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The Amygdala, Autism and Anxiety - DOC by eib63834


									To be published as part of the Novartis Foundation Symposium 251, “Autism:
Neural Basis and Treatment Possibilities”, June 2002

                   The Amygdala, Autism and Anxiety

        David G. Amaral, Ph.D.1,2 and Blythe A. Corbett, Ph.D.2
  Department of Psychiatry, Center for Neuroscience and California
Regional Primate Research Center
  The M.I.N.D. (Medical Investigation of Neurodevelopmental
Disorders) Institute
University of California, Davis, Center for Neuroscience, 1544
Newton Ct., Davis, CA, 95616

Number of pages: 20

Number of words: 3755

Number of tables: 0

Number of figures: 0

Running Title: Amygdala and Autism

Send correspondence and reprint requests to:

      David G. Amaral, Ph.D.
      Center for Neuroscience
      1544 Newton Court
      Davis, CA. 95616 USA

      Telephone (530) 757-8813
      Fax       (530) 754-7016

      Brothers (1990) has proposed that the amygdala is an
important component of the neural network that underlies social
cognition. And, Bauman and Kemper (1985) observed signs of
neuropathology in the amygdala of the postmortem autistic brain.
These findings, in addition to recent functional neuroimaging data,
have led Baron-Cohen et al. (2000) to propose that dysfunction of the
amygdala may be responsible, in part, for the impairment of social
functioning that is a hallmark feature of autism. Recent data from
studies in our laboratory on the effects of amygdala lesions in the
macaque monkey are at variance with a fundamental role for the
amygdala in social behavior. If the amygdala is not essential for
normal social behavior, as seems to be the case in both nonhuman
primates and selected patients with bilateral amygdala damage, then
it is unlikely to be the substrate for the abnormal social behavior of
autism. However, damage to the amygdala does have an effect on a
monkey’s response to normally fear-inducing stimuli, such as snakes,
and removes a natural reluctance to engage novel conspecifics in
social interactions. These findings lead to the conclusion that an
important role for the amygdala is in the detection of threats and
mobilizing an appropriate behavioral response, part of which is fear. If
the amygdala is pathological in subjects with autism, it may contribute
to their abnormal fears and increased anxiety rather than their
abnormal social behavior.


        In the best of biomedical research endeavors, there is a natural
symbiosis between basic, and often basic animal research, and
careful assessment of clinical populations. The issues raised in this
paper draw from efforts to establish the neurobiological basis of
primate social behavior, on the one hand, and attempts to determine
brain systems that are impacted in autism and lead to impairments of
social behavior, on the other hand. One effort has enormous potential
to inform the other. If for example, a neural system, let’s call it the
Social System, is established that underlies the various components
of social interaction, and given that impairments of social interaction
are a major deficit in autism spectrum disorders, then a reasonable
hypothesis might be that a region of primary brain pathology might be
in the Social System1. Conversely, if specific and reproducible areas
of brain pathology were identified in autism spectrum disorder, this
information might provide a useful heuristic as to which brain regions
might be components of the Social System.
        Life, of course, is rarely so simple and autism is certainly one of
the most complex of neurological disorders. It is complex because it
has many diverse symptoms including social impairment, language
problems and motor stereotypies. These symptoms are observed
heterogeneously throughout the population that makes up the autism
spectrum. There are also a number of co-morbid conditions, such as
sleep     disturbances,    gastrointestinal   distress   and   psychiatric

symptoms including anxiety and obsessive-compulsive behavior. The
following is a short summary of the thought and experimental process
that we have followed - starting with the notion that the amygdala is a
fundamental component of the Social System and likely to be heavily
involved in the pathophysiology of autism - to our current view that
the amygdala is involved in detecting and reacting to environmental
threats. And, if the amygdala is impaired in autism, it may be more
responsible for alterations in fear and anxiety rather than social

The Amygdala

         The primate amygdala is a relatively small brain region located
in the temporal lobe, just anterior to the hippocampus. In the
macaque monkey it is approximately 0.6 cm3 in volume and in the
human it is about 3.0 cc3. The amygdala is comprised of at least 13
nuclei and cortical regions, many of which are partitioned into two or
more        subdivisions.           The       amygdala           has       widespread            extrinsic
connections including those with the neocortex, hippocampal
formation, cholinergic basal forebrain, striatum, hypothalamus and
brainstem. While neocortical inputs to the amygdala arise mainly from
higher        order       unimodal           and       polymodal           association           cortices,
projections back to the neocortex extend monosynaptically even to
primary sensory areas such as visual area V1. There is an extensive
network of intrinsic connections within the amygdala that generally

