threshold for conscious
     contralateral (i.e. left) hemispace. Right neglect after    awareness – a phenomenon reminiscent of blindsight
     left hemisphere damage is much less common, which           in the cortically blind (Weiskrantz, 1986). Neglect is
     may be a result of spatial, attentional and emotional       also not necessarily limited to the visual modality, as
     processes (including those relating even to language)       tactile and auditory neglect are not uncommon.
     being commonly represented on the right. This raises            Clearly the neglect syndrome is a heterogeneous
     the possibility of whether unilateral (hemispatial)         condition, resulting from various combinations of
     neglect is a disorder of spatial perception or attention    component cognitive deficits involving injury to sev-
     (indeed, it is often referred to as hemi-inattention).      eral regions, circuits or systems, including the inferior
          Parton et al. (2004) and Bradshaw & Mattingley         parietal, inferior frontal, striatal or even medial tem-
     (1995) have both reported that patients typically           poral regions. One phenomenon, “extinction,” is still
     attend to items towards the same (ipsilesional) side        debated as to whether it is a mild form of neglect, or a
     as their brain damage. Patients with neglect may            syndrome in its own right. Extinction occurs when a
     habitually collide with “unnoticed” and often large         patient’s visual fields are intact, but he or she fails to
     obstacles on their left, or even be unaware of people       report a contralesional stimulus when it is presented
     in extrapersonal (left) space; however, there are cases     simultaneously with an ipsilesional stimulus; this can
     that require careful clinical testing before it becomes     sometimes occur in a different sensory modality. Just
     apparent. Individuals may not acknowledge or, in            as many regions of the brain participate at different
     severe cases, actively disown their own contralateral       levels and to different extents in different aspects of
     body parts. In such cases, if attention can somehow         attentional processes, so too in neuropsychiatric dis-
     be drawn towards their neglected side, the patient          turbances of attention we encounter different degrees
     may “confabulate” and ascribe it as belonging to            of perseveration and loss of range of component
     someone else. Some patients may also fail to use their      functions, often with fluctuating levels of insight,
     contralesional limbs even if they have little or no         depending upon vestibular factors (affecting orienta-
     weakness (commonly known as “motor neglect”).               tion), neurotransmitter status (arousal levels) and site
     Other patients can also deny that they have any per-        and extent of pathology.
     ceptual or motor control difficulties (anosognosia),
     if any are actually present.                                Asomatognosia and pathological
          Neglect, as a function of either individual differ-
     ences or of task requirements, may extend to the left       embodiment
     side of any object, irrespective of its location within     Patients with asomatognosia typically describe parts
     peripersonal space (object-based neglect); alterna-         of their body as missing from corporeal awareness.
18   tively, it may be linked specifically to the left side of   Despite the disturbance being usually attributed to
                                                       Chapter 2: Processes and mechanisms in neuropsychiatry



right parietal damage, the patient generally has pre-      patients may be unable to recognize them as their
servation of insight, in contrast to neglect or extinc-    own (Frith, 1992); it is as if there is a failure of the
tion syndromes (Arzy et al., 2006). Asomatognosia          ability to self-monitor and of the feedforward (re-
may be modified by touching or looking at the body         afference or corollary discharge) system that normally
part, suggesting multisensory (parietal) mechanisms        comes into play whenever we undertake voluntary
in awareness and embodiment of body parts. Arzy            actions. Such a goal-seeking and recursively error-
et al. (2006) present a case study of a patient who        correcting comparator system enables us to match
reported that parts of her left arm had disappeared,       forward projections (neural copies) of likely experi-
enabling her to see the table on which her arm was         ences of each upcoming response with the actual
resting, as if the latter was transparent.                 consequences and feedback of that action. The system
                                                           has to distinguish sensations caused directly by the
Hallucinations and delusions                               body’s own movement, from those arriving extrane-
                                                           ously from the environment. Our ability to do this and
Hallucinations involve perception without an external
                                                           to predict the consequences of our actions may explain
stimulus (Sims, 2003) and are common to both orga-
                                                           why we cannot successfully tickle ourselves, unless we
nic and psychiatric disorders. Verbal hallucinations in
                                                           create a simulacrum of alien control by introducing a
psychotic disorders and in temporal and parietal lobe
                                                           short time lag into a device that enables us to deliver
epilepsy have been linked to activity in cortical areas
                                                           delayed tickling stimuli to ourselves. Interestingly,
that are normally concerned with the perception of
                                                           in addition to possible disorders of self-attribution,
external speech (Behrendt & Young, 2004). Report-
                                                           patients with schizophrenia can experience self-tickling
edly, speaking or reading aloud is effective in allevia-
                                                           (Wolpert et al., 1998).
ting hallucinations, suggesting that it is possible that
                                                               Frith et al. (2000) propose a close variant of the
hallucinations may involve generation of inner speech
                                                           above formulation, suggesting that experience of alien
and rely on similar neural substrates as speech (Seal
                                                           control arises from a lack of awareness of predicted
et al., 2004). Delusions, that is, false beliefs held
                                                           limb positions; thus patients are unaware of the exact
with extraordinary conviction (Sims, 2003), are also
                                                           specification of the movement. They are aware of
common to psychiatric and organic conditions and
                                                           their goal, of the intention to move, and of the move-
are considered in greater detail below, in the context
                                                           ment having occurred, but not of having initiated
of passivity delusions and delusional misidentification
                                                           the movement. “It is as if the movement, although
disorders.
                                                           intended, has been initiated by some external force”
                                                           (Frith et al., 2000, p. 1784). They note, too, that
Delusions of control in psychosis                          patients have difficulty remembering the precise
Patients with schizophrenia often exhibit a failure of     details of actions made in the absence of feedback.
reality monitoring, claiming that their actions, emo-      They also have difficulty distinguishing between cor-
tions and thoughts are under external “alien” control,     rect visual feedback about the position of their hand,
rather than under their own volitional control – even      and false feedback when the image of the hand they
though what they actually end up doing may still be        see (via a system of mirrors and screens, see above) is
more or less appropriate (Bradshaw, 2001). This dif-       in fact that of another person making the same move-
ficulty in determining the agency of purposive actions     ment. Maruff et al. (2005) found that compared with
is known as passivity delusions (Sims, 2003). These        other patients with schizophrenia, those with passivity
abnormal experiences may arise through a lack of           delusions showed reductions in gray matter volume
awareness of one’s actual intentions or thought pro-       in the left prefrontal and the right parietal region,
cesses, which are misattributed to outside sources.        including parts of the primary somatosensory cor-
As with alien limb phenomena and unilateral neglect,       tex. Such observations are compatible with Frith’s
parietal and cingulate cortices are likely involved        hypothesis that passivity phenomena arise from dys-
(Maruff et al., 2005; Spence et al., 1997). Whether it     function in the prefrontal association cortex where
is a matter of subvocal speech, as in hallucinations,      intentions to act are generated, and in the parietal
or possibly of thought processes, as in delusions, or      association cortex where the sensory consequences
of actions demanded by the current situation, the          of motor actions are modeled.                              19
        Section 1: Neuropsychological processes



     Delusional misidentification syndromes                       of strangers in Frégoli and intermetamorphosis
                                                                  suggests impairment in visual processing. Frégoli
     Most patients suffering delusional misidentification
                                                                  patients may perform more poorly on face recogni-
     syndromes are diagnosed with schizophrenia or mania.
                                                                  tion relative to word recognition tasks, and show
     Misidentification syndromes are also associated with
                                                                  impaired ability to detect subtle visual differences in
     high rates of organic etiology e.g. Alzheimer’s disease,
                                                                  animal stimuli (Edelstyn et al., 1996). In light of these
     dementia and head trauma (Edelstyn & Oyebode,
                                                                  deficits in processing non-facial stimuli, and the fact
     1999). Capgras syndrome is the most frequently
                                                                  that inanimate objects are often implicated in mis-
     reported, characterized by the belief that a person,
                                                                  identification syndromes, the authors argued that
     usually someone well known to the patient, has been
                                                                  explanations of misidentification disorders should
     replaced by an almost identical impostor (Edelstyn &
                                                                  not be confined to models of face processing, but
     Oyebode, 1999). Thus a woman may believe that
                                                                  should be extended to models of visual recognition
     her spouse and children have been replaced by
                                                                  in general. However, Rojo et al. (1991) reported
     doubles, typically with evil intent. Small differences
                                                                  Capgras syndrome in a blind person, suggesting that
     in appearance or behaviour are often reported by
                                                                  it cannot be purely visual.
     patients to distinguish between the person and the
                                                                      A quarter of a century ago, Ungerleider &
     imagined impostor. Delusions can also involve
                                                                  Mishkin (1982) proposed the concept of two parallel,
     inanimate objects and animals. For example, Edelstyn
                                                                  though interconnected, visual systems within the
     et al. (1996) reported a case where a patient believed
                                                                  primate brain: a largely automatic and unconscious
     that family members were stealing his personal belon-
                                                                  “dorsal” system in the posterior parietal cortex
     gings and replacing them with identical but inferior
                                                                  which sets the spatial context within which objects,
     doubles.
                                                                  events and actions take place; and a “ventral” (inferior
         Frégoli syndrome, named after an Italian actor and
                                                                  occipito-temporal) pathway responsible at a more
     mimic who had great skill in changing his appearance,
                                                                  conscious level for object recognition. Quite separ-
     is characterized by the patient’s belief that a familiar
                                                                  ately, different classes of retinal ganglion cell have
     person is able to take on different physical forms and
                                                                  been identified which project to separate target layers
     adopt another’s appearance (Förstl et al., 1991). It is as
                                                                  in the lateral geniculate nucleus: the parvocellular
     if biographical information for a certain person is
                                                                  (P) and magnocellular (M) streams (Desimone &
     automatically accessed and applied, regardless of
                                                                  Ungerleider, 1989). Differing (amongst other features)
     whom is present (Bradshaw & Mattingley, 1995). In
                                                                  in their respective capacities to respond preferentially
     the syndrome of intermetamorphosis a person is
                                                                  to higher or lower spatial frequencies, projections
     believed to have been changed into someone else
                                                                  from the M stream are abundantly represented in
     entirely with altered identity and physical appearance
                                                                  the parietal cortex, and those from the P stream tend
     (Edelstyn & Oyebode, 1999). In the syndrome of sub-
                                                                  to terminate in the inferotemporal cortex.
     jective doubles, another person is believed to have
                                                                      More recently, the idea of two semi-independent
     taken on the physical characteristics and identity of
                                                                  but complementary visual systems has been further
     oneself (Bradshaw & Mattingley, 1995). The belief that
                                                                  developed (Goodale & Milner, 2004, p. 97); the ven-
     a physical location has been duplicated is referred to as
                                                                  tral stream is seen as delivering a rich, detailed and
     reduplicative paramnesia (Förstl et al., 1991). In this
                                                                  largely conscious representation of object identities
     condition, a patient may insist that the hospital he
                                                                  within the world scene, while the dorsal stream
     or she is in has been duplicated and relocated from
                                                                  delivers fast, accurate, automatic and largely uncon-
     one site to another, so that the two hospitals coexist in
                                                                  scious information about objects in the required ego-
     different places at the same time (Anderson, 1988).
                                                                  centric coordinates for action. This differentiation of
     Misidentification of place is the misidentification syn-
                                                                  visual processing was demonstrated in a case study by
     drome most frequently associated with neurological
                                                                  Goodale & Milner (2004) who describe a patient
     disease (Förstl et al., 1991).
                                                                  unable to consciously and deliberately copy a slant
         The face misidentification phenomena in mis-
                                                                  shown as a target display with a hand-held card, but
     identification disorders have led to comparisons with
                                                                  nevertheless retained the ability to adopt the requisite
     prosopagnosia, an organic condition in which recog-
20                                                                slanted posture so as to “post” the card in a tilted slot.
     nition of familiar faces is impaired. Misidentification
                                                                  Ellis & Young (1990) also suggested that Capgras
                                                       Chapter 2: Processes and mechanisms in neuropsychiatry



syndrome and prosopagnosia reflect differential            associated with vestibular sensations of elevation and
impairment in ventral and dorsal visual pathways.          floating and 180 degree inversion of one’s body.
The ventral pathway, responsible for conscious face            Brugger et al. (2006) distinguish between auto-
recognition, connects with the visual cortex, and may      scopic hallucinations (visual perception of an exact
be impaired in prosopagnosia. Similarly, the dorsal        mirror image of oneself, whole or part) and heauto-
pathway, responsible for giving the face its emotional     scopy (confrontation with one’s double, which may or
significance, connects the visual system with limbic       may not mirror one’s appearance). Heautoscopic
structures; it may be impaired in Capgras syndrome,        echopraxia (imitation of bodily movements by the
resulting in a distorted sense of familiarity. The cog-    double) gives rise to the illusion that it is the Doppel-
nitive dissonance resulting from normal face recogni-      gänger that contains the real mind, and may be
tion (intact ventral stream) coupled with the absence      accompanied by feelings of depersonalization, alien-
of the feeling of familiarity (impaired dorsal stream)     ation from one’s own body and dizziness. The authors
is proposed as the basis of this misidentification dis-    review cases of polyopic heautoscopy, with multiple
order. Evidence of absence of familiarity in Capgras       copies of the body and self, suggestive of multiple
patients comes from an experiment which recorded           mappings of the body. They emphasize the specific
skin conductance responses during the showing of a         importance of lesions at the temporo-occipito-
series of familiar and unfamiliar faces. Unlike con-       parietal junction.
trols, who showed greater skin conductance to famil-           Depersonalization symptoms are not only found
iar than unfamiliar faces, Capgras patients failed to      in near-death experiences or heautoscopic echo-
discriminate between such faces in terms of the            praxia, but also in a variety of psychiatric disorders.
degree of their autonomic arousal (Ellis et al., 1997).    Depersonalization symptoms in psychiatric patients
                                                           with depersonalization disorder positively correlate
Autoscopia, out-of-body                                    with increased parietal activity (Simeon et al., 2000).
                                                           Similarly, dissociative responses in patients with post-
and near-death experiences                                 traumatic stress disorder associate with greater acti-
Individuals with near-death experiences typically          vation in the parietal lobe, occipital lobe and middle
report dissociative symptoms like depersonalization,       temporal gyri, as well as increased activation in the
increased alertness and often give various descriptions    inferior frontal gyrus, medial prefrontal cortex, medial
of mystic consciousness (Sims, 2003). They often           frontal gyrus and anterior cingulate gyrus (Lanius
describe out-of-body experiences and the impression        et al., 2002). Out-of-body experiences and autoscopic
of seeing their own body (autoscopy) from their out-       hallucinations have been reported in various neuro-
of-body perspective. Autoscopy occurs in individuals       logical conditions, such as epilepsy and migraine,
with various psychiatric and organic conditions such       and psychiatric conditions such as schizophrenia,
as emotional disturbance, delirium, epilepsy, drug         depression, anxiety and dissociative disorders (Blanke
addiction and alcoholism (Hamilton, 1985). The             et al., 2004).
German folklore, that you will die if you see your             Out-of-body experiences may occur in 10% of the
double (“Doppelgänger”), may relate to the fact that       normal population (Blanke & Arzy, 2005). Parietal,
autoscopy is often associated with cerebrovascular         temporal and occipital lobe involvement has again
disorders or severe infectious diseases affecting the      been implicated (Zamboni et al., 2005). Blanke et al.
parietal lobe (Hamilton, 1985). Out-of-body experi-        (2002) reported a case where an out-of-body experi-
ences differ from autoscopic hallucinations, in that in    ence and visual body part illusions resulted after
the latter a double of oneself is seen without the         stimulation at the right temporoparietal junction.
sensation of having left one’s body. Blanke & Arzy         Blanke et al. (2004) postulate that an out-of-body
(2005) define an out-of-body experience as an experi-      experience follows failure to integrate sensory infor-
ence of “disembodiment (location of the self outside       mation regarding the body (proprioceptive, tactile
one’s body), the impression of seeing the world from       and visual information) coupled with vestibular dys-
a distant and elevated visuo spatial perspective (extra-   function, leading to disintegration between personal
corporeal egocentric perspective), and the impression      (vestibular) space and extrapersonal (visual) space.
of seeing one’s own body (or autoscopy) from this          Dysfunction in the temporoparietal junction, which          21
elevated perspective” (p. 11). These episodes are often    contains the vestibular cortex and is also implicated in
        Section 1: Neuropsychological processes



     neglect, is proposed. Brain damage to this area has          Anderson, D. N. (1988). The delusion of inanimate
     been associated with vestibular sensations and feel-           doubles: implications for understanding the Capgras
     ings of agency (Blanke & Arzy, 2005).                          phenomenon. British Journal of Psychiatry, 153,
                                                                    694–699.
                                                                  Arzy, S., Overney, L. S., Landis, T. & Blanke, O. (2006).
     Conclusion                                                     Neural mechanisms of embodiment: asomatognosia
     It is not coincidental that the parietal lobe, an area of      due to premotor damage. Archives of Neurology, 63,
     sensory convergence, plays a major role in most of the         1022–1025.
     conditions we have reviewed. While we discuss pos-           Behrendt, R. P. & Young, C. (2004). Hallucinations in
     sible sensory-perceptual underpinnings of abnormal             schizophrenia, sensory impairment, and brain disease:
     sensory processes, we note that Roediger (1990) em-            a unifying model. Behavioral and Brain Sciences, 27,
     phasized that there might be two potential processes           771–830.
     whereby an organism might perceive external objects          Blakemore, S. J., Bristow, D., Bird, G., Frith, C. & Ward, J.
     or events: a data-driven bottom-up hierarchical pro-            (2005). Somatosensory activations during the
     cess of gradual and successive combination of lower-            observation of touch and a case of vision-touch
     level analyses and outputs and also, in contrast, an            synaesthesia. Brain, 128(Pt 7), 1571–1583.
     “intelligent,” concept-driven, top-down process that is      Blanke, O. & Arzy, S. (2005). The out-of-body experience:
     almost akin to inspired guessing and which operates             disturbed self-processing at the temporo-parietal
                                                                     junction. Neuroscientist, 11(1), 16–24.
     from an acquired knowledge of stored statistical
     properties and predictive probabilities.                     Blanke, O., Landis, T., Spinelli, L. & Seeck, M. (2004).
          The motor theory of speech perception (Liberman            Out-of-body experience and autoscopy of neurological
                                                                     origin. Brain, 127, 243–258.
     et al., 1967), for example, embodies these principles.
     Speech perception involves the motor system in a             Blanke, O., Ortigue, S., Landis, T. & Seeck, M. (2002).
     process of auditory-to-articulatory mapping so as to            Stimulating illusory own-body perceptions. Nature, 419,
                                                                     269–270.
     access a phonetic code with motor properties (Wilson
     et al., 2004). Similarly, in conversation, we tend to        Bradshaw, J. L. (2001). Developmental Disorders of the
     hear just what we have come to expect from the                  Frontostriatal System: Neuropsychological
                                                                     Neuropsychiatric and Evolutionary Perspectives. Hove,
     statistical nature (probabilities) of the phonological
                                                                     UK: Psychology Press.
     or semantic context. Indeed the errors (“confusions”)
     made by listeners to “noisy” (i.e. unclear) speech tend      Bradshaw, J. L. & Mattingley, J. B. (1995). Clinical
                                                                     Neuropsychology: Behavioral and Brain Science. San
     to reflect the contextually likely upcoming articula-           Diego, CA: Academic Press.
     tory gestures of the speaker (as if the listener is trying
     in real time to guess-ahead the next utterance from          Brugger, P., Blanke, O., Regard, M., Bradford, D. T. &
                                                                     Landis, T. (2006). Polyopic heautoscopy: case report and
     the speaker’s vocal apparatus), rather than the resul-          review of the literature. Cortex, 42(5), 661–784.
     tant acoustic consequences (phonemes). The idea that
                                                                  Brugger, P., Kollias, S. S., Muri, R. M., Crelier, G. &
     perception is somehow linked, conceptually and prag-
                                                                     Hepp-Reymond, M. (2000). Beyond remembering;
     matically, to potential action is discussed in detail in        Phantom sensations of congenitally absent limbs.
     the following chapter.                                          Proceedings of the National Academy of Sciences USA,
          While anomalies of fundamental perceptual pro-             97(11), 6167–6172.
     cessing are good models, and partly explanatory of           Buxbaum, L. J. (2006). On the right (and left) track: twenty
     higher-level neuropsychiatric dysfunction, perception          years of progress in studying hemispatial neglect.
     drives potential action, and anomalies at both levels          Cognitive Neuropsychology, 23(1), 184–201.
     must play equal roles in understanding the syndromes         Desimone, R. & Ungerleider, L. G. (1989). Neural
     of neuropsychiatry.                                            mechanisms of visual processing in monkeys.
                                                                    In F. Boller & J. Grafman (Eds.), Handbook of
     References                                                     Neuropsychology (Vol. 2, pp. 267–299). Amsterdam:
     André, J. M., Martinet, N., Paysant, J., Beis, J. M. & Le      Elsevier.
       Chapelain, L. (2001). Temporary phantom limbs evoked       Edelstyn, N. M. J. & Oyebode, A. F. (1999). A review of the
       by vestibular caloric stimulation in amputees.               phenomenology and cognitive neuropsychological
22     Neuropsychiatry Neuropsychology and Behavioral               origins of the Capgras syndrome. International Journal
       Neurology, 14(3), 190–196.                                   of Geriatric Psychiatry, 14, 48–59.
                                                               Chapter 2: Processes and mechanisms in neuropsychiatry



Edelstyn, N. M. J., Riddoch, M. J., Oyebode, F., Humphreys,        Liberman, A. M., Cooper, F. S., Shankweiler, D. P. &
  G. W. & Forde, E. (1996). Visual processing in patients             Studdert-Kennedy, M. (1967). Perception of the speech
  with Frégoli syndrome. Cognitive Neuropsychiatry, 1(2),             code. Psychological Review, 74(6), 431–461.
  103–124.                                                         Maruff, P., Wood, S. J., Velakoulis, D. et al. (2005).
Ellis, H. D. & Young, A. W. (1990). Accounting for                   Reduced volume of parietal and frontal association
    delusional misidentifications. British Journal of                areas in patients with schizophrenia characterised
    Psychiatry, 157, 239–248.                                        by passivity delusions. Psychological Medicine, 35,
Ellis, H. D., Young, A. W., Quayle, A. H. & de Pauw, K. W.           783–789.
    (1997). Reduced autonomic responses to faces in                Mattingley, J. B., Rich, A. N., Yelland, G. & Bradshaw, J. L.
    Capgras delusion. Proceedings of the Royal Society of            (2001). Unconscious priming eliminates automatic
    London B, 264(1384), 1085–1092.                                  binding of colour and alphanumeric form in
First, M. B. (2005). Desire for amputation of a limb:                synaesthesia. Nature, 410(6828), 580–582.
   paraphilia, psychosis or a new type of identity disorder.       McGonigle, D. J., Hanninen, R., Salenius, S. et al. (2002).
   Psychological Medicine, 35, 919–928.                              Whose arm is it anyway? An fMRI case study of
Förstl, H., Almeida, O. P., Owen, A. M., Burns, A. &                 supernumerary phantom limb. Brain: a Journal of
   Howard, R. (1991). Psychiatric, neurological and                  Neurology, 125(6), 1265–1274.
   medical aspects of misidentification syndromes: a review        Melzack, R. (1990). Phantom limbs and the concept of a
   of 260 cases. Psychological Medicine, 21, 905–910.                neuromatrix. Trends in Neurosciences, 13(3), 88–92.
Frith, C. D. (1992). The Cognitive Neuropsychology of              Melzack, R., Isreal, R., Lacroix, R. & Schultz, G. (1997).
   Schizophrenia. Hove, UK: Lawrence Erlbaum Associates.             Phantom limbs in people with congenital limb
Frith, C. D., Blakemore, S. J. & Wolpert, D. M. (2000).              deficiency or amputation in early childhood. Brain,
   Abnormalities in the awareness and control of action.             120, 1603–1620.
   Philosophical Transactions of the Royal Society of London       Parton, A., Malhotra, P. & Husain, M. (2004). Hemispatial
   B Biological Sciences, 355(1404), 1771–1788.                       neglect. Journal of Neurology Neurosurgery and
Goodale, M. & Milner, D. (2004). Sight Unseen: An                     Psychiatry, 75(1), 13–21.
  Exploration of Conscious and Unconscious Vision.                 Paulesu, E., Harrison, J., Baron-Cohen, S. et al. (1995). The
  Oxford, UK: Oxford University Press.                                physiology of coloured hearing: a PET activation study
Giummarra, M., Gibson, S., Georgiou-Karistianis, N. &                 of colour-word synaesthesia. Brain, 118, 661–676.
   Bradshaw, J. (2007). Central mechanisms in phantom              Ramachandran, V. S. & Blakeslee, S. (1998). Phantoms in the
   limb perception: the past, present and future. Brain              Brain. New York, NY: William Morrow.
   Research Reviews, 54(1), 219–232.
                                                                   Rich, A. N. (2004). An Investigation of the Cognitive and
Hamilton, M. (1985). Fish’s Clinical Psychopathology                  Neural Mechanisms Underlying Lexical-Colour
  (2nd edn.). Bristol, UK: John Wright and Sons.                      Synaesthesia. PhD thesis. University of Melbourne,
Kell, C., von Kriegstein, K., Rosler, A., Kleinschmidt, A. &          Melbourne.
   Laufs, H. (2005). The sensory cortical representation           Rich, A. N. & Mattingley, J. B. (2002). Anomalous
   of the human penis: revisiting somatotopy in the                   perception in synaesthesia: a cognitive neuroscience
   male homunculus. Journal of Neuroscience, 25(25),                  perspective. Nature Reviews Neuroscience, 3(1), 43–52.
   5984–5987.
                                                                   Rich, A. N., Bradshaw, J. L. & Mattingley, J. B. (2005).
Kew, J. J., Halligan, P. W., Marshall, J. C., et al. (1997).          A systematic, large-scale study of synaesthesia:
  Abnormal access of axial vibrotactile input to                      implications for the role of early experience in lexical-
  deafferentated somatosensory cortex in human upper                  colour associations. Cognition, 98(1), 53–84.
  limb amputees. Journal of Neurophysiology, 77,
  2735–2764.                                                       Roediger, H. L. (1990). Memory metaphors in cognitive
                                                                     psychology. Memory and Cognition, 8, 231–246.
Knecht, S., Henninngsen, H., Hohling, C. et al. (1998).
  Plasticity of plasticity? Changes in the pattern of              Rojo, V. I., Caballero, L., Iruela, L. M. & Baca, E. (1991).
  perceptual correlates of reorganization after amputation.           Capgras syndrome in a blind patient. American Journal
  Brain, 121, 717–724.                                                of Psychiatry, 148, 1272.
Lanius, R. A., Williamson, P. C., Boksman, K. et al. (2002).       Seal, M. L., Aleman, A. & McGuire, P. K. (2004).
   Brain activation during script-driven imagery induced              Compelling imagery, unanticipated speech and deceptive
   dissociative responses in PTSD: a functional magnetic              memory: neurocognitive models of auditory verbal
   resonance imaging investigation. Biological Psychiatry,            hallucinations in schizophrenia. Cognitive
   52, 305–311.                                                       Neuropsychiatry, 9(1/2), 43–72.                              23
        Section 1: Neuropsychological processes



     Simeon, D., Guralnik, O., Hazlett, E. A. et al. (2000). Feeling    Ventre-Dominey, J., Nighoghossian, N. & Denise, P. (2003).
        unreal: A PET study of depersonalisation disorder.                Evidence for interacting cortical control of vestibular
        American Journal of Psychiatry, 157, 1782–1788.                   function and spatial representation in man.
     Sims, A. (2003). Symptoms in the Mind: An Introduction to            Neuropsychologia, 41, 1884–1898.
        Descriptive Psychopathology (3rd edn.). London: Saunders.       Weiskrantz, L. (1986). Blindsight: A Case Study and
     Spence, S. A., Brooks, D. J., Hirsch, S. R. et al. (1997). A PET     Implications. New York, NY: Oxford University Press.
        study of voluntary movement in schizophrenic patients           Wilson, S. M., Saygin, A. P., Sereno, M. I. & Iacoboni, M.
        experiencing passivity phenomena (delusions of alien              (2004). Listening to speech activates motor areas
        control). Brain, 120, 1997–2011.                                  involved in speech production. Nature Neuroscience,
     Starr, A. & Sporty, L. D. (1994). Similar disorders viewed           7(7), 701–702.
        with different perspectives. A challenge for neurology          Wolpert, D. M., Miall, R. C. & Kawato, M. (1998). Internal
        and psychiatry. Archives of Neurology, 51(10), 977–980.           models in the cerebellum. Trends in Cognitive Sciences, 2,
     Ungerleider, L. G. & Mishkin, M. (1982). Two cortical visual         338–347.
       systems. In D. Ingle, M. A. Goodale & R. J. W. Mansfield         Zamboni, G., Budriesi, C. & Nichell, P. (2005).
       (Eds.), Analysis of Visual Behavior (pp. 549–586).                 “Seeing oneself ”: a case of autoscopy. Neurocase, 11,
       Cambridge, MA: MIT Press.                                          212–215.




24
    Chapter




           3
                     Processes and mechanisms in
                     neuropsychiatry: motor-executive processes
                     Nicole Rinehart, Phyllis Chua and John L. Bradshaw



Introduction                                                   and substantia nigra. The caudate and putamen form
                                                               the striatum, and the putamen and globus pallidus are
“The irritating historical division between neurology          referred to as the lentiform nucleus. Generally speak-
and psychiatry is at its most arbitrary in the field           ing the striatum is the input layer of the basal ganglia
of movement disorders” (Lennox & Lennox, 2002,                 and lentiform nucleus the output layer. Basal ganglia
p. 28).                                                        efferents are inhibitory to the thalamus. The cerebel-
    The introduction and differentiation of “extrapy-          lar hemispheres are functionally analogous input
ramidal motor disorders” from “pyramidal disorders,”           layers of the cerebellum; however, unlike the striatum
by Wilson in 1912, heralded a major paradigm shift             which receives afferents directly from the cortices, the
(Rogers, 1992). Wilson conceptualized disorders that           cerebellum receives cortical input via pontine nuclei
had traditionally been regarded as “psychiatric” or            that then project via mossy fibers to the cortex of the
“functional,” such as Parkinson’s disease, as extra-           cerebellum. The three deep cerebellar structures, the
pyramidal. In addition, he also described a group of           fastigial, dentate and interposed nuclei, have excita-
patients with motor symptoms, the majority of whom             tory projections to the thalamus and can be conceived
also experienced psychiatric symptoms with diag-               in simple terms as the output layer.
noses of hysteria or schizophrenia. Although neurol-               The basal ganglia and cerebellum both project via
ogy and psychiatry have continued to develop along             the thalamus to widespread areas of the cortex, influ-
separate lines, disorders such as Parkinson’s disease,         encing motor and cognitive functioning. Disorders
Huntington’s disease and Gilles de la Tourette                 such as Parkinson’s disease and Huntington’s dis-
syndrome (GTS), which straddle the neurology and               eases, with discrete and well-defined neuropathology,
psychiatry boundary, highlight the importance of               have served as a model for basal ganglia dysfunction.
understanding both motor and psychological pro-                Similarly, diseases such as Friedreich’s ataxia with
cesses in these and other conditions. This may offer           known cerebellar pathology serve as models for cere-
insight into the neural correlates and clinical manage-        bellar influence on the cortex. While the basal ganglia
ment of these disorders.                                       play a central role in the initiation and mediation
    This chapter will discuss the relevance of the neu-        of movements, the cerebellum is more involved in
romotor circuitry and recent theoretical advances              controlling and tempering end-stage movement
in motor theories that relate to the underlying neuro-         (Bradshaw & Mattingley, 1995); for example, cerebel-
pathophysiology of these disorders.                            lar lesions result in movements which are inaccurate,
                                                               rough and variable (Robinson & Fuchs, 2001).
                                                               Although traditionally the roles of these structures
Neuromotor circuitry                                           were conceived as purely motor, there is converging
The basal ganglia and cerebellum are key neural struc-         evidence indicating damage to basal ganglia and cere-
tures in the brain’s motor circuitry. The basal ganglia        bellum can have deleterious consequences for cogni-
are comprised of the caudate, putamen, globus pallidus         tive functioning (Glickstein, 2006).



The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by         25
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



     Conceptual advances in motor theory:                        possibilities for action, namely its affordances, are
                                                                 built directly into its perceptual representation.
     affordances and mirror neurons, motor                       Therefore, perceptual and motor processes are inex-
     control models                                              tricably linked, i.e. perception as potential or implicit
     The general clumsiness (e.g. “dropping things”) so          action, and action in a perceptually relevant context.
     often described in psychiatric disorders may eventu-        Indeed, according to this view, objects may potentiate
     ally be more carefully re-defined and understood in         a range of actions associated with them, irrespective
     the context of “affordances.” Similarly, problems with      of the intentions of the viewer.
     motor imitation skills may lead to motor learning               When such potentiation overrides intentionality,
     difficulties to be interpretable via the concept of         we may see utilization behavior; this can occur when
     “mirror neurons.” Motor control models such as feed         distractedly picking up and toying with an object, or
     forward, motor overflow and the role of top-down            when prefrontal damage and inhibitory dysfunction
     influences, as well as attention, may contribute to         are present. Following bilateral medial frontal lobe
     our understanding of the more complex motor                 damage the patient may display a compulsive, inap-
     phenomena.                                                  propriate urge to use objects in sight. Such utilization
                                                                 behavior is thought to manifest from a supervisory-
                                                                 system deficit (Della Sala, 2005; Frith et al., 2000).
     Affordances                                                 The patient may offer confabulatory explanations
     The concept of two complementary visual systems             for such behavior, given that they often seem unaware
     (Ungerleider & Mishkin, 1982), a dorsal system              of the inappropriateness of the behavior. This situ-
     located in the posterior parietal cortex and a ventral      ation of course contrasts with our own realization
     system located in the inferior occipito-temporal            when abstractedly and absent-mindedly, for example,
     cortex responsible for unconscious and conscious            taking off all our clothes when we only intended to
     object identification respectively, underlies the notion    change our socks.
     of affordance. When picking up a cup, we typically do           An extreme example of such behavior is the
     so via the handle, not the body of the receptacle; many     anarchic hand phenomenon. While patients after pa-
     such objects elicit “use-appropriate” hand postures,        rietal damage with optic ataxia (Balint’s syndrome,
     reflecting the accessing of stored (“dorsal stream”)        see Perenin & Vighetto, 1988) or certain forms of
     information about object identity and potential util-       apraxia have great difficulty picking up, grasping or
     ity. Indeed, the central nervous system as a whole has      manipulating objects which they can see quite clearly,
     necessarily evolved in the service of potential action.     patients showing the anarchic hand sign may com-
     Such “preparation for action,” largely the province         plain that a hand makes apparently purposeful, com-
     of the dorsal stream, highlights an important new           plex, smooth and well-formed movements of its own
     theoretical concept of affordance, which is a central       accord, and quite contrary to the patient’s own inten-
     component of ecological psychology (Gibson, 1979).          tion or will (Della Sala, 2005). The patients are aware
     Affordances, generally, are properties of the environ-      of their limb’s bizarre and potentially hazardous
     ment taken relative to an observer’s standpoint.            behavior, but cannot inhibit it. They often refer to
     Thus representations for action that are elicited by        the feeling that one of their hands behaves as if it had
     an object’s visual affordance serve to potentiate motor     a will of its own, but never deny that this capricious
     components (a specific hand position or posture             hand is part of their own body – as can happen with
     to adopt), so that a response and action is initiated.      severe unilateral neglect (Parton et al., 2004). Thus
     Intraparietal regions may extract such affordance           self-ownership of actions is apparently separable from
     information for the premotor cortex in due course           awareness of actions; affected patients are aware of
     to initiate and execute appropriate action (Taira et al.,   their anarchic hand, which they know is part of their
     1990). How we represent the sensory or perceptual           own anatomy and not a robotic counterfeit, yet they
     world arises partly from affordances using a reper-         disown its actions. Affected patients typically have
     toire of stored actions; actions that are developed on      medial frontal lobe damage, in the vicinity of the
     the basis of interactions between the visual attributes     supplementary motor area (SMA), on the side con-
26   of an object and the conscious, deliberate and con-         tralateral to the wayward hand. The SMA is known
     textually relevant goal of the observer. An object’s        (Cunnington et al., 1996) to be responsible for
                                                           Chapter 3: Processes and mechanisms in neuropsychiatry



converting self-generated (as opposed to externally            simulation. Understanding others’ beliefs, intentions
initiated) intentions into self-initiated action se-           and actions is an important social ability – “theory of
quences or motor subroutines related to internal               mind” – possibly deficient in certain developmental
drives. Environmentally relevant movement sequences            disorders of the fronto-striatal system such as autism
can, instead, be initiated by the alternative, lateral,        (Happe, 1999) and schizophrenia (Brune, 2005).
premotor system. This system, remaining intact in              While a mere visual representation, without involve-
the patient with an anarchic hand, will now take over          ment of the motor system, can describe the superfi-
and drive the patient’s hand, to their consternation,          cial, visible aspects of another agent’s movement, it
according to triggering events or objects encountered          fails to provide information critical for understanding
in the external environment. Note that the term “alien         “action semantics” (Nelissen et al., 2005). That is,
hand,” often used as a synonym for the anarchic                what the action concerns, its goal and context.
hand (Marchetti & Della Sala, 1998), means a range             Likewise action information, without knowledge con-
of different things to different authors, and perhaps is       cerning object identity, again can only tell half the
best seen as uncooperative behavior or posturing by a          story. We need to combine information about object
hand which especially is felt to be somehow foreign to         identity with semantic information about the action.
or “estranged” from its owner (hemisomatognosia),              This may be the role of mirror neurons, in matching
and may or may not require alternative (to SMA                 observed actions with their corresponding internal
involvement) or additional callosal damage (Bundick            motor representations. Nelissen et al. (2005) report
& Spinella, 2000; Chan & Liu, 1999).                           that the monkey’s frontal lobe hosts multiple repre-
                                                               sentations of others’ actions. Representations located
                                                               caudally in F5 seem to be context-dependent, acti-
Mirror neurons                                                 vated only when the agent is seen, while representa-
This essential and inextricably linked interrelatedness        tions in rostral F5 and prefrontally code the action. In
of perception and action is also played out in the recent      humans area 44, a probable homolog of monkey F5,
discovery and account of mirror neurons (Arbib, 2005;          plays a fundamental role in speech; the motor theory
Rizzolatti & Craighero, 2004). Canonical neurons,              of speech perception (Liberman et al., 1967) posits an
abundant in the rear section of the monkey’s arcuate           active, if tacit, recreation of the speaker’s articulatory
sulcus (part of area F5), may fire whenever a particular       intentions. Parenthetically, it is also noteworthy that
object is seen, as a function of its shape, size and spatial   the canonical neurons of monkey F5 receive input
orientation. They may also fire when an animal is              from the anterior parietal sulcus in the form of neural
presented with a graspable object, irrespective of             codes for affordances e.g. grasping (Taira et al., 1990).
whether this is followed up by an actual grasping                  While the classical studies of the mirror system
response (cf. the concept of affordances, above), or           indicate that some of the same motor regions are
alternatively when a specific response or response             activated both when performing and when observing
sequence is initiated. They do not fire, however, when         a movement, there is also evidence that such motor
the individual merely observes actions performed by            activity may even occur prior to observing another’s
another. Conversely, mirror neurons, first identified in       action. Thus the mere knowledge of the likelihood of
the convexity of area F5 of the primate frontal cortex,        another’s upcoming movement may be sufficient to
and now thought to be widely distributed in the brain,         excite the observer’s mirror-motor system (Kilner
are active both when the monkey performs certain               et al., 2004). This would enable (as in the motor
actions, and when they observe actions performed by            theory of speech perception) one to anticipate rather
another monkey or person. In this way, unlike canon-           than to merely react to another’s actions.
ical neurons, mirror neurons do not respond when                   Neurons responding to the observation of actions
objects alone are presented (Rizzolatti & Craighero,           done by others are not present only in area F5. Move-
2004). Mirror neurons represent a mechanism for                ments effective in eliciting neural responses in the
object-directed action capable of coupling the obser-          cortex of the superior temporal sulcus include
vation of another’s actions and their execution, as if         walking, turning the head, bending the torso, and
they were performing the actions observed themselves.          goal-directed hand and arm movements (Rizzolatti &
    Consequently, we must now add a third term                 Craighero, 2004). However, the mirror system may             27
to the relation between perception and action;                 not necessarily be restricted to motor functions.
       Section 1: Neuropsychological processes



     Blakemore et al. (2005) report a new form of              tactile and kinesthetic sensations resulting from the
     synesthesia, where visual perception of touch elicited    movement (Frith, 2005). Environmentally appropri-
     conscious tactile experiences in the observer. This       ate responding towards a goal demands production
     may have occurred because the mirror system for           and control of sequences of requisite muscle contrac-
     touch (parietal and premotor cortices and superior        tions, in the context of initial sensory input and
     temporal sulcus) proved overactive (as shown by           feedback that is consequent upon action. Note must
     fMRI) and above the normal threshold for conscious        also be made of the current configurations of joint
     tactile perception. Pain, too, when observed in others,   angles and limb postures prior to implementation of
     may excite the observer’s mirror system and lead to       the motor commands (Frith et al., 2000). Just prior to
     painful sensations (Avenanti et al., 2005; Bradshaw &     movement initiation, a predictor, receiving an effer-
     Mattingley, 1995). As Singer & Frith (2005) note, we      ence copy from the initiating motor system, estimates
     all have a remarkable and largely involuntary capacity    the movements’ likely sensory consequences (reaffer-
     to share the experience of others; for example, yawns     ence). In this way compensation can be made for the
     are infectious, and we wince when we see another          sensory effects of movement and, secondly, in the
     person trap her fingers in a door.                        event of response error, corrections can be initiated.
         Two main hypotheses have been advanced on the             Several studies have shown that forward model-
     underlying function of mirror neurons; they might         ling is abnormal in patients with schizophrenia when
     mediate imitation or more likely are the basis of         they have to consciously attend to their actions; how-
     action understanding (Rizzolatti & Craighero, 2004).      ever no abnormalities in implicit, automatic use of
     Each time an individual sees an action performed          forward modelling such as anticipatory adjustments
     by another, neurons representing that action are          of grip force when picking up objects were noted in
     activated in the observer’s premotor cortex. This         such patients. Different areas may be involved: the
     automatically induced motor representation of the         frontal cortex for initiating actions, the sensory areas
     observed action corresponds to the representation         to process the consequences of actions, and the ante-
     that is spontaneously executed during self-generated      rior cingulate cortex to detect discrepancies. Discon-
     action. Thus, a role of the mirror system can be          nections between these brain areas may explain the
     regarded as the transformation of visual information      different symptoms reported in schizophrenia (Frith,
     into knowledge, and actions performed by another          2005), and disconnections between the frontal and
     become messages that are understood without               parietal regions may account for the misperception
     any cognitive mediation. On the basis of this, the        of limb positions in delusions of control. The absence
     mirror-neuron system provides a potential mecha-          of delusional explanations in neurological patients
     nism from which language may have evolved, prob-          with lesions in these brain regions, e.g. anarchic hand
     ably via an oral-manual stage. The mirror neuron          after parietal lobe lesions, is noteworthy. Additional
     hypotheses have been used to explain the diverse          concepts such as “intentional binding” which draws
     motor, social and communicative impairments which         together cause and effect in perceived time may
     characterize pervasive developmental disorders (see       bridge such gaps. Intentional binding occurs when,
     Williams et al., 2001), and may be invoked to account     for example, we put together cause (e.g. we push a
     for neuromotor impairments which we see across            button or watch someone else push a button) and
     the psychiatry spectrum.                                  effect (e.g. the resulting sound). There may be exagger-
                                                               ated intentional binding in patients with schizophre-
                                                               nia, perhaps explaining incorrect attribution of agency
     Motor control models                                      in those with delusions of control or persecution.
     Feed forward models
     Prior knowledge can also enable us to predict the
     sensory changes resulting from movements. The “for-       Motor control and attention
     ward model” proposes that prior knowledge based on        While we can attend to and be aware of our intended
     intended actions can modify perception. The “for-         movements and perform movement sequences in
     ward dynamic model” allows the prediction of the          imagination; fast, overlearnt and automatic respond-
28   trajectory of the limb movement in space and time,        ing is typically best achieved below the level of con-
     whilst the “forward output model” predicts the            scious awareness. We may only be aware of our
                                                      Chapter 3: Processes and mechanisms in neuropsychiatry



movements when they deviate from what we intend           to functional impairment in a psychiatric context.
or expect to occur.                                       Unlike the movement disorder of more classic neuro-
    It may be that young people with motor coordi-        logical disorders such as Parkinson’s disease, move-
nation problems who have difficulty with automatic        ment disorders that appear in a developmental
responding (e.g. catching a ball) are processing at a     psychiatric context, with multiple circuitry involve-
more conscious level that results in a slowed, awk-       ment (e.g. involving the thalamus, basal ganglia, cere-
ward motor response falling short of the target behav-    bellum, fronto-striatal region) are less likely to be
ior. Operating at a more conscious level in this way      “fixed” (e.g. shuffling, uncoordinated gait) or “con-
would perhaps place greater demands on the atten-         sistent” (e.g. continually postured arms), and may be
tional and executive control centers of the brain (i.e.   more contextually dependent.
the prefrontal and cortico-thalamo-cortical circuitry),
which are typically impaired in neurodevelopmental        Motor overflow
disorders.                                                Motor overflow refers to the involuntary movement
    This fits with the phenomenon of kinesia para-        which can sometimes accompany voluntary move-
doxa, where “the individual who typically experiences     ment. Three forms of motor overflow have been
severe difficulties with the most simple of move-         described: (1) associated movement when involuntary
ments” (e.g. running) “may suddenly perform com-          movement occurs in non-homologous muscles in
plex, skilled movements” (e.g. running and trying to      either the ipsilateral or contralateral limbs; (2) contra-
get a ball) (Leary & Hill, 1996, p. 41). For example,     lateral mirror movement when directly observable
individuals with Asperger’s disorder have been            involuntary movements occur in homologous muscles
described as showing considerable dexterity in draw-      contralateral to the voluntary movements; and (3)
ing, model building, or playing a computer game           contralateral motor irradiation when involuntary
(particularly if the topic is one of special interest,    movements detected on electromyogram occur in
and therefore benefits from the child’s directed atten-   homologous muscles contralateral to the voluntary
tion) (Leary & Hill, 1996). Yet, they show abnormal-      movements (Hoy et al., 2004). Most theories on the
ities in everyday, simple motor tasks such as walking     etiology of motor overflow such as transcallosal facili-
or catching a ball, often appearing uncoordinated and     tation and ipsilateral activation theory have focused
clumsy. It may be that individuals with autism or         on potential cortical origins, although the possibility
Asperger’s disorder exhibit more skillful movement        of subcortical contribution remains. Motor overflow
on these (seemingly) more difficult tasks because         has been described in several populations including
attention becomes more focused, either because they       normal adults under effortful conditions, children
become obsessed with a particular motor task (e.g.        under the age of ten, and the elderly, and is pro-
computer games) or more complex tasks have more           nounced in Huntington’s disease, Parkinson’s disease,
cues embedded (e.g. verbal instructions, visual cues)     obsessive-compulsive disorder and schizophrenia. In
to focus the individual’s attention, which enables        Huntington’s disease, abnormal intracortical inhibi-
motor functioning to become automated.                    tion and resultant disinhibition of ipsilateral descend-
    These observations suggest that prefrontal input      ing fibers have been postulated to be responsible
(mediating focused attention) to the cerebellum and       for the motor overflow (Hoy et al., 2004). In contrast,
possibly basal ganglia are able to play an important      there is evidence of corpus callosum abnormalities
modulatory role in motor behavior. In addition the        in patients with schizophrenia, which can result in
thalamus, an area that is neuroanatomically anom-         greater transcallosal facilitation (Hoy et al., 2004).
alous in autism (Tsatsanis et al., 2003), has major
connections to both the cerebellum and basal ganglia      Neuromotor dysfunction and mental
fronto-striatal circuitry; it has also been implicated
in such paradoxical motor improvements when com-          disorders
promised and may play a mediating role in such            Disorders usually first diagnosed in infancy,
“kinesia paradoxa” (Mennemeier et al., 1996).
    Our understanding of how attentional focus inter-     childhood or adolescence
acts with motor functioning is at the heart of under-     Neuromotor soft signs identified in early childhood          29
standing how movement abnormalities may translate         (e.g. 6–10 years of age) are now increasingly
        Section 1: Neuropsychological processes



     recognized as an early marker of various developmen-        the basal ganglia and cerebellum. These structures
     tal problems and later-onset psychiatric disorders          form cortico-thalamo-cortical re-entrant loops and
     (Bergman et al., 1997). As movement is affected by          play a key role in selecting, inhibiting, releasing,
     the aberrant neurodevelopmental processes which             filtering, modulating and automatizing cognitive-
     appear to be associated with, and in some cases             motor function (Bradshaw, 2001). There is a poten-
     define, many early-onset psychiatric disorders, neuro-      tial relationship between concomitant comorbid
     motor assessment tasks have much to offer in the            conditions and greater involvement of the cortico-
     way of improving diagnostic definition and concep-          thalamo-cortical circuitry (Bradshaw, 2001). It is
     tualizations of comorbidity. Neuromotor assessment          not uncommon to find that an individual with
     tools may also act as important neurobiological             autism or Asperger’s disorder may show clinically
     probes to brain dysfunction in disorders where              significant signs of motor coordination disorder,
     imaging has so far been unable to make strong               ADHD, depression and anxiety (Tonge et al., 1999).
     inroads into neuropathological processes. Thus, while            In relation to pervasive developmental disorders,
     neuromotor assessment may, on the surface, seem             in particular autism and Asperger’s disorder, there
     more at home with the study of “frank” movement             has been much speculation about several issues
     disorders, such as Parkinson’s and Huntington’s dis-        including: the validity of separate diagnostic labeling,
     ease, it is perhaps the neurodevelopmental psychiatric      issues of diagnostic comorbidity, the role of move-
     disorders associated with much less obvious struc-          ment abnormality in the clinical expression of the
     tural and discernable functional brain abnormality,         disorders, and the role of the basal ganglia and cere-
     which may stand to benefit the most from such               bellum. As a result these disorders are perhaps the
     investigations.                                             best “model” to exemplify how neuromotor investi-
          The majority of childhood psychiatric disorders        gation has advanced, and may further advance, clin-
     involve motor disturbance to a greater (e.g. autism) or     ical child psychiatry and psychology.
     lesser degree (e.g. learning disabilities). The inclusion
     of a seemingly “neurological” condition such as
     Developmental coordination disorder (DCD) in the
                                                                 Case focus: autism and Asperger’s disorder.
     Diagnostic and Statistical Manual of Mental Disorders       An example of how neuromotor
     (DSM – IV-TR; American Psychiatric Association,             investigation has the potential to offer new
     2000), underscores Lennox & Lennox’s (2002) point
     about the “irritating historical division between           insights into etiology and diagnosis
     neurology and psychiatry . . .” (p. 28). Developmental      The clinical focus in disorders such as autism and
     coordination disorder involves a range of possible          Asperger’s disorder has traditionally been directed to
     disruptions to motor development and activities             the more salient social and communicative impair-
     including delays in meeting motor milestones (e.g.          ments. Research criteria in DSM–IV-TR separates
     sitting, crawling and walking), general clumsiness          children with autism and Asperger’s disorder based
     (e.g. “dropping things”), subaverage performance in         on language and intellectual functioning criteria.
     sports and/or poor handwriting. It is interesting to        There is a tendency for individuals diagnosed with
     note that disorders such as autism and Asperger’s           Asperger’s disorder to continue to be conceptualized
     disorder, both associated with movement dis-                as having a “milder” variant of autism, with the terms
     orders, cannot be comorbidly diagnosed with DCD.            Asperger’s disorder (AD) and high-functioning
     Attention-deficit hyperactivity disorder (ADHD), on         autism (HFA) often used interchangeably.
     the other hand, a disorder which also involves marked           Instrumented gait analysis may play an important
     motor coordination impairment (Barkley, 1997), can          adjunctive role in the assessment and differential
     be comorbid with DCD, but not with autism and               diagnosis of psychiatric disorders. In the context of
     Asperger’s disorder. The issue of comorbidity has           autism and AD this approach has revealed distinct
     been described as an “important if vexatious issue in       patterns of cerebellar gait variability which are a dis-
     psychopathology” (Bradshaw, 2001, p. 259). It may be        tinguishing feature of autism (cf: non-clinical popula-
     that movement coordination problems are a risk              tions) in children from 4–6 years of age (usual age of
30   factor for a multitude of psychiatric disorders             diagnosis) through to adolescence (Rinehart et al.,
     which involve “extrapyramidal” structures such as           2006c, 2006d). Moreover, there is some evidence that
                                                        Chapter 3: Processes and mechanisms in neuropsychiatry



atypical movement disturbances impacting on                 from basal ganglia via the thalamus, and outputs to
crawling may be observable in autism as young as            the primary motor cortex and back to the basal gan-
infancy, and appear before the diagnostically relevant      glia) reveals a reduced early component of the MRP
social-communicative signs (Teitelbaum et al., 1998).       similar to that observed in patients with Parkinson’s
Similar retrospective findings have been reported           disease (Cunnington et al., 1995); this is consistent
in the schizophrenia literature (Schiffman et al.,          with the suggestion that autism may be associated
2004). The observation that autism is associated with       with difficulties in maintaining adequate “motor
greater “cerebellar” gait variability than AD (the latter   set.” The finding of normal post-movement MRP
is perhaps more a basal ganglia fronto-striatal gait        activity, which contrasts with Parkinson’s disease
disorder) is consistent with the general body of            (Cunnington et al., 1995), suggests the presence of
research which has particularly focused on cerebellar       an intact “motor cue” for efficient running of well-
deficits in autism (Courchesne, 1999). This is also         learned motor sequences, and is consistent with clin-
consistent with upper-body kinematic analysis               ical observation that individuals with autism do not
which reveals that individuals with autism, but not         have difficulty with well-learned movement sequences.
Asperger’s disorder, show cerebellar-like deficits in
accurately modulating later stages of movement in           Disorders usually first diagnosed in late
order to efficiently “home-in” on targets (Rinehart
et al., 2006a).                                             adolescence and adulthood
    DSM-IV-TR only hints that motor functioning is          The role of neuromotor investigation is well estab-
differentially affected by these disorders; for example,    lished in psychiatric research of adult mental dis-
“motor clumsiness and awkwardness” (p. 81) is               orders. A detailed criticism of these findings in
described as a feature of Asperger’s disorder, and          specific disorders will be covered in later chapters.
“abnormalities of posture” (for example, walking on         Neuromotor dysfunction in adult mental disorders
tiptoe, odd hand movements and body postures)               ranges from soft signs to more defined phenomena.
(p. 71) as a feature of autistic disorder. Neuromotor       In 1874, Kahlbaum described catatonia as an “insan-
investigations, however, may more accurately dissoci-       ity of tension” (Pfuhlmann & Stöber, 2001) referring
ate between these disorders. For example, in contrast       to the abnormal mental and motor manifestations
to the DSM-IV-TR description above, blindly rated           which he considered as a distinct clinical entity. Con-
video observational analysis by gait experts has            temporary psychiatric classification systems such as
revealed that both autism and AD may be associated          ICD–10 and DSM–IV consider catatonia as a subtype
with motor clumsiness; however, AD may be dissoci-          of schizophrenia, despite the occurrence of catatonic
ated from autism more on the basis of abnormalities         features in affective and medical conditions.
in terms of head and trunk posture (Rinehart et al.,            The interrelated nature of motor and psychiatric
2006b). These observable upper-body postural abnor-         phenomena is revealed in the observations of abnor-
malities fit well with Damasio & Maurer’s (1978)            mal activity ranging from seemingly aimless pacing,
“Parkinsonian” view of autism, given the putative role      restlessness or over- or under-activity, to more seem-
of the basal ganglia in regulating postural alignment       ingly purposeful behaviors such as compulsive
and axial motor control (Morris & Iansek, 1996).            touching, self-mutilation and aggressive behaviors in
    A key feature of basal ganglia dysfunction is that it   patients with severe psychiatric disorders preceding
leads to a failure to maintain preparedness for move-       the introduction of neuroleptics in 1954 (Rogers,
ment (“motor set”), and is thought to result clinically     1992). The side-effects associated with the introduc-
in a mismatch between desired and actual movement           tion of neuroleptics to treat psychosis, i.e. dystonia,
(Morris & Iansek, 1996). Anecdotally, individuals           akinesia and tardive dyskinesia, as well as antiparkin-
with HFA (and AD) report difficulty in playing              sonian medications to treat Parkinson’s disease, i.e.
sport because there is a mismatch between wanting           psychoses, visual hallucinations and acute brain syn-
to “catch a ball” and actually catching the ball, noting    drome, only serve to emphasize the integral role of
that they tend to “duck” from the ball or move              the basal ganglia and associated circuits in both
away at the last minute. Analysis of movement-              groups of disorder. Oculomotor disturbances in these
related-potential activity (MRPs) over the supplemen-       disorders suggest involvement of the dopaminergic         31
tary motor area (a region which receives main input         system and frontal lobe.
        Section 1: Neuropsychological processes



         A case exemplar of neuromotor and psychiatric           rituals being more common in non tic-related OCD,
     abnormality is Gilles de la Tourette’s syndrome             and the need to touch or rub, blinking or staring
     (GTS), which is characterized by multiple vocal and         rituals, the need for symmetry, and intrusive aggres-
     motor tics and accompanied by many comorbid                 sive images being more common in OCD with
     behavioral and cognitive problems such as obsessive-        comorbid tics. Kinematic analysis of handwriting to
     compulsive disorder, ADHD, learning difficulties,           assess subtle motor dysfunction found differences
     depression and anxiety (Bradshaw, 2001). The tics           between responders and non-responders to combined
     are preceded by an increasing sensation of tension          sertraline and behavior therapy (Mergl, 2005).
     relieved upon their release, which is often forceful             The high prevalence of depression in motor dis-
     and potentially self-injurious. Tics may be briefly         orders such as Parkinson’s disease, Huntington’s dis-
     suppressed or incorporated into a seemingly pur-            ease and Wilson’s disease, as well as the recognition of
     poseful movement. Although not common, GTS is               the psychomotor symptoms of depression, have led to
     often associated with repetitive or obscene gestures        increased interest in using these specific basal ganglia
     or speech such as echopraxia, echolalia, palilalia,         diseases as models to study depression (Sobin, 1998).
     copropraxia and coprolalia. Not surprisingly, a disin-      Some researchers continue to argue that the incidence
     hibitory response to the Simon task in the incongruent      of depression in these motor disorders is a psycho-
     condition has been observed in GTS (Bradshaw, 2001).        logical reaction to a chronic illness, whilst others view
     Deficits in visuomotor integration tasks such as Rey        the depression and the motor manifestations equally
     Osterrieth Complex Figure copying have been consis-         as manifestations of underlying brain abnormalities.
     tently reported (Bradshaw, 2001). It is unclear whether     The observation that depression can precede the onset
     deficits on motor tasks, such as Purdue Pegboard or         of motor symptoms of Huntington’s disease by many
     finger tapping, are secondary to this visuomotor            years, and can occur in those who may not be aware
     integration deficit. Eye movement abnormalities have        of their being at risk for the disorder, provides sup-
     also been found. The occurrence of tics in other patho-     port for the latter (Peyser & Folstein, 1990). The view
     logical conditions affecting this region such as carbon     that depression is reactive to stress and has no under-
     monoxide poisoning, encephalitis lethargica (Stern,         lying cerebral pathology should therefore be rejected.
     2000) and volumetric changes in the basal ganglia sup-           The psychomotor symptoms observed in major
     port a basal ganglia dysfunction theory. All evidence       depression including slowed movement, shuffling
     indicates failure of the striatopallidal gating of motor,   gait, stooped posture, soft and monotonous speech,
     cognitive and limbic pathways resulting in the inability    facial immobility and purposeless movements of the
     to suppress impulsivity. A more complex model involv-       limbs and trunk, closely mimic the symptoms of
     ing aberrant activity in the sensorimotor, executive,       Parkinson’s disease. Psychomotor retardation has
     language and paralimbic circuits has been suggested         been correlated with reduced blood flow in the left
     by PET studies (Stern, 2000).                               dorsolateral prefrontal cortex (DLPFC) and left angu-
         Obsessive-compulsive disorder (OCD) is often            lar gyrus (Bench, 1993). Similar neuroimaging find-
     seen as the cognitive counterpart of GTS, although          ings in patients with diminished speech in aphasia
     there are important differences such as the ideational      and chronic schizophrenia implicate the role of the
     component and the overfocusing of attention in              left DLPFC in volitional and intentional activities, and
     OCD. The main symptoms of OCD are recurrent,                in interconnecting with the anterior cingulate. The
     intrusive thoughts, impulses or images (obsessions)         angular gyrus plays an important role in visuospatial
     often accompanied by ritualistic behaviors (compul-         orientation and attention. In contrast, marked motor
     sions) that cannot be resisted without increasing anx-      agitation has been associated with increased blood
     iety. Recent research has hinted at subtle differences      flow in the inferior parietal lobe and the cingulate
     in OCD populations depending on the presence of             cortex, which plays a role in drive and affect and
     tics or soft neurological signs. Tic-related OCD has an     connects with the higher association cortex (Bench,
     earlier onset in childhood, is commoner in boys and         1993). Neuropsychological deficits of executive dys-
     responds less well to selective serotonin inhibitors        function in major depression provide further support
     alone (Bradshaw, 2001). The content of the OCD              for involvement of the frontostriatal circuit in some
32   symptoms varies depending on the presence or                subtypes of major depression (Bradshaw, 2001). Simi-
     absence of tics, with contamination themes and              lar neuroimaging and neurocognitive findings in
                                                        Chapter 3: Processes and mechanisms in neuropsychiatry



schizophrenia (described in Chapter 26) also implicate           Other relatively new technologies such as trans-
frontostriatal circuit abnormalities (Pantelis et al.       cranial magnetic stimulation (TMS) also open up new
1992, 1997).                                                possibilities for investigating psychiatric disorders.
    The significance of other motor abnormalities           Transcranial magnetic stimulation is a non-invasive
co-existing with other psychiatric phenomena is less        means of stimulating nerve cells (in excitatory or
well-defined. Neurological soft signs characterized by      inhibitory fashion) in superficial areas of the brain,
abnormalities in motor, sensory and integrative func-       providing a powerful method for the study of motor
tions have been used as probes for non-specific cen-        cortical function. Transcranial magnetic stimulation
tral nervous system defects. Neurological soft signs in     applied to the motor cortex of human subjects has
schizophrenia have been linked with genetic and             been extensively used to investigate normal motor
environmental factors, such as intrauterine and peri-       cortical physiology and disease states (Fitzgerald
natal trauma, and are hypothesized as non-specific          et al., 2002). Transcranial magnetic stimulation
markers of vulnerability to psychoses. A better under-      methods have a significant advantage over other
standing of the presence of neurological soft signs         methods of assessment of motor function as they are
in other mental disorders as diverse as antisocial          completely independent of motivation, attention and
personality disorder (Lindberg et al., 2004) and post-      other elements of higher cognitive function (Fitzger-
traumatic stress disorder (Gurvits et al., 1997) may        ald et al., 2002). Possible comorbid impairments must
elucidate the underlying pathology of these disorders       be taken into account when we are assessing neuro-
that have traditionally been regarded as falling more       motor functioning in a psychiatric context.
into the psychiatric realm.                                      Eye movements “whose premotor structures and
                                                            descending commands are the best understood of any
                                                            motor system” may also play a role in expanding our
Neuromotor assessment and research                          clinical and neurobiological understanding of psychi-
Formal neurological examination including gait anal-        atric disorders (Robinson & Fuchs, 2001). The most
ysis and assessment for extrapyramidal symptoms             important advantage of applying this approach to
as markers of basal ganglia involvement, e.g. muscular      these complex cognitive–motor disorders is that the
rigidity, bradykinesia, resting tremor and flexion          ocular motor system, truly a window directly in to the
posture, is an important part of neuropsychiatric assess-   brain, has a reduced number of degrees of freedom of
ment. Instruments such as the Geriatric Movement            movement and little in the way of plastic or inertial
Disorders Assessment that include ratings on the            forces. Therefore, output closely mirrors the com-
Simpson Extrapyramidal Side Effect Scale (Simpson &         mand signals and the cognitive influences on them.
Angus, 1970), the Abnormal Involuntary Movement                  While conventional clinical diagnosis of early-
Scale and the Neurological Evaluation Scale and             onset psychiatric disorders may take place informally
Unified Huntington’s Disease Rating Scale, can all pro-     (e.g. observation of skills during play, drawing),
vide quantitative measures for use in research. A variety   and sometimes with the use of standardized tests of
of tools such as ambulatory activity monitors with solid    motor ability such as the Bruininks–Osertesky test
state memory, along with kinematic analysis of hand-        (Bruininks, 1978) and the Movement Assessment
writing using digitizing graphic tablets (Mergl, 2005),     Battery for Children (Henderson & Sugden, 1992),
the Purdue Pegboard, and other reaction-timed and           future diagnosis of these disorders may include
motor-coordination tasks can enhance and quantify           instrumented gait analysis, motor cortical EEG analy-
clinically observable and more subtle motor behaviors.      sis, TMS, and ocular motor assessment; all of which
    While in the past instrumented neurological             will shed greater light on the neurobiological under-
examination (e.g. gait analysis) and EEG have been          pinnings of these disorders and thereby have early
described as “non-contributory” (p. 64) in a develop-       intervention and management implications.
mental psychiatric assessment context (Graham et al.,
2001), it might be that the future coupling of EEG and
movement tasks, together with systematic gait analy-        Summary
sis using clinical technologies that are commercially       The etiological relevance of neuromotor dysfunction
available, may greatly improve our definition of            has now been established as a key focus of clinical      33
early-onset psychiatric disorders.                          research for a number of psychiatric disorders such as
        Section 1: Neuropsychological processes



     autism and schizophrenia. Renewed interest in the               Bruininks, R. H. (1978). Bruininks–Oseretsky Test of Motor
     application of neuromotor assessment in the psychi-                Proficiency. Circle Pines, MN: American Guidance
     atric arena occurs in parallel to critical developments            Service.
     in our understanding of the neural connectivity of the          Brune, M. (2005). Theory of mind in schizophrenia: a
     prefrontal cortex, basal ganglia and cerebellum                    review of the literature. Schizophrenia Bulletin, 31(1),
     (Hoshi et al., 2005). Conceptual advances have been                21–42.
     made in our understanding of higher-order awareness             Bundick, T., Jr. & Spinella, M. (2000). Subjective experience,
     and control of “action,” mirror neurons, the concept              involuntary movement, and posterior alien hand
                                                                       syndrome. Journal of Neurology, Neurosurgery and
     of affordances, utilization behavior, and extreme
                                                                       Psychiatry, 68(1), 83–85.
     neurological motor conditions such as the anarchic
                                                                     Chan, J.-L. & Liu, A. B. (1999). Anatomical correlates of
     hand, all of which may form part of the larger land-
                                                                       alien hand syndromes. Neuropsychiatry Neuropsychology
     scape for understanding the complex cognitive–                    and Behavioral Neurology, 12(3), 149–155.
     motor processing dysfunctions that occurs in people
                                                                     Courchesne, E. (1999). An MRI study of autism: the
     with mental illness.
                                                                       cerebellum revisited. Neurology, 52(5), 1106–1107.
                                                                     Cunnington, R., Bradshaw, J. L. & Iansek, R. (1996). The
     References                                                        role of the supplementary motor area in the control of
     American Psychiatric Association (2000). Diagnostic               voluntary movement. Human Movement Science, 15,
       and Statistical Manual of Mental Disorders, Fourth              627–647.
       Edition – Text Revision. Washington, DC: American             Cunnington, R., Iansek, R., Bradshaw, J. L. & Phillips, J. G.
       Psychiatric Association Press.                                  (1995). Movement-related potentials in Parkinson’s
     Arbib, M. A. (2005). From monkey-like action recognition          disease: presence and predictability of temporal and
       to human language: an evolutionary framework for                spatial cues. Brain, 118, 935–950.
       neurolinguistics. Behavioral and Brain Sciences, 28(2),       Damasio, A. R. & Maurer, R. G. (1978). A neurological
       105–124.                                                        model for childhood autism. Archives of Neurology, 35,
     Avenanti, A., Bueti, D., Galati, G. & Aglioti, S. M. (2005).      777–786.
       Transcranial magnetic stimulation highlights the              Della Sala, S. (2005). The anarchic hand. The Psychologist,
       sensorimotor side of empathy for pain. Nature                   18(10), 606–609.
       Neuroscience, 8(7), 955–960.
                                                                     Fitzgerald, P. B., Brown, T. L. & Daskalakis, Z. J. (2002). The
     Barkley, R. A. (1997). Behavioral inhibition, sustained            application of transcranial magnetic stimulation in
        attention, and executive functions: constructing a              psychiatry and neurosciences research. Acta Psychiatrica
        unifying theory of ADHD. Psychological Bulletin, 121(1),        Scandinavica, 105, 324–340.
        65–94.
                                                                     Frith, C. (2005). The neural basis of hallucinations and
     Bench, C. J. (1993). Regional cerebral blood flow in               delusions. C.R. Biologies, 328, 169–175.
       depression measured by positron emission tomography:
       the relationship with clinical dimensions. Psychological      Frith, C. D., Blakemore, S. J. & Wolpert, D. M. (2000).
       Medicine, 23, 579–590.                                           Abnormalities in the awareness and control of action.
                                                                        Philosophical Transactions of the Royal Society of London
     Bergman, A. J., Wolfson, M. A. & Walker, E. E. (1997).             B Biological Sciences, 355(1404), 1771–1788.
        Neuromotor functioning and behaviour problems in
        children at risk for psychopathology. Joural of Abnormal     Gibson, J. J. (1979). The Ecological Approach to Visual
        Child Psychology, 25(3), 229–237.                               Perception. London: Erlbaum.

     Blakemore, S. J., Bristow, D., Bird, G., Frith, C. & Ward, J.   Glickstein, M. (2006). Thinking about the cerebellum.
        (2005). Somatosensory activations during the                    Brain, 129, 288–292.
        observation of touch and a case of vision-touch              Graham, P., Turk, J. & Verhulst, F. (2001). Child Psychiatry:
        synaesthesia. Brain, 128(7), 1571–1583.                        A Developmental Approach. Oxford: Oxford University
     Bradshaw, J. L. (2001). Developmental Disorders of the            Press.
        Frontostriatal System: Neuropsychological,                   Gurvits, T. S., Glibertson, M. W., Lasko, N. B., Orr, S. P. &
        Neuropsychiatric and Evolutionary Perspectives. Hove,          Pitman, R. K. (1997). Neurological status of combat
        UK: Psychology Press.                                          veterans and adult survivors of sexual abuse PTSD.
     Bradshaw, J. L. & Mattingley, J. B. (1995). Clinical              Annals of the New York Academy of Science, 21, 468–471.
        Neuropsychology: Behavioral and Brain Science. San           Happe, F. (1999). Autism: cognitive deficit or cognitive
34      Diego, CA: Academic Press.                                     style. Trends in Cognitive Sciences, 3, 216–222.
                                                               Chapter 3: Processes and mechanisms in neuropsychiatry



Henderson, S. E. & Sugden, D. A. (1992). Movement                  Parton, A., Malhotra, P. & Husain, M. (2004). Hemispatial
  Assessment Battery for Children. Sidcup, Kent: The                  neglect. Journal of Neurology, Neurosurgery and
  Psychological Corporation Ltd.                                      Psychiatry, 75(1), 13–21.
Hoshi, E., Tremblay, L., Feger, J., Carras, P. L., & Strick,       Perenin, M. T. & Vighetto, A. (1988). Optic ataxia: a specific
  P. L. (2005). The cerebellum communicates with the                  disruption in visuomotor mechanisms. I. Different
  basal ganglia. Nature Neuroscience, 11, 1491–1493.                  aspects of the deficit in reaching for objects. Brain,
Hoy, K. E., Fitzgerald, P. B., Bradshaw, J. L., Armatas, C. A.        111(3), 643–674.
  & Georgiou-Karistianis, N. (2004). Investigating the             Peyser, C. E. & Folstein, S. E. (1990). Huntington’s disease as
  cortical origins of motor overflow. Brain Research                  a model for mood disorders. Clues from neuropathology
  Reviews, 46, 315–327.                                               and neurochemistry. Molecular and Chemical
Kilner, J. M., Vargas, C., Duval, S., Blakemore, S. J. &              Neuropathology, 122, 99–119.
   Sirigu, A. (2004). Motor activation prior to observation        Pfuhlmann, B. & Stöber, G. (2001). The different
   of a predicted movement. Nature Neuroscience, 7(12),               conceptions of catatonia: historical overview and critical
   1299–1301.                                                         discussion. European Archives of Psychiatry and Clinical
Leary, M. R. & Hill, D. A. (1996). Moving on: autism                  Neurosciences, 251(Suppl.1), 1/4–1/7.
   and movement disturbance. Mental Retardation, 34(1),            Rinehart, N. J., Bellgrove, M. A., Bradshaw, J. L., Brereton,
   39–53.                                                             A. V. & Tonge, B. J. (2006a). An examination of
Lennox, B. R. & Lennox, G. G. (2002). Mind and movement:              movement kinematics in young people with
   the neuropsychiatry of movement disorders. Journal of              high-functioning autism and Asperger’s disorder:
   Neurology, Neurosurgery, and Psychiatry, 72(Suppl. 1),             further evidence for a motor planning deficit. Journal of
   28–31.                                                             Autism and Developmental Disorders, 36, 757–767.
Liberman, A. M., Cooper, F. S., Shankweiler, D. P. &               Rinehart, N. J., Tonge, B., Bradshaw, J. L. et al. (2006b).
   Studdert-Kennedy, M. (1967). Perception of the speech              Movement-related potentials in high-functioning autism
   code. Psychological Review, 74(6), 431–461.                        and Asperger’s disorder. Developmental Medicine and
                                                                      Child Neurology, 48, 272–277.
Lindberg, N., Tani, P., Stenberg, J.-H. et al. (2004).
   Neurological soft signs in homicidal men with antisocial        Rinehart, N. J., Tonge, B., Iansek, R. et al. (2006c). Gait
   personality disorder. European Psychiatry, 19, 433–437.            function in newly diagnosed children with autism:
                                                                      cerebellar and basal ganglia related motor disorder.
Marchetti, C. & Della Sala, S. (1998). Disentangling the
                                                                      Developmental Medicine and Child Neurology, 48,
  alien and anarchic hand. Cognitive Neuropsychiatry, 3,
                                                                      819–824.
  191–207.
                                                                   Rinehart, N. J., Tonge, B. J., Bradshaw, J. L., et al. (2006d).
Mennemeier, M., Crosson, B., Williamson, D. J. et al.
                                                                      Gait function in high-functioning autism and Asperger’s
  (1996). Tapping, talking and the thalamus: possible
                                                                      disorder: evidence for basal-ganglia and cerebellar
  influence of the intralaminar nuclei on basal ganglia
                                                                      involvement. European Child and Adolescent Psychiatry,
  function. Neuropsychologia, 35(2), 183–193.
                                                                      15, 256–264.
Mergl, R. (2005). Can a subgroup of OCD patients with
                                                                   Rizzolatti, G. & Craighero, L. (2004). The mirror-neuron
  motor abnormalities and poor therapeutic response be
                                                                      system. Annual Reviews of Neuroscience, 27, 169–192.
  identified? Psychopharmacology, 179, 826–837.
                                                                   Robinson, F. R. & Fuchs, A. F. (2001). The role of the
Morris, M. E. & Iansek, R. (1996). Characteristics of motor
                                                                     cerebellum in voluntary eye movements. Annual Review
  disturbance in Parkinson’s disease and strategies for
                                                                     of Neuroscience, 24, 981–1004.
  movement rehabilitation. Human Movement Science, 15,
  649–669.                                                         Rogers, D. (1992). Motor disorder in psychiatry. In Towards
                                                                     a Neurological Psychiatry. Chichester, UK: John Wiley
Nelissen, K., Luppino, G., Vanduffel, W., Rizzolatti, G. &
                                                                     and Sons.
  Orban, G. A. (2005). Observing others: multiple action
  representation in the frontal lobe. Science, 310(5746),          Schiffman, J., Walker, E., Ekstrom, M. et al. (2004).
  332–336.                                                            Childhood videotaped social and neuromotor precursors
                                                                      of schizophrenia: a prospective investigation. American
Pantelis, C., Barnes, T. R. E. & Nelson, H. E. (1992).
                                                                      Journal of Psychiatry, 161, 2021–2027.
  Is the concept of frontal-subcortical dementia relevant
  to schizophrenia? British Journal of Psychiatry, 160,            Simpson, G. M. & Angus, J. W. S. (1970). A rating scale for
  442–460.                                                            extrapyramidal side effects. Acta Psychiatrica
                                                                      Scandinavica, Suppl., 11–19.
Pantelis, C., Barnes, T. R. E., Nelson, H. E. et al. (1997).
  Frontal-striatal cognitive deficits in patients with chronic     Singer, T. & Frith, C. (2005). The painful side of empathy.       35
  schizophrenia. Brain, 120, 1823–1843.                               Nature Neuroscience, 8(7), 845–846.
        Section 1: Neuropsychological processes



     Sobin, C. (1998). The motor agitation and retardation         Tonge, B., Brereton, A., Gray, K. M. & Einfield, S. L. (1999).
        scale: a scale for the assessment of motor abnormalities     Behavioural and emotional disturbance in high
        in depressed patients. Journal of Neuropsychiatry, 10,       functioning autism and Asperger’s disorder. Autism,
        85–92.                                                       3(2), 117–130.
     Stern, E. (2000). A functional neuroanatomy of tics in        Tsatsanis, K. D., Rourke, B. P., Klin, A., et al. (2003).
        Tourette syndrome. Archives of General Psychiatry, 57,        Reduced thalamic volume in high-functioning
        741–748.                                                      individuals with autism. Biological Psychiatry, 53,
     Taira, M., Mine, S., Georgopoulos, A. P. & Murata, A. S. H.      121–129.
        (1990). Parietal cortex neurons of the monkey related to   Ungerleider, L. G. & Mishkin, M. (1982). Two cortical visual
        the visual guidance of hand movement. Experimental           systems. In D. J. Ingle, M. H. Goodale & J. W. Mansfield
        Brain Research, 83, 29–36.                                   (Eds.), Analysis of Visual Behavior (pp. 549–586).
     Teitelbaum, P., Teitelbaum, O., Nye, J. Fryman, J. &            Cambridge, MA: MIT Press.
        Maurer, R. G. (1998). Movement analysis in infancy         Williams, J. H. G., Whiten, A., Suddendorf, D. I. &
        may be useful for early diagnosis of autism. Proceedings     Perrett, D. I. (2001). Imitation, mirror neurons and
        of the National Academy of Sciences: Psychology, 95,         autism. Neuroscience and Biobehavioral Reviews, 25,
        13982–13987.                                                 287–295.




