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					                                              Schizophrenia Research 86 (2006) 45 – 53
                                                                                                            www.elsevier.com/locate/schres




          Evidence that brain tissue volumes are associated with HVA
                reactivity to metabolic stress in schizophrenia
             Machteld Marcelis a,⁎, John Suckling b , Paul Hofman c , Peter Woodruff d ,
                                   Ed Bullmore e , Jim van Os a,f
a
    Department of Psychiatry and Neuropsychology, South Limburg Mental Health Research and Teaching Network, EURON, Maastricht University,
                                          PO Box 616 (VIJV1), 6200 MD Maastricht, The Netherlands
              b
                Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
                             c
                               Department of Radiology, University Hospital Maastricht, Maastricht, The Netherlands
      d
        Department of Psychiatry, Sheffield Cognition and Neuroimaging Laboratory, Academic Clinical Psychiatry, University of Sheffield,
                                       The Longley Centre, Norwood Grange Drive, Sheffield, S5 7JT, UK
                                            e
                                              Department of Psychiatry, University of Cambridge, UK
                     f
                       Division of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK
                              Received 27 July 2005; received in revised form 1 May 2006; accepted 2 May 2006
                                                        Available online 27 June 2006



Abstract

Background: Although liability to psychosis is thought to have its origins in cerebral alterations, expressed as cerebral grey and
white matter loss, less is known about the degree to which such vulnerabilities impact on functional parameters, in particular altered
stress reactivity. Breier et al. [Breier, A., Davis, O.R., Buchanan, R.W., Moricle, L.A., Munson, R.C., 1993b. Effects of metabolic
perturbation on plasma homovanillic acid in schizophrenia. Relationship to prefrontal cortex volume. Arch. Gen. Psychiatry 50(7),
541–550] reported that lower prefrontal cortex volume was associated with altered metabolic stress response, but this finding has
never been replicated.
Methods: Thirty-one patients with psychosis underwent structural magnetic resonance imaging scanning and a metabolic stress
paradigm (glucoprivic 2-deoxyglucose (2DG) condition versus placebo condition) that yielded information on plasma
homovanillic acid (HVA) reactivity. Total cerebral tissue volumes were derived from automated segmentation procedures.
Associations between metabolic stress and tissue volumes (as well as their interactions) on the one hand, and plasma HVA level on
the other, were investigated using multilevel random regression techniques.
Results: Analysis revealed a significant increase in plasma HVA over time in the 2DG condition. The increase in HVA in the stress
condition was stronger in patients with lower grey and white matter volumes. There was no significant interaction between
metabolic stress and CSF volume.
Conclusion: Lower grey and white matter volumes in schizophrenia are associated with a dysregulated dopaminergic/noradrenergic
mediated stress response. These findings may support the hypothesis that alterations in cortico-subcortical connections affect
psychosis susceptibility through an altered stress response.
© 2006 Elsevier B.V. All rights reserved.

Keywords: Schizophrenia; Brain alteration; Magnetic resonance imaging; Metabolic stress; Homovanillic acid; Dopamine




    ⁎ Corresponding author. Tel.: +31 43 3688679/666; fax: +31 43 3688689.
      E-mail address: m.marcelis@sp.unimaas.nl (M. Marcelis).

0920-9964/$ - see front matter © 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2006.05.001
46                                   M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53