 Of course, this is not necessarily the case. It could well be that autism is due to brain dysfunction(s) at a
much more fundamental level of sensory or motor processing. And this dysfunction only manifests itself in

brings information from more laterally situated nuclei, such as the
lateral nucleus, to more medially situated nuclei, such as the central
nucleus.        The       amygdala          contains    a   plethora    of   neuroactive
substances           and has some of                   the highest     brain levels   of
benzodiazepine receptors and opiates. Detailed descriptions of the
neuroanatomy of the amygdala can be found in Amaral et al. (1992).
One can conclude from the neuroanatomy of the amygdala that it is
privy to much of the sensory processing that occurs in the neocortex
and, that through its widespread efferent connections, it has the
ability to influence the activity of numerous functional systems that
range from elemental physiological processes such as heart rate and
respiration to the highest processes of perception, attention and

The Amygdala and Social Behavior

        Several lines of evidence have indicated that the amygdala
plays an important role in socioemotional behavior. Macaque
monkeys with bilateral lesions that include the amygdala are typically
more tame than normal animals, demonstrate abnormal food
preferences and have alterations of sexual behavior (Brown and
Schafer 1887) (Kluver and Bucy 1938, 1939). Rosvold et al. (1954)
designed studies to explicitly evaluate changes in social behavior in
macaque monkeys following amygdala damage. They established
artificial social groups of male rhesus monkeys and studied the
dominance hierarchy that emerged. They then carried out two stage

complex situations such as social encounters.

bilateral destructive lesions of the amygdala of the most dominant
animal and studied the dominance hierarchy as the group
reorganized. They found that the lesions led to a decrease in social
dominance with the lesioned animal typically falling to the most
subordinate position of the group.
      A more extensive program of studies was carried out by Kling
and colleagues using both captive and free ranging nonhuman
primates (Kling et al. 1970, Kling and Cornell 1971) (Kling and Steklis
1976). Dicks et al. (1968), for example, retrieved rhesus monkeys
from social troops on the island of Cayo Santiago. These animals
were subjected to bilateral amygdalectomy and then returned to their
social groups. While it was difficult to follow the minute-to-minute
interactions of the lesioned animals, the typical finding was that they
were invariably ostracized and would often perish without the support
of the social group.
      From the results of these and similar studies carried out by
several laboratories, Brothers (1990) formalized the view that the
amygdala is one of a small group of brain regions that form the neural
substrate for social cognition. This view predicts that the amygdala is
essential for certain aspects of the interpretation and production of
normal social gestures such as facial expressions and body postures.
It also predicts, consistent with the literature that damage to the
amygdala would invariably lead to a decrease in the amount or
quality of conspecific social interactions.

The Amygdala and Autism

      In their seminal studies on the neuropathology of the autistic
brain, Bauman and Kemper (1985) noted that the medially situated
nuclei of the amygdaloid complex had clusters of small, tightly packed
neurons that were not observed in control brains. The amygdala
neuropathology was only one area among many that included
alterations in the hippocampus, septum, cerebellum and other
structures. Unfortunately, these observations have not yet been
independently replicated. Neuroimaging studies have thus far
produced conflicting results on whether there is a gross change in the
volume of the amygdala. Abell et al. (1999) reported an increased left
amygdala volume in cases of autism and Asperger syndrome.
Howard et al. (2000) also reported an increased amygdala volumes in
both hemispheres of the brain in subjects with autism. In contrast to
these studies, Aylward et al. (1999), reported the amygdala to be
decreased in volume compared to age matched control cases.
Pierce et al. (2001) also reported amygdala volumes to be
significantly smaller. Thus, these studies appear inconclusive as to
whether there is a size difference in the autistic amygdala. Even if the
size was significantly different, it is unclear whether this would imply
better or worse function.
      More suggestive evidence for a role of the amygdala in autism
comes from a variety of functional imaging studies. Individuals with
high functioning autism or Asperger syndrome showed significantly
less amygdala activation than control subjects during a task that
required them to judge what a person might be feeling or thinking
from images of their eyes (Baron-Cohen et al. 1999). A more recent
fMRI study, comparing adult males with autism to control subjects,