36
    Chapter




           4
                     The neurobiology of the emotion response:
                     perception, experience and regulation
                     Sarah Whittle, Murat Yücel and Nicholas B. Allen



Introduction                                                   likely lack a number of the higher-order neural func-
                                                               tions required for this task. Only relatively recently
Emotion is a complex phenomenon that influences,               has the recognition of these diverse aspects of emo-
and is influenced by, every aspect of human experi-            tion been translated into human neuropsychological
ence. It is unconditionally tied to our perceptions and        research. Particularly, research utilizing sophisticated
interpretation of stimuli; the content of our memories         neuroimaging techniques has begun to shed light on
and the means by which they are encoded and                    the complex spatial and temporal neural architecture
retrieved; our attentional capacity and other executive        of the emotion response.
functioning; and our motivations to think and act in               This chapter aims to present an integrated over-
specific ways. Given such widespread significance,             view of the neural bases of three major components of
it is not surprising that there have been centuries of         the emotion response: (1) emotion perception (i.e. the
research dedicated to understanding the neural bases           identification and appraisal of emotional stimuli); (2)
of emotion.                                                    emotion experience (i.e. the production of a specific
     Understanding how emotion is represented in the           affective state in response to a stimulus, including
brain has nevertheless proved to be a difficult task;          physiological arousal, conscious feeling and emotional
primarily due to its complexity, and the difficulty            behavior); and (3) the regulation of the affective state
in operationalizing and measuring this construct.              and emotional behavior, which may occur consciously
Emotion has been described as a set of physiological,          or unconsciously. For each component, relevant evi-
phenomenological and facial expression changes                 dence from human neuroimaging research (and also
evoked in relation to appraisals of situations (Beer &         from lesion studies, where appropriate) is presented.
Lombardo, 2007). Accordingly, a large amount of                These methodologies offer greater spatial resolution
research has been dedicated to understanding the               than previous methodologies for examining brain–
neural processes associated with the perception of             behavior relationships, and hence have provided the
emotional stimuli, and the production of physio-               means for more fine-grained investigation of the
logical arousal and subjective feeling states (Adolphs         neural correlates of the components of the emotion
& Damasio, 2000). Much of this research has treated            response. Following this, there will be a discussion of
these processes as a single entity; however, recent            how the identified brain regions might work together
evidence suggests that they may be governed by neur-           in neural circuits that underlie the unfolding emotion
ally distinct mechanisms. Further, emotion regulation          response. The chapter will conclude with a brief dis-
is also an important component of the emotion                  cussion of how deficits in the brain circuitry under-
response. Emotion regulation refers to control pro-            lying the emotion response may contribute to the
cesses aimed at manipulating when, where, how                  etiology of a number of psychiatric disorders.
and which emotions are experienced and expressed
(Ochsner & Gross, 2005). This aspect of emotional
functioning has traditionally been overlooked, which           Emotion perception
is largely attributable to the fact that most of the early     The initial identification and appraisal of an affective
emotion research was conducted with animals, which             stimulus is the first process comprising the emotion

The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by         37
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



     response. An affective stimulus may be a stimulus            1998; Zald, 2003). The apparent negative bias in the
     with inherent affective properties such as an emotion-       literature (i.e. majority of studies showing amygdala
     ally expressive face or sound, or a neutral stimulus         associations with negative stimuli) may arise from the
     that has been conditioned to elicit an affective res-        fact that aversive stimuli are usually arousing to a
     ponse. The amygdala and insula are two key structu-          greater degree than pleasant stimuli.
     res that have been implicated in emotion perception.             Recent research suggests that an individual’s
                                                                  characteristic style of perceiving and responding to
                                                                  affective stimuli may affect the degree of attentional
     The amygdala                                                 processing afforded to specific affective stimuli by
     The amygdala is an ovoid gray matter structure               the amygdala. Canli (2004) reported a series of fMRI
     situated bilaterally on the superomedial wall of the         studies whereby individual differences in trait extra-
     temporal lobes. Research suggests this structure is          version and neuroticism predicted differential amyg-
     involved in the modulation of vigilance to emotion-          dala responses to affective stimuli. In one study
     ally salient stimuli, and in the initial and largely         increased amygdala activation to pleasant pictures
     subconscious assignment of affective significance to         was correlated with self-reported extraversion, whilst
     sensory events (LeDoux, 1993; Ochsner & Schacter,            increased activation to negative stimuli was correlated
     2000). Widespread cortical and subcortical connec-           with neuroticism. Such findings highlight a complex
     tions subserve the transfer of information processed         role for the amygdala in affective processing, and
     in the amygdala for subsequent emotional learning            suggest that an important direction for future inves-
     and behavior. The amygdala has been primarily                tigation of the neural bases of emotion will be to
     implicated in the processing of negative affective           incorporate measures of trait-level individual differ-
     stimuli, particularly fearful or threatening in nature.      ence factors.
     Lesions of the amygdala have resulted in impairments
     in the response to fear stimuli in both visual (Young
     et al., 1995) and auditory (Scott et al., 1997) domains.     The insula
     Functional imaging (i.e. functional magnetic reso-           The insula cortex, a part of the extended limbic
     nance imaging [fMRI] or positron emission tomog-             system, lies bilaterally at the deepest point of the
     raphy [PET]) studies have documented increased               lateral sulcus, which separates the temporal lobe from
     amygdala activation during exposure to fearful and           the inferior parietal cortex. The anterior insula cortex
     other unpleasant stimuli (Schwartz et al., 2003; Zald,       in particular has been implicated in emotion percep-
     2003). Trait measures of behavioral inhibition or            tion, with evidence that it may convey representations
     anxiety (where there is chronic sensitivity to threat)       of affective sensory information to the amygdala, with
     have been correlated with amygdala activity during           which it has dense bilateral connections (Augustine,
     exposure to a range of affective stimuli (Etkin et al.,      1996). The insula cortex has been implicated in the
     2004; Reuter et al., 2004; Schienle et al., 2005).           recognition and processing of disgusting stimuli,
         Whilst there is a wealth of evidence for the             with patients with insula lesions exhibiting deficits
     involvement of the amygdala in the perception of             in the recognition of facial and vocal expressions of
     aversive stimuli, functional imaging studies have also       disgust (Calder et al., 2000). Functional MRI studies
     reported amygdala activity with exposure to pleasur-         have reported insula activation with the perception
     able stimuli, indicating a complex role for the amyg-        of facial expressions of disgust (Phillips et al., 1997)
     dala in affective processing. Amygdala activation has        and during unpleasant taste perception (Small et al.,
     been reported during exposure to positive photo-             1999). Although insula activation has been frequently
     graphs (Hamann et al., 2002), positive emotional             associated with disgust, there is increasing evidence
     words (Hamann & Mao, 2002), erotic stimuli (Ferretti         of a broader role for this brain structure in emotion
     et al., 2005) and pleasant tastes (Small et al., 2003). It   processing (Schienle et al., 2002). Insula activation
     has been suggested that the amygdala’s apparent role         has been implicated in the processing of fear stimuli
     in processing both negative and positive affective           (Buchel et al., 1998), pain perception (Gelnar et al.,
     stimuli may stem from its broader role in the process-       1999), and the making of judgments about facial
38   ing of any stimuli that are of biological relevance, and     expressions of a number of emotions including dis-
     also novel, ambiguous or highly arousing (Whalen,            gust and happiness (Gorno-Tempini et al., 2001).
                                                            Chapter 4: The neurobiology of the emotion response



Emotion production, experience                               pleasant taste (O’Doherty, 2004) and monetary
                                                             reward (Knutson et al., 2001). Drugs of abuse possess
and emotion-dependent learning                               extremely high appetitive motivational value in
and decision-making                                          drug-dependent individuals, and in such individuals,
Once a stimulus has been perceived as affectively            increased activation of the amygdala has been
salient, a myriad of responses may be triggered,             reported with craving (i.e. desire to use) and anticipa-
including autonomic and somatic symptoms, subject-           tion of drug administration (Bonson et al., 2002;
ive feeling, facial and other bodily expressions, and        Lingford-Hughes et al., 2003).
associated behavior. Paradigms employed to examine
these responses include conditioning and mood
induction via extended exposure to affective stimuli
                                                             The insula
or autobiographical recall. Success of the paradigm is       The insula cortex has also been implicated in the
typically assessed retrospectively via self-report. Trait    generation of affective states in response to emotional
mood measures (i.e. chronic emotional experience)            stimuli. For example, imaging studies have reported
may also be correlated with brain structure or func-         insula activation during induced sadness and antici-
tion. Incentive motivation and reward or punish-             patory anxiety, during recall of internally generated
ment-related decision-making paradigms can also be           emotion (Reiman et al., 1997) and during the exp-
integrated into a review of emotional experience, as         erience of guilt (Shin et al., 2000), highlighting the
these processes involve desire, attainment or avoid-         involvement of the insula in the generation of par-
ance of a particular favorable or unfavorable affective      ticularly aversive affective experience. The importance
state. Both the amygdala and the insula have been            of trait differences in emotional functioning has been
implicated in the experiential (in addition to the per-      suggested by findings that individuals that rate highly
ceptual) components of the emotional response. The           on measures of trait anxiety show particularly high
rostral and ventral anterior cingulate cortex (ACC),         insula activity during the anticipation of emotionally
medial orbitofrontal cortex and ventral striatum (VS)        negative stimuli (Simmons et al., 2006).
also appear to be uniquely involved in emotion                   Furthermore, associations between insula activa-
production and experience.                                   tion and autonomic arousal (e.g. heart rate and heart-
                                                             rate variability), and visceral changes associated
                                                             with facial emotion processing have been reported
The amygdala                                                 (Critchley et al., 2005). It has been suggested that
In addition to its role in the initial identification of     the insula cortex provides the neural substrate that
affective stimuli, the amygdala has been suggested to        links emotional distress, anticipatory processing and
be important for learning about the affective conse-         autonomic arousal (Simmons et al., 2006).
quences of stimuli, which is an important process for
guiding future affect-related decision-making and
behavior. Again, the majority of evidence suggests a         Ventral/rostral anterior cingulate cortex
primary involvement in aversive learning (Adolphs &          The anterior cingulate cortex (ACC) is situated bilat-
Damasio, 2000; Davidson & Irwin, 1999; Davidson              erally on the medial walls of the frontal lobes. It is a
et al., 2000a; Ochsner & Schacter, 2000). Fear condi-        functionally heterogeneous region, involved in a vast
tioning has been reported to be reduced in patients          array of cognitive, emotional, motor, nociceptive and
with amygdala lesions (Bechara et al., 1995), and has        visuospatial functions (Bush et al., 2000). There is
been associated with amygdala activation in healthy          strong evidence that the region of the ACC lying
individuals (Buchel et al., 1999). Amygdala activation       ventral and rostral to the corpus callosum is preferen-
has further been reported in response to both the            tially related to affective processes (Bush et al., 2000,
induction and maintenance of both positive and nega-         2002), with the ventral region particularly impli-
tive emotional states (Davidson et al., 1999; Schaefer       cated in the production of somatic and autonomic
et al., 2002). The size of the amygdala has been cor-        emotional responses via efferent connections to auto-
related with self-reported dysthymia in patient popu-        nomic, endocrine and visceral effectors (Nauta, 1971).
lations (Tebartz van Elst et al., 1999), whilst amygdala     Early animal studies report that electrical stimulation     39
activation has been reported during anticipation of          of the ventral ACC results in increased heart rate,
        Section 1: Neuropsychological processes



     blood pressure and respiration, as well as increased         emphasized, with the medial OFC related to the
     distress vocalizations and emotional facial expression       monitoring, learning and memory of the reward value
     (see Allman et al., 2001). Lesions to this area also         of stimuli, and the lateral OFC related to the evalu-
     cause a variety of changes in emotional behavior,            ation of punishers, which when detected may lead
     ranging from apathy to anxiety (Angelini et al.,             to a change in ongoing behavior (Elliott et al., 2000;
     1981; Levin & Duchowny, 1991). A number of func-             Öngür et al., 2003). A posterior-anterior distinction
     tional imaging studies have reported increased activ-        of function has also been suggested, with more com-
     ity in the ventral/rostral ACC with the induction of         plex or abstract reinforcers (such as monetary gain
     various emotions. For example, induced sadness in            and loss) represented more anteriorly and less com-
     healthy individuals has been reported to result in           plex reinforcers (such as taste) more posteriorly
     increased activity in the ventral/rostral ACC (Liotti        (Kringelbach & Rolls, 2004).
     et al., 2000), and higher resting activity in the ventral/       The medial OFC (which often includes parts of
     rostral ACC has been observed in individuals with            rostral and ventral ACC, and may be termed ventro-
     higher self-reported trait negative affectivity as mea-      medial PFC) has particularly been implicated in the
     sured by the Positive and Negative Affect Schedule           production of reward-related emotional states and
     (PANAS; Zald et al., 2002).                                  behaviors. Activation of the medial OFC has been
         The ventral and rostral ACC have also been impli-        reported during the monitoring of rewarding stimuli
     cated in reward processing and motivated behavior.           during gambling tasks (Rogers et al., 2004), and
     The ventral ACC appears to be involved in the experi-        with increased desire and craving in cocaine addicts
     ence of emotional states resulting from rewarding            during drug administration (Volkow et al., 2005).
     outcomes, whilst the rostral ACC appears to be               Kringelbach (2005) suggests that the medial OFC is
     involved in the mediation of the representation of           important for the subjective experience of positive
     reward values, and stimulating motivated behavior.           affect associated with rewarding stimuli, and cites
     Increased activity in these regions has been reported        studies that have demonstrated a correlation between
     during reward-based decision-making in gambling              medial OFC activation with the subjective pleasant-
     tasks (Bush et al., 2002; Rogers et al., 2004; Williams      ness of tastes and odors, as well as the feeling of
     et al., 2004); with craving, desire and positive mood in     rush associated with administration of stimulant
     cocaine addicts during drug administration (Breiter          drugs in drug-naïve subjects. Increased activation of
     et al., 1997; Volkow et al., 2005); and during sexual        the medial OFC has also been reported in mothers
     arousal in healthy men (Rauch et al., 1999).                 whilst viewing pictures of their infants, with the
         Increased rostral ACC activity has also been             increases proportional to the degree of increase in
     reported in the context of social affective functioning,     felt positive affect (Nitschke et al., 2004). Further,
     with activations reported to correlate with feelings of      increased activation in this region has been associated
     social exclusion (Somerville et al., 2006), with mater-      with emotional expression. For example, a PET study
     nal distress during exposure to sounds of infant cries       reported increased medial OFC activity to increase
     (Lorberbaum et al., 2002), but also with feelings of         with smiling and laughter during exposure to visual
     romantic and maternal love during exposure to visual         comics (Iwase et al., 2002).
     stimuli of loved ones (Bartels & Zeki, 2004).

                                                                  Ventral striatum
     Medial orbitofrontal cortex                                  The ventral striatum (VS) is the most inferomedial
     The orbitofrontal cortex (OFC) occupies the ventral          part of the striatal (or subcortical) part of the brain,
     surface of the frontal lobes of the cortex. The OFC has      which primarily comprises the nucleus accumbens.
     been ascribed a prime role in multi-modal stimulus-          The VS is a core region of the brain reward system
     reinforcement associative learning, which is the type        and associated dopaminergic innervations from the
     of learning that is often involved in emotion. It has        ventral tegmental area (Schultz, 2000). There is evi-
     been suggested that different subregions of the              dence that the VS plays a key role in encoding the
     OFC subserve different aspects of this function              motivational salience of stimuli and encouraging
40   (Kringelbach & Rolls, 2004). The functional importance       appetitive or reward-dependent behaviors (Berridge
     of a medial-lateral parcellation of the OFC has been         & Robinson, 2003). Although much of this evidence
                                                           Chapter 4: The neurobiology of the emotion response



comes from animal studies showing an involvement            physiological responding to emotional stimuli. Two
of the VS in the modulation of both unconditioned           main cognitive emotion-regulation strategies have
and learned rewarding behaviors (Berridge, 2003;            been identified in the literature: reappraisal and sup-
Cardinal et al., 2002), there is also some supportive       pression. Reappraisal involves the cognitive trans-
human evidence. For example, increased activity in          formation of emotional experience; for example,
this region has been reported with subjective mea-          reframing an aversive event in neutral or positive
sures of craving in cocaine users following cocaine         terms. Suppression involves the inhibition of reactions
infusion (Breiter et al., 1997). Dopamine release in the    to emotional stimuli; that is, changing one’s affective
VS has been associated with naturally rewarding             state once an emotion has been triggered by an affect-
experiences such as food, sex (Giuliano & Allard,           ive stimulus (e.g. thinking of a pleasant scenario when
2001) and the use of certain drugs (Heinz et al.,           in an aversive mood). Although these two types of
2004). It has been suggested that in substance abuse,       emotion-regulation strategies may differ in their
dopaminergic dysfunction in the ventral striatum may        effectiveness (John & Gross, 2004), both have impli-
bias the brain reward system toward excessive attri-        cated similar brain regions. Both automatic and cog-
bution of incentive salience to substance-associated        nitive regulation processes are considered below, with
stimuli.                                                    a relatively more detailed discussion presented for the
    It has been suggested that the VS is necessarily        roles of the hippocampus, lateral OFC, dorsolateral
involved in positive feeling states associated with the     prefrontal cortex (DLPFC) and dorsal ACC in cogni-
anticipation and attainment of rewarding stimuli            tive emotion regulation.
(Berridge & Robinson, 2003). Supporting this, activity
in the VS has been reported during picture-induced
positive affect (Sutton, 1997), exposure to positive        Automatic regulatory processes
auditory stimuli (Blood & Zatorre, 2001; Hamann &           In addition to a role in experiential aspects of emotion,
Mao, 2002) and during sexual arousal in men (Rauch          the medial OFC appears to have a role in the regulation
et al., 1999). Self-reported happiness with the antici-     of emotional behavior occurring at an unconscious
pation of increasing monetary reward has also               or automatic level. It has been suggested that this
been shown to correlate with activity in this region        may occur as a result of direct and indirect connec-
(Knutson et al., 2001).                                     tions with subcortical structures involved in eliciting
                                                            emotion-related autonomic responses, including the
                                                            amygdala and ventral striatum (Kim & Jung, 2006).
Emotion regulation                                          There is evidence from both human and animal studies
An individual’s ability to regulate their emotion           that the medial OFC is involved in the extinction of
governs the duration, intensity and type of emotion         conditioned fear. Enhanced activation in the medial
experienced, with important implications for mental         OFC has been reported with the extinction of olfactory
health. An increasing amount of theory and research         fear conditioning (Gottfried & Dolan, 2004). Further,
into emotion regulation has suggested the existence of      fear association has been found to remain post extinc-
a variety of regulation processes, which may occur at       tion, suggesting that the involvement of this region in
either the conscious or unconscious level, and may          extinction represented the regulation (or inhibition) of
develop or be emphasized at different stages of life        fear expression. Also, recall of fear extinction learned
(Gross, 1998; Rothbart & Derryberry, 1981). The             the previous day has been correlated with medial OFC
existing neuroimaging literature has highlighted an         fMRI activity (Phelps et al., 2004) and cortical thick-
important distinction between unconscious (or auto-         ness in this area (Milad et al., 2005).
matic) control processes and conscious (or cognitive/
effortful) control processes. Automatic control pro-
cesses have been investigated primarily by extinction       Cognitive regulatory processes
paradigms, which involve the cessation of a condi-          Dorsal anterior cingulate cortex
tioned affective response via repeated pairing of a
conditioned stimulus with a neutral outcome. Auto-          and dorsolateral prefrontal cortex
matic regulation has also been inferred from findings       There is evidence that the dorsal region of the ACC is      41
of increased brain activity correlated with decreased       preferentially involved in cognitive and executive
        Section 1: Neuropsychological processes



     processes. The dorsal ACC has been implicated in a          of negative emotional stimuli on subsequent behavior
     range of such processes including attention, error          (Beer et al., 2006).
     monitoring and inhibitory control (Bush et al.,
     2002). Strong reciprocal connections to the lateral         Hippocampus
     prefrontal cortex and supplementary and premotor
                                                                 The hippocampus has a long-established role in spa-
     areas are suggested to be important for the integration
                                                                 tial processing and certain forms of memory. It has
     of information processed in the dorsal ACC with
                                                                 become increasingly apparent however that the hip-
     higher cognitive processes (such as working memory)
                                                                 pocampus plays a more general role in information
     and the translation of cognitive processes into phys-
                                                                 processing and behavioral regulation, and that these
     ical action (Vogt et al., 1995). The DLPFC in particu-
                                                                 various functions may be distributed throughout the
     lar has been theorized to work closely with the dorsal
                                                                 hippocampus. It has been recently proposed that
     ACC in a network subserving cognitive control; while
                                                                 there are two main subregions of the hippocampus:
     the dorsal ACC is involved in evaluative processes
                                                                 a dorsal region that has a preferential role in spatial
     indicating when control needs to be engaged, the
                                                                 learning and memory, and a ventral region that has a
     DLPFC is responsible for the strategic implementa-
                                                                 preferential role in the regulation of anxiety-related
     tion of control over one’s thoughts and actions in
                                                                 behaviors (Bannerman et al., 2004; Gray, 1982; Gray &
     line with specific goals or task-oriented behaviors
                                                                 McNaughton, 2000). It has been suggested that when
     (Botvinick et al., 2001; MacDonald et al., 2000).
                                                                 there is conflict between the tendency to approach
         There is evidence that the dorsal ACC and DLPFC
                                                                 cues associated with reward and the tendency to avoid
     are involved in such control functions specifically
                                                                 cues associated with negative affect, the hippocampus
     related to affective behavior. Both reappraisal and
                                                                 outputs a signal that increases the weight or valence of
     suppression emotion-regulation paradigms have been
                                                                 affectively negative information, therefore decreasing
     found to elicit activation in the dorsal ACC and
                                                                 the tendency to approach a goal. Pathological anxiety
     DLPFC (Levesque et al., 2003, 2004; Ochsner et al.,
                                                                 is thought to result from hippocampal dysfunction
     2004; Ohira et al., 2006; Phan et al., 2005).
                                                                 (hyperactivity), whereby there is a greatly increased
                                                                 perception of threat in situations involving conflic-
     Lateral orbitofrontal cortex                                ting stimuli, and an increase in the suppression of
                                                                 approach-related actions and cognitions. Most of the
     It has been suggested that the primary role of the
                                                                 research driving this model has been with rodents,
     lateral OFC is to respond to signals of punishment
                                                                 however, there is a wealth of supportive human
     by regulating behavior and emotion to maximize
                                                                 research showing relationships between measures of
     adaptive outcomes (Elliott et al., 2000). The lateral
                                                                 hippocampal function and structure and anxiety-
     OFC has been implicated in the inhibition of aggres-
                                                                 related phenomena (Barros-Loscertales et al., 2006;
     sive and other socially inappropriate behaviors and
                                                                 Rauch et al., 2003; Rusch et al., 2001).
     emotions. Damage to this area results in increased
     general irritability, inappropriate overt emotional dis-
     plays (Barrash et al., 2000) and anger and hostility        Neural systems for emotion
     (Berlin et al., 2004). Lateral OFC activation has been      Thus far, evidence has been presented for the contri-
     reported during the viewing of angry faces (Blair           bution of a number of cortical, limbic and subcortical
     et al., 1999) and induction of anger via autobiograph-      brain regions in three major components of emotion:
     ical recall (Dougherty et al., 1999). In these studies it   the perception/identification of emotional stimuli, the
     is suggested that the observed activation may repre-        production and experience of the affective state, and
     sent attempts to inhibit reactions to, or feelings of       the regulation of this state. A few specific cortical
     anger. Lateral OFC activation, in addition to the           regions have been shown to be important for more
     dorsal ACC and DLPFC (to which the lateral OFC is           than one of these cognitive processes. The amygdala
     highly interconnected), is also often reported with         and insula have been implicated in the identification
     conscious efforts to regulate emotional response by         of the emotional significance of an environmental
     suppression or reappraisal strategies (Levesque et al.,     stimulus, as well as the production of the affective
42   2003; Ochsner et al., 2004). Activity in this region has    state and emotional behavior. Although it is difficult
     also been associated with suppression of the influence      to design paradigms to examine the neural correlates
                                                           Chapter 4: The neurobiology of the emotion response



of these components separately (e.g. passive viewing        important for the effortful rather than automatic
of emotional stimuli indexes emotion perception             regulation of affective states.
but will also likely trigger a felt and expressed aff-          A relationship between these two systems is sug-
ective state), findings do indicate that there are          gested by evidence that components of each often
some brain structures likely to be involved in a single     exhibit concerted activity in functional imaging
component. For example, the ventral ACC appears             studies of cognitive and affective processing. For
to be preferentially involved in the production of          example, during the down-regulation of emotion via
autonomic responses accompanying the experience             reappraisal, but also with other paradigms whereby
of emotion (Blumberg et al., 2000). Although not            effortful cognitive processing is required, increased
given substantial focus in this chapter, there does         activity in dorsal ACC, DLPFC and lateral OFC, in
appear to be some neural specificity for different          concert with decreases in amygdala and/or ventrome-
types of emotions. For example, the ventral ACC             dial PFC activity, have been observed (Hariri et al.,
has been predominantly implicated in sadness,               2003; Ochsner et al., 2004). Conversely, during mood
whilst the ventral striatum appears to be particularly      induction, a reciprocal pattern of activity in dorsal
involved in pleasant emotion and reward-related             regions and ventral ACC has been reported; speci-
behaviors. Hemispheric laterality may be an impor-          fically, negative mood has been associated with
tant factor influencing the type and valence of emo-        decreases in dorsal ACC and DLPFC and increases
tional response; this issue is covered in greater detail    in ventral ACC activity (Mayberg et al., 1999).
in Chapter 16.                                                  It must be noted that this idea of two intercon-
    A point of discussion critical to a comprehensive       nected systems underlying emotion is certain to be
understanding of the neural bases of emotion con-           oversimplified. These systems are likely to be made up
cerns neural circuits or systems. Animal and post-          of subsystems, and include a number of other cortical
mortem research has provided much knowledge                 and subcortical structures not mentioned in the
about anatomical connections in the brain. More             current discussion (see Tekin & Cummings, 2002).
recently, with the rapid advancement in brain-              However, the proposed model is a useful framework
imaging technologies, functional and structural brain       for thinking about the neural basis of emotion, and
connectivity can be studied in vivo. Together, this         provides a testable basis for future research.
research is strongly suggestive of the aforementioned
regions working together in neural systems under-
lying the unfolding emotional response; from the            Implications for psychopathology
perception of emotional stimuli, to the production,         Specific abnormalities in the functioning of the dorsal
experience and regulation of the emotional state and        and/or ventral emotion systems, or the connections
behavior. Consistent with what is known about cor-          between these systems, may be associated with abnor-
tical architecture, a number of such neural models          malities in emotional behavior or regulation, and
have recently been proposed (Mayberg, 2003; Phillips        result in the generation of symptomatology character-
et al., 2003a). These models are consistent in empha-       istic of a range of psychiatric disorders. Although a
sizing the contribution of two reciprocally connec-         thorough discussion of the links between affective
ted brain systems underlying emotion. A “ventral”           neuroscience and psychopathology is beyond the
system, including the amygdala, insula, ventral stria-      scope of this chapter, and indeed has been attempted
tum, and ventromedial PFC (including ventral/rostral        elsewhere (e.g. Phillips et al., 2003b), we can provide
regions of the ACC and medial OFC), appears to be           a general heuristic that can be used to organize
important for the identification of the emotional sig-      the potential associations between the structures
nificance of affective stimuli, the production of affec-    and systems reviewed in the chapter and some of the
tive states, and the automatic regulation of autonomic      basic dimensions of psychiatric symptomatology. For
responses to affective stimuli. A “dorsal” system,          example, Krueger (1999) examined the underlying
including the hippocampus, dorsal ACC and lateral           structure of symptoms of common mental disorders
areas of the dorsal PFC and OFC, exerts a predomi-          in a large community sample. He found that two
nant role in higher-order executive processes such          broad factors accounted for most of the variance;
as attention, error monitoring, response selection,         internalizing and externalizing. Within the internal-     43
working memory, and planning, and appears to be             izing factor there were two distinguishable subfactors
        Section 1: Neuropsychological processes



     that included symptoms of fear versus anxious misery.       dysfunction of the connections between dorsal and
     Such empirically driven models of the structure of          ventral system structures might be key to many of
     symptoms are a good starting place to explore the           these disorders (Mayberg et al., 1999; Phillips et al.,
     potential association between the neurobiological           2003b). As such, further research aiming to investi-
     systems that underlie affective functioning and symp-       gate the functioning of the identified neural structures
     toms of psychopathology.                                    and systems underlying the emotion response will
         Dysfunction of the dorsal system and its regula-        likely be a fruitful approach to a more informative
     tory connections with the ventral system (particularly      characterization of psychopathology, and a greater
     those regions implicated in negative affect such as the     understanding of etiological mechanisms and eventu-
     amygdala and insula) may result in uncontrolled             ally treatment planning.
     functioning of ventral structures. This may trigger
     exaggerated affective and autonomic responses and
     behavior that are driven by somewhat primitive or           References
     instinctive reactions to affective stimuli. This type of    Adolphs, R. & Damasio, A. R. (2000). Neurobiology of
     dysfunction may underlie symptoms characteristic of           emotion at a systems level. In J. C. Borod (Ed.), The
     fear disorders such as attentional biases toward nega-        Neuropsychology of Emotion (pp. 194–213). New York,
                                                                   NY: Oxford University Press.
     tive emotional stimuli and the experience of excess
     levels of negative emotions, as well as deficits in         Allman, J. M., Hakeem, A., Erwin, J. M., Nimchinski, E. &
     various executive skills (Davidson et al., 2002).              Hof, P. (2001). The anterior cingulate cortex: the
                                                                    evolution of an interface between emotion and
     Hyperfunction of certain dorsal system structures              cognition. Annals of the New York Academy of Sciences,
     (particularly the hippocampus) may also result                 935, 107–117.
     in mood and anxiety-related symptomatology (cf.
                                                                 Angelini, L., Mazzucchi, A., Picciotto, F., Nardocci, N. &
     anxious misery; Krueger, 1999) in the case where              Broggi, G. (1981). Focal lesion of the right cingulum: a
     there is excessive inhibition of ventral regions (such        case report in a child. Journal of Neurology Neurosurgery
     as the ventral striatum and medial OFC) involved in           and Psychiatry, 44(4), 355–357.
     reward-based motivation and approach behaviors              Augustine, J. R. (1996). Circuitry and functional aspects of
     (Gray & McNaughton, 2000). Dysfunction of dorsal              the insular lobe in primates including humans. Brain
     structures such as the lateral OFC might also explain         Research Reviews, 22, 229–244.
     symptomatology characteristic of certain externaliz-        Bannerman, D. M., Rawlins, J. N. P., McHugh, S. B. et al.
     ing disorders, such as abnormally increased levels of         (2004). Regional dissociations within the hippocampus –
     anger, aggression, or tendencies to approach rewards          memory and anxiety. Neuroscience and Biobehavioral
     in a socially inappropriate manner (Davidson et al.,          Reviews, 28, 273–283.
     2000b). Additionally, hypofunction of the ventral           Barrash, J., Tranel, D. & Anderson, S. W. (2000). Acquired
     system might underlie externalizing symptomatology,            personality disturbances associated with bilateral
     whereby individuals may engage in risky or socially            damage to the ventromedial prefrontal region.
                                                                    Developmental Neuropsychology, 18(3), 355–381.
     inappropriate behaviors as a compensatory mechanism
     for low baseline-levels of affect, particularly low fear-   Barros-Loscertales, A., Meseguer, V., Sanjuan, A. et al.
     fulness and sensitivity to punishment (Chambers &              (2006). Behavioral inhibition system activity is
                                                                    associated with increased amygdala and hippocampal
     Potenza, 2003). These conjectures regarding the links
                                                                    gray matter volume: a voxel-based morphometry study.
     between the neural systems of emotion and mental               Neuroimage, 33(3), 1011–1015.
     illness are merely illustrative, but do show how exam-
                                                                 Bartels, A. & Zeki, S. (2004). The neural correlates
     ining the neuropsychology of basic affective processes         of maternal and romantic love. Neuroimage, 21(3),
     may motivate innovative conceptualizations of eti-             1155–1166.
     ology, nomenclature and potentially even treatment.
                                                                 Bechara, A., Tranel, D., Damasio, H., Adolphs, R.,
     However, a significant research effort will be required        Rockland, C. & Damasio, A. (1995). Double dissociation
     before such promises are realized.                             of conditioning and declarative knowledge relative to the
         There is much existing evidence for both struc-            amygdala and hippocampus in humans. Science,
     tural and functional abnormalities in a number of              269(5227), 1115–1118.
44   the above-mentioned structures in a variety of psy-         Beer, J. S. & Lombardo, M. V. (2007). Insights into emotion
     chopathologies, as well as emerging evidence that              regulation from neuropsychology. In J. J. Gross (Ed.),
                                                                   Chapter 4: The neurobiology of the emotion response



   Handbook of Emotion Regulation (pp. 69–86). New York,            Calder, A. J., Keane, J., Manes, F., Antoun, N. & Young,
   NY: Guilford Publications.                                          A. W. (2000). Impaired recognition and experience of
Beer, J. S., Knight, R. T. & D’Esposito, M. (2006).                    disgust following brain injury. Nature Neuroscience, 3,
   Controlling the integration of emotion and cognition –              1077–1078.
   the role of frontal cortex in distinguishing helpful             Canli, T. (2004). Functional brain mapping of extraversion
   from hurtful emotional information. Psychological                  and neuroticism: learning from individual differences
   Science, 17(5), 448–453.                                           in emotion processing. Journal of Personality, 72(6),
                                                                      1105–1132.
Berlin, H. A., Rolls, E. T. & Kischka, U. (2004). Impulsivity,
   time perception, emotion and reinforcement sensitivity           Cardinal, R. N., Parkinson, J. A., Hall, J. & Everitt, B. J.
   in patients with orbitofrontal cortex lesions. Brain,              (2002). Emotion and motivation: the role of the
   127(5), 1108–1126.                                                 amygdala, ventral striatum, and prefrontal cortex.
                                                                      Neuroscience and Biobehavioral Reviews, 26, 321–352.
Berridge, K. C. (2003). Pleasures of the brain. Brain and
   Cognition, 52, 106–128.                                          Chambers, R. A. & Potenza, M. N. (2003).
                                                                      Neurodevelopment, impulsivity, and adolescent
Berridge, K. C. & Robinson, T. E. (2003). Parsing reward.             gambling. Journal of Gambling Studies, 19(1), 53–84.
   Trends in Neurosciences, 26(9), 507–513.
                                                                    Critchley, H. D., Rotshtein, P., Nagai, Y. et al. (2005).
Blair, R. J. R., Morris, J. S., Frith, C. D., Perrett, D. I. &         Activity in the human brain predicting differential heart
   Dolan, R. J. (1999). Dissociable neural responses to                rate responses to emotional facial expressions.
   facial expressions of sadness and anger. Brain, 122,                Neuroimage, 24, 751–762.
   883–893.
                                                                    Davidson, R. J. & Irwin, W. (1999). The functional
Blood, A. J. & Zatorre, R. J. (2001). Intensely pleasurable           neuroanatomy of emotion and affective style. Trends in
   responses to music correlate with activity in brain                Cognitive Sciences, 3(1), 11–21.
   regions implicated in reward and emotion.
   Proceedings of the National Academy of Sciences, 98(20),         Davidson, R. J., Abercrombie, H., Nitschke, J. B. &
   11818–11823.                                                       Putnam, K. (1999). Regional brain function, emotion
                                                                      and disorders of emotion. Current Opinion in
Blumberg, H. P., Stern, E., Martinez, D. et al. (2000).               Neurobiology, 9, 228–234.
   Increased anterior cingulate and caudate activity in
   bipolar mania. Biological Psychiatry, 48, 1045–1052.             Davidson, R. J., Jackson, D. C. & Kalin, N. H. (2000a).
                                                                      Emotion, plasticity, context, and regulation: perspectives
Bonson, K. R., Grant, S. J. & Contoreggi, C. S. (2002).               from affective neuroscience. Psychological Bulletin, 126
  Neural systems and cue-induced cocaine craving.                     (6), 890–909.
  Neuropsychopharmacology, 263, 376–386.
                                                                    Davidson, R. J., Pizzagalli, D., Nitschke, J. B. & Putnam, K.
Botvinick, M. M., Braver, T. S., Barch, D. M., Carter, C. S. &        (2002). Depression: perspectives from affective
   Cohen, J. D. (2001). Conflict monitoring and cognitive             neuroscience. Annual Review of Psychology, 53, 545–574.
   control. Psychological Review, 108(3), 624–652.
                                                                    Davidson, R. J., Putnam, K. M. & Larson, C. L. (2000b).
Breiter, H. C., Gollub, R. L., Weisskoff, R. M. et al. (1997).        Dysfunction in the neural circuitry of emotion
   Acute effects of cocaine on human brain activity and               regulation: a possible prelude to violence. Science, 289
   emotion. Neuron, 19(3), 591–611.                                   (5479), 591–594.
Buchel, C., Dolan, R. J., Armony, J. L. & Friston, K. J. (1999).    Dougherty, D. D., Shin, L. M., Alpert, N. M. et al. (1999).
  Amygdala-hippocampal involvement in human aversive                  Anger in healthy men: a PET study using script-driven
  trace conditioning revealed through event-related                   imagery. Biological Psychiatry, 46(4), 466–472.
  functional magnetic resonance imaging. Journal of                 Elliott, R., Dolan, R. J. & Frith, C. D. (2000). Dissociable
  Neuroscience, 19(24), 10869–10876.                                    functions in the medial and lateral orbitofrontal cortex:
Buchel, C., Morris, J., Dolan, R. J. & Friston, K. J. (1998).           evidence from human neuroimaging studies. Cerebral
  Brain systems mediating aversive conditioning: an                     Cortex, 10, 308–317.
  event-related fmri study. Neuron, 20, 947–957.                    Etkin, A., Klemenhagen, K. C., Dudman, J. T. et al. (2004).
Bush, G., Luu, P. & Posner, M. I. (2000). Cognitive and                Individual differences in trait anxiety predict the
  emotional influences in anterior cingulate cortex.                   response of the basolateral amygdala to unconsciously
  Trends in Cognitive Sciences, 4(6), 215–222.                         processed fearful faces. Neuron, 44(6), 1043–1055.
Bush, G., Vogt, B. A., Holmes, J. et al. (2002). Dorsal             Ferretti, A., Caulo, M., Del Gratta, C. et al. (2005).
  anterior cingulate cortex: a role in reward-based                    Dynamics of male sexual arousal: distinct components of
  decision making. Proceedings of the National Academy                 brain activation revealed by fMRI. Neuroimage, 26(4),
  of Sciences, 99(1), 523–528.                                         1086–1096.                                                   45
        Section 1: Neuropsychological processes



     Gelnar, P. A., Krauss, B. R., Sheehe, P. R., Szeverenyi, N. M.       selectively recruits nucleus accumbens. Journal of
        & Apkarian, A. V. (1999). A comparative fMRI study                Neuroscience, 21(16), RC159.
        of cortical representations for thermal painful,               Kringelbach, M. L. (2005). The human orbitofrontal cortex:
        vibrotactile, and motor performance tasks. Neuroimage,            linking reward to hedonic experience. Nature Reviews
        10(4), 460–482.                                                   Neuroscience, 6(9), 691–702.
     Giuliano, F. & Allard, J. (2001). Dopamine and sexual             Kringelbach, M. L. & Rolls, E. T. (2004). The functional
        function. International Journal of Impotence Research,            neuroanatomy of the human orbitofrontal cortex:
        3(Suppl.), S18–S28.                                               evidence from neuroimaging and neurophysiology.
     Gorno-Tempini, M. L., Pradelli, S., Serafini, M. et al. (2001).      Progress in Neurobiology, 72, 341–372.
       Explicit and incidental facial expression processing: an        Krueger, R. F. (1999). The structure of common mental
       fMRI study. Neuroimage, 14(2), 465–473.                           disorders. Archives of General Psychiatry, 56, 921–926.
     Gottfried, J. A. & Dolan, R. J. (2004). Human orbitofrontal       LeDoux, J. E. (1993). Emotional networks in the brain.
       cortex mediates extinction learning while accessing               In M. Lewis & J. M. Haviland (Eds.), Handbook of
       conditioned representations of value. Nature                      Emotions (pp. 109–118). New York, NY: Guilford Press.
       Neuroscience, 7(10), 1144–1152.
                                                                       Levesque, J., Eugene, F., Joanette, Y. et al. (2003). Neural
     Gray, J. A. (1982). The Neuropsychology of Anxiety.                  circuitry underlying voluntary suppression of sadness.
       Oxford: Oxford University Press.                                   Biological Psychiatry, 53(6), 502–510.
     Gray, J. A. & McNaughton, N. (2000). The Neuropsychology          Levesque, J., Joanette, Y., Mensour, B. et al. (2004). Neural
       of Anxiety (2nd edn.). Oxford: Oxford University Press.            basis of emotional self-regulation in childhood.
     Gross, J. J. (1998). The emerging field of emotion                   Neuroscience, 129(2), 361–369.
       regulation: an integrative review. Review of General            Levin, B. & Duchowny, M. (1991). Childhood obsessive-
       Psychology, 2(3), 271–299.                                         compulsive disorder and cingulate epilepsy. Biological
     Hamann, S. B. & Mao, H. (2002). Positive and negative                Psychiatry, 30(10), 1049–1055.
       emotional verbal stimuli elicit activity in the left            Lingford-Hughes, A. R., Davies, S. J. C., McIver, S. et al.
       amygdala. Neuroreport, 13(1), 15–19.                               (2003). Addiction. British Medical Bulletin, 65, 209–222.
     Hamann, S. B., Ely, T. D., Hoffman, J. M. & Kilts, C. D.          Liotti, M., Mayberg, H. S., Brannan, S. L. et al. (2000).
       (2002). Ecstasy and agony: activation of the human                 Differential limbic-cortical correlates of sadness and
       amygdala in positive and negative emotion. Psychological           anxiety in healthy subjects: implications for affective
       Science, 13(2), 135–141.                                           disorders. Biological Psychiatry, 48, 30–32.
     Hariri, A. R., Mattay, V. S., Tessitore, A., Fera, F. &           Lorberbaum, J. P., Newman, J. D., Horwitz, A. R. et al.
       Weinberger, D. R. (2003). Neocortical modulation of the            (2002). A potential role for thalamocingulate circuitry in
       amygdala response to fearful stimuli. Biological                   human maternal behavior. Biological Psychiatry, 51(6),
       Psychiatry, 53(6), 494–501.                                        431–445.
     Heinz, A., Siessmeier, T., Wrase, J. et al. (2004).               MacDonald, A. W., Cohen, J. D., Stenger, V. A. &
       Correlation between dopamine d2 receptors in the                  Carter, C. S. (2000). Dissociating the role of the
       ventral striatum and central processing of alcohol cues           dorsolateral prefrontal and anterior cingulate cortex in
       and craving. American Journal of Psychiatry, 161(10),             cognitive control. Science, 288(5472), 1835–1838.
       1783–1789.
                                                                       Mayberg, H. S. (2003). Modulating dysfunctional
     Iwase, M., Ouchi, Y., Okada, H. et al. (2002). Neural               limbic-cortical circuits in depression: towards
        substrates of human facial expression of pleasant                development of brain-based algorithms for diagnosis
        emotion induced by comic films: A PET study.                     and optimised treatment. British Medical Bulletin, 65,
        Neuroimage, 17(2), 758–768.                                      193–207.
     John, O. P. & Gross, J. J. (2004). Healthy and unhealthy          Mayberg, H. S., Liotti, M., Brannan, S. K. et al. (1999).
        emotion regulation: personality processes, individual            Reciprocal limbic-cortical function and negative mood:
        differences, and life span development. Journal of               converging PET findings in depression and normal
        Personality, 72(6), 1301–1333.                                   sadness. American Journal of Psychiatry, 156(5),
     Kim, J. J. & Jung, M. W. (2006). Neural circuits and                675–682.
       mechanisms involved in pavlovian fear conditioning:             Milad, M. R., Quinn, B. T., Pitman, R. K. et al. (2005).
       a critical review. Neuroscience and Biobehavioral                 Thickness of ventromedial prefrontal cortex in
       Reviews, 30(2), 188–202.                                          humans is correlated with extinction memory.
46   Knutson, B., Adams, C. M., Fong, G. W. & Hommer, D.                 Proceedings of the National Academy of Sciences, 102(30),
       (2001). Anticipation of increasing monetary reward                10706–10711.
                                                                 Chapter 4: The neurobiology of the emotion response



Nauta, W. J. H. (1971). The problem of the frontal lobe:             disorders. Annals of the New York Academy of Sciences,
  a reinterpretation. Journal of Psychiatric Research, 8,            985, 389–410.
  167–187.                                                        Reiman, E., Lane, R., Ahern, G. et al. (1997).
Nitschke, J. B., Nelson, E. E., Rusch, B. D. et al. (2004).          Neuroanatomical correlates of externally and internally
   Orbitofrontal cortex tracks positive mood in mothers              generated human emotion. American Journal of
   viewing pictures of their newborn infants. Neuroimage,            Psychiatry, 154(7), 918–925.
   21(2), 583–592.
                                                                  Reuter, M., Stark, R., Hennig, J. et al. (2004). Personality and
O’Doherty, J. P. (2004). Reward representations and                 emotion: test of Gray’s personality theory by means of an
  reward-related learning in the human brain: insights              fMRI study. Behavioral Neuroscience, 118(3), 462–469.
  from neuroimaging. Current Opinion in Neurobiology,
                                                                  Rogers, R. D., Ramnani, N., Mackay, C. et al. (2004).
  14(6), 769–776.
                                                                    Distinct portions of anterior cingulate cortex and medial
Ochsner, K. N. & Gross, J. J. (2005). The cognitive control of      prefrontal cortex are activated by reward processing in
  emotion. Trends in Cognitive Sciences, 9(5), 242–249.             separable phases of decision-making cognition.
Ochsner, K. N. & Schacter, D. L. (2000). A social cognitive         Biological Psychiatry, 55(6), 594–602.
  neuroscience approach to emotion and memory. In J. C.           Rothbart, M. K. & Derryberry, D. (1981). Development of
  Borod (Ed.), The Neuropsychology of Emotion (pp. 163–             individual differences in temperament. In M. E. Lamb &
  193). New York, NY: Oxford University Press.                      A. L. Brown (Eds.), Advances in Developmental
Ochsner, K. N., Ray, R. D., Cooper, J. C. et al. (2004). For        Psychology (Vol. 1, pp. 37–86). Hillsdale, NJ: Lawrence
  better or for worse: neural systems supporting the                Erlbaum Associates.
  cognitive down- and up-regulation of negative emotion.          Rusch, B. D., Abercrombie, H. C., Oakes, T. R.,
  Neuroimage, 23(2), 483–499.                                       Schaefer, S. M. & Davidson, R. J. (2001). Hippocampal
Ohira, H., Nomura, M., Ichikawa, N. et al. (2006).                  morphometry in depressed patients and control
  Association of neural and physiological responses                 subjects: relations to anxiety symptoms. Biological
  during voluntary emotion suppression. Neuroimage,                 Psychiatry, 50(12), 960–964.
  29(3), 721–733.                                                 Schaefer, S. M., Jackson, D. C., Davidson, R. J. et al. (2002).
Öngür, D., Ferry, A. T. & Price, J. L. (2003).                       Modulation of amygdalar activity by the conscious
  Architectonic subdivision of the human orbital and                 regulation of negative emotion. Journal of Cognitive
  medial prefrontal cortex. Journal of Comparative                   Neuroscience, 14(6), 913–921.
  Neurology, 460, 425–449.                                        Schienle, A., Schafer, A., Stark, R., Walter, B. & Vaitl, D.
Phan, K. L., Fitzgerald, D. A., Nathan, P. J. et al. (2005).         (2005). Relationship between disgust sensitivity, trait
  Neural substrates for voluntary suppression of negative            anxiety and brain activity during disgust induction.
  affect: a functional magnetic resonance imaging study.             Neuropsychobiology, 51(2), 86–92.
  Biological Psychiatry, 57(3), 210–219.                          Schienle, A. C., Stark, R., Walter, B. et al. (2002). The insula
Phelps, E. A., Delgado, M. R., Nearing, K. I. & LeDoux, J. E.        is not specifically involved in disgust processing: an
  (2004). Extinction learning in humans: role of the                 fMRI study. Neuroreport, 13(16), 2023–2026.
  amygdala and VMPFC. Neuron, 43(6), 897–905.                     Schultz, W. (2000). Multiple reward systems in the brain.
Phillips, M. L., Drevets, W. C., Rauch, S. L. & Lane, R. D.          Nature Reviews Neuroscience, 1, 199–207.
   (2003a). Neurobiology of emotion perception i: the             Schwartz, C. E., Wright, C. I., Shin, L. M. et al. (2003).
   neural basis of normal emotion perception. Biological             Differential amygdalar response to novel versus newly
   Psychiatry, 53(5), 504–514.                                       familiar neutral faces: a functional MRI probe developed
Phillips, M. L., Drevets, W. C., Rauch, S. L. & Lane, R. D.          for studying inhibited temperament. Biological
   (2003b). The neurobiology of emotion perception ii:               Psychiatry, 53, 854–862.
   implications for major psychiatric disorders. Biological       Scott, S. K., Young, A. W., Calder, A. J. et al. (1997).
   Psychiatry, 53(5), 515–528.                                       Impaired auditory recognition of fear and anger
Phillips, M. L., Young, A. W., Senior, C. et al. (1997).             following bilateral amygdala lesions. Nature, 385(6613),
   A specific neural substrate for perceiving facial                 254–257.
   expressions of disgust. Nature, 389(6650), 495–498.            Shin, L. M., Dougherty, D. D., Orr, S. P. et al. (2000).
Rauch, S. L., Shin, L. M., Dougherty, D. D. et al. (1999).           Activation of anterior paralimbic structures during
  Neural activation during sexual and competitive arousal            guilt-related script-driven imagery. Biological Psychiatry,
  in healthy men. Psychiatry Research, 91(1), 1–10.                  48(1), 43–50.
Rauch, S. L., Shin, L. M. & Wright, C. I. (2003).                 Simmons, A., Strigo, I., Matthews, S. C., Paulus, M. P. &          47
  Neuroimaging studies of amygdala function in anxiety               Stein, M. B. (2006). Anticipation of aversive visual
        Section 1: Neuropsychological processes



        stimuli is associated with increased insula activation         maps, and cytoarchitecture. Journal of Comparative
        in anxiety-prone subjects. Biological Psychiatry, 60(4),       Neurology, 359(3), 490–506.
        402–409.                                                    Volkow, N. D., Wang, G. J., Ma, Y. M. et al. (2005).
     Small, D. M., Gregory, M. D., Mak, Y. E. et al. (2003).          Activation of orbital and medial prefrontal cortex by
       Dissociation of neural representation of intensity and         methylphenidate in cocaine-addicted subjects but not in
       affective valuation in human gustation. Neuron, 39(4),         controls: relevance to addiction. Journal of Neuroscience,
       701–711.                                                       25(15), 3932–3939.
     Small, D. M., Zald, D. H., Jones-Gotman, M. et al. (1999).     Whalen, P. J. (1998). Fear, vigilance, and ambiguity:
       Human cortical gustatory areas: a review of functional         initial neuroimaging studies of the human amygdala.
       neuroimaging data. Neuroreport, 10(1), 7–13.                   Current Directions in Psychological Science, 7(6),
     Somerville, L. H., Heatherton, T. F. & Kelley, W. M. (2006).     177–188.
       Anterior cingulate cortex responds differentially to         Williams, Z. M., Bush, G., Rauch, S. L., Cosgrove, G. R. &
       expectancy violation and social rejection. Nature              Eskandar, E. N. (2004). Human anterior cingulate
       Neuroscience, 9(8), 1007–1008.                                 neurons and the integration of monetary reward
     Sutton, S. K. (1997). Asymmetry in prefrontal glucose            with motor responses. Nature Neuroscience, 7(12),
        metabolism during appetitive and aversive emotional           1370–1375.
        states: An FDG-PET study. Psychophysiology, 34, S89.        Young, A. W., Aggleton, J. P., Hellawell, D. J. et al. (1995).
     Tebartz van Elst, L., Woermann, F. G., Lemieux, L. &             Face processing impairments after amygdalotomy.
       Trimble, M. R. (1999). Amygdala enlargement in                 Brain, 118(1), 15–24.
       dysthymia – a volumetric study of patients with              Zald, D. H. (2003). The human amygdala and the emotional
       temporal lobe epilepsy. Biological Psychiatry, 46,              evaluation of sensory stimuli. Brain Research Reviews,
       1614–1623.                                                      41(1), 88–123.
     Tekin, S. & Cummings, J. L. (2002). Frontal-subcortical        Zald, D. H., Mattson, D. L. & Pardo, J. V. (2002). Brain
       neuronal circuits and clinical neuropsychiatry: an              activity in ventromedial prefrontal cortex correlates
       update. Journal of Psychosomatic Research, 53, 647–654.         with individual differences in negative affect.
     Vogt, B. A., Nimchinsky, E. A., Vogt, L. J. & Hof, P. R.          Proceedings of the National Academy of Sciences
       (1995). Human cingulate cortex – surface-features, flat         USA, 99(4), 2450–2454.




48
    Chapter




           5
                      Frontal asymmetry in emotion, personality
                      and psychopathology: methodological issues
                      in electrocortical and hemodynamic
                      neuroimaging
                      John D. Herrington, Nancy S. Koven, Wendy Heller, Gregory A. Miller and Jack B. Nitschke

Introduction                                                    associated with euphoric mood states, whereas
                                                                damage to the left hemisphere results in dysphoric
It is well established that depression and anxiety              mood states (Borod, 1992; Gainotti, 1972). These
are associated with abnormal patterns of asymmetric             findings parallel some studies of patients undergoing
brain activity, particularly in frontal regions (Heller         intracarotid sodium amytal testing, where one hemi-
et al., 1998). Data in support of this finding have             sphere of the brain is temporarily deactivated (Alema
highlighted the relative roles of left and right frontal        et al., 1961; Lee et al., 1987; but see Stabell et al.,
regions in positive and negative emotions, respectively         2004). Eye movement, electroconvulsive therapy
(Davidson & Irwin, 1999). In recent years it has                (ECT) and epilepsy studies have shown a similar
become increasingly clear that asymmetric brain func-           pattern (Bear & Fedio, 1977; Decina et al., 1985;
tion can be understood not only in terms of theories of         Flor-Henry, 1979; Myslobodsky & Horesh, 1978).
emotion, but also in terms of specific personality con-         Finally, over the past two decades, numerous EEG
structs. Despite decades of EEG research identifying            studies have documented both state and trait changes
frontal asymmetries in emotion and personality, these           in affect related to lateralized activity in frontal
findings have been largely unreplicated by hemody-              regions (Coan & Allen, 2004; Davidson et al., 2002).
namic studies (e.g. functional MRI and PET). This                   Findings regarding the role of the frontal cortex in
chapter will briefly review evidence regarding the              emotion and personality have been informed by spe-
contribution of frontal brain asymmetries to under-             cific models of the structure of emotion. Factor-
standing components of emotion, motivation and                  analytic and multidimensional scaling approaches
personality. The review will be followed by a more              have shown that basic emotions (e.g. happiness, fear,
detailed consideration of how frontal brain asymmet-            etc.) can be represented by a two-dimensional structure
ries can and should be measured using hemodynamic               with axes representing valence (pleasant vs unpleasant)
imaging. Examples of recent studies from our labora-            and arousal (Russell, 1980). This structure is the basis
tories that illustrate some of the methodologies dis-           for the circumplex model of emotion, which has
cussed will also be presented (Herrington et al., 2005;         been applied to the interpretation of brain activity
Herrington et al., under review; Nitschke et al., 2006).        (Heller et al., 1997, 1998; Nitschke et al., 1999). We
                                                                and others have suggested that the pleasant/unpleasant
Emotion and frontal brain asymmetries                           axis (valence) can be used to describe patterns of rela-
Evidence in favor of frontal brain asymmetries for              tive activity in the frontal cortex among non-clinical
emotion, personality and psychopathology comes                  samples, and that abnormalities in these patterns are
from numerous methodologies. Clinical case studies              related to personality (Schmitke & Heller, 2004) and
have shown that damage to the right hemisphere is               psychopathology, particularly depression and anxiety


Note: Portions of this chapter were previously published in The Biology of Personality and Individual Differences
edited by Turhan Canli, and are reprinted here with permission from Guilford Press (pending).
The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by          49
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



     disorders (for review, see Coan & Allen, 2004; Heller       comorbidity is seldom controlled in studies of depres-
     et al., 1998).                                              sion and anxiety. An additional possibility is that both
         The study of frontal lateralization of function has     negative affect and anxious apprehension dimensions
     advanced the understanding of various forms of              capture unique variance in frontal lateralization. Depres-
     psychopathology, particularly mood and anxiety dis-         sion and anxiety may therefore share brain asymme-
     orders. For example, Heller and colleagues (Heller          tries in some regions of frontal cortex but not others.
     et al., 1995, 1997; Keller et al., 2000; Nitschke et al.,   Appropriate electromagnetic or hemodynamic imaging
     1999) have argued that it is important to interpret         studies using well-characterized clinical samples will be
     frontal asymmetries for emotion and psychopath-             essential to answering these questions.
     ology in the context of the common co-occurrence
     of depression and anxiety. Their work is informed by
     an influential model positing that mood and anxiety         Personality and frontal brain asymmetries
     disorders share a general distress factor referred to as    In recent years it has become increasingly apparent
     negative affect (Clark & Watson, 1991). Like the cir-       that frontal brain asymmetries can also be understood
     cumplex model, negative affect is a concept derived         in terms of specific personality dimensions. Numer-
     from factor analytic studies of emotion. In fact, posi-     ous studies have posited that frontal lateralization
     tive and negative affect are terms for the axes formed      associated with emotion reflects approach and avoid-
     after implementing a factor rotation on the circum-         ance motivation; with left activity more associated
     plex model (Watson & Tellegen, 1985). The two               with approach motivation, and right activity reflect-
     dimensions of Watson and Tellegen’s rotated circum-         ing avoidance motivation (Davidson, 1992, 1998).
     plex model differ interpretively from the original in       Because most positive emotions are associated with
     that they subsume arousal, and place pleasant and           approach motivation and negative emotions with
     unpleasant emotions on separate dimensions (rather          avoidance motivation, the valence and motivation
     than on a single valence dimension). Hence, the             perspectives are highly overlapping. Anger, however,
     rotated model better characterizes variance when            typically involves both unpleasant valence and
     positive and negative affect function in parallel, oper-    approach motivation. Based on findings examining
     ating simultaneously but independently. Given that          anger, a series of studies have argued that the
     depression and anxiety are commonly viewed as               valence/arousal dimensions may not account for the
     sharing high negative affect but not low positive           frontal asymmetry data as well as a motivational
     affect (characteristic of depression alone), the rotated    dimension dichotomized as approach/withdrawal
     circumplex model is an appealing framework from             (Harmon-Jones, 2004). Recent work by Wacker
     which to examine these two conditions (Clark &              et al. (2003), however, has emphasized that affective
     Watson, 1991).                                              states can be characterized by both valence and motiv-
         Because elevated negative affect is related to          ational direction (e.g. anger is unpleasant, but could
     frontal asymmetry in favor of the right hemisphere,         be accompanied by approach motivation or with-
     depression and anxiety would both be expected to            drawal motivation, depending on the circumstances).
     show right-lateralized patterns of frontal activity         Furthermore, recent evidence suggests that the left-
     (Davidson, 2004). This common pattern would                 lateralized activity associated with anger is attribut-
     appear to suggest that measures of frontal lateraliza-      able to a dimension of anger that is associated with
     tion cannot be used to distinguish depression and           anxious apprehension, rather than approach motiv-
     anxiety. However, some research suggests that frontal       ation (Stewart et al., 2008). Regardless, evidence that
     lateralization may be related to other dimensions of        valence may be an important source of variance in the
     emotion along which depression and anxiety do               degree to which different brain regions are involved
     differ. In particular, several studies have shown that      in cognition (Herrington et al., 2005; Perlstein et al.,
     a specific dimension of anxiety called anxious appre-       2002) indicates that it remains an important variable
     hension (e.g. worry) is related to increased left hemi-     in investigations of emotion/cognition interactions.
     sphere activity, possibly resulting in a pattern of             A central goal of personality psychology has been
     frontal asymmetry distinct from depression (Heller          to identify the basic structures of personality, and the
50   et al., 1997, 1998; Nitschke et al., 1999). The robust-     valence and motivation models are just two of several
     ness and reliability of this finding remain unclear, as     approaches that have been used to classify personality
                                      Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



dimensions. These also include trait adjective systems             Recent support for the intersection of personality,
(e.g. yielding descriptors such as extraversion, intro-        psychopathology and emotional dimensions comes
version). Although debate continues regarding                  from work in our laboratory examining the relation-
the nature of proposed dimensions (e.g. nomenclat-             ship of approach and avoidance temperament, as
ure, number and orthogonality), these systems                  defined by Elliot & Thrash (2002), to performance
share the same core tenet that personality, at a basic         on neuropsychological tests sensitive to lateralized
level, consists of stable, heritable, biologically instanti-   brain activity (Koven, 2003). In this study, relation-
ated sensitivities to positive and negative stimuli            ships between approach and avoidance temperament,
(Elliot & Thrash, 2002). How one responds emotion-             patterns of anterior brain asymmetry, situational
ally to positive and negative stimuli, how one                 strategies to regulate negative emotion (suppression
regulates this response, and how the regulated                 and reappraisal), and the outcomes of these strategies
response is characterized across experiential, lan-            on emotion processes were examined. Emotional
guage, behavioral, physiological and interpersonal             responses to a situational stressor were measured via
domains are all questions that extend from this                self-report, facial affect coding and salivary cortisol.
premise. Scholars have identified conceptual overlap           Individuals characterized by approach temperament
between neuroticism–extraversion and negative                  used reappraisal more advantageously than they did
temperament–positive temperament (Carver et al.,               suppression. Reappraisal instructions were effective in
2000), behavioral inhibition–behavioral activation             reducing the degree of emotional responding in the
and negative temperament–positive temperament                  self-report, behavioral and physiological domains.
(Watson, 2000), and neuroticism–extraversion and               Individuals characterized by avoidance temperament,
behavioral inhibition–behavioral activation (Carver            in contrast, were more adept at using suppression to
et al., 2000). Further empirical work, through factor-         achieve the same results. The suppression technique
analytic and correlational studies, has identified             facilitated approximately the same magnitude of emo-
relationships between extraversion and positive tem-           tion regulation for avoidance-biased individuals as
perament and neuroticism and negative temperament              the reappraisal technique did for approach-biased
(Clark & Watson, 1999); negative temperament and               individuals. However, suppression was slightly less
behavioral inhibition, as well as positive temperament         effective for avoidance temperament participants than
and behavioral activation (Carver & White, 1994);              reappraisal was for approach temperament partici-
extraversion and behavioral activation (Gomez et al.,          pants in down-regulating cortisol reactivity.
2000); and neuroticism and behavioral inhibition                   Of greatest relevance to this chapter, approach-
(Diaz & Pickering, 1993).                                      biased participants outperformed avoidance-biased
    Elliot & Thrash (2002) proposed that variance              individuals on neuropsychological tests that required
shared among these constructs be interpreted as                specialized cognitive functions of the left prefrontal
approach and avoidance temperaments. “Approach                 cortex; whereas, avoidance-temperament participants
temperament” subsumes the personality qualities                excelled on neuropsychological tests involving spe-
associated with extraversion, the affective style associ-      cialized cognitive functions of the right prefrontal
ated with positive temperament, and the behavior               cortex (see Figure 5.1). These data complement find-
patterns associated with the behavioral activation             ings from other studies that have used neuropsy-
system (BAS). In contrast, “avoidance temperament”             chological techniques in non-clinical samples to map
subsumes personality qualities associated with neur-           relationships between patterns of anterior brain
oticism, the affective style associated with negative          asymmetry and personality-, mood- and coping-
temperament, and behavior patterns associated with             related variables such as euphoric/dysphoric affect
the behavioral inhibition system (BIS) (Elliot &               (Bartolic et al., 1999; Gray, 2001; Greene & Noice,
Thrash, 2002). This theoretical heuristic has been             1988; Isen & Daubman, 1984; Isen et al., 1987),
supported empirically through factor-analytic studies          hostility (Williamson & Harrison, 2003), anxiety
showing that measures of extraversion, neuroticism,            (Everhart & Harrison, 2002), verbal/non-verbal cog-
positive temperament, negative temperament, BAS                nitive style (Elfgren & Risberg, 1998; Gevins & Smith,
and BIS yield a two-factor structure (approach tem-            2000), extraversion/introversion (Henderson, 1992),
perament and avoidance temperament) that is                    self-control (O’Connell et al., 1987), flexibility/rigidity   51
unaffected by response bias (Elliot & Thrash, 2002).           (Regard, 1983), engagement/disengagement (Fogel,
                   Section 1: Neuropsychological processes



                    70


                    60


                    50                                                                                        Temperament
                                                                                                                 type
     Mean change




                    40
                                                                                                                Approach
                                                                                                                Avoidance
                    30


                    20


                    10


                     0
                          Verbal      TOL*      Digit span*      RFFT*            CPT*       Spatial span*
                         fluency
                                             Neuropsychological measure
     Figure 5.1. Mean change in neuropsychological test performance for approach- and avoidance-biased participants. The x-axis represents
     groups of individuals classified as having either an approach or avoidance temperament, according to a two-factor solution from a principal
     components analysis using subscales of the NEO Five Factor Inventory (Costa & McCrae, 1992), General Temperament Survey (Watson & Clark,
     1993), and the Behavioral Inhibition System and Behavioral Activation System scales (Carver & White, 1994). The x-axis also represents
     neuropsychological tests related to left (Verbal Fluency Test: Gladsjo et al., 1999; Tower of London (TOL): Culbertson & Zillmer, 2001; Digit Span
     subtest of the Wechsler Memory Scale, Third Edition: Wechsler, 1997) and right (Ruff Figural Fluency Test (RFFT): Ruff, 1996; Conners’
     Continuous Performance Test (CPT), Second Edition: Conners, 2000; Spatial Span subtest of the Wechsler Memory Scale, Third Edition:
     Wechsler, 1997) frontal hemisphere functions. The y-axis shows mean scores in T-score units. * indicates that mean difference between
     temperament types for the specified neuropsychological test is significant at P < 0.05. Figure based on Koven (2003).


     2000) and self-enhancement coping style (Tomarken                          literature have been mixed in this regard, Schmidtke
     & Davidson, 1994). These studies provide strong evi-                       & Heller (2004) reported that increased neuroticism
     dence for hemisphericity of temperament variables.                         was associated with decreased alpha activity (indicat-
     Specifically, that approach temperament which reflects                     ing elevated brain activity) recorded over the right
     behavioral approach, extraversion and positive tem-                        hemisphere. However, this lateralization was localized
     perament, is associated with greater left-trait anterior                   to posterior and not anterior regions. Although the
     brain activity, whilst in contrast, avoidance tempera-                     lack of frontal findings failed to provide evidence
     ment that encompasses behavioral inhibition, introver-                     for anterior asymmetries, the posterior findings were
     sion and negative temperament, is associated with                          consistent with the hypothesis that neuroticism would
     greater right-trait anterior brain activity. Moreover,                     be positively correlated with arousal, as indexed by
     these neuropsychological findings provide additional                       activity in right posterior cortex. Other studies have
     support for earlier studies suggesting that the two-                       provided support for asymmetries in the predicted
     dimensional models of extraversion/neuroticism, posi-                      direction in anterior regions (Canli et al., 1998).
     tive/negative temperament, and behavioral inhibition/                          In summary, a substantial amount of evidence
     activation are different conceptualizations of the same                    indicates that lateralized activity in the frontal cortex
     psychobiological substrates that contribute to personal-                   is associated with specific dimensions of emotion and
     ity, affective and motivation traits.                                      motivation; particularly positive emotion/approach
          The considerable conceptual overlap between                           motivation in favor of left frontal cortex, and negative
     extraversion and neuroticism, approach and avoid-                          emotion/avoidance motivation in favor of right
     ance motivation, pleasant and negative emotion, and                        frontal cortex. Data in support of this pattern comes
     positive and negative affect suggests that extraversion                    from numerous methodologies, including brain-
52   and neuroticism should be associated with lateralized                      injury studies, intracarotid sodium amytal testing,
     brain function (Koven, 2003). Although results in the                      EEG and others (Borod, 1992; Davidson, 2004;
                                      Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



Heller et al., 1997, 1998; Lee et al., 1987; Nitschke          asymmetry have not capitalized on these advances.
et al., 1999). This lateralization appears to have both        Very few of these EEG studies have reliably identified
state and trait components, responding to experimen-           electrical signals from deep frontal regions (e.g.
tally induced changes in mood and characterizing the           orbital and medial frontal cortex), as the observed
emotional experience of individuals with depression            scalp distribution of signals from these regions is often
and anxiety (Coan & Allen, 2003). Studies examining            difficult to disambiguate from signals closer to the
frontal lateralization have traversed a variety of theo-       scalp (Davidson, 2004). The incorporation of struc-
retical perspectives in psychology, including emotion,         tural and functional MRI information can greatly
psychopathology and personality. The prominence of             improve our ability to localize EEG signal in deep
frontal brain lateralization research in human neuro-          structures, but to date few studies of depression and
science attests to its potential importance for parsing        anxiety have capitalized on this combined approach.
complex, overlapping constructs such as depression                 Positron emission tomography and fMRI have
and anxiety, or motivation and personality.                    been used extensively in recent years to localize spe-
                                                               cific regions related to emotion, depression and anx-
Frontal asymmetry, electrophysiology                           iety (for reviews see Wager et al., 2003, and Murphy
                                                               et al., 2003). Studies using these techniques can
and hemodynamics                                               provide somewhat better localization information
Numerous EEG studies have found lateralized frontal            than EEG, particularly for deep structures. It is thus
activity in emotion and personality, but studies using         striking that virtually no PET or fMRI studies have
hemodynamic imaging generally have not (Coan &                 robustly replicated the EEG asymmetry findings
Allen, 2004; Wager et al., 2003). We argue that this           (Wager et al., 2003). As discussed in the recent litera-
replication failure may stem from the widespread               ture, this represents a significant problem, calling into
use of data-analytic strategies that are inapprop-             question either the asymmetry itself or the methods
riate for identifying asymmetric brain activity. This          used to measure it (Canli, 1999; Davidson, 1998, 2002;
section will review neurophysiological techniques for          Davidson & Irwin, 1999; Herrington et al., 2005;
examining lateralized brain activity, with particular          Nitschke et al., 2006).
emphasis on techniques used in hemodynamic                         In their recent meta-analysis, Wager et al. (2003)
imaging studies.                                               concluded that there was only “limited support for
                                                               valence-specific lateralization of emotional activity in
EEG and the study of frontal asymmetries                       frontal cortex” (p. 513) in the hemodynamic litera-
Coan & Allen (2004) estimated that over 70 published           ture. When analyzing studies designed to assess brain
EEG studies have examined frontal asymmetries in               activity during approach/withdrawal and positive/
emotion. As EEG methods have advanced, so has                  negative affective states, they found only a trend
knowledge of the dynamics of these asymmetries.                toward increased activity in left versus right frontal
For example, analyses of spectral activity across              cortex for approach versus withdrawal, and no effect
frontal electrode sites have shown that important              of hemisphere for positive compared with negative
differences in left and right frontal activity in depres-      stimuli or states. However, an examination of their
sion and anxiety are relative rather than absolute             methods calls this null finding into question. Of crit-
(Bell et al., 1998; Bruder et al., 1997; Gotlib et al.,        ical importance is that most of the studies used in
1998). Although data from EEG studies using few                their meta-analysis did not actually directly test later-
electrodes have generally supported the finding that           ality effects. In an effort to compensate for this critical
individuals with depression and anxiety show rela-             shortcoming, Wager et al. (2003) used a form of
tively less left frontal activity, the limited spatial reso-   conjunction analysis in order to infer laterality effects
lution of this methodology constrains the ability to           in the studies they examined.1 As explained below,
localize this activity within the frontal cortex. Recent       conjunction analyses are frequently insensitive to
years have seen dramatic improvements in the spatial           laterality effects in PET and fMRI. Thus, reliance on
resolution of EEG, due primarily to increased elec-            this approach limits the conclusions that can be drawn.
trode densities, more common availability of struc-            This criticism also applies to a meta-analysis by
tural MRIs, and improved source localization                   Murphy et al. (2003), who also examined PET and               53
techniques. However, many previous studies of brain            fMRI studies to test the anterior asymmetry
        Section 1: Neuropsychological processes



     hypothesis in non-clinical populations. They                1990; Starkstein & Robinson, 1988). Studies examining
     concluded that theories of anterior asymmetries             self-reported emotional experience typically rely either
     “may be too coarse, in terms of both their neural           on experimental mood manipulations or comparisons
     underpinnings and the aspect of emotion under               between groups of individuals exhibiting abnormal,
     consideration” (p. 227). However, in the absence of         stable patterns of emotional function (e.g. depression
     hemodynamic imaging studies using robust asymmetry          or anxiety). Canli (1999) noted that many hemody-
     analyses, the conclusions of these meta-analyses            namic imaging studies of emotion have focused only
     cannot be accepted with confidence.                         on the perception of affective stimuli rather than on
         Because of the failure of hemodynamic methods           other aspects of emotion processing, such as emotional
     to replicate EEG, it remains to be seen which (if any)      experience. It is unclear whether hemodynamic studies
     specific areas of prefrontal cortex are driving the EEG     have employed paradigms that examine changes in
     laterality effects. Some researchers have argued that       emotional experience to a lesser extent than have EEG
     dorsolateral prefrontal cortex (DLPFC) is the key           studies. If so, robust laterality findings would be
     region relating frontal EEG lateralization to emo-          expected to occur less frequently in hemodynamic
     tional valence and motivation (Davidson, 2004;              imaging studies.
     Herrington et al., 2005; Nitschke et al., 2006). How-           Another critical issue is the extent to which
     ever, it is quite possible that, due to the relative ease   specific psychophysiological measures alter moods.
     with which EEG can detect signals from regions near         Although few, if any, data exist comparing individ-
     the scalp surface, electrical activity from DLPFC may       uals’ emotional reactions to hemodynamic versus
     overshadow important lateralized activity in deeper         electrophysiological procedures, there is reason to
     structures. For example, in addition to DLPFC, ven-         suspect that the former may in fact be significantly
     tromedial prefrontal cortex (VMPFC) and regions             more anxiety-inducing in ways that could artifactually
     of anterior cingulate cortex play important roles in        foster different results for the two types of measures –
     emotion (Damasio, 1994; Davidson et al., 2000;              both PET and MRI involve placement in tightly
     Drevets et al., 1997; Davidson & Irwin, 1999; Milad         enclosed spaces, PET involves an intravenous injec-
     & Quirk, 2002). Although relatively few studies to          tion and MRI involves very loud noise. It is unclear
     date have postulated functional asymmetries in these        what effect these procedural factors have on experi-
     regions, few direct tests of asymmetries have been          ments concerning the neurobiology of emotion and
     applied to them.                                            personality. It is possible that a procedurally induced
         Because of the relative consistency of EEG tech-        baseline increase in negative affect may attenuate the
     niques and findings in this area over the past two          relative effect of an experimental mood manipulation
     decades, it can be argued that limitations in hemody-       or group comparison. Ultimately, this attenuation
     namic imaging paradigms, techniques and analyses            may play some part in the failure of hemodynamic
     are central to the failure of hemodynamic imaging           imaging studies of emotion to replicate the EEG
     to replicate EEG findings regarding frontal lateraliza-     frontal asymmetry findings.
     tion. The following sections examine theoretical and
     methodological areas where hemodynamic imaging
     studies may be falling short.                               Hemodynamic measures of brain asymmetry
                                                                 Positron emission tomography and fMRI techniques for
                                                                 measuring brain asymmetry generally employ a few
     Hemodynamic imaging and the manipulation                    basic approaches, such as size/mass difference analyses,
     of emotion                                                  conjunction analyses, factorial designs and connectivity
     Findings regarding frontal asymmetries in emotion           analyses (Friston, 2003). Almost no studies directly
     turn crucially on what component of the emotion con-        compared relative strengths and weaknesses of these
     struct is under investigation. The distinction between      four approaches. The following section briefly examines
     recognition and experience of different emotions            the utility of these approaches in revealing lateralized
     is particularly important, as self-reported emotional       brain activity. An examination of 52 hemodynamic
     experience is more frequently related to patterns of        imaging studies of frontal asymmetries in emotion indi-
54   frontal lateralization than is recognition performance      cates that only a very small number used analyses that
     (Canli, 1999; Heller, 1990; Davidson, 1992; Ekman et al.,   were sufficiently sensitive to hemispheric asymmetries.
                                     Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



Size/mass difference analysis                                and Friston (2003), this approach is problematic, as
Some studies (Canli et al., 1998) have examined later-       it does not directly test the size of the difference
ality by counting the number of voxels within an             between a given region and its contralateral homo-
active cluster, and comparing that with the number           logue. Failure to conduct a direct comparison violates
of voxels in an active cluster in the same region of the     basic tenets of conventional ANOVA. This approach
contralateral hemisphere. It would be important in a         drastically increases the vulnerability to both false-
study using this method to specify the criteria used to      positives and false-negatives.
select a contralateral cluster – e.g. what sort of search
field is allowed to consider a contralateral cluster truly   Factorial designs
homologous. This issue is both difficult and non-            A direct comparison of asymmetric activity can be
trivial, given that in many respects the brain is not        obtained using a factorial design, where hemisphere is
truly symmetric structurally or functionally. For            included as one of the factors (Davidson & Irwin,
example, the volume that is contralateral according          1999; Friston, 2003). Very few hemodynamic studies
to 3D coordinates may fall in a neighboring gyrus,           examining the contribution of frontal regions to emo-
such as a different portion of a somatotopic map, etc.       tion have implemented this analytic strategy, and it
As a consequence, it is difficult to assess the validity     is remarkably rare in hemodynamic studies in the
or generalizability of this approach in testing asym-        cognitive neuroscience literature more generally.
metries. Furthermore, this technique is vulnerable to        Although Friston (2003) outlined how it can be
a more significant problem – it may take only cluster        implemented in the program Statistical Parametric
size into account and not cluster intensity. Some            Mapping (SPM, one of the most widely used neuro-
studies attempt to overcome this limitation by deriv-        imaging statistical packages, http://www.fil.ion.ucl.ac.
ing some type of index that reflects both the size and       uk/spm), it is not directly integrated into the analysis
intensity of a cluster (such as “cluster mass”) or sim-      component of the program or in most other com-
ultaneously using size and intensity thresholds              monly used programs. This is surprising, as the inclu-
(Maddock et al., 2003). A third limitation of this           sion of hemisphere as a factor in an ANOVA design
strategy is that it ignores voxels that are just below       is consistent with basic statistical approaches across
the specified significance threshold. As a result, it is     numerous disciplines, and is analytically trivial rela-
possible that a putative cluster in one hemisphere           tive to the computations carried out by most hemo-
has a substantial amount of subthreshold activity,           dynamic imaging analysis packages.
yet an observed voxel significance count of zero.
Lastly, hemispheric asymmetries may be present in
areas where activity in neither hemisphere reaches the
                                                             Connectivity analyses
a priori statistical threshold for inclusion in a cluster.   Connectivity analysis is another approach to examin-
A size/mass difference analysis would overlook such          ing hemispheric asymmetries (Friston, 2003). This
regions; even if a region fails to meet a statistical        approach examines coactivation patterns in two or
threshold in each hemisphere, they may still differ          more brain regions. It can be implemented in many
from one another were the test done. Overall, this           ways, most simply with correlational designs using
technique can lead to unacceptably high false-positive       voxels or clusters of voxels as inputs over time, con-
or false-negative laterality findings.                       ditions or subjects. For example, Irwin et al. (2004)
                                                             examined fronto-limbic correlations in depressed
                                                             and non-depressed samples. A group-wise compari-
Conjunction analysis                                         son of correlations between frontal and amygdalar
A so-called conjunction analysis involves a binary           regions using Fisher’s R-to-Z test showed a significant
comparison of significant activity in two regions,           group difference.
conditions or groups (Friston, 2003). If a particular            Structural equation modeling, independent com-
region is considered active based on a specific signifi-     ponents analysis and dynamic causal modeling are
cance threshold, activity in that region can be con-         techniques for testing specific relationships among
sidered asymmetric if the analogous region in the            brain regions (Friston et al., 1997). These techniques
contralateral hemisphere does not exceed that same           are presently rare in hemodynamic imaging studies,         55
threshold. As discussed by Davidson & Irwin (1999)           as they are computationally intensive and unfamiliar
        Section 1: Neuropsychological processes



     to most researchers, but they are receiving increasing      neighbors. This has the effect of decreasing spatial
     attention.                                                  resolution (mm scale) while expanding signal across
         Connectivity analyses can be used to address            larger areas that can be more reliably identified
     questions regarding brain asymmetries by examin-            (many mm or cm).
     ing the relationship between homologous (or non-                However, because many areas of the brain lack
     homologous) regions in contralateral hemispheres.           obvious morphological landmarks that are discern-
     For example, a significant correlation between a            able from fMRI images, even these larger areas may
     frontal region in both hemispheres during an emo-           be difficult to define stereotactically. This problem is
     tional task can indicate coordinated, bilateral activity.   generally handled by creating some other type of
     Correlations between paired regions can be calculated       boundary criterion to define signal from a number
     separately by subject group and then statistically          of voxels grouped together – either a predefined shape
     compared to examine group differences in lateralized        (e.g. a sphere encompassing all voxels within a speci-
     activity. Dynamic causal modeling and structural            fied radius) or a set of contiguous voxels that indi-
     equation modeling can further the understanding of          vidually meet some statistical threshold. It is often
     this sort of bilateral activity by testing whether acti-    unclear which of these approaches will most effect-
     vity in a subregion of one hemisphere is mediated           ively minimize localization error on a given dataset.
     or moderated by activity in a contralateral region          Few studies have systematically compared them, and
     (Friston, 2003). These and other techniques warrant         none has done so within the context of measuring
     considerably wider use in the systematic evaluation of      brain asymmetries.
     brain asymmetries.

     Methodological complexities in asymmetry analyses           Examples of lateralized activity
     Although some of the statistical techniques discussed       measured by fMRI
     above are relatively trivial to implement, additional       Recently, some studies have emerged that imple-
     methodological complexities exist that may be res-          ment direct tests of brain asymmetry using hemody-
     ponsible for their underutilization. There is a great       namic imaging techniques (Herrington et al., 2005;
     deal of confusion in fMRI research regarding exactly        Herrington et al., under review; Nitschke et al., 2006).
     what, where and how much brain data should                  Three of these will be examined here, with emphasis
     be submitted to statistical analyses. Functional MRI        placed on their contributions to the neuroscience of
     studies collect voxels of data that generally range in      emotion, as well as their approaches to measuring
     size from 1–10 mm per dimension, and then align and         brain asymmetries.
     scale them to a standard anatomical template so that            Herrington et al. (2005) examined brain asym-
     ideally each voxel for each participant will be coregis-    metries associated with emotion using fMRI in an
     tered. Commonly, statistics are then carried out inde-      unselected sample of participants. The experimental
     pendently for each voxel. However, variations in            paradigm was a variant on the color–word Stroop
     participants’ brain anatomy and imperfections in            task using pleasant, neutral and unpleasant words as
     standardization procedures essentially preclude each        stimuli. In this emotional Stroop task participants
     recorded voxel aligning with an identical part of the       name the color ink in which a series of emotional
     brain across an entire sample or vis-à-vis a standard       and neutral words are written while ignoring the
     brain template. This problem is particularly relevant       meaning of the word. Changes in response time for
     to analyses carried out between homologous voxels           emotionally valenced words are regarded as evidence
     in different hemispheres, as the two hemispheres            of an effect of emotional information on cognition.
     often differ morphologically in ways that are not           This experiment set out to examine prefrontal cortical
     readily accounted for using typical fMRI alignment          asymmetries for positive emotion using a factorial
     procedures.                                                 design.
         A number of strategies can be employed to                   Analyses explored a variety of techniques for iso-
     address this problem. Most fMRI studies do not draw         lating bilateral regions in DLPFC. The most effective
     conclusions based on the findings of individual             technique combined low-pass spatial filtering with the
56   voxels. Low-pass spatial filters are typically applied,     selection of a set of contiguous voxels in left DLPFC
     blurring the signal from individual voxels across their     that was statistically significant on a per-voxel basis
                                            Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



when comparing data from the pleasant and unpleas-                       comparing each t value to a Gaussianized t distribu-
ant word conditions. Data from this cluster, as well as                  tion that follows a z distribution.
the homologous region in the right hemisphere were                           For analyses across participants, z-maps represent-
extracted and included as levels of an ANOVA factor.                     ing the difference between pleasant and unpleasant
Functional image processing and analyses were                            word conditions for each participant were registered
implemented using FEAT (FMRI Expert Analysis                             into a common stereotactic space (Talairach &
Tool, FMRIB’s Software Library, http://www.fmrib.                        Tornoux, 1988) using automated linear registration
ox.ac.uk/analysis/research/feat/) and SPSS. Each fMRI                    software (FMRIB’s Linear Image Registration Tool,
time series was motion-corrected, high-pass filtered                     FMRIB’s Software Library). Statistical analyses were
(to remove drift in signal intensity), intensity normal-                 carried out with MEDx v3.4 via paired t-tests compar-
ized, and spatially smoothed using a 3D Gaussian                         ing each participant’s Z map to zero (zero indicating no
kernel (FWHM ¼ 7 mm) prior to analysis.                                  valence effect for that voxel). For ease of interpretation,
    Statistical maps were generated for each partici-                    the resulting t-values for each voxel were then
pant’s time-series data by applying a regression analy-                  converted into z statistics following a Gaussianized
sis to each intracerebral voxel (Woolrich et al., 2001).                 t distribution (as above for individual participant’s
The fitted model was designed to predict observed                        z-maps). This analysis was intended to identify specific
brain activity from explanatory variables representing                   regions for subsequent region of interest (ROI) ana-
pleasant and unpleasant trial blocks separately, con-                    lyses. The probability of obtaining false positives was
volved with a gamma variate function to model the                        minimized by assigning a relatively liberal statistical
hemodynamic response (Aguirre et al., 1998; Miezin                       threshold concurrently with requiring a large cluster
et al., 2000). Each explanatory variable in these                        size. Thus, voxels were considered to show a significant
analyses yielded a voxel-by-voxel map of parameter                       valence effect if the z-score greater than 2.3 or less
estimates (b) representing the correlation between the                   than À2.3 (P < 0.01, two-tailed, uncorrected) and
explanatory variable (e.g. pleasant and unpleasant                       comprised at least 20 contiguous voxels (Compton
word conditions) and the observed data. These maps                       et al., 2003; Forman et al., 1995).
were then converted to t statistic maps by dividing                          This analysis revealed a significant cluster of
each b by its standard error. Finally, each voxel in the                 greater activity for pleasant words in left DLPFC
t statistic maps was converted into a z statistic by                     (see Figure 5.2). The center of mass for this cluster

       Left and right ROIs in DLPFC
                                                                  Average ROI z-scores for pleasant
                                                                     and unpleasant conditions
                                                      .4

                                                           Pleasant
                                                      .3

                                                      .2

                                                                                       Pleasant
                                                      .1

                                                      0
                                                                                                  Unpleasant
                                                    –.1

                                                                       Unpleasant
   L                                       R        –.2
                                                                Left DLPFC                 Right DLPFC
Figure 5.2. Differences in brain activity during presentation of pleasant versus unpleasant words. Left panel: Regions of interest (ROIs) used
to quantify activity in left and right dorsolateral prefrontal cortex (DLPFC) on an axial image in radiological orientation (right hemisphere
displayed on left) at a z coordinate of 34 mm. Right panel: Mean z-scores for pleasant and unpleasant word conditions in right and left DLPFC.
Z-scores representing the relationship between brain activity and pleasant or unpleasant word conditions were averaged for all voxels inside
the DLPFC ROIs. Figure and caption taken from Herrington et al. (2005).
                                                                                                                                                 57
       Section 1: Neuropsychological processes



     was located at x ¼ À32, y ¼ 24 and z ¼ 42 in Talairach &   This problem is readily addressed with an ANOVA
     Tournoux (1988) coordinate space. The cluster was          design that reflects hypotheses about hemispheric
     located in inferior and medial frontal gyri, with          differences.
     small intrusions into superior frontal and precentral          Although the approach in the Herrington et al.
     gyri (between z coordinates of 20 and 62). In order        (2005) study of isolating activity in one hemisphere
     to test the hypothesis regarding the conjoint effects      and examining its exact contralateral homolog proved
     of emotion, laterality and executive function, an          sensitive to hemispheric asymmetries, this approach
     ANOVA was implemented to examine activity                  may overlook asymmetries in regions that are not
     within this DLPFC cluster and its homolog in the           exact mirror images of one another across hemi-
     right hemisphere. Average z-scores were calculated         spheres. Nitschke et al. (2006) demonstrated one solu-
     for this cluster within each participant’s z-maps          tion to this problem. Their study focused on the role
     representing significant activity during pleasant          of emotion circuitry in anticipating aversive events.
     and unpleasant conditions. A repeated-measures             The paradigm used in their study involved the pre-
     ANOVA was carried out on these ROI scores to               sentation of negative, high-arousal stimuli and
     examine main effects and interactions for word             neutral, low-arousal stimuli. A cue immediately pre-
     valence (pleasant or unpleasant) and hemisphere.           ceding the stimulus indicated to participants whether
     In line with the voxel-wise t-tests in the left hemi-      a negative or neutral stimulus was about to be pre-
     sphere, the ANOVA revealed a main effect for               sented. Using an event-related design with variable
     valence, F(1, 19) ¼ 5.216, P ¼ 0.034, with more bilat-     intertrial intervals, the authors were able to examine
     eral DLPFC activity for pleasant than for unpleasant       brain activity during the anticipation, as well as
     words. Importantly, the valence effect varied by           perception of negative stimuli. The central finding
     hemisphere, F(1, 19) ¼ 6.712, P ¼ 0.018, indicating        of their study was that the anticipation of an aversive
     more left than right DLPFC activity for pleasant           event engaged many of the same brain regions as the
     than for unpleasant words. There was no main               actual experience of the event – namely, amygdala,
     effect of hemisphere, F(1, 19) ¼ 0.017, ns.                anterior insula, anterior cingulate cortex, dorsolateral
         As predicted, the results revealed an asymmetric       prefrontal cortex and orbitofrontal cortex.
     activation in favor of the left-hemisphere dorsolateral        As with the Herrington et al. (2005) study,
     prefrontal cortex (DLPFC) for pleasant relative to         Nitschke et al. (2006) tested hypotheses about frontal
     unpleasant stimuli. This study is thus among the first     asymmetries in emotion processes using a two-way
     to effectively use fMRI to complement EEG findings         ANOVA with stimulus valence (negative or neutral)
     of asymmetric brain activity for emotion and to local-     and hemisphere as repeated measures. A comparison
     ize these findings within a specific frontal region.       of activity between the negative and neutral trials
         Another important component of the study con-          revealed two significant clusters of activity in right
     cerned the use of multiple techniques for isolating        DLPFC (see Figure 5.3). Instead of using these clus-
     homologous regions. Although the paper focused on          ters to delineate a contralateral region for asymmetry
     an area of DLPFC shown to be statistically significant     analyses (as in Herrington et al., 2005), they first
     on a per-voxel basis, other techniques were initially      dilated these clusters by 250%. The two-way ANOVA
     used as well, including extracting spherically shaped      within these dilated clusters yielded significant condi-
     regions of data centered on the area of highest statis-    tion by hemisphere interactions in the predicted dir-
     tical significance within left DLPFC. These techniques     ection (greater activity in right DLPFC compared
     yielded comparable results, converging on a signifi-       with left, for negative compared with neutral trials),
     cant interaction between pleasant versus unpleasant        F(1, 20) ¼ 18.12, P < 0.001, and F(1, 20) ¼ 17.87,
     word conditions and left versus right DLPFC.               P < 0.001, respectively. Furthermore, the increase in
         In summary, the results of Herrington et al.           right DLPFC activity during the anticipation of nega-
     (2005) suggest that the consistency between EEG            tive versus neutral stimuli was significantly predicted
     and fMRI studies of emotion and laterality will            by levels of state and trait negative affect in the
     improve, to the extent that analysis methods in the        sample, r ¼ 0.71, P < 0.001, and r ¼ 0.67, P < 0.001
     two domains are similar. Including hemisphere as a         respectively, as measured by the Positive and Negative
58   factor in one’s ANOVA is de rigeur in the EEG litera-      Affect Scale (PANAS; Watson & Clark, 1991). The
     ture but is remarkably rare in the fMRI literature.        same pattern of results was observed when dilations
                                                                            Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



                              R                                                                                       L




                                                                            y = 49
                                    0.15                                             0.25
                Signal change (%)




                                    0.10                                             0.20

                                                                                     0.15
                                    0.05
                                                                                     0.10
                                    0.00
                                                                                     0.05

                                    0.05                                             0.00
                                           C   P P       10     15      20                  Anticipation       Picture
                                                       Time (s)

                                0.4

                                    0.3
Signal change (%)




                                    0.2

                                    0.1

                                    0.0

                        –0.1
                                               10            20               30       10              20                 30
                                                    State negative affect                     Trait negative affect

Figure 5.3. This figure is also reproduced in the color plate section. It illustrates greater activation for aversive than neutral trials across
anticipation and picture periods in right dorsolateral prefrontal cortex (DLPFC) (Nitschke et al., 2006). The brain image in the top left panel
displays the results of a conjunction analysis, which identifies areas that activate more for aversive than neutral trials during both the
anticipation period and the picture period when analyzed separately. For the top right brain image, colored areas showed a Valence main
effect for the voxel-wise Period  Valence ANOVA (P < 0.05, corrected). Blue areas also showed greater activation for aversive than neutral trials
during the anticipation period but not the picture period (aversive–neutral contrasts as indicated by corresponding voxel-wise t tests, P < 0.05,
corrected). In contrast, purple areas also showed greater activation for aversive than neutral trials during the picture period but not the
anticipation period (aversive–neutral contrasts, as noted above). Yellow areas showed greater activation for aversive than neutral trials for the
Valence effect and for the aversive–neutral contrast for each period, whereas green areas for the Valence main effect did not meet the P < 0.05
(corrected) threshold for either contrast. The middle left panel shows time series plots of the circled clusters illustrating average percentage
signal change across all time points of the aversive (red) and neutral (blue) trials. The onset of the 1-s picture presentation (P) occurred 3 s after
warning cue (W) onset on half of the trials and 5 s after cue onset on the other half. In the middle right panel, bar graphs of the circled clusters
illustrate average percentage signal change for the anticipation period and picture period separately. Error bars for time series plots and bar
graphs are for confidence intervals (Cumming & Finch, 2005) around the mean after adjusting for between-subject variance (Loftus & Masson,
1994). The bottom panel shows scatter plots illustrating the positive relationship between negative affect and right DLPFC activation during
the anticipation of aversive pictures.
    Plots illustrate the relationship of greater activation for aversive than neutral trials during the anticipation period in the right dorsolateral
prefrontal area depicted in the top panel to increases in state negative affect (left bottom panel; r ¼ 0.71, P < 0.001) and trait negative
affect (right bottom panel; r ¼ 0.67, P < 0.001), as measured by the Positive and Negative Affect Schedule (PANAS; Watson et al., 1988).
R ¼ right. L ¼ left.
                                                                                                                                                         59
        Section 1: Neuropsychological processes



     smaller than 250% were used and when no dilation            as a function of emotional valence (pleasant versus
     was used, similar to the strategy employed by               unpleasant words) and hemisphere. Although not of
     Herrington et al. (2005). Like Herrington et al.            interest by itself, the full ANOVA model included the
     (2005), Nitschke et al. (2006) successfully replicated      random effect of participants within group in order
     EEG findings of asymmetric frontal activity as a func-      to calculate appropriate mixed model error terms
     tion of emotional valence. In addition, the findings of     for each main effect and interaction of interest (see
     Nitschke and colleagues underscored the importance          Kirk, 1994). Family-wise error was controlled by
     of examining how this asymmetry is modulated by             using Monte Carlo simulations to determine the
     individual difference variables (in their case, state and   probability of observing clusters of activity at a per-
     trait negative affect).                                     voxel threshold of P < 0.01.
         Individual differences were central to another              Two areas of DLPFC were shown to be active in
     study by Herrington (in preparation). Participants          this study when implementing separate planned com-
     were selected by screening large groups of under-           parisons for Depression and Anxious Arousal groups
     graduates and inviting selected subsets to participate      versus Control, F(1, 27) ¼ 14.8, P ¼ 0.001 and F(1,
     in laboratory research. These subsets were chosen           30) ¼ 8.5, P ¼ 0.007, respectively (see Figures 5.4 and
     based on dimensions of depression and anxiety that          5.5). Responses to the pleasant word condition are
     have been shown to distinguish between these highly         particularly informative. The Control group activated
     comorbid conditions (Nitschke et al., 1999): the            DLPFC bilaterally for pleasant words, whereas the
     Anhedonic Depression and Anxious Arousal scales             Depression group activated primarily the left DLPFC.
     of the Mood and Anxiety Symptom Questionnaire               These data suggest that depression may be character-
     (MASQ; Watson et al., 1995a, 1995b) and the Penn            ized by an inability to bring DLPFC online bilaterally
     State Worry Questionnaire (PSWQ; Meyer et al.,              when presented with positive information. This is
     1990; Molina & Borkovec, 1994). This study also used        consistent with decades of literature showing abnor-
     the emotional Stroop including blocks of pleasant,          mal responsiveness to pleasant affect (i.e. anhedonia)
     unpleasant or neutral trials. The primary hypothesis        among individuals with depression (Klein, 1974; Rush &
     of this study was that both depression and anxiety          Weissenburger, 1994; Willner, 1993).
     would be associated with similar, abnormal patterns             In contrast, when compared with the Anxious
     of frontal asymmetry within DLPFC.                          Arousal group, the Control group showed a latera-
         Both Herrington et al. (2005) and Nitschke et al.       lized pattern of activity for the pleasant word condi-
     (2006) examined asymmetries by averaging activity           tion. This difference may reflect the fact that anxiety,
     differences across voxels within regions of interest        unlike depression, is generally not associated with a
     and submitting these averages to statistical analyses.      lack of responsivity to positive stimuli per se (i.e.
     Herrington et al. (under review) demonstrated               anhedonia; Watson et al., 1995a). It is possible that
     another approach: instead of averaging across clusters      the Depression versus Control contrast highlighted a
     of activity, they tested hemisphere effects separately      region of DLPFC that is particularly responsive to
     for each voxel and its contralateral homolog. This          pleasant stimuli among non-depressed individuals,
     approach has been proposed by Friston (2003), but           manifesting as bilateral rather than unilateral activity.
     to our knowledge has never been used in studies             As the Anxious Arousal group did not differ from the
     of hemispheric asymmetry in emotion (Matlab and             Control group in self-reported Anhedonic depression,
     Cþþ software had to be written expressly for this           the location of the cluster in that contrast may have
     design, as none of the standard hemodynamic image           been driven less by activity during the pleasant word
     analysis packages include it).                              condition than was the case for the Depression versus
         Statistical analyses followed a two-stage approach.     Control contrast.
     At the first stage, parameter estimates were calculated         These findings are consistent with decades of EEG
     representing the effect of pleasant and unpleasant          research on abnormal frontal asymmetries in depres-
     words. The second stage focused on analyses across          sion and anxiety. However, they also raise new possi-
     groups, conditions and hemispheres. A three-way             bilities regarding where these asymmetries may be
     mixed model ANOVA was implemented that esti-                localized. In particular, the depression and anxiety
60   mated the fixed effects of group (Anxious Arousal,          groups both showed three-way interactions in
     Anhedonic Depression and Control), brain activity           the predicted direction, but in adjacent regions of
                                              Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



                                                                                                 16
                                                                                                 14




                                                                       Mean parameter estimate
                                                                                                 12
                                                                                                 10
                                                                                                  8
                                                                                                                                                     Pleasant words
                                                                                                  6
                                                                                                                                                     Unpleasant words
                                                                                                  4
                                                                                                  2
                                                                                                  0
                                                                                                 –2
                                                                                                 –4
                                                                                                      Left       Right          Left        Right
                                                                                                       Depression                     Control
Figure 5.4. Significant three-way interaction between group (Depression versus Control), valence and hemisphere within the dorsolateral
prefrontal cortex (DLPFC). The black circle in the left panel outlines the cluster, centered at Æ50, 18, 20 in the coordinate space of Talairach &
Tournoux (1988). The right panel displays histograms for parameter estimates at each factor level. The three-way interaction of average
parameter estimates within this cluster is significant at P < 0.001 (corrected).



                                                                                                  8

                                                                                                  6
                                                             Mean parameter estimate




                                                                                                  4

                                                                                                  2                                                 Pleasant words
                                                                                                  0                                                 Unpleasant words

                                                                                                 –2

                                                                                                 –4

                                                                                                 –6
                                                                                                      Left       Right         Left        Right
                                                                                                      Anxious arousal                 Control

Figure 5.5. Significant three-way interaction between group (Anxious arousal versus Control), valence and hemisphere within the
dorsolateral prefrontal cortex (DLPFC). The black circle in the left panel outlines the cluster, centered at Æ-47, 24, 30 in the coordinate space of
Talairach & Tournoux (1988). The right panel displays histograms for parameter estimates at each factor level. The three-way interaction of
average parameter estimates within this cluster is significant at P < 0.007 (corrected).




DLPFC. Given the differences between the two clus-                                                           Conclusion
ters in average parameter estimates for the pleasant
                                                                                                             Recent research examining frontal brain function
word condition, it is possible that specific areas of
                                                                                                             has demonstrated the benefit of integrating multiple
DLPFC are more responsive to positive emotion than
                                                                                                             theoretical perspectives from personality psychology
other areas. Very few studies have examined func-
                                                                                                             with decades-old theories regarding the frontal
tional heterogeneity within DLPFC, and no studies
                                                                                                             lateralization of emotion (Elliot & Thrash, 2002;
to date have done so with respect to emotion pro-
                                                                                                             Schmidtke & Heller, 2004; Wacker et al., 2003). As
cesses. Additional research is therefore critical to
                                                                                                             pointed out by Wacker et al. (2003), the valence
understanding whether the differential locations of
                                                                                                             perspective on frontal asymmetry has persisted for
these clusters maps reflect different components of
                                                                                                             about 20 years with very little direct examination of      61
depression and anxiety.
                                                                                                             whether related constructs such as motivation or
       Section 1: Neuropsychological processes



     behavioral activation/inhibition may in fact capture
     the lateralization as well or better. Considerably more     Endnote
     research is needed before findings regarding frontal
     asymmetry converge on one or more dimensions or             1. This description of Wager et al.’s (2003) analysis holds if one
     resolve disagreements in favor of one dichotomy over           defines conjunction analysis as including the binary examination
     another; for example, Wacker et al. (2003) and Elliot &        of multiple regions within the same group or condition. Wager
     Thrash (2002) reached somewhat different conclusions           et al. (2003) conducted their meta-analysis by tallying the
                                                                    presence or absence of bilateral activity findings across emotion
     regarding whether one or many dimensions may be
                                                                    studies and statistically testing for the likelihood of obtaining
     related to frontal lateralization. Whereas Wacker et al.       these tallies. They went beyond typical conjunction analyses by
     found motivation (approach/avoidance temperament)              directly testing the probabilities of finding multiple studies
     to subsume numerous other constructions (extraver-             that had lateralized findings in a particular direction. But the
     sion and neuroticism, emotional valence, and behav-            underlying principle they used was conjunction – examining the
                                                                    co-occurrence, or lack thereof, of homologous activity across
     ioral activation and inhibition), Elliot & Thrash (2002)
                                                                    hemispheres.
     argued that the behavioral activation/inhibition best
     accounted for frontal lateralization and that valence
     and motivation models did not.
                                                                 References
                                                                 Aguirre, G. K., Zarahn, E. & D’Esposito, M. (1998). The
         Which psychological construct best explains
                                                                   variability of human BOLD hemodynamic response.
     frontal lateralization may ultimately be dependent on         Neuroimage, 8, 360–369.
     which area of the frontal cortex is being examined. Few
                                                                 Alema, G. Rosadini, G. & Rossi, G. F. (1961). Psychic
     researchers have tried to reconcile models of specific         reactions associated with intracarotid amytal injections and
     frontal regions related to emotion with patterns of            relation to brain damage. Excerpta Medica, 37, 154–155.
     EEG frontal lateralization. Perspectives on the roles
                                                                 Bartolic, E. I., Basso, M. R., Schefft, B. K., Glauser, T. &
     of frontal subregions in emotion generally focus on            Titanic-Schefft, M. (1999). Effects of experimentally-
     DLPFC, VMPFC and regions of anterior cingulate                 induced emotional states on frontal lobe cognitive task
     cortex (Davidson & Irwin, 1999). Although it has been          performance. Neuropsychologia, 37, 677–683.
     suggested that the DLPFC in particular accounts for         Bear, D. M. & Fedio, P. (1977). Quantitative analysis of
     patterns of frontal EEG asymmetry (Davidson, 2004;             interictal behavior in temporal lobe epilepsy. Archives
     Herrington et al., 2005), VMPFC and anterior cingulate         of Neurology, 34, 454–467.
     may also show lateralized activity patterns. For example,   Bechara, A., Damasio, A., Damasio, H. & Anderson, S.
     lateralized activity in VMPFC may be more related to           (1994). Insensitivity to future consequences following
     approach/avoidance motivation or BIS/BAS than to               damage to human prefrontal cortex. Cognition, 50(1–3),
     valence, as VMPFC has been shown to play a role in             5–15.
     the anticipation of rewards and punishments (Bechara        Bell, I. R., Schwartz, G. E., Hardin, E. E., Baldwin, C. M. &
     et al., 1994). Hemodynamic imaging could be an invalu-         Kline, J. P. (1998). Differential resting quantitative
     able tool for addressing this and many other questions,        electroencephalographic alpha patterns in women with
                                                                    environmental chemical intolerance, depressives, and
     if appropriate data-analytic techniques are used.
                                                                    normals. Biological Psychiatry, 43, 376–388.
                                                                 Borod, J. C. (1992). Interhemispheric and intrahemispheric
     Acknowledgments                                               control of emotion: a focus on unilateral brain damage.
                                                                   Journal of Consulting and Clinical Psychology, 60(3),
     This work was supported by NIDA R21-DA14111,                  339–348.
     NIMH R01-MH61358, NIMH R01-MH74847,
                                                                 Bruder, G. E., Stewart, J. W., Mercier, M. A. et al. (1997).
     NIMH K08-MH63984, NIMH T32-MH19554, NIMH
                                                                    Outcome of cognitive-behavioral therapy for depression:
     T32-MH14257, NIMH T32-MH18931, NICCHD P30-                     relation to hemispheric dominance for verbal
     HD03352 to the Waisman Center, Carle Clinic, the               processing. Journal of Abnormal Psychology, 106,
     Beckman Institute, and the HealthEmotions Research             138–144.
     Institute. The authors thank Aprajita Mohanty, Joscelyn     Canli, T. (1999). Hemispheric asymmetry in the experience
     Fisher, Jennifer Stewart, Marie Banich, Andrew Webb,          of emotion: a perspective from functional imaging. The
     Joseph Barkmeier, Sid Sarinopoulos, Hillary Schaefer,         Neuroscientist, 5(4), 201–207.
62   Richie Davidson and Tracey Wszalek for their contri-        Canli, T., Desmond, J. E., Zhao, Z., Glover, G. & Gabrieli,
     butions to this research.                                     J. D. E. (1998). Hemispheric asymmetry for emotional
                                         Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



   stimuli detected with fMRI. Neuroreport, 9(14),                 Davidson, R. J. (2002). Anxiety and affective style: role
   3233–3239.                                                        of prefrontal cortex and amygdala. Biological Psychiatry,
Carver, C. S. & White, T. (1994). Behavioral inhibition,             51, 68–80.
  behavioral activation, and affective responses to                Davidson, R. J. (2004). What does the prefrontal cortex “do”
  impending reward and punishment: the BIS/BAS                       in affect: perspectives on frontal EEG asymmetry
  scales. Journal of Personality and Social Psychology, 67,          research. Biological Psychology, 67, 219–233.
  319–333.                                                         Davidson, R. J. & Irwin, W. (1999). The functional
Carver, C. S. Sutton, S. & Scheier, M. F. (2000). Action,            neuroanatomy of emotion and affective style. Trends
  emotion, and personality: emerging conceptual                      in Cognitive Sciences, 3, 11–21.
  integration. Personality and Social Psychology Bulletin,         Davidson, R. J., Pizzagalli, D., Nitschke, J. B. & Putnam, K.
  26, 741–751.                                                       (2002). Depression: perspectives from affective
Clark, L. A. & Watson, D. (1991). Tripartite model of                neuroscience. Annual Review of Psychology, 53(1),
   anxiety and depression: psychometric evidence and                 545–574.
   taxonomic implications. Journal of Abnormal Psychology,
                                                                   Davidson, R. J., Putnam, K. M. & Larson, C. L. (2000).
   100, 316–336.
                                                                     Dysfunction in the neural circuitry of emotion
Clark, L. A. & Watson, D. (1999). Temperament: a new                 regulation – a possible prelude to violence. Science,
   paradigm for trait psychology. In L. Pervin & O. John             289, 519–594.
   (Eds.), Handbook of Personality: Theory and Research
                                                                   Decina, P., Sackeim, H. A., Prohovnik, I., Portnoy, S. &
   (2nd edn), (pp. 399–423). New York, NY: Guilford Press.
                                                                     Malitz, S. (1985). Case report of lateralized affective
Coan, J. A. & Allen, J. J. (2003). The state and trait nature of     states immediately after ECT. American Journal of
  frontal EEG asymmetry in emotion. In K. Hugdahl                    Psychiatry, 142, 129–131.
  & R. J. Davidson (Eds.), The Asymmetrical Brain
                                                                   Diaz, A. & Pickering, A. (1993). The relationship
  (pp. 565–615). Cambridge, MA: MIT Press.
                                                                      between Gray’s and Eysenck’s personality spaces.
Coan, J. A. & Allen, J. J. (2004). Frontal EEG asymmetry              Personality and Individual Differences, 15, 297–305.
  as a moderator and mediator of emotion. Biological
                                                                   Drevets, W. C., Price, J. L., Simpson, J. R. et al. (1997).
  Psychology, 67, 7–50.
                                                                     Subgenual prefrontal cortex abnormalities in mood
Compton, R. J., Banich, M. T., Mohanty, A. et al. (2003).            disorders. Nature, 386, 824–827.
  Paying attention to emotion: an fMRI investigation of
                                                                   Ekman, P., Davidson, R. J. & Friesen, W. V. (1990).
  cognitive and emotional stroop tasks. Cognitive, Affective
                                                                     Duchenne’s smile: emotional expression and brain
  and Behavioral Neuroscience, 3(2), 81–98.
                                                                     physiology, II. Journal of Personality and Social
Conners, C. K. (2000). Conners’ Continuous Performance               Psychology, 58, 342–353.
  Test II: Computer Technical Guide and Software Manual.
  [Computer software]. North Tonawanda, NY: Multi-                 Elfgren, C. I. & Risberg, J. (1998). Lateralized frontal
  Health Systems.                                                     blood flow increases during fluency tasks:
                                                                      influences of cognitive strategy. Neuropsychologia, 36,
Costa, P., & McCrae, R. (1992). Revised NEO Personality               505–512.
  Inventory (NEO-PI-R) and Five Factor Inventory
  (NEO-FFI) Professional Manual. Odessa, Fl.:                      Elliot, A. J., & Thrash, T. M. (2002). Approach-avoidance
  Psychological Assessment Resources.                                  motivation in personality: approach and avoidance
                                                                       temperaments and goals. Journal of Personality and
Culbertson, W. C., & Zillmer, E. A. (2001). Tower of                   Social Psychology, 82, 804–818.
  London – Drexel University (TOLDX). North
  Tonawanda, NY: Multi-Health Systems.                             Everhart, D. E. & Harrison, D. W. (2002). Heart rate and
                                                                      fluency performance among high- and low-anxious men
Cumming, G. & Finch, S. (2005). Inference by eye:                     following autonomic stress. International Journal of
  Confidence intervals and how to read pictures of data.              Neuroscience, 112, 1149–1171.
  American Psychologist 60, 170–180.
                                                                   Flor-Henry, P. (1979). On certain aspects of the
Damasio, A. (1994). Descarte’s Error: Emotion, Reason and             localization of the cerebral systems regulating
  the Human Brain. New York, NY: Avon Books.                          and determining emotion. Biological Psychiatry,
Davidson, R. J. (1992). Emotion and affective style:                  14, 677–698.
  hemispheric substrates. Psychological Science, 3, 39–43.         Fogel, T. G. (2000). Patterns of perceptual asymmetries
Davidson, R. J. (1998). Anterior electrophysiological                in the perception of chimeric faces: influences of
  asymmetries, emotion, and depression: conceptual                   depression, anxiety, and approach and withdrawal styles
  and methodological conundrums. Psychophysiology, 35,               of coping. Dissertation Abstracts International: Section B:   63
  607–614.                                                           The Sciences and Engineering, 60, 5223.
        Section 1: Neuropsychological processes



     Forman, S. D., Cohen, J. D., Fitzgerald, M. et al. (1995).          types of anxiety. Journal of Abnormal Psychology,
        Improved assessment of significant activation in                 106, 376–385.
        functional magnetic resonance imaging. Magnetic               Heller, W., Nitschke, J. B. & Miller, G. A. (1998).
        Resonance in Medicine, 33(5), 636–647.                          Lateralization in emotion and emotional disorders.
     Friston, K. J. (2003). Characterizing functional asymmetries       Current Directions in Psychological Science, 7, 26–32.
        with brain mapping. In K. Hugdahl & R. J. Davidson            Henderson, J. R. (1992). Introverts’ and extroverts/
        (Eds.), The Asymmetrical Brain (pp. 162–196).                   performance on the Wechsler Memory Scale – Revised.
        Cambridge, MA: MIT Press.                                       Dissertation Abstracts International, 53, 1064.
     Friston, K. J., Buechel, C., Fink, G. R. et al. (1997).          Herrington, J. D., Mohanty, A., Koven, N. S. et al. (2005).
        Psychophysiological and modulatory interactions in              Emotion-modulated performance and activity in left
        neuroimaging. Neuroimage, 6, 218–229.                           dorsolateral prefrontal cortex. Emotion, 5, 200–207.
     Gainotti, G. (1972). Emotional behavior and hemispheric          Herrington, J. D., Heller, W., Mohanty, A. et al. (under
       side of the lesion. Cortex, 8, 41–55.                            review). Localization of asymmetric brain function in
     Gevins, A. & Smith, M. E. (2000). Neuropsychological               emotion and depression.
       measures of working memory and individual differences          Irwin, W., Anderle, M. J., Abercrombie, H. C. et al. (2004).
       in cognitive ability and cognitive style. Cerebral Cortex,        Amygdalar interhemispheric functional connectivity
       10, 829–839.                                                      differs between the non-depressed and depressed human
     Gladsjo, J. A., Miller, S. W. & Heaton, R. K. (1999). Norms         brain. Neuroimage, 21, 674–686.
        for Letter and Category Fluency: Demographic Corrections      Isen, A. M. & Daubman, K. A. (1984). The influence of
        for Age, Education, and Ethnicity. Odessa, FL:                   affect on categorization. Journal of Personality and Social
        Psychological Assessment Resources.                              Psychology, 46, 1206–1217.
     Gomez, R., Cooper, A. & Gomez, A. (2000). Susceptibility         Isen, A. M., Daubman, K. A. & Nowicki, G. P. (1987).
       to positive and negative mood states: test of Eysenck’s,          Positive affect facilitates creative problem solving. Journal
       Gray’s, and Newman’s theories. Personality and                    of Personality and Social Psychology, 52, 1122–1131.
       Individual Differences, 29, 351–365.                           Keller, J., Nitschke, J. B., Bhargava, T. et al. (2000).
     Gotlib, I., Ranganath, C. & Rosenfeld, P. (1998). Frontal           Neuropsychological differentiation of depression and
       EEG alpha asymmetry, depression, and cognitive                    anxiety. Journal of Abnormal Psychology, 109(1), 3–10.
       functioning. Cognition and Emotion, 12, 449–478.               Kirk, R. (1994). Experimental Design: Procedures for the
     Gray, J. R. (2001). Emotional modulation of cognitive               Behavioral Sciences. Pacific Grove, CA: Brooks/Cole
       control: approach-withdrawal states double-dissociate             Publishing.
       spatial from verbal two-back task performance. Journal         Klein, D. (1974). Endogenomorphic depression. Archives of
       of Experimental Psychology: General, 130, 436–452.                General Psychiatry, 31, 447–451.
     Greene, T. R. & Noice, H. (1988). Influence of positive affect   Koven, N. S. (2003). An individual differences approach to
       upon creative thinking and problem solving in children.          emotion regulation using a neuropsychological model of
       Psychological Reports, 63, 895–898.                              approach and avoidance temperament. Unpublished
     Harmon-Jones, E. (2004). Contributions from research on            doctoral dissertation, University of Illinois at
       anger and cognitive dissonance to understanding the              Urbana-Champaign, Illinois.
       motivational functions of asymmetrical frontal brain           Lee, G. P., Loring, D. W., Meador, K. J. & Flanagan, H. F.
       activity. Biological Psychology, 67, 51–76.                       (1987). Emotional reactions and behavioral
     Heller, W. (1990). The neurospychology of emotion:                  complications following intracarotid sodium amytal
       developmental patterns and implications for                       injection. Journal of Clinical and Experimental
       psychopathology. In N. L. Stein, B. Leventhal & T.                Neuropsychology, 37, 565–610.
       Trabasso (Eds.), Psychological and Biological Approaches       Loftus, G. R. & Masson, M. E. (1994). Using confidence
       to Emotion. Hillsdale, NJ: Lawrence Erlbaum Associates.           intervals in within-subjects designs. Psychonomic
     Heller, W., Etienne, M. A. & Miller, G. A. (1995). Patterns         Bulletin & Review 1, 476–490.
       of perceptual asymmetry in depression and anxiety:             Maddock, R. J., Buonocore, M. H., Kile, S. J. & Garrett, A. S.
       implications for neuropsychological models of emotion            (2003). Brain regions showing increased activation by
       and psychopathology. Journal of Abnormal Psychology,             threat-related words in panic disorder. Neuroreport,
       104, 327–333.                                                    14(3), 325–328.
     Heller, W., Nitschke, J. B., Etienne, M. A. & Miller, G. A.      Miezin, F. M., Maccotta, L., Ollinger, J. M., Petersen, S. E. &
64     (1997). Patterns of regional brain activity differentiate        Buckner, R. L. (2000). Characterizing the hemodynamic
                                       Chapter 5: Frontal asymmetry in emotion, personality and psychopathology



   response: effects of presentation rate, sampling                related to extraversion and neuroticism. Personality and
   procedure, and the possibility of ordering brain                Individual Differences, 36, 717–732.
   activity based on relative thinking. Neuroimage, 11,         Stabell, K. E., Andresen, S., Bakke, S. J. et al. (2004).
   735–739.                                                        Emotional responses during unilateral amobarbital
Milad, M. R. & Quirk, G. J. (2002). Neurons in medial              anesthesia: differential hemispheric contributions?
  prefrontal cortex signal memory for fear extinction.             Acta Neurologica Scandinavica, 110, 313–321.
  Nature, 420, 70–74.                                           Starkstein, S. E. & Robinson, R. G. (1988). Lateralized
Meyer, T. J., Miller, M. L., Metzger, R. L. & Borkovec, T. D.      emotional responses following stroke. In M. Kinsbourne
  (1990). Development and validation of the Penn State             (Ed.), Cerebral Hemisphere Function in Depression.
  Worry Questionnaire. Behavior Research and Therapy,              Washington, DC: American Psychiatric Press.
  28, 487–495.                                                  Stewart, J. L., Levin-Stilton, R., Sass, S. M., Heller, W. &
Molina, S. & Borkovec, T. D. (1994). The Penn State Worry          Miller, G. A. (2008). Anger style, psychopathology, and
  Questionnaire: psychometric properties and associated            regional brain activity. Emotion, 8(5), 701–713.
  characteristics. In G. C. L. Davey & F. Tallis (Eds.),        Talairach, J. & Tornoux, P. (1988). Co-planar Stereotactic
  Worrying: Perspectives on Theory, Assessment and                 Atlas of the Human Brain. Stuttgart: Thieme.
  Treatment (pp. 265–283). Chichester: John Wiley & Sons.       Tomarken, A. J. & Davidson, R. J. (1994). Frontal brain
Murphy, F. C., Nimmo-Smith, I. & Lawrence, A. D. (2003).          activation in repressors and nonrepressors. Journal of
  Functional neuroanatomy of emotions: a meta-analysis.           Abnormal Psychology, 103(2), 339–349.
  Cognitive, Affective, and Behavioral Neuroscience, 3(3),      Wacker, J., Heldmann, M. & Stemmler, G. (2003).
  207–233.                                                        Separating emotion and motivational direction in fear
Myslobodsky, M. S. & Horesh, N. (1978). Bilateral                 and anger: effects on frontal asymmetry. Emotion, 3(2),
  electrodermal activity in depressive patients. Biological       167–193.
  Psychology, 6(2), 111–120.                                    Wager, T. D., Phan, K. L., Liberzon, I. & Taylor, S. F.
Nitschke, J. B., Heller, W., Palmieri, P. A. & Miller, G. A.      (2003). Valence, gender, and lateralization of functional
   (1999). Contrasting patterns of brain activity in anxious      brain anatomy in emotion: a meta-analysis of findings
   apprehension and anxious arousal. Psychophysiology, 36,        from neuroimaging. Neuroimage, 19(3), 513–531.
   628–637.                                                     Watson, D. (2000). Mood and Temperament. New York,
Nitschke, J. B., Sarinopoulos, I., Mackiewicz, K. L.,             NY: Guilford Press.
   Schaefer, H. S. & Davidson, R. J. (2006). Functional         Watson, D. & Clark, L. (1991). The PANAS-X: Manual for
   neuroanatomy of aversion and its anticipation.                 the Positive and Negative Affect Schedule – Expanded
   Neuroimage, 29, 106–116.                                       Form. University of Iowa.
O’Connell, T. R., Tucker, D. M. & Scott, T. B. (1987).          Watson, D., & Clark, L. A. (1993). Behavioral disinhibition
  Self-report of neuropsychological dimensions of self-           versus constraint: A dispositional perspective. In
  control. In A. Glass (Ed.), Individual Differences in           D. Wegener & J. Pennebaker (Eds.), Handbook of Mental
  Hemispheric Specialization (pp. 267–282). NATO ASI              Control, (pp. 506–527). New York: Prentice Hall.
  Series A: Life Sciences, 130.
                                                                Watson, D., Clark, L. A., & Tellegen, A. (1988).
Perlstein, W. M., Elbert, T. & Stenger, V. A. (2002).             Development and validation of brief measures of
   Dissociation in human prefrontal cortex of affective           positive and negative affect: the PANAS scales. Journal of
   influences on working memory-related activity.                 Personality and Socical Psychology, 54(6), 1063–70.
   Proceedings of the National Academy of Science USA,
   99(3), 1736–1741.                                            Watson, D., Clark, L. A., Weber, K. et al. (1995a).
                                                                  Testing a tripartite model: II. Exploring the symptom
Regard, M. (1983). Cognitive rigidity and flexibility: a          structure of anxiety and depression in student, adult,
  neuropsychological study. Dissertation Abstracts                and patient samples. Journal of Abnormal Psychology,
  International, 43, 2714.                                        104, 15–25.
Ruff, R. M. (1996). Ruff Figural Fluency Test. Odessa, FL:      Watson, D. & Tellegen, A. (1985). Toward a consensual
  Psychological Assessment Resources.                             structure of mood. Psychological Bulletin, 98(2), 219–235.
Rush, A. & Weissenburger, J. (1994). Melancholic                Watson, D., Weber, K., Assenheimer, J. S. et al. (1995b).
  symptoms features and DSM–IV. American Journal                  Testing a tripartite model: I. Evaluating the convergent
  of Psychiatry, 151, 489–498.                                    and discriminant validity of anxiety and depression
Schmidtke, J. I. & Heller, W. (2004). Personality, affect         symptom scales. Journal of Abnormal Psychology, 104,
   and EEG: predicting patterns of regional brain activity        3–14.                                                        65
        Section 1: Neuropsychological processes



     Wechsler, D. (1997). Wechsler Memory Scale – Third        Willner, P. (1993). Anhedonia. In C. G. Costello (Ed.),
       Edition: Administration and Scoring Manual. San           Symptoms of Depression (Wiley Series on Personality
       Antonio, TX: The Psychological Corporation.               Processes) (pp. 63–84). Oxford: John Wiley & Sons.
     Williamson, J. B. & Harrison, D. W. (2003). Functional    Woolrich, M. W., Ripley, B. D., Brady, M. & Smith, S. M.
       cerebral asymmetry in hostility: a dual task approach     (2001). Temporal autocorrelation in univariate
       with fluency and cardiovascular regulation. Brain and     linear modeling of fMRI data. Neuroimage, 14,
       Cognition, 52, 167–174.                                   1370–1386.




66
    Chapter




           6
                     Behavioral and electrophysiological
                     approaches to understanding language
                     dysfunction in neuropsychiatric disorders:
                     insights from the study of schizophrenia
                     Gina R. Kuperberg, Tali Ditman, Donna A. Kreher and Terry E. Goldberg

Introduction                                                   we conclude by discussing how a deeper understand-
                                                               ing of the cognitive basis of language abnormalities
Language disturbances are characteristic of several            might inform the design and interpretation of neuro-
neuropsychiatric disorders including schizophrenia,            anatomical and neuropharmacological studies, and
mania, Alzheimer’s disease (and other dementias)               how such a multifaceted approach might give new
and developmental disorders such as the autistic spec-         information about the underlying neuropathology of
trum disorders. Yet it is only over the last 25 years          schizophrenia and other neuropsychiatric disorders.
that researchers have begun to study the language
system in neuropsychiatric disorders from cognitive,
psycholinguistic and neurophysiological perspectives.
This chapter aims to review a selection of such studies        Clinical language disturbances
to illustrate this progress, focusing primarily on             in psychosis: thought disorder
schizophrenia. We begin with a summary of how clin-
ical language disturbances in adult psychiatric disorders      and beyond
have traditionally been viewed. We then review selected        Clinically, the most obvious manifestation of lan-
studies at three basic levels of the language code –           guage disturbances in adult psychiatric disorders is
words (focusing on conceptual relationships within             the disorganized unintelligible speech produced by
semantic memory), sentences (focusing on how words             patients during psychosis. This has traditionally been
are combined to build up linguistic context and pro-           termed “thought disorder,” reflecting the original per-
positional meaning), and discourse (focusing on the            spective of psychopathologists who considered it an
generation of coherence links across more than one             underlying disorder of thinking rather than a pri-
sentence). We then examine the relationship between            mary disturbance of language (Bleuler, 1911/1950;
abnormalities at each of these levels of language with         Kraepelin, 1971). Today, however, the term “thought
cognitive dysfunction in more general domains, such as         disorder” is used purely descriptively without any
attention and working memory.                                  assumptions about the complex relationship between
    The functional neuroimaging literature examining           thought and language (DSM–IV; American Psychia-
the neuroanatomical basis of language abnormalities            tric Association, 1990). Thought disorder occurs in
in neuropsychiatric disorders has generally lagged be-         mania as well as schizophrenia, but its most detailed
hind the cognitive behavioral and electrophysiological         characterization has been in schizophrenia. Building
literatures (but see Kuperberg, 2009, for an overview          upon the detailed phenomenological descriptions of
of potential links between cognitive, electrophysio-           Schneider (1930) and others, clinical assessments of
logical and fMRI studies of language in schizophre-            thought disorder such as the Thought, Language
nia). Although the focus of this chapter is on studies         and Communication (TLC) scale (Andreasen, 1979a,
using behavioral and electrophysiological methods,             1979b), emphasize the “form” rather than the content



The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by        67
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



     of thought/speech, i.e. the way words and sentences         processing mechanisms that may also be impaired
     are strung together. They include phenomena ranging         during speech production. Moreover, the study of
     from tangentiality (the shift in speech from one            such mechanisms may also give insights into other
     topic to another without obvious links between              symptoms of schizophrenia.
     them), through neologisms (the use of non-words),               These observations, together with the identifica-
     as well as poverty of speech. Studies in the late 1970s     tion of language disturbances in children at risk for
     and early 1980s established that some of these phe-         schizophrenia (Cannon et al., 2002; Fuller et al., 2002;
     nomena (including tangentiality, derailment, and            Ott et al., 2001), as well as in patients in their first
     incoherent speech) tended to occur more often in            episode of psychosis (Fuller et al., 2002; Hoff et al.
     patients with positive than negative symptoms               1999), suggest that a systematic study of the language
     (Andreasen, 1979a, 1979b; Harvey et al., 1984; Olt-         system may give new insights into the neuropatho-
     manns et al., 1985). These phenomena constitute             genesis of schizophrenia as a whole.
     “positive thought disorder.” In contrast, phenomena
     such as “poverty of speech” co-occurred primarily
     with negative symptoms and were termed “negative            Single words and concepts: semantic
     thought disorder.” Subsequent factor-analytic studies       memory structure and function
     showed that positive thought disorder occurred more         Most studies at the level of single words in neuropsy-
     frequently with disorganized, non-goal directed             chiatric disorders have examined how words are
     behavior as opposed to hallucinations and delusions         stored and accessed within semantic memory – an
     (Liddle, 1987, 1992; Andreasen et al., 1995). In            approach inspired by the observation that the speech
     DSM–IV (1990) positive thought disorder and disor-          of some psychotic patients is characterized by strings
     ganized behavior are now grouped together as cons-          of word associations (Chaika, 1974). This section
     tituting the “disorganization” subsyndrome of               reviews studies adopting this perspective: we consider
     schizophrenia.                                              studies that have examined how patients with schizo-
          Original attempts to explain the various phenom-       phrenia identify and name concepts, as well as investi-
     ena constituting positive thought disorder proposed         gations that have used both explicit and implicit
     concepts such as “loosening of association” (Bleuler,       measures to explore how such concepts are linked
     1911/1950), “overinclusive thinking” (a tendency of         together through perceptual attributes, hierarchical
     patients to use concepts beyond their usual boundar-        relationships and semantic associations.
     ies; Cameron, 1939, 1964), and concrete thinking (an
     inability to think abstractly; Goldstein, 1944). Some of
     these concepts, particularly Bleuler’s “loosening of        Semantic identification and naming
     associations,” were intended not only to describe the       The identification and distinction of objects in the
     origins of positive thought disorder (disorganized          visual world is dependent on a hierarchical ventral
     speech output) itself, but to help explain the under-       visual pathway (Ungerleider & Haxby, 1994) that runs
     lying cognitive basis of schizophrenia as a whole. In       from primary visual cortex (V1) to extrastriate visual
     keeping with this idea, although many of the studies        areas (V2 and V4) to the inferotemporal cortex, and is
     reviewed in the current chapter were originally             a major source of input to the prefrontal cortex. Some
     inspired by the disorganized language output pro-           of the observed impairments in conceptual classifica-
     duced by some patients, it has become increasingly          tion and identification in schizophrenia, discussed
     apparent that language abnormalities in schizophre-         below, may arise because of deficits in visual per-
     nia are not confined to patients with positive thought      ception rather than in cognitive semantic function.
     disorder (although they are often more prominent in         Although it has often been assumed that the ventral
     such patients), or to the language production system.       visual pathway is intact in schizophrenia, there has
     Patients, with and without clinical evidence of             been surprisingly little research to back up this
     thought disorder, can show clear abnormalities in           assumption. In one of the few paradigms to explicitly
     language comprehension. Clinically, these abnorma-          examine basic object identification in schizophrenia,
     lities are usually subtler than the abnormalities evident   Elvevaag et al. (2002b) asked patients to watch pic-
68   in thought-disordered speech, but their study can           tures of objects (e.g. a pear) morph into other objects
     yield valuable insights into fast, online word-by-word      (e.g. a lightbulb) and to indicate the frame in the
                                                    Chapter 6: Approaches to understanding language dysfunction



morphing sequence at which the first object was no             Explicit production: semantic fluency
longer identifiable. Performances of patients and con-         In semantic fluency tasks, participants are required to
trols were nearly identical, suggesting that basic object      generate as many exemplars as possible from a given
perception was intact.                                         category (e.g. animals) in a defined time period (often
    In humans, basic object identification is linked to        one minute), with the assumption that abnormalities
the language system through our ability to name                in the number and types of items produced will reveal
objects. Naming involves the activation and retrieval          abnormalities in the storage and retrieval of categor-
of lexical representations of both meaning and                 ical semantic information. Patients with schizophre-
phonological form. Anomia, a word-finding impair-              nia show mild-to-moderate difficulties on this test,
ment, is characteristic of several types of aphasic            producing fewer items per category than control par-
syndromes as well as other neurological disorders              ticipants. This impairment appears to be at least
characterized by a loss of lexico-semantic knowledge           somewhat specific to producing semantic categorical
such as Alzheimer’s disease. Given the hypothesis that         information; several studies have demonstrated that
schizophrenia is associated with abnormalities in              patients are relatively less impaired on letter fluency
semantic processing, it has been of particular interest        tasks in which the requirement is to produce words
to determine how well patients with schizophrenia              beginning with a particular letter (Feinstein et al.,
perform on naming tasks. Early studies suggested that          1998; Goldberg et al., 1998; Gourovitch et al., 1996).
patients with schizophrenia performed worse than               A recent meta-analysis of studies directly comparing
controls on simple naming tasks (Faber & Reichstein,           category and letter fluency, and controlling for factors
1981), and in some cases as poorly as patients with            like motivation, cooperation, symptomatology and IQ,
fluent aphasia (Landre et al., 1992) or Alzheimer’s            confirmed a selective deficit on category fluency (Bokat
disease (Davidson et al., 1996). Unlike Alzheimer’s            & Goldberg, 2003). Kremen et al. (2003) came to a
patients, however, schizophrenia patients improved             similar conclusion based upon a large well-controlled
their performance when given appropriate semantic              study that compared the performance of schizophrenia
cues (Laws et al., 1998; Maas & Katz, 1992; McKenna            patients, bipolar patients and healthy controls.
et al., 1994), suggesting that any deficit lay in the access       The relationship between categorical fluency and
and use of lexical knowledge rather than the loss of this      thought disorder in schizophrenia is still unclear,
knowledge. A more recent study of object naming by             however. While Aloia et al. (1996) found that the
Denke & Goldberg (unpublished data) demonstrated               difference score between letter and semantic fluency
that schizophrenia patients performed as well as               performance accounted for a significant portion of
healthy controls and significantly better than patients        thought disorder variability, later studies have not
with mild Alzheimer’s disease; there was no associ-            replicated this finding (Bokat & Goldberg, 2003).
ation between naming deficits and severity of positive             Several approaches have been developed to exam-
thought disorder within the schizophrenia group – a            ine the pattern of responses produced on semantic
finding that is consistent with previous observations          categorical fluency tasks. Allen & Frith (1983) and
(Aloia et al., 1998; Goldberg et al., 2000).                   Allen et al. (1993) developed a methodology in which
                                                               semantic fluency tests were repeatedly administered
Explicit knowledge and use of semantic                         and the number of novel exemplars generated in each
                                                               session tallied. They demonstrated that, given enough
category                                                       time, patients do eventually produce the same total
Concepts are not represented in isolation of one               number of category exemplars as controls. Elvevaag
another, but are thought to be organized hierar-               et al. (2002a) replicated this finding and went on to
chically according to domains and categories of                demonstrate that patients showed no category-specific
knowledge within semantic memory. It is therefore              deficits. These findings were interpreted as suggesting
important to examine whether schizophrenia patients’           that there is no overall loss of semantic knowledge in
disordered use of concepts results from their abnormal         schizophrenia patients: the impairment is in retrieving
organization within semantic memory. This issue has            this knowledge in response to specific task demands.
been investigated using both semantic production and               Others have used multidimensional scaling,
categorization tasks.                                          pathfinder and clustering techniques to examine            69
        Section 1: Neuropsychological processes



     relationships between words within superordinate                  A third method of probing categorical knowledge
     categories in more depth (Allen & Frith, 1983; Aloia          is to ask participants to classify words or objects using
     et al., 1996; Paulsen et al., 1996). These studies have       unspecified categories or dimensions. In the “triadic
     suggested that patients are less likely than controls to      comparisons” test, participants view groups of three
     group superordinate exemplars into related clusters           words and are asked to select the two words that are
     and are more likely to produce bizarre associations.          most similar. Each word triplet is a permutation
     In addition, patients are slower than controls to pro-        derived from an overall word list in which words vary
     duce items within a semantic cluster and to produce           on two continuous dimensions: (1) living and non-
     items that transition from one semantic cluster to            living and (2) “associated with humans” and “not
     the next. Taken together, these findings suggest that         associated with humans.” This information is not
     either the underlying organization of items stored            conveyed to the participants. Participants’ responses
     within semantic memory is abnormal or that the                are analyzed using multidimensional scaling methods
     process of retrieval is more disorganized in patients         to generate graphic maps of the structure of their
     than in controls.                                             semantic memories. Tallent et al. (2001) used this
                                                                   task with schizophrenia patients and demonstrated
     Explicit processing: knowledge of semantic                    less-disorganized maps in patients than healthy con-
                                                                   trols. Interestingly, the degree of disorganization within
     category and semantic attributes                              these maps predicted severity of thought disorder over
     Although potentially useful, semantic fluency tasks           time. Moreover, in an unpublished study, Denke &
     are relatively uncontrolled, in that each individual          Goldberg showed that these disorganized maps were
     generates different word lists and it is often difficult      specific to thought-disordered (TD) patients; they were
     to derive objective quantitative measures of perform-         not found in non-TD patients, patients with Alzheimer’s
     ance. To probe semantic memory structure in a more            disease or in healthy children.
     controlled fashion, several studies have examined par-            Impairments in patients’ use of categorical know-
     ticipants’ explicit semantic categorization judgments         ledge are also evident in declarative memory para-
     on controlled sets of stimuli.                                digms. When healthy controls learn a list of words,
         The most basic type of categorization paradigm is to      their recall is better if the list can be organized into
     simply ask participants to decide whether or not an           semantic categories than if it consists of a sequence of
     exemplar comes from a specified superordinate sem-            unrelated words. This is thought to reflect the ten-
     antic category. There is some evidence that schizophre-       dency to organize words in semantic memory during
     nia patients are slower and less accurate than controls       encoding (Craik & Lockhart, 1971; Kintsch, 1968).
     in classifying common prototypes versus marginal              There is now fairly compelling evidence that patients
     exemplars. In two early studies, patients, relative to        with schizophrenia fail to spontaneously use such
     healthy controls, were slower to make a decision about        semantic categorization strategies during encoding.
     whether a sparrow is a bird (a prototype) relative to         Several studies have reported that patients often pro-
     whether a penguin is a bird (a marginal exemplar)             duce largely unorganized word lists at recall (e.g.
     (Chen et al., 1994; Clare et al., 1993; Gurd et al., 1997).   Iddon et al., 1998; Koh et al., 1973). Interestingly,
     However, later studies did not replicate this finding         most of these studies (Iddon et al., 1998; Koh &
     (Elvevaag et al., 2002b; McKenna et al., 1994).               Kayton, 1974), although not all (Gold et al., 1992),
         A second way of probing semantic knowledge is to          have reported that if material is pre-organized, or if
     ask participants to compare objects according to a            patients are given enough time to organize material
     particular perceptual semantic attribute, e.g. size.          during encoding, they do have the capacity to use
     Cohen et al. (2005) capitalized on the so-called “dis-        semantic information to improve recall. Once again
     tance effects” in size among real-world objects; this         these results suggest that there is no overall loss of
     pertains to the longer reaction time (RT) to make size        semantic knowledge in schizophrenia.
     similarity judgments about two words or pictures that             There has not been nearly as much study of
     represent real-world objects of the same size versus          semantic memory in bipolar disorder as in schizo-
     different sizes. Despite having slower overall RTs,           phrenia. However, recent studies suggest some
70   patients demonstrated a principled distance effect that       impairments; Deckersbach et al. (2004, 2005)
     did not differ from that of healthy controls.                 reported that bipolar patients can exhibit poorer
                                                 Chapter 6: Approaches to understanding language dysfunction



organization during encoding than healthy controls,        findings using this measure confirmed that schizo-
while other studies suggest that, despite using normal     phrenia patients’ word associations were less seman-
semantic clustering strategies during encoding,            tically cohesive than those of healthy controls.
patients fail to make use of such strategies during        Moreover, the associations produced by TD patients
recall (Bearden et al., 2006a, 2006b).                     were less cohesive than those produced by non-TD
                                                           patients.

Implicit knowledge of semantic                             Implicit processing: semantic priming
and associative relationships                              An even more objective method of implicitly assess-
Another way of probing the structure and use of            ing semantic memory structure and function is
semantic memory is to manipulate semantic relation-        through the use of the semantic priming paradigm
ships between words but conceal the purpose of the         using an implicit task, such as lexical decision (LD:
study altogether from participants by asking parti-        deciding whether a target word is a real word or a
cipants to perform an orthogonal task. This yields         non-word) or word pronunciation (simply naming
implicit measures, which not only give information         the target word). The semantic priming effect des-
about the nature of categorical relationships between      cribes the faster response to target words (e.g. stripes)
words within semantic memory, but also provide             that are preceded by semantically related words (e.g.
information about associative relationships between        tiger), relative to semantically unrelated words (e.g.
words that may not necessarily have semantic features      table) (Meyer & Schvaneveldt, 1971; Neely, 1991).
in common. For example, “surgeon” and “scalpel” are        This behavioral priming effect also has a neuro-
associatively related but they are not categorically       physiological correlate: the attenuation of the N400
related and do not share semantic features.                event-related potential (ERP) – a negative-going wave-
                                                           form evoked c. 400 ms after the onset of a word – to
                                                           primed versus unprimed targets (Bentin et al., 1985;
Implicit production: word association tasks                Rugg, 1985). This attenuation of the N400 amplitude is
and the Latent Semantic Analysis                           known as the N400 effect.
                                                               There have been numerous studies of semantic
The classic method of probing implicit associative
                                                           priming in schizophrenia over the past two decades
knowledge has been to use word association tasks in
                                                           and the literature is often contradictory: studies have
which participants are given a word and then asked to
                                                           reported normal priming, increased priming and
generate the first word (or series of words) that
                                                           decreased priming in patients relative to controls.
come to mind. Word association studies have a long
                                                           Nonetheless, some consistencies do emerge, particu-
history in psychiatry. Early experiments carried out
                                                           larly when findings are examined in relation to types
by Bleuler, C. G. Jung and Kraepelin demonstrated
                                                           of experimental conditions (automatic versus con-
that schizophrenia patients produced more idiosyn-
                                                           trolled) used in each study. Below is a brief review
cratic associations than normal controls (Jung, 1981).
                                                           of behavioral and ERP semantic priming studies in
These findings were confirmed by some later studies
                                                           schizophrenia (for a more detailed review of the
(reviewed by Spitzer et al., 1992). However, as dis-
                                                           behavioral literature up to 2002, see Minzenberg
cussed above with respect to semantic fluency,
                                                           et al., 2002; for a recent meta-analysis of the behav-
because word associations differ from individual to
                                                           ioral literature, see Pomarol-Clotet et al., 2008, and
individual, it is often difficult to objectively measure
                                                           for a review of the ERP semantic priming literature,
the output produced.
                                                           see Kuperberg, Kreher & Ditman, in press).
    Elvevaag et al. (2007) have recently addressed this
issue by measuring the semantic coherence of words
produced on association tasks using a Latent Seman-        Automatic semantic priming in schizophrenia
tic Analysis (LSA). The LSA derives a measure of           Experimental conditions that bias towards automa-
coherence not simply on the basis of co-occurrence         tic semantic priming are those in which the interval
frequency, but also through examining the similarity       between the presentation of the prime and target
of contexts in which words occur in a large text           (the stimulus onset asynchrony, SOA) is short (usu-         71
corpus (Landauer et al., 1998). Elvevaag et al.’s          ally less than c. 400 ms), and in which the proportion
       Section 1: Neuropsychological processes



     of related words in the stimulus set (the relatedness          All of the studies reviewed above used directly
     proportion, RP) is small (usually less than 33%)           related word pairs (e.g. tiger-stripes). However, since
     (Neely, 1977). The mechanism most often invoked            closely associated words are presumably automatically
     to explain the semantic priming effect under these         activated by both schizophrenia patients and controls,
     conditions is the spread of activation within semantic     the use of indirectly related word pairs during
     memory (Anderson, 1983; Collins & Loftus, 1975),           semantic priming paradigms may be a more stringent
     whereby the presentation of the first word (or prime)      test for a heightened activation (or reduced inhibition)
     activates its internal representation, leading to an       (Spitzer, 1993). In indirect semantic priming para-
     implicit, automatic spread of activation to nearby         digms, the prime and target are related only through
     and related representations. If a second word, the         an unseen mediating word (e.g. “lion-stripes” via
     target, corresponding to one of these partially pre-       “tiger”) (Balota & Lorch, 1986; Chwilla & Kolk, 2002;
     activated or primed representations is then presented,     Kiefer et al., 1998; Kreher et al., 2006; McNamara &
     the individual’s response to that target will be           Altarriba, 1988; Weisbrod et al., 1999). Unlike direct
     facilitated.                                               priming, indirect semantic priming cannot be
         One theory proposed to account for the                 accounted for by alternative models of automatic
     “loosening of associations” seen in thought disorder       semantic priming, and is best explained by spreading
     (TD) is that the spread of activation within semantic      activation theory (Kreher et al., 2006; McNamara &
     memory is abnormally heightened, leading to speech         Altarriba, 1988; Neely, 1991). The unseen mediating
     that is difficult to follow because it is dominated by     word is thought to be activated by the prime, and this
     such associations. Evidence for this theory is provided    spread of activation activates the target.
     by findings that schizophrenia patients exhibit                Spitzer et al. (1993) were the first to report increased
     increased semantic priming under more automatic            indirect priming using a LD task under automatic con-
     processing conditions. Manschreck et al. (1988) were       ditions in TD patients, relative to both healthy individ-
     the first to demonstrate increased semantic priming        uals and non-TD patients (see also Moritz et al., 2001b).
     in TD patients relative to non-TD patients, psychi-        This finding has been replicated both using lateralized
     atric controls and healthy controls (using a LD task).     presentation (Weisbrod et al., 1998) and using a word
     Subsequent studies have confirmed “hyper-priming”          pronunciation task (Moritz et al., 2002).
     in TD patients across a variety of SOAs (Spitzer et al.,       In an ERP study by Mathalon et al. (2002),
     1994), during word pronunciation tasks (Moritz             patients showed a smaller amplitude of the N400 than
     et al., 2001a; Moritz et al., 2002) and even when par-     controls to target words that were moderately (but
     ticipants viewed triplets, rather than pairs of words      not closely) related to their picture primes. This was
     (Chenery et al., 2004). Others have reported increased     interpreted as reflecting increased activation to these
     cross-modal (across auditory and visual modalities)        targets in schizophrenia patients. Of note, however,
     semantic priming (Surguladze et al., 2002), as well        these word-pairs were not indirectly related, as they
     as increased priming, particularly to high-frequency       belonged to the same superordinate categories (e.g.
     words (Rossell & David, 2006) in patients with             camel – fox). In a more recent ERP study, Kreher
     schizophrenia.                                             et al. (2008) used a short SOA and an implicit task
         Other researchers, however, have failed to show        (semantic monitoring just on filler trials) to demon-
     increases in direct priming in schizophrenia under         strate increased spreading activation in TD schizo-
     automatic conditions: equal priming in patients and        phrenia patients. In the early part of the N400 time
     controls has been demonstrated using LD (Barch et al.,     window (300–400 ms after target word onset), TD
     1996; Blum & Freides, 1995), double LD (Besche-            patients showed increased indirect semantic priming
     Richard et al., 2005; Chapin et al., 1989), and word       relative to non-TD patients and healthy controls,
     pronunciation (Ober et al., 1995; Vinogradov et al.,       while the degree of direct semantic priming was
     1992) tasks. And a few behavioral studies (Henik           increased in only the most severely thought-
     et al., 1992; Ober et al., 1997; Vinogradov et al.,        disordered patients. By 400–500 ms after target word
     1992) and two ERP studies (Condray et al., 2003;           onset, both direct and indirect semantic priming were
     Mathalon et al., 2002) have reported reduced direct        generally equivalent across the three groups. These
72   semantic priming using LD tasks in schizophrenia           findings suggest that under automatic conditions,
     using short SOAs.                                          activation across the semantic network spreads further,
                                                 Chapter 6: Approaches to understanding language dysfunction



within a shorter period of time, in specific association   priming in schizophrenia. Using a pronunciation task,
with positive thought disorder in schizophrenia.           Aloia et al. (1998) found that TD patients exhibited less
    However, experimental task also appears to play a      priming to both highly associated and moderately
role in whether hyper- or hypoactivation will be           associated targets than non-TD patients, and less
observed in schizophrenia patients relative to con-        priming to the highly associated targets than healthy
trols, even under “automatic” conditions. Kreher           controls. Reduced priming in TD patients at longer
et al. (2009) used an explicit relatedness ratings task    SOAs has also been demonstrated using a LD task
with the same group of patients and matched con-           (Besche et al., 1997; Passerieux et al., 1997) and a
trols, who were presented with the same directly           variant of the double LD task with a low RP (Besche-
related, indirectly related and unrelated word pairs       Richard et al., 2005). Studies using multiple SOAs have
using the same SOA, and found that schizophrenia           found either reduced (Barch et al., 1996; Chenery et al.,
patients, as a whole, showed reduced direct and indir-     2004) or normal (Henik et al., 1995) priming effects in
ect N400 priming effects compared with healthy con-        patients relative to controls at long SOAs.
trols. Similarly, Kiang et al. (2008) reported reduced         ERP studies have also reported reduced priming
N400 effects to both directly and indirectly related       under controlled conditions in patients relative to
targets in schizophrenia patients, compared with           controls (although see Koyama et al., 1991, 1994).
controls, using a LD task with a short SOA.                For example, Grillon et al. (1991) reported two dis-
    In sum, studies examining semantic priming             tinct subgroups of schizophrenic patients: one in
under automatic conditions have generally revealed         which there was a reduced N400 effect, and one in
normal direct priming in schizophrenia patients as a       which the N400 effect did not differ from that of
whole, suggesting that implicit associative activity       controls, and Bobes et al. (1996) found that schizo-
within the semantic network is normal in such              phrenia patients showed a smaller N400 effect than
patients. However, there is some evidence that TD          controls in a picture priming paradigm. There have
patients show increased direct priming, and even           also been reports of a reduced N400 effect using LD
more consistent evidence that TD patients show             tasks by Kostova et al. (2003, 2005), particularly in TD
increased indirect priming under these automatic           patients. Others have reported reduced N400 effects
conditions. This suggests that, in patients with severe    both in medicated patients (Condray et al., 1999) and
thought disorder, automatic activation may spread          unmedicated patients (Condray et al., 1999; Hokama
further (and possibly faster) across the semantic net-     et al., 2003) at longer SOAs. Using a LD task, Kiang
work. This may be due to hyperactivity and/or a            et al. (2008) reported reduced N400 effects in schizo-
failure of inhibition. Additionally, requiring a deci-     phrenia patients to both directly and indirectly related
sion to each target word, through relatedness judg-        words at a long SOA; the reduction in semantic
ments or lexical decision can lead to a reduction in       priming was correlated with delusions and hallucin-
semantic priming in schizophrenia patients even            ations, but not with thought disorder. Another consist-
when a short SOA and indirectly related word pairs         ent finding under controlled processing conditions is
are used. This is likely to occur because of the engage-   that the peak latency of the N400 is delayed (Bobes
ment of controlled semantic mechanisms which, as           et al., 1996; Condray et al., 1999; Grillon et al., 1991;
discussed below, are impaired in patients.                 Hokama et al., 2003; Koyama et al., 1991).
                                                               In sum, behavioral and ERP studies of controlled
Controlled semantic priming in schizophrenia               semantic priming suggest that priming is reduced in
Controlled priming mechanisms involve the gener-           patients with schizophrenia relative to controls. This
ation of predictions or expectations (Becker, 1980),       has generally been attributed to impaired controlled
as well as attempts to match the semantic relationship     mechanisms of accessing information within seman-
between prime and target (Neely et al., 1989). They        tic memory.
have most often been studied under experimental
conditions using a long SOA and a high RP.                 Single words and concepts: summary
    With the exception of Spitzer et al. (1993, 1994)
who reported increased semantic priming in patients        and discussion
relative to controls, most studies carried out under       The findings reviewed here suggest that semantic            73
such controlled conditions have demonstrated reduced       memory structure and function in schizophrenia
       Section 1: Neuropsychological processes



     requires further clarification. There are clearly aspects   level of sentences. We focus again on schizophrenia,
     of semantic memory that are intact: patients perform        as most of the work has been carried out in this area.
     just as well as healthy controls on simple object per-      We consider studies that have examined the predict-
     ception and some aspects of semantic categorization.        ability of the speech produced by schizophrenia
     Semantic fluency is impaired but, when given enough         patients, as well as studies exploring patients’ abilities
     time, patients produce as many exemplars as controls.       to predict words within text and to detect and inte-
     Moreover, under automatic experimental conditions           grate semantic anomalies in sentences. In addition,
     patients generally show the same degree of semantic         we review studies exploring the syntactic structure
     priming as healthy controls, and indeed, patients           of patients’ speech and examining how patients com-
     with thought disorder can show even greater priming         bine syntactic structure with the meaning of individ-
     effects than controls, suggesting that there may be         ual words during comprehension. Finally, we discuss
     some automatic hyperactivity within the network             studies that have explored patients’ ability to select the
     in these patients.                                          most appropriate meanings of ambiguous words in
         This set of findings is important because it sets       context, and studies of non-literal language.
     schizophrenia apart from disorders such as Alzheimer’s
     disease. There does not appear to be an overall loss of
     knowledge in schizophrenia: the main semantic prob-         Semantic predictability and congruity
     lem appears to be one of access and/or retrieval, i.e. of   The traditional way of measuring language predict-
     using semantic knowledge effectively. This manifests in     ability is through the use of the Cloze technique,
     both explicit and implicit measures. On explicit seman-     which requires healthy participants to produce the
     tic fluency, word association and categorization tasks,     missing words in text (Taylor, 1953). If they tend to
     the pattern of responses in patients reveals an abnor-      produce the same word, then this indicates that the
     mality in the organization of semantic memory. Behav-       text was highly predictable. An early schizophrenia
     ioral and ERP studies of implicit semantic memory           study confirmed the clinical impression that patients’
     function examining the semantic priming effect under        speech output was unpredictable (Salzinger et al., 1964).
     controlled experimental conditions, suggest that            Moreover, when participants were provided with
     patients fail to employ strategic semantic mechanisms       more context, it was harder to predict patients’ speech
     to prime targets, leading to reduced priming.               (Salzinger et al., 1970, 1979). Later studies, however,
                                                                 suggested that unpredictable speech was only pro-
     Sentences, ambiguity and figurative                         duced by patients with thought disorder (Hart &
                                                                 Payne, 1973; Manschreck et al., 1979). Impairments
     language                                                    in the ability to make predictions about upcoming
     As discussed above, thought-disordered speech can be        words in normal speech or text have also been identi-
     dominated by associations between individual words.         fied in schizophrenia (Blaney, 1974; Honigfeld, 1963).
     Importantly, such associations can result in a failure      This has been demonstrated using reverse Cloze
     to build coherence within and across sentences. Con-        procedures in which patients are asked to predict
     sider the following sample of speech produced by a          upcoming words in speech transcripts of healthy
     patient with schizophrenia, quoted by Maher (1983):         adults. Unlike healthy controls, the performance of
     “If you think you are being wise to send me a bill for      acute schizophrenia patients deteriorates when more
     money I have already paid, I am in nowise going to do       context is provided (de Silva & Hemsley, 1977).
     so unless I get the whys and wherefores from you to             Another method used to examine how patients
     me. But where the fours have been, then fives will be,      use context within sentences is to introduce words
     and other numbers and calculations and accounts to          that violate semantic contextual constraints. Some
     your no-account . . .” In this speech sample, the asso-     studies suggest that chronic schizophrenia patients
     ciations between the individual words are clear; what       can accurately judge the appropriateness of semantic-
     is unclear is the overall message the patient wishes to     ally anomalous sentences (Miller & Phelan, 1980);
     convey.                                                     however, acutely psychotic patients (Anand et al.,
         In this section we review studies examining how         1994) and TD patients (Kuperberg et al., 1998) appear
74   patients process and make use of contextual infor-          to be relatively impaired. Furthermore, this relative
     mation within written and spoken language, at the           insensitivity to semantic anomalies appears to be
                                                    Chapter 6: Approaches to understanding language dysfunction



related to the state (i.e. impairment related to symp-         1965; Garrett et al., 1966). In these studies, patients
tom exacerbation) rather than the trait (i.e. impair-          and controls perceived the click as occurring at or
ment independent of symptom exacerbation) of                   near a clause boundary, suggesting that patients were
thought disorder (Kuperberg et al., 2000).                     using normal syntactic constraints to guide percep-
    Measurement of ongoing brain activity using                tion (Carpenter, 1976; Grove & Andreasen, 1985;
ERPs can also offer insight into the effects of semantic       Rochester et al., 1973), and that at least some implicit
anomalies. Event-related potential studies of sentence         aspects of syntactic structural processing remained
processing, like those of single words, have focused           intact. This type of paradigm, however, does not
on the N400 waveform. In sentences, the N400 is                index how well patients can combine syntactic struc-
evoked by words that are semantically incongruous              ture with semantic information to assign thematic
or unexpected with their preceding context (Kutas &            roles and build up overall meaning.
Hillyard, 1980, 1984) and is thought to reflect the                Thematic roles are the semantic roles that are
difficulty of semantically integrating words into their        occupied by each constituent of a sentence around a
preceding context (Holcomb, 1993). Although most               given action; these are generalizable across a variety of
studies have reported that the size of the N400 effect         sentence meanings. For example, the Agent of a sen-
is normal in schizophrenia (Andrews et al., 1993;              tence is the performer of the main action and the
Kuperberg et al., 2006d; Nestor et al., 1997;                  Theme is the entity that undergoes the action. While
Niznikiewicz et al., 1997; Ruchsow et al., 2003), there        thematic roles are assigned by the syntax, they are
have been some investigations demonstrating that it            considered semantic in nature as they determine
can be abnormally reduced (Adams et al., 1993;                 “who does what to whom” in a sentence. During
Mitchell et al., 1991; Ohta et al., 1999; Sitnikova            normal language production and comprehension,
et al., 2002). A reduced N400 effect is most evident           syntax and semantics are combined, word by word,
when the anomalous words fall at the sentence-final            to assign thematic roles (although it is debated
position, which is when there are relatively high pro-         whether this combination occurs in a single stage of
cessing demands (see below for further discussion).            processing in a parallel constraint-based model (e.g.
    A number of investigators have also identified             MacDonald et al., 1994), or at a second stage of
more negative N400 amplitudes to congruous words               processing in a serial model (e.g. Frazier & Rayner,
(Mitchell et al., 1991; Nestor et al., 1997; Niznikiewicz      1982)). In patients with schizophrenia, there is grow-
et al., 1997; Ohta et al., 1999), and incongruous words        ing evidence for abnormalities in this combination of
(Nestor et al., 1997; Niznikiewicz et al., 1997) in            semantic and syntactic information.
patients relative to controls. These data may reflect              One situation in which there is an increased
increased difficulty in semantically integrating words,        demand for syntactic structure to be combined with
regardless of whether the context is congruous or              the meaning of individual words is during the pro-
incongruous. Other studies, however, have failed               duction or processing of syntactically complex sen-
to find such differences (Kuperberg et al., 2006d;             tences. In simple “canonical” sentences, the semantic
Ruchsow et al., 2003). Finally, some studies report            order of constituents of English sentences (e.g. Agent–
that the peak of the N400 is delayed, suggesting               Action–Theme) corresponds to the syntactic order of
that integrative semantic processing occurs later in           constituents (e.g. Subject–Verb–Object). This is not
patients than controls (Mitchell et al., 1991; Nestor          necessarily true of more complex, non-canonical
et al., 1997; Niznikiewicz et al., 1997; Ohta et al., 1999).   sentences where there is an increased demand on the
                                                               production and processing systems to use syntactic
Syntax and the semantic-syntactic                              rules to assign thematic roles. There is fairly compel-
                                                               ling evidence that patients with schizophrenia are
interface                                                      relatively impaired in processing syntactic complex-
Syntactic processing has often been considered rela-           ity during both speech production and language
tively unimpaired in patients with schizophrenia. The          comprehension.
evidence supporting this assumption comes from                     The speech produced by schizophrenia patients is
three early studies using the “click” paradigm in              less complex than that of matched controls (Morice &
which a short burst of noise (the click) is delivered          Ingram, 1982; Thomas et al., 1990). Reduced syntactic       75
in the middle of a spoken clause (Fodor & Bever,               complexity is associated with negative symptoms and
        Section 1: Neuropsychological processes



     seems to be relatively unresponsive to treatment             breakfast the boys would eat . . .” and sentences
     (Thomas et al., 1990). Although some researchers             that were only incongruous with real-world know-
     have postulated that it may represent a premorbid            ledge, e.g. “Every morning for breakfast the boys
     marker of schizophrenia (Thomas et al., 1990), a             would plant . . . .”
     study examining the writing samples of children                  Further evidence that patients show impairments
     who later developed schizophrenia, compared with             in combining semantic and syntactic information
     matched controls, did not find differences in syntactic      comes from ERP studies. First, as mentioned above,
     complexity (Done et al., 1998).                              in most of the ERP studies documenting an abnor-
          Complementing these findings in language pro-           mally reduced N400 effect to semantic anomalies
     duction, studies of language comprehension have              (versus non-violated words) within sentences, the
     revealed impairments in patients’ abilities to compre-       anomalies occurred on the sentence-final word
     hend grammatically complex sentences. Condray                (Adams et al., 1993; Mitchell et al., 1991; Ohta et al.,
     et al. (1996, 2002) compared patients’ accuracy on           1999; Sitnikova et al., 2002). The demands of inte-
     comprehension questions tapping into the assign-             grating semantic with syntactic information are
     ments of thematic roles (e.g. “Who did what to               particularly great at the sentence-final position, when
     whom?”) and compared more complex, object-                   there is often an attempt to evaluate and “wrap-up”
     relative sentences (e.g. The senator that the reporter       the meaning of the sentence as a whole (Friedman
     attacked admitted the error) to less complex, subject-       et al., 1975).
     relative sentences (e.g. The accountant that sued the            Second, there have also been several reports of a
     lawyer read the paper). These sentences were pre-            reduced Late Positivity (or P600) following the N400
     sented at normal (i.e. conversational) and accelerated       during sentence processing in schizophrenia (Adams
     rates. Initial results (Condray et al., 1996) demon-         et al., 1993; Andrews et al., 1993; Mitchell et al., 1991;
     strated that accuracy in both schizophrenia patients         Nestor et al., 1997). Although the theoretical rele-
     and healthy adult controls was negatively impacted by        vance of the P600 has been debated (see Coulson
     both fast presentation rates and grammatical com-            et al., 1998; Kuperberg, 2007; Osterhout & Hagoort,
     plexity. These results were replicated and extended          1999), there is evidence that it reflects the increased
     by Bagner et al. (2003) using a larger sample size.          demands of integrating semantic and syntactic infor-
     A later study by Condray et al. (2002) indicated that,       mation under certain circumstances. For example,
     although both patients and controls were more accur-         when there is a potentially plausible semantic-
     ate in answering questions about information in the          thematic relationship (“eggs”–“eat”), but the actual
     main clause compared to embedded clause, the drop            interpretation dictated by the syntax is impossible
     in accuracy between main and embedded clause ques-           (“At breakfast the eggs would eat . . .”) (Kuperberg
     tions was greater in patients than in controls.              et al., 2003c, 2006a, 2007), it is harder to integrate
          A second situation in which there are increased         semantic and syntactic information to come up with
     demands for syntactic structure to be combined with          this interpretation and a P600 effect is evoked.
     the meaning of individual words is when potentially              A recent study by Kuperberg et al. (2006d) dem-
     plausible thematic-semantic relationships contradict         onstrated that, unlike healthy controls, schizophrenia
     the implausible syntactic assignment of thematic             patients failed to evoke a Late Positive effect to these
     roles. For example, in the sentence, “Every morning          types of anomalies. Yet, in this study the same
     for breakfast the eggs would eat . . .”, there is a poten-   patients produced a normal N400 effect to violations
     tially plausible thematic-semantic relationship              of real-world knowledge, suggesting that they had no
     between “eggs” and “eat” (eggs can be eaten) but the         problem in accessing and combining the meanings
     actual interpretation dictated by the syntax is impos-       of individual words based on real-world knowledge
     sible. Kuperberg et al. (2006c) recently showed that,        alone.
     when asked to judge the acceptability of such sen-               One important question is whether patients’ poor
     tences, patients with schizophrenia were less sensitive      performance when required to combine semantic and
     to these types of anomalies than healthy controls:           syntactic information is due to their impaired work-
     relative to controls, they showed smaller reaction           ing memories (Lee & Park, 2005). The relationship
76   time differences between these sentences and both            between working memory function and syntactic-
     non-violated sentences, e.g. “Every morning for              semantic combinatory processes has been extensively
                                               Chapter 6: Approaches to understanding language dysfunction