measured the neural activation in areas of the brain that are
associated with a social perception task (Ashwin et al. 2001).
Subjects were shown images of real faces that varied in intensity of
facial affect from neutral expressions to extreme fear expressions, as
well as scrambled faces. The subject was simply required to press a
button every time they saw a picture on the screen. During this social
perception task, the subjects with autism showed less activation of
the amygdala and orbitofrontal cortex. Moreover, the subjects with
autism showed increased activity (implying greater reliance) on the
superior temporal gyrus and anterior cingulate cortex. These data
would appear to suggest that when normal subjects are carrying out
tasks that require social evaluation, the amygdala is activated. And
this activation is decreased in individuals with autism.

The Amygdala Theory of Autism

      Based on these converging lines of evidence, Baron-Cohen et
al (2000) wrote a very compelling review that concluded, “The
amygdala is therefore proposed to be one of several neural regions
that are abnormal in autism.” An implication of the paper is that
pathology of the amygdala leads to an impairment in social
intelligence, which is a hallmark feature of autism. That the amygdala
might be at the heart of the pathophysiology of autism was also
suggested somewhat earlier by Bachevalier (1994, 1996) based on
observations of neonatal macaque monkeys who had been subjected
to bilateral medial temporal lobe lesions. Bachevalier described these
monkeys (at 6 months of age) as dramatically decreasing their social

behavior as compared to controls in dyadic social encounters with
conspecifics. The lesioned animals actively avoided social contacts
and had “blank, inexpressive faces and poor body expression (i.e.
lack of normal playful posturing) and they displayed little eye contact.
Furthermore, animals with early medial temporal lobe lesions
developed    locomotor     stereotypies   and   self-directed   activities”
(Bachevalier 1994). Since selective lesions of the hippocampus did
not produce this pattern of behavioral alterations, Bachevalier
attributed them to damage of the amygdala.
      The literature that figured prominently in the generation of the
amygdala theory of autism and the notion that the amygdala is
essential for normal social behavior was very influential on our own
program of studies aimed at unraveling the neurobiology of primate
social behavior. While we would have been delighted to have
generated data consistent with the hypothesis that the amygdala is
central to social behavior, the data we did generate has led us to a
distinctly different conclusion.

The Amygdala is not Essential for Social Behavior in the Adult

      We have carried out a series of experimental studies to re-
examine the role of the amygdala in conspecific social behavior using
the rhesus monkey as a model system (Emery et al. 2001). Adult,
male rhesus monkeys with bilateral ibotenic acid lesions of the
amygdala, and age, sex and dominance matched control monkeys
were observed during dyadic interactions with “stimulus monkeys”

(two males and two females). This stereotaxic, neurotoxic lesion
technique has the merit of removing the neurons of the amygdala
while sparing fibers that pass through it. A variety of both affiliative
(groom, present sex etc.) and agonistic, (aggression, displace etc.)
behaviors were quantitatively recorded while animals interacted in a
large (18ft X 7ft X 6.5ft) chain link enclosure. Each experimental
animal interacted with each stimulus animal for four, twenty-minute
periods in what we called the unconstrained dyad format. In what was
initially a very surprising observation, the amygdala-lesioned
monkeys generated significantly greater amounts of affiliative social
behavior towards the stimulus monkeys than the control monkeys.
Control monkeys, when they first met the stimulus monkeys,
demonstrated a typical and appropriate reluctance to engage in social
interactions. They appeared to go though a period of evaluation to
determine the intentions of the other animal. The lesioned monkeys,
in contrast, appeared to be socially uninhibited since they did not go
through the normal period of evaluation of the social partner before
engaging in social interactions.
      The inevitable conclusion from this study is that in dyadic social
interactions, monkeys with extensive bilateral lesions of the amygdala
can interpret and generate social gestures and initiate and receive
more affiliative social interactions than normal controls. In short, they
are clearly not critically impaired in carrying out social behavior. We
would suggest that the lesions have produced a socially uninhibited
monkey since their normal reluctance to engage a novel animal
appears to have been eliminated. This, as well as evidence that the
amygdala-lesioned animals are not fearful of normally fear-inducing

stimuli such as snakes, has led us to the hypothesis that a primary
role of the amygdala is to evaluate the environment for potential
threats or dangers. Without a functioning amygdala, macaque
monkeys do not evaluate other novel conspecifics as potential
adversaries and whatever system(s) are involved in mediating social
interactions run in default mode of approach.