discussed in normal language processing (Caplan &        pattern of results: both groups used the dominant
Waters, 1999; Fedorenko et al., 2006), and there is      interpretation. Interestingly, when a biasing context
increasing evidence that the language processing         preceded the homograph, TD patients relative to
system is influenced by top-down executive function      healthy controls and non-TD patients, failed to make
and is therefore more dynamic than has been previ-       use of this information and completed the sentences
ously assumed (Kuperberg, 2007). There is some evi-      according to the contextually inappropriate dominant
dence that impairments on some of the measures           meaning of the homograph.
discussed here are correlated with more general              Titone et al. (2000) also examined the processing
cognitive impairments (this is discussed later in this   of homonyms using a cross-modal priming paradigm
chapter). However, the precise nature and mechan-        and a LD task. Participants listened to prime stimuli
isms of such links remain to be explored.                consisting of homonyms embedded in contexts that
                                                         either moderately or strongly biased towards their
                                                         subordinate meanings. Targets were related to either
Lexical ambiguity                                        the dominant or subordinate meaning of the homo-
Being able to effectively build up and use context       nym. Priming of targets related to the dominant
by combining semantic with syntactic information is      meanings of the homonyms indicated an ability to
particularly important for interpreting words that are   inhibit a prepotent response, as such targets were
lexically ambiguous. Context plays a critical role in    never contextually appropriate. Priming of targets
constraining and selecting the most appropriate          related to the subordinate meanings of the homo-
meaning of such words. One well-studied source of        nyms indicated an ability to build-up and use context.
lexical ambiguity comes from homonyms – words            Healthy adults only showed priming of words related
that sound (homophones) and/or look (homographs)         to the subordinate meanings of the homographs,
the same but have different conceptual representa-       regardless of the strength of the context biasing, sug-
tions. For example, in order to interpret the word       gesting that they were able to inhibit the prepotent
“pen” in the sentence, “When the farmer bought a         response as well as build-up and use context appro-
herd of cattle, he needed a new pen,” one must use       priately. Patients also showed priming of words rela-
the preceding context to inhibit the inappropriate       ted to the subordinate meaning of the homographs
dominant meaning (a writing instrument) and to           under both contextual biasing conditions. However,
select the contextually appropriate subordinate mean-    with a moderately biasing context, the dominant
ing (a place where animals live).                        meaning was also activated, suggesting an inability
    In an early study, Chapman et al. (1964) asked       to inhibit this meaning. When the context strongly
healthy adults and schizophrenia patients to indicate    biased towards the subordinate meaning of the homo-
the meaning (by selecting a response from several        graph, patients were able to inhibit the dominant
choices) of sentences containing homonyms, similar       meaning. Thus, in patients, a strong global context
to the sentence above. Patients were more likely than    was necessary to inhibit local, lexico-semantic
healthy adults to misinterpret homonyms in terms of      associations.
their dominant meanings, suggesting that they failed         Finally, there have been a few recent studies using
to use context to inhibit the prepotent response and     ERPs to study how homographs are processed as
to select the most appropriate meaning (see also         language is built-up online. Using sentences that
Benjamin & Watt, 1969). In a more recent study,          did not include any disambiguating context prior to
Bazin et al. (2000) examined the use of context to       the homonym (e.g. “The toast was sincere”), Salisbury
disambiguate homographs. Participants read senten-       and colleagues demonstrated that patients with
ces containing homographs that were preceded by          schizophrenia were more likely to misinterpret homo-
contexts that biased towards the subordinate meaning     graphs when the correct interpretation of a sentence
of the homograph. In addition, they viewed sentence      required the subordinate meaning. This was reflected
fragments without a biasing context. Resolution of the   by larger N400 amplitude to sentence-final words that
homograph was measured by whether participants           were consistent with a subordinate interpretation
completed sentence fragments according to the dom-       (Salisbury et al., 2000; Salisbury et al., 2002). Taking
inant or subordinate meaning. When no context was        this a step further, Sitnikova et al. (2002) constructed   77
given, both patients and controls showed a similar       sentences that included a disambiguating context
        Section 1: Neuropsychological processes



     prior to the homograph. Specifically, the first clause      asked to interpret the proverb, “Gold goes in at any
     of each sentence biased towards either the domi-            gate except heaven’s,” one patient responded, “There’s
     nant meaning (e.g. “Diving was forbidden from the           jewelry, there’s platinum. They use it on your teeth for
     bridge . . .”) or the subordinate meaning (e.g. “The        filling. There’s gold in churches. There’s gold in the
     guests played bridge . . .”) of a homograph, followed       mosque areas; like Lincoln’s tomb” (example taken
     by a second clause that contained a critical word that      from Harrow & Quinlan, 1985). Consistent with these
     was always semantically associated with the dominant        clinical observations, several studies have indicated
     meaning of the homonym (e.g. “. . . because the river       that schizophrenia patients often choose concrete
     had rocks in it”). As expected, healthy adults pro-         interpretations when asked to interpret figurative
     duced an N400 effect to contextually inappropriate          language (Chapman, 1960; Brune & Bodenstein,
     words (e.g. to “river” when the initial context was         2005; Kiang et al., 2007).
     “The guests played bridge”). Schizophrenia patients,             There have been several investigations using
     however, showed an attenuated N400 effect, sugges-          behavioral and/or ERP measures to test the hypoth-
     ting that they failed to use context to inhibit the         esis that patients are specifically impaired in inhibit-
     dominant meaning of the homograph (“bridge”)                ing the literal meaning of idioms and metaphors
     that primed “river”. Critically, the same patients          during comprehension. Titone et al. (2002) con-
     in the same study showed a normal N400 effect to            ducted a priming experiment in which the priming
     unambiguously contextually incongruous words that,          context constituted idioms with both literal and fig-
     in half the sentences, were introduced towards the          urative meanings (ambiguous idioms, e.g. “kick the
     end of the second clause (e.g. “cracks” in “. . . because   bucket”) or idioms with only figurative meanings
     the river had cracks in it.”). Taken together, these        (non-ambiguous idioms, e.g. “be on cloud nine”).
     findings suggest that patients were able to use some        In healthy controls, the figurative meanings of both
     aspects of context (perhaps the lexico-semantic rela-       types of idioms primed semantically related target
     tionships between individual words), but that they          words (e.g. “death” for the first example, and “elated”
     had specific difficulty in using global context to          for the second example); in addition, the literal mean-
     inhibit contextually inappropriate, dominant mean-          ing of the ambiguous idioms primed semantically
     ings of homographs.                                         related target words (Titone & Connine, 1994). In
                                                                 patients with schizophrenia, however, only non-
                                                                 ambiguous idioms (without literal meanings) were
     Figurative language                                         effective in priming targets that were semantically
     Figurative language is often, by its very nature,           related to their idiomatic meanings; ambiguous
     ambiguous. Proverbs, metaphors and many idioms              idioms only primed targets that were related to their
     have both literal as well as figurative interpretations,    literal meanings, suggesting that a failure to inhibit
     posing a particular challenge to the comprehension          the literal meanings of these idioms prevented
     system to select their most appropriate meaning.            patients’ access to their figurative meanings. Consist-
     Healthy adults very quickly and easily understand           ent findings were reported by Strandburg et al. (1997)
     the meanings of familiar idioms (e.g. Titone &              who measured ERPs as participants judged the mean-
     Connine, 1994). Similarly, most healthy adults are          ingfulness of word-pairs that were idiomatic (“pot
     able to interpret metaphor, although there is some          luck”), literal (“vicious dog”), or that made no sense
     debate over whether both the literal and figura-            (“square wind”). Note that in this experiment all idio-
     tive meanings or only the figurative meanings remain        matic expressions were unambiguous, i.e. no plausible
     active during online processing (e.g. Kintsch, 2000).       literal interpretation was possible. Relative to healthy
         Patients with schizophrenia have particular diffi-      controls, patients took longer to respond and showed
     culties in understanding figurative language. Indeed,       more errors and larger N400 amplitudes to the second
     proverb interpretation is commonly used clinically to       word of the idiomatic, relative to the literal, word-
     assess language and thought disturbances in schizo-         pairs, suggesting that they had particular difficulty in
     phrenia (it constitutes one item on the PANSS; Kay          accessing the figurative meaning of the idioms.
     et al., 1987). Misinterpretations usually take the form          In contrast to these two studies, Iakimova et al.
78   of an over-reliance on the literal meaning, sometimes       (2005) did not find specific impairments in pro-
     triggering semantic associations. For example, when         cessing metaphors in schizophrenia. Healthy adults
                                                   Chapter 6: Approaches to understanding language dysfunction



and schizophrenia patients made meaningfulness               to specific problems in resolving lexical ambiguity
judgments while reading metaphorical, literal and            where context plays a particularly important role in
incongruous sentences. All participants showed a simi-       determining whether the dominant meaning of a
lar pattern of results: incongruous sentences elicited       homonym is inhibited and the subordinate meaning
the most negative N400 amplitudes, followed by a             is appropriately selected. Finally, there is some evi-
medium-sized N400 to literal sentence endings, and           dence that it may lead to specific impairments with
the smallest amplitude N400 to metaphorical endings.         inhibiting contextually inappropriate literal interpre-
However, in schizophrenia patients, there was an over-       tations of figurative expressions (Titone et al., 2002),
all delay in the latency of both the N400 and Late           although others have failed to find such specific def-
Positivity components. In addition, the negativity of        icits (Iakimova et al., 2005).
the N400 was greater and the amplitude of the Late
Positivity was reduced. Thus, the authors concluded          Discourse
that patients are impaired in integrating the semantic
                                                             Language comprehension and production go beyond
context of sentences (both figurative and literal), rather
                                                             accessing the meaning of individual words and com-
than showing a specific deficit in metaphor processing.
                                                             bining this with syntactic structure to build up mean-
    One reason for these discrepancies may be differ-
                                                             ing of sentences. When healthy adults produce and
ences in the symptom profiles of patients participat-
                                                             comprehend language, they are able to integrate ideas
ing in these studies: some researchers have implicated
                                                             across multiple sentences to generate or construct a
delusions as being specifically related to metaphor
                                                             coherent discourse model. This connected discourse
interpretation (Rhodes & Jakes, 2004), whereas others
                                                             has two main properties: cohesion and coherence
have associated poor metaphor comprehension with
                                                             (Halliday & Hasan, 1976; Sanford & Garrod, 1994).
negative symptoms (Langdon & Coltheart, 2004).
                                                             Coherence can be established through linguistic cohe-
                                                             sive devices that specifically link information within
Sentences, ambiguity and figurative                          and across sentences (e.g. “the man,” “he,” “the show-
language: summary and conclusion                             off ” must each be linked to a single referent). In
                                                             addition we must establish logical and psychological
There is now fairly compelling evidence that patients
                                                             consistency between events (e.g. through the gener-
with schizophrenia show impairments in building
                                                             ation of causal inferences).
up sentence context, which leads to unpredictable
                                                                 Clinically, patients with schizophrenia show prom-
speech and also to problems in predicting words within
                                                             inent abnormalities at the level of discourse (Andrea-
speech and text. Although patients appear to be able to
                                                             sen et al., 1995; for reviews, see Covington et al., 2005;
use semantic relationships between individual words
                                                             McKenna & Oh, 2005; Pavy, 1968). Indeed, tangenti-
within sentences to generate some representation of
                                                             ality and derailment – shifts in speech from one topic
meaning (leading to normal N400 effects under many
                                                             to another without obvious links between them – are
circumstance), both behavioral and electrophysio-
                                                             amongst the most common phenomena described in
logical abnormalities are observed when the demands
                                                             thought-disordered speech (Andreasen, 1979a, 1979b;
of combining the meaning of individual words with
                                                             Earle-Boyer et al., 1986; Mazumdar et al., 1995). Below
syntactic structure are high. This occurs at the final
                                                             we review evidence that patients with schizophrenia
word of sentences when comprehenders usually wrap-
                                                             show abnormalities in establishing coherence during
up sentence meaning, in producing and processing
                                                             language production and processing (also see Mitchell
syntactically complex sentences, and in comprehend-
                                                             & Crow, 2005, for a discussion of the potential role of
ing sentences in which semantic relationships between
                                                             the right hemisphere in discourse impairments, and
individual words contradict overall meaning.
                                                             see Ditman & Kuperberg (in press) for a framework
    Many of these abnormalities are evident in
                                                             for exploring the breakdown of links across clause
patients without prominent positive thought disorder,
                                                             boundaries in schizophrenia).
although they may be more marked in thought-
disordered patients. Impairments in building up con-
text may lead to speech that is dominated by semantic        Referential coherence
associative relationships between individual words           In a seminal study, Rochester & Martin (1979) exam-          79
at the expense of whole meaning. It may also lead            ined the use of cohesion markers in the speech
       Section 1: Neuropsychological processes



     produced by patients with schizophrenia. Irrespective    associations, leading to their prolonged, inappropriate
     of thought disorder, schizophrenia patients failed to    influence at later stages of processing.
     use cohesion markers to the same degree as healthy           Finally, there is some intriguing evidence for
     controls and had a tendency to point to (rather than     correlations between referential communication
     verbally identify) referents. However, more specific     measures and performance on neuropsychological
     impairments in the use of cohesion markers did dis-      tasks indexing more general cognitive functions, such
     tinguish between patients with and without thought       as working memory and other executive functions
     disorder. Non-TD schizophrenia patients used fewer       (discussed later in the chapter). This hypothesis could
     indirect references than healthy controls, whereas TD    be further tested in the future using psycholingui-
     patients used more obscure referents and were more       stic paradigms that have been developed in healthy
     likely to refer to information that had not been         individuals to specifically tap into these working
     presented.                                               memory processes (Anderson & Holcomb, 2005;
         Findings of cohesion impairments in schizophre-      Swaab et al., 2004; van Berkum et al., 1999).
     nia have been replicated and described in more detail
     by other researchers (Docherty et al., 1996a; Hoffman
     et al., 1985; Noel-Jorand et al., 1997). For example,    Other types of discourse coherence
     Docherty and colleagues have developed a compre-         One way of examining how patients construct links
     hensive measure that captures a range of referential     between sentences and concepts is to ask them to
     communication failures including vague, confused         describe or recall what they see, read, or hear, and
     and missing references. Interestingly, there is evi-     then transcribe the speech produced and examine its
     dence that some types of referential impairments         discourse structure in detail. Hoffman and colleagues
     are trait markers of schizophrenia. Specifically, this   took this approach and constructed “discourse trees”
     evidence suggests that (1) some types of referential     that depicted relationships between propositions
     impairment are stable over time (Docherty et al.,        within discourse. Normal discourse exhibits a syste-
     2003), and (2) first-degree family members of            matic hierarchical structure in which propositions
     schizophrenia patients have more referential disturb-    branch out from a central proposition. The tran-
     ances than first-degree family members of controls       scripts of psychotic speech showed a more disorgan-
     (Docherty et al., 1998; Docherty & Gottesman,            ized tree structure than that of controls and manic
     2000). On the other hand, in some patients,              patients (Hoffman, 1986; Hoffman et al., 1982).
     these impairments can improve with medication                Another approach was taken in a study by Allen
     (Abu-Akel, 1997).                                        (1984) in which patients were asked to describe pic-
         Although there has been little work to determine     tures and speech transcripts that were decomposed
     whether patients with schizophrenia are specifically     into “ideas” (individual sentences, semantic propos-
     impaired in referential processes (linking anaphors      itions, phrases and words), and then rated them
     to their antecedents) during online language com-        according to whether they were appropriate to the
     prehension, one recent ERP study provides some           picture or inferential. Thought-disordered patients
     neural evidence that, with a sufficiently strong con-    produced significantly fewer inferences than controls,
     text, patients are able to use both semantic and con-    but exhibited a trend towards an increase in the
     textual information to disambiguate anaphors during      number of ideas classified as inappropriate.
     online comprehension, similar to healthy controls            In a more recent study, Leroy et al. (2005) asked
     (Ditman & Kuperberg, 2008). When later asked to          healthy adults and linguistically skilled patients with
     explicitly resolve the anaphors, however, patients       schizophrenia to read a story aloud and then, imme-
     were more likely than controls to erroneously resolve    diately after, to recall its contents. In healthy adults,
     anaphors with contextually inappropriate, but seman-     the discourse macrostructure (the structure related to
     tically related, words. Thus, strong contextual          the global discourse topic) normally functions to con-
     constraints led to discourse-appropriate neural          strain its microstructure (its more detailed structure)
     responses but later decisions were more likely guided    (Kintsch & van Dijk, 1978), so that irrelevant infor-
     by semantic associations. One possible explanation       mation is inhibited and generalizations are made.
80   for this pattern of findings is that patients failed     Although patients generated similar discourse
     to use control mechanisms to suppress such               plans with the same overall numbers of micro- and
                                                  Chapter 6: Approaches to understanding language dysfunction



macro-propositions as controls, they had an increased           Finally, one can examine whether schizophrenia
tendency to connect micro-propositions. This was            patients can construct coherence links between indi-
interpreted as reflecting an impairment in inhibiting       vidual sentences by determining whether they are able
irrelevant information.                                     to benefit from such links when later asked to recall
    Another way of probing the coherence links con-         such sentences. Healthy adults’ ability to recall indi-
structed during discourse comprehension is by exam-         vidual sentences is improved when the encoded
ining the overall content of what is extracted and          material is organized into a coherent discourse, rela-
recalled. In a classic study, Bransford & Franks            tive to when it is presented as random disconnected
(1971) established that healthy adults combine prop-        sentences. Schizophrenia patients fail to show this
ositions to extract an overall “gist.” They presented       improvement in recall (Harvey et al., 1986). These
healthy adults with groups of sentences, e.g. “The ants     findings could not be attributed to poorer general
were in the kitchen. The ants ate the jelly. The jelly      memory performance. In another study, TD patients
was sweet.” On a later memory test, healthy partici-        (a mixed group of mania and schizophrenia patients)
pants misremembered (as measured by confidence              showed superior recall than controls to sentences that
ratings), encoding larger sentences, e.g. “The ant in       were presented in random order during encoding
the kitchen ate the sweet jelly.” In other words, they      (Speed et al., 1991). Schizophrenia patients have
integrated the individual propositions to create a global   also been found to perform worse than controls
representation of the discourse. Knight & Sims-Knight       when asked to organize pictures depicting various
(1979) examined whether patients with schizophrenia         aspects of a story into a coherent discourse (Brune
extracted the gist of a discourse message in a similar      & Bodenstein, 2005).
way. Results suggested that patients with a history             Despite the evidence reviewed above that patients’
of poor (or lower level) functioning (compared with         speech is less coherent than that of controls, and that
controls and patients with good premorbid histories)        they are impaired in their use of coherence links to
were not able to extract the gist. However, a subse-        improve recall of individual sentences, there has been
quent study using the gist paradigm by Grove &              very little work examining whether patients can
Anderson (1985) failed to find group differences            establish coherence links between sentences during
between healthy adults, patients with mania and             online processing. Ditman & Kuperberg (2007) have
schizophrenia patients.                                     some preliminary evidence supporting this hypoth-
    Healthy individuals are not only able to combine        esis; they measured ERPs as patients and healthy
individual propositions to construct an overall gist;       controls read three-sentence discourse scenarios.
they can also extract messages during everyday con-         While healthy controls showed a robust N400 effect
versations, even when normal communication norms            to critical words within congruous sentences that
are violated (i.e. Grice’s maxim; Grice, 1975). In          were completely unrelated and intermediately related
normal conversation, these norms may be violated            with their preceding two-sentence discourse context,
under certain circumstances, requiring the compre-          patients failed to show such N400 effects. This is
hender to infer the intentions of the speaker to fully      interesting as the N400 effect in schizophrenia is
understand the conversation. For example, the res-          often normal to semantic anomalies within single
ponse “Is the Pope Catholic?” to the question “Did          sentences (as described above), and it therefore
Mike get drunk last night?” violates the maxim of           suggests that patients were unable to construct coher-
relevance but indirectly communicates the speaker’s         ence links between sentences and build up global
opinion about Mike’s drinking habits. Importantly,          discourse context.
an inability to draw this inference would lead to a
communication breakdown. Tényi et al. (2002) exam-
ined the ability of paranoid schizophrenia patients         Discourse: summary and conclusion
and healthy adult controls to comprehend conversa-          There is now fairly robust evidence that the speech
tional vignettes in which the maxim of relevance was        of patients with schizophrenia lacks coherence in
flouted. Patients made more errors than controls in         comparison with that produced by healthy controls.
interpreting the true meaning intended by the char-         Patients’ speech lacks normal referential links and has
acters in the vignettes, suggesting an inability to infer   an abnormal discourse structure. In addition, patients    81
communicators’ intentions.                                  fail to benefit from coherent links between sentences
       Section 1: Neuropsychological processes



     to improve recall, although it remains controversial       mechanism for this less “focused” activity may be
     whether they are able to extract the gist of messages.     reduced executive control. In line with this hypoth-
         There has been very little investigation of how        esis, there have been some recent reports of signifi-
     coherence links are established as discourse is built      cant correlations between measures of executive
     up during online processing in schizophrenia.              functioning and semantic priming. In healthy partici-
                                                                pants, Keifer et al. (2005) found that decreased wor-
                                                                king memory capacity was associated with increased
     Relationship between language                              semantic priming, and indirect semantic priming in
     abnormalities and other cognitive                          particular. Poole et al. (1999) administered measures
     dysfunction                                                of executive dysfunction, response inhibition, motor
                                                                coordination and intelligence to patients with schizo-
     Each level of language processing can be influenced
                                                                phrenia, and found that only decreased response
     by cognitive systems and processes that are used in
                                                                inhibition was correlated with increased automatic
     domains other than language, such as attention, work-
                                                                priming (using a short SOA and low RP). Neither
     ing memory and executive function. Given that schi-
                                                                motor dyscoordination nor general intelligence was
     zophrenia is a disorder that affects multiple domains of
                                                                associated with any measures of semantic priming.
     cognitive function, understanding these relationships
                                                                Interestingly, decreased executive functioning was
     will prove essential to understanding language dys-
                                                                associated with diminished controlled semantic
     function in this disorder. Thus far, the approach
                                                                priming, suggesting that different aspects of executive
     taken to understand such links has been to correlate
                                                                function may interact with automatic and controlled
     clinical and psychological measures of language
                                                                mechanisms of priming.
     disturbances with patients’ performance in various
     neuropsychological tasks. Below, we review a selec-
     tion of such studies.                                      Sentences
                                                                Earlier in the chapter we discussed evidence that
                                                                patients with schizophrenia are impaired in compre-
     Thought disorder                                           hending syntactically complex sentences, possibly
     There have now been several studies reporting correl-      because of difficulties in combining semantic with
     ations between positive thought disorder in schizo-        syntactic information to assign thematic roles.
     phrenia and various neuropsychological measures,           Condray et al. (1996) demonstrated that, in both
     including distractibility (Docherty & Gordinier,           patient and control groups, working memory capacity,
     1999; Harvey & Serper, 1990), selective attention as       as measured using a reading span task, predicted
     measured by the Stroop task (Barch et al., 1999),          comprehension accuracy. The authors concluded
     sustained attention as measured by the Continuous          that observed language comprehension deficits may
     Performance Test (Nuecheterlein et al., 1986;              be related to working memory impairments (see
     Pandurangi et al., 1994; Strauss et al., 1993), measures   Bagner et al., 2003, for similar findings; and see
     of executive dysfunction (Nestor et al., 1998) and         Kiang et al., 2007, for similar findings with proverb
     lower-level information processing deficits such as        comprehension).
     prepulse inhibition (Dawson et al., 2000; Perry &
     Braff, 1994). In a recent meta-analysis, Kerns &
     Berenbaum (2002) reported a strong association
                                                                Discourse
     between thought disorders and impaired executive           The most careful documentation of associations bet-
     functioning.                                               ween various measures of clinical and referential
                                                                language disturbances and performance on various
                                                                neuropsychological tasks comes from studies by
     Single words and concepts                                  Docherty and colleagues. This group has focused on
     As discussed earlier in the chapter there is some evi-     their detailed measure of referential coherence during
     dence that, under automatic experimental conditions,       language output (discussed above) and has demon-
     a faster and/or wider spread of activation across          strated associations between referential communica-
82   words within the semantic network may underlie             tion disturbances and poor performance on tasks of
     positive thought disorder in schizophrenia. One            immediate auditory memory (Docherty & Gordinier,
                                                  Chapter 6: Approaches to understanding language dysfunction



1999), auditory distractibility (Docherty & Gordinier,          Given these associations and our understanding
1999; Hotchkiss & Harvey, 1990), working memory             of schizophrenia as a disorder that affects multiple
and attention (Docherty et al., 1996b). In more recent      domains of cognitive function, it becomes particularly
studies, they have confirmed associations between           important to understand how the mechanisms of lan-
referential impairments and performance on tasks            guage dysfunction in schizophrenia interact with these
indexing sustained attention, immediate auditory            systems. The normal language processing system does
memory, and conceptual sequencing (Docherty,                not act in isolation, but is closely linked with working
2005). Moreover, referential communication failures         memory and executive mechanisms. There is increas-
appear to be better predictors of performance on            ing evidence that variation in working-memory func-
sustained attention and sequencing tasks than global        tion may account for individual variability in language
“thought disorder,” as measured using the Thought           function amongst healthy individuals, and researchers
Language and Communication Scale or structural              have developed a number of theories describing the
discourse abnormalities (Docherty, 2005; Docherty           nature of interactions between the language system
et al., 1996b).                                             and cognitive functions in other domains (Caplan &
    Interestingly, a study by the same group demon-         Waters, 1999; Just & Carpenter, 1992). More recently,
strated a more specific association between the fre-        neuroimaging studies have demonstrated overlaps
quency of one specific type of referential failure          in the neural circuitry subserving working memory,
(missing information references) and performance on         semantic memory and language function (Barde &
a source-monitoring task (Nienow & Docherty, 2005).         Thompson-Schill, 2002; Thompson-Schill, 2003). The
The authors hypothesized that missing information           challenge now is to understand the nature of such links
references might arise from the speaker being unable        more precisely so as to determine how they are dis-
to distinguish what they had just thought and what          turbed in disorders such as schizophrenia. This can
they had vocalized aloud. This finding is interesting as    be investigated through studies examining relation-
source memory deficits have been hypothesized to            ships between measures of verbal working memory
underlie other symptoms of schizophrenia such as            and attention that are believed to specifically interact
hallucinations (Ditman & Kuperberg, 2005), and also         with the language system, and patients’ performance
because such deficits have been previously related to       on selected psycholinguistic tasks.
global measures of thought disorder (Harvey, 1985;
Harvey & Serper, 1990) and theoretically linked to
mechanisms of thought disorder (Frith, 1992).               Implications and future directions
                                                            Clinical implications
Language abnormalities and other                            Clinical abnormalities of language and communica-
cognitive dysfunction: summary                              tion in schizophrenia can be very disabling, impacting
                                                            on all aspects of daily living. In schizophrenia, posi-
and conclusions                                             tive thought disorder is a strong predictor of mal-
In sum, there is fairly compelling evidence that clinical   adaptive social and vocational functioning (Harrow &
and cognitive measures of language dysfunction in           Quinlan, 1985; Hoffmann & Kupper, 1997; Norman
schizophrenia can be linked with dysfunction in             et al., 1999). Yet there have been few attempts to
domains other than language. At the word level,             alleviate it via cognitive methods. As reviewed above,
reduced inhibitory control has been associated with         the majority of evidence suggests that there is no
increased semantic priming under conditions which           overall loss of items stored in semantic memory;
bias toward more automatic processing, both in healthy      rather patients seem impaired in accessing and using
controls and patients with schizophrenia. In addition,      items appropriately. Encouragingly, the use of strat-
reduced executive functioning has been related to           egies such as semantic cuing can improve perform-
decreased controlled semantic priming in schizophre-        ance in some semantic tasks, providing some hope
nia patients. At the sentence level, working-memory         that such deficits may be remediable. Cognitive reme-
measures predict comprehension accuracy, while at           diation programs in schizophrenia have thus far
the level of discourse, measures of sustained attention     focused on improving executive, memory and attention       83
and sequencing predict referential impairments.             functions in schizophrenia, and are in their infancy.
       Section 1: Neuropsychological processes



     It is also not clear how far they generalize to improv-    in indirect semantic priming (as assessed by reaction
     ing communication or quality of life. Understanding        time on a speeded lexical decision task) in healthy
     the cognitive basis of language and communication          participants when they were administered 100 mg of
     abnormalities in schizophrenia will allow the develop-     L-dopa. This reduced controlled priming may be due
     ment of more specific strategies for remediation.          to D1/D2 activity; Roesch-Ely reported that pergolide
                                                                (a D1/D2 agonist), but not bromocriptine (a selective
     Implications for understanding brain                       D2 agonist), reduced controlled semantic priming
                                                                within the right hemisphere in healthy individuals
     dysfunction in schizophrenia                               (Roesch-Ely et al. 2006). Reduced controlled priming
     Another major implication of understanding the cog-        has also been reported in healthy individuals in asso-
     nitive basis of language abnormalities in neuro-           ciation with the acute administration of ketamine
     psychiatric disorders is that, in combination with         (an NMDA receptor antagonist leading to increased
     neuroanatomical and neurochemical measures, it             glutamatergic activity) (Morgan et al., 2006). This
     may give new insights into the neurobiology of such        is particularly interesting as the administration of
     disorders as a whole. Functional neuroimaging stud-        ketamine in healthy individuals can lead to clinical
     ies in healthy individuals have established that lan-      language disturbances that are similar to thought
     guage and semantic processing are dependent on             disorder (Adler et al., 1998, 1999).
     activity within a widespread network, distributed par-         It remains unclear how such cognitive, func-
     ticularly across prefrontal, inferior parietal and tem-    tional neuroanatomical, structural neuroanatomical
     poral cortices. Many of the same regions are               and neurochemical findings are related. But it is
     modulated by semantic relationships between indi-          possible that widespread temporal-prefrontal cor-
     vidual words in priming paradigms (Kuperberg               tical thinning may reflect widespread abnormalities
     et al., 2008a; Rossell et al., 2003), sentences (Kuper-    in cortical synaptic function. This could potentially
     berg et al., 2003b, 2008b) and whole discourse             lead to an inappropriate increase in cortical activity
     (Kuperberg et al., 2006b).                                 through specific disruption of inhibitory circuitry,
         In schizophrenia, neuroimaging studies indicate        and in schizophrenia lead to overdependence on
     that many of these regions are abnormally modulated        semantic associative links at the expense of building
     during semantic processing (Kubicki et al., 2003;          up context through normal modulatory activity. For
     Ragland et al., 2004, 2005; Weiss et al., 2003). In a      example, Cohen & Servan-Schreiber (1992, 1993)
     recent study, Kuperberg et al. demonstrated that           have proposed that dopamine modulates the
     patients, relative to controls, showed inappropriate       signal-to-noise ratio in cortical information pro-
     increases in activity within temporal and prefrontal       cessing and have suggested that increased noise in
     cortices to semantically associated (relative to unre-     the activity of the dopamine system leads to abnor-
     lated) word pairs (Kuperberg et al., 2007). At the level   mal “gating” of information into prefrontal cortex,
     of sentences, when integration demands are high,           thereby leading to impairments in both the main-
     patients, relative to controls, show reduced activity      tenance and updating of contextual information
     within the superior dorsolateral prefrontal and par-       (Braver et al., 1999).
     ietal cortices when integration demands were particu-          Such relationships are currently speculative. How-
     larly high (Kuperberg et al., 2008b).                      ever, with the development of theoretically grounded
         In schizophrenia, there is also evidence of subtle     cognitive models of language processing in neuropsy-
     but significant cortical gray matter thinning in many      chiatric disorders, it may be possible to draw more
     of the same temporal and prefrontal regions that           specific links with synaptic and molecular models of
     show functional abnormalities (Kuperberg et al.,           brain dysfunction.
     2003a). Finally, there is some preliminary evidence
     that semantic abnormalities in schizophrenia may
     arise from abnormalities within the dopaminergic           Conclusions
     systems and/or the glutamatergic systems. Increasing       In this review, we have shown how paradigms at the
     dopaminergic and glutamatergic activity can lead to        level of words, sentences and discourse can be used to
84   reduced semantic priming under controlled condi-           study neuropsychiatric disorders, and we have revie-
     tions. Kischka et al. (1996) demonstrated a decrease       wed evidence suggesting that schizophrenia patients
                                                Chapter 6: Approaches to understanding language dysfunction



show deficits at all these levels of the language code.   abnormalities to understand the pathogenesis of such
We are not yet at the point where we can account for      disorders as a whole.
all these abnormalities by postulating a single neuro-
cognitive deficit. However, we can provide a broad        Acknowledgments
theoretical framework to help understand the rela-
                                                          Gina Kuperberg, Tali Ditman and Donna Kreher
tionships between these levels of dysfunction and to
                                                          were supported by NIMH (R01 MH071635). Gina
help pave the way towards future theoretically moti-
                                                          Kuperberg is also supported by NARSAD (with the
vated studies.
                                                          Sidney Baer Trust) and a Claflin Distinguished Scholars
     Abnormalities in semantic memory function and
                                                          Award from Massachusetts General Hospital. We
in building up linguistic context in schizophrenia
                                                          thank Kana Okano for her help with manuscript
have often been viewed as being distinct deficits. We
                                                          preparation.
suggest that they may be functionally related, reflect-
ing two sides of the same coin. For example, in
schizophrenia, patients’ relative dependence on           References
semantic relationships between individual words           American Psychiatric Press (1990). Diagnostic and
may contribute to their impairments in combining            Statistical Manual of Mental Disorders (DSM–IV).
meaning with syntactic structure (see Kuperberg,            Washington, DC: American Psychiatric Press.
2007 for a more theoretical discussion). Under most       Abu-Akel, A. (1997). A study of cohesive patterns and
circumstances, patients’ relatively unimpaired ability      dynamic choices utilized by two schizophrenic patients
                                                            in dialog, pre-and post-medication. Language and
to use semantic relationships between words within
                                                            Speech, 40(4), 331–351.
sentences would lead to an accurate representation of
sentence meaning. However, impairments in combin-         Adams, J., Faux, S. F., Nestor, P. G. et al. (1993). ERP
                                                            abnormalities during semantic processing in
ing syntactic with semantic information to build up         schizophrenia. Schizophrenia Research, 10(3), 247–257.
context could lead to particular problems in selecting
                                                          Adler, C. M., Goldberg, T. E., Malhotra, A. K., Pickar, D. &
the most appropriate meaning of ambiguous words
                                                            Breier, A. (1998). Effects of ketamine on thought
(e.g. homonyms) and expressions (e.g. metaphor or           disorder, working memory, and semantic memory
ambiguous idioms). It could also lead to significant        in healthy volunteers. Biological Psychiatry, 43(11),
problems at the level of discourse, where the build-up      811–816.
of an overall representation of meaning of each sen-      Adler, C. M., Malhotra, A. K., Elman, I. et al. (1999).
tence is critical to the generation of coherent links       Comparison of ketamine-induced thought disorder
between sentences.                                          in healthy volunteers and thought disorder in
     Such impairments might account for the clinical        schizophrenia. American Journal of Psychiatry,
observation that the meaning of sentences tends to          156(10), 1646–1649.
be driven by semantic relationships between individ-      Allen, H. A. (1984). Positive and negative symptoms and the
ual words, whilst the meaning of discourse tends to          thematic organisation of schizophrenic speech. British
be driven by the meaning of individual sentences,            Journal of Psychiatry, 144, 611–617.
i.e. that local context tends to inappropriately over-    Allen, H. A. & Frith, C. D. (1983). Selective retrieval and free
ride the build-up of global context in schizophrenia.        emission of category exemplars in schizophrenia. British
                                                             Journal of Psychology, 74(4), 481–490.
The real challenge to researchers of language dysfunc-
tion in neuropsychiatric disorders is to define           Allen, H. A., Liddle, P. F. & Frith, C. D. (1993). Negative
the nature of these global-local contextual interac-         features, retrieval processes and verbal fluency in
                                                             schizophrenia. British Journal of Psychiatry, 163,
tions more precisely in relation to psycholinguistic
                                                             769–775.
models of normal language processing, and to under-
                                                          Aloia, M. S., Gourovitch, M. L., Missar, D. et al. (1998).
stand the mechanisms by which they are impacted
                                                             Cognitive substrates of thought disorder, II: specifying a
upon by working memory, attentional, and executive           candidate cognitive mechanism. American Journal of
dysfunction. Tackling these questions seems well             Psychiatry, 155(12), 1677–1684.
worth our while as it has major implications              Aloia, M. S., Gourovitch, M. L., Weinberger, D. R. &
for how we attempt to treat such language and                Goldberg, T. E. (1996). An investigation of semantic
communication disorders, as well as for linking              space in patients with schizophrenia. Journal of the            85
between cognitive, neuroanatomical and neurochemical         International Neuropsychology Society, 2(4), 267–273.
        Section 1: Neuropsychological processes



     Anand, A., Wales, R. J., Jackson, H. J. & Copolov, D. L.        Bearden, C. E., Glahn, D. C., Monkul, E. S. et al. (2006a).
       (1994). Linguistic impairment in early psychosis. Journal        Sources of declarative memory impairment in
       of Nervous and Mental Diseases, 182(9), 488–493.                 bipolar disorder: mnemonic processes and
     Anderson, J. & Holcomb, P. (2005). An electrophysiological         clinical features. Journal of Psychiatric Research, 40,
       investigation of the effects of coreference on word              47–58.
       repetition and synonymy. Brain and Language, 94,              Bearden, C. E., Glahn, D. C., Monkul, E. S. et al. (2006b).
       200–216.                                                         Patterns of memory impairment in bipolar disorder and
     Anderson, J. R. (1983). A spreading activation theory of           unipolar major depression. Psychiatry Research, 142,
       memory. Journal of Verbal Learning and Verbal                    139–150.
       Behaviour, 22, 261–295.                                       Becker, C. A. (1980). Semantic context effects in visual word
     Andreasen, N. C. (1979a). Thought, language and                    recognition. Memory and Cognition, 8, 493–512.
       communication disorders: I. Clinical assessment,              Benjamin, T. B. & Watt, N. F. (1969). Psychopathology and
       definition of terms, and evaluation of their reliability.       semantic interpretation of ambiguous words. Journal of
       Archives of General Psychiatry, 36, 1315–1321.                  Abnormal Psychology, 74(6), 706–714.
     Andreasen, N. C. (1979b). Thought, language and                 Bentin, S., McCarthy, G. & Wood, C. C. (1985).
       communication disorders. II. Diagnostic significance.           Event-related potentials, lexical decision and semantic
       Archives of General Psychiatry, 36, 1325–1330.                  priming. Electroencephalography and Clinical
     Andreasen, N. C., Arndt, S., Alliger, R., Miller, D. &            Neurophysiology, 60, 343–355.
       Flaum, M. (1995). Symptoms of schizophrenia. Methods,         Besche, C., Passerieux, C., Segui, J. et al. (1997). Syntactic
       meanings, and mechanisms. Archives of General                    and semantic processing in schizophrenic patients
       Psychiatry, 52(5), 341–351.                                      evaluated by lexical-decision tasks. Neuropsychology,
     Andrews, S., Shelley, A., Ward, P. B. et al. (1993). Event-        11, 498–505.
       related potential indices of semantic processing in           Besche-Richard, C., Passerieux, C. & Hardy-Bayle, M. C.
       schizophrenia. Biological Psychiatry, 34, 443–458.               (2005). Double-decision lexical tasks in
     Bagner, D. M., Melinder, M. R. & Barch, D. M. (2003).              thought-disordered schizophrenic patients: a path
        Language comprehension and working memory                       towards cognitive remediation? Brain and Language,
        language comprehension and working memory deficits              95(3), 395–401.
        in patients with schizophrenia. Schizophrenia Research,
                                                                     Blaney, P. H. (1974). Two studies on the language behavior
        60(2–3), 299–309.
                                                                        of schizophrenics. Journal of Abnormal Psychology, 83,
     Balota, D. A. & Lorch, Jr., R. F. (1986). Depth of automatic       23–31.
        spreading activation: Mediated priming effects in
                                                                     Bleuler, E. (1911/1950). Dementia Praecox, or the Group
        pronunciation but not in lexical decision. Journal of
                                                                        of Schizophrenias. New York, NY: International
        Experimental Psychology: Learning, Memory, and
                                                                        Universities Press.
        Cognition, 12, 336–345.
                                                                     Blum, N. A. & Freides, D. (1995). Investigating thought
     Barch, D. M., Cohen, J. D., Servan-Schreiber, D. et al.
                                                                        disorder in schizophrenia with the lexical decision task.
        (1996). Semantic priming in schizophrenia: an
                                                                        Schizophrenia Research, 16(3), 217–224.
        examination of spreading activation using word
        pronunciation and multiple SOAs. Journal of                  Bobes, M. A., Lei Xiao, Z., Ibanez, S., Yi, H. &
        Abnormal Psychology, 105, 592–601.                             Valdes-Sosa, M. (1996). Semantic matching of pictures
                                                                       in schizophrenia: A cross-cultural ERP study. Biological
     Barch, D. M., Carter, C. S., Perlstein, W. et al. (1999).
                                                                       Psychiatry, 40, 189–202.
        Increased Stroop facilitation effects in schizophrenia are
        not due to increased automatic spreading activation.         Bokat, C. E. & Goldberg, T. E. (2003). Letter and category
        Schizophrenia Research, 39(1), 51–64.                          fluency in schizophrenic patients: a meta-analysis.
                                                                       Schizophrenia Research, 64(1), 73–78.
     Barde, L. H. & Thompson-Schill, S. L. (2002). Models of
        functional organization of the lateral prefrontal cortex     Bransford, J. D. & Franks, J. J. (1971). The abstraction of
        in verbal working memory: evidence in favor of the              linguistic ideas. Cognitive Psychology, 2, 331–350.
        process model. Journal of Cognitive Neuroscience, 14(7),     Braver, T. S., Barch, D. M. & Cohen, J. D. (1999). Cognition
        1054–1063.                                                      and control in schizophrenia: a computational model of
     Bazin, N., Perruchet, P., Hardy-Bayle, M. C. & Feline, A.          dopamine and prefrontal function. Biological Psychiatry,
        (2000). Context-dependent information processing in             46(3), 312–328.
        patients with schizophrenia. Schizophrenia Research,         Brune, M. & Bodenstein, L. (2005). Proverb comprehension
86      45(1–2), 93–101.                                                reconsidered – ‘theory of mind’ and the pragmatic use
                                                       Chapter 6: Approaches to understanding language dysfunction



   of language in schizophrenia. Schizophrenia Research,          Cohen, J. D. & Servan-Schreiber, D. (1993). A theory
   75(2–3), 233–239.                                                of dopamine function and its role in cognitive
Cameron, N. (1939). Schizophrenic thinking in a                     deficits in schizophrenia. Schizophrenia Bulletin, 19(1),
  problem-solving situation. Journal of Mental Science,             85–104.
  85, 1012–1035.                                                  Cohen, J. R., Elvevaag, B. & Goldberg, T. E. (2005).
Cameron, N. (1964). Experimental analysis of                        Cognitive control and semantics in schizophrenia: an
  schizophrenia thinking. In J. Kasanin (Ed.), Language             integrated approach. American Journal of Psychiatry,
  and Thought in Schizophrenia (pp. 50–63). Berkeley,               162(10), 1969–1971.
  CA: University of California Press.                             Collins, A. M. & Loftus, E. F. (1975). A spreading activation
Cannon, M., Caspi, A., Moffitt, T. E. et al. (2002). Evidence       theory of semantic processing. Psychological Review, 82,
  for early-childhood, pan-developmental impairment                 407–428.
  specific to schizophreniform disorder: results from a           Condray, R., Siegle, G. J., Cohen, J. D., van Kammen,
  longitudinal birth cohort. Archives of General Psychiatry,        D. P. & Steinhauer, S. R. (2003). Automatic activation of
  59(5), 449–456.                                                   the semantic network in schizophrenia: evidence from
Caplan, D. & Waters, G. S. (1999). Verbal working memory            event-related brain potentials. Biological Psychiatry,
  and sentence comprehension. Behavior and Brain                    54(11), 1134–1148.
  Sciences, 22(1), 77–94; discussion 95–126.                      Condray, R., Steinhauer, S. R., Cohen, J. D., van Kammen,
Carpenter, M. D. (1976). Sensitivity to syntactic structure:        D. P. & Kasparek, A. (1996). Working memory capacity
  Good versus poor premorbid schizophrenics. Journal                predicts language comprehension in schizophrenic
  of Abnormal Psychology, 85, 41–50.                                patients. Schizophrenia Research, 20(1–2), 1–13.
Chaika, E. (1974). A linguist looks at ‘schizophrenic’            Condray, R., Steinhauer, S. R., Cohen, J. D., van Kammen,
  language. Brain and Language, 1, 257–276.                         D. P. & Kasparek, A. (1999). Modulation of language
                                                                    processing in schizophrenia: effects of context and
Chapin, K., Vann, L. E., Lycaki, H., Josef, N. & Meyendorff, E.
                                                                    haloperidol on the event-related potential. Biological
  (1989). Investigation of the associative network in
                                                                    Psychiatry, 45(10), 1336–1355.
  schizophrenia using the semantic priming paradigm.
  Schizophrenia Research, 2, 355–360.                             Condray, R., Steinhauer, S. R., Cohen, J. D., van Kammen,
Chapman, L. J. (1960). Confusion of figurative and literal          D. P. & Kasparek, A. (2002). The language system in
  usages of words by schizophrenics and brain damaged               schizophrenia: effects of capacity and linguistic
  patients. Journal of Abnormal Social Psychology,                  structure. Schizophrenia Bulletin, 28(3), 475–90.
  60, 412–416.                                                    Coulson, S., King, J. & Kutas, M. (1998). Expect the
Chapman, L. J., Chapman, J. P. & Miller, G. A. (1964).              unexpected: Event-related brain responses to
  A theory of verbal behaviour in schizophrenia. Progress           morphosyntactic violations. Language and Cognitive
  in Experimental Personality Research, 1, 49–77.                   Processes, 13, 21–58.
Chen, E. Y. H., Wilkins, A. J. & McKenna, P. J. (1994).           Covington, M. A., He, C., Brown, C. et al. (2005).
  Semantic memory is both impaired and anomalous in                 Schizophrenia and the structure of language: the
  schizophrenia. Psychological Medicine, 24, 193–202.               linguist’s view. Schizophrenia Research, 77(1), 85–98.
Chenery, H. J., Copland, D. A., McGrath, J. & Savage, G.          Craik, F. & Lockhart, R. (1971). Levels of processing: a
  (2004). Maintaining and updating semantic context                  framework for memory research. Journal of Verbal
  in schizophrenia: an investigation of the effects of               Learning and Verbal Behavior, 11, 671–684.
  multiple remote primes. Psychiatry Research, 126(3),            Davidson, M., Harvey, P., Welsh, K. A. et al. (1996).
  241–252.                                                          Cognitive functioning in late-life schizophrenia: a
Chwilla, D. J. & Kolk, H. H. (2002). Three-step priming in          comparison of elderly schizophrenic patients and
  lexical decision. Memory and Cognition, 30(2), 217–225.           patients with Alzheimer’s disease. American Journal
                                                                    of Psychiatry, 153(10), 1274–1279.
Clare, L., McKenna, P. J., Mortimer, A. M. & Baddeley, A. D.
   (1993). Memory in schizophrenia: what is impaired              Dawson, M. E., Schell, A. M., Hazlett, E. A., Nuechterlein,
   and what is preserved? Neuropsychologia, 31(11),                 K. H. & Filion, D. L. (2000). On the clinical and cognitive
   1225–1241.                                                       meaning of impaired sensorimotor gating in
Cohen, J. D. & Servan-Schreiber, D. (1992). Context, cortex,        schizophrenia. Psychiatry Research, 96(3), 187–197.
  and dopamine: a connectionist approach to behaviour             de Silva, W. P. & Hemsley, D. R. (1977). The influence
  and biology in schizophrenia. Psychological Review,                of context on language perception in schizophrenia. British
  99(1), 45–77.                                                      Journal of Social and Clinical Psychology, 16(4), 337–345.    87
        Section 1: Neuropsychological processes



     Deckersbach, T., Savage, C. R., Dougherty, D. D. et al.           schizophrenic patients. Journal of Nervous and Mental
       (2005). Spontaneous and directed application of verbal          Diseases, 186(12), 761–768.
       learning strategies in bipolar disorder and obsessive-       Donchin, E. & Coles, M. G. H. (1988). Is the P300
       compulsive disorder. Bipolar Disorder, 7(2), 166–175.          component a manifestation of context updating?
     Deckersbach T., Savage, C. R., Reilly-Harrington, N. et al.      Behavior and Brain Sciences, 11, 355–372.
       (2004). Episodic memory impairment in bipolar                Done, D. J., Leinoneen, E., Crow, T. J. & Sacker, A. (1998).
       disorder and obsessive-compulsive disorder: the role           Linguistic performance in children who develop
       of memory strategies. Bipolar Disorder, 6, 233–244.            schizophrenia in adult life. Evidence for normal syntactic
     Ditman, T. & Kuperberg, G. R. (2005). A source-monitoring        ability. British Journal of Psychiatry, 172, 130–135.
        account of auditory verbal hallucinations in patients
                                                                    Earle-Boyer, E. A., Levinson, J. C., Grant, R. & Harvey, P. D.
        with schizophrenia. Harvard Review of Psychiatry, 13(5),
                                                                       (1986). The consistency of thought disorder in mania
        280–299.
                                                                       and schizophrenia. II. An assessment at consecutive
     Ditman, T. & Kuperberg, G. R. (2007). The time course             admissions. Journal of Nervous and Mental Diseases,
        of building global coherence in schizophrenia: an              174(8), 443–447.
        electrophysiological investigation. Psychophysiology,
                                                                    Elvevaag, B., Fisher, J. E., Gurd, J. M. & Goldberg, T. E.
        44, 991–1001.
                                                                       (2002a). Semantic clustering in verbal fluency:
     Ditman, T. & Kuperberg, G. R. (2008). An ERP examination          schizophrenic patients versus control participants.
        of lexico-semantic and contextual influences across            Psychological Medicine, 32(5), 909–917.
        sentence boundaries in schizophrenia. Poster presented
                                                                    Elvevaag, B., Weickert, T., Wechsler, M. et al. (2002b). An
        at the 15th Annual Meeting of the Cognitive
                                                                       investigation of the integrity of semantic boundaries in
        Neuroscience Society (Abstract B41).
                                                                       schizophrenia. Schizophrenia Research, 53(3), 187–198.
     Ditman, T. & Kuperberg, G. R. (2009). Building coherence:
                                                                    Elvevaag, B., Foltz, P. W., Weinberger, D. R. & Goldberg,
        a framework for exploring the breakdown of links across
                                                                       T. E. (2007). Quantifying incoherence in speech: an
        clause boundaries in schizophrenia. Journal of Neuro-
                                                                       automated methodology and novel application to
        linguistics. In press.
                                                                       schizophrenia. Schizophrenia Research, 93(1–3):
     Docherty, N. M. (2005). Cognitive impairments and                 304–316.
       disordered speech in schizophrenia: thought disorder,
       disorganization, and communication failure                   Faber, R. & Reichstein, M. B. (1981). Language dysfunction
       perspectives. Journal of Abnormal Psychology, 114(2),           in schizophrenia. British Journal of Psychiatry, 139,
       269–278.                                                        519–522.
     Docherty, N. M., Cohen, A. S., Nienow, T. M., Dinzeo,          Fedorenko, E., Gibson, E. & Rohde, D. (2006). The nature of
       T. J. & Dangelmaier, R. E. (2003). Stability of formal          working memory capacity in sentence comprehension.
       thought disorder and referential communication                  Journal of Memory and Language, 54, 541–553.
       disturbances in schizophrenia. Journal of Abnormal           Feinstein, A., Goldberg, T. E., Nowlin, B. & Weinberger,
       Psychology, 112(3), 469–475.                                    D. R. (1998). Types and characteristics of remote
     Docherty, N. M., DeRosa, M. & Andreasen, N. C.                    memory impairment in schizophrenia. Schizophrenia
       (1996a). Communication disturbances in schizophrenia            Research, 30(2), 155–163.
       and mania. Archives of General Psychiatry, 53(4), 358–364.   Fodor, J. A. & Bever, T. G. (1965). The psychological reality
     Docherty, N. M. & Gordinier, S. W. (1999). Immediate             of linguistic segments. Journal of Verbal Learning and
       memory, attention and communication disturbances in            Verbal Behavior, 4, 414–420.
       schizophrenia patients and their relatives. Psychological    Ford, J. M. (1999). Schizophrenia: the broken P300 and
       Medicine, 29(1), 189–197.                                       beyond. Psychophysiology, 36(6), 667–682.
     Docherty, N. M. & Gottesman, II (2000). A twin study of        Frazier, L. & Rayner, K. (1982). Making and correcting
       communication disturbances in schizophrenia. Journal            errors during sentence comprehension: eye movements
       of Nervous and Mental Diseases, 188(7), 395–401.                in the analysis of structurally-ambiguous sentences.
                                                                       Cognitive Psychology, 14, 178–210.
     Docherty, N. M., Hawkins, K. A., Hoffman, R. E.
       et al. (1996b). Working memory, attention, and               Frith, C. D. (1992). The Cognitive Neuropsychology of
       communication disturbances in schizophrenia. Journal            Schizophrenia. Hove, UK: Lawrence Erlbaum Associates.
       of Abnormal Psychology, 105(2), 212–219.                     Friedman, D., Simson, R., Ritter, W. & Rapin, I. (1975).
     Docherty, N. M., Rhinewine, J. P., Labhart, R. P. &               The late positive component (P300) and information
       Gordinier, S. W. (1998). Communication disturbances             processing in sentences. Electroencephalography and
88     and family psychiatric history in parents of                    Clinical Neurophysiology, 38, 255–262.
                                                       Chapter 6: Approaches to understanding language dysfunction



Fuller, R., Nopoulos, P., Arndt, S. et al. (2002).                Harvey, P. D. (1985). Reality monitoring in mania and
   Longitudinal assessment of premorbid cognitive                   schizophrenia: the association of thought disorder and
   functioning in patients with schizophrenia through               performance. Journal of Nervous and Mental Diseases,
   examination of standardized scholastic test                      173, 67–73.
   performance. American Journal of Psychiatry, 159(7),           Harvey, P. D. & Serper, M. R. (1990). Linguistic and
   1183–1189.                                                       cognitive failures in schizophrenia. Journal of Nervous
Garrett, M., Bever, T. G. & Fodor, J. (1966). The active use        and Mental Disease, 178, 487–493.
  of grammar in speech perception. Perception and                 Harvey, P. D., Earle-Boyer, E. A. & Wielgus, M. S. (1984).
  Psycholinguistics, 1, 30–32.                                      The consistency of thought disorder in mania and
Gold, J. M., Randolph, C. et al. (1992). Forms of memory            schizophrenia. An assessment of acute psychotics. Journal
  failure in schizophrenia. Journal of Abnormal Psychology,         of Nervous and Mental Diseases, 172(8), 458–463.
  101(3), 487–494.                                                Harvey, P. D., Earle-Boyer, E. A., Wielgus, M. S. & Levinson,
Goldberg, T. E., Aloia, M. S., Gourovitch, M. L. et al. (1998).     J. C. (1986). Encoding, memory, and thought disorder in
  Cognitive substrates of thought disorder, I: the                  schizophrenia and mania. Schizophrenia Bulletin, 12,
  semantic system. American Journal of Psychiatry,                  252–261.
  155(12), 1671–1676.                                             Henik, A., Nissimov, E., Priel, B. & Umansky, R. (1995).
Goldberg, T. E., Dodge, M., Aloia, M., Egan, M. F. &                Effects of cognitive load on semantic priming in patients
  Weinberger, D. R. (2000). Effects of neuroleptic                  with schizophrenia. Journal of Abnormal Psychology,
  medications on speech disorganization in                          104, 576–584.
  schizophrenia: biasing associative networks                     Henik, A., Priel, B. & Umansky, R. (1992). Attention and
  towards meaning. Psychological Medicine, 30(5),                   automaticity in semantic processing of schizophrenic
  1123–1130.                                                        patients. Neuropsychiatry, Neuropsychology and
                                                                    Behavioural Neurology, 5, 161–169.
Goldstein, K. (1944). Methodological approach to the
  study of schizophrenic thought disorder. In J. Kasanin          Hoff, A. L., Sakuma, M., Wieneke, M. et al. (1999).
  (Ed.), Language and Thought in Schizophrenia                      Longitudinal neuropsychological follow-up study of
  (pp. 17–40). Berkeley, CA: University of California               patients with first-episode schizophrenia. American
  Press.                                                            Journal of Psychiatry, 156(9), 1336–1341.
Gourovitch, M. L., Goldberg, T. E. & Weinberger, D. R.            Hoffmann, H. & Kupper, Z. (1997). Relationships between
  (1996). Verbal fluency deficits in patients with                  social competence, psychopathology and work
  schizophrenia: semantic fluency is differentially                 performance and their predictive value for vocational
  impaired as compared with phonologic fluency.                     rehabilitation of schizophrenic outpatients.
  Neuropsychology, 10(4), 573–577.                                  Schizophrenia Research, 23(1), 69–79.
Grice, P. (1975). Logic and Conversation. New York, NY:           Hoffman, R. E. (1986). Tree structures, the work of
   Academic Press.                                                  listening, and schizophrenic discourse: a reply to
                                                                    Beveridge and Brown. Brain and Language, 27(2),
Grillon, C., Rezvan, A. & Glazer, W. M. (1991). N400 and            385–392.
   semantic categorization in schizophrenia. Biological
   Psychiatry, 29, 467–480.                                       Hoffman, R. E., Hogben, G. L., Smith, H. & Calhoun, W. F.
                                                                    (1985). Message disruptions during syntactic processing
Grove, W. M. & Andreasen, N. C. (1985). Language and                in schizophrenia. Journal of Community Disorders, 18(3),
  thinking in psychosis: is there an input abnormality?             183–202.
  Archives of General Psychiatry, 42, 26–32.
                                                                  Hoffman, R. E., Kirstein, L., Stopek, S. & Cicchetti, D. V.
Gurd, J. M., Elvevaag, B. & Cortina-Borja, M. (1997).               (1982). Apprehending schizophrenic discourse: a
  Semantic category word search impairment in                       structural analysis of the listener’s task. Brain and
  schizophrenia. Cognitive Neuropsychiatry, 2, 291–302.             Language, 15(2), 207–233.
Halliday, M. & Hasan, R. (1976). Cohesion in English.             Hokama, H., Hiramatsu, K., Wang, J., O’Donnell, B. F. &
  London: Longman.                                                  Ogura, C. (2003). N400 abnormalities in unmedicated
Harrow, M. & Quinlan, D. M. (1985). Disordered Thinking             patients with schizophrenia during a lexical decision
  and Schizophrenic Psychopathology. New York, NY:                  task. International Journal of Psychophysiology, 48(1),
  Gardner.                                                          1–10.
Hart, D. S. & Payne, R. W. (1973). Language structure and         Holcomb, P. J. (1993). Semantic priming and stimulus
  predictability in overinclusive patients. British Journal of      degradation: implications for the role of the N400 in
  Psychiatry, 123(577), 643–652.                                    language processing. Psychophysiology, 30, 47–61.             89
        Section 1: Neuropsychological processes



     Honigfeld, G. (1963). The ability of schizophrenics to           Kintsch, W. & van Dijk, T. (1978). Toward a model of
       understand normal, psychotic and pseudo-psychotic                 text comprehension and production. Psychological
       speech. Diseases of the Nervous System, 24, 692–694.              Review, 85(5), 363–394.
     Hotchkiss, A. P. & Harvey, P. D. (1990). Effect of distraction   Kischka, U., Kammer, T., Maier, S. et al. (1996).
       on communication failures in schizophrenic patients.              Dopaminergic modulation of semantic network
       American Journal of Psychiatry, 147(4), 513–515.                  activation. Neuropsychologia, 34(11), 1107–1113.
     Iakimova, G., Passerieux, C., Laurent, J. P. & Hardy-Bayle,      Knight, R. A. & Sims-Knight, J. E. (1979). Integration of
        M. C. (2005). ERPs of metaphoric, literal, and                  linguistic ideas in schizophrenics. Journal of Abnormal
        incongruous semantic processing in schizophrenia.               Psychology, 88(2), 191–202.
        Psychophysiology, 42(4), 380–390.                             Koh, S. D. & Kayton, L. (1974). Memorization of
     Iddon, J. L., McKenna, P. J., Sahakian, B. J. & Robbins, T. W.     “unrelated” word strings by young nonpsychotic
        (1998). Impaired generation and use of strategy in              schizophrenics. Journal of Abnormal Psychology,
        schizophrenia: evidence from visuospatial and verbal            83(1), 14–22.
        tasks. Psychological Medicine, 28(5), 1049–1062.              Koh, S. D., Kayton, L. & Berry, R. (1973). Mnemonic
     Jung, C. G. (1981). Reaction time ratio in the association         organization in young nonpsychotic schizophrenics.
        experiment. In H. Read, M. Forman & G. Alder (Eds.),            Journal of Abnormal Psychology, 81(3), 299–310.
        The Collected Works of C. G. Jung (pp. 227–265).              Kostova, M., Passerieux, C., Laurent, J. P. & Hardy-Bayle,
        Princeton, NJ: Princeton University Press.                      M. C. (2003). An electrophysiologic study: can
     Just, M. A. & Carpenter, P. A. (1992). A capacity theory of        semantic context processes be mobilized in patients with
        comprehension: individual differences in working                thought-disordered schizophrenia? Canadian Journal of
        memory. Psychological Review, 99(1), 122–149.                   Psychiatry, 48(9), 615–623.
     Kay, S. R., Fiszbein, A. & Opler, L. A. (1987). The positive     Kostova, M., Passerieux, C., Laurent, J. P. & Hardy-Bayle,
       and negative syndrome scale (PANSS) for schizophrenia.           M. C. (2005). N400 anomalies in schizophrenia are
       Schizophrenia Bulletin, 13(2), 261–276.                          correlated with the severity of formal thought disorder.
     Keifer, M., Ahlegian, M. & Spitzer, M. (2005). Working             Schizophrenia Research, 78(2–3), 285–291.
        memory capacity, indirect semantic priming, and stroop        Koyama, S., Hokama, H., Miyatani, M. et al. (1994). ERPs in
        interference: patterns of interindividual prefrontal            schizophrenic patients during word recognition task and
        performance differences in healthy volunteers.                  reaction times. Electroencephalography and Clinical
        Neuropsychology, 19(3), 332–344.                                Neurophysiology, 92, 546–554.
     Kerns, J. G. & Berenbaum, H. (2002). Cognitive                   Koyama, S., Nageishi, Y., Shimokochi, M. et al. (1991).
       impairments associated with formal thought disorder in           The N400 component of event-related potentials in
       people with schizophrenia. Journal of Abnormal                   schizophrenic patients: a preliminary study.
       Psychology, 111(2), 211–224.                                     Electroencephalography and Clinical Neurophysiology,
     Kiang, M., Kutas, M., Light, G. A. & Braff, D. L. (2008) An        78, 124–132.
        event-related brain potential study of direct and indirect    Kraepelin, E. (1971). Dementia Praecox and Paraphrenia.
        semantic priming in schizophrenia. American Journal of          New York, NY: Krieger.
        Psychiatry, 165, 74–81.                                       Kravariti, E., Dixon, T., Frith, C. Murray, R. & McGuire, P.
     Kiang, M., Light, G. A., Prugh, J. et al. (2007). Cognitive,       (2005). Association of symptoms and executive function
        neurophysiological, and functional correlates of                in schizophrenia and bipolar disorder. Schizophrenia
        proverb interpretation abnormalities in schizophrenia.          Research, 74(2–3), 221–231.
        Journal of the International Neuropsychological Society,      Kreher, D. A., Holcomb, P. J., Goff, D. & Kuperberg, G. R.
        13, 653–663.                                                     (2008). Neural evidence for faster and further automatic
     Kiefer, M., Weisbrod, M., Kern, I., Maier, S. & Spitzer, M.         spreading activation in schizophrenic thought disorder.
        (1998). Right hemisphere activation during indirect              Schizophrenia Bulletin, 34, 473–482.
        semantic priming: evidence from event-related                 Kreher, D. A., Goff, D. C. & Kuperberg, G. R. (2009). Why
        potentials. Brain and Language, 64(3), 377–408.                  all the confusion? Experimental task explains discrepant
     Kintsch, W. (1968). Recognition and free recall of organised        semantic priming effects in schizophrenia under
        lists. Journal of Experimental Psychology General, 78,           “automatic” conditions: evidence from event-related
        481–487.                                                         potentials. Schizophrenia Research, 111, 174–181.
     Kintsch, W. (2000). Metaphor comprehension: a                    Kreher, D. A., Holcomb, P. J. & Kuperberg, G. R. (2006). An
90      computational theory. Psychonometric Bulletin                    electrophysiological investigation of indirect semantic
        Review, 7(2), 257–266.                                           priming. Psychophysiology, 43, 550–563.
                                                     Chapter 6: Approaches to understanding language dysfunction



Kremen, W. S., Seidman, L. J., Faraone, S. V. & Tsuang,        Kuperberg, G. R., McGuire, P. K. & David, A. (2000).
   M. T. (2003). Is there disproportionate impairment            Sensitivity to linguistic anomalies in spoken sentences:
   in semantic or phonemic fluency in schizophrenia?             a case study approach to understanding thought
   Journal of the International Neuropsychological Society,      disorder in schizophrenia. Psychological Medicine,
   9(1), 79–88.                                                  30(2), 345–357.
Kubicki, M., McCarley, R. W., Nestor, P. G. et al. (2003).     Kuperberg, G. R., Sitnikova, T., Caplan, D. & Holcomb, P. J.
  An fMRI study of semantic processing in men with               (2003c). Electrophysiological distinctions in
  schizophrenia. Neuroimage, 20(4), 1923–1933.                   processing conceptual relationships within
Kuperberg, G. R. (2007). Neural mechanisms of language           simple sentences. Cognitive Brain Research, 17(1),
  comprehension: challenges to syntax. Brain Research            117–129.
  (Special Issue, Mysteries of Meaning), 1146, 23–49.          Kuperberg, G. R., Sitnikova, T., Goff, D. & Holcomb, P. J.
Kuperberg, G. R. (2009). What can studying language tell us      (2006d). Making sense of sentences in schizophrenia:
  about schizophrenia (and vice versa)? Language and             electrophysiological evidence for abnormal
  Linguistics Compass. In preparation.                           interactions between semantic and syntactic
Kuperberg, G. R., Broome, M. R., McGuire, P. K. et al.           processing. Journal of Abnormal Psychology, 115(2),
  (2003a). Regionally localized thinning of the cerebral         243–256.
  cortex in schizophrenia. Archives of General Psychiatry,     Kuperberg, G. R., West, W. C., Lakshmanan, B. M. & Goff,
  60(9), 878–888.                                                D. C. (2008b). fMRI reveals neuroanatomical
Kuperberg, G., Caplan, D., Sitnikova, T., Eddy, M. &             dissociations during semantic integration in
  Holcomb, P. (2006a). Neural correlates of processing           schizophrenia. Biological Psychiatry, 64, 407–418.
  syntactic, semantic and thematic relationships in            Kutas, M. & Hillyard, S. A. (1980). Reading senseless
  sentences. Language and Cognitive Processes, 21(5),            sentences: brain potentials reflect semantic incongruity.
  489–530.                                                       Science, 207, 203–205.
Kuperberg, G., Deckersbach, T., Holt, D., Goff, D. & West,     Kutas, M. & Hillyard, S. A. (1984). Brain potentials during
  W. C. (2007a). Increased temporal and prefrontal               reading reflect word expectancy and semantic
  activity to semantic associations in schizophrenia.            association. Nature, 307, 161–163.
  Archives of General Psychiatry, 64, 138–151.
                                                               Landauer, T. K., Foltz, P. W. & Dumais, S. T. (1998).
Kuperberg, G. R., Holcomb, P. J., Sitnikova, T. et al.            Introduction to latent semantic analysis. Discourse
  (2003b). Distinct patterns of neural modulation during          Processes, 25, 259–284.
  the processing of conceptual and syntactic anomalies.
  Journal of Cognitive Neuroscience, 15(2), 272–293.           Landre, N. A., Taylor, M. A. & Kearns, K. P. (1992).
                                                                  Language functioning in schizophrenic and aphasic
Kuperberg, G. R., Kreher, D. A. & Ditman, T. (2009). What         patients. Neuropsychiatry, Neuropsychology, and
  can event-related potentials tell us about language, and        Behavioral Neurology, 5, 7–14.
  perhaps even thought in schizophrenia? International
  Journal of Psychophysiology, In press.                       Langdon, R. & Coltheart, M. (2004). Recognition of
                                                                  metaphor and irony in young adults: the impact of
Kuperberg, G. R., Kreher, D. A., Goff, D., McGuire, P. K. &
                                                                  schizotypal personality traits. Psychiatry Research,
  David, A. S. (2006c). Building up linguistic context in
                                                                  125(1), 9–20.
  schizophrenia: evidence from self-paced reading.
  Neuropsychology, 20(4), 442–452.                             Larson, E. R., Shear, P. K., Krikorian, R., Welge, J. &
                                                                  Strakowski, S. M. (2005). Working memory and
Kuperberg, G., Lakshmanan, B., Caplan, D. & Holcomb, P.
                                                                  inhibitory control among manic and euthymic patients
  (2006b). Making sense of discourse: an fMRI study of
                                                                  with bipolar disorder. Journal of the International
  causal inferencing across sentences. Neuroimage, 33,
                                                                  Neuropsychology Society, 11(2), 163–172.
  343–361.
                                                               Laws, K. R., McKenna, P. J. & Kondel, T. K. (1998). On
Kuperberg, G. R., Lakshmanan, B. M. & West, W. C.
                                                                 the distinction between access and store disorders in
  (2008a). Task and semantic relationship influence both
                                                                 schizophrenia: a question of deficit severity?
  the polarity and localization of hemodynamic
                                                                 Neuropsychologia, 36, 313–321.
  modulation during lexico-semantic processing. Human
  Brain Mapping, 29(5), 544–561.                               Lee, J. & Park, S. (2005). Working memory impairments in
                                                                  schizophrenia: a meta-analysis. Journal of Abnormal
Kuperberg, G. R., McGuire, P. K. & David, A. (1998).
                                                                  Psychology, 114(4), 599–611.
  Reduced sensitivity to linguistic context in schizophrenic
  thought disorder: evidence from online monitoring for        Leroy, F., Pezard, L., Nandrino, J. L. & Beaune, D. (2005).
  words in linguistically-anomalous sentences. Journal of         Dynamical quantification of schizophrenic speech.           91
  Abnormal Psychology, 107, 423–434.                              Psychiatry Research, 133(2–3), 159–171.
        Section 1: Neuropsychological processes



     Liddle, P. F. (1987). The symptoms of chronic                   Minzenberg, M. J., Ober, B. A. & Vinogradov, S. (2002).
        schizophrenia. A re-examination of the                         Semantic priming in schizophrenia: a review and
        positive-negative dichotomy. British Journal of                synthesis. Journal of the International Neuropsychological
        Psychiatry, 151, 145–151.                                      Society, 8(5), 699–720.
     Liddle, P. F. (1992). Syndromes of schizophrenia on factor      Mitchell, P. F., Andrews, S., Fox, A. M. et al. (1991). Active
        analysis. British Journal of Psychiatry, 161, 861.             and passive attention in schizophrenia: an ERP study of
     Maas, J. W. & Katz, M. M. (1992). Neurobiology and                information processing in a linguistic task. Biological
       psychopathological states: are we looking in the right          Psychiatry, 32, 101–124.
       place? Biological Psychiatry, 31, 757–758.                    Mitchell, R. L. & Crow, T. J. (2005). Right hemisphere
     MacDonald, M. C., Pearlmutter, N. J. & Seidenberg, M. S.          language functions and schizophrenia: the forgotten
       (1994). The lexical nature of syntactic ambiguity               hemisphere? Brain, 128(5), 963–978.
       resolution. Psychological Review, 101, 676–703.               Morgan, C. J., Rossell, S. L., Pepper, F. et al. (2006).
     Maher, B. A. (1983). A tentative theory of schizophrenic          Semantic priming after ketamine acutely in
       utterences. In B. A. Maher & W. B. Maher (Eds.),                healthy volunteers and following chronic
       Progress in Experimental Personality Research (Vol. 12,         self-administration in substance users. Biological
       pp. 1–52). San Diego, CA: Academic Press.                       Psychiatry, 59(3), 265–272.
     Manschreck, T. C., Maher, B. A., Milavetz, J. J. et al.         Morice, R. D. & Ingram, J. C. L. (1982). Language analysis in
       (1988). Semantic priming in thought disordered                  schizophrenia: diagnostic implications. Australian and
       schizophrenic patients. Schizophrenia Research,                 New Zealand Journal of Psychiatry, 16, 11–21.
       1, 61–66.                                                     Moritz, S., Mersmann, K., Kloss, M. et al. (2001a).
     Manschreck, T. C., Maher, B. A., Rucklos, M. E. & White,          Enhanced semantic priming in thought-disordered
       M. T. (1979). The predictability of thought disordered          schizophrenic patients using a word pronunciation task.
       speech in schizophrenic patients. British Journal of            Schizophrenia Research, 48(2–3), 301–305.
       Psychiatry, 134, 595–601.
                                                                     Moritz, S., Mersmann, K., Kloss, M. et al. (2001b).
     Mathalon, D. H., Faustman, W. O. & Ford, J. M. (2002).            Hyper-priming in thought-disordered schizophrenic
       N400 and automatic semantic processing abnormalities            patients. Psychological Medicine, 31(2), 221–229.
       in patients with schizophrenia. Archives of General
       Psychiatry, 59(7), 641–648.                                   Moritz, S., Woodward, T. S., Kuppers, D., Lausen, A. &
                                                                       Schickel, M. (2002). Increased automatic spreading of
     Mazumdar, P. K., Chaturvedi, S. K. & Gopinath, P. S.              activation in thought-disordered schizophrenic patients.
       (1995). A comparative study of thought disorder in acute        Schizophrenia Research, 59(2–3), 181–186.
       and chronic schizophrenia. Psychopathology, 28(4),
       185–189.                                                      Neely, J. H. (1977). Semantic priming and retrieval
                                                                       from lexical memory: roles of inhibitionless
     McKenna, P. K. & Oh, T. M. (2005). Schizophrenic Speech.          spreading activation and limited-capacity attention.
       Cambridge: Cambridge University Press.                          Journal of Experimental Psychology: General, 106,
     McKenna, P. K., Mortimer, A. M. & Hodges, J. R. (1994).           226–254.
       Semantic memory and schizophrenia. In A. S. Davis &           Neely, J. H. (1991). Semantic priming effects in visual
       J. C. Cutting (Eds.), The Neuropsychology of                    word recognition: a selective review of current findings
       Schizophrenia (pp. 163–178). Hove, UK: Psychology               and theories. In D. Besner & G. W. Humphreys (Eds.),
       Press.                                                          Basic Processes in Reading and Visual Word Recognition,
     McNamara, T. P. & Altarriba, J. (1988). Depth of spreading        pp. 264–333. Hillsdale, NJ: Lawrence Erlbaum
       activation revisited: semantic mediated priming occurs          Associates.
       in lexical decisions. Journal of Memory and Language,         Neely, J. H., Keefe, D. E. & Ross, K. (1989). Semantic
       27, 545–559.                                                    priming in the lexical decision task: roles of
     Meyer, D. E. & Schvaneveldt, R. W. (1971). Facilitation in        prospective prime-generated expectancies and
       recognizing pairs of words: evidence of a dependence            retrospective semantic matching. Journal of
       between retrieval operations. Journal of Experimental           Experimental Psychology: Learning, Memory and
       Psychology, 20, 227–234.                                        Cognition, 15, 1003–1019.
     Miller, W. K. & Phelan, J. G. (1980). Comparison of adult       Nestor, P. G., Kimble, M. O., O’Donnell, B. F. et al. (1997).
       schizophrenics with matched normal native speakers of           Aberrant semantic activation in schizophrenia: a
       English as to “acceptability” of English sentences. Journal     neurophysiological study. American Journal of
92     of Psycholinguistic Research, 9(6), 579–593.                    Psychiatry, 154(5), 640–646.
                                                    Chapter 6: Approaches to understanding language dysfunction



Nestor, P. G., Shenton, M. E., Wible, C. et al. (1998).       Passerieux, C., Segui, J., Besche, C. et al. (1997).
  A neuropsychological analysis of schizophrenic thought         Heterogeneity in cognitive functioning of schizophrenic
  disorder. Schizophrenia Research, 29(3), 217–225.              patients evaluated by a lexical decision task. Psychological
                                                                 Medicine, 27(6), 1295–1302.
Nienow, T. M. & Docherty, N. M. (2005). Internal source
   monitoring and communication disturbance in patients       Paulsen, J. S., Romero, R., Chan, A. et al. (1996).
   with schizophrenia. Psychological Medicine, 35(12),          Impairment of the semantic network in schizophrenia.
   1717–1726.                                                   Psychiatry Research, 63(2–3), 109–121.
Niznikiewicz, M. A., O’Donnell, B. F., Nestor, P. G. et al.   Pavy, D. (1968). Verbal behavior in schizophrenia: a
   (1997). ERP assessment of visual and auditory language        review of recent studies. Psychological Bulletin, 70(3),
   processing in schizophrenia. Journal of Abnormal              164–178.
   Psychology, 106, 85–94.                                    Perry, W. & Braff, D. L. (1994). Information-processing
Noel-Jorand, M. C., Reinert, M., Giudicelli, S. & Dassa, D.      deficits and thought disorder in schizophrenia. American
  (1997). A new approach to discourse analysis in                Journal of Psychiatry, 151(3), 363–367.
  psychiatry, applied to a schizophrenic patient’s speech.    Pomarol-Clotet, E, Oh, T. M., Laws, K. R. & McKenna, P. J.
  Schizophrenia Research, 25(3), 183–198.                       (2008). Semantic priming in schizophrenia: systematic
Norman, R. M., Malla, A. K., Cortese, L. et al. (1999).         review and meta-analysis. British Journal of Psychiatry,
  Symptoms and cognition as predictors of community             192(2), 92–97.
  functioning: a prospective analysis. American Journal       Poole, J. H., Ober, B. A., Shenaut, G. K. & Vinogradov, S.
  of Psychiatry, 156(3), 400–405.                               (1999). Independent frontal-system deficits in
Nuecheterlein, K. H., Edell, W. S., Norris, M. & Dawson, M.     schizophrenia: cognitive, clinical, and adaptive
  (1986). Attentional vulnerability indicators, thought         implications. Psychiatry Research, 85(2), 161–176.
  disorder, and negative symptoms. Schizophrenia Bulletin,    Ragland, J. D., Gur, R. C., Valdez, J. et al. (2004). Event-
  12, 408–426.                                                  related fMRI of frontotemporal activity during word
Ober, B. A., Vinogradov, S. & Shenaut, G. K. (1995).            encoding and recognition in schizophrenia. American
  Semantic priming of category relations in schizophrenia.      Journal of Psychiatry, 161(6), 1004–1015.
  Neuropsychology, 9(2), 220–228.                             Ragland, J. D., Gur, R. C., Valdez, J. et al. (2005). Levels-
Ober, B. A., Vinogradov, S. & Shenaut, G. K. (1997).            of-Processing effect on frontotemporal function in
  Automatic versus controlled semantic priming in               schizophrenia during word encoding and recognition.
  schizophrenia. Neuropsychology, 11(4), 506–513.               American Journal of Psychiatry, 162(10), 1840–1848.
                                                              Rhodes, J. E. & Jakes, S. (2004). The contribution of
Ohta, K., Uchiyama, M., Matsushima, E. & Toru, M. (1999).
                                                                metaphor and metonymy to delusions. Psychology and
  An event-related potential study in schizophrenia
                                                                Psychotherapy, 77(1), 1–17.
  using Japanese sentences. Schizophrenia Research, 40(2),
  159–170.                                                    Rochester, S. & Martin, J. R. (1979). Crazy Talk: A Study of
                                                                the Discourse of Schizophrenic Speakers. New York, NY:
Oltmanns, T. F., Murphy, R., Berenbaum, H. &
                                                                Plenum Press.
   Dunlop, S. R. (1985). Rating verbal communication
   impairment in schizophrenia and affective disorders.       Rochester, S. R., Harris, J. & Seeman, M. V. (1973). Sentence
   Schizophrenia Bulletin, 11(2), 292–299.                      processing in schizophrenic listeners. Journal of
                                                                Abnormal Psychology, 82, 350–356.
Osterhout, L. & Hagoort, P. (1999). A superficial
   resemblence does not necessarily mean you are part of      Roesch-Ely, D., Weiland, S., Scheffel, H. et al. (2006).
   the family: counterarguments to Coulson, King and            Dopaminergic modulation of semantic priming
   Kutas (1998) in the P600/SPS-P300 debate. Language           in healthy volunteers. Biological Psychiatry, 60(6),
   and Cognitive Processes, 14, 1–14.                           604–611.
Ott, S. L., Allen, J. & Erlenmeyer-Kimling, L. (2001).        Rossell, S. L. & David, A. S. (2006). Are semantic deficits in
   The New York High-Risk Project: observations                 schizophrenia due to problems with access or storage?
   on the rating of early manifestations of                     Schizophrenia Research, 82(2–3), 121–134.
   schizophrenia. American Journal of Medical Genetics,       Rossell, S. L., Price, C. J. & Nobre, A. C. (2003). The
   105(1), 25–27.                                               anatomy and time course of semantic priming
Pandurangi, A. K., Sax, K. W., Pelonero, A. L. &                investigated by fMRI and ERPs. Neuropsychologia,
  Goldberg, S. C. (1994). Sustained attention and               41(5), 550–564.
  positive formal thought disorder in schizophrenia.          Ruchsow, M., Trippel, N., Groen, G., Spitzer, M. &
  Schizophrenia Research, 13, 109–116.                          Kiefer, M. (2003). Semantic and syntactic processes             93
        Section 1: Neuropsychological processes



        during sentence comprehension in patients with                    information processing in schizophrenics. Biological
        schizophrenia: evidence from event-related potentials.            Psychiatry, 42(7), 596–608.
        Schizophrenia Research, 64(2–3), 147–156.                      Strauss, M. E., Buchanan, R. W. & Hale, J. (1993). Relations
     Rugg, M. D. (1985). The effects of semantic priming and              between attentional deficits and clinical symptoms in
       word repetition on event-related potentials.                       schizophrenic outpatients. Psychiatric Research, 47,
       Psychophysiology, 22, 642–647.                                     205–213.
     Salisbury, D. F., O’Donnell, B. F., McCarley, R. W., Nestor,      Surguladze, S., Rossell, S., Rabe-Hesketh, S. & David, A. S.
        P. G. & Shenton, M. E. (2000). Event-related potentials           (2002). Cross-modal semantic priming in schizophrenia.
        elicited during a context-free homograph task in normal           Journal of the International Neuropsychology Society,
        versus schizophrenic subjects. Psychophysiology, 37(4),           8(7), 884–892.
        456–463.
                                                                       Swaab, T., Camblin, C. & Gordon, P. (2004).
     Salisbury, D. F., Shenton, M. E., Nestor, P. G. &                   Electrophysiological evidence for reversed lexical
        McCarley, R. W. (2002). Semantic bias, homograph                 repetition effects in language processing. Journal of
        comprehension, and event-related potentials in                   Cognitive Neuroscience, 16(5), 715–726.
        schizophrenia. Clinical Neurophysiology, 113(3),
        383–395.                                                       Tallent, K. A., Weinberger, D. R. & Goldberg, T. E. (2001).
                                                                          Associating semantic space abnormalities with formal
     Salzinger, K., Pisoni, D. B., Portnoy, S. & Feldman, R. S.           thought disorder in schizophrenia: use of triadic
        (1970). The immediacy hypothesis and response-                    comparisons. Journal of Clinical and Experimental
        produced stimuli in schizophrenic speech. Journal of              Neuropsychology, 23(3), 285–296.
        Abnormal Psychology, 76, 258–264.
                                                                       Taylor, W. (1953). Cloze’ procedure: a new tool for
     Salzinger, K., Portnoy, S. & Feldman, R. S. (1964). Verbal
                                                                         measuring readability. Journal Quarterly, 30, 415–433.
        behavior of schizophrenic and normal subjects. Annals
        of the New York Academy of Sciences, 105, 845–860.             Tenyi, T., Herold, R., Szili, I. M. & Trixler, M. (2002).
                                                                         Schizophrenics show a failure in the decoding of
     Salzinger, K., Portnoy, S. & Feldman, R. S. (1979). The
                                                                         violations of conversational implicatures.
        predictability of speech in schizophrenic patients [letter].
                                                                         Psychopathology, 35(1), 25–27.
        British Journal of Psychiatry, 135, 284–287.
                                                                       Thomas, P., King, K., Fraser, W. I. & Kendell, R. E. (1990).
     Sanford, A. & Garrod, S. (1994). Selective Processing in Text
                                                                         Linguistic performance in schizophrenia: a comparison
        Understanding. San Deigo, CA: Academic Press, Inc.
                                                                         of acute and chronic patients. British Journal of
     Schneider, C. (1930). Psychologie der Schizophrenie. Leipzig.       Psychiatry, 156, 204–210.
     Sitnikova, T., Salisbury, D. F., Kuperberg, G. & Holcomb,         Thompson-Schill, S. L. (2003). Neuroimaging studies of
        P. I. (2002). Electrophysiological insights into language        semantic memory: inferring “how” from “where”.
        processing in schizophrenia. Psychophysiology, 39(6),            Neuropsychologia, 41(3), 280–292.
        851–860.
                                                                       Titone, D. A. & Connine, C. M. (1994). Comprehension
     Speed, M., Shugar, G. & Di Gasbarro, I. (1991). Thought              of idiomatic expressions: effects of predictability
        disorder and verbal recall in acutely psychotic patients.         and literality. Journal of Experimental Psychology:
        Journal of Clinical Psychology, 47, 735–744.                      Learning, Memory and Cognition, 20(5),
     Spitzer, M. (1993). The psychopathology, neuropsychology,            1126–1138.
        and neurobiology of associative and working memory in
                                                                       Titone, D., Holzman, P. S. & Levy, D. L. (2002). Idiom
        schizophrenia. European Archives of Psychiatry and
                                                                          processing in schizophrenia: literal implausibility saves
        Clinical Neuroscience, 243, 57–70.
                                                                          the day for idiom priming. Journal of Abnormal
     Spitzer, M., Braun, U., Maier, S., Hermle, L. & Maher, B.            Psychology, 111(2), 313–320.
        (1993). Indirect semantic priming in schizophrenic
                                                                       Titone, D., Levy, D. L. & Holzman, P. S. (2000). Contextual
        patients. Schizophrenia Research, 11, 71–80.
                                                                          insensitivity in schizophrenic language processing:
     Spitzer, M., Weisker, I., Winter, M. et al. (1994). Semantic         evidence from lexical ambiguity. Journal of Abnormal
        and phonological priming in schizophrenia. Journal of             Psychology, 109(4), 761–767.
        Abnormal Psychology, 103, 485–494.
                                                                       Ungerleider, L. G. & Haxby, J. V. (1994). ‘What’ and ‘where’
     Spitzer, R. L., Williams, J. B., Gibbon, M. & First, M. B.          in the human brain. Current Opinion of Neurobiology,
        (1992). The Structured Clinical Interview for                    4(2), 157–165.
        DSM–III–R (SCID) I: History, rationale and description.
                                                                       van Berkum, J. J., Brown, C. M. & Hagoort, P. (1999).
        Archives of General Psychiatry, 4, 642–649.
                                                                          Early referential context effects in sentence processing:
94   Strandburg, R. J., Marsh, J. T., Brown, W. S. et al. (1997).         evidence from event-related brain potentials. Journal of
        Event-related potential correlates of linguistic                  Memory and Language, 41, 147–182.
                                                      Chapter 6: Approaches to understanding language dysfunction



Vinogradov, S., Ober, B. A. & Shenaut, G. K. (1992).            Weisbrod, M., Maier, S., Harig, S., Himmelsbach, U. &
   Semantic priming of word pronunciation and lexical             Spitzer, M. (1998). Lateralised semantic and indirect
   decision in schizophrenia. Schizophrenia Research, 8,          semantic priming effects in people with schizophrenia.
   171–181.                                                       British Journal of Psychiatry, 172, 142–146.
Weisbrod, M., Kiefer, M., Winkler, S. et al. (1999).            Weiss, A. P., Schacter, D. L., Goff, D. et al. (2003). Impaired
  Electrophysiological correlates of direct versus indirect       hippocampal recruitment during normal modulation of
  semantic priming in normal volunteers. Cognitive Brain          memory performance in schizophrenia. Biological
  Research, 8(3), 289–298.                                        Psychiatry, 53(1), 48–55.




                                                                                                                                  95
         Chapter




               7
                          Associative memory

                          Marc L. Seal and Anthony P. Weiss



       Memory is the mother of all wisdom                           stand mental disorders, it is appropriate to review the
       Aeschylus, Prometheus Bound (525–456 BC)                     ways in which researchers and clinicians measure this
                                                                    neuropsychological construct. In the broadest sense,
                                                                    associative memory refers to the set of processes
     Introduction                                                   involved in the binding of the features of a memory
     The formation of a memory involves the creation of             during encoding, in addition to the successful storage
     new and enduring representations of our experiences.           and retrieval of the memory for the event and relevant
     These representations contain detailed contextual              relational information. Poor performance on an asso-
     information, markers of the time and place in which            ciative memory task could be due to a number of
     an event was experienced. Potentially, all elements            causes including incomplete encoding of relational
     of our experience are stored: our affective and phys-          information, the compromised storage of relational
     iological state at the time, a record of the cognitive         information, inefficient identification of existing rela-
     processes occurring at that moment and, crucially, the         tional ties, incomplete retrieval of associated details or
     extent to which this new experience reconciles with            a combination of all the above factors. It is not sur-
     existing similar memories. During the encoding pro-            prising, then, that there exist different methodological
     cess, existing memories and their network of rela-             techniques to measure associative memory.
     tional information may be updated and modified                     First, there are tests that directly assess the ability
     in the face of a new experience. The efficient storage         to link information about one item with another.
     and subsequent successful retrieval of a memory is             Typically these tasks involve the novel pairing of
     dependent on the unique and idiosyncratic organiza-            information during the encoding or learning phase.
     tion of contextual information that makes up a                 For example, subjects attempting a form of the Verbal
     memory. These relational networks make it possible             Paired Associates Task (the most widely used is
     to put the right name to a familiar face or to correctly       contained in versions of the Weschler Memory Scales;
     remember your passwords for your various computer              Weschler, 1987, 1997) are required to learn the pair-
     accounts. Impairment in the ability to generate or             ings of combinations of words (e.g. flower – petal,
     access this relational information can have debilitat-         crush – dark). Following the presentation of the pairs,
     ing consequences in an individual’s daily life. In this        participants are provided with the first item of each
     chapter we will examine the nature of associative or           pair and asked to recall what other word was paired
     relational memory processes and what potential def-            with it. Some versions of this task manipulate these
     icits in this cognitive domain can inform us about the         pairings to involve words that are semantically linked,
     nature of mental disorders.                                    easy pairs (e.g. flower – petal) and other pairings
                                                                    which are not semantically linked, hard pairs (e.g.
                                                                    crush – dark). In general, it is easier to form and
     Measuring associative memory                                   recall relational information between items that
     Before we commence our discussion of the applica-              already have established contextual and semantic
     tion of associative memory in order to better under-           links. Other tasks require subjects to form more


96   The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by
     Cambridge University Press. # Cambridge University Press 2009.
                                                                                    Chapter 7: Associative memory



complex, abstract links across modalities, such as the         was different from what person B said?”), memories
pairing of unfamiliar faces with unfamiliar names, or          of internally generated events (i.e. What I thought or
remembering the identity of an abstract figure as well         imagined and what I actually said), or memories of
as its location/position on the presentation screen.           the actions of self and another (i.e. “Did you do that
These tasks avoid the potential confounding influence          or did I?”). Accurate source monitoring relies on the
of previously learned associations. An additional,             quality of information associated with a memory,
more sophisticated way of testing associative memory           the effectiveness of the retrieval strategy adopted and
involves examining the phenomenon of transitive                the efficiency of post-retrieval decision processes
inference (see Dusek & Eichenbaum, 1997). That is,             (Johnson et al., 1993). Memories of externally gener-
our capacity to infer possible relationships between           ated events or perceived events are believed to have
apparently indirectly related items based on previous          more perceptual and contextual information associ-
learning. In practice, this involves the subject learning      ated with them. That is, associated with a memory for
a stimulus hierarchy (A > B > C > D > E) via the               hearing a lecture is sensory information about the
presentation of a sequence of overlapping pairs (i.e.          tone, volume and character of the lecturer’s voice, as
if A > B and B > C, then A > C). In order to success-          well as information regarding what time of day and
fully complete this task subjects must form and appre-         day of the week the lecture occurred. In contrast,
ciate a series of relationships between novel stimuli.         memories of self-generated actions contain distinctive
Performance on this paradigm has been extensively              contextual cues that make them more readily identi-
investigated in animals (Eichenbaum, 2004), as well as         fied than memories of externally or other generated
via functional neuroimaging investigations involving           events: the so-called generation effect (Raye et al.,
healthy human subjects (Heckers et al., 2004). The             1980). Simply, you are more likely to remember
findings of these studies suggest that there are disso-        things said or done by you than by another, because
ciable regions in the medial temporal lobe (MTL) for           your memory of these events is associated with
recognizing relevant relational information. Recogni-          privileged information; that is, your intention to act,
tion of previously learnt items involves widespread            motor information and the perceptual information
MTL activation with the focal point in the parahippo-          related to performing the action.
campal gyrus, whereas the accurate recollection of the             The last group of associative memory tasks
relational information between items is centered in            involves assessing associative memory via the phe-
the hippocampus.                                               nomenology of the experience of recollection. One
    The second group of associative memory tasks are           popular example of testing these phenomena, the
generally referred to as source memory tasks, as they          Remember–Know paradigm, requires participants to
attempt to assess the ability of individuals to embed          rate the experience of recollection (see Gardiner,
an item within its context or source. The term source          2001). Subjects are asked to distinguish between
itself, refers to a set of characteristics that collectively   memories that are accompanied with rich contextual
define the conditions or context under which a                 and relational details (e.g. “I clearly remember you
memory is acquired (e.g. “Where did I read about               saying that word before”) and those recollective
associative memory again?”). Since our memory for              experiences that are unaccompanied by any contex-
such details is demonstrably fallible, the source moni-        tual information (e.g. “The word feels familiar but
toring framework also incorporates the set of pro-             I don’t remember hearing you say it before”). Indi-
cesses underlying attributions about the origins of            viduals who have difficulties storing and retrieving
memories, knowledge and beliefs (for a review see              relational information are less likely to describe their
Johnson et al., 1993). Well-designed source memory             recollective experiences as containing rich phenom-
tasks assess memory for items and the source/context           enological detail. For example, there is consistent
of the item memory, as well as an individual’s idio-           evidence that individuals with schizophrenia are less
syncratic response bias to say an item was acquired            likely to desscribe their subjective recollective experi-
in a particular context (i.e. “I must have read that           ences as like a “Remember” response, suggesting
in that book on Neuropsychology and Mental                     that their typical experience of recollection is accom-
Disorders”). Source memory tasks can involve dis-              panied by less relational information (Danion et al.,
criminating between memories of two externally                 2005; Seal et al., 1997). This deficit has been inter-      97
generated events (i.e. “What did person A say that             preted as failure to form a comprehensive and stable
                              Section 1: Neuropsychological processes



     relational network during the encoding stage (Danion                               clues to the underlying pathophysiological mecha-
     et al., 1999).                                                                     nisms of these disorders. This follows from the logical
         Given the broad definition of associative memory,                              deduction that if memory impairment is characteris-
     the presented information is certainly not exhaustive                              tic of a particular mental illness, then those brain
     and there are other descriptions in the literature;                                areas important for memory processing are somehow
     however, it provides a framework for the following                                 dysfunctional. Second, the underlying psychological
     discussion of the assessment of associative memory.                                processes that are involved in memory may, when
                                                                                        abnormal, also help to explain some of the symptoms
                                                                                        seen in individuals with mental illness. For example,
     Grounds for investigating associative                                              individuals prone to hallucinations show impair-
     memory function in mental disorders                                                ments in recognizing the source of self-generated
     The past decade has seen a tremendous increase                                     actions. Finally, memory dysfunction is a critical
     in interest in the relationship between memory                                     component of the overall functional impairment seen
     abnormalities and mental illness. Indeed, as seen in                               in individuals with mental illness. The level of one’s
     Figure 7.1, the number of publications on this topic                               memory capacity is in many ways a gauge on poten-
     has shown exponential growth. This trend has been                                  tial social and occupational performance, with poor
     particularly strong in the area of schizophrenia                                   memory being a significant barrier to reintegration,
     research; in 2005 one out of every seven papers pub-                               despite adequate symptom control.
     lished on schizophrenia focused on memory abnor-
     malities in this disorder.                                                         Reason 1: Improving our understanding
         We contend that there are three overarching
     reasons for studying the relationship between                                      of underlying neuropathology
     memory and mental illness. First, the study of                                     Memory is not a unitary concept, neither semanti-
     memory in patients with mental illness may provide                                 cally or neurobiologically. Converging findings from

                                                                         Publications 1990–2005

                                                                  Schizophrenia        Depression          PTSD

                              500



                              400
     Number of publications




                              300



                              200



                              100



                                0
                                    1990   1991   1992   1993   1994   1995   1996   1997   1998    1999   2000   2001   2002   2003   2004   2005
     Figure 7.1. Publications over time for the intersection of memory and three major mental illnesses (schizophrenia, major depression,
     and post-traumatic stress disorder (PTSD)). Data obtained through a query of the ISI Web of Science (Thomson Scientific, Stamford CT ) on
98   May 2, 2006 using the terms “memory,” “schizophrenia,” “major depression OR depressive,” and “post traumatic OR PTSD.” The search
     was limited to English language full-length articles.
                                                                                               Chapter 7: Associative memory



                                                                         elements” (the who, what and how of the experience),
                           left                    right                 which are then “sequentially organized” in a distinc-
                                                                         tive representational network so as to preserve all the
  Encoding
                                                                         detail of the memory and to assist with accurate
                                                                         retrieval. Consequently, associative memory processes
                                                                         operate within representational networks and between
                                                                         separate memories.
                                                                             For those mental disorders in which associative
  Recognition                                                            memory impairment is a significant and characteris-
                                                                         tic feature of the illness, it is reasonable to postulate
                                                                         that brain regions involved in the memory network
                                                                         detailed above are in some way dysfunctional. How-
                                                                         ever, while associative memory deficits may imply
                                                                         that these brain regions are impaired in a particular
Figure 7.2. This figure is also reproduced in the color plate section.
                                                                         disorder, it does not necessarily implicate them in the
Brain regions involved in associative memory processes (unpublished      pathogenesis of the disorder. In order to make such
fMR neuroimaging data from the authors). Note the important role of      a link you need to track the development of the
coordinated anterior-posterior activity associated with both encoding
and retrieval processes. Data acquired from n ¼ 17 healthy control
                                                                         memory deficit and the neuropathology across the
subjects completing verbal encoding and retrieval tasks.                 course of the illness. For example, recent reviews
                                                                         suggest that chronic schizophrenia is characterized
clinical case studies involving individuals with local-                  by a significant associative memory deficit (Aleman
ized brain damage, as well as functional neuroim-                        et al., 1999) and functional neuroimaging studies
aging research on healthy adults indicate that there                     have identified atypical brain activity related to epi-
are multiple forms of memory in the brain, served                        sodic memory processing in schizophrenia (Achim &
by a range of cortical–subcortical–cerebellar systems                    Lepage, 2005). In addition, while volumetric find-
(Squire, 2004). Nyberg et al. (2002) have character-                     ings are variable, there is consistent and converging
ized memory as consisting of a series of independent                     evidence that the hippocampus is abnormal in
but interacting systems. To varying degrees, encoding                    schizophrenia neuropathologically (Harrison, 2004),
and retrieval networks include: the hippocampus and                      structurally (Honea et al., 2005; Pantelis et al., 2005;
surrounding medial temporal cortex, the lateral pre-                     Weiss et al., 2005) and functionally (Weiss et al.,
frontal cortex (BA 9/46), parietal cortex (BA 7, 39/40),                 2003). Further, there is evidence of hippocampal
anterior cingulate (BA 32/24) and cerebellum (see                        volume deficits and memory deficits in individuals
Figure 7.2). Although most work has focused on the                       with first-episode psychosis.
medial temporal lobe and prefrontal cortex, Wagner                           Taken together these findings imply that hippo-
et al. (2005) in a recent review highlight the consistent                campal pathology is a feature of schizophrenia, but it
finding of posterior regions in episodic memory                          is not clear if this pathology pre-dates the onset of
retrieval (parietal, posterior cingulate and precuneus),                 psychosis. Recently this question was addressed by the
which appear to be preferentially activated when the                     largest published study to date comparing hippocam-
subject is required to focus on the phenomenological                     pal and amygdala volumes between groups with
experience of recollection.                                              chronic schizophrenia, first-episode psychosis and
    Efficient and accurate memory function is                            those at ultra-high risk of developing psychosis
dependent on the integrity of this network. Com-                         (Velakoulis et al., 2006). Significantly, compared with
promise of the brain structures and/or connections                       healthy controls no structural changes were observed
between these regions results in observable associative                  in the MTL until after the onset of a psychotic illness.
memory deficits (Squire, 2004). Eichenbaum (2004)                        These findings suggest that the changes to the MTL
has proposed a model of declarative memory in which                      and accompanying associative memory deficits are
the hippocampus and medial temporal lobe (MTL)                           the consequence of the brain changes involving tran-
receive information (sensory, affective, cognitive)                      sition to schizophrenia psychosis. Further, the pattern
from a multitude of sites in the brain. This infor-                      of structural change differed according to the type of       99
mation is indexed as “associative representational                       psychosis in the first-episode psychosis (affective versus
        Section 1: Neuropsychological processes



      schizophrenia). Individual with non-schizophrenia         2001; McGuire et al., 1995) have used increasingly
      psychosis had significantly enlarged amygdala but         sophisticated verbal self-monitoring paradigms to
      normal hippocampal volumes. Consequently it is            consistently demonstrate that hallucination-prone
      possible to use neuroanatomical abnormalities and         individuals are impaired at monitoring the gener-
      corresponding memory deficits to inform the onset         ation and perception of their own speech compared
      and progression of mental disorders. This particular      with control groups. These findings suggest that
      methodology represents the first step in developing       from the outset there is an impairment in linking
      clinically useful neuroimaging techniques to aid clini-   relevant relational information (the source of the
      cians in diagnosis, prognosis and treatment monitor-      speech) with the action (speaking aloud). Further,
      ing; a substantial advance in the field of psychiatry.    there is substantial evidence from the application of
                                                                source memory paradigms (“Do you remember who
      Reason 2: Informing the origins of                        said that word before?”) that hallucinating subjects
                                                                are selectively impaired to remember the source of
      neuropsychiatric symptomatology                           a spoken item (self or other) (see Brébion et al.,
      The application of neurocognitive models to study         2005; Keefe et al., 2002). It is important to note
      abnormal cognition in mental disorders has been           that amongst hallucinating subjects this relational
      influential in increasing our understanding of the        memory deficit is often accompanied by an inap-
      origins of these illnesses (see Halligan & David,         propriately liberal response bias. That is, when uncer-
      2001). The systematic application of comprehensive        tain about the context of a memory hallucinating
      cognitive neuropsychiatric models to mental disorders     subjects tend to claim that they had said or done
      has been very useful in increasing our understanding      something before. It has yet to be established if this
      of neurocognitive deficits, as well as the extent to      response bias represents a learnt coping mechanism
      which these deficits correspond to functional imp-        in response to demonstrable poor relational memory or
      airments, symptomatology and compromised brain            signifies some form of post-retrieval monitoring
      function and structure. For example in schizophrenia      failure.
      neuropsychiatric models of the following cognitive
      domains have informed our understanding of the            Reason 3: Understanding functional
      neurocognitive substrates of the disorder; working
      memory (Goldman-Rakic, 1994), semantic processing         impairment
      (Spitzer, 1997), motor imagery (Danckert et al., 2004),   The final link focuses on a newly recognized connec-
      social cognition (Green & Phillips, 2004), theory of      tion between associative memory impairment and
      mind (Langdon et al., 1997) and olfactory memory          the overall functional level of the patient with
      (Pantelis & Brewer, 1995).                                mental illness. In schizophrenia, for example, there
          A salient example of this approach has been the       has been a relatively recent shift in thinking regarding
      ongoing investigation of the potential relationship       the goal of treatment, away from pure symptom con-
      between impaired associative memory function and          trol and toward a more holistic concept of remission
      the experience of auditory verbal hallucinations (for     or recovery (Davidson et al., 2005). As many patients
      a recent review see Seal et al., 2004). Disturbances      with schizophrenia demonstrate a poor functional
      in associative memory processes can result in frag-       outcome (Hegarty et al., 1994; Jobe & Harrow,
      mented retrieval of memories, potentially causing         2005) despite adequate control of positive symptoms
      confusion over the origin or source of a memory:          (i.e. hallucinations and delusions), other factors,
      “Did that really happen or did I imagine it?” The         including cognitive performance, have come under
      notion that disorders of self-awareness are an expres-    intense study.
      sion of specific cortical damage is not a new concept          Although cognitive deficits, including impair-
      in neuropsychology. Johnson (1997) examined the           ments of memory, have long been seen as a compo-
      phenomenon of confabulation in organic brain-             nent of the schizophrenia syndrome (Hull, 1917), the
      disease patients and related it to an inability to        link between these features of the illness and poor
      monitor recall of experience and subsequent attribu-      functional outcome was strengthened by a series of
100   tion processes. In a series of experiments McGuire        influential papers in the last decade (Green, 1996;
      and colleagues (Allen et al., 2007; Johns et al.,         Green et al., 2000; Green & Neuchterlein, 1999).
                                                                                Chapter 7: Associative memory



Of particular relevance here, the 1996 literature          2003). Taken as a whole, it now appears that at least
review by Michael Green (which has now been cited          some patients with schizophrenia can benefit from
more than 750 times) described the predictive rela-        intensive cognitive remediation approaches, although
tionship between verbal memory and overall commu-          the degree to which the observed cognitive benefit
nity functioning in patients with schizophrenia            actually leads to functional improvement remains to
(Green, 1996). Subsequent to this work a number of         be seen.
other studies have been published substantiating this          At present there are no established, FDA-
link (for a recent review see Kurtz, 2006).                approved, pharmacological treatments available to re-
     As the majority of this work has been cross-          verse the memory impairment seen in schizophrenia,
sectional, it remains unclear whether the relationship     although the recent launch of two large-scale
between memory impairment and functional out-              NIMH-funded projects MATRICS (Measurement
come is indeed a causal one. It is possible that           and Treatment Research to Improve Cognition in
memory impairment is simply associated with a              Schizophrenia; Green & Neuchterlein, 2004; Marder
second factor (e.g. negative symptoms) that has a          & Fenton, 2004), and TURNS (Treatment Units
more direct causal link with social functioning. That      for Research on Neurocognition and Schizophrenia,
said, there is strong evidence linking memory per-         www.turns.ucla.edu/index.shtml) may serve as a har-
formance to the critical skills necessary for successful   binger of pharmacological successes to come.
social and occupational functioning (Corrigan &
Toomey, 1995; Corrigan et al., 1994; Mueser et al.,
1991). It is therefore likely that cognitive limitations   Conclusion
are associated with deficiencies in skill acquisition,     This chapter has presented an overview of the neu-
and thus poor functional outcome. If this were cor-        ropsychological construct associative memory and
rect, improving cognition would allow patients to          highlighted various ways in which measuring it can
acquire the core skills necessary for social interaction   improve our understanding of mental disorders.
and adequate job performance, thereby improving            Given the abundance of neuropsychological research
their overall level of well-being in society. This per-    associated with schizophrenia, the practical illustra-
spective has been adopted widely, and has propelled        tions we have presented have focused on this disorder;
cognitive dysfunction (and memory in particular)           however, we contend that that these benefits apply to
into a position as a prime target for treatment in         all mental disorders. In fact we encourage our col-
order to enhance the functional status of patients with    leagues to explore the potential connections between
schizophrenia (Sharma & Antonova, 2003).                   associative memory and other mental illnesses, espe-
     The best evidence thus far is in support of cog-      cially major depression, obsessive-compulsive and
nitive remediation approaches, akin to the rehabi-         post-traumatic stress disorder. Several challenges exist
litation provided to patients with brain injury            for associative memory research in mental illness. The
(Krabbendam & Aleman, 2003; Kurtz et al., 2001).           consequence of increasing the sensitivity and specifi-
This work represents a clinical extension of the find-     city of associative memory tasks will be a more useful
ings from a handful of cognitive psychology studies        tool for understanding heterogeneous presentations
showing that patients with schizophrenia can utilize       of mental disorders. For example, the successful com-
novel cognitive strategies to improve memory per-          pletion of associative memory tasks often relies on
formance (Koh et al., 1976; Kubicki et al., 2003;          executive processes such as post-retrieval monitoring.
Ragland et al., 2005; Weiss et al., 2003). Although a      Accordingly, there is a need to partition out com-
2002 review of the extant literature in this area sug-     ponent elements of tasks to identify processes such
gested that there was no clinical benefit from this        as retrieval effort and post-retrieval monitoring
type of cognitive remediation (Pilling et al., 2002), a    (Buckner & Wheeler, 2001). Further, the application
number of subsequent papers have shown significant         of increasingly sophisticated memory paradigms with
cognitive improvements associated with this interven-      greater selectivity of individual regions of the MTL
tion (Bell et al., 2004; Penades et al., 2006; Sartory     and hippocampus will assist in understanding the
et al., 2005), including two studies that have demon-      specificity of neurocognitive abnormalities in the
strated persisting benefits over a period of longitu-      MTL (Preston et al., 2005). Finally, a recent review       101
dinal follow-up (Fiszdon et al., 2004; Wykes et al.,       by Harrison & Weinberger (2005) has emphasized
         Section 1: Neuropsychological processes



      the role of particular candidate genes resulting in              Dusek, J. A. & Eichenbaum, H. (1997). The hippocampus
      abnormal synaptogenesis and neurotransmission in                   and memory for orderly stimulus relations.
      schizophrenia. The next challenge for researchers is               Proceedings of the National Academy of Sciences USA,
                                                                         94(13), 7109–7114.
      to determine which structural and functional hippo-
      campal anomalies consistently identified in mental               Eichenbaum, H. (2004). Hippocampus: cognitive processes
      illness can be accounted for by a molecular and                     and neural representations that underlie declarative
                                                                          memory. Neuron, 44, 109–120.
      genetic mechanism.
                                                                       Fiszdon, J. M., Bryson, G. J., Wexler, B. E. & Bell, M. D.
                                                                          (2004). Durability of cognitive remediation training
      References                                                          in schizophrenia, performance on two memory tasks at
      Achim, A. M. & Lepage, M. (2005). Episodic memory-                  6-month and 12-month follow-up. Psychiatry Research,
        related activation in schizophrenia: meta-analysis. British       125, 1–7.
        Journal of Psychiatry, 187, 500–509.                           Gardiner, J. M. (2001). Episodic memory and autonoetic
      Aleman, A., Hijman, R., de Haan, E. H. F. & Kahn, R. S.            consciousness: a first-person approach. Philosophical
         (1999). Memory impairment in schizophrenia: a meta-             Transactions of the Royal Society of London Series B,
         analysis. American Journal of Psychiatry, 156, 1358–1366.       Biological Sciences, 356(1413), 1351–1361.
      Allen, P., Amaro, E., Fu, C. H. et al. (2007). Neural            Goldman-Rakic, P. S. (1994). Working memory dysfunction
         correlates of the misattribution of speech in                   in schizophrenia. Journal of Neuropsychiatry, 6, 348–357.
         schizophrenia. British Journal of Psychiatry, 190,            Green, M. F. (1996). What are the functional consequences
         162–169.                                                        of neurocognitive deficits in schizophrenia? American
      Bell, M. D., Fiszdon, J., Bryson, G. & Wexler, B. E. (2004).       Journal of Psychiatry, 153, 321–330.
         Effects of neurocognitive enhancement therapy in
                                                                       Green, M. F. & Neuchterlein, K. H. (1999). Should
         schizophrenia: normalisation of memory performance.
                                                                         schizophrenia be treated as a neurocognitive disorder?
         Cognitive Neuropsychiatry, 9, 199–211.
                                                                         Schizophrenia Bulletin, 25, 309–319.
      Brébion, G., David, A. S., Jones, H. & Pilowsky, L. S. (2005).
                                                                       Green, M. F. & Neuchterlein, K. H. (2004). The MATRICS
         Hallucinations, negative symptoms, and response bias in
                                                                         initiative, developing a consensus cognitive battery for
         a verbal recognition task in schizophrenia.
                                                                         clinical trials. Schizophrenia Research, 72, 1–3.
         Neuropsychology, 19(5), 612–617.
      Buckner, R. L. & Wheeler, M. E. (2001). The cognitive            Green, M. F., Kern, R. S., Braff, D. L. & Mintz, J. (2000).
        neuroscience of remembering. Nature Reviews                      Neurocognitive deficits and functional outcome in
        Neuroscience, 2(9), 624–634.                                     schizophrenia, are we measuring the “right stuff”?
                                                                         Schizophrenia Bulletin, 26, 119–136.
      Corrigan, P. W. & Toomey, R. (1995). Interpersonal
        problem solving and information-processing in                  Green, M. J. & Phillips, M. L. (2004). Social threat
        schizophrenia. Schizophrenia Bulletin, 21, 395–403.              perception and the evolution of paranoia. Neuroscience
                                                                         and Biobehavioral Reviews, 28(3), 333–342.
      Corrigan, P. W., Wallace, C. J., Schade, M. L. & Green, M. F.
        (1994). Cognitive dysfunctions and psychosocial skill          Halligan, P. W. & David, A. S. (2001). Cognitive
        learning in schizophrenia. Behavior Therapy, 25, 5–15.           neuropsychiatry: towards a scientific psychopathology.
                                                                         Nature Reviews Neuroscience, 2(3), 209–215.
      Danckert, J., Saoud, M. & Maruff, P. (2004). Attention,
        motor control and motor imagery in schizophrenia:              Harrison, P. J. (2004). The hippocampus in schizophrenia:
        implications for the role of the parietal cortex.                a review of the neuropathological evidence and its
        Schizophrenia Research, 70(2–3), 241–261.                        pathophysiological implications. Psychopharmacology,
                                                                         174(1), 151–162.
      Danion, J. M., Rizzo, L. & Bruant, A. (1999). Functional
        mechanisms underlying impaired recognition memory              Harrison, P. J. & Weinberger, D. R. (2005). Schizophrenia
        and conscious awareness in patients with schizophrenia.          genes, gene expression, and neuropathology: on the
        Archives of General Psychiatry, 56(7), 639–644.                  matter of their convergence. Molecular Psychiatry, 10(1),
                                                                         40–68.
      Danion, J. M., Cuervo, C., Piolino, P. et al. (2005).
        Conscious recollection in autobiographical memory: an          Heckers, S., Zalesak, M., Weiss, A. P., Ditman, T. &
        investigation in schizophrenia. Conscious and Cognition,         Titone, D. (2004). Hippocampal activation during
        14(3), 535–547.                                                  transitive inference in humans. Hippocampus, 14(2),
      Davidson, L., Lawless, M. S. & Leary, F. (2005). Concepts of       153–162.

102     recovery, competing or complementary? Current                  Hegarty, J. D., Baldessarini, R. J., Tohen, M., Waternaux, C.
        Opinion in Psychiatry, 18, 663–667.                              & Oepen, G. (1994). One hundred years of
                                                                                         Chapter 7: Associative memory



   schizophrenia, a meta-analysis of the outcome literature.        the development of agents for improving cognition in
   American Journal of Psychiatry, 151, 1409–1416.                  schizophrenia. Schizophrenia Research, 72, 5–9.
Honea, R., Crow, T. J., Passingham, D. & Mackay, C. E.           McGuire, P. K., Silbersweig, D. A., Wright, I. et al. (1995).
  (2005). Regional deficits in brain volume in                     Abnormal monitoring of inner speech: a physiological
  schizophrenia: a meta-analysis of voxel-based                    basis for auditory hallucinations. Lancet, 346(8975),
  morphometry studies. American Journal of Psychiatry,             596–600.
  162(12), 2233–2245.                                            Mueser, K. T., Bellack, A. S., Douglas, M. S. & Wade, J. H.
Hull, C. L. (1917). The formation and retention of                 (1991). Prediction of social skill acquisition in
  associations among the insane. American Journal of               schizophrenic and major affective disorder patients
  Psychology, 28, 419–435.                                         from memory and symptomatology. Psychiatry Research,
                                                                   37, 281–296.
Jobe, T. H. & Harrow, M. (2005). Long-term outcome of
   patients with schizophrenia, a review. Canadian Journal       Nyberg, L., Forkstam, C., Petersson, K. M., Cabeza, R. &
   of Psychiatry, 50, 892–900.                                     Ingvar, M. (2002). Brain imaging of human memory
                                                                   systems: between-systems similarities and within-system
Johns, L. C., Rossell, S., Frith, C. et al. (2001). Verbal
                                                                   differences. Brain Research: Cognitive Brain Research,
   self-monitoring and auditory verbal hallucinations in
                                                                   13(2), 281–292.
   patients with schizophrenia. Psychological Medicine,
   31(4), 705–715.                                               Pantelis, C. & Brewer, W. (1995). Neuropsychological and
                                                                   olfactory dysfunction in schizophrenia: relationship of
Johnson, M. K. (1997). Source monitoring and memory                frontal syndromes to syndromes of schizophrenia.
   distortion. Philosophical Transactions of the Royal Society     Schizophrenia Research, 17(1), 35–45.
   of London Series B, 352, 1733–1745.
                                                                 Pantelis, C., Yucel, M., Wood, S. J. et al. (2005). Structural
Johnson, M. K., Hashtroudi, S. & Lindsay, D. S. (1993).            brain imaging evidence for multiple pathological
   Source monitoring. Psychological Bulletin, 114, 3–28.           processes at different stages of brain development in
Keefe, R. S., Arnold, M. C., Bayen, U. J., McEvoy, J. P. &         schizophrenia. Schizophrenia Bulletin, 31(3), 672–696.
  Wilson, W. H. (2002). Source-monitoring deficits for           Penades, R., Catalan, R., Salamero, M. et al. (2006).
  self-generated stimuli in schizophrenia: multinomial              Cognitive remediation therapy for outpatients with
  modeling of data from three sources. Schizophrenia                chronic schizophrenia. A controlled and randomized
  Research, 57(1), 51–67.                                           study. Schizophrenia Research, 87(1–3), 323–331.
Koh, S. D., Kayton, L. & Peterson, R. A. (1976). Affective       Pilling, S., Bebbington, P., Kuipers, E. et al. (2002).
  encoding and subsequent remembering in schizophrenic               Psychological treatments in schizophrenia, II. Meta-
  young adults. Journal of Abnormal Psychology, 85,                  analyses of randomized controlled trials of social skills
  156–166.                                                           training and cognitive remediation. Psychological
Krabbendam, L. & Aleman, A. (2003). Cognitive                        Medicine, 32, 783–791.
  rehabilitation in schizophrenia, a quantitative analysis of    Preston, A. R., Shohamy, D., Tamminga, C. A. &
  controlled studies. Psychopharmacology, 169, 376–382.             Wagner, A. D. (2005). Hippocampal function,
Kubicki, M., McCarley, R. W., Nestor, P. G. et al. (2003).          declarative memory, and schizophrenia: anatomic and
  An fMRI study of semantic processing in men with                  functional neuroimaging considerations. Current
  schizophrenia. Neuroimage, 20, 1923–1933.                         Neurology and Neuroscience Reports, 5(4), 249–256.
Kurtz, M. M. (2006). Symptoms versus neurocognitive skills       Ragland, J. D., Gur, R. C., Valdez, J. N. et al. (2005).
  as correlates of everyday functioning in severe mental           Levels-of-processing effect on frontotemporal function
  illness. Expert Review of Neurotherapeutics, 6, 47–56.           in schizophrenia during word encoding and recognition.
Kurtz, M. M., Moberg, P. J., Gur, R. C. & Gur, R. E. (2001).       American Journal of Psychiatry, 162, 1840–1848.
  Approaches to cognitive remediation of                         Raye, C. L., Johnson, M. K. & Taylor, T. H. (1980). Is
  neuropsychological deficits in schizophrenia, a review           there something special about memory for internally
  and meta-analysis. Neuropsychology Review, 11, 197–210.          generated information? Memory and Cognition,
Langdon, R., Michie, P. T., Ward, P. B. et al. (1997).             8, 141–148.
   Defective self and/or other mentalising in schizophrenia:     Sartory, G., Zorn, C., Groetzinger, G. & Windgassen, K.
   a cognitive neuropsychological approach. Cognitive               (2005). Computerized cognitive remediation improves
   Neuropsychiatry, 2, 167–193.                                     verbal learning and processing speed in schizophrenia.
Marder, S. R. & Fenton, W. (2004). Measurement and                  Schizophrenia Research, 75, 219–223.
  Treatment Research to Improve Cognition in                     Seal, M. L., Aleman, A. & McGuire, P. K. (2004).
  Schizophrenia: NIMH MATRICS initiative to support                 Compelling imagery, unanticipated speech and deceptive        103
         Section 1: Neuropsychological processes



         memory: neurocognitive models of auditory verbal             psychosis, and ultra-high-risk individuals. Archives of
         hallucinations in schizophrenia. Cognitive                   General Psychiatry, 63(2), 139–149.
         Neuropsychiatry, 9(1/2), 43–72.                           Wagner, A. D., Shannon, B. J., Kahn, I., & Buckner, R. L.
      Seal, M. L., Crowe, S. F. & Cheung, P. (1997). Deficits        (2005). Parietal lobe contributions to episodic memory
         in source monitoring in subjects with auditory              retrieval. Trends in Cognitive Sciences, 9(9), 445–453.
         hallucinations may be due to differences in verbal        Wechsler, D. (1987). Wechsler Memory Scale-Revised
         intelligence and verbal memory. Cognitive                   (WMS-R). San Antonio, TX: The Psychological
         Neuropsychiatry, 2(4), 273–290.                             Corporation.
      Sharma, T. & Antonova, L. (2003). Cognitive function in      Wechsler, D. (1997). Wechsler Memory Scale – Third Edition
         schizophrenia. Deficits, functional consequences, and       (WMS–III). San Antonio, TX: The Psychological
         future treatment. Psychiatric Clinics of North America,     Corporation.
         26, 25–40.
                                                                   Weiss, A. P., Schacter, D. L., Goff, D. C. et al. (2003).
      Spitzer, M. (1997). A cognitive neuroscience view of           Impaired hippocampal recruitment during normal
         schizophrenic thought disorder. Schizophrenia Bulletin,     modulation of memory performance in schizophrenia.
         23, 29–50.                                                  Biological Psychiatry, 53, 48–55.
      Squire, L. R. (2004). Memory systems of the brain: a brief   Weiss, A. P., Dewitt, I., Goff, D., Ditman, T. & Heckers, S.
         history and current perspective. Neurobiology of            (2005). Anterior and posterior hippocampal volumes in
         Learning and Memory, 82(3), 171–177.                        schizophrenia. Schizophrenia Research, 73(1), 103–112.
      Velakoulis, D., Wood, S. J., Wong, M. T. et al. (2006).      Wykes, T., Reeder, C., Williams, C. et al. (2003). Are the
         Hippocampal and amygdala volumes according to               effects of cognitive remediation therapy (CRT) durable?
         psychosis stage and diagnosis: a magnetic resonance         Results from an exploratory trial in schizophrenia.
         imaging study of chronic schizophrenia, first-episode       Schizophrenia Research, 61, 163–174.




104
    Chapter




           8
                     The neural basis of attention

                     Susan M. Ravizza, George R. Mangun and Cameron S. Carter



Introduction                                                       The neural correlates of selective attention have
                                                               been the focus of intense investigation and a discus-
The sensory world is rich in information, but our              sion of current neural mechanisms and models of
nervous system necessarily limits how much informa-            attention will be the focus of this chapter. We will
tion can be processed at any given time due to intrinsic       first consider the neural correlates of early and late
limitations on processing capacity. By enhancing the           attentional selection, especially within the context of
processing of relevant information and/or by inhibiting        voluntary attention. Next, we will discuss how these
irrelevant or distracting events and actions, selective        selection processes are controlled by top-down atten-
attention provides a means by which organisms regulate         tion networks. Finally, we will consider the neural
the flow of information. This attention-related priori-        mechanisms of reflexive attention and contrast the
tization in processing has been termed selection, a con-       control of these processes with those that are involved
cept from cognitive psychology (Deutsch & Deutsch,             in voluntary attention.
1963) that refers to the manner in which attended infor-
mation is tagged (selected) for further processing while
competing information is rejected. We will use the term
selection to refer to the outcome of the attentional
                                                               Levels of selection: early
modulation of information processing, but without              and late selection
implying that unattended information has no effect or          For more than a century, philosophers and scientists
influence on cognition or behavior (Vogel et al., 1998).       have asked how attention affects information process-
    During the processing of information, selective            ing. Hermann von Helmholtz, the great physicist and
attention affects how an individual perceives or               sensory psychologist, suggested that when one attends
experiences a stimulus, as well as how they respond            selectively to a region of visual space, this somehow
to it. For example, selective attention to a location in       influences the sensory signals entering the brain
the visual field (spatial attention) facilitates processing    (Helmholtz, 1962/1924–25). This idea permeated
of stimuli appearing at the attended location: reaction        early studies of attention and came to be one of the
times (RT) are faster and discrimination accuracy is           key questions about selective attention: How does
enhanced for events at attended versus unattended              attention influence sensory information processing?
locations (Downing, 1988; Handy et al., 1996; Hawkins          In the 1960s this question formed the basis of a debate
et al., 1990; Heinze & Mangun, 1995; Luck et al., 1994;        within psychology and neuroscience that lasted
Posner & Cohen, 1984). Recent studies have revealed            30 years, coming to be known as the “early versus
that spatial attention can also alter stimulus appear-         late selection debate.” Some argued that attention
ance by altering the apparent contrast, spatial fre-           could influence elementary sensory processing, which
quency and size of stimuli (Carrasco et al., 2004;             would lead to early attentional selection (Broadbent,
Gobell & Carrasco, 2005). It is important to note that         1962). Others argued for the late selection model,
attention can also be directed to non-spatial stimulus         which proposes that sensory processing continued to
features and objects (Duncan, 1998) and to all sensory         completion prior to attention acting to modulate
modalities (Macaluso & Driver, 2005 for a review).             information analysis at higher stages of decision and

The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by        105
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



      response (Deutsch & Deutsch, 1963). Current models          transmission of information in the ascending visual
      of attention hold that selection does not occur at any      pathways in a spatially specific manner (reviewed
      single point in the information processing stream; but      in Luck et al., 2000; Mangun, 1995). Though ERP
      rather that it can occur early, at low levels of sensory    evidence for modulations of V1 with spatial atten-
      pathways, or later, including at the level of specific      tion has been inconsistent, recent studies reveal that
      responses. Both the modulation of perceptual process-       ERPs generated in V1 can also be modulated by
      ing (early selection) and decision and action networks      spatial attention under some circumstances (Khoe &
      (late selection) ensure appropriate responses to rele-      Hillyard, 2005).
      vant stimuli in the face of distracting information.            Consequently, most studies in awake, behaving
      Current research on attentional mechanisms therefore        non-human primates have also focused on attentional
      focuses more on understanding the mechanisms by             modulation of neural responses in sensory areas
      which attention acts to modulate information at various     (Reynolds & Chelazzi, 2004; Salinas & Sejnowski,
      stages of input and output processing, and on specifying    2001). Attentional modulation of sensory processing
      the conditions under which early or late selection mech-    in monkeys has been described at the level of single
      anisms are differentially engaged (Hopf et al., 2006).      neurons in several areas of cortex, including striate
          Many functional neuroimaging studies have               (V1) (McAdams & Maunsell, 1999; McAdams & Reid,
      focused on the role attention plays in the early selec-     2005) and extrastriate visual areas V2–V4 (Chelazzi
      tion of perceptual information. Early studies using         et al., 1993, 2001; Maunsell & Cook, 2002; Moran &
      positron emission tomography (PET) provided evi-            Desimone, 1985; Reynolds & Chelazzi, 2004; Treue,
      dence that selective attention to stimulus features         2001, 2003). Selective attention has also been shown
      (Corbetta et al., 1990) or spatial locations (Heinze        to influence higher-order perceptual processing in the
      et al., 1994) modulated activity in human visual            ventral stream, as in inferotemporal cortex (Spitzer &
      cortex. More recently, using functional magnetic res-       Richmond, 1991), and also in dorsal stream, as in
      onance imaging (fMRI), it has been shown in greater         motion processing areas MT and MST (Recanzone
      detail that attention to visual stimuli increases neural    et al., 1993; Treue & Martínez-Trujillo, 1999). Animal
      activation in multiple visual areas (Hopfinger et al.,      studies of spatial attention demonstrate that a cell’s
      2000; Kastner et al., 1998, 1999; Tootell et al., 1998),    response to a stimulus presented in its receptive field
      and attention to specific visual features such as           is highly sensitive to where the animal is attending.
      motion and color selectively modulates areas associ-        For example, Moran & Desimone (1985) recorded
      ated with processing those features (Giesbrecht et al.,     from V4 of the macaque monkey and found that
      2003; Liu et al., 2003). Likewise, attention to auditory    spatial attention gated the response to the cell’s pre-
      stimuli modulates auditory cortex (Petkov et al., 2004;     ferred stimulus; the response to a stimulus that was
      Sevostianov et al., 2002). Also, attending to smell modu-   effective in driving a cell was dramatically reduced if
      lates frontal piriform cortex, one of two main regions      the monkey was attending to a different stimulus
      involved in olfactory processing (Zelano et al., 2005).     within the receptive field, but only minimally reduced
          The effects of early selection can also be observed     if the monkey was attending to a different stimulus
      in electrophysiological studies of attention, where the     outside the receptive field (see also Luck et al., 1997;
      time course of information processing can be trac-          Reynolds et al., 1999).
      ked on a millisecond-to-millisecond basis. Sensory-             While many studies have explored attentional
      evoked event-related potentials (ERPs) recorded from        selection in primary and secondary perceptual areas,
      electrodes placed on the human scalp are sensitive to       a smaller number have examined it at later stages of
      the direction of selective attention. These sensory ERP     processing, along the perception–action continuum.
      components are greater in amplitude for attended-           Late selection processes can include attention to
      location stimuli than for the same physical stimuli at      actions, either imminent or already partially executed,
      an ignored location (Van Voorhis & Hillyard, 1977).         and also to the goal selection processes that govern
      Because these sensory ERPs begin within 70–80 ms of         decision-making that leads to action. In one study,
      stimulus onset and arise from visual cortical areas         Cook & Maunsell (2002) trained monkeys on a
      V1–V4 (Heinze et al., 1994; Khoe et al., 2005), the         motion-detection task and measured neural activity
106   finding that spatial attention affects their amplitudes     in MT and the ventral intraparietal area (VIP) in
      suggests that attention operates by modulating the          relation to the animal’s behavior. The monkeys were
                                                                          Chapter 8: The neural basis of attention



required to release a lever when they detected the            reflect attentional selection, which is the effective
onset of coherent random-dot motion, which could              selection of behaviorally relevant inputs, thoughts
occur either at an attended or unattended location.           and actions. A key question for neuroscience is to
There was some attentional modulation of the neural           understand how these attentional selection processes
activity in area MT, but this modulation was insuffi-         are controlled in the brain and how attentional bias-
cient to explain the behavior changes, suggesting that        ing processes are engaged. In the next section we
attention also operates at later levels of processing.        consider attentional control mechanisms for volun-
    Similar to that involved in early selection, studies      tary attention.
reveal that a fronto-parietal network is active and
coupled with action representations in the motor              Voluntary attentional control
cortex during attention to action (Rowe et al., 2002,
2005). As with attentional modulation of perceptual           mechanisms
areas, attention to action affects activity in motor          Models of attention have differentiated attentional con-
cortices. For example, attending to finger movements          trol processes, and how these processes influence a site
enhances activation in motor area 4p (Binkofski et al.,       of action, such as the perceptual system (Posner &
2002). However, it is not known whether late selection        Petersen, 1990). In the preceding section, we review-
effects are topographically organized according to            ed work on the site of action (early versus late) in
effectors; one study reported effector-independent            information processing and asked which brain
activation of the intraparietal sulcus (IPS) and the          systems provide the control signals that result in
frontal eye fields (Astafieve et al., 2003). It is expected   selective processing at early and late stages of proces-
that activation patterns within the motor cortex              sing. Research in animals, patients with neuro-
during attention to action will be effector-specific, in      logical dysfunction, and healthy human subjects
the same way that attentional modulation in sensory           using ERPs and neuroimaging, suggests that the top-
cortices is modality-specific. Topographic organiza-          down control of visual spatial attention involves a
tion of premotor and motor cortices has been clearly          complex network of widely distributed areas, includ-
demonstrated during imagination (Johnson et al.,              ing dorsolateral prefrontal cortex (DLPFC), anterior
2002; De Lange et al., 2005) and observation (Buccino         cingulate cortex, posterior parietal cortex and thal-
et al., 2001) of action. However, direct evidence of          amic and midbrain structures (Bushnell et al., 1981;
topographical organization of attention effects during        Goldberg & Bruce, 1985; Harter et al., 1989; Knight
late selection is lacking to date.                            et al., 1995; Mesulam, 1981; La Berge, 1997; Miller,
    The foregoing studies demonstrate that focused            2000). Event-related fMRI has recently identified
attention can influence the neural responses to               superior frontal, inferior parietal and superior tem-
attended and ignored stimuli. This has been liken-            poral regions that are selectively activated during
ed to a gain control mechanism, which relatively              attentional control processing (Corbetta et al., 2000;
increases the gain of neurons coding attended stimuli         Hopfinger et al., 2000). Current models hypothesize
or actions, while relatively turning down the gain of         that these networks reflect top-down (voluntary)
neurons coding ignored events and action. What does           attentional influences that result in changes in levels
this sort of gain control accomplish? One current             of excitability in multiple visual cortical areas that
concept is that it leads to a biasing in the neural           work to achieve selective sensory processing of
responses to attended items versus ignored events.            relevant visual targets (reviewed in Kanwisher &
Attentional biasing is the idea that attention influ-         Wojciulik, 2000; Kastner & Ungerleider, 2000).
ences the outcome of neural competition in neural                 Goal-directed behavior in an ever-changing envir-
networks at a variety of stages of information process-       onment requires our brain to select relevant sensory
ing (Desimone & Duncan, 1995). Neural competition             information and flexibly link relevant stimuli to
arises from the local and global neural networks              appropriate actions. The prefrontal cortex may pro-
involved in sensory, cognitive or motor function,             vide the necessary attention control signals, but the
where models of attentional control propose that this         actual “rewiring” of the information flow may occur
competition can be biased in favor of attended inputs,        in more posterior areas (Miller & Cohen, 2001). Par-
thoughts and actions. In such models, the resultant           ietal cortex would be well-suited for a key role in this   107
biased processes and their outputs are thought to             function since it is located at the interface between
         Section 1: Neuropsychological processes



      sensory input and motor control. Non-human primate            is still uncertain how the need for attentional control
      studies suggest that the parietal cortex is a collection of   is initially signaled. We have argued a role for the
      planning areas for goal-directed movements or shifts          anterior cingulate cortex (ACC) in the detection of
      of visual spatial attention. However, recent evidence         conflict, which is used to signal the need for cogni-
      suggests that it might also carry signals related to          tive control (Carter et al., 1998; Kerns et al., 2004;
      “cognitive set” (Stoet & Snyder, 2004).                       MacDonald et al., 2000). Using the Stroop color-
           How the circuitry applying these signals to the          naming task, Kerns et al. (2004) demonstrated that
      sensory-motor-transformation process might work               activity of the ACC predicts adjustments in behavior
      in the parietal cortex is currently unknown. It may           on the next trial. Typically, activity of the ACC is not
      be that “input neurons” in parietal areas carry both          observed in studies of selective attention unless high
      task-relevant and task-irrelevant sensory information         levels of control are needed (situations in which com-
      (that probably already has undergone some, but                petition among potential responses exists, and/or in
      insufficient, attentional modulation). The network            speeded tasks where error rate is high). In our cued
      might then be reconfigured so that task-irrelevant            spatial attention task, ACC activity increased as dif-
      sensory information is filtered out and task-relevant         ference between two cues increased in difficulty
      information is linked to an appropriate action. If true,      (Walsh et al., 2005). However, the ACC was not
      one would expect to find parietal neurons that are            responsive to cues in general; that is, the ACC was
      selective for a particular action (eye movement, etc.)        not recruited when cues were informative as to the
      and also for the sensory stimulus informing this              direction in which to shift spatial attention compared
      action (similar to prefrontal or supplementary motor          with neutral cues.
      neurons during the learning of new stimulus-                      Activity of the ACC not only results in improved
      response-associations; Asaad et al., 1998; Chen &             performance on the next trial, but activity of the
      Wise, 1995). So far, parietal activity has usually been       DLPFC is also greater in consequence (Kerns et al.,
      tested in experimental situations with a fixed associ-        2004a). We have proposed that the ACC signals the
      ation between stimuli and responses, and so this              DLPFC to exert greater attentional control to the task
      hypothesis has not been tested.                               at hand. One way to directly assess whether the
           Functional imaging has greatly enhanced the abil-        DLPFC is involved in attentional control is to show
      ity to investigate widespread cortical networks partici-      that it is engaged in preparatory attention. The use of
      pating in cognitive functions such as attentional             cueing paradigms to signal subjects to prepare and
      control, but relatively little work has analyzed sub-         hence engage attentional control systems has a long
      cortical structures, such as the pulvinar nuclei of the       tradition in cognitive psychology and cognitive
      thalamus, that have been implicated in attention.             neuroscience (Posner et al., 1980), and provides a
      Rafal & Posner (1987) provided evidence of                    means to dissociate attentional control from attention
      attentional-orienting deficits with thalamic infarcts         selection processes. In this context, cue-related activ-
      that included the pulvinar in two of their three              ity has often been found in DLPFC and posterior
      patients. La Berge (1997) proposed a role for the pul-        parietal cortex (PPC); this has occurred in tasks in
      vinar in his triangular circuit model of attention, which     which the cue instructs participants which of several
      argued that frontal and parietal cortices influence per-      stimulus-response (S-R) mappings to use to react to a
      ceptual cortical processing via interactions with the         subsequent target stimulus (Barber & Carter, 2005;
      pulvinar. His studies using positron emission tomog-          Corbetta et al., 2000, 2002; Corbetta & Shulman,
      raphy (PET) implicated the pulvinar in the filtering of       2002; DeSouza et al., 2003; Kincade et al., 2005; Nobre
      distracters. Also supporting a role for the pulvinar in       et al., 2000; Weissman et al., 2004; Woldorff et al.,
      attention, a recent human lesion study showed deficits        2004). An effect of attentional preparation is mani-
      in attentional processing with damage to this region          fested as a relative increase in activity; that is, DLPFC
      (Michael & Desmedt, 2004). More current models                activation is higher when the cue tells the participant
      similarly implicate the pulvinar in attention (Sherman        to prepare for the more demanding task. For instance,
      & Guillery, 2002; Shipp, 2004), but still little additional   during the Stroop task, MacDonald et al. (2000)
      evidence has been generated for such a model.                 found increased DLPFC activity when a cue
108        While the pulvinar is proposed to modulate per-          instructed the person to respond to the color rather
      ceptual processing as a result of attentional control, it     than the word.
                                                                       Chapter 8: The neural basis of attention



Supramodal attention                                       we earlier reviewed, bottom-up or “stimulus-driven”
                                                           mechanisms are triggered by the properties of sensory
Both early and late selection appear to be modality-
                                                           inputs. There are two general types of bottom-up influ-
specific, while the implementation of goals needed
                                                           ences in information processing. The first is the sensory
to overcome more reflexive attentional adaptation
                                                           influence of a stimulus itself, which, depending on its
may depend upon the engagement of frontal and
                                                           properties such as stimulus saliency, may bias neural
parietal systems, which may operate in a more
                                                           competition (Robinson & Petersen, 1992). A second
modality-dependent manner. Surprisingly, it is largely
                                                           aspect, described as attentional in nature, occurs
unknown to what extent regions involved in atten-
                                                           when bottom-up sensory signals trigger an automatic
tional control such as the DLPFC are dependent upon
                                                           or “reflexive” orienting of attention (Hopfinger &
stimulus or response modality. De Souza et al. (2003)
                                                           Mangun, 1998; Klein, 2000; Posner & Cohen, 1984).
found that a cue indicating an anti-saccade response
                                                           Bottom-up factors and top-down influences do not act
elicits greater activity in right DLPFC and the frontal
                                                           in isolation from each other, but rather interact, some-
eye fields (FEF). The FEF are involved with the con-
                                                           times competing for the control of neural activity and
trol of overt eye movements and also with the control
                                                           therefore control of behavior. Indeed, top-down atten-
of covert spatial attention shifts (Corbetta et al.,
                                                           tional control is most relevant when goals and strategies
1998); they are activated to cues instructing the direc-
                                                           are in competition with bottom-up stimulus-driven
tion of a subsequent eye movement or a covert shift of
                                                           influences or prepotent response tendencies (Beck &
spatial attention (Kincade et al., 2005). The De Souza
                                                           Kastner, 2005). In the following we consider the
study shows, however, that the FEF are activated by
                                                           neural correlates and control mechanisms for reflexive
contextual cues too, suggesting that the attention con-
                                                           attention.
trol functions supported by this region might include
                                                               The distinction between voluntary and reflexive
response modality-specific regions of the lateral PFC.
                                                           attention was demonstrated in behavioral studies that
Similarly, little is known about whether cue-related
                                                           established the parameters of each form of attention
activation of the PFC is stimulus modality-specific.
                                                           in terms of performance. The bottom-up attentional
Weissman et al. (2004), using a task in which partici-
                                                           influences of sensory events (Jonides, 1980, 1981;
pants were instructed to respond to subsequent audi-
                                                           Yantis, 1996) are more rapidly and transiently
tory or visual stimuli, showed that target-related
                                                           engaged than those associated with voluntary atten-
activity was increased in the auditory cortex when
                                                           tion (Jonides, 1981; Posner et al., 1980). In addition,
participants were instructed to attend to auditory
                                                           the engagement of reflexive (stimulus-driven) atten-
targets and in visual cortex following a cue to visual
                                                           tion is followed by inhibition, or a relative slowing in
targets. However, no stimulus modality-specific PFC
                                                           response time at that location (Posner & Cohen,
activation was observed.
                                                           1984). This latter effect is known as inhibition of
    Similarly, the parietal cortex has been implicated
                                                           return (IOR), and it may enable the sensory reflexive
as the proximal source of attentional control across
                                                           system to favor novel locations, promoting effective
domains (Kanwisher & Wojciulik, 2000; see Behrmann
                                                           search of the scene (Wolfe et al., 1989).
et al., 2004 for a review). One neuroimaging study
                                                               Human ERP and fMRI studies of reflexive atten-
demonstrated that overlapping parietal regions were
                                                           tion have demonstrated that when attention is reflex-
engaged by a variety of spatial and non-spatial
                                                           ively captured to a visual field location, subsequent
tasks such as peripheral shifting, conjunction search
                                                           stimuli presented to that location receive enhanced
and object matching (Kanwisher & Wojciulik,
                                                           cortical visual processing (Hopfinger & Mangun,
2000). Thus, while early and late selection appear
                                                           1998, 2001). Subsequent work has now shown that
linked to the modulation of discrete, topographically
                                                           the earliest signs of reflexive attention in the ERPs are
organized sensory and motor systems, it is less clear
                                                           automatic (Hopfinger & Maxwell, 2005) and occur
that there is modality-specificity within attention-
                                                           even when test stimuli are not task-relevant and
control networks.
                                                           the observers are engaged in unrelated visual tasks.
                                                           Based on this sort of evidence, one can propose that
Reflexive attention mechanisms                             reflexive attention influences early visual cortical pro-
In contrast to the top-down processes that are engaged     cessing as well as subcortical motor systems (Rafal &       109
by the goals and intentions of the individual that         Henik, 1994; Sapir et al., 1999). Imaging research has
         Section 1: Neuropsychological processes



      demonstrated that these early effects of reflexive           for voluntary attention. However, evidence suggests
      attention on visual processing occur in multiple early       that partially different neural mechanisms regulate
      visual areas, including V1 (Liu et al., 2005), but may       these two forms of orienting, with subcortical regions
      involve mechanisms operating at the level of LGN             controlling reflexive orienting and cortical regions
      via interactions of LGN and V1.                              controlling voluntary orienting (Corbetta et al.,
          Although the attentional modulation of reflexes,         1993; Posner & Peterson, 1990; Rafal & Henik,
      social behavior and eye movements have all been stud-        1994). This fits with the general concept of reflexive
      ied using animal models (e.g. reflexes, Schicatano et al.,   attention being driven by “bottom-up” processes,
      2000; social behavior, Emery et al., 1997 and Lorincz        while voluntary attention is considered a “top-down”
      et al., 1999; eye movements, Andersen, 1989), few single     process. However, a more likely framework involves
      unit recording studies of reflexive attention effects on     the interaction of subcortical and cortical regulatory
      visual processing have been conducted in animals. Until      systems for both voluntary and reflexive attention
      recently, there was no animal study counterpart to the       with different regulatory networks; this interaction
      cognitive literature (Yantis & Jonides, 1990) or human       may be weighted more toward subcortical systems
      neurophysiological literature (Hopfinger & Mangun,           for reflexive attention (Sapir et al., 1999) and cortical
      1998, 2001) on reflexive attention effects on visual pro-    systems for voluntary attentional control (Coull et al.,
      cessing. Most work on attention in non-human pri-            2000; Rosen et al., 1999).
      mates involved voluntary (goal-driven) mechanisms                 Several functional neuroimaging studies have
      (Cook & Maunsell, 2004; Moran & Desimone, 1985).             suggested that voluntary and reflexive attention are
      There are, however, two main lines of work on reflexive      regulated by largely the same neural architecture
      attention using animal models: one in monkeys, investi-      (Corbetta et al., 1993; Nobre et al., 1997; Peelen
      gating the superior colliculus (SC), and one in rats,        et al., 2004; Rosen et al., 1999), indicating a unitary
      investigating the thalamus.                                  attentional regulatory mechanism that can be engaged
          Recently, in macaques, Fecteau et al. (2004)             through somewhat different means (i.e. top-down
      investigated the role of the SC in reflexive spatial         or bottom-up). A more recent neuroimaging study
      attention. They demonstrated that the SC is influ-           (Mayer et al., 2004) compared exogenous and
      enced by reflexive attention in a pattern similar to         endogenous orienting using the cue-to-target inter-
      that found in human behavioral and ERP studies.              vals expected to yield the strongest facilitation effects
      However, how the SC mechanisms interact with                 for each type of attention (i.e. shorter cue-target
      thalamo-cortical processing during reflexive attention       intervals for exogenous cuing). This critical aspect
      remains unknown.                                             of the design allowed the authors to find evidence
          In the second study, Weese et al. (1999) used            for a greater differentiation between these systems,
      a variant of a non-predictive peripheral cuing para-         with much of the typical attentional network
      digm to study subcortical mechanisms of attention            (i.e. frontal eye fields, intraparietal sulcus, superior
      in a rat model. Their findings suggested that reflexive      temporal gyrus, temporo-parietal junction) being
      attention effects in the visual pathways may be mediated     activated by endogenous attention but not by exogen-
      by circuitry at the level of the thalamus and V1 via         ous attention. In addition, a recent fMRI study of
      feedback of the cortico-thalamic afferents by the reticu-    overt attention similarly found distinct differences
      lar nucleus of the thalamus. However, Weese et al.           between the neural systems supporting voluntary
      (1999) did not investigate the result on visual cortical     versus reflexive saccades (Mort et al., 2003). This is
      processing, as they measured behavior following lesions      in line with more recent ERP evidence from how
      restricted to subcortical sites. Nonetheless, their model    reflexive and voluntary attention affects visual infor-
      suggests that reflexive cues may not engage fronto-          mation processing, which suggests that these different
      parietal networks involved in voluntary attention, an        forms of attention are mediated by partially or wholly
      important consideration for models of reflexive atten-       distinct mechanisms that act with characteristic time
      tional control. However, the work of Weese et al. (1999)     courses at different levels of information processing
      cannot address this question directly because they did       (Hopfinger & West, 2006). Further research is war-
      not record from the cortex.                                  ranted to assess the extent to which dissociable neural
110       As noted above, the neural correlates of sensory         control networks underlie reflexive versus voluntary
      reflexive attention are less well understood than those      attention.
                                                                          Chapter 8: The neural basis of attention



Attentional deficits in psychiatric                          their orienting to emotional information in the
                                                             environment, which may contribute to the develop-
disorders                                                    ment and maintenance of their symptoms. On
Abnormalities of attention are common subjective             a number of different measures, people with depres-
complaints in a range of mental disorders, including         sion and anxiety disorders tend to selectively process
anxiety, mood and psychotic disorders. The degree to         negative emotional material (e.g. sad faces, angry
which these abnormalities have been investigated             faces, emotional words) while non-depressed or anx-
using the tools and constructs of cognitive neurosci-        ious individuals tend to orient away from this kind of
ence has varied. For example, the majority of studies        information (Leyman et al., 2007; Mogg et al., 2000).
of cognition in depression have used standardized            This pattern has been seen in individuals who are in
batteries of clinical neuropsychological tasks that do       the active phases of their illness and also in remission
not readily distinguish between deficits in attention        (Joormann & Gotlib, 2007). Functional neuroimaging
versus other aspects of higher cognition, or even            studies have suggested that explicit processing of
between specific cognitive deficits, general psycho-         emotional information in depression is associated
motor slowing and/or poor motivation. The results            with overactivation of the amygdala, an effect that
of these studies are varied, although most report some       resolves with effective treatment (Seigle et al., 2002;
degree of impaired performance, which is present to a        Sheline et al., 2001). This finding is difficult to recon-
degree in remitted patients, but greatest in acutely ill     cile with the observation that attentional biases in
patients (Gualtieri et al., 2006; Den Hartog et al.,         depression and anxiety are stable traits in at-risk
2003; Paelecke-Habermann et al., 2005). Interpret-           individuals, and more research is needed to clarify
ation of these studies is difficult given the variability    what kinds of processing biases are risk factors for
across studies and the fact that many depressed sub-         mood disorders and what kinds are state-related.
jects continue to experience residual symptoms after             In contrast to mood disorders, attention in schizo-
treatment. A few studies using the Stroop task gener-        phrenia has been studied intensively using modern
ally find a lack of impairment in patients with major        experimental methods from cognitive neuroscience.
depression, with the possible exception of patients          The emerging picture is that basic attentional
with the more severe melancholic subtype (Markela-           orienting and selection mechanisms are intact in
Lerenc et al., 2006; Rogers et al., 2004). Several studies   schizophrenia, while cognitive control mechanisms
have used the CANTAB battery, a computerized                 that are involved in detecting and overcoming conflict
assessment that bridges standardized neuropsycho-            appear to be consistently impaired at all stages of the
logical approaches with more theoretically based             illness (Luck & et al., 2006). Functional neuroimaging
experimental cognitive tasks (Purcell et al., 1997;          studies suggest that these deficits in executive atten-
Sweeney et al., 2000). Using this approach has pro-          tion appear to be related to abnormalities in dorso-
duced mixed results with one study showing predom-           lateral prefrontal and anterior cingulate cortex (Snitz
inantly memory deficits (Sweeney et al., 2000) and           et al., 2005), while more posterior attentional control
another predominantly executive (set shifting) deficits      systems appear to be intact. These abnormalities in
(Purcell et al., 1997). Previous research has therefore      attentional control have been recognized as very
not clarified the nature and significance of deficits in     important since they are highly correlated with
attention in depression, despite the frequency with          functional disability in the illness and refractory to
which patients complain of these deficits. Since the         our currently available treatments (Green, 1996).
numbers of subjects studied to date is small, more           Developing effective therapies, either pharmaco-
work is needed using a more cognitive experimental           logical or neurobehavioral, has become one of the
approach before we have a clearer understanding of           highest priorities for modern clinical neuroscience.
the nature and severity of deficits, if any, in attention
in major depression.
    While the attention deficits per se in mood              Conclusion
disorders is unclear and in need of further investi-         Attentional control and selection involves a dynamic
gation, a large and consistent literature supports the       set of neural mechanisms acting at multiple stages
fact that individuals with both depression and anxiety       of information processing to enable efficient stimulus       111
disorders have content-specific attentional biases in        analysis, decisions and response execution. The ability
         Section 1: Neuropsychological processes



      to control attention involves the interaction of                  Behrmann, M., Geng, J. J. & Shomstein, S. (2004). Parietal
      specific cortical and subcortical neural networks that              cortex and attention. Current Opinions in Neurobiology,
      establish modulatory influences at multiple stages of               14, 212–217.
      information processing to bias processing in favor of             Binkofski, F., Fink, G. R., Geyer, S. et al. (2002). Neural
      attended events and actions. The modulation of atten-                activity in human primary motor cortex areas 4a and 4p
      tional selection on perceptual and action systems                    is modulated differentially by attention to action. Journal
                                                                           of Neurophysiology, 88, 514–519.
      is established dynamically, changing on a moment-
      to-moment basis as a function of changing goals,                  Broadbent, D. E. (1962). Attention and the Perception of
                                                                           Speech. New York: W.H. Freeman and Co.
      strategies, and stimulus and task demands. Moreover,
      the nature of attentional selection in perception and             Buccino, G., Binkofski, F., Fink, G. R. et al. (2001). Action
                                                                          observation activates premotor and parietal areas in a
      action is highly constrained by local neuronal and
                                                                          somatotopic manner: an fMRI study. European Journal
      neural network properties that are specific to the sensory          of Neuroscience, 13, 400–404.
      system or perceptual or response processes involved.
                                                                        Bushnell, M. C., Goldberg, M. E. & Robinson, D. L. (1981).
          This view incorporates the idea that attentional
                                                                          Behavioral enhancement of visual responses in monkey
      phenomena do not rely on mechanisms acting at                       cerebral cortex. I. Modulation in posterior parietal cortex
      unitary stages of information processing or only at                 related to selective visual attention. Journal of
      particular levels of neural analysis, but rather that               Neurophysiology, 46, 755–772.
      mechanisms at the neuronal, local neuronal circuit                Carrasco, M., Ling, S. & Read, S. (2004). Attention alters
      and global neural network levels are all relevant                   appearance. Nature Neuroscience, 7, 308–313.
      during attentional control and selection. Therefore,              Carter, C. S., Braver, T. S., Barch, D. M. et al. (1998).
      to elucidate the neural mechanisms of attention it is               Anterior cingulate cortex, error detection and the online
      essential to investigate and characterize attentional               monitoring of performance. Science, 280, 747–749.
      processes at a variety of levels of information process-          Chelazzi, L., Miller, E. K., Duncan, J. & Desimon, R. (1993).
      ing. Moreover, this work can help to characterize                   A neural basis for visual search in inferior temporal
      potential attention deficits associated with psychiatric            cortex. Nature, 363, 345–347.
      disorders that may also have a neurological basis.                Chelazzi, L., Miller, E. K., Duncan, J. & Desimon, R. (2001).
                                                                          Responses of neurons in macaque area V4 during
      Acknowledgments                                                     memory-guided visual search. Cerebral Cortex, 11, 345–347.