Early Amygdala Lesions do not Eliminate Social Behavior

     One caveat of this conclusion that the amygdala is not essential
for social behavior is that these experiments were carried out in
mature monkeys. One might argue that while the amygdala is not
necessary for generating social behavior, perhaps it is essential for
gaining social knowledge. We have carried out a series of studies in
which the amygdala is lesioned bilaterally in primates at two weeks of
age (Prather et al. 2001). This is at a point in time when infant
macaque monkeys are mainly found in ventral contact with their
mothers and there is virtually no play or other types of social
interactions with other animals. We found that the interactions of the
lesioned animals with their mothers was similar to that of control
animals. Moreover, we found that, like adult animals with bilateral
amygdala lesions, they showed little fear of normally fear-provoking
objects such as rubber snakes. However, they showed increased
fear, as indicated by more fear grimaces and more screams during
novel dyadic social interactions. Most germane to the discussion,
however, is the finding that the lesioned animals generated
substantial social behavior that was similar to that generated by age-

matched controls. In a larger replication study that is currently under
way (Prather et al., unpublished observations 2002) the quality and
quantity of social interactions in a number of social formats is being
investigated and there may be subtle differences in these
parameters. However, the inescapable conclusion from observation
of these animals is that there are none that are markedly impaired in
generating species typical social behaviors such as grooming, play
and facial expressions. All of the animals appear to be visually
attentive of the other animals when they are involved in large “play
groups” comprised of 2 control animals, 2 animals with amygdala
lesions and 2 animals with hippocampal lesions as well as male and
female adult animals. And none appear to have developed motor
stereotypies despite the fact that they have now reached one year of
       The results from studies carried out both in adult and mature
rhesus monkeys with complete bilateral lesions of the amygdala have
forced us to consider the conclusion that the amygdala is not
essential either for interpretation or expression of species typical
social behaviors or for gaining social knowledge. If the amygdala is
not a central component of the Social System, it is unlikely that
pathology of it would lead directly to the impairments of social
behavior that are observed in autism.

Subject S.M.

       There are relatively few human subjects who have bilateral and
discrete lesions of the amygdala. One outstanding exception is

patient S.M. who has been extensively studied by Adolphs and
colleagues (Adolphs et al. 1994, Adolphs et al. 1995). Patient S.M.
suffers from Urbach-Wiethe syndrome that has produced bilateral
space occupying lesions of the amygdala. Interestingly, she is
impaired in her ability to identify fearful faces despite the fact that she
can reliably detect happiness and other emotions in faces. S.M. is
also unable to determine which individuals would typically be
considered untrustworthy based on their facial appearance (Adolphs
et al. 1998).
      Despite these difficulties, patient S.M. leads a reasonably
normal life. She is capable of holding a job, has been married and is
raising children. One is impressed not so much with the deficits in this
subject who has no amygdala but rather by how intact is much of her
everyday behavior, including social behavior. A similar conclusion
can be drawn from patient H.M. who had bilateral temporal
lobectomies for intractable seizures. His surgery has completely
removed the amygdala and rostral half of the hippocampal formation
(Corkin et al. 1997). While H.M. is densely amnesic, he is
nonetheless capable of normal social interactions. And neither he nor
patient S.M. demonstrate typical autistic symptomatology. These
patients would seem to support the contention that the amygdala is
not essential for normal social behavior and that damage to the
amygdala does not necessarily lead to autistic behavior.