      Supported by NIMH grants K02MH064190 and                          Chen, L. L. & Wise, S. P. (1995). Neuronal activity in
                                                                          the supplementary eye field during acquisition of
      RO1MH059883 to C.S.C. and MH55714 and
                                                                          conditional oculomotor associations. Journal of
      MH02019 to G.R.M.                                                   Neurophysiology, 73, 1101–1121.
                                                                        Cook, E. P. & Maunsell, J. H. (2002). Attentional
      References                                                          modulation of behavioral performance and neuronal
      Andersen, R. A. (1989). Visual and eye movement functions           responses in middle temporal and ventral intraparietal
        of the posterior parietal cortex. Annual Review of                areas of macaque monkey. Journal of Neuroscience, 22,
        Neuroscience, 12, 377–403.                                        1994–2004.
      Asaad, W. F., Rainer, G. & Miller, E. K. (1998). Neural           Cook, E. P. & Maunsell, J. H. (2004). Attentional
        activity in the primate prefrontal cortex during                  modulation of motion integration of individual neurons
        associative learning. Neuron, 21, 1399–1407.                      in the middle temporal visual area. Journal of
                                                                          Neuroscience, 24, 7964–7977.
      Astafieve, S. V., Shulman, G. L., Stanley, C. M. et al. (2003).
         Functional organization of human intraparietal and             Corbetta, M. & Shulman, G. (2002). Control of goal-
         frontal cortex for attending, looking, and pointing.             directed and stimulus-driven attention in the brain.
         Journal of Neuroscience, 23, 4689–4699.                          Nature Reviews Neuroscience, 3, 201–215.
      Barber, A. D. & Carter, C. S. (2005). Cognitive control           Corbetta, M., Akbudak, E., Conturo, T. E. et al. (1998).
         involved in overcoming prepotent response                        A common network of functional areas for attention and
         tendencies and switching between tasks. Cerebral Cortex,         eye movements. Neuron, 21, 761–773.
         15, 899–912.                                                   Corbetta, M., Kincade, J. M., Ollinger, J. M., McAvoy, M. P.
      Beck, D. M. & Kastner, S. (2005). Stimulus context                  & Shulman, G. L. (2000). Voluntary orienting is
112      modulates competition in human extrastriate cortex.              dissociated from target detection in human posterior
         Nature Neuroscience, 8, 1110–1116.                               parietal cortex. Nature Reviews Neuroscience, 3, 292–297.
                                                                               Chapter 8: The neural basis of attention



Corbetta, M., Kincade, J. M. & Shulman, G. L. (2002).            Giesbrecht, B., Woldorff, M. G., Song, A. W. & Mangun,
  Neural systems for visual orienting and their                     G. R. (2003). Neural mechanisms of top-down control
  relationships to spatial working memory. Journal                  during spatial and feature attention. Neuroimage, 19,
  of Cognitive Neuroscience, 14, 508–523.                           496–512.
Corbetta, M., Miezin, F. M., Dobmeyer, S., Shulman, G. L. &      Gobell, J. & Carrasco, M. (2005). Attention alters the
  Petersen, S. E. (1990). Attentional modulation of neural         appearance of spatial frequency and gap size.
  processing of shape, color, and velocity in humans.              Psychological Science, 16, 644–651.
  Science, 248, 1556–1559.                                       Goldberg, M. E. & Bruce, C. J. (1985). Cerebral cortical
Corbetta, M., Miezin, F., Shulman, G. L. & Petersen, S. E.         activity associated with the orientation of visual attention
  (1993). A PET study of visuospatial attention. Journal           in the rhesus monkey. Vision Research, 25, 471–481.
  of Neuroscience, 13, 1202–1226.                                Green, M. F. (1996). What are the functional consequences
Coull, J. T., Frith, C. D., Büchel, C. & Nobre, A. C. (2000).      of neurocognitive deficits in schizophrenia? American
  Orienting attention in time: behavioral and                      Journal of Psychiatry, 153, 321–330.
  neuroanatomical distinction between exogenous and              Handy, T., Kingstone A. & Mangun, G. R. (1996). Spatial
  endogenous shifts. Neuropsychologia, 38, 808–819.                distribution of visual attention: perceptual sensitivity
Den Hartog, H. M., Derix, M. M., Van Bemmel, A. L.,                and response latency. Perception and Psychophysics,
  Kremer, B. & Jolles, J. (2003). Cognitive functioning in         58, 613–627.
  young and middle-aged unmedicated out-patients with            Harter, M. R., Miller, S. L., Price, N. J., LaLonde, M. E. &
  major depression: testing the effort and cognitive speed         Keyes, A. L. (1989). Neural processes involved in
  hypotheses. Psychological Medicine, 33, 1443–1451.               directing attention. Journal of Cognitive Neuroscience,
De Lange, F. P., Hagoort, P. & Toni, I. (2005). Neural             1, 223–237.
  topography and content of movement representations.            Hawkins, H. L., Hillyard, S. A., Luck, S. J. et al. (1990).
  Journal of Cognitive Neuroscience, 17, 97–112.                   Visual attention modulates signal detectability. Journal
De Souza, J. F., Menon, R. S. & Everling, S. (2003).               of Experimental Psychology: Human Perception and
  Preparatory set associated with pro-saccades and anti-           Performance, 16, 802–811.
  saccades in humans investigated with event-related             Heinze, H. J. & Mangun, G. R. (1995). Electrophysiological
  FMRI. Journal of Neurophysioogy, 89, 1016–1023.                  signs of sustained and transient attention to spatial
Desimone, R. & Duncan, J. (1995). Neural mechanisms of             locations. Neuropsychologia, 33, 889–908.
  selective visual attention. Annual Review Neuroscience,        Heinze, H. J., Mangun, G. R., Burchert, W. et al. (1994).
  18, 193–222.                                                     Combined spatial and temporal imaging of spatial
Deutsch, J. A. & Deutsch, D. (1963). Attention: some               selective attention in humans. Nature, 392, 543–546.
  theoretical considerations. Psychological Review, 70, 51–60.   Helmholtz, H. von (1962/1924–25). Treatise on
Downing, C. J. (1988). Expectancy and visual-spatial               Physiological Optics (3rd edn.). Edited by J. P. C.
  attention: effects on perceptual quality. Journal of             Southall. New York: Dover Publications.
  Experimental Psychology: Human Perception and                  Hopf, J., Luck, S. J., Boelmans, K. et al. (2006). The neural
  Performance, 14, 188–202.                                        site of attention matches the spatial scale of perception.
Duncan, J. (1998). Converging levels of analysis in the            Journal of Neuroscience, 26, 3532–3540.
  cognitive neuroscience of visual attention. Philosophical      Hopfinger, J. B. & Maxwell, J. S. (2005). Appearing
  Transactions of the Royal Society of London, Series B, 353,      and disappearing stimuli trigger a reflexive modulation
  1307–1317.                                                       of visual cortical activity. Cognitive Brain Research,
Emery, N., Lorincz, E., Perrett, D., Oram, M. & Baker, C.          25(1), 48–56.
  (1997). Gaze following and joint attention in rhesus           Hopfinger, J. B. & Mangun, G. R. (1998). Reflexive
  monkeys (Macaca mulatta). Journal of Comparative                 attention modulates processing of visual stimuli
  Psychology, 111, 286–293.                                        in human extrastriate cortex. Psychological Science,
Fecteau, J. H., Bell, A. H. & Munoz, D. P. (2004). Neural          9, 441–447.
   correlates of the automatic and goal-driven biases in         Hopfinger, J. B. & Mangun, G. R. (2001). Tracking the
   orienting spatial attention. Journal of Neurophysiology,        influence of reflexive attention on sensory and cognitive
   92, 3, 1728–1737.                                               processing. Cognitive, Affective and Behavioral
Gualtieri, C. T., Johnson, L. G. & Benedict, K. B. (2006).         Neuroscience, 1, 56–65.
  Neurocognition in depression: patients on and off              Hopfinger, J. B & West, V. M. (2006). Interactions between
  medication versus healthy comparison subjects. Journal of        endogenous and exogenous attention on cortical visual          113
  Neuropsychiatry and Clinical Neurosciences, 18, 217–225.         processing. Neuroimage, 31, 774–789.
         Section 1: Neuropsychological processes



      Hopfinger, J. B., Buonocore, M. H. & Mangun, G. R. (2000).       Leyman, L., De Raedt, R., Schacht, R. & Koster, E. H. (2007).
        The neural mechanisms of top-down attentional control.            Attentional biases for angry faces in unipolar depression.
        Nature Neuroscience, 3, 284–291.                                  Psychological Medicine, 37, 393–402.
      Johnson, S. H., Rotte, M., Grafton, S. T. et al. (2002).         Liu, T., Pestilli, F. & Carrasco, M. (2005). Transient
         Selective activation of a parietofrontal circuit                 attention enhances perceptual performance and FMRI
         during implicitly imagined prehension. Neuroimage,               response in human visual cortex. Neuron, 45, 469–477.
         17, 1693–1704.                                                Liu, T., Slotnick, S. D., Serences, J. T. & Yantis, S. (2003).
      Jonides, J. (1980). Towards a model of the mind’s                   Cortical mechanisms of feature-based attentional
         eye’s movement. Canadian Journal of Psychology,                  control. Cerebral Cortex, 13, 1334–1343.
         34, 103–112.                                                  Lorincz, E. N., Baker, C. & Perrett, D. I. (1999). Visual cues
      Jonides, J. (1981). Voluntary versus automatic control              for attention following in rhesus monkeys. Cahiers de
         over the mind’s eye movement. In J. B. Long & A. D.              Psychologie Cognitive, 18, 973–1003.
         Baddeley (Eds.), Attention and Performance IX                 Luck, S. J., Chelazzi, L., Hillyard, S. A. & Desimone, R.
         (pp. 187–203). Hillsdale, NJ: Lawrence Erlbaum                  (1997). Neural mechanisms of spatial selective attention
         Associates.                                                     in areas V1, V2 and V4 of macaque visual cortex. Journal
      Joormann, J. & Gotlib, I. H. (2007). Selective attention           of Neurophysiology, 77, 24–42.
         to emotional faces following recovery from depression.        Luck, S. J., Hillyard, S. A., Mouloua, M. et al. (1994).
         Journal of Abnormal Psychology, 116, 80–85.                     Effects of spatial cuing on luminance detectability:
      Kanwisher, N. & Wojciulik, E. (2000). Visual attention:            psychophysical and electrophysiological evidence for
        insights from brain imaging. Nature Reviews                      early selection. Journal of Experimental Psychology:
        Neuroscience, 1, 91–100.                                         Human Perception and Performance, 20, 887–904.
      Kastner, S. & Ungerleider, L. (2000). Mechanisms of visual       Luck, S. J., Woodman, G. F. & Vogel, E. K. (2000). Event-
        attention in the human cortex. Annual Review of                  related potential studies of attention. Trends in Cognitive
        Neuroscience, 23, 315–341.                                       Science, 4, 432–440.
      Kastner, S., DeWeerd, P., Desimone, R. & Ungerleider, L. C.      Luck, S. J., Fuller, R. L., Braun, E. L. et al. (2006). The speed
        (1998). Mechanisms of directed attention in the human            of visual attention in schizophrenia: electrophysiological
        extrastriate cortex as revealed by functional MRI.               and behavioral evidence. Schizophrenia Research, 85,
        Science, 282, 108–111.                                           174–195.
      Kastner, S., Pinsk, M. A., De Weerd, P., Desimone, R. &          Macaluso, E. & Driver, J. (2005). Multisensory spatial
        Ungerleider, L. G. (1999). Increased activity in human           interactions: a window onto functional integration in the
        cerebral cortex during directed attention in the absence         human brain. Trends in Neuroscience, 28, 264–271.
        of visual stimulation. Neuron, 22, 751–761.                    MacDonald, A. W., 3rd, Cohen, J. D., Stenger, V. A. &
      Kerns, J. G., Cohen, J. D., MacDonal, A. W. et al. (2004a).        Carter, C. S. (2000). Dissociating the role of the
        Anterior cingulate conflict monitoring and adjustments           dorsolateral prefrontal and anterior cingulated cortex
        in control. Science, 303, 1023–1026.                             in cognitive control. Science, 288, 1835–1838.
      Khoe, W., Mitchell, J. F., Reynolds, J. H. & Hillyard, S. A.     Mangun, G. R. (1995). Neural mechanisms of visual
        (2005). Exogenous attentional selection of transparent           selective attention in humans. Psychophysiology, 32, 4–18.
        superimposed surfaces modulates early event-related            Markela-Lerenc, J., Kaiser, S., Fiedler, P., Weisbrod, M. &
        potentials. Vision Research, 45, 3004–3014.                      Mundt, C. (2006). Stroop performance in depressive
      Kincade, J. M., Abrams, R. A., Astafiev, S. V., Shulman, G. L.     patients: a preliminary report. Journal of Affective
         & Corbetta M. (2005). An event-related functional               Disorders, 94, 261–267.
         magnetic resonance imaging study of voluntary and             Maunsell, J. H. & Cook, E. P. (2002). The role of attention
         stimulus-driven orienting of attention. Journal of              in visual processing. Philosophical Transactions of the
         Neuroscience, 18, 4593–4604.                                    Royal Society of London: Series B Biological Sciences, 357,
      Klein, R. M. (2000). Inhibition of return. Trends in Cognitive     1063–1072.
         Science, 4, 138–147.                                          Mayer, A. R., Dorflinger, J. M., Rao, S. M. & Seidenberg, M.
      Knight, R. T., Grabowecky, M. F. & Scabini, D. (1995).             (2004). Neural networks underlying endogenous
        Role of human prefrontal cortex in attention control.            and exogenous visual-spatial orienting. Neuroimage,
        Advances in Neurology, 66, 21–34.                                23, 534–541.
      La Berge, D. (1997). Attention, awareness, and                   McAdams, C. J. & Maunsell, J. H. (1999). Effects of attention
114      the triangular circuit. Consciousness and Cognition,            on the reliability of individual neurons in monkey visual
         6, 149–181.                                                     cortex. Neuron, 23, 765–773.
                                                                              Chapter 8: The neural basis of attention



McAdams, C. & Reid, C. (2005). Attention modulates               Posner, M. I. & Petersen, S. E. (1990). The attention system
  the responses of simple cells in monkey primary                   of the human brain. Annual Review of Neuroscience,
  visual cortex. Journal of Neuroscience, 25(47),                   13, 25–42.
  11023–11033.                                                   Posner, M. I., Snyder, C. R. R. & Davidson, B. J. (1980).
Mesulam, M. M. (1981). A cortical network for directed              Attention and the detection of signals. Journal of
  attention and unilateral neglect. Annals of Neurology, 10,        Experimental Psychology: General, 109, 160–174.
  309–325.                                                       Purcell, R., Maruff, P., Kyrios, M. & Pantelis, C. (1997).
Michale, G. & Desmedt, S. (2004). The human pulvinar and           Neuropsychological function in young patients with
  attentional processing of visual distractors. Neuroscience       unipolar major depression. Psychological Medicine,
  Letters, 362, 176–181.                                           27, 1277–1285.
Miller, E. K. (2000). The neural basis of top-down control of    Rafal, R. D. & Henik, A. (1994). The neurology of
  visual attention in the prefrontal cortex. In J. Driver & S.      inhibition. In T. Carr & D. Dagenbach (Eds.), Inhibitory
  Monsell (Eds.), Attention and Performance XVIII: The              Processes in Attention, Memory and Language (pp. 1–51).
  Control Over Cognitive Processes (pp. 511–534).                   New York, NY: Academic Press.
  Cambridge, MA: MIT Press.                                      Rafal, R. D. & Posner, M. I. (1987). Deficits in human
Miller, E. K. & Cohen, J. D. (2001). An integrative theory of       visual spatial attention following thalamic lesions.
  prefrontal cortex function. Annual Review Neuroscience,           Proceedings of the National Academy of Sciences, USA,
  24, 167–202.                                                      84, 7349–7353.
Mogg, K., Millar, N. & Bradley, B. P. (2000). Biases in eye      Recanzone, G. H., Wurtz, R. H. & Schwarz, U. (1993).
  movements to threatening facial expressions in                    Attentional modulation of neuronal responses in MT
  generalized anxiety disorder and depressive disorder.             and MST of a macaque monkey performing a visual
  Journal of Abnormal Psychology, 109, 695–704.                     discrimination task. Society for Neuroscience Abstract,
Moran, J. & Desimone, R. (1985). Selective attention gates          19, 973.
  visual processing in the extrastriate cortex. Science, 229,    Reynolds, J. H. & Chelazzi, L. (2004). Attentional
  782–784.                                                         modulation of visual processing. Annual Review
Mort, D. J., Perry, R. J., Mannan, S. K. et al. (2003).            Neuroscience, 27, 611–647.
  Differential cortical activation during voluntary and          Reynolds, J. H., Chelazzi, L. & Desimone, R. (1999).
  reflexive saccades in man. Neuroimage, 18, 231–246.              Competitive mechanisms subserve attention in macaque
Nobre, A. C., Gitelman, D. R., Dias, E. C. & Mesulam, M. M.        areas V2 and V4. Journal of Neuroscience, 19, 1736–1753.
  (2000). Covert visual spatial orienting and saccades:          Robinson, D. L. & Petersen, S. E. (1992). The pulvinar and
  overlapping neural systems. Neuroimage, 11, 210–216.             visual salience. Trends in Neuroscience, 15, 127–132.
Nobre, A. C., Sebestyen, G. N., Gitelman, D. R. et al. (1997).   Rogers, M. A., Bellgrove, M. A., Chiu, E., Mileshkin, C. &
  Functional localization of the system for visuospatial           Bradshaw, J. L. (2004). Response selection deficits in
  attention using positron emission tomography. Brain,             melancholic but not nonmelancholic unipolar major
  120, 515–533.                                                    depression. Journal of Clinical Experimental
Paelecke-Habermann, Y., Pohl, J. & Leplow, B. (2005).              Neuropsychology, 26, 169–179.
   Attention and executive functions in remitted                 Rosen, A., Rao, S., Caffarra, P. et al. (1999). Neural basis
   major depression patients. Journal of Affective Disorders,      of endogenous and exogenous spatial orienting: a
   89, 125–135.                                                    functional MRI study. Journal of Cognitive Neuroscience,
Peelen, M. V., Heslenfeld, D. J. & Theeuwes, J. (2004).            11, 135–152.
   Endogenous and exogenous attention shifts are mediated        Rowe, J., Friston, K., Frackowiak, R. & Passingham, R. E.
   by the same large-scale neural network. Neuroimage, 22,         (2002). Attention to action: specific modulation of
   822–830.                                                        corticocortical interactions in humans. Neuroimage, 17,
Petkov, C. I., Kang, X., Alho, K. et al. (2004). Attentional       988–998.
   modulation of human auditory cortex. Nature                   Rowe, J. B., Stephan, K. E., Friston, K., Frackowiak, R. S. &
   Neuroscience, 7, 658–663.                                       Passingham, R. E. (2005). The prefrontal cortex shows
Posner, M. I. (1980). Orienting of attention. Quarterly            context-specific changes in effective connectivity to
   Journal of Experimental Psychology, 32, 3–25.                   motor or visual cortex during the selection of action or
Posner, M. I. & Cohen, Y. (1984). Components of visual             colour. Cerebral Cortex, 15, 85–95.
   orienting. In H. Bouma & D. Bouwhis (Eds.), Attention         Salinas, E. & Sejnowski, T. J. (2001). Gain modulation in the
   and Performance X (pp. 531–556). Hillsdale, NJ:                  central nervous system: where behavior, neurophysiology,     115
   Lawrence Erlbaum Associates.                                     and computation meet. Neuroscientist, 7, 430–440.
         Section 1: Neuropsychological processes



      Sapir, A., Soroker, N., Berger, A. & Henik, A. (1999).             Treue, S. (2001). Neural correlates of attention in primate
         Inhibition of return in spatial attention: direct                  visual cortex. Trends in Neuroscience, 24, 295–300.
         evidence for collicular generation. Nature Neuroscience,        Treue, S. (2003). Visual attention: the where, what, how and
         2, 1053–1054.                                                      why of saliency. Current Opinion in Neurobiology, 13,
      Schicatano, E. J., Peshori, K. R., Gopalaswamy, R.,                   428–432.
         Sahay, E. & Evinger, C. (2000). Reflex excitability
                                                                         Treue, S. & Martínez-Trujillo, J. C. (1999). Feature-based
         regulates prepulse inhibition. Journal of Neuroscience,
                                                                            attention influences motion processing gain in macaque
         20, 4240–4247.
                                                                            visual cortex. Nature, 399, 575–579.
      Sevostianov, A., Fromm, S., Nechaev, V., Howitz, B. &
                                                                         Van Voorhis, S. & Hillyard, S. A. (1977). Visual evoked
         Braun, A. (2002). Effect of attention on central auditory
                                                                           potentials and selective attention to points in space.
         processing: an fMRI study. International Journal of
                                                                           Perception and Psychophysics, 22, 54–62.
         Neuroscience, 112, 587–606.
                                                                         Vogel, E. K., Luck, S. J. & Shaprio, K. L. (1998).
      Sheline, Y. I., Barch, D. M., Donnelly, J. M. et al. (2001).
                                                                           Electrophysiological evidence for a postperceptual locus
         Increased amygdala response to masked emotional faces
                                                                           of suppression during the attentional blink. Journal of
         in depressed subjects resolves with antidepressant
                                                                           Experimental Psychology: Human Perception and
         treatment: an fMRI study. Biological Psychiatry, 50,
                                                                           Performance, 24, 1656–1676.
         651–658.
      Sherman, S. M. & Guillery, R. (2002). The role of the              Walsh, B. J., Fannon, S. P., Giesbrecht, B. & Mangun, G. R.
         thalamus in the flow of information to the cortex.                (May, 2005). Dissecting attentional control systems.
         Philosophical Transactions of the Royal Society of London:        Poster presented at the Annual Meeting of the American
         Series B Biological Sciences, 357(1428), 1695–1708.               Psychological Society, Los Angeles, CA.

      Shipp, S. (2004). The brain circuitry of attention. Trends in      Weese, G. D., Phillips, J. M. & Brown, V. J. (1999).
         Cognitive Science, 8, 223–230.                                    Attentional orienting is imparied by unilateral lesions of
                                                                           the thalamic reticular nucleus in the rat. Journal of
      Siegle, G. J., Steinhauer, S. R., Thase, M. E., Stenger, V. A. &     Neuroscience, 19, 10135–10139.
         Carter, C. S. (2002). Can’t shake that feeling: event-
         related fMRI assessment of sustained amygdala activity          Weissman, D. H., Warner, L. M. & Woldorff, M. G. (2004).
         in response to emotional information in depressed                 The neural mechanisms for minimizing cross-
         individuals. Biological Psychiatry, 51, 693–707.                  modal distraction. Journal of Neuroscience, 24,
                                                                           10941–10949.
      Snitz, B. E., MacDonald, A. 3rd, Cohen, J. D. et al. (2005).
         Lateral and medial hypofrontality in first-episode              Woldorff, M. G., Hazlett, C. J., Fichtenholtz, H. M. et al.
         schizophrenia: functional activity in a medication-naive          (2004). Functional parcellation of attentional control
         state and effects of short-term atypical antipsychotic            regions of the brain. Journal of Cognitive Neuroscience,
         treatment. American Journal of Psychiatry, 162,                   16, 149–165.
         2322–2329.                                                      Wolfe, J. M., Cave, K. R. & Franzel, S. L. (1989). Guided
      Spitzer, H. & Richmond, B. J. (1991). Task difficulty:               search: an alternative to the feature integration model for
         ignoring, attending to, and discriminating a visual               visual search. Journal of Experimental Psychology:
         stimulus yield progressively more activity in inferior            Human Perception and Performance, 15, 419–433.
         temporal neurons. Experimental Brain Research,                  Yantis, S. (1996). Attentional capture in vision. In
         83, 340–348.                                                      A. Kramer, M. G. H. Coles & G. D. Logan (Eds.),
      Stoet, G. & Snyder, L. H. (2004). Single neurons in posterior        Converging Operations in the Study of Visual Selective
         parietal cortex of monkeys encode cognitive set. Neuron,          Attention (pp. 45–76). Washington, DC: American
         42, 1003–1012.                                                    Psychiatric Association.
      Sweeney, J. A., Kmiec, J. A. & Kupfer, D. J. (2000).               Yantis, S. & Jonides, J. (1990). Abrupt visual onsets and
        Neuropsychologic impairments in bipolar and unipolar               selective attention: evidence from visual search. Journal
        mood disorders on the CANTAB neurocognitive battery.               of Experimental Psychology: Human Perception and
        Biological Psychiatry, 48, 674–684.                                Performance, 16, 121–134.
      Tootell, R. B., Hadjikhani, N., Hall, E. K. et al. (1998). The     Zelano, C., Bensafi, M., Porter, J. et al. (2005). Attentional
        retinotopy of visual spatial attention. Neuron, 21,                 modulation in human primary olfactory cortex. Nature
        1409–1422.                                                          Neuroscience, 8, 114–120.


116
    Chapter




           9
                     The role of executive functions
                     in psychiatric disorders
                     Renée Testa and Christos Pantelis



Introduction                                                   Defining the executive system
Executive function (EF) deficits are the most consistently     The frontal lobes play a pivotal role in mediating and
described impairments found in studies of neuro-               integrating higher level, neurocognitive processes
cognition in psychiatric disorders. More recent                of the brain referred to as executive functions
research suggests that EF deficits are most promi-             (Burgess, 2000; Chayer & Freedman, 2001). These pro-
nent in psychiatric disorders that have their onset            cesses are considered to act globally across all cognitive
during the late childhood and adolescence period,              domains and impact upon all types of behavior. While
including schizophrenia, bipolar disorder, obsessive-          there has been considerable debate about what cons-
compulsive disorder (OCD) and depression. There-               titutes EFs (Stuss, 2006), in the last decade there has
fore, neurodevelopmental mechanisms affecting these            been rapid progress in developing conceptual models
functions are likely to play an important role in the          of the executive system and in delineating the relevant
emergence of these psychiatric conditions or, alter-           neural networks that underlie such functions.
natively, the emergence of these disorders may                     General descriptions of EFs as “cognitive skills
adversely affect such functions. As we discuss below,          required for the successful execution and completion
the EF system is continuing to mature into adole-              of complex, goal-directed behaviour” are often imple-
scence and early adulthood and we suggest that                 mented in the literature, but it has proved more
understanding the nature and extent of deficits in             difficult to identify the specific cognitive processes
psychiatric disorders will depend on the interaction           involved (Stuss, 2006). Although there is no compre-
between the stage of brain maturation and the age              hensive list of skills that definitively comprise the
of onset of psychiatric pathology.                             executive system, some agreement exists regarding
    In this chapter we first discuss issues relevant           specific situations in which this system is activated
to EFs. We argue that understanding the challenges             (Elliott, 2003; Salmon & Collette, 2005), and behav-
within this field can offer valuable insight to guide          ioral and neuropsychological observations in individ-
the assessment process. We discuss the difficulties            uals with frontal lobe damage (Bennett et al., 2005)
in operationally defining EFs, and provide a brief             have helped delineate their functional outcomes.
overview of the evidence for associating EF to                 Executive deficits are most evident when an individ-
frontal lobe structures. Secondly, we discuss the              ual is confronted with complex, novel situations
relevance of the frontal lobe/executive system and             requiring inhibition of over-learned responses and
its maturation to understanding the development of             generation of novel or non-automatic responses,
mental illness and schizophrenia in particular, and            necessitating an ability to be self-directed, flexible
finally we suggest that this provides the context              and adaptive (Spikman et al., 2000). The generation
within which to understand brain–behavior rela-                of new responses in this way is the culmination
tionships relevant to EF and how these are affected            of several executive processes, including planning,
in mental disorders.                                           decision-making, inhibitory control, cognitive




The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by           117
Cambridge University Press. # Cambridge University Press 2009.
        Section 1: Neuropsychological processes



      flexibility, emotion regulation, reasoning and judg-        decisions, which was unexpected given his premorbid
      ment (Shimamura, 2000; Stuss & Alexander, 2000;             abilities (Macmillan, 2000a, 2000b).
      Yamasaki et al., 2002). Damage to the cognitive                 This landmark case provided important insights
      systems underlying these abilities results in a reliance    about functional localization within the frontal lobes,
      on over-learned responses, and use of inappropriate         demonstrating that the integrity of the frontal lobes
      behavioral strategies that are inefficient (Bennett         was critical to the operation of a collection of higher-
      et al., 2005; Burgess & Shallice, 1996; Stuss, 2006).       level skills that would later be termed executive func-
          Early attempts to understand the neuroanatomical        tions (Burgess, 2000; Spikman et al., 2000). Gage’s
      correlates of the executive system were centered upon       case also provided clues about functional specificity
      the role of the frontal lobes as the “mediator” of these    within subregions of the frontal cortex. In a recent
      skills and were largely focused upon a localizationist      study of Gage’s skull, Damasio et al. (1994) used
      viewpoint (Shimamura, 2000; Stuss, 1992; Stuss &            modern imaging techniques to accurately identify
      Alexander, 2000; Yamasaki et al., 2002). Recent devel-      the damage. Projected trajectories of the iron bar that
      opments demonstrate this view to be overly simplis-         pierced his skull suggested that, whilst the dorsolateral
      tic, with evidence from both neuropsychology and            region was spared, significant damage was sustained
      neuroimaging (e.g. functional, structural, neurochem-       in ventromedial regions (Brodmann’s areas 8 to 12,
      ical) (Smith & Jonides, 1999; Szameitat et al., 2002;       24, 32). Such evidence implicated the ventromedial
      Tamm et al., 2002; Taylor et al., 2004; Tekin &             prefrontal cortex (VMPFC) in causing Gage’s deficits.
      Cummings, 2002) suggesting that more detailed con-          Reciprocal connections between the VMPFC and the
      ceptualizations of the executive system are required,       amygdala and hypothalamus, which have also been
      including evidence that executive dysfunction can           implicated in these cognitive processes, support this
      occur following damage to non-frontal regions               notion (Macmillan, 2000b; Tekin & Cummings,
      (Fassbender et al., 2004; Himanen et al., 2005; Roth &      2002). Gage’s case is also informative about regions
      Saykin, 2004; van der Werf et al., 2000a). Such studies     that were spared, namely the dorsolateral prefrontal
      are also elucidating a greater range of cognitive skills    cortex (DLPFC), suggesting that those higher-level
      as being part of the EF system through a process of         abilities that were preserved, including language and
      fractionating and dissociating its component parts          attentional abilities, may be attributable to this or
      (Burgess et al., 1998; Pantelis & Brewer, 1995).            other spared regions (Macmillan, 2000a, 2000b).
                                                                      Subsequent research based on frontal lesion
      The association between the frontal lobes                   models, including work in primates, has provided
                                                                  further evidence to support functional specialization
      and executive functions                                     within frontal subregions, particularly of DLPFC and
      There is consensus that the integrity of the frontal        the orbitofrontal cortex (OFC) (Baddeley, 1996;
      lobes is critical to the operation of EFs, although other   Bechara et al., 2000; Duncan & Owen, 2000; Levine
      brain regions are also important. This was illustrated      et al., 1998; Shallice & Burgess, 1991; Stuss & Levine,
      famously in the case of Phineas Gage, a young railway       2002). More recent ideas posit that these regions are
      foreman, who in 1848 sustained significant frontal          differentially responsible for “cold” (DLPFC) and
      lobe damage (Wagar & Thagard, 2004). Despite the            “hot” (OFC) cognitive processes. “Cold” cognition
      penetrating brain injury, Gage made a rapid and appar-      refers to logical decision-making processes, including
      ently full recovery with little impact on his general       judgment and reasoning abilities, whilst “hot” cogni-
      intelligence, memory and language (Ratiu & Talos,           tion incorporates affective processes mediating and
      2004; Stuss et al., 1992). However, Gage showed marked      controlling emotion, motivation and social influences
      behavioral changes. Once considered a likeable, respon-     (Unsworth & Engle, 2005).
      sible and trusted person, post-injury Gage’s behavior
      became socially inappropriate. He was rude, irrespon-
      sible and indifferent to social conformities (Bechara       Functions of the dorsolateral prefrontal
      et al., 1994) and was unable to monitor his emotional
      responses, resulting in marked and uncharacteristic         cortex and orbitofrontal cortex
118   behavioral exhibitions (Damasio et al., 1994; Ratiu         The DLPFC has been implicated in various cognitive
      et al., 2004). He was also incapable of making logical      abilities associated with planning, decision-making
                                               Chapter 9: The role of executive functions in psychiatric disorders



and problem-solving. Deficits commonly observed             appreciation of future consequences and the capacity
following damage to this region include difficulties        to form and maintain interpersonal relationships
in evaluating contextual information, problems in           have also been attributed to the OFC (Cicerone &
efficiently formulating and executing a plan, poor          Tanenbaum, 1997; Eslinger & Damasio, 1985), as
capacity to adhere to designated rules, poor ability        have higher-level olfactory abilities (Brewer et al.,
to be flexible and adaptable within the environment,        2006). Impairments arising from damage to this
and difficulty with multitasking, organization and          region include a range of characteristic problems,
everyday decision-making skills (Aron et al., 2004;         including inability to be aware of, or to understand
Burgess, 2000; Shallice & Burgess, 1991). Such deficits     and integrate different social and emotional cues
were thought to be commonly exhibited as an inabi-          present in the environment, difficulty with decision-
lity to consider and select different behavioral strat-     making tasks related to social and personal matters,
egies and to respond to environmental demands or            anosmia, amnesia, disinhibition and perseveration
contingencies, as well as an inability to follow time       (Damasio et al., 1990; Eslinger & Damasio, 1985).
constraints, keep appointments and/or meet deadlines            Given the strong emphasis on understanding
(Burgess, 2000; Levine et al., 1998). Frith et al. (2000)   neurocognitive processes within the prefrontal cortex,
have also demonstrated that patients with lateral PFC       the DLPFC, which is largely responsible for more
damage experience difficulty in assessing and placing       “classical” cognitive skills such as decision-making
constraints on possible strategic solutions or behavioral   and planning abilities, has received greater attention
responses, which leads to the adoption of a trial-and-      than the OFC. This disparity is also reflected in the
error approach (Fletcher et al., 2000; Reverberi et al.,    development of tests to assess the integrity of these
2005b). In everyday situations, this type of approach       regions. While various tasks have been developed
is inefficient, time consuming and lacks coherence and      to assess the DLPFC, the OFC has proved more
organization (Burgess, 2000; Reverberi et al., 2005a).      difficult in this regard and there is still a lack of
     The mediation of attentional capacities including      reliable and validated tests to assess OFC integrity.
attentional set-shifting, selective attention and sus-      This is also reflected in fewer studies that assess these
tained attention, in addition to the strategic “use” of     abilities in psychiatric disorders. More recently, work
memory, incorporating the coordination, elaboration         has begun to focus on the OFC in order to understand
and interpretation of different associations within         how emotion and motivation impact upon decision-
working memory, have also been attributed to this           making and on other cognitive processes, and how
region (Stuss, 2006). Bechara and colleagues also pos-      best to measure these (Happaney et al., 2004). Several
tulated that deficits in the inhibition of inappropriate    gambling tasks, including The Iowa Gambling Task
responses arise from an inability to hold and utilize       and the Cambridge Gambling Task, have been
internal self-representations within working memory,        designed specifically to examine the interaction bet-
leading to the selection of behavioral responses with       ween affective, motivational and decision-making
poorer long-term outcomes (Bechara et al., 1994,            processes, and have been used successfully to assess
2000; Stuss & Levine, 2002). The relationship of the        this region (Bechara et al., 1994, 1998; Clark & Manes,
DLPFC and the executive system to working memory            2004). Higher-level smell identification ability is
is currently a topic of contentious debate in the litera-   attributed to the OFC and olfactory tasks have also
ture (Bechara et al., 1998; D’Esposito et al., 2006).       proved useful in probing this region in psychiatric
     These skills are distinct and contrast with those      and neurological disorders (Brewer et al., 2006).
attributed to the OFC, which include cognitive abil-            As noted from the above descriptions, the DLPFC
ities related to social, affective, motivational and        and the OFC have been largely characterized by
personality issues. Such skills are essential to an indi-   descriptions of specific neurocognitive functions or
vidual’s capacity for emotional and behavioral self-        dysfunctions that arise following damage to these
regulation, in addition to the integration of subjective    regions. In addition to this approach, several authors
experiences required for self-awareness and indivi-         have attempted to further elucidate the collection of
duality (Cicerone et al., 1997; Stuss & Levine, 2002).      reported deficits which manifest when damage is sus-
Other skills, including the ability to regulate and         tained to either these specific prefrontal regions or
select appropriate behavioral responses, reasoning          to pathways connecting these regions to subcortical         119
and problem-solving within the social domain, the           areas (Cummings, 1995; Mega & Cummings, 1994;
         Section 1: Neuropsychological processes



      Pantelis & Brewer, 1995; Pantelis & Maruff, 2002).                Broadening the network of executive
      Damage to the DLPFC is thought to result in a “pseudo-
      depressive” personality, characterized by apathetic               functions
      and withdrawn behaviors, inability to engage in goal-             Advances in brain-imaging technologies have pro-
      directed behavior, and neglect for future-orientated              vided new insights, highlighting the inadequacy of
      consequences. In contrast, OFC damage, previously                 a strict localizationist approach to the study of EFs
      considered to result in a “pseudo-psychopathic”                   and the overly simplistic view of equating frontal
      personality, has more recently been characterized                 lobes and EFs (Blakemore & Choudhury, 2006;
      and differentiated in terms of whether damage is to               Zimmerman et al., 2006). Both clinical and imaging
      medial or lateral OFC. The former has been associated             studies in normal populations have identified that
      with personality changes including irritability, emo-             EFs also involve non-frontal regions, various neural
      tional lability, impulsiveness, disinhibition, lack of            networks and many subordinate cognitive processes
      concern for others, marked changes in personality,                (Aron et al., 2004; Carter et al., 1999; Storey et al.,
      environmental dependency, mood disorders (lability                1999; Stuss & Alexander, 2000). More recent work
      and mania) and obsessive-compulsive disorder (OCD),               by Harrison et al. (2006) and Zakzanis & Graham
      whilst lateral OFC damage results in mood disorders               (2005) has investigated the neuroanatomical correl-
      of depression and dysphoria, also OCD, and perso-                 ates and possible neural networks underpinning
      nality changes comprising anhedonia (Cummings,                    the executive system, identifying both frontal and
      1995; Mega & Cummings, 1994; Tekin & Cummings,                    non-frontal (e.g. cerebellum and left middle and
      2002). Mega & Cummings (1994) argued that an                      superior temporal gyri) regions involved. Further,
      increase in metabolic activity in the OFC (and caudate)           reports identifying anterior cingulate cortex (ACC)
      could lead to OCD, whilst hypofunction (and increased             activity suggest that it is an integral part of the execu-
      amygdala activity) in the OFC was associated with                 tive system (Cohen et al., 2000; Fornito et al., 2004;
      depressive symptoms.                                              Peterson et al., 1999). This is particularly relevant to
          Pantelis and colleagues (Pantelis & Brewer, 1995;             morbid conditions such as schizophrenia, depression
      Pantelis et al., 2003b) argued that disturbances in               and OCD, in which morphological and functional
      fronto-striato-thalamic pathways result in different              variability of the ACC is reported (Harrison et al.,
      behavioral and neuropsychological syndromes of                    2006; Mayberg et al., 1997; Yucel et al. 2003, 2007).
      schizophrenia that are comparable to the Cummings’                    The approach of clinical executive function inves-
      frontal syndromes (Curson et al., 1999). It is possible           tigations has also changed to examine patients with
      that associating different behavioral and cognitive               a range of extra-frontal cortical, subcortical, develop-
      features of psychiatric disorders to these frontal syn-           mental and acquired injuries and, increasingly, to
      dromes may provide insights about the underlying                  understand the distributed neural systems involved
      neural mechanisms in disorders like schizophrenia,                in various psychiatric disorders manifesting executive
      depression, OCD and attention-deficit hyperactivity               deficits (Collette & Van der Linden, 2002; Szameitat
      disorder (ADHD) (Barnett et al., 1999; Maruff et al.,             et al., 2002; Taylor et al., 2004). Executive deficits
      2003; Mega & Cummings, 1994; Pantelis & Brewer,                   have been identified within different neurological
      1995; Pantelis & Maruff, 2002) Certainly, there is evi-           groups involving both localized and diffuse injuries
      dence that dysfunction of DLPFC has a significant role            (Crawford & Channon, 2002; Hanninen et al., 1997;
      in depression and OCD, as evident by neuropsycho-                 Levine et al., 1998; Paul et al., 2005; Sweeney et al.,
      logical studies (Purcell et al., 1997), while deficits in smell   2001), and following damage to regions connecting
      identification implicate OFC in OCD (Barnett et al.,              to the frontal lobes, including ACC (Baird et al., 2006;
      1999). Thus, while it may be possible to differentiate            Fassbender et al., 2004; Rogers et al., 2004), thalamus
      distinct neuropsychological profiles and psychiatric              (van der Werf et al., 2000b), hippocampus (Himanen
      disorders brought about by damage to these regions,               et al., 2005), cerebellum (Collette et al., 2005; Rao
      there is also considerable overlap. Further, while the            et al., 1997; Riva & Giorgi, 2000; Roth & Saykin,
      notion of frontal-striatal-thalamic systems suggests a            2004) and basal ganglia (Monchi et al., 2006).
      network of brain structures, a neuropsychological app-                It is noteworthy that in these investigations the
120   roach has not adequately delineated how such a network            additional regions identified as relevant to EFs involve
      may be involved in or across various disorders.                   structures and networks intimately linked with
                                                Chapter 9: The role of executive functions in psychiatric disorders



prefrontal cortical regions. However, it remains             between executive tasks (Burgess et al., 1998; Miyake
uncertain as to what aspects of EF are subserved by          et al., 2000; Robbins et al., 1998). Investigators
each of the nodes, and whether the frontal regions are       (Duncan et al., 1995; Engle et al., 1999) proposing
necessarily involved in mediating or controlling such        a “unitary” view argue that a common mechanism
functions. Current literature has, however, demon-           across different EFs underlies different executive
strated that the frontal region is a necessary compo-        components, comparable to a “domain-general” pro-
nent of the neural networks subserving the executive         cess (Stuss, 2006). This focuses upon the integrative
system, given that they are activated regardless of          and coordinating role of the frontal lobes to account
what other non-frontal regions are implicated.               for this unity of function, where the fluid recruitment
    The fluid nature of frontal lobe functions and           of different cognitive processes enables the individual
relevant networks makes it difficult to identify, define     to successfully adapt to changing task and environ-
or fractionate the processes involved, given that their      mental demands (Stuss, 2006). Similarly, several
inherent and characteristic nature is to act in a flexible   researchers (Paine & Tani, 2004; Peers et al., 2005)
and adaptable manner (Duncan & Owen, 2000). This             have focused upon notions of “top-down” or
lack of “constancy” raises questions about whether           “bottom-up” processes, which are related to the inte-
identifying the characteristic features or markers of        gration and assimilation of information that is gat-
frontal processes is feasible, as it is such a dynamic       hered from both frontal and non-frontal cortical and
and responsive system. It also suggests that different       subcortical regions. It is argued that the greater the
approaches are needed in order to adequately ana-            system is required to be flexible and adaptable, the
lyze a system that changes rapidly in response to            greater the degree of integration and assimilation
the characteristics of any given task or situation. To       from other networks that is required, which is said
capture deficits of frontal processes methodological         to be mediated by the frontal lobes (Bialystok et al.
designs that can measure the temporal characteristics        2004, 2005). A reduced capacity to undertake this
of these processes are required, integrating a number        control of cognitive processes is said to lead to greater
of imaging modalities to localize the networks invol-        performance variability when individuals are pre-
ved, together with techniques to assess the temporal         sented with demanding tasks (West & Alain, 2000).
changes with millisecond resolution. A small number              The capacity to integrate and coordinate multiple
of investigations (Mathalon et al., 2003; Wolff et al.,      processes across and within different neural networks
2003) have examined measures including fMRI and              is particularly relevant to furthering our understand-
ERPs; but these have been undertaken independently.          ing of psychiatric disorders. It has been proposed that
To our knowledge, simultaneous, multimodal meas-             a “breakdown” in the connectivity in the brain under-
urements of EFs are yet to be published. Further work        lies many serious psychiatric disorders, such as
with fMRI, offering high spatial resolution, and ERPs        schizophrenia (Friston, 1998). This “disconnection
and MEG that provide high temporal resolution,               hypothesis” argues that the fluid processes required
would be informative, as would the use of transcranial       for the functional integration of cortical systems
magnetic stimulation (TMS) and PET, which can help           necessary for cognition are dysfunctional, and that
to examine functional connectivity between brain             the aberrant connections should be portrayed as
regions (Banich & Weissman, 2000). Such research             functional and not necessarily anatomical in nature.
would provide important insights about the nature            Therefore, it may not necessarily be specific regions
of distributed brain activations during complex              that are not adequately functioning, but rather the
cognitive processes and provide novel methods to             ability to integrate functional processes across the
investigate how these processes are disrupted in neu-        brain that is dysfunctional. It is acknowledged that
ropsychiatric disorders.                                     region-specific abnormalities may be evident, but
                                                             these occur secondary to the dysfunctional integration
                                                             (Friston, 1998). This is supported by the suggestion
What is the role of the frontal lobes?                       that the symptoms associated with schizophrenia are
There is continuing debate about reconciling the             likely a result from aberrant interactions between dif-
notion of a fractionated view of the EF system, with         ferent cognitive processes rather than a deficit in one
descriptions of the “unity” or commonality that exists       specific cognitive function.                                121
        Section 1: Neuropsychological processes



          More recent literature has demonstrated altera-        are a consistent and robust finding in such dis-
      tions between specific cortical and subcortical regions,   orders, particularly schizophrenia. Working memory
      including both reductions and enhancements in              is a central component to the development and func-
      functional connectivity; these include the DLPFC           tioning of many other cognitive processes including
      and the hippocampus (Meyer-Lindenberg et al., 2005),       attention, language and executive functioning. There-
      networks between the prefrontal, cerebellar and            fore, understanding the basis for working-memory
      thalamic regions (Schlosser et al., 2003a, 2003b),         deficits may explain deficits in cognition and beha-
      and also the prefrontal, temporal and limbic areas         vior and their impact on daily functioning in these
      (Weinberger & Lipska, 1995). A loss of “synchrony”         disorders. Further, because different processes and
      may also result from white-matter abnormalities            domains of working memory develop throughout
      often reported in schizophrenia; this may cause a          the lifespan from early childhood to early adulthood,
      slowing of neural transmission speed and efficiency        disorders manifesting at different ages will likely mani-
      required to support the integration of neural net-         fest different profiles of impairment, including differ-
      works (Bartzokis, 2002). Another possibility is            ences at different illness stages. Thus, documenting
      presented by Callicott et al. (2003) who argue that        the growth trajectory of these deficits in concert with
      given patients with schizophrenia require greater          the development of illness will provide a better under-
      prefrontal resources and are more inefficient when         standing of the nature and extent of the observed
      undertaking working-memory tasks, deficits may             impairments and the mechanisms underlying them.
      result from an inability to maintain the network of            In order to ascertain how these processes
      activity and undertake neural strategies for man-          become dysfunctional in psychiatric populations, a
      aging or dealing with information that require             working definition and a comparative “normal” model
      DLPFC involvement.                                         of working memory is required. Working memory
          Tasks such as those of new learning and memory         is commonly regarded as the process of holding and
      (Friston et al., 1998), and spatial working-memory         manipulating incoming, task-relevant information.
      and inhibition tasks (Sweeney et al., 2007; Wood           This also permits the integration of other information
      et al., 2003) that call upon a widely distributed net-     from long-term memory or “working on memory”
      work of cortical activity, may consequently provide        during the performance of cognitive tasks (Baddeley,
      some insight into an individual’s capacity to perform      1996; Baddeley & Della Sala, 1996; Moscovitch, 1992).
      such cognitive (or functional) acts. Indeed, functional    Perhaps because of this link to memory systems, the
      connectivity in the brain may never develop ade-           status of working memory as part of the executive
      quately in patients, and may be the cause of their         domain has been the subject of considerable debate.
      failure on such demanding tasks, even in the early         However, given that working memory is effortful and
      stages of illness or pre-illness onset (Brewer et al.,     places considerable demands on an individual’s cog-
      2005; Wood et al., 2003). Given this, the need to          nitive resources, requiring the individual to have
      better understand these fluid and interactive processes    direct intent and the strategic or controlled allocation
      in the normally developing and functioning brain           of attentional resources to perform working-memory
      is vital, in order to understand how these processes       tasks, executive function skills are arguably required.
      may break down or inappropriately develop in psy-          Further, given the complexity of working-memory
      chiatric illnesses.                                        processes within different domains (verbal, visual,
                                                                 visuospatial etc.), there has been much debate regarding
                                                                 its conceptualization. Several different processes
      Working memory                                             have been proposed, including a storage capacity, a
      Investigation into components and processes involved       rehearsal or maintenance process, and a controller pro-
      in working memory and its maturational trajectory          cess that permits mental coordination and manipula-
      is important in understanding the cognitive mechan-        tion of information (Bayliss et al., 2003; Rypma &
      isms underlying several psychiatric disorders, such        D’Esposito, 1999). Storage components are considered
      as schizophrenia, bipolar disorder, OCD and ADHD,          responsible for domain-specific processes (visual,
      which have neurodevelopmental origins and manifest         verbal, spatial) (D’Esposito et al., 2006; Ravizza
122   throughout adolescence. Working-memory deficits            et al., 2006; Smith & Jonides, 1999; Ventre-Dominey
                                             Chapter 9: The role of executive functions in psychiatric disorders



et al., 2005), while higher-level manipulative and        established until adulthood, which suggests that best
integrative functions of working memory involve           performance in SWM tasks would not be possible
domain-general processes (Bayliss et al., 2003; Engle     until this time, when frontal lobe and associated
et al., 1999; Smith et al., 1996).                        networks are fully developed (De Luca et al.,
    The evidence regarding the dissociability of          2003; Luna & Sweeney, 2001). In line with this
storage and manipulation components of working            Schweinsburg et al. (2005) reported that younger
memory demonstrates that the more attentionally de-       teenagers rely more on spatial rehearsal rather than
manding and effortful components required for active      engaging encoding processes in a SWM task, and
rehearsal, integration and coordination involves          therefore are not as efficient in using strategies to
primarily frontal, executive processes. Neuroimaging      optimize performance (Scherf et al., 2006). Sweeney
investigations consistently demonstrate activations       et al. (2007) also suggested that there is a develop-
within the frontal regions, including the DLPFC,          mental transition from reliance on striatal regions in
when participants are engaged in working-memory           childhood when performing this task, to a more
tasks, and that these activations can be differentiated   widely distributed and efficient circuitry including
(in level of activation and regions) from those of        prefrontal, premotor and posterior parietal regions
simpler short-term memory tasks that predomi-             in adolescence. Poor performance on SWM tasks
nantly engage posterior cortices including the right      may then reflect an inability to efficiently integrate
middle and right inferior parietal lobe (Ackerman         and coordinate cognitive processes in a specialized
et al., 2005; Collette et al., 1999; D’Esposito et al.,   and organized fashion.
2006; Duncan & Owen, 2000; Gerton et al., 2004;               These notions regarding the late development of
Passingham & Sakai, 2004; Wager & Smith, 2003).           SWM provide some insight into mechanisms under-
Primate work (Castner et al., 2004; Fuster, 2000;         lying the nature and severity of deficits in schizophre-
Levy & Goldman-Rakic, 1999) has also demonstra-           nia and other psychiatric disorders including ADHD
ted differentiation between short-term memory and         and OCD. The finding that in schizophrenia clini-
working-memory systems, with working-memory               cally high-risk adolescents show deficits on a SWM
tasks activating distributed networks including and       task, before onset of illness (Smith et al., 2006;
beyond that of the frontal lobe region, while short-      Wood et al., 2003), suggests that aberrant networks
term memory activates predominantly regions in            are present before the illness manifests. As SWM is
the parietal lobe.                                        not fully matured until early adulthood (De Luca
                                                          et al., 2003), this skill may never fully develop as
The relevance of spatial working                          onset of the disorder or its prodrome may interfere
                                                          with maturation leading to “developmental arrest.”
memory to psychiatric disorders                           Studies investigating child and adult ADHD
As discussed earlier, examining abilities that develop    (Martinussen & Tannock, 2006; Rhodes et al., 2006;
at the time of illness onset may also offer some          Vance et al., 2007) and/or OCD (Barnett et al., 1999;
insight into the underlying mechanisms that take          Purcell et al., 1998a, 1998b; van der Wee et al.,
place at the time of its emergence. Spatial working       2007) have reported SWM deficits in these groups,
memory (SWM) has often been studied in individuals        but not in those with major depression (Purcell et al.,
at high risk for, and with first-episode and/or chronic   1997, 1998b) or, surprisingly, in Tourette’s syndrome
schizophrenia, with consistent findings of significant    (Watkins et al., 2005). Interestingly, only bipolar
deficits in comparison with controls. Indeed, poor        patients who also present with psychosis exhibit
performance on SWM tasks may represent a precur-          SWM deficits (Badcock et al., 2005; Glahn et al.,
sor to the development of psychosis (Lencz et al.,        2007; Pirkola et al., 2005). This questions what
2006; Saperstein et al., 2006; Wood et al., 2003).        comparable neurodevelopmental mechanisms are
    Spatial working memory requires a good ability        occurring in these disorders that do not permit
to integrate and coordinate multiple cognitive pro-       and/or hinder the networks required for SWM to
cesses from and across different cognitive networks,      fully develop appropriately. A comprehensive under-
with involvement of the frontal lobes to control the      standing of brain maturational processes relevant
integration of multiple processes simultaneously          to EFs is required in order to better understand such      123
(Fuster, 1991). Maturation of this ability is not         impairments.
        Section 1: Neuropsychological processes



      Brain development and the                                                                                                      a
                                                                                                                                     b




                                                                 Level of cognitive ability
      maturation of executive functions:                                                                                             c
      a hypothesis for the emergence of
      executive function deficits in                                                                                                 d

      neuropsychiatric disorders
      Features that characterize many of the psychiatric
      disorders discussed in this volume include onset
                                                                                                  Age
      during adolescence or young adulthood and the pres-
      ence of EF deficits, often associated with brain           Figure 9.1. Graph depicting possible neurodevelopmental
      functional and structural abnormalities involving          trajectories of cognitive abilities during maturation. (a) normal
                                                                 development; (b) neurodevelopmental lag; (c) neurodevelopmental
      prefrontal brain regions. For example, deficits in EF      arrest; (d) neurodegeneration. At the point of intersection of dotted
      are reported in schizophrenia (Barnett et al., 2007a;      lines, individuals with very different developmental trajectories have
      Pantelis et al., 1997; Simon et al., 2006; Tan et al.,     the same degree of impairment.
      2006), depression (Herrmann et al., 2007; Porter
      et al., 2007; Purcell et al., 1997; Westheide et al.,
      2007), bipolar disorder (Glahn et al., 2007; Stoddart      and Average intelligent children only showed a slower
      et al., 2007), OCD (Bannon et al., 2006; Purcell et al.,   but comparable decline that commenced from early
      1998a,b; Roth et al., 2005; van der Wee et al., 2007)      to late childhood. These results not only demonstrate
      and ADHD (Barnett et al., 2001; Biederman et al.,          that level of intelligence is related to dynamic changes
      2004, 2007; Doyle, 2006; Wodka et al., 2007). In this      in cortical thickness, but also that the adoption of a
      context, an understanding of the nature, severity and      longitudinal, as opposed to cross-sectional approach
      progression of EF deficits in these disorders should       provides greater insight into developmental patterns
      take account of the developmental (maturational) tra-      of cortical change and the fluid nature of the relation-
      jectory of EF abilities and examine this in relation to    ships between cognitive and cortical measures.
      other brain changes occurring developmentally (e.g.             The benefit of adopting such an approach was
      changes in cortical gray matter. The growth curves in      illustrated in a study by Gochman et al. (2005) investi-
      individuals developing psychiatric disorders can           gating IQ in childhood-onset schizophrenia (COS).
      be compared with those in normal young people,             Early notions considered that intelligence declined in
      and will provide evidence as to whether abnormalities      both child- and adult-onset groups, consistent with
      (a) result from failed or arrested development, (b)        a deterioration of cognitive skills over the illness period;
      represent a normal trajectory that is below average        however, Gochman et al. (2005) examined raw scores
      or (c) are indicative of progressive deterioration (see    from the Wechsler Intelligence Scale within a longitu-
      Figure 9.1). An informative longitudinal study by          dinal framework, as opposed to age-scaled scores that
      Shaw et al. (2006) characterized the relationship          can obscure the nature of changes occurring during a
      between cortical development and intelligence in a         dynamic period of normal growth. They reported that
      large group of children and adults who ranged              IQ does not decrease and actually stabilizes from
      between 3.8–29 years of age. Results demonstrated          approximately 2 years post illness onset. These findings
      that level of intelligence during childhood and adoles-    are consistent with “neurodevelopmental arrest,” where
      cence was related to the pattern of growth, including      cognitive abilities that have already matured are not
      increases and decreases, in cortical thickness. Further-   “lost” via neurodegenerative processes, but rather there
      more, an interaction between age and level (Average,       is failure of further maturation (see Figure 9.1).
      High Average and Superior) of intelligence was noted            The identification of whether cognitive deficits
      in relation to the trajectories of change in cortical      manifest as a result of “neurodevelopmental arrest”
      thickness, most notably within the prefrontal cortex.      or “neurodegeneration” requires comment about how
      Whilst the Superior intelligent children initially         the frontal lobe develops neuroanatomically and
      demonstrated thinner cortex that markedly increased        functionally.
124   at approximately 11 years of age, and then rapidly              The frontal region is one of the last brain struc-
      declined from early adolescence, the High Average          tures to develop, with maturation progressing from
                                               Chapter 9: The role of executive functions in psychiatric disorders



posterior to anterior cerebral regions from childhood       Pantelis et al., 1997), the impact on DLPFC versus
to adulthood (Segalowitz & Rose-Krasnor, 1992).             OFC in these disorders may be dependent on the
Thus, cerebral processes that take place throughout         developmental stage of the brain at the time of their
development including dendritic arborization, mye-          onset (Brewer et al., 2006). Structurally, OFC matures
lination, synaptogenesis and cortical synapse elimin-       later than DLPFC, although myelination occurs
ation (i.e. synaptic pruning) occur later in the frontal    earlier than that occurring in DLPFC (Yakovlev &
lobes than in other brain regions (Bartzokis et al.,        Lecours, 1967; Gogtay et al., 2004). Such differential
2001; Fuster, 1993; Jernigan & Tallal, 1990; Kolb,          rates of change across brain development may have
1989; Paus et al., 1999). The morphological matur-          implications for the nature and extent of functional
ation of the frontal cortex, including cell differenti-     abnormalities observed, depending on the age of
ation and division into sublayers is considered to          onset of psychiatric disorders along this trajectory
reach completion when an individual approaches              (Pantelis et al., 2003b).
puberty, yet developmental changes continue into                Normative investigations have established that the
early adulthood (Orzhekhovskaya, 1981). Myelination         development of executive functions follows a multi-
begins during the second trimester of gestation, con-       stage process, with different EFs emerging throughout
tinuing well into the third decade of life (Benes et al.,   childhood and adolescence at various stages. Accele-
1994), progressing in a graded fashion from inferior        rated growth periods, thought to reflect underlying
to superior and posterior to anterior, with the cere-       cortical maturation (Levin et al., 1991), have been
bellum developing first and the frontal lobes last          reported in the frontal region between birth and
(Yakovlev & Lecours, 1967). The apoptotic elimin-           2 years of age, 7–9 years, 11–13 years, 14–16 years
ation of excess synapses results in remodeling and          and finally at 18–20 years (Hudspeth & Pribram,
refinement of the neural circuitry, which is thought        1992; Thatcher, 1992; Thatcher et al., 1987). The
to strengthen the remaining functional connections          initial and last growth periods are greatest in magni-
and reduce competition from suboptimal associ-              tude and are associated with an increase in cognitive
ations. While the result of this essentially Darwinian      functioning (Thatcher, 1992), so that maturation of
process is improved and more efficient neuronal             the EF system parallels development of the frontal
communication, it is important to note that this also       region. Neuropsychological literature supports this
leads to reduced redundancy available in the brain.         and has identified that the emergence of executive
This may be particularly relevant to understanding          abilities follows a timeline, with some skills coming
the longitudinal trajectory of behavioral and neuro-        “online” considerably earlier than others (Anderson
psychological features observed in young people             et al., 2001; Brewer et al., 2006; De Luca et al., 2003;
developing psychopathology (Brewer et al., 2006;            Levin et al., 1991). The higher-level cognitive changes
Pantelis et al., 2005).                                     apparent in adolescence also occur in concert with
    These processes of myelination and synaptic             maturation of social interaction and increase in
pruning that occur later in frontal regions are con-        risk-taking behavior (Spear, 2000) and are accompan-
sistent with the observed changes on MRI that               ied by improved capacity in social cognition, response
have illustrated maturational changes in vivo during        inhibition, monitoring, emotion regulation and the
adolescence (Giedd, 2004; Giedd et al., 1999;               capacity for abstract, reflective and hypothetical
Gogtay et al., 2004; Reiss et al., 1996). Using diffusion   thinking (Nelson et al., 2005; Paus, 2005).
tensor imaging to examine axonal integrity in the               Smith et al. (1992) supported these notions in
frontal lobes of children and adults, Klingberg et al.      their study demonstrating incremental improvement
(1999) found that white matter continues to increase        on frontal-lobe tasks between age 10–13 years, includ-
into the second decade of life in this region, with         ing the obtainment of a number of executive func-
the white matter increase located in dorsal                 tions similar to that of an adult. At this age children
prefrontal rather than orbitofrontal cortex (Reiss          start to develop the cognitive capabilities to maximize
et al., 1996). While both these prefrontal regions are      executive functioning, to deal with situations requir-
implicated in early-onset disorders, such as autistic       ing novel strategies, and capacity for independent
spectrum disorders, ADHD, OCD and schizophrenia             and purposeful behavior. In their investigation of EF
(Barnett et al., 1999; Brewer et al., 1996, 2001, 2006;     maturation, Levin et al. (1991) found significant age-     125
Kopala et al., 1989, 1993, 1994; Moberg et al., 1999;       related increments in ability between age 9–12 years,
         Section 1: Neuropsychological processes



      specifically in the ability to problem solve, plan, form    stages. Executive functions will also depend on the
      concepts, verbal reasoning and strategy use. Anderson       development of several other cognitive processes, such
      et al. (2001) also noted that cognitive flexibility and     as attentional control and processing speed, which are
      monitoring had reached adult levels of maturity by          closely aligned and necessary for good executive
      11 years, that planning and goal-setting skills showed      performance (Luna et al., 2004; Luna & Sweeney,
      some maturation around 12 years of age, but that            2004). Thus, during adolescence and early adulthood
      attentional control and processing speed demon-             individuals undertake and coordinate such abilities
      strated the most rapid growth spurts between 7–9            more efficiently, allowing greater mastery of increas-
      years and 15 years of age.                                  ingly complex executive skills (Tamm et al., 2002).
          Conklin et al. (2007) specifically investigated             Additionally, EF maturation may be better asses-
      working memory development and also noted a pro-            sed by measuring the neural system changes relevant
      tracted trajectory, with forward digit and spatial span     to undertaking such skills with greater efficiency,
      (13–15 years and 11–12 years) developing earlier than       as demonstrated by recent fMRI studies examining
      backward conditions of these tasks (16–17 years and         inhibitory control in subjects from childhood to
      13–15 years), due to the more demanding manipula-           adulthood (Luna et al., 2004; Tamm et al., 2002). In
      tion requirements. Age-related developments were            the study by Tamm et al. (2002), whilst there were no
      however noted on SWM tasks until 16–17 years of             behavioral differences identified in performance, with
      age, possibly due to strategic and planning demands         all ages (8–20 years) making relatively few errors, the
      requiring greater cognitive maturity. The authors           younger age group activated greater regions of the
      noted that the order in which these skills developed        prefrontal cortex to perform the same task as their
      closely paralleled the development of the neural sub-       older counterparts, who demonstrated increasingly
      strates thought to underlie these cognitive skills. In      selective activation in distinct regions implicated in
      their cross-sectional study across the life span from       response inhibition. The greater cortical involvement
      age 8–65, De Luca et al. (2003) found that ability on a     seen in the younger group was considered to result
      SWM task gradually improved during adolescence              from inefficient recruitment of cortical regions and
      and early adulthood, with optimal performance in            poor management of multiple demands. Luna et al.
      early adulthood (mid-20s), and a gradual deterior-          (2004) found comparable results, reporting that
      ation after age 30. A significant gender effect was also    although the ability to inhibit a response could be
      found, with males outperforming females at all ages         observed in very young children, efficiency at per-
      on this spatial task. Taking account of such gender         forming this skill was not achieved until late adoles-
      effects and changes across the life span is relevant to     cence, supporting the notion of parallel development
      assessing patients at different developmental stages        in cognition and cortical (neural) maturation. Docu-
      and at different phases of illness.                         menting the growth curves that map the emergence
          Despite the above-mentioned studies, there are          and maturation (to adult levels) of cognitive skills
      inconsistencies in the literature as to when a number       together with longitudinal imaging to assess changes
      of executive abilities are fully developed. This reflects   at the neural level will help future studies that seek to
      the multifaceted nature of the system and the meth-         understand the emergence of deficits in psychiatric
      odological issues in their assessment, given that           disorders and the neural systems that underpin them.
      executive function tests differ in their complexity             The relevance to psychiatric disorders is that these
      and the degree to which they require other executive        disorders often have their onset during adolescence
      and non-executive type skills. Further, there may be        at a time when the brain is showing considerable
      discrepancies between documenting when an EF skill          change, particularly in the prefrontal cortex and in
      emerges and is identifiable via a child’s ability to        maturation of EF abilities. It is likely that the onset
      complete a test, versus the time at which it is fully       of disorder at this stage of maturation disrupts the
      matured. Luna et al. (2004) describe a useful “change       normal developmental trajectory and may disturb the
      point” analysis technique that documents the time           developmental processes at a neural as well as func-
      at which improvement in performance plateaus.               tional level. Plotting the growth curves of brain struc-
      Such developments may be difficult to detect on             ture and function in these disorders and identifying
126   standardized tests and may require different tests          the nature of the disruption in brain maturation
      (or versions of) relevant to various developmental          caused by or preceding the onset of psychiatric
                                                 Chapter 9: The role of executive functions in psychiatric disorders



conditions may help explain the severity of the               genes to psychiatric disorders. For example, evidence
executive function deficits observed in such condi-           of an association between genes and performance on
tions. Thus, in schizophrenia, functions that mature          neuropsychological measures associated with frontal-
early in life when the brain is more adaptable show           subcortical networks has generated interest in psy-
fewer deficits in comparison with functions that              chiatric disorders in which these networks are
develop later, such as executive abilities (Pantelis          dysfunctional, such as schizophrenia and depressive
et al., 2003b, 2005). Therefore, in order to understand       disorder. Further, gene–environment interactions
the deficits in executive function in psychiatric dis-        have differing effects on various brain regions at spe-
orders, it is important to consider these in the context      cific developmental stages (Cannon, 2005; Winterer &
of brain maturational changes affecting the executive         Goldman, 2003), suggesting a complex interplay
system and their neural substrate.                            between developmental stage, brain region, type of
    The notion that the emergence of a psychiatric or         disorder and time of onset. Given disorders such as
neurological disorder at a critical stage of develop-         schizophrenia have been proposed to be neurodeve-
ment is associated with “developmental arrest” of key         lopmental in nature, this has significant implications
functions that should be emerging at particular mat-          for understanding the emergence of different cogni-
urational stages has a number of implications. First, it      tive deficits at different stages of the illness.
would suggest that deficits in those cognitive domains            Current research aims to identify genes that
that have yet to develop would be observed across a           increase susceptibility to schizophrenia and/or con-
range of disorders that have their onset early during         tribute to the observed cognitive deficits. Evidence for
critical developmental stages. There is evidence to           the heritability of cognitive deficits in schizophrenia
support this notion, for example, deficits in SWM             is demonstrated in familial studies showing that
are observed at all stages of schizophrenia (Brewer           non-affected relatives manifest comparable deficits
et al., 2006; Pantelis et al., 1997; Wood et al., 2003), in   to patients (Weinberger et al., 2001). Such evidence
OCD (Purcell et al., 1998), and in ADHD (Barnett              has been used to suggest that schizophrenia-relevant
et al., 1999). Second, earlier age of onset would be          genes also disrupt cognition and, therefore, greater
associated with more profound deficits, though there          severity of such deficits will be observed in those at
is limited evidence to support this as yet, and this          greater genetic risk for the disorder (Faraone et al.,
may depend upon whether the neural substrate has              2000; Johnson et al., 2003). Given that such a genetic
already been damaged at earlier developmental stages,         basis has been found, it should be possible to identify
such that patients “grow into deficit” (Lipska &              the specific genes mediating this relationship.
Weinberger, 2000; Lipska et al., 1993; Weinberger,                A number of genes are being examined in assess-
1987). Third, as already suggested, the dynamic inter-        ing the relationship between cognition and genetic
play of the emergence of illness and brain maturation         vulnerability to schizophrenia, including COMT
during childhood and adolescence suggests that the            (Barnett et al., 2007b, 2007c; Harrison, 2007;
approach to early-onset disorders, like schizophrenia,        MacDonald et al., 2007), TRAX (Cannon et al.,
should be to examine whether the disorder is a                2005; Thomson et al., 2005; Zhang et al., 2005),
consequence of anomalous trajectories in brain                MAO-A (Norton et al., 2002; Zammit et al., 2004)
maturation, both structurally and functionally, from          and MTHFR (Roffman et al., 2007a, 2007b). How-
childhood through to adulthood. If this is the case, it       ever, interest has primarily centered on the COMT
raises interesting questions about the factors driving        gene, which plays a significant role in the uptake,
such anomalous development, including genetic and             processing and catabolism of dopamine in the frontal
non-genetic influences on brain development.                  lobe region. Dopamine has been strongly implicated
                                                              in cognition, including working-memory processes
                                                              (Ho et al., 2005; Sawaguchi & Goldman-Rakic,
Genetic influences on executive                               1991), and the degree of heritability for short-term
                                                              memory and working memory capacity (verbal and
functions                                                     spatial) has been reported to be almost 50% (Shah &
Studies have begun to examine the relevance of gen-           Miyake, 1996). The transmission of a specific allele
etic factors to the development of the frontal lobes          of the COMT gene (Val) has been related to poorer          127
and executive functions and the relevance of these            prefrontal cortex functioning; in contrast, the Met
        Section 1: Neuropsychological processes



      allele confers a lower level of activity and therefore a   of psychiatric disorders. Tunbridge et al. (2007b) has
      reduced level of dopamine catabolism, leading to           similarly mapped changes in COMT activity in
      better bioavailability of dopamine and better cogni-       comparable age groups and reported a significant
      tive performance (Weinberger et al., 2001).                increase in COMT enzyme activity from the neonate
          While promising, however, the majority of studies      to adulthood period, with a specific increase or peak
      fail to find a significant relationship to support the     occurring at approximately adulthood (31–43 years
      COMT gene as a susceptibility locus for schizophre-        of age) and a further non-significant decrease
      nia (Egan et al., 2001; Goldberg et al., 2003; Joober      between 68–86 years of age. Further, Barnett et al.
      et al., 2002; Strous et al., 1997). Further, studies       (2007b) in a study of male children showed that COMT
      examining the relationship between COMT and EF             had a significant effect on EF and IQ tests, particularly
      performance have been mixed. The most consistent           when stage of pubertal development was considered.
      evidence shows that patients with the Val allele per-          These data suggest that protracted developmental
      form more poorly on EF tasks, including WCST and           changes in dopamine activity are occurring in the
      working-memory tasks, although the effect size has         prefrontal cortex during this postnatal period. Fur-
      been small (Egan et al., 2001; Goldberg et al., 2003;      ther investigation of dopamine and COMT on the
      Joober et al., 2002). This may result from poorer          maturation of the frontal lobe region is clearly war-
      prefrontal cortical efficiency due to the higher dopa-     ranted, especially considering that other dopaminer-
      mine catabolism produced by this genotype. Interest-       gic markers have been found to reach adult levels
      ingly, this relationship is reported irrespective of       prior to adolescence, suggesting that this gene may
      diagnosis, suggesting that the influence of COMT is        play a specific role in the maturation of these later-
      generic. Therefore, COMT does not appear related to        developing executive skills (Tunbridge et al., 2007a).
      the risk for schizophrenia, although it may play a role        We suggest that a better understanding of the
      in mediating cognitive activity associated with the        relationship between onset of a psychiatric disorder,
      PFC via its influence on dopamine.                         executive functions and genetics, requires exami-
          Further, a number of studies have failed to dem-       nation of a gene’s influence on the development of
      onstrate a relationship between COMT and EF neuro-         the frontal lobe and maturation of different executive
      psychological performance. For example, Ho et al.          skills at different stages of childhood and adulthood.
      (2005) found no significant relationship between           This will provide greater insight into how vulnerabil-
      COMT genotype and clinical diagnosis, no relation-         ity to a particular disorder, such as predisposition
      ship between COMT and EFs, and no significant              for schizophrenia, interacts or disrupts this relation-
      interaction between COMT genotype, EF perform-             ship at a critical developmental stage, resulting in
      ance and clinical diagnosis. However, using more           aberrant maturational and neurobiological processes
      sensitive electrophysiological measures of EF, Ehlis       that lead to the features of the illness, including
      et al. (2007) recently found a strong relationship         neuropsychological deficits.
      between COMT genotype and cognition in schizo-
      phrenia. Thus, more sensitive measures of cortical
      activity may be required to elucidate this relationship    Conclusions
      (Winterer & Goldman, 2003).                                Despite the uncertainty regarding the underlying
          As above, it may be relevant to examine the gen-       components comprising the EF system, the available
      etics of schizophrenia from a developmental (brain         evidence supports its fractionation into subcompo-
      maturational) perspective. Recent work (Tunbridge          nents, with different executive tests assessing unique
      et al., 2007a, 2007b; Weickert et al., 2007) has exam-     cognitive abilities (Duncan et al., 1997; Miyake et al.,
      ined the expression of specific dopamine-related           2000). These abilities may be differentially affected in
      genes or dopamine markers across the postnatal             different psychiatric disorders, and we suggest that
      period. Weickert et al. (2007) found changes in dif-       the nature and extent of the EF deficits observed
      ferent pre- and postsynaptic dopamine markers in the       may depend on the timing of the onset of the disorder
      frontal lobe during postnatal development ranging          in the context of the stage of maturation of such
      from early infancy to old age. In particular, a peak       functions. This is particularly the case for psychiatric
128   found in the dopamine D1 receptor in early adult-          disorders of childhood and adolescence, which
      hood/adolescence may be relevant to the emergence          develop during a critical period when EFs and their
                                                  Chapter 9: The role of executive functions in psychiatric disorders



neural substrates are still maturing; with different EFs        Badcock, J. C., Michiel, P. T. & Rock, D. (2005). Spatial
maturing at different rates and stages over this time.            working memory and planning ability: contrasts
The onset of disorder at a critical stage of such matur-          between schizophrenia and bipolar I disorder. Cortex,
                                                                  41(6), 753–763.
ation may result in “developmental arrest” of such
ability; this is exemplified most profoundly for spatial        Baddeley, A. (1996). The fractionation of working memory.
working memory in patients developing schizophrenia.              Proceedings of the National Academy of Sciences USA,
                                                                  93(24), 13468–13472.
Further, an understanding of the genetics relevant to
such abilities needs to take account of how genes rele-         Baddeley, A. & Della Sala, S. (1996). Working memory and
vant to brain maturation interact with ability develop-           executive control. Philosophical Transactions of the Royal
                                                                  Society London Series B Biological Sciences, 351(1346),
ment; this is needed before examining how such genes              1397–1403; discussion 1403–1394.
may relate to the genes that code specific disorders.
    To conclude, the following should be considered             Baird, A., Dewar, B. K., Critchley, H. et al. (2006). Cognitive
                                                                   functioning after medial frontal lobe damage including
in understanding the relevance of the executive                    the anterior cingulate cortex: a preliminary investigation.
system in psychiatric disorders:                                   Brain and Cognition, 60(2), 166–175.
(1) The need to use a developmental and longitudinal            Banich, M. T. & Weissman, D. H. (2000). One of twenty
    framework to understand psychiatric illness;                  questions for the twenty-first century: how do brain
    examination of “growth curves” in comparison                  regions interact and integrate information? Brain and
    with healthy individuals will provide important               Cognition, 42(1), 29–32.
    information about how deficits arise.                       Bannon, S., Gonsalvez, C. J., Croft, R. J. & Boyce, P. M.
(2) Understanding the differential development of EF              (2006). Executive functions in obsessive-compulsive
    skills is likely to be relevant to the nature and             disorder: state or trait deficits? Australian and New
    progression of deficits in psychiatric illness. We            Zealand Journal of Psychiatry, 40(11–12), 1031–1038.
    propose that functions developing early may be              Barnett, J. H., Croudace, T. J., Jaycock, S. et al. (2007a).
    relatively spared, at least initially, while late-             Improvement and decline of cognitive function in
    developing abilities will be more severely affected.           schizophrenia over one year: a longitudinal investigation
                                                                   using latent growth modelling. British Medical Council
(3) The diagnostic specificity of EF deficits may
                                                                   Psychiatry, 7, 16.
    depend on the nature of the disorder, and the
    timing of its onset in relation to maturational stage.      Barnett, J. H., Heron, J., Ring, S. M. et al. (2007b).
                                                                   Gender-specific effects of the catechol-O-
(4) A maturational perspective may also be relevant to             methyltransferase Val108/158Met polymorphism
    understanding the genetics of various psychiatric              on cognitive function in children. American Journal
    disorders, particularly when examining the                     of Psychiatry, 164(1), 142–149.
    relationship to the EF system.                              Barnett, J. H., Jones, P. B., Robbins, T. W. & Muller, U.
                                                                   (2007c). Effects of the catechol-O-methyltransferase
Acknowledgments                                                    Val158Met polymorphism on executive function: a
We thank David Griffiths for help in generating the                meta-analysis of the Wisconsin Card Sort Test in
Figure on neurodevelopmental trajectories. This work               schizophrenia and healthy controls. Molecular
                                                                   Psychiatry, 12(5), 502–509.
was supported by grants from the NHMRC Australia
(350241 & 566529).                                              Barnett, R., Maruff, P., Purcell, R. et al. (1999). Impairment
                                                                   of olfactory identification in obsessive-compulsive
References                                                         disorder. Psychological Medicine, 29(5), 1227–1233.
Ackerman, P. L., Beier, M. E. & Boyle, M. O. (2005).            Barnett, R., Maruff, P., Vance, A. et al. (2001). Abnormal
  Working memory and intelligence: the same or different           executive function in attention deficit hyperactivity
  constructs? Psychological Bulletin, 131, 30–60.                  disorder: the effect of stimulant medication and age on
                                                                   spatial working memory. Psychological Medicine, 31(6),
Anderson, V. A., Anderson, P., Northam, E., Jacobs, R. &
                                                                   1107–1115.
  Catroppa, C. (2001). Development of executive functions
  through late childhood and adolescence in an Australian       Bartzokis, G. (2002). Schizophrenia: breakdown in the well-
  sample. Developmental Neuropsychology, 20(1), 385–406.           regulated lifelong process of brain development and
                                                                   maturation. Neuropsychopharmacology, 27(4), 672–683.
Aron, A. R., Robbins, T. W. & Poldrack, R. A. (2004).
  Inhibition and the right inferior frontal cortex. Trends in   Bartzokis, G., Beckson, M., Lu, P. H. et al. (2001). Age-         129
  Cognitive Science, 8(4), 170–177.                                related changes in frontal and temporal lobe volumes in
         Section 1: Neuropsychological processes



         men: a magnetic resonance imaging study. Archives of                 hygiene deficits in men with negative symptom
         General Psychiatry, 58(5), 461–465.                                  schizophrenia. Biological Psychiatry, 40(10), 1021–1031.
      Bayliss, D. M., Jarrold, C., Gunn, D. M. & Baddeley, A. D.           Brewer, W. J., Francey, S. M., Wood, S. J. et al. (2005).
         (2003). The complexities of complex span: explaining                 Memory impairments identified in people at ultra-high
         individual differences in working memory in children                 risk for psychosis who later develop first-episode
         and adults. Journal of Experimental Psychology: General,             psychosis. American Journal of Psychiatry, 162(1), 71–78.
         132(1), 71–92.                                                    Brewer, W. J., Pantelis, C., Anderson, V. et al. (2001).
      Bechara, A., Damasio, A. R., Damasio, H. & Anderson,                    Stability of olfactory identification deficits in
         S. W. (1994). Insensitivity to future consequences                   neuroleptic-naive patients with first-episode psychosis.
         following damage to human prefrontal cortex. Cognition,              American Journal of Psychiatry, 158(1), 107–115.
         50(1–3), 7–15.                                                    Brewer, W. J., Wood, S. J., Phillips, L. J. et al. (2006).
      Bechara, A., Damasio, H., & Damasio, A. R. (2000).                      Generalized and specific cognitive performance in
         Emotion, decision making and the orbitofrontal cortex.               clinical high-risk cohorts: a review highlighting potential
         Cerebral Cortex, 10(3), 295–307.                                     vulnerability markers for psychosis. Schizophrenia
                                                                              Bulletin, 32(3), 538–555.
      Bechara, A., Damasio, H., Tranel, D. & Anderson, S. W.
         (1998). Dissociation of working memory from decision              Burgess, P. W. (2000). Strategy application disorder: the role
         making within the human prefrontal cortex. Journal of               of the frontal lobes in human multitasking. Psychological
         Neuroscience, 18(1), 428–437.                                       Research, 63(3–4), 279–288.
      Benes, F. M., Turtle, M., Khan, Y. & Farol, P. (1994).               Burgess, P. W. & Shallice, T. (1996). Bizarre responses,
        Myelination of a key relay zone in the hippocampal                   rule detection and frontal lobe lesions. Cortex, 32(2),
        formation occurs in the human brain during childhood,                241–259.
        adolescence and adulthood. Archives of General                     Burgess, P. W., Alderman, N., Evans, J., Emslie, H. &
        Psychiatry, 51, 477–484.                                             Wilson, B. A. (1998). The ecological validity of tests
      Bennett, P., Ong, B. & Ponsford, J. (2005). Assessment                 of executive function. Journal of the International
        of executive dysfunction following traumatic brain                   Neuropsychology Society, 4(6), 547–558.
        injury: comparison of the BADS with other clinical                 Callicott, J. H., Mattay, V. S., Verchinski, B. A. et al. (2003).
        neuropsychological measures. Journal of the                           Complexity of prefrontal cortical dysfunction in
        International Neuropsychological Society, 11(5),                      schizophrenia: more than up or down. American Journal
        606–613.                                                              of Psychiatry, 160(12), 2209–2215.
      Bialystok, E., Craik, F. I., Grady, C. et al. (2005). Effect of      Cannon, T. D. (2005). The inheritance of intermediate
         bilingualism on cognitive control in the Simon task:                phenotypes for schizophrenia. Current Opinion in
         evidence from MEG. Neuroimage, 24(1), 40–49.                        Psychiatry, 18(2), 135–140.
      Bialystok, E., Craik, F. I., Klein, R. & Viswanathan, M.             Cannon, T. D., Hennah, W., van Erp, T. G. et al. (2005).
         (2004). Bilingualism, aging, and cognitive control:                 Association of DISC1/TRAX haplotypes with
         evidence from the Simon task. Psychology and Aging,                 schizophrenia, reduced prefrontal gray matter, and
         19(2), 290–303.                                                     impaired short- and long-term memory. Archives of
      Biederman, J., Monuteaux, M. C., Doyle, A. E. et al. (2004).           General Psychiatry, 62(11), 1205–1213.
         Impact of executive function deficits and attention-              Carter, C. S., Botvinick, M. M. & Cohen, J. D. (1999). The
         deficit/hyperactivity disorder (ADHD) on academic                   contribution of the anterior cingulate cortex to executive
         outcomes in children. Journal of Consulting Clinical and            processes in cognition. Reviews in Neuroscience, 10(1),
         Psychology, 72(5), 757–766.                                         49–57.
      Biederman, J., Petty, C. R., Fried, R. et al. (2007). Stability of   Castner, S. A., Goldman-Rakic, P. S. & Williams, G. V.
         executive function deficits into young adult years: a               (2004). Animal models of working memory: insights
         prospective longitudinal follow-up study of grown up                for targeting cognitive dysfunction in schizophrenia.
         males with ADHD. Acta Psychiatrica Scandinavica,                    Psychopharmacology (Berlin), 174(1), 111–125.
         116(2), 129–136.
                                                                           Chayer, C. & Freedman, M. (2001). Frontal lobe
      Blakemore, S. J. & Choudhury, S. (2006). Development of                functions. Current Neurology and Neuroscience Report,
         the adolescent brain: implications for executive function           1(6), 547–552.
         and social cognition. Journal of Child Psychology and             Cicerone, K. D. & Tanenbaum, L. N. (1997). Disturbance of
         Psychiatry, 47(3–4), 296–312.                                        social cognition after traumatic orbitofrontal brain
      Brewer, W. J., Edwards, J., Anderson, V., Robinson, T. &                injury. Archives of Clinical Neuropsychology, 12(2),
130      Pantelis, C. (1996). Neuropsychological, olfactory, and              173–188.
                                                    Chapter 9: The role of executive functions in psychiatric disorders



Clark, L. & Manes, F. (2004). Social and emotional                Doyle, A. E. (2006). Executive functions in attention-deficit/
   decision-making following frontal lobe injury.                   hyperactivity disorder. Journal of Clinical Psychiatry,
   Neurocase, 10(5), 398–403.                                       67 (Suppl 8), 21–26.
Cohen, J. D., Botvinick, M. & Carter, C. S. (2000). Anterior      Duncan, J. & Owen, A. M. (2000). Common regions of the
  cingulate and prefrontal cortex: who’s in control? Nature         human frontal lobe recruited by diverse cognitive
  Neuroscience, 3(5), 421–423.                                      demands. Trends in Neuroscience, 23(10), 475–483.
Collette, F. & Van der Linden, M. (2002). Brain imaging of        Duncan, J., Burgess, P. & Emslie, H. (1995). Fluid
  the central executive component of working memory.                intelligence after frontal lobe lesions. Neuropsychologia,
  Neuroscience and Biobehavioral Review, 26(2), 105–125.            33(3), 261–268.
Collette, F., Salmon, E., Van der Linden, M. et al. (1999).       Duncan, J., Johnson, R., Swales, M. & Freer, C. (1997).
  Regional brain activity during tasks devoted to the               Frontal lobe deficits after head injury: unity and diversity
  central executive of working memory. Brain Research:              of function. Cognitive Neuropsychology, 14(5), 713–741.
  Cognitive Brain Research, 7(3), 411–417.                        Egan, M. F., Goldberg, T. E., Kolachana, B. S. et al. (2001).
Collette, F., Van der Linden, M., Laureys, S. et al. (2005).         Effect of COMT Val108/158 Met genotype on frontal
  Exploring the unity and diversity of the neural substrates         lobe function and risk for schizophrenia. Proceedings
  of executive functioning. Human Brain Mapping, 25(4),              of the National Academy of Sciences USA, 98(12),
  409–423.                                                           6917–6922.
Conklin, H. M., Luciana, M., Hooper, C. J. & Yarger, R. S.        Ehlis, A. C., Reif, A., Herrmann, M. J., Lesch, K. P. &
  (2007). Working memory performance in typically                    Fallgatter, A. J. (2007). Impact of catechol-O-
  developing children and adolescents: behavioral evidence           methyltransferase on prefrontal brain functioning
  of protracted frontal lobe development. Developmental              in schizophrenia spectrum disorders.
  Neuropsychology, 31(1), 103–128.                                   Neuropsychopharmacology, 32(1), 162–170.
Crawford, S. & Channon, S. (2002). Dissociation between           Elliott, R. (2003). Executive functions and their disorders.
   performance on abstract tests of executive function and            British Medical Bulletin, 65, 49–59.
   problem solving in real-life-type situations in normal         Engle, R. W., Tuholski, S. W., Laughlin, J. E. & Conway,
   aging. Aging and Mental Health, 6(1), 12–21.                     A. R. (1999). Working memory, short-term memory,
Cummings, J. L. (1995). Anatomic and behavioral aspects of          and general fluid intelligence: a latent-variable approach.
  frontal-subcortical circuits. Annals of the New York              Journal of Experimental Psychology: General, 128(3),
  Academy of Science, 769, 1–13.                                    309–331.
Curson, D. A., Duke, P. J., Harvey, C. A., Pantelis, C. &         Eslinger, P. J. & Damasio, A. R. (1985). Severe disturbance
  Barnes, T. R. (1999). Four behavioural syndromes of                of higher cognition after bilateral frontal lobe ablation:
  schizophrenia: a replication in a second inner-London              patient EVR. Neurology, 35(12), 1731–1741.
  epidemiological sample. Schizophrenia Research, 37(2),          Faraone, S. V., Seidman, L. J., Kremen, W. S. et al. (2000).
  165–176.                                                           Neuropsychologic functioning among the nonpsychotic
D’Esposito, M., Cooney, J. W., Gazzaley, A., Gibbs, S. E. &          relatives of schizophrenic patients: the effect of genetic
   Postle, B. R. (2006). Is the prefrontal cortex necessary for      loading. Biological Psychiatry, 48(2), 120–126.
   delay task performance? Evidence from lesion and FMRI          Fassbender, C., Murphy, K., Foxe, J. J. et al. (2004).
   data. Journal of the International Neuropsychology                A topography of executive functions and their
   Society, 12(2), 248–260.                                          interactions revealed by functional magnetic resonance
Damasio, A. R., Tranel, D. & Damasio, H. (1990).                     imaging. Brain Research Cognitive Brain Research, 20(2),
  Individuals with sociopathic behavior caused by frontal            132–143.
  damage fail to respond autonomically to social stimuli.         Fletcher, P. C., Shallice, T. & Dolan, R. J. (2000). “Sculpting
  Behavior and Brain Research, 41(2), 81–94.                         the response space” – an account of left prefrontal
Damasio, H., Grabowski, T., Frank, R., Galaburda, A. M. &            activation at encoding. Neuroimage, 12(4), 404–417.
  Damasio, A. R. (1994). The return of Phineas Gage: clues        Fornito, A., Whittle, S., Wood, S. J. et al. (2006). The
  about the brain from the skull of a famous patient.                influence of sulcal variability on morphometry of the
  Science, 264(5162), 1102–1105.                                     human anterior cingulate and paracingulate cortex.
                                                                     Neuroimage, 33(3), 843–854.
De Luca, C. R., Wood, S. J., Anderson, V. et al. (2003).
  Normative data from the CANTAB. I: development                  Fornito, A., Yucel, M., Wood, S. et al. (2004). Individual
  of executive function over the lifespan. Journal of                differences in anterior cingulate/paracingulate
  Clinical and Experimental Neuropsychology, 25(2),                  morphology are related to executive functions in healthy
  242–254.                                                           males. Cerebral Cortex, 14(4), 424–431.                        131
         Section 1: Neuropsychological processes



      Friston, K. J. (1998). The disconnection hypothesis.              Harrison, B. J., Yucel, M., Shaw, M. et al. (2006).
         Schizophrenia Research, 30(2), 115–125.                          Dysfunction of dorsolateral prefrontal cortex in
      Friston, K. J., Fletcher, P., Josephs, O. et al. (1998).            antipsychotic-naive schizophreniform psychosis.
         Event-related fMRI: characterizing differential                  Psychiatry Research, 148(1), 23–31.
         responses. Neuroimage, 7(1), 30–40.                            Harrison, P. J. (2007). Schizophrenia susceptibility genes
      Frith, C. D., Blakemore, S. J. & Wolpert, D. M. (2000).             and neurodevelopment. Biological Psychiatry, 61(10),
         Abnormalities in the awareness and control of action.            1119–1120.
         Philosophical Transactions of the Royal Society London         Herrmann, L. L., Goodwin, G. M. & Ebmeier, K. P. (2007).
         Series B Biological Science, 355(1404), 1771–1788.               The cognitive neuropsychology of depression in the
      Fuster, J. M. (1991). The prefrontal cortex and its relation to     elderly. Psychological Medicine, 37, 1–10.
         behavior. Progress in Brain Research, 87, 201–211.             Himanen, L., Portin, R., Isoniemi, H. et al. (2005). Cognitive
      Fuster, J. M. (1993). Frontal lobes. Current Opinion in             functions in relation to MRI findings 30 years after
         Neurobiology, 3(2), 160–165.                                     traumatic brain injury. Brain Injury, 19(2), 93–100.
      Fuster, J. M. (2000). Prefrontal neurons in networks              Ho, B. C., Wassink, T. H., O’Leary, D. S. et al. (2005).
         of executive memory. Brain Research Bulletin, 52(5),             Catechol-O-methyl transferase Val158Met gene
         331–336.                                                         polymorphism in schizophrenia: working memory,
                                                                          frontal lobe MRI morphology and frontal cerebral blood
      Gerton, B. K., Brown, T. T., Meyer-Lindenberg, A. et al.            flow. Molecular Psychiatry, 10(3), 229, 287–298.
        (2004). Shared and distinct neurophysiological
        components of the digits forward and backward tasks as          Hudspeth, W. J. & Pribram, K. H. (1992).
        revealed by functional neuroimaging. Neuropsychologia,            Psychophysiological indices of cerebral maturation.
        42(13), 1781–1787.                                                International Journal of Psychophysiology, 12(1), 19–29.
      Giedd, J. N. (2004). Structural magnetic resonance imaging        Jernigan, T. L. & Tallal, P. (1990). Late childhood changes in
         of the adolescent brain. Annals of the New York Academy           brain morphology observable with MRI. Developmental
         of Sciences, 1021, 77–85.                                         Medicine and Child Neurology, 32(5), 379–385.
      Giedd, J. N., Blumenthal, J., Jeffries, N. O. et al. (1999).      Johnson, J. K., Tuulio-Henriksson, A., Pirkola, T. et al.
         Brain development during childhood and adolescence: a             (2003). Do schizotypal symptoms mediate the
         longitudinal MRI study. Nature Neuroscience, 2(10),               relationship between genetic risk for schizophrenia and
         861–863.                                                          impaired neuropsychological performance in co-twins of
                                                                           schizophrenic patients? Biological Psychiatry, 54(11),
      Glahn, D. C., Bearden, C. E., Barguil, M. et al. (2007). The
                                                                           1200–1204.
         neurocognitive signature of psychotic bipolar disorder.
         Biological Psychiatry, 62(8), 910–916.                         Joober, R., Gauthier, J., Lal, S. et al. (2002). Catechol-O-
                                                                           methyltransferase Val-108/158-Met gene variants
      Gochman, P. A., Greenstein, D., Sporn, A. et al. (2005).
                                                                           associated with performance on the Wisconsin Card
        IQ stabilization in childhood-onset schizophrenia.
                                                                           Sorting Test. Archives of General Psychiatry, 59(7),
        Schizophrenia Research, 77(2–3), 271–277.
                                                                           662–663.
      Gogtay, N., Giedd, J. N., Lusk, L. et al. (2004). Dynamic
                                                                        Klingberg, T., Vaidya, C. J., Gabrieli, J. D. E., Moseley, M. E.
        mapping of human cortical development during
                                                                           & Hedehus, M. (1999). Myelination and organization of
        childhood through early adulthood. Proceedings of
                                                                           the frontal white matter in children: a diffusion tensor
        the National Academy of Sciences USA, 101(21),
                                                                           MRI study. Neuroreport, 10, 2817–2821.
        8174–8179.
                                                                        Kolb, B. (1989). Brain development, plasticity, and
      Goldberg, T. E., Egan, M. F., Gscheidle, T. et al. (2003).
        Executive subprocesses in working memory: relationship            behavior. American Psychologist, 44(9), 1203–1212.
        to catechol-O-methyltransferase Val158Met genotype              Kopala, L., Clark, C. & Hurwitz, T. A. (1989). Sex
        and schizophrenia. Archives of General Psychiatry,                differences in olfactory function in schizophrenia.
        60(9), 889–896.                                                   American Journal of Psychiatry, 146(10), 1320–1322.
      Hanninen, T., Hallikainen, M., Koivisto, K. et al. (1997).        Kopala, L. C., Clark, C. & Hurwitz, T. (1993). Olfactory
        Decline of frontal lobe functions in subjects with                deficits in neuroleptic naive patients with schizophrenia.
        age-associated memory impairment. Neurology, 48(1),               Schizophrenia Research, 8(3), 245–250.
        148–153.                                                        Kopala, L. C., Good, K. P. & Honer, W. G. (1994).
      Happaney, K., Zelazo, P. D. & Stuss, D. T. (2004).                  Olfactory hallucinations and olfactory identification
        Development of orbitofrontal function: current                    ability in patients with schizophrenia and other
132     themes and future directions. Brain and Cognition,                psychiatric disorders. Schizophrenia Research, 12(3),
        55(1), 1–10.                                                      205–211.
                                                   Chapter 9: The role of executive functions in psychiatric disorders



Lencz, T., Smith, C. W., McLaughlin, D. et al. (2006).              language learning disorders. Journal of Clinical and
   Generalized and specific neurocognitive deficits in              Experimental Neuropsychology, 28(7), 1073–1094.
   prodromal schizophrenia. Biological Psychiatry, 59(9),        Maruff, P., Wilson, P. & Currie, J. (2003). Abnormalities of
   863–871.                                                        motor imagery associated with somatic passivity
Levin, H., Culhane, K. A., Hartmann, J. et al. (1991).             phenomena in schizophrenia. Schizophrenia Research,
   Developmental changes in performance on tests of                60(2–3), 229–238.
   purported frontal lobe functioning. Developmental             Mathalon, D. H., Bennett, A., Askari, N. et al. (2003).
   Neuropsychology, 7(3), 377–395.                                 Response-monitoring dysfunction in aging and
Levine, B., Stuss, D. T., Milberg, W. P. et al. (1998). The        Alzheimer’s disease: an event-related potential study.
   effects of focal and diffuse brain damage on strategy           Neurobiology of Aging, 24(5), 675–685.
   application: evidence from focal lesions, traumatic brain     Mayberg, H. S., Brannan, S. K., Mahurin, R. K. et al. (1997).
   injury and normal aging. Journal of the International           Cingulate function in depression: a potential predictor of
   Neuropsychology Society, 4(3), 247–264.                         treatment response. Neuroreport, 8(4), 1057–1061.
Levy, R. & Goldman-Rakic, P. S. (1999). Association of           Mega, M. S. & Cummings, J. L. (1994). Frontal-subcortical
   storage and processing functions in the dorsolateral            circuits and neuropsychiatric disorders. Journal of
   prefrontal cortex of the nonhuman primate. Journal of           Neuropsychiatry and Clinical Neuroscience, 6(4),
   Neuroscience, 19(12), 5149–5158.                                358–370.
Lipska, B. & Weinberger, D. (2000). To model a psychiatric       Meyer-Lindenberg, A. S., Olsen, R. K., Kohn, P. D. et al.
   disorder in animals: schizophrenia as a reality test.           (2005). Regionally specific disturbance of dorsolateral
   Neuropsychopharmacology, 23(3), 223–239.                        prefrontal-hippocampal functional connectivity in
Lipska, B. K., Jaskiw, G. E. & Weinberger, D. R. (1993).           schizophrenia. Archives of General Psychiatry, 62(4),
   Postpubertal emergence of hyperresponsiveness to                379–386.
   stress and to amphetamine after neonatal excitotoxic          Miyake, A., Friedman, N. P., Emerson, M. J. et al. (2000).
   hippocampal damage: a potential animal model of                 The unity and diversity of executive functions and
   schizophrenia. Neuropsychopharmacology, 9(1),                   their contributions to complex “Frontal Lobe” tasks:
   67–75.                                                          a latent variable analysis. Cognitive Psychology, 41(1),
Luna, B. & Sweeney, J. A. (2001). Studies of brain and             49–100.
  cognitive maturation through childhood and                     Moberg, P. J., Agrin, R., Gur, R. E. et al. (1999). Olfactory
  adolescence: a strategy for testing neurodevelopmental           dysfunction in schizophrenia: a qualitative and
  hypotheses. Schizophrenia Bulletin, 27(3), 443–455.              quantitative review. Neuropsychopharmacology, 21(3),
Luna, B. & Sweeney, J. A. (2004). The emergence of                 325–340.
  collaborative brain function: FMRI studies of the              Monchi, O., Ko, J. H. & Strafella, A. P. (2006). Striatal
  development of response inhibition. Annals of the New            dopamine release during performance of executive
  York Academy of Sciences, 1021, 296–309.                         functions: a [(11)C] raclopride PET study. Neuroimage,
Luna, B., Garver, K. E., Urban, T. A., Lazar, N. A. &              33(3), 907–912.
  Sweeney, J. A. (2004). Maturation of cognitive processes       Moscovitch, M. (1992). Memory and working with
  from late childhood to adulthood. Child Development,             memory: A component process model based on modules
  75(5), 1357–1372.                                                and central systems. Journal of Cognitive Neuroscience, 4,
MacDonald, A. W., 3rd, Carter, C. S., Flory, J. D.,                257–267.
  Ferrell, R. E. & Manuck, S. B. (2007). COMT val158Met          Nelson, E. E., Leibenluft, E., McClure, E. B. & Pine, D. S.
  and executive control: a test of the benefit of specific         (2005). The social re-orientation of adolescence: a
  deficits to translational research. Journal of Abnormal          neuroscience perspective on the process and its
  Psychology, 116(2), 306–312.                                     relation to psychopathology. Psychological Medicine,
Macmillan, M. (2000a). Nineteenth-century inhibitory               35(2), 163–174.
  theories of thinking: Bain, Ferrier, Freud (and Phineas        Norton, N., Kirov, G., Zammit, S. et al. (2002).
  Gage). History of Psychology, 3(3), 187–217.                     Schizophrenia and functional polymorphisms in the
Macmillan, M. (2000b). Restoring Phineas Gage: a 150th             MAOA and COMT genes: no evidence for association or
  retrospective. Journal of the History of Neuroscience, 9(1),     epistasis. American Journal of Medical Genetics, 114(5),
  46–66.                                                           491–496.
Martinussen, R. & Tannock, R. (2006). Working memory             Orzhekhovskaya, N. S. (1981). Fronto-striatal relationships
  impairments in children with attention-deficit                   in primate ontogeny. Neuroscience and Behavioral
  hyperactivity disorder with and without comorbid                 Physiology, 11(4), 379–385.                                   133
         Section 1: Neuropsychological processes



      Paine, R. W. & Tani, J. (2004). Motor primitive and                 schizophrenia and bipolar disorder. Biological
         sequence self-organization in a hierarchical recurrent           Psychiatry, 58(12), 930–936.
         neural network. Neural Networks, 17(8–9), 1291–1309.          Porter, R. J., Bourke, C. & Gallagher, P. (2007).
      Pantelis, C. & Brewer, W. (1995). Neuropsychological and            Neuropsychological impairment in major depression: its
        olfactory dysfunction in schizophrenia: relationship of           nature, origin and clinical significance. Australian and
        frontal syndromes to syndromes of schizophrenia.                  New Zealand Journal of Psychiatry, 41(2), 115–128.
        Schizophrenia Research, 17(1), 35–45.                          Purcell, R., Maruff, P., Kyrios, M. & Pantelis, C. (1997).
      Pantelis, C. & Maruff, P. (2002). The cognitive                    Neuropsychological function in young patients with
        neuropsychiatric approach to investigating the                   unipolar major depression. Psychological Medicine,
        neurobiology of schizophrenia and other disorders.               27(6), 1277–1285.
        Journal of Psychosomatic Research, 53(2), 655–664.             Purcell, R., Maruff, P., Kyrios, M. & Pantelis, C. (1998a).
      Pantelis, C., Barnes, T. R., Nelson, H. E. et al. (1997).          Cognitive deficits in obsessive-compulsive disorder on
        Frontal-striatal cognitive deficits in patients with chronic     tests of frontal-striatal function. Biological Psychiatry,
        schizophrenia. Brain, 120(10), 1823–1843.                        43(5), 348–357.
      Pantelis, C., Velakoulis, D., McGorry, P. D. (2003a).            Purcell, R., Maruff, P., Kyrios, M. & Pantelis, C. (1998b).
        Neuroanatomical abnormalities before and after onset             Neuropsychological deficits in obsessive-compulsive
        of psychosis: a cross-sectional and longitudinal MRI             disorder: a comparison with unipolar depression, panic
        comparison. Lancet, 361(9354), 281–288.                          disorder, and normal controls. Archives of General
      Pantelis, C., Yucel, M., Wood, S. J., McGorry, P. D. &             Psychiatry, 55(5), 415–423.
        Velakoulis, D. (2003b). Early and late                         Rao, S. M., Harrington, D. L., Haaland, K. Y. et al. (1997).
        neurodevelopmental disturbances in schizophrenia                 Distributed neural systems underlying the timing
        and their functional consequences. Australia and                 of movements. Journal of Neuroscience, 17(14),
        New Zealand Journal of Psychiatry, 37(4), 399–406.               5528–5535.
      Pantelis, C., Yucel, M., Wood, S. J. et al. (2005). Structural   Ratiu, P. & Talos, I. F. (2004). Images in clinical medicine.
        brain imaging evidence for multiple pathological                  The tale of Phineas Gage, digitally remastered. New
        processes at different stages of brain development in             England Journal of Medicine, 351(23), e21.
        schizophrenia. Schizophrenia Bulletin, 31(3), 672–696.
                                                                       Ratiu, P., Talos, I. F., Haker, S., Lieberman, D. & Everett, P.
      Passingham, D. & Sakai, K. (2004). The prefrontal cortex            (2004). The tale of Phineas Gage, digitally remastered.
         and working memory: physiology and brain imaging.                Journal of Neurotrauma, 21(5), 637–643.
         Current Opinion in Neurobiology, 14(2), 163–168.
                                                                       Ravizza, S. M., McCormick, C. A., Schlerf, J. E. et al. (2006).
      Paul, R. H., Clark, C. R., Lawrence, J. et al. (2005). Age-        Cerebellar damage produces selective deficits in verbal
         dependent change in executive function and gamma 40             working memory. Brain, 129(2), 306–320.
         Hz phase synchrony. Journal of Integrated Neuroscience,
                                                                       Reiss, A. L., Abrams, M. T., Singer, H. S., Ross, J. L. &
         4(1), 63–76.
                                                                          Denckla, M. B. (1996). Brain development, gender and
      Paus, T. (2005). Mapping brain maturation and cognitive             IQ in children: a volumetric imaging study. Brain, 119,
         development during adolescence. Trends in Cognitive              1763–1774.
         Science, 9(2), 60–68.
                                                                       Reverberi, C., Lavaroni, A., Gigli, G. L., Skrap, M. &
      Paus, T., Zijdenbos, A., Worsley, K. et al. (1999).                Shallice, T. (2005a). Specific impairments of rule
        Structural maturation of neural pathways in children             induction in different frontal lobe subgroups.
        and adolescents: in vivo study. Science, 283(5409),              Neuropsychologia, 43(3), 460–472.
        1908–1911.
                                                                       Reverberi, C., Toraldo, A., D’Agostini, S. & Skrap, M.
      Peers, P. V., Ludwig, C. J., Rorden, C. et al. (2005).             (2005b). Better without (lateral) frontal cortex? Insight
         Attentional functions of parietal and frontal cortex.           problems solved by frontal patients. Brain, 128(12),
         Cerebral Cortex, 15(10), 1469–1484.                             2882–2890.
      Peterson, B. S., Skudlarski, P., Gatenby, J. C. et al. (1999).   Rhodes, S. M., Coghill, D. R. & Matthews, K. (2006). Acute
         An fMRI study of Stroop word-color interference:                neuropsychological effects of methylphenidate in
         evidence for cingulate subregions subserving multiple           stimulant drug-naive boys with ADHD II – broader
         distributed attentional systems. Biological Psychiatry,         executive and non-executive domains. Journal of Child
         45(10), 1237–1258.                                              Psychology and Psychiatry, 47(11), 1184–1194.
      Pirkola, T., Tuulio-Henriksson, A., Glahn, D. et al. (2005).     Riva, D. & Giorgi, C. (2000). The cerebellum contributes to
         Spatial working memory function in twins with                    higher functions during development: evidence from a
134
                                                    Chapter 9: The role of executive functions in psychiatric disorders



   series of children surgically treated for posterior fossa         performance in schizophrenia: a study with fMRI and
   tumours. Brain, 123(5), 1051–1061.                                structural equation modeling. Neuroimage, 19(3),
Robbins, T. W., James, M., Owen, A. M. et al. (1998).                751–763.
  A study of performance on tests from the CANTAB                 Schlosser, R., Gesierich, T., Kaufmann, B., Vucurevic, G. &
  battery sensitive to frontal lobe dysfunction in a large           Stoeter, P. (2003b). Altered effective connectivity in
  sample of normal volunteers: implications for theories of          drug free schizophrenic patients. Neuroreport, 14(17),
  executive functioning and cognitive aging. Cambridge               2233–2237.
  Neuropsychological Test Automated Battery. Journal              Schweinsburg, A. D., Nagel, B. J. & Tapert, S. F. (2005).
  of the International Neuropsychology Society, 4(5),                fMRI reveals alteration of spatial working memory
  474–490.                                                           networks across adolescence. Journal of the International
Roffman, J. L., Weiss, A. P., Deckersbach, T. et al. (2007a).        Neuropsychology Society, 11(5), 631–644.
  Effects of the methylenetetrahydrofolate reductase              Segalowitz, S. J. & Rose-Krasnor, L. (1992). The construct of
  (MTHFR) C677T polymorphism on executive function                   brain maturation in theories of child development. Brain
  in schizophrenia. Schizophrenia Research, 92(1–3),                 and Cognition, 20(1), 1–7.
  181–188.
                                                                  Shah, P. & Miyake, A. (1996). The separability of working
Roffman, J. L., Weiss, A. P., Purcell, S. et al. (2007b).            memory resources for spatial thinking and language
  Contribution of methylenetetrahydrofolate reductase                processing: an individual differences approach. Journal
  (MTHFR) polymorphisms to negative symptoms in                      of Experimental Psychology: General, 125(1), 4–27.
  schizophrenia. Biological Psychiatry, 63(1), 43–48.
                                                                  Shallice, T. & Burgess, P. W. (1991). Deficits in strategy
Rogers, M. A., Kasai, K., Koji, M. et al. (2004). Executive          application following frontal lobe damage in man. Brain,
  and prefrontal dysfunction in unipolar depression: a               114(2), 727–741.
  review of neuropsychological and imaging evidence.
                                                                  Shaw, P., Greenstein, D., Lerch, J. et al. (2006). Intellectual
  Neuroscience Research, 50(1), 1–11.
                                                                     ability and cortical development in children and
Roth, R. M., Milovan, D., Baribeau, J. & O’Connor, K.                adolescents. Nature, 440(7084), 676–679.
  (2005). Neuropsychological functioning in early- and
                                                                  Shimamura, A. P. (2000). Toward a cognitive neuroscience
  late-onset obsessive-compulsive disorder. Journal of
                                                                     of metacognition. Conscious Cognition, 9(2), 313–323;
  Neuropsychiatry and Clinical Neuroscience, 17(2),
                                                                     discussion 324–316.
  208–213.
                                                                  Simon, A. E., Berger, G. E., Giacomini, V., Ferrero, F. &
Roth, R. M. & Saykin, A. J. (2004). Executive dysfunction in         Mohr, S. (2006). Insight, symptoms and executive
  attention-deficit/hyperactivity disorder: cognitive and            functions in schizophrenia. Cognitive Neuropsychiatry,
  neuroimaging findings. Psychiatric Clinics of North                11(5), 437–451.
  America, 27(1), 83–96, ix.
                                                                  Smith, C. W., Park, S. & Cornblatt, B. (2006). Spatial
Rypma, B. & D’Esposito, M. (1999). The roles of prefrontal          working memory deficits in adolescents at clinical high
  brain regions in components of working memory: effects            risk for schizophrenia. Schizophrenia Research, 81(2–3),
  of memory load and individual differences. Proceedings            211–215.
  of the National Academy of Sciences USA, 96(11),
  6558–6563.                                                      Smith, E. E. & Jonides, J. (1999). Storage and executive
                                                                    processes in the frontal lobes. Science, 283(5408),
Salmon, E. & Collette, F. (2005). Functional imaging of             1657–1661.
   executive functions. Acta Neurologica Belgica, 105(4),
   187–196.                                                       Smith, E. E., Jonides, J. & Koeppe, R. A. (1996). Dissociating
                                                                    verbal and spatial working memory using PET. Cerebral
Saperstein, A. M., Fuller, R. L., Avila, M. T. et al. (2006).       Cortex, 6(1), 11–20.
   Spatial working memory as a cognitive endophenotype
                                                                  Smith, M., Kates, J. & Vriezen, E. R. (1992). The
   of schizophrenia: assessing risk for pathophysiological
                                                                    development of frontal-lobe functions. In S. J. Segalowitz
   dysfunction. Schizophrenia Bulletin, 32(3), 498–506.
                                                                    & J. Rapin (Eds.), Handbook of Neuropsychology (Vol. 7).
Sawaguchi, T. & Goldman-Rakic, P. S. (1991). D1 dopamine            Amsterdam: Elsevier.
   receptors in prefrontal cortex: involvement in working
                                                                  Spear, L. P. (2000). The adolescent brain and age-related
   memory. Science, 251(4996), 947–950.
                                                                     behavioral manifestations. Neuroscience and Biobehavior
Scherf, K. S., Sweeney, J. A. & Luna, B. (2006). Brain basis of      Review, 24(4), 417–463.
   developmental change in visuospatial working memory.           Spikman, J. M., Deelman, B. G. & van Zomeren, A. H.
   Journal of Cognitive Neuroscience, 18(7), 1045–1058.              (2000). Executive functioning, attention and frontal
Schlosser, R., Gesierich, T., Kaufmann, B. et al. (2003a).           lesions in patients with chronic CHI. Journal of Clinical      135
   Altered effective connectivity during working memory              and Experimental Neuropsychology, 22(3), 325–338.
         Section 1: Neuropsychological processes



      Stoddart, S. D., Craddock, N. J. & Jones, L. A. (2007).            Tekin, S. & Cummings, J. L. (2002). Frontal-subcortical
         Differentiation of executive and attention impairments            neuronal circuits and clinical neuropsychiatry: an
         in affective illness. Psychological Med, 37, 1–11.                update. Journal of Psychosomatic Research, 53(2),
      Storey, E., Forrest, S., Shaw, J., Mitchell, P. & Gardner, R. M.     647–654.
         (1999). Spinocerebellar ataxia type 2: clinical features of     Thatcher, R. W. (1992). Cyclic cortical reorganization
         a pedigree displaying prominent frontal-executive                 during early childhood. Brain and Cognition, 20(1),
         dysfunction. Archives of Neurology, 56(1), 43–50.                 24–50.
      Strous, R. D., Bark, N., Woerner, M. & Lachman, H. M.              Thatcher, R. W., Walker, R. A. & Giudice, S. (1987). Human
         (1997). Lack of association of a functional catechol-O-           cerebral hemispheres develop at different rates and ages.
         methyltransferase gene polymorphism in schizophrenia.             Science, 236(4805), 1110–1113.
         Biological Psychiatry, 41(4), 493–495.                          Thomson, P. A., Wray, N. R., Millar, J. K. et al. (2005).
      Stuss, D. T. (1992). Biological and psychological                    Association between the TRAX/DISC locus and
         development of executive functions. Brain and                     both bipolar disorder and schizophrenia in the
         Cognition, 20(1), 8–23.                                           Scottish population. Molecular Psychiatry, 10(7),
      Stuss, D. T. (2006). Frontal lobes and attention: processes          657–668, 616.
         and networks, fractionation and integration. Journal            Tunbridge, E. M., Lane, T. A. & Harrison, P. J. (2007a).
         of the International Neuropsychology Society, 12(2),              Expression of multiple catechol-o-methyltransferase
         261–271.                                                          (COMT) mRNA variants in human brain. American
      Stuss, D. T. & Alexander, M. P. (2000). Executive functions          Journal of Medical Genetics Part B (Neuropsychiatric
         and the frontal lobes: a conceptual view. Psychological           Genetics), 144B(6), 834–839.
         Research, 63(3–4), 289–298.                                     Tunbridge, E. M., Weickert, C. S., Kleinman, J. E. et al.
      Stuss, D. T. & Levine, B. (2002). Adult clinical                     (2007b). Catechol-o-methyltransferase enzyme activity
         neuropsychology: lessons from studies of the frontal              and protein expression in human prefrontal cortex
         lobes. Annual Review of Psychology, 53, 401–433.                  across the postnatal lifespan. Cerebral Cortex, 17(5),
                                                                           1206–1212.
      Stuss, D. T., Gow, C. A. & Hetherington, C. R. (1992). “No
         longer Gage”: frontal lobe dysfunction and emotional            Unsworth, N. & Engle, R. W. (2005). Individual differences
         changes. Journal of Consulting and Clinical Psychology,           in working memory capacity and learning: evidence
         60(3), 349–359.                                                   from the serial reaction time task. Memory and
      Sweeney, J. A., Luna, B., Keedy, S. K., McDowell, J. E. &            Cognition, 33(2), 213–220.
        Clementz, B. A. (2007). fMRI studies of eye movement             Van der Wee, N. J., Ramsey, N. F., van Megen, H. J. et al.
        control: investigating the interaction of cognitive and            (2007). Spatial working memory in obsessive-
        sensorimotor brain systems. Neuroimage, 36 (Suppl. 2),             compulsive disorder improves with clinical response:
        T54–T60.                                                           a functional MRI study. European Journal of
      Sweeney, J. A., Rosano, C., Berman, R. A. & Luna, B. (2001).         Neuropsychopharmacology, 17(1), 16–23.
        Inhibitory control of attention declines more than               Van der Werf, S. P., Prins, J. B., Jongen, P. J., van der
        working memory during normal aging. Neurobiology of                Meer, J. W. & Bleijenberg, G. (2000a). Abnormal
        Aging, 22(1), 39–47.                                               neuropsychological findings are not necessarily a sign of
      Szameitat, A. J., Schubert, T., Muller, K. & Von Cramon,             cerebral impairment: a matched comparison between
         D. Y. (2002). Localization of executive functions in dual-        chronic fatigue syndrome and multiple sclerosis.
         task performance with fMRI. Journal of Cognitive                  Neuropsychiatry, Neuropsychology and Behavioral
         Neuroscience, 14(8), 1184–1199.                                   Neurology, 13(3), 199–203.
      Tamm, L., Menon, V. & Reiss, A. L. (2002). Maturation of           Van der Werf, Y. D., Witter, M. P., Uylings, H. B. &
        brain function associated with response inhibition.                Jolles, J. (2000b). Neuropsychology of infarctions in the
        Journal of the American Academy of Child and Adolescent            thalamus: a review. Neuropsychologia, 38(5), 613–627.
        Psychiatry, 41(10), 1231–1238.                                   Vance, A., Silk, T. J., Casey, M. et al. (2007). Right parietal
      Tan, H. Y., Sust, S., Buckholtz, J. W. et al. (2006).                dysfunction in children with attention deficit
        Dysfunctional prefrontal regional specialization and               hyperactivity disorder, combined type: a functional MRI
        compensation in schizophrenia. American Journal of                 study. Molecular Psychiatry, 12, 826–832.
        Psychiatry, 163(11), 1969–1977.                                  Ventre-Dominey, J., Bailly, A., Lavenne, F. et al. (2005).
      Taylor, S. F., Welsh, R. C., Wager, T. D. et al. (2004).             Double dissociation in neural correlates of visual
        A functional neuroimaging study of motivation and                  working memory: a PET study. Brain Research: Cognitive
136     executive function. Neuroimage, 21(3), 1045–1054.                  Brain Research, 25(3), 747–759.
                                                   Chapter 9: The role of executive functions in psychiatric disorders



Wagar, B. M. & Thagard, P. (2004). Spiking Phineas Gage:           young-adult and aged 5-HT1BKO mice as assessed in a
  a neurocomputational theory of cognitive-affective               radial-arm water maze. Learning and Memory, 10(5),
  integration in decision making. Psychological Review,            401–409.
  111(1), 67–79.                                                Wood, S. J., Pantelis, C., Proffitt, T. et al. (2003). Spatial
Wager, T. D. & Smith, E. E. (2003). Neuroimaging                  working memory ability is a marker of risk-for-
  studies of working memory: a meta-analysis.                     psychosis. Psychological Medicine, 33(7), 1239–1247.
  Cognitive and Affective Behavioral Neuroscience, 3(4),        Yakovlev, P. & Lecours, A. (1967). The myelogenetic cycles
  255–274.                                                        of regional maturation of the brain. In A. Minkowski
Watkins, L. H., Sahakian, B. J., Robertson, M. M. et al.          (Ed.), Regional Development of the Brain in Early Life
  (2005). Executive function in Tourette’s syndrome and           (pp. 3–70). Oxford: Blackwell.
  obsessive-compulsive disorder. Psychological Medicine,        Yamasaki, H., LaBar, K. S. & McCarthy, G. (2002).
  35(4), 571–582.                                                 Dissociable prefrontal brain systems for attention and
Weickert, C. S., Webster, M. J., Gondipalli, P. et al.            emotion. Proceedings of the National Academy of Sciences
  (2007). Postnatal alterations in dopaminergic markers           USA, 99(17), 11447–11451.
  in the human prefrontal cortex. Neuroscience, 144(3),
                                                                Yucel, M., Lubman, D. I., Harrison, B. J. et al. (2007). A
  1109–1119.
                                                                  combined spectroscopic and functional MRI investigation
Weinberger, D. R. (1987). Implications of normal brain            of the dorsal anterior cingulate region in opiate addiction.
  development for the pathogenesis of schizophrenia.              Molecular Psychiatry, 12(7), 611, 691–702.
  Archives of General Psychiatry, 44(7), 660–669.
                                                                Yucel, M., Wood, S. J., Fornito, A. et al. (2003). Anterior
Weinberger, D. R., Egan, M. F., Bertolino, A. et al. (2001).      cingulate dysfunction: implications for psychiatric
  Prefrontal neurons and the genetics of schizophrenia.           disorders? Journal of Psychiatry and Neuroscience, 28(5),
  Biological Psychiatry, 50(11), 825–844.                         350–354.
West, R. & Alain, C. (2000). Evidence for the transient         Zakzanis, K. K., Mraz, R. & Graham, S. J. (2005). An fMRI
  nature of a neural system supporting goal-directed              study of the Trail Making Test. Neuropsychologia,
  action. Cerebral Cortex, 10(8), 748–752.                        43(13), 1878–1886.
Westheide, J., Wagner, M., Quednow, B. B. et al. (2007).        Zammit, S., Jones, G., Jones, S. J. et al. (2004).
  Neuropsychological performance in partly remitted               Polymorphisms in the MAOA, MAOB, and COMT
  unipolar depressive patients: focus on executive                genes and aggressive behavior in schizophrenia.
  functioning. European Archive of Psychiatry and Clinical        American Journal of Medical Genetics Part
  Neuroscience, 257(7), 389–395.                                  B (Neuropsychiatric Genetics), 128(1), 19–20.
Winterer, G. & Goldman, D. (2003). Genetics of human            Zhang, X., Tochigi, M., Ohashi, J. et al. (2005). Association
  prefrontal function. Brain Research: Brain Research             study of the DISC1/TRAX locus with schizophrenia in a
  Review, 43(1), 134–163.                                         Japanese population. Schizophrenia Research, 79(2–3),
Wodka, E. L., Mahone, E. M., Blankner, J. G. et al. (2007).       175–180.
  Evidence that response inhibition is a primary deficit in     Zimmerman, M. E., Brickman, A. M., Paul, R. H. et al.
  ADHD. Journal of Clinical and Experimental                      (2006). The relationship between frontal gray matter
  Neuropsychology, 29(4), 345–356.                                volume and cognition varies across the healthy adult
Wolff, M., Benhassine, N., Costet, P. et al. (2003).              lifespan. American Journal of Geriatric Psychiatry,
  Delay-dependent working memory impairment in                    14(10), 823–833.




                                                                                                                                 137
          Chapter




        10
                           Decision-making

                           Luke Clark and Trevor W. Robbins



      Introduction: relevance of                                     The relationship between psychology
      decision-making to neuropsychiatry                             and economics in decision-making
      Decision-making is a collection of processes that              To refine our psychological definition, the term
      allow humans to adopt flexible goal-directed behavior          decision-making refers to the processes that govern
      in an ever-changing environment. Impairments in                choice behavior when the individual is confronted with
      decision-making are central features of a number of            situations that have multiple response options. In this
      psychiatric and neurological disorders, and are often          chapter, we will focus on affective aspects of decision-
      referred to specifically in the diagnostic (DSM–IV)            making, where the response options differ in their
      criteria. Within the affective disorders, difficulty           potential to cause positive and negative outcomes.
      and slowness in decision-making characterize clinical          These options may vary along at least three dimen-
      depression, whereas bipolar manic patients show a              sions: (1) the magnitude of expected gain or loss, (2)
      tendency to make decisions associated with the poten-          the probability of gain or loss, and (3) the delay
      tial for painful consequences (e.g. excessive spending         between choosing the option and receipt of the gain
      or sexual indiscretions) (American Psychiatric Asso-           or loss (Ho et al., 1999). In economic approaches to
      ciation, 2000). Substance-use disorders, and other             decision-making, the expected value (EV) of a given
      forms of addictive behavior like pathological gambl-           option is calculated from the magnitude of that
      ing, can be formulated as the persistent choice of an          option, weighted by the probability of that out-
      option (drug administration, gambling) with the                come occurring. By this account, choice is based
      potential for negative long-term effects on health,            on the straightforward selection of the option that
      finances and personal relationships (Elster & Skog,            maximizes EV. Similar models have been developed
      1999; Vuchinich & Heather, 2003). Substance users              to account for choice behavior between options that
      may persist in drug taking despite insight into                differ in delay (reviewed by Frederick et al., 2002).
      these negative consequences. Obsessive-compulsive              In a widely used scenario, the subject is given the
      disorder (OCD) may also relate to pathology in                 choice between a small reward available soon (e.g.
      decision-making processes: the obsessive component             $10 delivered tomorrow) versus a larger reward avail-
      may relate to prolonged deliberation, whereas the              able in the future ($30 delivered in one month).
      compulsive component may arise from repeated                   Humans and other animals (e.g. rats, pigeons) typi-
      selection of a response option long after that                 cally discount future rewards. The degree of temporal
      option has ceased to be beneficial or contextually             discounting has been found to follow a hyperbolic
      appropriate. Characterization of decision-making               function, where discounting is steeper at short delays
      at a neuropsychological level may indicate novel               compared with long delays (Mazur, 1987; Rachlin
      forms of treatment for these disorders, and may                et al., 1991). This hyperbolic model can explain
      provide an objective marker for quantifying treat-             the phenomenon of preference reversal (Kirby &
      ment response.                                                 Herrnstein, 1995), where a conservative decision



138   The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by
      Cambridge University Press. # Cambridge University Press 2009.
                                                                                  Chapter 10: Decision-making



made far in advance (e.g. preferring $11 in 366 days           The examples reviewed above demonstrate a
over $10 in 365 days) may be reversed as the point of      number of situations where human behavior deviates
delivery draws close ($10 now versus $11 tomorrow).        from strict models of rationality based on mathemat-
    The concept of risk can be introduced to decision-     ical utility. Fundamentally, in many real-world situ-
making scenarios in a number of guises. The subject        ations it may be better to make a suboptimal decision
could be offered a choice between a certain $10 win        rapidly than to slowly reach a perfect decision. More-
and a gamble with 0.5 probability of winning $50 or        over, the concept of value in the standard economic
a 0.5 probability of losing $30. The EV of these two       framework is inherently subjective (i.e. expected
options is identical (($50 Â 0.5) – ($30 Â 0.5) ¼ $10),    utility), and many real-life decisions require the com-
and therefore a strictly rational model might predict      parison of options that represent value on different
equal choice behavior. The gamble may be considered        scales; for example, how do we decide between the
the more risky option for two distinct reasons: first,     pleasures of eating luxurious foods versus the costs
the outcome variance is greater, and second, there         of being overweight (e.g. in terms of health or social
is potential for monetary loss (or other aversive          evaluation)? To compare apples and oranges, an
consequences) (see Lopes, 1987; Mellers et al., 1999).     intuitive hypothesis is that the brain must convert
Healthy subjects do not display equal choice in            these values into an “independent metric” (Sanfey
these circumstances, and consistently select the safe      et al., 2006). The integration of economics theory with
secure win, a phenomenon known as loss aversion            ideas from psychology and neuroscience represents a
(Tversky & Kahneman, 1991). There are also consist-        burgeoning field of research that has recently been
ent differences in risk preference depending on            labeled “neuroeconomics” (Glimcher & Rustichini,
whether the gamble has a winning or losing context         2004; Sanfey et al., 2006).
(more commonly known as a positive or negative
frame) (Gonzalez et al., 2005; Tversky & Kahneman,         The neuropsychology of
1981). When offered the choice between a certain
small win ($10) and a gamble that may yield a large        decision-making
win ($20) or no win ($0), subjects typically prefer        Damage to the ventromedial and orbitofrontal aspects
the small certain option. Hence, in these positive         of the prefrontal cortex (PFC) is associated with a
frames (where there is no capacity for losing points),     complex behavioral syndrome in humans that inclu-
healthy subjects can be described as risk averse. In a     des gross alterations in social and emotional behavior.
negative frame, given the choice between a certain         Other cognitive domains including perception, lan-
loss ($10) and the chance of losing a larger amount        guage, memory and even certain aspects of executive
($20) or losing nothing ($0), subjects are typically       functions may be preserved in these patients. The
risk preferent: they are prepared to take a chance to      core changes in the orbitofrontal syndrome include
avoid a loss.                                              emotional lability, impulsivity, socially inappropriate
    The economic literature also emphasizes a distinc-     behavior and poor judgment in everyday life (Malloy
tion between decision-making under risk and decision-      et al., 1993). The syndrome is sometimes known
making under uncertainty (Camerer & Weber, 1992;           as frontal disinhibition syndrome or acquired socio-
Ellsberg, 1961). This refers to the level of knowledge     pathy (Damasio et al., 1990). Deficits in decision-
about the outcome probabilities at the point of            making have been proposed to lie at the core of this
decision: when these probabilities are explicit, this      syndrome (Damasio, 1994). In single case studies,
is known as decision-making under risk, whereas if         these patients display a consistent tendency to make
the outcome probabilities are unknown, this is known       financial, occupational and interpersonal decisions
as decision-making under uncertainty. Decision-            based on short-term benefits, without considering
makers are typically risk averse when probabilities        (or caring about) the long-term ramifications (Cato
are unknown, which is labeled the ambiguity effect         et al., 2004; Damasio, 1994; Dimitrov et al., 1999;
(Ellsberg, 1961). In most decision-making contexts,        Eslinger & Damasio, 1985).
there is a middle ground where the subject has an esti-        The precise anatomical substrates of the orbito-
mate of the probabilities involved, which is continually   frontal syndrome remain somewhat unclear. The
adjusted on the basis of ongoing feedback. We refer        ventral portion of the prefrontal cortex represents a     139
to this situation as decision-making under ambiguity.      large and anatomically heterogeneous region (Ongur
         Section 1: Neuropsychological processes




        WIN
      START


                         You have won $100!!
                                                                               TOTAL = 100                                  75




                                                                                                RED             BLUE
                A              B              C              D


      Figure 10.1. In the Iowa Gambling Task (left), the subject makes 100 card choices from four decks. Decks A and B offer high rewards
      ($100 per choice) but higher losses. Decks C and D offer only $50 per choice, but small losses resulting in profit over time. Patients with
      ventromedial prefrontal lesions persist in selecting from the risky decks despite accruing high debts. In the Cambridge Gamble Task (right;
      see www.camcog.com), the subject must decide if a hidden token is under a red or blue box (there are always 10 boxes in total). On this trial,
      the subject has selected blue, the most likely outcome. After making this probabilistic judgment they must place a bet on their confidence in
      their decision.


      et al., 2003). The orbitofrontal cortex covers the lower                 many measures of executive function (e.g. working me-
      surface of the frontal lobe above the orbits of the                      mory and cognitive flexibility) and knowledge of social
      eyes (Brodmann Area (BA) 10, 11, 12, 13, 11/47).                         conventions (Eslinger & Damasio, 1985; Saver &
      It extends from the medial wall to the lateral surface.                  Damasio, 1991). The Iowa Gambling Task (IGT)
      Elsewhere in the literature, groups refer to the ventro-                 (Bechara et al., 1994) was developed by this group in
      medial PFC (Bechara et al., 2000; Fellows & Farah, 2003;                 an effort to quantify the deficits in real-life judgment
      Shamay-Tsoory et al., 2003), which includes the                          that were displayed by patients like EVR. During this
      medial part of the orbitofrontal region (BA 10, 11,                      task, the subject makes a series of 100 choices from
      12) and the more ventral sectors of the anterior cin-                    four card decks (decks A, B, C, D). Each card choice
      gulate cortex and the medial PFC (BA 25 and lower                        results in a monetary win, but occasional choices also
      24, 32). This region also includes the so-called “sub-                   result in monetary loss, and the four decks differ in
      genual” anterior cingulate region (BA 25) implicated                     the profile of wins and losses (see Figure 10.1). At
      in the neuroanatomy of depression (Drevets et al.,                       the start of the task, the subject has no information
      1997). It is increasingly likely that the inferior frontal               about the four decks, and must learn to choose
      gyrus (IFG; BA 44 and 45), particularly in the right                     advantageously based on trial-by-trial feedback.
      hemisphere, also contributes to the frontal disinhibi-                   Decks A and B are “risky” decks, associated with high
      tion syndrome. This region is reliably activated in                      immediate wins ($100 per choice) but dramatically
      functional imaging studies using Go–No Go and                            large occasional penalties that result in net loss over
      Stop Signal tasks of response inhibition (Horn et al.,                   time. Decks C and D are “safe” decks, associated with
      2003; Rubia et al., 2003), and the volume of damage                      smaller immediate wins ($50 per choice) but negli-
      in right (but not left) IFG in lesion cases has been                     gible long-term losses, such that subjects accumulate
      shown to correlate with deficits on the Stop Signal                      gradual profit from choosing these decks. Healthy
      test of response inhibition (Aron et al., 2003; Clark                    subjects typically develop a preference for the safe
      et al., 2007).                                                           decks during the task, whereas ventromedial PFC
                                                                               lesion patients maintain a preference for the risky
                                                                               decks throughout the task, despite accruing signifi-
      The Iowa Gambling Task and somatic                                       cant debt (Bechara et al., 1994, 2000).
      marker hypothesis                                                            By monitoring autonomic responses during per-
140   Extensive neuropsychological evaluation of Damasio’s                     formance of the IGT, Bechara et al. (1996) identified
      case EVR showed remarkably intact performance on                         an “anticipatory” skin conductance response (SCR)
                                                                                  Chapter 10: Decision-making



in healthy subjects in the 5-second window prior          responses to decision outcomes (wins and losses)
to choice. These anticipatory responses developed         were also disrupted (Bechara et al., 1999). These
throughout the task and were greater before risky         appraisal responses were intact in ventromedial PFC
decisions. These somatic responses were argued to         patients, but they were unable to re-evoke these
reflect the accumulating knowledge about the long-        responses to guide future behavior.
term negative consequences of these decisions. Patients       As a further component of the decision-making
with ventromedial PFC lesions did not show antici-        circuit, the somatosensory cortex/insula region was
patory SCRs, but exhibited intact verbal “appraisal”      proposed to hold the visceral and emotional rep-
responses to winning and losing feedback. In sum-         resentations that were associated with secondary
mary, Bechara, Damasio and colleagues argued that         inducers. These representations are accessed by the
the behavior of the ventromedial PFC patients was         ventromedial PFC during decision-making, and the
driven by the short-term benefits associated with the     ventromedial PFC integrates this information with
risky decks, rather than the long-term punishments.       the cognitive representations of the decision-making
This profile was labeled “myopia for the future”          option. By this account, patients with damage to the
(Bechara et al., 1994).                                   somatosensory cortex/insula region should also dis-
    The early studies with the IGT formed the corner-     play quantitatively similar decision-making impair-
stone of the somatic marker hypothesis (Damasio,          ments and problems with emotional behavior to
1994). In essence, this theory proposes that decision-    ventromedial PFC lesion patients (Bar-On et al.,
making is covertly biased by visceral and emotio-         2003; Shiv et al., 2005). Whilst any distinct contribu-
nal signals. When faced with a decision, visceral and     tions of somatosensory/insula cortex and the ventro-
emotional responses that have previously been asso-       medial PFC have yet to be confirmed, a number of
ciated with each option are re-activated. Options         functional-imaging studies have reported insula acti-
that have previously yielded reward are promoted,         vations during risky decisions (Kuhnen & Knutson,
and options that have previously yielded punishment       2005; Paulus et al., 2003). Insula activity has also been
are suppressed. In this manner, the overall number        reported during the “Ultimatum Game,” where the
of available options is narrowed down, and deli-          participant and an illusory second player are asked to
beration time could be greatly reduced relative to a      split a sum of money. On any given trial, the second
purely economic cost–benefit analysis. The ventro-        player may propose a “fair” (e.g. 50:50) or an “unfair”
medial PFC was proposed to be the crucial structure       (e.g. 10% to you, 90% to them) split, and the partici-
that integrates the cognitive representations of the      pant must decide whether to accept or reject the offer.
various response options with their associated            By accepting the offer, both players receive their
somatic markers. Thus, patients with ventromedial         cut, but by rejecting the offer, both players receive
PFC lesions are unable to retrieve the emotional con-     nothing. In this manner, all rejections may be viewed
sequences of their prior decisions. As a result, their    as economically irrational, as acceptance will always
decision-making may become driven by the informa-         yield a win of some magnitude. Sanfey et al. (2003b)
tion held in working memory (“Deck A won $100             reported insula activity during receipt of unfair offers,
the last time”).                                          and particularly during rejection of unfair offers.
    In addition to the ventromedial PFC, the somatic      These data are consistent with an emotional response,
marker hypothesis proposed an extended neural cir-        perhaps mediated by visceral signals, which may be
cuit supporting decision-making, which also includes      able to over-ride more rational routes to effective
the amygdala and the somatosensory cortex/insula          decision-making.
region. The amygdala was proposed to process “pri-            The IGT is currently the most widely used mea-
mary inducers”: innate or learned stimuli that directly   sure of decision-making in neuropsychiatric studies
trigger pleasurable or aversive states. In contrast,      (see Dom et al., 2005; Dunn et al., 2006 for review).
the ventromedial PFC was argued to process “second-       However, the IGT and the somatic marker hypothe-
ary inducers”; thoughts or memories that, once            sis have both attracted criticism on a number of
re-activated, can trigger emotional experiences. Amyg-    grounds. With regard to the task itself, a number of
dala lesion patients also showed impaired perfor-         distinct mechanisms have been proposed to explain
mance on the IGT, but their autonomic signature           IGT impairments, such as impaired reversal learning         141
was distinct: the feedback (appraisal) autonomic          (Fellows & Farah, 2005b), impaired inhibition (Dunn
         Section 1: Neuropsychological processes



      et al., 2006), impaired working memory (Hinson et al.,      towards high-risk alternatives. This is similar to ideas
      2002) and increased risk preference (Rogers et al.,         from personality theory of sensation-seeking and ven-
      1999). The use of a fixed pseudo-random trial               turesomeness (Eysenck & Eysenck, 1978; Zuckerman,
      sequence ensures that early in the IGT, the risky decks     1979). For example, a driver may take a blind corner
      actually have a higher expected utility until the initial   on the wrong side of the road, in full awareness that
      punishments have been received. In this short time,         this maneuver is dangerous, in order to derive an
      the subject may develop a response “set” to the risky       illicit thrill from the experience. In a neuropsycho-
      decks, and thus may have to perform a response              logical context, a subject may prefer high-risk options
      reversal to the safe decks in order to display advanta-     for a number of ancillary reasons, including an
      geous decision-making. Impaired reversal learning,          increased sensitivity to reward, a reduced sensitivity
      exemplified by perseveration to the previously rein-        to punishment or an attenuation of naturally conser-
      forced stimulus, has been reported in several studies       vative decision-making biases such as loss aversion.
      in patients with ventral prefrontal lesions (Fellows &           It is difficult to isolate risk preference on the IGT
      Farah, 2003; Hornak et al., 2004; Rolls et al., 1994). By   because of the emphasis on learning, which is central
      shuffling the order of cards in the early trials so that    to the somatic marker hypothesis. The Cambridge
      penalties were introduced very early on, Fellows &          Gamble Task (CGT) was developed to assess decision-
      Farah (2005a) showed that the impairment in ventro-         making without placing such a demand on learning.
      medial PFC patients was alleviated, consistent with a       On each trial on the CGT, the subject is presented
      deficit in reversal learning rather than decision-          with an array of 10 red and blue boxes. A token is
      making per se.                                              hidden underneath one of the 10 boxes, and the
          The anatomical specificity of the IGT to the ventral    subject must decide whether the token is hidden
      PFC has also been questioned. Several lesion studies        under a red box or a blue box. This initial decision
      have demonstrated IGT impairments in patients with          is a relatively simple probability judgment that does
      focal dorsolateral PFC lesions (Clark et al., 2003;         not entail risk processing. Following this judgment,
      Fellows & Farah, 2005b; Manes et al., 2002), and func-      the subject is invited to bet a number of points on
      tional imaging studies using the IGT have implicated        their red/blue decision. If their judgment of box color
      a large frontal network supporting optimal perfor-          was correct, their bet is added to their total score,
      mance (Adinoff et al., 2003; Bolla et al., 2004; Ernst      enabling a higher bet to be placed on the next trial.
      et al., 2002). There is evidence for lateralization of      If their red/blue judgment is incorrect, the bet is
      decision-making processes to the right frontal cortex       subtracted from their total score. Analysis of betting
      (Clark et al., 2003; Tranel et al., 2002), although this    behavior provides a more direct index of risk-taking,
      laterality effect may be gender-dependent (Bolla et al.,    and by displaying the probability information (i.e. the
      2004; Tranel et al., 2005). Studies using a dual-task       ratio of red to blue boxes) on each trial, the CGT does
      methodology, where IGT performance has been                 not place any demands on working memory or learn-
      combined with an executive working-memory task              ing mechanisms. In choosing the bet, the subject is
      (random sequence generation), have suggested that           offered a sequence of fixed bets, presented in either an
      executive processes may interfere with development          ascending or descending order (e.g. in the Ascending
      of advantageous decision-making (Hinson et al., 2002;       condition, the presented bets are 5%, 25%, 50%, 75%
      Jameson et al., 2004). As such, the dorsolateral PFC        and 90% of the current points total). Comparison of
      involvement in the IGT may be linked to working             Ascend and Descend blocks enables the separation
      memory representations for the four card decks.             of risk-preferent behavior from an effect of motor
                                                                  impulsivity or delay aversion. Impulsive or delay-averse
                                                                  subjects would be expected to select a high bet in the
      Preference for risk                                         Descend condition (where the bets start at the max-
      In the somatic marker hypothesis, patients may make         imum), but a low bet in the Ascend condition (where
      apparently ‘risky’ choices because they are unaware of      the bets start very small). Healthy subjects make the
      the potential negative consequences that have been          majority of probability judgments towards the box color
      associated previously with those options. An alterna-       in the majority, and their betting behavior is moderated
142   tive account is that patients may prefer decks A and B      by the ratio of red to blue boxes, such that subjects place
      because of a more conscious, explicit preference            higher bets at a 9:1 ratio compared with a 6:4 ratio.
                                                                                  Chapter 10: Decision-making



    A number of studies have shown abnormal CGT            (fMRI), Hsu et al. (2005) found that the level of
performance in patient groups with pathology               ambiguity during decision-making correlated posi-
affecting the ventral PFC. In the initial study (Rogers    tively with the neural response in the amygdala and
et al., 1999), a small group of patients with orbito-      the lateral orbitofrontal cortex. In the same study,
frontal cortex lesions showed impaired probability         patients with orbitofrontal cortex lesions (n ¼ 5)
judgment (i.e. reduced preference for the box color        showed attenuated aversion to both ambiguous and
in the majority) coupled with reduced betting behav-       risky decisions. Using a similar fMRI design, Huettel
ior. Several subsequent studies have found increases in    et al. (2006) found that activity within the lateral
betting behavior (i.e. larger bets), coupled with intact   prefrontal cortex predicted the degree of preference
probability judgment, in patients with large frontal       to uncertain gambles. The response in this region was
lesions including the orbitofrontal cortex (Manes          negatively correlated with a questionnaire measure of
et al., 2002), in patients with subarachnoid hemor-        impulsivity, suggesting that this region may imple-
rhage of the anterior communicating artery (the            ment control over impulsive responses. In the Huettel
major blood vessel supplying the ventral and medial        study, the degree of preference to explicitly risky
aspects of the frontal lobes) (Mavaddat et al., 2000),     gambles was predicted by activity in the posterior
and in patients with fronto-temporal dementia              parietal cortex. It remains unclear whether patients
(Rahman et al., 1999) (see below). In each of these        with lesions to this area show actual changes in affect-
three examples, it is likely that the damage extends       ive decision-making. The lack of orbitofrontal cortex
outside the ventral PFC. However, in a recent dataset      activity is surprising in the Huettel experiment and
(Clark et al., 2008), we have shown that betting behav-    may relate to signal drop-out from the orbitofrontal
ior is increased in a group of patients with selective     cortex region due to inhomogeneities in the magnetic
ventromedial PFC lesions, but not in a group of            field.
lesion controls with dorsolateral PFC damage. The              Risk-taking may also be considered in terms of
ventromedial PFC group again displayed intact prob-        outcome variance (Lopes, 1987). Sanfey et al. (2003a)
ability judgment. The increase in betting could not be     tested a group of ventromedial PFC patients and
explained by changes in impulsivity or delay aversion      healthy controls on a modified version of the IGT
(the ventromedial PFC patients placed higher bets          where the four decks were equated for EV but varied
in both the ascending and descending conditions).          in outcome variance. The healthy subjects showed
The ventromedial PFC group also experienced more           strong risk aversion, preferring the decks with low
“bankruptcies” during the CGT, where the block is          outcome variance. Performance in the ventromedial
terminated if the points score reaches zero (see also      PFC patients was heterogeneous, and patients could
Mavaddat et al., 2000). This latter effect confirms that   be divided into two subgroups: one subgroup who
increased betting on the CGT is “risky” and dysfunc-       behaved like controls, and another who preferred
tional, and results in overall loss.                       the high variance decks. There were no observable
    Comparison of the CGT and IGT also highlights          differences in lesion location between the two sub-
the distinction between decision-making under risk         groups. A study by Tomb et al. (2002) further high-
and decision-making under uncertainty. In the CGT,         lighted the potential importance of outcome variance.
the outcome probabilities are indicated explicitly by      Tomb et al. (2002) initially replicated the anticipatory
the ratio of red to blue boxes, and hence this task        SCR effect reported by Bechara et al. (1996), but were
primarily assesses decision-making under risk. At the      concerned that the effect may relate to the higher
start of the IGT, participants’ decisions are made         immediate benefits of the risky decks rather than the
from a point of complete uncertainty, as there is no       long-term negative consequences. They measured
information provided about the probabilities of win-       autonomic responses on a variant of the IGT where
ning and losing on the four decks. During the course       the safe decks produced greater magnitude wins and
of the task, the participant develops subjective esti-     losses compared with the risky decks. Here, healthy
mates for the probability distributions of the four        subjects showed relatively greater anticipatory
decks, best described as decision-making under ambi-       responses to the safe decks, even though this was
guity. Preliminary evidence suggests that this distinc-    now the advantageous strategy. It is difficult to disen-
tion may be significant at a neuropsychological            tangle the causal nature of the anticipatory SCR effect,   143
level. Using functional magnetic resonance imaging         but from this study it is possible that the anticipatory
        Section 1: Neuropsychological processes



      SCRs signal the riskiness of the response in terms of      uncertain reinforcer (Mobini et al., 2002). In contrast,
      outcome variance (see Dunn et al., 2006 for other          Winstanley et al. (2004) found that lesions of the rat
      explanations).                                             orbitofrontal cortex made after training produced
          A number of other decision-making tasks have           enhanced choice for the large delayed reward. How-
      been developed to assess riskiness. Shiv et al. (2005)     ever, lesions of the basolateral amygdala (projecting
      used an investment task based on a simplified stock        to the core region of the nucleus accumbens) also
      market. Across each of 20 trials, the subject had to       induced impulsive choice, as did lesions to the
      decide whether to invest in a coin-toss gamble, or         nucleus accumbens (Cardinal et al., 2001). This latter
      to not invest and skip the go. Although the EV of          effect contrasted with unchanged performance
      investing was positive, healthy subjects displayed loss    following lesions to the anterior cingulate cortex,
      aversion on the task, and became more conservative         and a possible effect on temporal discrimination
      after both winning and losing on investment gambles.       following medial PFC lesions (Cardinal et al., 2001).
      A combined group of lesion patients with ventrome-         These data suggest that choice between delayed
      dial PFC or somatosensory cortex/insula damage             rewards may be supported by a limbic fronto-striatal
      made more profit than controls, after investing for a      circuit comprising the amygdala, the orbitofrontal
      greater number of trials. Shiv et al. argued that in       cortex and the nucleus accumbens.
      healthy subjects, somatic signals may interfere with a          An fMRI study in human volunteers is broadly
      rational cost–benefit analysis in some circumstances,      consistent with these data. McClure et al. (2004)
      and these situations may enable ventromedial PFC           presented subjects with a series of choices between
      lesion patients to show superior performance to con-       imaginary delayed rewards during scanning. In an
      trols. Other tasks have measured risk-taking as the        event-related analysis, choice of the small immediate
      persistence of a response with incrementing degrees        reward was associated with a response in the ventral
      of reward and punishment, such as in the Balloon           striatum (subsuming the nucleus accumbens), and
      Analogue Risk Task (Lejuez et al., 2003) or Risky          also in the medial and the orbitofrontal cortex.
      Gains procedure (Paulus et al., 2003). Tasks of this       A second circuit, comprising the dorsolateral PFC
      type are discussed below in relationship to substance-     and posterior parietal cortex was activated during
      use disorders and alcoholism.                              delayed choice regardless of the delay interval, and
                                                                 was argued to reflect reasoning and logical processing.
                                                                 Comparison of the two systems showed relatively
      Choice between delayed rewards                             greater activity in the dorsolateral PFC, with the pari-
      The IGT and CGT primarily emphasize the process-           etal network predicting choice of the large reward.
      ing of probability and magnitude of loss/reward            However, a single study in human lesion cases has
      in decision-making. Decision processes between dela-       failed to substantiate orbitofrontal (or dorsolateral
      yed outcomes have received less attention in neuro-        PFC) involvement. Fellows & Farah (2005a) found
      psychological research at the present time, despite a      intact temporal discounting functions in ventrome-
      large body of work investigating intertemporal choice      dial PFC lesion and dorsolateral PFC lesion groups,
      in various forms of addiction (for review, see Bickel &    with the patients with ventromedial PFC lesions dis-
      Marsch, 2001). Temporal discounting tasks have             playing shortened time perspectives on a question-
      also been widely used in rodents, where preference         naire measure. Impaired orienting to the future may
      for a small immediate reward can be treated as             contribute to everyday difficulties in ventromedial
      an index of impulsivity. The delay to the large reinfor-   PFC patients, although this deficit was associated with
      cer can be varied across blocks of the task to ascer-      ratings of apathy and not impulsivity.
      tain the indifference point, where the two options are
      valued equally (Mazur, 1987). Orbitofrontal cortex
      lesions (using quinolinic acid administered before
                                                                 Information sampling and ‘reflection
      task training) increased preference for small immedi-      impulsivity’
      ate rewards over large delayed rewards in rodents          The majority of tests used to assess decision-making
      (Mobini et al., 2002). This effect generalized to a        present an array of information at the start of each
144   probability discounting procedure, increasing pre-         trial, from which the subject is expected to make a
      ference for a small certain reward over a larger           response. In many real-life situations, it is necessary
                                                                                 Chapter 10: Decision-making



to gather and evaluate information over a period of       lesions, mainly affecting the dorsolateral PFC (Berlin
time, before making a decision (for example, when         et al., 2004). Fellows (2006) has recently examined
buying a car, renting a flat or simply deciding whether   information-gathering behavior on a more complex
to take an umbrella out in the morning). In these         decision-making task where the subject must decide
scenarios, inadequate sampling of information will        which of six apartments to rent by gathering infor-
have an inevitable impact on the accuracy of the          mation on several different attributes (e.g. the rent
eventual decision (Evenden, 1999). Other recent data      payment, space and noise level). Healthy subjects and
suggest that some complex decisions involving mul-        patients with dorsolateral PFC lesions showed an
tiple attributes may be performed better in situations    “attribute-based” strategy on the task where they
where the subject is distracted from cogitating           focused on specific attributes in turn and compared
or reflecting on the decision (Dijksterhuis et al.,       the six apartments. Whilst the ventromedial PFC
2006). The construct of “reflection impulsivity” was      patients sampled a similar total amount of informa-
developed by Kagan (1966) to refer to consistent          tion, they employed a qualitatively different strategy
individual differences in information-gathering           for acquiring information by assessing several attri-
behavior and the speed–accuracy relationship. In the      butes for each apartment, before moving to the next
Matching Familiar Figures Test (MFFT), subjects are       apartment (i.e. an “alternative-based” strategy). In
presented with a template picture (e.g. a bicycle) and    more open-ended and uncertain contexts, this differ-
six variants. Of the variants, only one is a perfect      ence in acquisition style may have concomitant effects
match, and the other five pictures vary subtly along      on decision-making accuracy.
a number of dimensions (e.g. number of spokes,
shape of handle-bars, tire thickness). Healthy children
displayed a bimodal pattern of performance on the         Decision-making in neuropsychiatric
MFFT, where some children consistently responded          patient groups
very rapidly but with poor accuracy, whereas the
other subgroup took much longer over each decision        Frontal variant fronto-temporal dementia
and were very accurate. The first group was labeled       Frontal variant fronto-temporal dementia (fvFTD)
“impulsive” and the second group “reflective” (Kagan,     is one of the most prevalent forms of early-onset
1966). The impulsive style has been associated with       dementia (Ratnavalli et al., 2002). Patients typically
attention-deficit hyperactivity disorder (Messer, 1976)   present with a florid disinhibition syndrome that can
and responds to psychostimulant treatment (Brown &        profoundly affect interpersonal function. Neurocog-
Sleator, 1979). However, interpretation of MFFT           nitive testing has revealed a pattern of impairment in
findings can be problematic given the task’s substan-     fvFTD comparable with patients with ventromedial
tial demands on perception and working memory.            PFC lesions. For example, Rahman et al. (1999) ori-
     Several recent studies have suggested that orbito-   ginally reported impaired reversal learning on the
frontal and ventromedial PFC lesions may disrupt          IDED attentional shifting task, and increased betting
information-gathering behavior and create an impul-       (coupled with intact probability judgment) on the
sive decision-making style. Dimitrov et al. (1999)        CGT. Torralva et al. (2007) have confirmed that
reported a single case study of a Vietnam war veteran     fvFTD patients are also impaired on the IGT, as well
(MGS) who was retired from service after a shrapnel       as on measures of social cognition and Theory of
wound to the right orbitofrontal region. On return        Mind, although these deficits are not intercorrelated
home, MGS’s personality changed dramatically and          (see also Gregory et al., 2002). Neuroanatomical evi-
he was married and divorced three times in the space      dence for orbitofrontal cortex dysfunction has been
of several years to a runaway, a drug addict and a        borne out in subsequent neuroimaging studies (Diehl
prostitute. On neuropsychological assessment, MGS         et al., 2004; Ibach et al., 2004). For example, a Euro-
showed a consistent shift in the speed–accuracy rela-     pean multicenter PET study showed that the ventro-
tionship across several different tests, towards rapid    medial frontopolar cortex was critically affected in
but low-accuracy decisions. In a group study of 23        every one of 29 fvFTD cases (Salmon et al., 2003).
orbitofrontal cortex lesion patients, increased MFFT          We have recently explored the neurochemical sub-
impulsivity was seen in the OFC group compared            strates of the increased betting effect in frontal        145
with both healthy controls and non-OFC frontal lobe       dementia cases. In a placebo-controlled crossover
               Section 1: Neuropsychological processes



                                                                                 80
               90
               80                                                                75
               70
               60                                                                70




                                                                        % bets
      % bets




               50
                                                                                 65
               40
               30                                                                60
                                                          Drug
               20                                         Placebo
                                                                                 55
               10
                0                                                                50
                      9:1        8:2         7:3            6:4                          Placebo             Drug                Healthy*
                                 Ratio of boxes
      Figure 10.2. Betting behavior on the Cambridge Gamble Task is significantly increased in patients with frontal variant fronto-temporal
      dementia (Rahman et al., 1999). Single dose treatment with methylphenidate (40 mg) significantly reduced betting behavior and effectively
      normalized the impairment. *Healthy data from the placebo condition of Turner et al. (2003) Psychopharmacology, 168, 455–464. Data
      reproduced from Rahman et al. (2006).



      design, an acute dose of methylphenidate (Ritalin;                         further impetus from studies implicating orbitofron-
      40 mg) significantly reduced betting in eight cases with                   tal cortex circuitry in drug craving and drug expect-
      frontal dementia, to the level of healthy elderly controls                 ancy (Goldstein & Volkow, 2002 for review). A wealth
      (Rahman et al., 2006) (see Figure 10.2). A similarly                       of research has demonstrated deficient decision-
      designed study found no effects of acute paroxetine,                       making on the IGT in drug users dependent upon a
      a selective serotonin reuptake inhibitor (SSRI) (Deakin                    variety of substances including stimulants, opiates,
      et al., 2004). Methylphenidate is a psychostimulant                        alcohol and marijuana (see Dom et al., 2005 for
      drug that increases extracellular levels of dopamine                       review). For example, Bechara & Damasio (2002)
      and noradrenaline via blockade of the reuptake trans-                      examined IGT performance in 46 individuals atten-
      porters. How this beneficial effect of methylphenidate                     ding drug rehabilitation at an inpatient center. Most
      is mediated is presently unclear. It is possible that                      subjects abused multiple substances (“poly-drug”
      methylphenidate acts to replenish depleted catecho-                        users) but there were similar numbers of subjects
      lamine levels in patients with fvFTD (Sjogren et al.,                      whose preferred drug was cocaine, amphetamine or
      1998). However, this account would predict remedia-                        alcohol. Performance on the IGT showed a bimodal
      tion of other neurocognitive measures, like executive                      distribution in the substance users, with 63% of sub-
      function, which was not seen in the Rahman et al.                          jects preferring the risky decks, and the remaining 37%
      study. The specific effect on decision-making may be                       behaving similarly to controls. Task impairment did
      explained by an action on reward signaling, or the                         not covary with drug of choice, and psychophysio-
      stimulation of central somatic markers carried by                          logical recording confirmed the absence of anticipa-
      the ascending catecholamine projections.                                   tory SCRs in the behavioraly impaired subgroup.
                                                                                     Although these studies with the IGT demonstrate
                                                                                 reliable statistically significant differences between
      Substance abuse and alcoholism                                             substance-user groups and healthy controls, not all
      Addictive disorders appear to reflect a breakdown                          studies found an actual preference for the risky decks
      of rational decision-making processes. Patients with                       in the substance users (Goudriaan et al., 2005; Mazas
      substance-abuse disorders continue to select the                           et al., 2000; Stout et al., 2005). Risk-preferent biases
      short-term reward of drug administration above the                         in decision-making have been explored with a variety
      long-term negative consequences for their health,                          of other tasks. The CGT was used to demonstrate
      finances and interpersonal relationships. Research                         qualitative differences in decision-making quality
146   aiming to characterize the profile of abnormal                             in groups of stimulant and opiate abusers. Deficits
      decision-making in substance abuse has received                            in this measure correlated significantly with the
                                                                                                                    Chapter 10: Decision-making



                                                                                                    0.9


   WIN 100                                                                                         0.85
   LOSE 100




                                                                          P(correct) at decision
                                                                                                    0.8


                                                                                                   0.75


                                                                                                    0.7


                                                                                                   0.65


                                                                                                    0.6
                                                                                                          Control   Amph      Opiate    Ex-user
Figure 10.3. The Information Sampling Task (see www.camcog.com). Each trial commences (left) with presentation of 25 gray boxes
arranged in a 5 Â 5 matrix, covering a random assortment of two colors of squares; these two colors are displayed on panels at the foot of the
screen. When the subject touches a box (middle), it opens to reveal its color. The subject must decide which of the two colors lies in the
majority on the board. They are told they can open as many boxes as they wish in order to make this decision. They are told to touch the
corresponding panel at the foot of the screen (bottom right) once they have decided which color is in the majority. Amphetamine-dependent
(Amph) subjects, opiate-dependent subjects, and ex-users of amphetamines or opiates opened fewer boxes than non-drug-using controls, and
tolerate a lower probability of making a correct response at the time of decision. This is thought to indicate altered reflection impulsivity
in current and former drug users. Reproduced from Clark et al. (2006) Biological Psychiatry, 60, 512–522, with permission. Copyright # 2006
Society of Biological Psychiatry.

duration of substance use (Rogers et al., 1999). How-                    larger rewards available in the future (see Bickel &
ever, neither group of drug users showed evidence of                     Marsch, 2001 for review). Steeper rates of temporal
increased betting, motor impulsivity or delay aversion                   discounting have been seen with hypothetical mone-
on the CGT.                                                              tary rewards or quantities of drug-of-choice, and also
    In the Risky Gains procedure (Paulus et al., 2003),                  with abstract rewards like health or freedom (Baker
the numbers 20, 40 and 80 appear on a computer                           et al., 2003; Johnson & Bickel, 2002; Madden et al.,
screen in an ascending order. Selection of the 20                        1997). This preference was correlated with the
guarantees a 20-point gain (the safe option). By                         number of disadvantageous decisions on the IGT in
waiting to select 40 or 80, the subject may win more                     a group of cocaine users (Monterosso et al., 2001).
points (40 or 80). However, there is also a risk of                      Preference for small immediate reward has also been
punishment: if 40 or 80 appear in an alternative color,                  demonstrated on a delayed reward task with genuine
these points are deducted (the risky option). Recre-                     “experiential” delays (e.g. 5 cents in 5 seconds, versus
ational stimulant users selected more risky responses                    15 cents after 15 seconds) (Allen et al., 1998; Moeller
than stimulant-naïve controls (Leland & Paulus,                          et al., 2002). As an important demonstration of eco-
2005). The Balloon Analogue Risk Task (BART) is a                        logical validity, steeper rates of temporal discounting
similar procedure, where the subject may continue                        have been associated with shared needle use in opiate
pumping air into the balloon to attain more points,                      users (Odum et al., 2000).
but if the balloon explodes, all points are lost. Lejuez                     Substance users may show consistent differences
et al. (2003) showed that the BART – but not the                         in the gathering and evaluation of information at the
IGT – was able to discriminate current cigarette                         pre-decisional stage. Work on recreational MDMA
smokers from never-smokers. Increased risky res-                         (“Ecstasy”) users has shown impulsive patterns of
ponses were also demonstrated in alcohol-dependent                       performance on the Matching Familiar Figures Test
subjects on a similar task (Bjork et al., 2004).                         (Morgan, 1998; Morgan et al., 2002, 2005), putatively
    Substance use has also been associated with                          related to the neurotoxic effects on MDMA on sero-
impulsive choice on measures of delayed reward and                       tonergic neurons. We developed a novel task (see
temporal discounting, where drug users consistently                      Figure 10.3) of information-sampling behavior to                         147
prefer small rewards available at short delays over                      minimize the visual search and strategic demands of
         Section 1: Neuropsychological processes



      the MFFT, which may be independently impaired in            trait impulsivity (Vitaro et al., 1999) may pre-date
      substance users (Fox et al., 2002). We administered         addictive disorders, and that impaired decision-
      this test as part of a neuropsychological assessment to     making (on the IGT and temporal discounting tasks)
      chronic stimulant and opiate users (Clark et al.,           may be present in pathological gamblers where
      2006). Current and former substance users both              neurotoxic and neuroadaptive effects seem unlikely
      sampled less information on the task than healthy           (Cavedini et al., 2002b; Petry, 2001). The separation
      controls and tolerated a lower probability of making        of cause and effect in addiction may be studied more
      a correct decision. These effects were seen regardless      directly through research on experimental animals
      of drug preference (stimulants or opiates). As a            (Perry et al., 2005).
      consequence of reduced information sampling, the                In summary, a wealth of research has demon-
      substance users also made more errors on the task,          strated impairments in decision-making ability in
      suggesting that a tendency to make decisions based          substance users with a variety of preferred drugs
      on inadequate pre-decisional processing may have            of abuse (including stimulants, opiates and alcohol).
      concomitant effects on real-life decision accuracy.         Recent studies have begun to investigate specific
          Decision-making impairments in drug users are           subcomponents of decision-making, where substance
      mirrored in abnormal patterns of frontal lobe activity      users again display robust impairments in multiple
      during decision-making performance. Ersche et al.           processes, including choice of delayed rewards, pro-
      (2005) employed a variant of the CGT (the Risk Task)        cessing of probability and risk, and pre-decisional
      adapted for PET imaging. In the Risk Task, a fixed bet      reflection. Functional imaging studies have impli-
      is associated with either box color, and on each trial      cated PFC abnormalities in these behavioral deficits.
      the subject is offered a choice between a small but         These data are consistent with neurobiological theo-
      more likely reward, and a larger but less likely reward.    ries of addiction that highlight the loss of inhibitory
      During decision-making blocks (compared against a           control over reward-driven behavior, governed in the
      visuo-motor control condition), current opiate users        healthy brain by the frontal cortex (Goldstein &
      and current amphetamine users displayed altered             Volkow, 2002; Jentsch & Taylor, 1999).
      patterns of blood flow between the left and right
      orbitofrontal cortex, coupled with decreased blood
      flow in dorsolateral PFC (Ersche et al., 2005). These       Obsessive-compulsive disorder
      changes appear to persist across long periods of            Decision-making processes have been less widely
      abstinence from drug use: ex-users of opiates or            studied in relation to other neuropsychiatric dis-
      amphetamines who had been abstinent from all illicit        orders. Choice behavior and response selection are
      drugs for at least one year also differed from healthy      clearly relevant to the symptomatology of OCD, and
      controls and showed a similar pattern of brain acti-        imaging data have implicated orbitofrontal cortex
      vation to the current users. Somewhat similar effects       and ventral striatal circuitry in the pathophysiology
      were reported in abstinent cocaine users (Bolla et al.,     of this condition (Chamberlain et al., 2005). More-
      2003). Detoxified alcoholics who were abstinent for         over, ventromedial frontal leucotomy is an effective
      over 6 years on average also still displayed robust         treatment for severe and refractory OCD (Irle et al.,
      impairments on the IGT (Fein et al., 2004).                 1998). However, decision-making processes have
          It remains unclear whether these changes in             been examined in only a handful of studies in OCD
      decision-making occur as an irreversible consequence        to date. Performance on the IGT was examined in 34
      of chronic drug use, or whether these changes in fact       OCD patients, 34 healthy controls and a smaller
      pre-date drug-taking and are associated with the vul-       group of panic disorder patients (n ¼ 16) to control
      nerability to addiction. There is evidence that both        for anxiety levels (Cavedini et al., 2002a). The OCD
      pathways are at least plausible. Structural imaging         group were impaired relative to both control groups,
      studies have shown gray matter reductions in the            and significantly preferred the risky decks over the
      frontal cortex of stimulant, opiate and alcohol users       safe decks. In this study, disadvantageous decision-
      (Franklin et al., 2002; Lyoo et al., 2006; Wilson et al.,   making also predicted a poor response to a 10-week
      1996), presumably related to long-term neurotoxicity.       course of SSRI treatment, demonstrating the potential
148   However, there is also evidence that impaired behav-        clinical benefits of neuropsychological assessment
      ioral inhibition (Tarter et al., 2004) and increased        in guiding treatment selection. However, a similarly
                                                                                      Chapter 10: Decision-making



powered study published at the same time reported             Sahakian, 2006). Patients with affective disorder may
no significant difference in IGT performance between          also show structural brain abnormalities in the medial
OCD patients and controls (Nielen et al., 2002), and a        and orbital aspects of the PFC (Drevets et al., 1997;
later study found similar performance in patients with        Lacerda et al., 2004). An assessment of IGT perfor-
schizophrenia, with and without obsessive symptoms            mance in a group of manic patients yielded equivocal
(Whitney et al., 2004). A single study using the CGT          findings: the manic group were significantly impaired
also reported no impairment in an OCD group                   relative to controls but did not clearly prefer either
(Watkins et al., 2005). At the present time, studies          the risky decks or the safe decks (Clark et al., 2001).
assessing decision-making in OCD using complex                As such, the deficit did not fully resemble the ventro-
tasks like the IGT have yielded equivocal results.            medial PFC profile, and their poor performance
Future research may benefit from fractionating spe-           could be attributable to deficient learning or inatten-
cific components of the decision-making process,              tion. On the CGT, manic patients showed approxi-
including aspects of inhibitory control and (compul-          mately normal betting behavior on the task, although
sive) perseveration of previously reinforced choices.         they were less able to adjust their betting according
These studies will also need to control carefully for         to the ratio of boxes compared with controls (Murphy
comorbid depression and anxiety levels, and SSRI              et al., 2001). Further, the manic group showed
medication status.                                            impaired probability judgment and increased deliber-
                                                              ation times, and the deficit in probability judgment
                                                              correlated with manic symptom ratings on the Young
Schizophrenia and affective disorders                         scale. Probability judgment was intact in a control
The research on decision-making is similarly incon-           group of patients with unipolar depression (Murphy
sistent in schizophrenia, where the extent of orbito-         et al., 2001) and in remitted patients with bipolar
frontal cortex dysfunction remains controversial. On          disorder (Rubinsztein et al., 2000), suggesting that
the CGT, first-episode patients and chronic patients          the deficit in probability judgment is a state-related
with schizophrenia displayed slower deliberation              abnormality specific to mania. A subsequent PET
times and attenuated risk adjustment (i.e. betting            imaging experiment measured regional cerebral
behavior was less affected by the ratio of boxes). The        blood flow in manic patients during the CGT variant
chronic patients showed an additional impairment in           (Risk) task used in the Ersche et al. (2005) study
probability judgment, where they selected the unlikely        (described above). In the manic group, brain activa-
box color more often (Hutton et al., 2002). Studies           tions associated with decision-making were increased
employing the IGT in groups of patients with schizo-          in the anterior cingulate cortex (BA 32) but reduced
phrenia have reported mixed results including prefer-         in the inferior frontal gyrus (BA 47), suggesting a
ence for the risky decks (Bark et al., 2005; Ritter et al.,   dysregulation of medial and ventral prefrontal cir-
2004), no overall impairment (Wilder et al., 1998),           cuitry in mania.
increased preference for infrequent punishment (i.e.              There are currently a paucity of studies examining
decks B and D over decks A and C) (Shurman et al.,            decision-making in unipolar depression (Major Dep-
2005), and performance dependent upon medication              ressive Illness), despite the listing of “indecisiveness”
status (Beninger et al., 2003). Given the generalized         as one of the key cognitive symptoms of depression in
pattern of background neuropsychological impair-              the DSM–IV. A control group of unipolar depressed
ment in schizophrenia, combined with the demands              patients included in the Murphy et al. (2001) study
for learning and cognitive flexibility that are inherent      showed longer deliberation times than healthy con-
to the IGT, it is likely that more specific measures          trols on the CGT, although this could relate to gener-
may be necessary to elucidate the subcomponents of            alized psychomotor slowing rather than a specific
decision-making in schizophrenia.                             decision-making impairment. Overall, given the
    In affective illness, decision-making has been            quantity of neuropsychological research investigating
examined mainly in relation to the manic phase of             executive function in affective and psychotic illnesses,
bipolar disorder. Some of the cardinal symptoms of            it is perhaps surprising that measures of decision-
mania, like socially inappropriate remarks, impulsiv-         making have received so little examination. Prelimi-
ity and poor judgment, bear a strong resemblance to           nary evidence of decision-making abnormalities in           149
the orbitofrontal cortex lesion syndrome (Clark &             bipolar mania are particularly intriguing, given the
         Section 1: Neuropsychological processes



      core tendency of manic patients to make “risky” deci-       theoretical models that relate salient task variables
      sions with the potential for painful consequences, and      such as magnitude and delay of reward to the value
      the clear similarities between mania and the orbito-        of each response option. However, it now seems likely
      frontal lesion syndrome.                                    that “prospective” discounting, typically involving
                                                                  long delays stretching into the future (days to weeks),
                                                                  and “experiential” discounting, involving real delays
      Conclusions                                                 over much shorter timeframes (typically under one
      This chapter has reviewed the increasing evidence           minute), may depend on distinct neural circuitry and
      of impaired decisional processes following frontal          may reflect different components of complex process-
      brain damage and in a number of neuropsychiatric            ing that are somehow integrated to provide appar-
      disorders in which prefrontal cortical pathology is         ently orderly “discounting” behavior. The majority of
      suspected. The major advance has been the introduc-         this research involves discounting of the former type,
      tion of a number of well-designed tests of human            typically tested using questionnaires (“Would you
      decision-making that take into account the multiple         prefer $10 today or $30 in 7 days?”) (Kirby et al.,
      dimensions that contribute to performance, includ-          1999). More recent studies using experiential delays
      ing, for example, the utility of the decisions and their    are more comparable with the extensive literature on
      framing. Pioneering and still prominent among these         experimental animals (Cardinal et al., 2001; Mazur,
      tests is the IGT (Bechara et al. 1994), which has a rich    1987; Winstanley et al., 2004). It can, however, be
      structure and considerable ecological validity. This        difficult to implement these experiential discount-
      test can be exquisitely sensitive to orbitofrontal cortex   ing tasks in human subjects, because of strategy use
      deficits, and coupled with psychophysiological re-          and the potentially confounding effects of abnormal
      cording, such as skin conductance responses, has led        delay processing.
      to novel hypotheses of decision-making based upon               It has also been recognized that information
      “somatic markers” (Damasio, 1994). However, the             gathering is an important precondition for effective
      IGT is a complex task and has a strong loading on           decision-making, and that deficits in “reflection” can
      learning and working-memory functions, which may            lead to impulsive decision-making (Evenden, 1999;
      confound the assessment of decision-making per se.          Fellows, 2006; Kagan, 1966). The traditional test of
      Researchers have also questioned the extent to which        reflection impulsivity, the MFFT, has been another
      deficits on the IGT can be synthesized from other           classic instrument, especially for testing impulsivity
      component impairments commonly produced by                  in children; however, possible confounding factors
      frontal damage, such as reversal learning, response         such as perceptual and attentional processing may
      inhibition, and aspects of delay discounting and            potentially produce inflated indices of impulsivity.
      reinforcement sensitivity.                                  A novel measure of reflection impulsivity (Clark
          Consequently, there has been much recent activity       et al., 2006) overcomes many of these difficulties,
      directed at isolating subcomponents of decision-            but like many of the newer tasks described above,
      making with a variety of new instruments. For exam-         it requires further refinement and validation in key
      ple, the CGT (Rogers et al., 1999) presents explicit        patient groups like ventromedial PFC lesion cases.
      choices with defined contingencies that minimizes               An over-arching difficulty with these “objective”
      learning across the task. The CGT also incorporates         tests of decision-making is the relationship with sub-
      measures of decisional quality, as well as the propen-      jective evaluation of traits such as impulsivity. Thus
      sity to gamble, but its measures of reward-driven and       the well-known and useful Barratt Impulsivity Scale
      loss-avoidant processing are somewhat conflated.            (Patton et al., 1995) contains a subscale of “non-
      Other tests of risk-preferent biases include the Risky      planning impulsivity” (see also Whiteside & Lynam,
      Gains procedure (Leland & Paulus 2005; Paulus et al.,       2001), which should be closely related to some of the
      2003) and the Balloon Analogue Risk Task (Lejuez            variables measured objectively in the tests we have
      et al., 2003). Temporal discounting paradigms are           described. However, correlations between laboratory
      also becoming increasingly popular because of               tests and trait self-report measures are notoriously
      their clear implications for framing decisions about        erratic (Carrillo-de-la-Pena et al., 1993; Lijffijt et al.,
150   future health status, for example, in substance abuse.      2004; Swann et al., 2002). Future research must
      These methods have the advantage of quantitative            focus on the reasons for this, and enable the further
                                                                                           Chapter 10: Decision-making



development of such scales as well as tests of decision-        American Psychiatric Association (2000). Diagnostic and
making cognition.                                                 Statistical Manual of Mental Disorders – Text Revision
    Impaired decision-making, impulsivity and loss                (5th edn.). Washington, DC: APA.
of inhibitory control are fundamental concepts in               Aron, A. R., Fletcher, P. C., Bullmore, E. T., Sahakian, B. J. &
current descriptions of a number of neuropsychiatric              Robbins, T. W. (2003). Stop-signal inhibition disrupted
disorders. Neuropsychological analysis of these com-              by damage to right inferior frontal gyrus in humans.
                                                                  Nature Neuroscience, 6, 115–116.
plex multifactorial processes, and detailed description
of the underlying neural circuitry, promises to have            Baker, F., Johnson, M. W. & Bickel, W. K. (2003). Delay
                                                                  discounting in current and never-before cigarette smokers:
implications for psychological and pharmacological                similarities and differences across commodity, sign, and
treatments. Within this chapter, we have focused pri-             magnitude. Journal of Abnormal Psychology, 112, 382–392.
marily on the relevance of decision-making to sub-              Bark, R., Dieckmann, S., Bogerts, B. & Northoff, G. (2005).
stance abuse, frontal dementia, OCD and affective                  Deficit in decision making in catatonic schizophrenia: an
disorders, but these principles may be applied equally             exploratory study. Psychiatry Research, 134, 131–141.
to other conditions including ADHD, personality                 Bar-On, R., Tranel, D., Denburg, N. L. & Bechara, A. (2003).
disorders and eating disorders, where the research in              Exploring the neurological substrate of emotional and
these areas is currently in its infancy. It is also critical       social intelligence. Brain, 126, 1790–1800.
to acknowledge the neurodevelopmental changes in                Bechara, A. & Damasio, H. (2002). Decision-making and
these cognitive abilities, where the relatively late               addiction (part I): impaired activation of somatic states
development of prefrontal cortical control mechan-                 in substance dependent individuals when pondering
isms (which do not reach full maturity until early                 decisions with negative future consequences.
adulthood) may be able to explain the typical onset                Neuropsychologia, 40, 1675–1689.
of several forms of psychopathology during the                  Bechara, A., Damasio, A. R., Damasio, H. & Anderson, S. W.
period of adolescence (Chambers et al., 2003). Identi-             (1994). Insensitivity to future consequences following
                                                                   damage to human prefrontal cortex. Cognition, 50, 7–15.
fication of the environmental and biological factors
that convey vulnerability to – and resilience against –         Bechara, A., Damasio, H., Damasio, A. R. & Lee, G. P.
                                                                   (1999). Different contributions of the human amygdala
these forms of psychopathology will represent a for-               and ventromedial prefrontal cortex to decision-making.
midable challenge for the coming period.                           Journal of Neuroscience, 19, 5473–5481.
                                                                Bechara, A., Tranel, D. & Damasio, H. (2000).
Acknowledgments                                                    Characterization of the decision-making deficit of
                                                                   patients with ventromedial prefrontal cortex lesions.
This work was funded by a Wellcome Trust pro-                      Brain, 123, 2189–2202.
gramme grant to T.W.R., B. J. Sahakian, B. J. Everitt           Bechara, A., Tranel, D., Damasio, H. & Damasio, A. R.
and A. C. Roberts, and completed within the Univer-                (1996). Failure to respond autonomically to anticipated
sity of Cambridge Behavioural and Clinical Neuro-                  future outcomes following damage to prefrontal cortex.
science Institute supported by a consortium award                  Cerebral Cortex, 6, 215–225.
from the Wellcome Trust and Medical Research                    Beninger, R. J., Wasserman, J., Zanibbi, K. et al. (2003).
Council. L. C. and T. W. R. consult for Cambridge                 Typical and atypical antipsychotic medications
Cognition plc (www.camcog.com) who distribute sev-                differentially affect two nondeclarative memory tasks in
eral of the tasks described, including the Cambridge              schizophrenic patients: a double dissociation.
                                                                  Schizophrenia Research, 61, 281–292.
Gamble Task and Information Sampling Task.
                                                                Berlin, H. A., Rolls, E. T. & Kischka, U. (2004). Impulsivity,
                                                                   time perception, emotion and reinforcement sensitivity
References                                                         in patients with orbitofrontal cortex lesions. Brain, 127,
Adinoff, B., Devous, M. D., Sr., Cooper, D. B. et al. (2003).      1108–1126.
  Resting regional cerebral blood flow and gambling task        Bickel, W. K. & Marsch, L. A. (2001). Toward a behavioral
  performance in cocaine-dependent subjects and healthy            economic understanding of drug dependence: delay
  comparison subjects. American Journal of Psychiatry,             discounting processes. Addiction, 96, 73–86.
  160, 1892–1894.                                               Bjork, J. M., Hommer, D. W., Grant, S. J. & Danube, C.
Allen, T. J., Moeller, F. G., Rhoades, H. M. & Cherek, D. R.       (2004). Impulsivity in abstinent alcohol-dependent
   (1998). Impulsivity and history of drug dependence.             patients: relation to control subjects and type 1-/type         151
   Drug and Alcohol Dependence, 50, 137–145.                       2-like traits. Alcohol, 34, 133–150.
         Section 1: Neuropsychological processes