Anxiety in Autism

      How does the concept of threat detection figure into the picture
of autism? In Kanner’s (1943) original report on autism, not only did
he describe social and language impairments, but he also highlighted
the anxious behavior exhibited in his initial sample of children. Fear of
threatening events is considered a common experience among
primates and an adaptive response in humans (Reynolds and
Richmond 1994).      Anxiety, on the other hand, is an emotional
response evoked when an individual perceives a situation as
threatening even in the absence of direct danger. We would suggest
that dysregulation of the amygdala might manifest itself in the
individual with autism as alterations either of fear or anxiety. Although
the presence of anxiety has been alluded to in descriptions (American
Psychological Association 1994) and classifications of autism
(Rescorla 1988, Wing and Gould 1979), the characteristics and
pervasiveness of this has not been well studied. However, recent
studies suggest that anxiety is an extremely common feature of the
autism spectrum disorders.
      Muris et al. (1998) examined the presence of co-occurring
anxiety symptoms in 44 children with autism spectrum disorder. The
sample included 15 children with autism, and 29 with pervasive
developmental disorder-not otherwise specified (PDD-NOS). They
found that 84.1% of the children met criteria for at least one anxiety
disorder. In descending order, the percentage of children meeting
diagnostic criteria for an anxiety disorder were as follows: simple
phobia (63.6%), agoraphobia (45.5%), separation anxiety (27.3%),
overanxious (22.7%), social phobia (20.5%), avoidant disorder
(18.2%), obsessive-compulsive disorder (11.4%), and panic disorder

(9.1%). While the authors raised the caveat that anxiety symptoms
were assessed via parental interview, they noted that parents often
underreport internalizing symptoms, such an anxiety.
     More recently, Gillott et al. (2001) compared high-functioning
children with autism to two control groups including children with
specific language impairment and normally developing children on
measures of anxiety and social worry. Children with autism were
found to be more anxious on both indices. In fact, four of the six
factors on the anxiety scale were elevated with obsessive-compulsive
disorder and separation anxiety showing the highest elevations.
     These    studies   do   not   provide   much    insight   into   the
pervasiveness of anxiety in autism. Both clinical and parental reports
indicate that not all children with autism demonstrate symptoms of
anxiety. The DSM-IV summarizes that children with autism may
exhibit “a lack of fear in response to real dangers, and an excessive
fearfulness in response to harmless objects” (APA 1994, p. 68). Wing
and Gould (1979) highlighted the heterogeneity in the occurrence of
anxiety in their classification system. Specifically, the active-but-odd
subtype tend to exhibit extreme reactions to social situations,
whereas the aloof subtype may be completely oblivious to
environmental changes. Rescorla (1988), conducted a factor and
cluster analysis using the Child Behavior Checklist (CBCL,
Achenbach 1991), a general instrument of childhood behavior, to
distinguish boys with autism from other disorders. Among many
differences, the analysis demonstrated that the more severe cases of
autism were distinguished from the milder ones based on the
presence or absence of anxiety.

The Amygdala and Anxiety

     A number of recent studies have provided evidence that the
amygdala may be dysregulated in emotional disorders such as
anxiety and depression (Davidson et al. 1999). Tillfors et al. (2001),
for example, demonstrated increased blood flow in the amygdala in
social phobics anticipating a public presentation. Recently, Thomas et
al. (2001) used fearful faces as probes and demonstrated that the
amygdala of anxious children showed heightened activity in the
amygdala. De Bellis (2000) also showed that the right amygdala of
children with generalized anxiety disorder was larger than age
matched controls. These findings are consistent with the results of
our studies in nonhuman primates in that removal of the amygdala
produced animals that were less fearful of inanimate objects as well
as other monkeys.


     The amygdala has been proposed to play an essential role in
the elucidation of normal social behavior. And, its dysfunction has
been proposed to play a role in the social pathology of autism.
Studies both in the rhesus monkey and data from human subjects
with bilateral lesions of the amygdala indicate that the amygdala is
not essential for many facets of normal social interaction. Rather, it
appears that the amygdala may have a more selective role in
detecting threats in the environment. If this proves to be correct, it

would be unlikely that dysfunction of the amygdala alone could
provide the substrate for the impairments of social interaction that are
a hallmark feature of autism. If, however, the amygdala is indeed
dysfunctional in autism, this could contribute to the abnormalities of
fear and anxiety that appear to be a common feature of autism. If this
were the case, one might expect the amygdala to be hyperfunctional
in autism rather than hypofunctional as predicted by the current
theories of the role of the amygdala in autism.


This original research described in this paper was supported, in part,
by grants from the National Institute of Mental Health and by the base
grant of the California National Primate Research Center. This work
was also supported through the Early Experience and Brain
Development Network of the MacArthur Foundation.

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