      Bolla, K. I., Eldreth, D. A., London, E. D. et al. (2003).                memory in adult ADHD: a link to right frontal cortex
         Orbitofrontal cortex dysfunction in abstinent cocaine                  pathology. Biological Psychiatry, 61, 1395–1401.
         abusers performing a decision-making task. Neuroimage,              Clark, L., Iversen, S. D. & Goodwin, G. M. (2001).
         19, 1085–1094.                                                         A neuropsychological investigation of prefrontal cortex
      Bolla, K. I., Eldreth, D. A., Matochik, J. A. & Cadet, J. L. (2004).      involvement in acute mania. American Journal of
         Sex-related differences in a gambling task and its                     Psychiatry, 158, 1605–1611.
         neurological correlates. Cerebral Cortex, 14, 1226–1232.
                                                                             Clark, L., Manes, F., Antoun, N., Sahakian, B. J. &
      Brown, R. T. & Sleator, E. K. (1979). Methylphenidate in                  Robbins, T. W. (2003). The contributions of lesion
         hyperkinetic children: differences in dose effects on                  laterality and lesion volume to decision-making
         impulsive behavior. Pediatrics, 64, 408–411.                           impairment following frontal lobe damage.
      Camerer, C. & Weber, M. (1992). Recent developments in                    Neuropsychologia, 41, 1474–1483.
        modelling preferences: uncertainty and ambiguity.                    Clark, L., Robbins, T. W., Ersche, K. D. & Sahakian, B. J.
        Journal of Risk and Uncertainty, 5, 325–370.                            (2006). Reflection impulsivity in current and former
      Cardinal, R. N., Pennicott, D. R., Sugathapala, C. L.,                    substance users. Biological Psychiatry, 60, 512–522.
        Robbins, T. W. Everitt, B. J. (2001). Impulsive choice               Damasio, A. (1994). Descartes’ Error: Emotion, Reason and
        induced in rats by lesions of the nucleus accumbens core.              the Human Brain. New York, NY: G.P. Putnam.
        Science, 292, 2499–2501.
                                                                             Damasio, A. R., Tranel, D. & Damasio, H. (1990).
      Carrillo-de-la-Pena, M. T., Otero, J. M. & Romero, E. (1993).            Individuals with sociopathic behavior caused by frontal
        Comparison among various methods of assessment of                      damage fail to respond autonomically to social stimuli.
        impulsiveness. Perceptual and Motor Skills, 77, 567–575.               Behavioral Brain Research, 41, 81–94.
      Cato, M. A., Delis, D. C., Abildskov, T. J. & Bigler, E. (2004).       Deakin, J. B., Rahman, S., Nestor, P. J., Hodges, J. R. &
         Assessing the elusive cognitive deficits associated with              Sahakian, B. J. (2004). Paroxetine does not improve
         ventromedial prefrontal damage: a case of a modern-day                symptoms and impairs cognition in frontotemporal
         Phineas Gage. Journal of the International                            dementia: a double-blind randomized controlled trial.
         Neuropsychological Society, 10, 453–465.                              Psychopharmacology (Berlin), 172, 400–408.
      Cavedini, P., Riboldi, G., D’Annucci, A. et al. (2002a). Decision-     Diehl, J., Grimmer, T., Drzezga, A. et al. (2004). Cerebral
        making heterogeneity in obsessive-compulsive disorder:                  metabolic patterns at early stages of frontotemporal
        ventromedial prefrontal cortex function predicts different              dementia and semantic dementia. A PET study.
        treatment outcomes. Neuropsychologia, 40, 205–211.                      Neurobiology of Aging, 25, 1051–1056.
      Cavedini, P., Riboldi, G., Keller, R., D’Annucci, A. & Bellodi,        Dijksterhuis, A., Bos, M. W., Nordgren, L. F. & van
        L. (2002b). Frontal lobe dysfunction in pathological                    Baaren, R. B. (2006). On making the right choice: the
        gambling patients. Biological Psychiatry, 51, 334–341.                  deliberation-without-attention effect. Science, 311,
      Chamberlain, S. R., Blackwell, A. D., Fineberg, N. A.,                    1005–1007.
        Robbins, T. W. Sahakian, B. J. (2005). The                           Dimitrov, M., Phipps, M., Zahn, T. P. & Grafman, J. (1999).
        neuropsychology of obsessive compulsive disorder: the                  A thoroughly modern Gage. Neurocase, 5, 345–354.
        importance of failures in cognitive and behavioural
        inhibition as candidate endophenotypic markers.                      Dom, G., Sabbe, B., Hulstijn, W. & van den Brink, W.
        Neuroscience and Biobehavioral Reviews, 29, 399–419.                   (2005). Substance use disorders and the orbitofrontal
                                                                               cortex: systematic review of behavioural decision-
      Chambers, R. A., Taylor, J. R. & Potenza, M. N. (2003).
                                                                               making and neuroimaging studies. British Journal of
        Developmental neurocircuitry of motivation in
                                                                               Psychiatry, 187, 209–220.
        adolescence: a critical period of addiction vulnerability.
        American Journal of Psychiatry, 160, 1041–1052.                      Drevets, W. C., Price, J. L., Simpson, J. R., Jr. et al. (1997).
                                                                               Subgenual prefrontal cortex abnormalities in mood
      Clark, L. & Sahakian, B. J. (2006). Neuropsychological and
                                                                               disorders. Nature, 386, 824–827.
         biological approaches to understanding bipolar disorder.
         In S. Jones and R. P. Bentall (Eds.), The Psychology of             Dunn, B. D., Dalgleish, T. & Lawrence, A. D. (2006).
         Bipolar Disorder (pp. 139–178) Oxford: Oxford                         The somatic marker hypothesis: a critical evaluation.
         University Press.                                                     Neuroscience and Biobehavioral Reviews, 30, 239–271.
      Clark, L., Bechara, A., Damasio, H. et al. (2008). Differential        Ellsberg, D. (1961). Risk, ambiguity and the Savage axioms.
         effects of insula and ventromedial prefrontal cortex                    Quarterly Journal of Economics, 75, 643–669.
         lesions on risky decision-making. Brain, 131, 1311–1322.
                                                                             Elster, J. & Skog, O.-J. (Eds.) (1999). Getting Hooked:
      Clark, L., Blackwell, A. D., Aron, A. R. et al. (2007).                   Rationality and Addiction. Cambridge: Cambridge
152      Association between response inhibition and working                    University Press.
                                                                                             Chapter 10: Decision-making



Ernst, M., Bolla, K., Mouratidis, M. et al. (2002).                Goldstein, R. Z. & Volkow, N. D. (2002). Drug addiction
   Decision-making in a risk-taking task: a PET study.               and its underlying neurobiological basis: neuroimaging
   Neuropsychopharmacology, 26, 682–691.                             evidence for the involvement of the frontal cortex.
Ersche, K. D., Fletcher, P. C., Lewis, S. J. et al. (2005).          American Journal of Psychiatry, 159, 1642–1652.
   Abnormal frontal activations related to decision-making         Gonzalez, C., Dana, J., Koshino, H. & Just, M. (2005). The
   in current and former amphetamine and opiate                      framing effect and risky decisions: examining cognitive
   dependent individuals. Psychopharmacology (Berlin),               functions with fMRI. Journal of Economic Psychology,
   180, 612–623.                                                     26, 1–20.
Eslinger, P. J. & Damasio, A. R. (1985). Severe disturbance        Goudriaan, A. E., Oosterlaan, J., de Beurs, E. & van den
   of higher cognition after bilateral frontal lobe ablation:        Brink, W. (2005). Decision making in pathological
   patient EVR. Neurology, 35, 1731–1741.                            gambling: a comparison between pathological gamblers,
Evenden, J. L. (1999). The pharmacology of impulsive                 alcohol dependents, persons with Tourette syndrome,
   behaviour in rats V: the effects of drugs on responding           and normal controls. Brain Research: Cognitive Brain
   under a discrimination task using unreliable visual               Research, 23, 137–151.
   stimuli. Psychopharmacology (Berlin), 143, 111–122.             Gregory, C., Lough, S., Stone, V. et al. (2002). Theory of
Eysenck, S. B. & Eysenck, H. J. (1978). Impulsiveness and            mind in patients with frontal variant frontotemporal
   venturesomeness: their position in a dimensional system           dementia and Alzheimer’s disease: theoretical and
   of personality description. Psychological Reports, 43,            practical implications. Brain, 125, 752–764.
   1247–1255.                                                      Hinson, J. M., Jameson, T. L. & Whitney, P. (2002). Somatic
Fein, G., Klein, L., Finn, P. (2004). Impairment on a                markers, working memory, and decision making.
   simulated gambling task in long-term abstinent                    Cognitive, Affective and Behavioral Neuroscience, 2,
   alcoholics. Alcohol: Clinical and Experimental Research,          341–353.
   28, 1487–1491.                                                  Ho, M. Y., Mobini, S., Chiang, T. J., Bradshaw, C. M. &
Fellows, L. K. (2006). Deciding how to decide: ventromedial          Szabadi, E. (1999). Theory and method in the
   frontal lobe damage affects information acquisition in            quantitative analysis of “impulsive choice” behaviour:
   multi-attribute decision making. Brain, 129, 944–952.             implications for psychopharmacology.
                                                                     Psychopharmacology (Berlin), 146, 362–372.
Fellows, L. K. & Farah, M. J. (2003). Ventromedial
   frontal cortex mediates affective shifting in humans:           Horn, N. R., Dolan, M., Elliott, R., Deakin, J. F. & Woodruff,
   evidence from a reversal learning paradigm. Brain, 126,           P. W. (2003). Response inhibition and impulsivity: an
   1830–1837.                                                        fMRI study. Neuropsychologia, 41, 1959–1966.
Fellows, L. K. & Farah, M. J. (2005a). Dissociable elements        Hornak, J., O’Doherty, J., Bramham, J. et al. (2004).
   of human foresight: a role for the ventromedial frontal           Reward-related reversal learning after surgical
   lobes in framing the future, but not in discounting future        excisions in orbito-frontal or dorsolateral prefrontal
   rewards. Neuropsychologia, 43, 1214–1221.                         cortex in humans. Journal of Cognitive Neuroscience,
Fellows, L. K. & Farah, M. J. (2005b). Different underlying          16, 463–478.
   impairments in decision-making following ventromedial           Hsu, M., Bhatt, M., Adolphs, R., Tranel, D. & Camerer, C. F.
   and dorsolateral frontal lobe damage in humans.                   (2005). Neural systems responding to degrees of
   Cerebral Cortex, 15, 58–63.                                       uncertainty in human decision-making. Science, 310,
Fox, H. C., McLean, A., Turner, J. J. et al. (2002).                 1680–1683.
  Neuropsychological evidence of a relatively selective            Huettel, S. A., Stowe, C. J., Gordon, E. M., Warner, B. T. &
  profile of temporal dysfunction in drug-free MDMA                  Platt, M. L. (2006). Neural signatures of economic
  (“ecstasy”) polydrug users. Psychopharmacology (Berlin),           preferences for risk and ambiguity. Neuron, 49, 765–775.
  162, 203–214.                                                    Hutton, S. B., Murphy, F. C., Joyce, E. M. et al. (2002).
Franklin, T. R., Acton, P. D., Maldjian, J. A. et al. (2002).        Decision making deficits in patients with first-episode
   Decreased gray matter concentration in the insular,               and chronic schizophrenia. Schizophrenia Research, 55,
   orbitofrontal, cingulate, and temporal cortices of cocaine        249–257.
   patients. Biological Psychiatry, 51, 134–142.                   Ibach, B., Poljansky, S., Marienhagen, J. et al. (2004).
Frederick, S., Loewenstein, G. & O’Donaghue, T. (2002).               Contrasting metabolic impairment in frontotemporal
   Time discounting and time preference: a critical review.           degeneration and early onset Alzheimer’s disease.
   Journal of Economic Literature, 40, 351–401.                       Neuroimage, 23, 739–743.
Glimcher, P. W. & Rustichini, A. (2004). Neuroeconomics:           Irle, E., Exner, C., Thielen, K., Weniger, G. & Ruther, E.
   the consilience of brain and decision. Science, 306, 447–452.       (1998). Obsessive-compulsive disorder and ventromedial       153
         Section 1: Neuropsychological processes



         frontal lesions: clinical and neuropsychological findings.      dependent patients and non-drug-using control
         American Journal of Psychiatry, 155, 255–263.                   participants: drug and monetary rewards. Experimental
      Jameson, T. L., Hinson, J. M. & Whitney, P. (2004).                and Clinical Psychopharmacology, 5, 256–262.
         Components of working memory and somatic markers             Malloy, P., Bihrle, A., Duffy, J. & Cimino, C. (1993). The
         in decision making. Psychonomic Bulletin and Reviews,          orbitomedial frontal syndrome. Archives of Clinical
         11, 515–520.                                                   Neuropsychology, 8, 185–201.
      Jentsch, J. D. & Taylor, J. R. (1999). Impulsivity resulting    Manes, F., Sahakian, B., Clark, L. et al. (2002). Decision-
         from frontostriatal dysfunction in drug abuse:                 making processes following damage to the prefrontal
         implications for the control of behavior by reward-            cortex. Brain, 125, 624–639.
         related stimuli. Psychopharmacology (Berlin), 146,           Mavaddat, N., Kirkpatrick, P. J., Rogers, R. D. & Sahakian,
         373–390.                                                       B. J. (2000). Deficits in decision-making in patients with
      Johnson, M. W. & Bickel, W. K. (2002). Within-subject             aneurysms of the anterior communicating artery. Brain,
         comparison of real and hypothetical money rewards in           123, 2109–2117.
         delay discounting. Journal of the Experimental Analysis      Mazas, C. A., Finn, P. R. & Steinmetz, J. E. (2000).
         of Behavior, 77, 129–146.                                      Decision-making biases, antisocial personality, and
      Kagan, J. (1966). Reflection-impulsivity: the generality and      early-onset alcoholism. Alcohol: Clinical and
        dynamics of conceptual tempo. Journal of Abnormal               Experimental Research, 24, 1036–1040.
        Psychology, 71, 17–24.                                        Mazur, J. (1987). An adjusting procedure for studying
      Kirby, K. N. & Herrnstein, R. J. (1995). Preference reversals     delayed reinforcement. In M. L. Commons, J. E.
         due to myopic discounting of delayed reward.                   Mazur, J. A. Nevin & H. Rachlin (Eds.), Quantitative
         Psychological Science, 6, 83–89.                               Analysis of Behavior. The effect of Delay and of
      Kirby, K. N., Petry, N. M. & Bickel, W. K. (1999). Heroin         Intervening Events on Reinforcement Value (vol. 5,
         addicts have higher discount rates for delayed rewards         pp. 55–74). Hillsdale, NJ: Lawrence Erlbaum Associates.
         than non-drug-using controls. Journal of Experimental        McClure, S. M., Laibson, D. I., Loewenstein, G. & Cohen,
         Psychology: General, 128, 78–87.                               J. D. (2004). Separate neural systems value immediate
      Kuhnen, C. M. & Knutson, B. (2005). The neural basis of           and delayed monetary rewards. Science, 306, 503–507.
        financial risk taking. Neuron, 47, 763–770.                   Mellers, B. A., Schwartz, A. & Ritov, I. (1999). Emotion-
      Lacerda, A. L., Keshavan, M. S., Hardan, A. Y. et al. (2004).     based choice. Journal of Experimental Psychology:
         Anatomic evaluation of the orbitofrontal cortex in major       General, 128, 332–345.
         depressive disorder. Biological Psychiatry, 55, 353–358.     Messer, S. B. (1976). Reflection-impulsivity: a review.
      Lejuez, C. W., Aklin, W. M., Jones, H. A. et al. (2003). The      Psychological Bulletin, 83, 1026–1052.
         Balloon Analogue Risk Task (BART) differentiates             Mobini, S., Body, S., Ho, M. Y. et al. (2002). Effects of
         smokers and nonsmokers. Experimental and Clinical              lesions of the orbitofrontal cortex on sensitivity to
         Psychopathology, 11, 26–33.                                    delayed and probabilistic reinforcement.
      Leland, D. S. & Paulus, M. P. (2005). Increased risk-taking       Psychopharmacology (Berlin), 160, 290–298.
         decision-making but not altered response to punishment       Moeller, F. G., Dougherty, D. M., Barratt, E. S. et al. (2002).
         in stimulant-using young adults. Drug and Alcohol              Increased impulsivity in cocaine dependent subjects
         Dependence, 78, 83–90.                                         independent of antisocial personality disorder and
      Lijffijt, M., Bekker, E. M., Quik, E. H. et al. (2004).           aggression. Drug and Alcohol Dependence, 68, 105–111.
          Differences between low and high trait impulsivity are      Monterosso, J., Ehrman, R., Napier, K. L., O’Brien, C. P. &
          not associated with differences in inhibitory motor           Childress, A. R. (2001). Three decision-making tasks in
          control. Journal of Attention Disorders, 8, 25–32.            cocaine-dependent patients: do they measure the same
      Lopes, L. L. (1987). Between fear and hope: the psychology        construct? Addiction, 96, 1825–1837.
        of risk. In L. Berkowitz (Ed.), Advances in Experimental      Morgan, M. J. (1998). Recreational use of “ecstasy”
        Social Psychology (pp. 255–295) New York, NY:                   (MDMA) is associated with elevated impulsivity.
        Academic Press.                                                 Neuropsychopharmacology, 19, 252–264.
      Lyoo, I. K., Pollack, M. H., Silveri, M. M. et al. (2006).      Morgan, M. J., McFie, L., Fleetwood, H. & Robinson, J. A.
         Prefrontal and temporal gray matter density decreases in       (2002). Ecstasy (MDMA): are the psychological
         opiate dependence. Psychopharmacology (Berlin), 184,           problems associated with its use reversed by prolonged
         139–144.                                                       abstinence? Psychopharmacology (Berlin), 159, 294–303.
154   Madden, G. J., Petry, N. M., Badger, G. J. & Bickel, W. K.      Morgan, M. J., Impallomeni, L. C., Pirona, A. & Rogers,
        (1997). Impulsive and self-control choices in opioid-           R. D. (2005). Elevated impulsivity and impaired
                                                                                             Chapter 10: Decision-making



   decision-making in abstinent Ecstasy (MDMA) users               Rogers, R. D., Everitt, B. J., Baldacchino, A. et al. (1999).
   compared to polydrug and drug-naive controls.                     Dissociable deficits in the decision-making cognition of
   Neuropsychopharmacology, 31(7), 1562–1573.                        chronic amphetamine abusers, opiate abusers, patients
Murphy, F. C., Rubinsztein, J. S., Michael, A. et al. (2001).        with focal damage to prefrontal cortex, and tryptophan-
  Decision-making cognition in mania and depression.                 depleted normal volunteers: evidence for mono-
  Psychological Medicine, 31, 679–693.                               aminergic mechanisms. Neuropsychopharmacology,
                                                                     20, 322–339.
Nielen, M. M., Veltman, D. J., de Jong, R., Mulder, G. & den
   Boer, J. A. (2002). Decision making performance in              Rolls, E. T., Hornak, J., Wade, D. & McGrath, J. (1994).
   obsessive compulsive disorder. Journal of Affective                Emotion-related learning in patients with social and
   Disorders, 69, 257–260.                                            emotional changes associated with frontal lobe damage.
                                                                      Journal of Neurology, Neurosurgery and Psychiatry, 57,
Odum, A. L., Madden, G. J., Badger, G. J. & Bickel, W. K.             1518–1524.
  (2000). Needle sharing in opioid-dependent outpatients:
                                                                   Rubia, K., Smith, A. B., Brammer, M. J. & Taylor, E. (2003).
  psychological processes underlying risk. Drug and
                                                                     Right inferior prefrontal cortex mediates response
  Alcohol Dependence, 60, 259–266.
                                                                     inhibition while mesial prefrontal cortex is responsible
Ongur, D., Ferry, A. T. & Price, J. L. (2003). Architectonic         for error detection. Neuroimage, 20, 351–358.
  subdivision of the human orbital and medial prefrontal
                                                                   Rubinsztein, J. S., Michael, A., Paykel, E. S. &
  cortex. Journal of Comparative Neurology, 460, 425–449.
                                                                     Sahakian, B. J. (2000). Cognitive impairment in
Patton, J. H., Stanford, M. S. & Barratt, E. S. (1995). Factor       remission in bipolar affective disorder. Psychological
   structure of the Barratt impulsiveness scale. Journal of          Medicine, 30, 1025–1036.
   Clinical Psychology, 51, 768–774.
                                                                   Salmon, E., Garraux, G., Delbeuck, X. et al. (2003).
Paulus, M. P., Rogalsky, C., Simmons, A., Feinstein, J. S. &          Predominant ventromedial frontopolar metabolic
   Stein, M. B. (2003). Increased activation in the right insula      impairment in frontotemporal dementia. Neuroimage,
   during risk-taking decision making is related to harm              20, 435–440.
   avoidance and neuroticism. Neuroimage, 19, 1439–1448.
                                                                   Sanfey, A. G., Hastie, R., Colvin, M. K. & Grafman, J.
Perry, J. L., Larson, E. B., German, J. P., Madden, G. J. &           (2003a). Phineas gauged: decision-making and the
   Carroll, M. E. (2005). Impulsivity (delay discounting) as          human prefrontal cortex. Neuropsychologia, 41,
   a predictor of acquisition of IV cocaine self-                     1218–1229.
   administration in female rats. Psychopharmacology
                                                                   Sanfey, A. G., Loewenstein, G., McClure, S. M. & Cohen,
   (Berlin), 178, 193–201.
                                                                      J. D. (2006). Neuroeconomics: cross-currents in research
Petry, N. M. (2001). Pathological gamblers, with and                  on decision-making. Trends in Cognitive Science, 10,
   without substance use disorders, discount delayed                  108–116.
   rewards at high rates. Journal of Abnormal Psychology,          Sanfey, A. G., Rilling, J. K., Aronson, J. A., Nystrom, L. E. &
   110, 482–487.                                                      Cohen, J. D. (2003b). The neural basis of economic
Rachlin, H., Raineri, A. & Cross, D. (1991). Subjective               decision-making in the Ultimatum Game. Science, 300,
  probability and delay. Journal of the Experimental                  1755–1758.
  Analysis of Behavior, 55, 233–244.                               Saver, J. L. & Damasio, A. R. (1991). Preserved access and
Rahman, S., Robbins, T. W., Hodges, J. R. et al. (2006).              processing of social knowledge in a patient with acquired
  Methylphenidate (‘Ritalin’) can ameliorate abnormal                 sociopathy due to ventromedial frontal damage.
  risk-taking behavior in the frontal variant of                      Neuropsychologia, 29, 1241–1249.
  frontotemporal dementia. Neuropsychopharmacology,                Shamay-Tsoory, S. G., Tomer, R., Berger, B. D. & Aharon-
  31, 651–658.                                                        Peretz, J. (2003). Characterization of empathy deficits
Rahman, S., Sahakian, B. J., Hodges, J. R., Rogers, R. D. &           following prefrontal brain damage: the role of the right
  Robbins, T. W. (1999). Specific cognitive deficits in mild          ventromedial prefrontal cortex. Journal of Cognitive
  frontal variant frontotemporal dementia. Brain, 122,                Neuroscience, 15, 324–337.
  1469–1493.                                                       Shiv, B., Loewenstein, G., Bechara, A., Damasio, H. &
Ratnavalli, E., Brayne, C., Dawson, K. & Hodges, J. R.                Damasio, A. R. (2005). Investment behavior and the
   (2002). The prevalence of frontotemporal dementia.                 negative side of emotion. Psychological Science, 16,
   Neurology, 58, 1615–1621.                                          435–439.
Ritter, L. M., Meador-Woodruff, J. H. & Dalack, G. W.              Shurman, B., Horan, W. P. & Nuechterlein, K. H. (2005).
   (2004). Neurocognitive measures of prefrontal cortical            Schizophrenia patients demonstrate a distinctive pattern
   dysfunction in schizophrenia. Schizophrenia Research,             of decision-making impairment on the Iowa Gambling              155
   68, 65–73.                                                        Task. Schizophrenia Research, 72, 215–224.
         Section 1: Neuropsychological processes



      Sjogren, M., Minthon, L., Passant, U., Blennow, K. &             Tversky, A. & Kahneman, D. (1991). Loss aversion in
         Wallin, A. (1998). Decreased monoamine metabolites in           riskless choice: a reference dependent model. Quarterly
         frontotemporal dementia and Alzheimer’s disease.                Journal of Economics, 106, 1039–1061.
         Neurobiology of Aging, 19, 379–384.                           Vitaro, F., Arseneault, L. & Tremblay, R. E. (1999).
      Stout, J. C., Rock, S. L., Campbell, M. C., Busemeyer, J. R. &      Impulsivity predicts problem gambling in low SES
         Finn, P. R. (2005). Psychological processes underlying           adolescent males. Addiction, 94, 565–575.
         risky decisions in drug abusers. Psychology of Addictive      von Neumann, J. & Morganstern, O. (1944). Theory of
         Behavior, 19, 148–157.                                           Games and Economic Behavior. Princeton, NJ: Princeton
      Swann, A. C., Bjork, J. M., Moeller, F. G. & Dougherty,             University Press.
        D. M. (2002). Two models of impulsivity: relationship to       Vuchinich, R. E. & Heather, N. (Eds.) (2003). Choice,
        personality traits and psychopathology. Biological               Behavioural Economics and Addiction. Amsterdam:
        Psychiatry, 51, 988–994.                                         Elsevier.
      Tarter, R. E., Kirisci, L., Habeych, M., Reynolds, M. &          Watkins, L. H., Sahakian, B. J., Robertson, M. M. et al.
         Vanyukov, M. (2004). Neurobehavior disinhibition in             (2005). Executive function in Tourette’s syndrome and
         childhood predisposes boys to substance use disorder by         obsessive-compulsive disorder. Psychological Medicine,
         young adulthood: direct and mediated etiologic                  35, 571–582.
         pathways. Drug and Alcohol Dependence, 73, 121–132.
                                                                       Whiteside, S. P. & Lynam, D. R. (2001). The five factor
      Tomb, I., Hauser, M., Deldin, P. & Caramazza, A. (2002).           model and impulsivity: using a structural model of
        Do somatic markers mediate decisions on the gambling             personality to understand impulsivity. Personality and
        task? Nature Neuroscience, 5, 1103–1104.                         Individual Differences, 30, 669–689.
      Torralva, T., Kipps, C., Hodges, J. R. et al. (2007). The        Whitney, K. A., Fastenau, P. S., Evans, J. D. & Lysaker, P. H.
        relationship between affective decision-making and               (2004). Comparative neuropsychological function in
        theory of mind in frontal variant frontotemporal                 obsessive-compulsive disorder and schizophrenia with
        dementia. Neuropsychologia, 45, 342–349.                         and without obsessive-compulsive symptoms.
      Tranel, D., Bechara, A. & Denburg, N. L. (2002).                   Schizophrenia Research, 69, 75–83.
         Asymmetric functional roles of right and left                 Wilder, K. E., Weinberger, D. R. & Goldberg, T. E. (1998).
         ventromedial prefrontal cortices in social conduct,             Operant conditioning and the orbitofrontal cortex in
         decision-making, and emotional processing. Cortex,              schizophrenic patients: unexpected evidence for intact
         38, 589–612.                                                    functioning. Schizophrenia Research, 30, 169–174.
      Tranel, D., Damasio, H., Denburg, N. L. & Bechara, A.            Wilson, J. M., Kalasinsky, K. S., Levey, A. I. et al. (1996).
         (2005). Does gender play a role in functional                   Striatal dopamine nerve terminal markers in human,
         asymmetry of ventromedial prefrontal cortex? Brain,             chronic methamphetamine users. Nature Medicine, 2,
         128, 2872–2881.                                                 699–703.
      Turner, D. C., Robbins, T. W., Clark, L. et al. (2003).          Winstanley, C. A., Theobald, D. E., Cardinal, R. N. &
        Relative lack of cognitive effects of methylphenidate            Robbins, T. W. (2004). Contrasting roles of basolateral
        in elderly male volunteers. Psychopharmacology,                  amygdala and orbitofrontal cortex in impulsive choice.
        168, 455–464.                                                    Journal of Neuroscience, 24, 4718–4722.
      Tversky, A. & Kahneman, D. (1981). The framing of                Zuckerman, M. (1979). Sensation Seeking: Beyond the
        decisions and the psychology of choice. Science,                 Optimal level of Arousal. New York, NY: Lawrence
        211, 453–458.                                                    Erlbaum Associates.




156
    Chapter




    11
                     The neuropsychology of social cognition:
                     implications for psychiatric disorders
                     Tamara A. Russell and Melissa J. Green



Social cognition in an evolutionary                            domain-general cognitive domains (e.g. attention,
                                                               memory, working memory, executive functioning;
framework                                                      this issue is addressed in later discussion).
Social cognition refers to cognitive processes neces-              In a seminal review, Brothers proposed an evolu-
sary for the accurate perception and interpretation of         tionary argument for the existence of distinct neural
information conveyed by conspecifics (other individ-           architecture subserving specific social cognitive func-
uals of the same species). This is particularly relevant       tions that developed in response to the demands of
to higher cognitive processes that underpin the for-           living in large social groups (Brothers, 1990). Further-
mulation of appropriate and flexible behavioral                more, primate neocortex volume is argued to have
responses that are required in everyday social inter-          evolved in direct proportion to the size of the social
actions (Adolphs, 1999; Ostrom, 1984).                         group. As the size of the social group increased, so did
     Social information is distinct from non-social            the cognitive demands of living within a complex
information in several ways. Non-social cognitive              social order, requiring a brain capable of responding
stimuli are most commonly of neutral valence (e.g.             to subtle social cues (such as eye gaze and facial
auditory tones, visual shapes, letters or numbers),            displays of emotion) and representing the intentions
while social cognitive stimuli are often personally            of others. Indeed, neocortex size in primates is correl-
relevant and take the form of dynamic bi-directional           ated with five separate indices of social complexity,
interactions, insofar as each participant’s responses          including social group size, grooming clique size, the
can influence the social exchange (Fiske, 1991). Also,         extent to which social skills are used in male mating
social inferences are often based upon the perception          strategies, the frequency of tactical deception and
of fleeting information (i.e. dynamic displays of facial       the frequency of social play (Byrne & Corp, 2004;
emotion), or the perception of unobservable charac-            Dunbar, 2003). Thus, evolutionary approaches to social
teristics requiring inference from subtle behavioral           cognition predict the existence of specialized neural
displays (e.g. judgments about personality character-          networks facilitating prosocial behaviors such as
istics may be based on the observation of interper-            cooperation and altruism (thereby increasing access
sonal behavior, but cannot be observed per se); these          to reliable food sources, security from predators and
types of inference are not as common in non-social             better mate choice), as well as manipulative behaviors
cognition (Fiske, 1991). Social cognition may also be          such as coercion and deception of conspecifics in
seen as distinct from non-social cognition given that          response to the increased competition for food and
adequate skills in this domain are required for effi-          mates. The existence of cognitive mechanisms facili-
cient social behavior and social functioning (Pinkham          tating the manipulation of one’s own and others’
et al., 2003). Given these distinctions, social cognitive      behavior for the effective negotiation of the social
skills are not typically assessed by standard neuro-           environment is evident in many primates, including
psychological tools. However, effective social cogni-          Homo sapiens (Dunbar, 2003). Furthermore, these
tion may certainly rely upon effective functioning in          mechanisms range from low-level perceptual skills



The Neuropsychology of Mental Illness, ed. Stephen J. Wood, Nicholas B. Allen and Christos Pantelis. Published by         157
Cambridge University Press. # Cambridge University Press 2009.
         Section 1: Neuropsychological processes



         Table 11.1 DSM–IV and ICD–10 criteria related to social functioning for different psychiatric diagnoses.

        Disorder                                         Emotion-related symptoms related to social functioning*
        Conduct disorder                                 Criteria A: repetitive and persistent pattern of behavior in which the basic
                                                         rights of others or major age-appropriate societal norms or rules are violated.
                                                         Criteria B: behavior causes clinically significant impairment in social, academic
                                                         or occupational functioning
        Schizophrenia, schizoaffective disorder,         Affective flattening, anhedonia
        schizophreniform disorder
        Major depressive disorder                        Depressed mood, anhedonia
        Social phobia                                    Marked and persistent fear, anxious anticipation (related to interpersonal or
                                                         social situations)
        Obsessive-compulsive disorder                    Marked anxiety or distress
        Post-traumatic stress disorder                   Irritability, anger, physiological reactivity, distress, anhedonia, restricted range
                                                         of affect
        Acute stress disorder                            Symptoms of anxiety or increased arousal
        Generalized anxiety disorder                     Excessive anxiety and worry, irritability
        Paranoid personality disorder                    Quick to react angrily
        Schizoid personality disorder                    Emotional coldness, detachment, flattened affectivity
        Schizotypal personality disorder                 Inappropriate or constricted affect, excessive social anxiety
        Antisocial personality disorder                  Lack of remorse, irritability
        Borderline personality disorder                  Affective instability due to marked reactivity of mood, inappropriate intense
                                                         anger, or difficulty controlling anger
        Histrionic personality disorder                  Rapidly shifting and shallow expressions of emotions
        Narcissistic personality disorder                Lacks empathy
        Avoidant personality disorder                    Fear of criticism, disapproval or rejection
        Dependent personality disorder                   Fear of being unable to care for self, being left alone
      Note: Parts of this table have been adapted from Kring & Werner (2004).


      (such as gaze direction detection), which may be                          abnormal social brain, showing profound deficits in
      common to all social species, to high-level species-                      social cognition, exemplified by the inability to repre-
      specific processes (such as belief representation) that                   sent the mental states of others as distinct from their
      may be unique to humans.                                                  own representation of the world (Baron-Cohen,
          In humans, specific social cognitive skills include                   1995). Various social cognitive impairments have also
      the recognition of a relative or friend (through the                      been demonstrated in schizophrenia (Corrigan &
      analysis of facial features and/or gait), decoding dis-                   Penn, 2001), bipolar disorder (Kerr et al., 2003) and
      plays of emotion (facial and vocal affect processing),                    unipolar depression (Suslow et al., 2001) and some of
      and inferring what someone believes about the state                       the more severe personality disorders (Skodol et al.,
      of the world in order to predict and explain behavior                     2002). Impairments in moral reasoning and decision-
      (“Theory of Mind,” ToM; Premack & Woodruff,                               making are evident in socially deviant individuals
      1978). It is usually apparent when an individual has                      (Blair, 1997). Indeed, it is notable that some form of
      difficulties in the social domain. Individuals with                       decline in social functioning forms part of the diag-
      autism and Aspergers’ syndrome may be seen to                             nostic criteria for the majority of severe psychiatric
158   represent a particularly salient example of the                           illnesses (Table 11.1). Also, in some disorders (e.g.
                                                              Chapter 11: The neuropsychology of social cognition



schizophrenia), social problems are likely to pre-date        and interpretation of social behavior, including the
the manifestation of overt symptoms. The investiga-           perception of biological motion,1 facial identity and
tion of various psychiatric disorders from a social           emotion recognition, right through to complex attri-
cognitive perspective may therefore aid in elucidating        butions, personality judgments and inferences about
the cause of some symptoms of mental disorder                 the mental states of others. In this section we review
(Brune, 2001; Brune & Brune-Cohrs, 2006).                     the evidence from recent brain-imaging studies to
    In the following sections of this chapter, we explore     examine the notion of specialized neural circuits for
evidence from neuropsychology and neuroscience                the processing of social information.
regarding the sovereignty of social cognition. That
is, the question of whether social cognition can be
regarded as comprising a range of specialized cognitive       Face perception
processes devoted to the performance of social                Face perception is mediated by a widely distributed
tasks (domain-specific processes) or whether social-          neural system in humans that consists of multiple,
cognitive skills depend upon basic neuropsychological         bilateral regions of the ventral temporal and associ-
processes such as attention, executive functioning or         ation cortices (Haxby et al., 2002). The functional
memory (domain-general processes). To assume the              organization of this system includes the representa-
domain-specificity of social cognition one would need         tion of invariant aspects of faces that, as compared to
to show a dissociation between these two types of             houses and other classes of objects, is the basis for
processes in a single individual, by demonstrating the        recognizing individuals, and which is located in a
existence of either (a) impairments in social-cognitive       region of the posterior temporal and extrastriate
skills alongside intact domain-general neuropsycho-           cortex (fusiform face area, FFA; Kanwisher et al.,
logical skills, or (b) intact social cognition alongside      1997).2 It has been shown, however, that activation
specific neuropsychological deficits. We thus explore         of the (ventral) temporal cortex in response to the
evidence for dissociation between cognitive and social-       representation of faces and object categories extends
cognitive performance in individuals with specific            beyond regions that demonstrate category-related
neurological abnormalities or psychiatric disorders,          response preferences (such as the FFA) and includes
following a brief review of the evidence from social-         regions that respond both maximally and submaxi-
cognitive neuroscience regarding the role of specialized      mally, as well as other cortical areas (Haxby et al.,
neural networks for the processing of social informa-         2001). In contrast, the representation of changeable
tion (such as facial emotion and ToM skills). While           aspects, such as eye gaze, expression and lip move-
there exists specialized neuroanatomy and cognitive           ment, which underlies the perception of information
architecture to subserve some aspects of social infor-        that facilitates social communication, is located in the
mation processing, the evidence regarding the domain-         lateral temporal cortex, including the superior tem-
specificity of higher order social-cognitive skills such as   poral sulcus (STS) (Beauchamp et al., 2003; Haxby
ToM remains equivocal. Thus, we conclude that it is           et al., 2004).
unlikely that social-cognitive skills can be presumed to          However, convergent evidence suggests that these
function adequately without intact domain-general             regions are not limited to the processing of such
cognitive capacities.                                         information from faces, given their role in broader
                                                              biological motion processing. Early visual analysis
The neural basis of social cognition                          of faces is mediated by a core system comprising
                                                              occipito-temporal regions in extrastriate visual cortex,
in healthy humans                                             while an extended system of regions including neural
Evidence from lesion, neuroimaging and electro-               systems involved in other cognitive functions acts in
physiological studies converges to support the exist-         concert with the core system to extract meaning from
ence of distributed “social brain” networks that involve      faces. Within the extended system for face perception,
the primary visual cortices, amygdala, superior tem-          the amygdala plays a central role in processing the
poral sulcus, medial frontal cortex, orbitofrontal            social relevance of information gleaned from faces,
cortex and right parietal and anterior cingulate cortices     particularly when that information may signal a
(Adolphs, 2003). This network guides our perception           potential threat (Haxby et al., 2002).                     159
         Section 1: Neuropsychological processes



      Facial emotion recognition                                   studies exploring the role of the amygdala in fear
                                                                   conditioning. Animals with amygdala lesions demon-
      Despite early studies implying a greater involvement
                                                                   strate impaired fear conditioning alongside a profile
      of the non-dominant (usually right) hemisphere,
                                                                   of abnormal social behaviors, including social dis-
      including the somatosensory cortices, for the detec-
                                                                   inhibition and inappropriate approach/avoidance
      tion, recognition and representation of facial expres-
                                                                   responses alongside otherwise healthy functioning
      sions of emotion (Adolphs et al., 2000; see Borod
                                                                   (Bauman et al., 2004; Diergaarde et al., 2004). While
      et al., 2002 for a review), recent neuroimaging studies
                                                                   it has been argued that the amygdala plays a key role
      suggest that facial emotion is processed bilaterally
                                                                   in learning via positive/negative reinforcement and
      (Phan et al., 2004; Phillips et al., 2003a) or may be
                                                                   the “tagging” of emotional significance to a particular
      predominantly processed in the left hemisphere of
                                                                   context (via feedback loops with other limbic network
      right-handed people (Stone et al., 1996). The disparity
                                                                   structures such as the ventromedial frontal cortex),
      of findings from neuropsychology and neuroimaging
                                                                   the temporal dynamics of this complex interplay are
      studies regarding the laterality of emotion processing
                                                                   yet to be fully elucidated (Damasio, 1996). Other
      may be due to task-related performance demands,
                                                                   brain regions have been implicated for the recogni-
      such as verbal labeling. For example, in a patient with
                                                                   tion of specific facial emotions: for example, the
      a severed corpus collosum it has been demonstrated
                                                                   insula in response to facial and vocal expressions of
      that verbal catagorization of emotion was better when
                                                                   disgust (Phillips et al., 1997, 1998), the OFC and ACC
      stimuli were presented to the right visual hemi-field
                                                                   for facial expressions of anger (Blair et al., 1999), and
      (stimulating the left hemisphere), while presentations
                                                                   the amygdala, insula and ACC in response to facial
      to the left visual hemi-field (stimulating the right
                                                                   expressions of fear (Morris et al., 1996).
      hemisphere) resulted in improved performance on
      an association task (Stone et al., 1996). Similarly, field
      potentials recorded with MEG during explicit verbal          Theory of Mind
      catagorization have been shown to engage the left            Considerable evidence suggests that ToM abilities in
      posterior temporal lobe (Liu et al., 1999), while covert     humans involve a network of regions within the
      emotion-recognition tasks (requiring participants to         medial prefrontal cortex, the temporal poles and the
      attend to gender rather than facial emotion) engage          temporo-parietal junction (Frith & Frith, 2003). For
      the right posterior temporal lobe (Krolak-Salmon             example, early studies implicated a role for the medial
      et al., 2001). Differences in performance demands            frontal lobes in the appreciation of stories requiring
      may also influence the distribution of brain respon-         the understanding of the story protagonist’s mental
      ses to emotional faces in neuroimaging studies. For          state (Fletcher et al., 1995), or simple mental state
      example, explicit (verbal emotion-labeling) tasks result     inferences (Goel et al., 1995). More recent studies
      in activation of a wider network (including the ventral      using both verbal and non-verbal ToM tasks have
      frontal cortex and temporal cortex), while implicit          revealed support for the role of the medial prefrontal
      (gender- or age-discrimination) tasks maximally acti-        cortex (Castelli et al., 2000; Gallagher et al., 2000;
      vate subcortical structures such as the hippocampus          McCabe et al., 2001; Vogeley et al., 2001).
      and amygdala (Critchley et al., 2000; Hariri et al., 2000;       The study of brain responses during ToM tasks
      Lange et al., 2003).                                         in individuals with known social-cognitive difficul-
          Recent studies exploring the recognition of spe-         ties has corroborated the above findings. For
      cific emotions implicate a primary, but by no means          example, activation of the medial prefrontal cortex
      exclusive, role for the amygdala in the detection of         has been shown to be absent in individuals with
      negative emotions (Adolphs, 2001; Adolphs et al.,            autism and Asperger’s syndrome, compared with
      1999), particularly fear (Morris et al., 1998; Phillips      healthy controls, when performing mentalizing con-
      et al., 1997). The amygdala is believed to operate at        ditions of Happé’s cartoon task (Happé et al., 1996).
      both an unconscious level of awareness for rapid,            Similarly, a study of mentalizing using Baron-
      automatic evaluation of threat, and at a conscious           Cohen’s Eyes Task in individuals with Asperger’s
      level for the effortful reappraisal of a threat stimulus     syndrome revealed an absence of activity in the
      once it is detected (Adolphs, 2003; LeDoux, 1998).           amygdala and superior temporal gyrus (structures
160   These proposals build upon a long tradition of animal        that would normally be activated in healthy controls
                                                              Chapter 11: The neuropsychology of social cognition



in the comparison of mentalizing and non-mentalizing          distinguishing the cognitive architecture of social and
conditions; Baron-Cohen et al., 1999). Using this task        non-social cognition. What is critical in these studies is
in a study of schizophrenia patients, a reduction in          the ability to separate the contribution of domain-
activation in a region of the left frontal lobe, as well as   general processes (such as language or executive func-
the left superior temporal gyrus, was observed (Russell       tion) with regard to their impact on social-cognitive
et al., 2000).                                                task performance and competence. For example, patients
                                                              with impaired working memory might fail false-belief
                                                              tasks (used to tap ToM ability) because they cannot
Social cognition: distinct from                               maintain and update crucial social information that is
                                                              necessary to perform the task (i.e. performance
traditional neuropsychology?                                  demands). Alternatively, if belief reasoning is carried
Inferences about the feelings and intentions of other         out by a domain-general reasoning system, impaired
agents may be crucially dependent upon the adequate           working memory would necessarily lead to impaired
development of non-social cognitive processing cap-           competence on the task even if performance demands
acities. One example of these domain-general pro-             are adequately controlled (Apperly et al., 2005). Fur-
cesses is context-dependent information processing,           thermore, if components of ToM are carried out by
as a function of working memory. In particular, def-          domain-specific processes (Leslie & Thaiss, 1992),
icits in representing others’ mental states may reflect       then there should be no effect of impairments in
difficulty maintaining representations of context             working memory on belief-reasoning tasks if perform-
derived from verbal information, and/or difficulty            ance demands are adequately controlled. Clarification
constructing an appropriate representation of context         of the cognitive basis of social-information processing
from abstract visual information (such as gestures or         thus requires methods that allow clear separation
facial expressions). For example, a classic paradigm          of performance and competence demands, as well as
for the investigation of ToM ability is the “Sally Anne       sufficiently precise measures of competence (Apperly
Task” (Baron-Cohen et al., 1985). In this task, sub-          et al., 2005). A summary of the tasks used to
jects must correctly interpret the meaning of visually        measure specific social-cognitive abilities and the
presented drawings of social scenes, in order to repre-       domain-general processes implicated in each is pre-
sent and maintain the beliefs of two characters separ-        sented in Table 11.2.
ately, and then use this information to coordinate
the actual state of affairs. The correct inference in         Dissociation of social and non-social
this task therefore relies on the accurate formation
and maintenance of contextual information, held in            cognitive function
working memory, in the form of each character’s               One line of evidence in support for the relative inde-
belief about the particular situation. This relatively        pendence of social cognition from basic non-social
simple task reflects the complex interaction between          cognition (or neurocognition) comes from the disso-
the appreciation of other minds and working-                  ciation of specific cognitive skills in single case studies
memory requirements that are necessary for accurate           with focal brain damage. For example, individuals
ToM performance.                                              with selective brain damage to the prefrontal cortex
    In this section we will review the evidence for           (Anderson et al., 1999) or amygdala (Fine et al., 2001)
dissociation of cognitive processes subserving social         demonstrate aberrant social behavior and impaired
and non-social cognition. Evidence will be drawn from         social functioning alongside intact cognitive skills
neuropsychological investigations of individuals with         such as memory and language. Furthermore, in fur-
focal brain lesions, and the study of disordered popu-        ther single case studies reporting a dissociation
lations known to exhibit deficits in specific domain-         between ToM abilities and executive function (Bird
general cognitive domains (including the genetic dis-         et al., 2004; Fine et al., 2001; Rowe et al., 2001),
order William’s syndrome and psychiatric disorders            impaired executive functioning did not necessarily
such as autism, schizophrenia and bipolar disorder).          predict difficulties with ToM tasks (Bird et al., 2004),
We will be particularly concerned with issues sur-            and gross impairments in ToM were seen in the
rounding experimental design and the implications             context of normal performance on tests of executive           161
of findings from particular diagnostic categories for         functioning (Fine et al., 2001). In addition, one study
162
 Table 11.2 Theory of mind tasks.

 Task                               Description of task                          Control condition                      Non-social-cognitive components
 Sally Anne Task                    The experimenter uses two dolls,             Control questions can be used to       Context-dependent processing:
 (Wimmer & Perner, 1983)            “Sally” and “Anne.” Sally has a basket;      determine how well the basics of the   working memory, holding in mind
                                    Anne has a box. Experimenters show           situation have been grasped (i.e. by   two conflicting beliefs
                                    the participants (usually children) a        asking who moved the ball, or what
                                    simple skit, in which Sally puts a marble    object was moved)
                                    in her basket and then leaves the
                                    scene. While Sally is away, Anne takes
                                    the marble out of Sally’s basket and
                                    puts it into her box. Sally then returns
                                    and the participant is asked where they
                                    think Sally will look for her marble.
                                    A child is said to “pass” the test if they
                                    understand that Sally will first look
                                    inside her basket (on the basis of her
                                    false belief) before realizing that her
                                    marble isn’t there. The participant has
                                    to understand that even though Anne
                                    has moved the ball, Sally still has in
                                    mind the original location of the
                                    object and will therefore look in the
                                    wrong place
 Happé story task                   Written stories which require either a       Matched control stories requiring a    Verbal/reading ability, working
 (Happé et al., 1999)               mental or physical state inference in        physical inference for their           memory (although the latter
                                    order for a correct response to be           understanding. Control questions to    depends on how the task is
                                    given. Correct response normally             check memory and understanding can     administered).
                                    relates to how a particular character        also be incorporated
                                    will act and includes an explanation of
                                    why the character acts that way –
                                    usually need to understand that
                                    someone has a false belief about
                                    something and therefore may behave
                                    in a particular way on the basis of that
                                    false belief.
 Happé cartoon task                      A task based on cartoons taken from         Matched control cartoons requiring         Visual attention and visual search,
 (Happé et al., 1999)                    American newspapers. There are two          inference of physical as opposed to        intact visual grouping (early stage
                                         conditions – one set of cartoons            mental states                              context processing), perspective
                                         requires a mental state inference and                                                  taking
                                         one requires a physical state inference.
                                         Responses are marked according to
                                         whether or not the person “got” the
                                         joke, scoring criteria are provided
 Eyes Task                               Individuals have to determine the           A control task has sometimes been          Knowledge of complex emotions
 (Baron-Cohen et al.,                    mental state expressed by an eye pair       included in this assessment in which       and mental states
 1997) Revised version                   from one of four complex mental state       individuals have to determine the
 (Baron-Cohen et al., 2001).             terms displayed alongside the eye           gender of the eyes
                                         image. A glossary of word meanings is
                                         provided. Adult and child versions are
                                         available
 Hinting Task                            A verbal task in which one character        No specific control condition although     Verbal (reading ability), working
 (Corcoran et al., 1995)                 drops a verbal hint to another person       prompting questions could                  memory (if written information does
                                         in order to get them to do something        additionally be given to the participant   not remain in front of the individual),
                                                                                                                                knowledge of social norms
 Picture arrangement tasks               In this task participants typically have    Physical, non-social or mechanical         Logical reasoning, visual attention
 Original Version: Baron-Cohen et al.    to arrange 3 or 4 pictures so that they     picture arrangement tasks have been        (visual search; attention to detail;
 (1986). Other versions: Langdon         make a coherent story. Some of these        used as matched within-task controls       intact visual grouping/ early stage
 et al. (1997); Sarfati et al. (1997);   stories or situations will require the                                                 context processing), knowledge of
 Brunet et al. (2003)                    individual to have an understanding of                                                 social norms
                                         the intention or desire/goal/belief of a
                                         character in order to sequence the
                                         cards correctly. Variations on this task
                                         have been used by a number of
                                         authors with different populations
                                         (including Langdon et al., Sarfati et al.
                                         and Brunet et al.)




163
        Section 1: Neuropsychological processes



      has demonstrated the statistical independence of           brain regions. Further evidence for this proposal comes
      social and non-social cognitive skills even when per-      from the finding of modest correlations between per-
      formance in both domains was impaired (Rowe et al.,        formance on a ToM task (Happé’s cartoon task) and
      2001). Similarly, individuals with prosopagnosia show      executive function in fronto-temporal dementia
      a selective impairment in their ability to recognize       (Snowden et al., 2003). However, using the strategy
      familiar faces despite the retention of other non-social   of covarying for executive functioning in the perfor-
      perceptual abilities, suggesting that face processing      mance of fronto-temporal dementia patients on the
      recruits domain-specific neural mechanisms (Haxby          same task, Lough et al. (2006) concluded that the
      et al., 2001; Kanwisher, 2000).                            influence of executive functioning was not specific to
          Further evidence for the independence of social        mentalizing ability. Opposing findings have been
      cognition comes from the comparison of the neuro-          reported in a group of patients with frontal lobe epi-
      cognitive and social-cognitive profiles of genetic dis-    lepsy (Farrant et al., 2005), where no significant cor-
      orders such as William’s syndrome and autism. On           relations between neuropsychological test variables and
      the one hand, high-functioning individuals with            a range of social cognitive tasks (including Happé’s
      autism and Asperger’s syndrome display dysfunc-            cartoons and stories, the faux pas test and Baron-
      tional social behavior and impaired social cognition       Cohen’s Eyes Task) were reported in the clinical group,
      that is not associated with general cognitive capacity.    but moderate correlations were found between execu-
      In contrast, individuals with Williams’ syndrome           tive function, non-mental state inference cartoons and
      (who tend to be socially extroverted, displaying en-       performance on the Eyes Task in the control group.
      hanced empathy and hyposociality) demonstrate a                The relative contribution of working memory,
      relative sparing of social-cognitive skills (such as the   language demands and inferential capabilities to
      ability to recognize other people’s mental states and      ToM performance (using Happé’s cartoons and stor-
      emotions from information contained in their eyes),        ies tasks) has also been examined in patients with
      while at the same time showing impairments in tasks        various forms of traumatic brain injury (TBI) (Bibby
      requiring spatial cognition and fine motor control         & McDonald, 2005). In this study, neuropsychological
      (Bellugi et al., 1999; Tager-Flusberg et al., 1998).       factors did contribute to (and in some cases predict)
      These findings provide evidence for distinct social        performance on the ToM tasks, but they did not
      processing networks in the form of a dissociation of       completely explain the impairment in the TBI group.
      social and non-social cognitive function across two        Similarly, modest correlations between social and
      clinical conditions.                                       non-social tasks have been reported in individuals
                                                                 with amygdala damage and healthy controls, yet the
      Correlations with neuropsychological                       majority of group differences in social cognitive tasks
                                                                 remained when executive function, logical memory
      performance                                                and general intelligence were included as covariates
      In order to determine the relative contribution of         (Shaw et al., 2005). Lastly, a single case study of an
      domain-general processes to social cognition, one          individual with orbitofrontal damage reports that
      can statistically account for any concomitant neuro-       ToM and affect-processing abilities were independent
      psychological impairment when analysing social-            of executive functioning (Bach et al., 2000).
      cognitive performance. Using this strategy, significant        Recent studies of ToM and neurocognitive per-
      correlations were revealed between scores on a men-        formance in schizophrenia similarly suggest that
      talizing task and executive function in a sample of        executive function and verbal working memory are
      patients with anterior and posterior lobe damage           associated with impaired social perception and cogni-
      (Channon & Crawford, 2000) while, in contrast, fewer       tion, but that deficits in executive functioning and
      correlations of this kind were found in the healthy IQ-    memory can only partially account for impaired
      matched control sample. This raises the interesting        social cognition in schizophrenia (Brune, 2005; Greig
      question of whether the potential links between social     et al., 2004; Lancaster et al., 2003). For example,
      and non-social cognitive processes are likely to be        Lancaster et al. (2003) report that performance on
      strengthened in individuals whose pathology may            the Wisconsin Card Sort Test (WCST) accounted
164   have resulted in (or indeed been caused by) the devel-     for only 35% of the variance in social-cue perception
      opment of aberrant connectivity between particular         in schizophrenia, while memory contributed to only
                                                               Chapter 11: The neuropsychology of social cognition



8% of the variance in social cognition in the study by         and ToM impairment was considered to be due to the
Greig and colleagues. Using a different method of              low IQ scores in the manic group.
analysis, Brune (2005) showed that social-cognitive                These studies converge to suggest that while
performance was the strongest predictor of schizo-             executive processes or general intellectual functioning
phrenia group membership (94.4% correctly classified           may play a role in social cognitive skills, deficits in
by ToM), over WCST performance (70%) and other                 these domain-general abilities cannot completely
measures of executive function, whereas by contrast            account for ToM dysfunction in disordered popula-
an earlier study (Brune, 2003) reported that no differ-        tions. It is notable that this pattern of findings appears
ences in ToM performance were found between                    in both neuropsychological investigations of brain-
schizophrenia and control subjects after controlling           damaged patients and studies of patients with psychi-
for IQ. A study of bipolar affective disordered patients       atric disorder.
has also revealed an association between executive
functioning deficits and ToM impairments during
the euthymic phase of illness (Olley et al., 2005).            Within-task non-social control conditions
     A further strategy adopted by some authors is to          In some ToM studies, the inclusion of a non-ToM (or
examine the role of general intellectual functioning           non-mental state inference) control question or con-
(assessed by IQ tests) in relation to social cognitive         dition (matched for all elements of processing bar the
performance. This is particularly important in popu-           mental state inference) is used to isolate ToM skills.
lations (such as schizophrenia) where there are likely         Demonstration of difficulties on the ToM condition
to be group differences in general intellectual func-          alone, with intact performance on the matched con-
tioning. A strong correlation between IQ and scores            trol condition, implies that a relatively selective ToM
on the Hinting task has been reported in schizophre-           mechanism has been affected by the damage, while
nia but not in controls (Corcoran et al., 1995),               domain-general cognitive processes required for the
although group differences on ToM tasks have been              overall comprehension and interpretation of the
shown to remain after controlling for IQ (Corcoran             stimulus are spared. Tasks such as Happé’s cartoon
et al., 1995; Sarfati et al., 1997). In a later study, after   task and Happé’s stories fall into this category as they
controlling for IQ, ToM deficits were found in separ-          include matched, non-mental state inference condi-
ate comparisons between control subjects and par-              tions. Disproportionate impairment on cartoons that
ticular subgroups of schizophrenia patients defined            require mental state inference (as opposed to those
in terms of a hierarchical classification of symptoms          requiring physical inference) has been identified in
(i.e. paranoid, behavioral signs, and passivity phe-           different patients including those with right hemi-
nomena; Corcoran et al., 1997). However, two studies           sphere damage (Happé et al., 1999), a single case
which have explored the role of IQ in ToM perform-             study of an individual who underwent stereotactic
ance in schizophrenia report no differences between            anterior capsulotomy (Happé et al., 2001), individuals
control and patient groups when the groups are                 with fronto-temporal dementia (Lough et al., 2006),
matched for IQ (Brune, 2003; Pickup & Frith, 2001).            and paranoid patients with schizophrenia (Corcoran
     Use of this strategy in affective-disordered patients     et al., 1997). Note that this last study used a set of
has yielded mixed results. A study by Inoue et al.             cartoon stimuli created by Corcoran, while the other
(2004) reports no association between IQ and ToM               studies used Happé’s cartoon task. Furthermore, per-
in a large mixed sample of patients with both unipolar         formance on Happé’s task by a patient with left amyg-
and bipolar depression; the affective disordered group         dala damage revealed scores within the normal range
showed clear impairments in ToM using a picture                for the cartoons requiring physical inference, but well
sequencing task. In contrast, ToM deficits revealed            below the normal range on the mental state inference
in another study of bipolar-disordered patients were           cartoons; this suggests specificity of the mentalizing
significantly correlated with IQ, although this rela-          deficit (Fine et al., 2001). In another study (Pickup &
tionship disappeared when those in the manic phase             Frith, 2001) ‘mentalizing’ and ‘non-mentalizing’ ver-
of the illness were excluded from the analyses (Kerr           sions of other first-order and second-order ToM tasks
et al., 2003). Since the manic patients in this sample         were administered to a group of individuals with
had significantly lower IQ than those in the euthymic          schizophrenia. Using composite scores of the mental          165
phase of illness, the original association between IQ          and non-mental data across tasks, there was no
         Section 1: Neuropsychological processes



      significant difference between psychiatric and healthy      requiring physical-state inference (Baron-Cohen
      controls on the non-mental composite, but highly            et al., 1986). Langdon et al. (1997) used a picture-
      significant group differences for the mentalizing com-      sequencing task that included physical, causal and
      posite scores.                                              mentalizing conditions in order to isolate the ability
          Using Happé’s cartoons, Bibby & McDonald                to infer causal mental states. Selective mentalizing
      (2005) found no evidence for specific ToM impair-           deficits were found in some schizophrenia patients,
      ment in subjects with traumatic brain injury; that is,      while others (e.g. those with severe thought disorder)
      performance on the mental state and physical state          made general sequencing errors in both types of stor-
      cartoons was impaired to the same degree (Bibby &           ies. A similar approach was taken by Brunet et al.
      McDonald, 2005). A failure to demonstrate a specific        (2003) in contrasting performance on sequencing
      ToM impairment using this task has also been                tasks requiring either attribution of intention or attri-
      reported in studies of patients with epilepsy (Snowden      bution of physical causality (for example reasoning
      et al., 2003), fronto-temporal dementia group (Lough        about the weight, location or speed of an object), in
      et al., 2006), anorexia nervosa (Tchanturia et al.,         stories with and without human characters. Overall
      2004) and a group of individuals with paranoid              individuals with schizophrenia showed impairments
      schizophrenia (Russell, 2002). While poor perform-          in the attribution of intention condition; this result
      ance on both cartoon conditions suggests that these         was found even when only participants with good
      groups have no specific mentalizing impairment,             performance on the physical logic condition were
      these findings may also be due to methodological            included for analysis and verbal IQ was covaried.
      shortcomings of the task itself. That is, individuals       These studies suggest a specific deficit in mental state
      may find both physical and mental state inferences          inference/attribution in schizophrenia. However, this
      difficult due to common task demands that are not           specificity may not be as clearly apparent in patients
      directly related to mental state inference (for example,    with more generalized cognitive deficits, such as those
      low-level visual perceptual abilities e.g. related to       with chronic negative symptoms (see Langdon et al.,
      visual grouping, or context processing; controlled          1997). A set of studies by Sarfati and colleagues (1997,
      visual attention; or problems with “metarepresenta-         1999) has demonstrated an impaired ability to
      tion” itself ). To address this point, Russell (2002)       sequence cards referring mental-state inference in
      prompted paranoid individuals to attend to the rele-        thought-disordered schizophrenia patients, however,
      vant aspects of the cartoons as a means to ensure that      these studies did not include appropriate physical or
      they were taking in the correct information from the        mechanical comparisons, and are therefore limited in
      stimulus. This method improved performance, how-            their capacity to reveal specific ToM deficits.
      ever, mental state cartoons were still less well under-         Finally, a study by Pickup & Frith (2001) found
      stood than physical state cartoons. This pattern fits       that ToM deficits remain in schizophrenia patients,
      with the suggestion above that while underlying cog-        even after controlling for their poor recall perform-
      nitive processes may help to solve social cognitive         ance in relation to items on Corcoran’s Hinting Task.
      problems, they do not provide the whole picture.            The use of additional items to probe memory for
      A further suggestion is that the very nature of car-        details of the ToM task is a useful test of the ability
      toons (i.e. the cartoonist intends the joke to be funny)    to meet performance demands that may interfere with
      results in both conditions involving an element of          competence on the ToM task. This method has simi-
      mentalizing (i.e. interpreting intentions).                 larly been employed in other studies of patients with
          Cartoon-type stimuli (in the form of picture            fronto-temporal dementia (Rowe et al., 2001) and
      arrangement tasks) have also been utilized to study         bipolar affective disorder (Kerr et al., 2003). In these
      the ToM performance of individuals with schizophre-         studies, ToM performance was found to be impaired
      nia (Brunet et al., 2003; Langdon et al., 1997; Sarfati &   in each of the clinical groups after memory was con-
      Hardy-Bayle, 1999; Sarfati et al., 1997, 1999). These       trolled for.
      studies followed on from Baron-Cohen’s earlier work             In regards to the use of within-task control condi-
      demonstrating that children with autism show im-            tions in the face-processing literature, it is common
      paired performance when sequencing cards that               for non-emotional face-processing tasks (such as
166   require the inference of mental states compared with        identity, age or gender discrimination) to be empl-
      near normal performance arranging picture stimuli           oyed alongside emotion-recognition tasks in order to
                                                           Chapter 11: The neuropsychology of social cognition



delineate specific difficulties in the recognition of      study, schizophrenia and brain-damaged groups were
emotions within the context of intact recognition of       impaired on all tasks relative to controls, with no
other facial features. Studies of patients with focal      difference in performance between the two clinical
brain lesions provide evidence that impaired recogni-      groups after controlling for face-recognition perform-
tion of emotional facial expressions may exist along-      ance. Some individuals with schizophrenia have also
side intact processing of other facial characteristics     shown impairments on tests sensitive to amygdala da-
such as identity recognition, and inferences of gender     mage, such as fear perception, to a degree that distin-
or age (Adolphs et al., 1994, 1996; Bowers et al., 1985;   guishes them from depressed individuals (Evangeli &
Calder et al., 1996; Sprengelmeyer et al., 1996; Tranel    Broks, 2000).
et al., 1988; Young et al., 1993). Furthermore, single         Several studies have examined whether difficulties
case studies have shown that patients with bilateral       in facial-affect perception in schizophrenia stem from
damage to the amygdala or insula have specific diffi-      a more generalized face-processing dysfunction (Kerr &
culties in recognizing facial displays of emotion (fear    Neale, 1993). Some studies have revealed evidence
and disgust, respectively) alongside intact recognition    for an affect-specific deficit (Bryson et al., 1997;
of other emotions and spared function in other cog-        Heimberg et al., 1992; Morrison et al., 1988; Walker
nitive domains (Adolphs et al., 1994; Calder et al.,       et al., 1984), while others report generalized face-
1996, 2000). For example, Case SM (who has bilateral       processing impairments in schizophrenia (Addington
calcification of the amygdalae) demonstrates intact        & Addington, 1998; Archer et al., 1994; Borod et al.,
recognition of all emotions except fear, and to a lesser   1993; Feinberg et al., 1986; Gessler et al., 1989; Kerr &
extent surprise, alongside entirely normal neuro-          Neale, 1993; Mueser et al., 1997; Novic et al., 1984;
psychological and executive functioning (Adolphs           Salem et al., 1996; Schneider et al., 1995). In some
et al., 2005).                                             studies, affect-specific deficits have been shown to
    A particularly noteworthy and challenging strat-       remain robust even when controlling for identity
egy for delineating the neurocognitive basis of specific   recognition (Borod et al., 1993; Novic et al., 1984),
emotion-processing deficits is to examine the per-         while other evidence suggests that facial-affect recog-
formance tasks of psychiatric and lesioned subject         nition deficits are related to specific neurocognitive
groups on various face-processing tasks (Adolphs           dysfunctions in visual attention (Kee et al., 1998),
et al., 2001). For example, Adolphs et al. (2001)          memory and language abilities (Addington &
examined individuals with autism and a group with          Addington, 1998; Kohler et al., 2000; Mandal &
amygdala damage on a number of face-processing             Palchoudhury, 1989; Schneider et al., 1995).
tasks (including face recognition, emotion labeling,
emotional intensity discrimination, social judgment        Social cognition: implications
from faces and social judgment from lexical stimuli).
In general the autistic individuals had no difficulty in   for psychiatry
the identification of faces, emotions or in rating the     In the previous sections we have reviewed evidence
intensity of emotional expressions, nor in social judg-    from the neuropsychological and neuroscience litera-
ments from lexical stimuli. The group with amygdala        ture that provides support for the relative independ-
damage showed impairments in emotion-processing            ence of social cognition from non-social cognition.
tasks but not facial identity recognition or social        The elucidation of the neural networks subserving
judgments from the lexical task. However, both groups      social cognition may prove to be particularly impor-
were very impaired in their judgment of trustworthi-       tant for identifying the neuropathology of major psy-
ness from faces, suggesting that cognitive processes for   chiatric disorders such as autism and schizophrenia,
both emotion recognition and facial identity are dis-      and will be pertinent to the formulation of effective
tinct from those used to make more ambiguous social        treatments for social-cognitive disturbances in these
judgments such as “trustworthiness” from faces. One        individuals. With respect to schizophrenia, a number
recent study has also conducted a comparison of            of models pertaining specifically to social-cognitive
patients with right-brain damage, chronic schizophre-      dysfunction have been offered in recent years to
nia and healthy controls on tasks of emotion labeling,     account for the symptoms of psychosis (Bentall
emotion recognition and facial identity recognition        et al., 2001; Burns, 2004; Green & Phillips, 2004;          167
(Kucharska-Pietura & Klimkowski, 2002). In this            Grossberg, 2000; Lee et al., 2004). It is notable that
         Section 1: Neuropsychological processes



      abnormal neural circuitry in schizophrenia has been          complex problem underlies the autistic problem with
      reported in regions corresponding with those impli-          facial emotion perception.
      cated in social cognition, such as dysfunctional pre-            In schizophrenia, a number of neuroimaging
      frontal-thalamic and temporo-limbic or cerebellar            studies have explored face processing (reviewed in
      connections (Andreasen et al., 1998; Weinberger              Russell et al., 2007a), most commonly within an emo-
      et al., 1992), as well as abnormalities in cells and         tion-specific deficit framework. Brain regions of
      functional integrity of temporo-limbic structures (e.g.      interest in these studies have usually included only
      amygdala, thalamus, hippocampus, parahippocampal             those related to the processing of emotion-specific
      gyri) and the orbitofrontal and anterior cingulate           stimuli (such as the amygdala in studies of fear per-
      cortex (Andreasen et al., 1999; Benes, 1999; Bogerts         ception). However, two recent imaging studies in
      et al., 1993; Chua et al., 1997; Gray et al., 1995; Liddle   schizophrenia that included face-processing regions
      et al., 1992). A comprehensive review of the structural      in their analyses reported reduced activity in the
      and functional abnormalities in schizophrenia within         occipital face area and the FFA in response to emo-
      regions important for emotion processing and social          tion and gender discrimination from faces (Johnston
      cognition has recently been provided elsewhere               et al., 2005; Quintana et al., 2003). This implies that
      (Phillips et al., 2003b). Similar conceptualizations of      emotion-specific deficits may be secondary to early
      autism as a disorder of social-cognitive functioning         visual-processing difficulties, which may themselves
      have been dominant in recent decades (Baron-Cohen,           be influenced by domain-general processes such as
      1995; Baron-Cohen et al., 1985). Furthermore, follow-        attention. It is here that we come full circle, with the
      ing recent reports of impairments in ToM ability             implication that despite the existence of specific brain
      during both the affective and euthymic phases of             regions or networks specialized for social material,
      bipolar disorder (Inoue et al., 2004; Kerr et al., 2003;     these networks may still be modulated by domain-
      Olley et al., 2005), specific social-cognitive dysfunc-      general processes (see Pessoa et al., 2005 for commen-
      tion may soon also feature in etiological models of the      tary on the role of attention). Further understanding
      affective disorders (see Green & Malhi, 2006; Nelson         of these complex reciprocal interactions will be im-
      et al., 2005).                                               portant for those studies making tentative steps to-
          We turn now to a final discussion of specific            ward remediation of social-cognitive skills in clinical
      findings from the study of social-cognitive disturb-         populations (Frommann et al., 2003; Russell et al.,
      ances with reference to their implications for the           2006).
      major psychiatric disorders. Beginning with face pro-            Abnormalities in facial emotion perception
      cessing, as outlined above, the Fusiform Face Area           (Bozikas et al., 2006; George et al., 1998; Getz et al.,
      (FFA) has been delineated in studies of healthy indi-        2003; Lembke & Ketter, 2002; Lennox et al., 2004;
      viduals as a region responding preferentially (but not       McClure et al., 2003) and Theory of Mind (Bora
      exclusively) to faces. It is notable that this region is     et al., 2005; Inoue et al., 2004; Kerr et al., 2003; Olley
      less active in autistic individuals when they are pas-       et al., 2005) have been recently demonstrated in bipo-
      sively viewing facial expressions of emotion (Pierce         lar affective disorder, and may comprise the first
      et al., 2001; Schultz et al., 2003). This has led to the     stages of dysfunction in the regulation of emotion
      suggestion that individuals with autism fail to become       (see Green & Malhi, 2006). For example, over-reactive
      face “experts,” insofar as the key brain regions of the      limbic responses during appraisal of emotional
      social network are not activated when processing             material such as facial expressions (Chen et al.,
      human faces. Whilst this proposal may be taken to            2006), or abnormal inhibitory processing of emo-
      suggest that the functional integrity of specific social-    tional material (Murphy et al., 1999) in bipolar dis-
      processing regions (such as the FFA) are impaired in         order may contribute to the generation of extreme
      autism, a recent case study of an autistic child who         emotional responses that are difficult to regulate. In
      demonstrates expertise with specific cartoon charac-         support of this proposal, abnormal neural responses
      ters revealed that his fusiform area responded               during the generation of affect in bipolar disorder
      to cartoon images but not human faces, implying              have been associated with both periods of depression
      that the cognitive architecture underlying high-level        (Malhi et al., 2004b) and mania (Malhi et al., 2004a).
168   expertise is in fact intact and highly plastic (Grelotti     Current theoretical accounts of major depressive dis-
      et al., 2005). Clearly this finding suggests that a more     order as an adaptive response to the threat of social
                                                            Chapter 11: The neuropsychology of social cognition



exclusion also highlight the importance of social           decisions about trustworthiness, morality and friend-
cognitive processes in affective disorder (Allen &          liness are often made on the basis of a fleeting glance
Badcock, 2006).                                             at a novel face. These less tangible aspects of social
    It is clear from the evidence reviewed in this          cognition may be seen to be evading experimental
chapter that the issue of domain specificity with           techniques designed to measure cognition within the
respect to social cognitive processes has yet to be         social domain. Future progress on the delineation of
definitively determined. Whilst neuropsychological          the social brain depends crucially upon the develop-
studies suggest that social cognition cannot be fully       ment of tasks that allow social-cognitive processes to
accounted for by the domain-general processes (such         be distinguished