1. Introduction                                                       with patients showing an increased dopamine (DA)/
                                                                      noradrenaline (NA) response compared to controls
    The liability to schizophrenia is thought to have its             (Marcelis et al., 2004). The aim of the present inves-
origins in cerebral alterations, expressed as structural              tigation was to independently replicate the earlier
abnormalities such as reductions in total brain volume,               findings of a relationship between brain tissue and the
and grey and white matter volume (Wright et al., 2000).               HVA response to metabolic stress (Breier et al., 1993b),
However, very little is known about how such                          but now in a much larger sample.
vulnerabilities impact on functional measures, in partic-                 We hypothesized that functional cerebral vulnerabil-
ular the response to stress.                                          ity, conceptualized in terms of heightened DA/NA
    The altered stress response in schizophrenia is                   responsivity during 2DG perturbation is associated with
thought to be associated with the process of dopamine                 changes in brain structure in psychosis. Increasing
sensitization, referring to hyperresponsiveness of DA                 evidence indicates that temporolimbic–prefrontal dys-
neurons to environmental stimuli, in which exposure to                function in schizophrenia is associated with enhanced
even moderate levels of stress are associated with an                 subcortical dopamine release (Heinz et al., 2003).
excessive DA response (Davis et al., 1991; Glenthoj,                  Alterations in the capacity of a stress buffering system,
1995; Laruelle, 2000; Laruelle and Abi-Dargham,                       such as prefrontal dopaminergic function, may result
1999). In schizophrenia, a dysregulated, hyperdopami-                 from aberrant development of cortical cytoarchitecture
nergic state may lead to stimulus-independent release of              (Weinberger and Lipka, 1995). During mild stress,
dopamine and to aberrant assignment of salience to                    dopamine release and metabolism is preferentially
experiences, which may serve as a framework for the                   increased in the mesocortical system, compared to the
emergence of psychotic symptoms (Kapur, 2003).                        mesolimbic and nigrostriatal systems. This increase in
    An experimental paradigm to examine perturbation                  prefrontal dopamine following mild stress is thought to
on dopamine function following stress exposure                        inhibit subcortical dopamine transmission, thereby
involves glucose deprivation by intravenous infusion                  providing protection against positive symptoms (Deutch
of 2-deoxyglucose (2DG) (Breier, 1989; Breier et al.,                 et al., 1990; Vermetten and Bremner, 2002). By
1992b; Mitropoulou et al., 2004). The glucose-analog                  impacting negatively on mesocortical dopamine func-
2DG causes glucoprivation by competing with glucose-                  tion, reduced cortical volume in schizophrenia may thus
6-phospate during the early stage of glycolysis and                   affect the stress-buffering system and lead to increases
inhibits intracellular glucose utilization. As glucose is             in subcortical dopamine activity following even mild
the primary energy source for the central nervous                     stressors (Laruelle, 2000).
system, disruption of glucose metabolism is a potent                      Dysfunctional connections between the cortex and
CNS stressor. This metabolic stress paradigm has been                 the midbrain may be reflected by white matter
found to produce robust activation of the hypothalamic–               reduction. We tested whether reduced cerebral grey
pituitary–adrenal (HPA) axis, as well as elevations of                and white matter is associated with an increased DA/
epinephrine and of behavioral (stress/anxiety) and                    NA-mediated stress response following 2DG-adminis-
physiologic (heart rate/blood pressure) measures (Breier              tration in patients with psychosis.
et al., 1992b; Elman et al., 1999). Moreover, it strongly
affects central and peripheral dopamine function, as well             2. Methods
as the plasma levels of homovanillic acid (HVA), a
breakdown product of dopamine as well as noradren-                    2.1. Study sample
aline. Plasma HVA, although largely derived from the
periphery, is thought to reflect, at least partly, the central           The patient sample is part of the Maastricht
dopamine response to stress (Breier, 1989; Breier et al.,             Psychosis Study (Marcelis et al., 2003a,b, 2004). MRI
1993b).                                                               and HVA data were available for 31 out of 50 patients
    Measuring plasma HVA repetitively during metabolic                with psychosis.
stress, Breier et al. (1993b) not only found that patients               Patients between 16 and 55 years with a life-time
with schizophrenia had significantly greater 2DG-                     history of psychosis according to the RDC criteria
induced plasma HVA elevations as compared to controls,                (Spitzer et al., 1978), who were not currently in need of
but also that these elevations in HVA levels were                     in-patient treatment, intensive case management home
associated with lower prefrontal cortex volumes. In a                 care, or case management crisis intervention, were
recent study using the same paradigm, this finding of                 recruited at the community mental health center in
altered stress response in schizophrenia was replicated,              Maastricht, the Netherlands.
                                   M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53                              47


   Other inclusion criteria included being in good                  was generated from linear scale-space features derived
health, as determined by a physical examination,                    from the PD weighted images (Suckling et al., 1999a).
electrocardiography, and routine laboratory investiga-              Each voxel in the mask was then categorised in terms of
tions. Individuals with a history of severe head trauma,            the proportion occupied by grey matter, white matter,
neurological disorders, and/or other medical disorders              CSF or dura/blood vessels. This algorithm partitioned
that might have significantly affected brain function or            the feature space formed by the two MR echoes (PD and
structure were excluded, as well as individuals who used            T2-weighting), using a four-class modified fuzzy
alcohol in excess of five standard units per day or illicit         clustering scheme, and assigned continuous member-
drugs on a weekly basis.                                            ship of each tissue class to every voxel (Suckling et al.,
   The study was approved by the local medical ethics               1999b). Axial non-uniformity of image contrast, due to
committee, and all the subjects gave written informed               the reduction in sensitivity at the edges of the
consent in accordance with the committee's guidelines.              transmitting/receiving coil, was corrected with a moving
                                                                    window scheme. Classifying data in this manner allows
2.2. Clinical and diagnostic procedures                             for changes in the distribution of voxels in feature space.
                                                                    For a detailed description, see Suckling et al. (1999b).
   Patients were interviewed with the Life Chart (WHO,              Total cerebral tissue volumes were obtained by
1992), BPRS (Lukoff et al., 1986; Overall and Gorham,               summing over all proportions and multiplying by
1962), the PANNS (Kay et al., 1987, 1988) and were                  voxel volume.
additionally screened for symptoms listed in the OCCPI
(McGuffin et al., 1991). The computerised program                   2.4. Metabolic stress paradigm (2-deoxy-glucose
OPCRIT (McGuffin et al., 1991) yielded the following                protocol)
RDC-diagnoses: schizophrenia (n = 25) and schizo-
affective disorder (n = 6). To determine life-time history              A full description of this paradigm applied to a larger
of alcohol and drug use, the Composite International                sample can be found elsewhere (Marcelis et al., 2004).
Diagnostic Interview (CIDI) (Smeets and Dingemans,                  In brief, all subjects underwent double-blind adminis-
1993) was administered. All current medications were                tration of the glucose analog 2DG and placebo, in
recorded.                                                           randomized order. The 2DG doses were 50 mg/kg
                                                                    mixed in 100 ml of isotonic saline. Placebo was a
2.3. Image acquisition and processing                               comparable volume of isotonic saline (NaCl, 0.9%).
                                                                    Both conditions (2DG/placebo) were given within one
2.3.1. Image acquisition                                            week, with at least two days in between. Subjects had to
    MRI scans were obtained at the Department of                    fast from midnight prior to both test days and were
Radiology, University Hospital Maastricht, The Nether-              allowed to drink only water ad libitum. During the test,
lands, with a Gyroscan NT T-I1 (Philips Medical                     subjects rested supine in bed from 8:45 a.m. until 12:30
Systems) operating at 1.5 T. Three millimetre thick                 p.m. At 8:45 a.m., an intravenous catheter was inserted
interleaved two-dimensional dual-echo fast spin-echo                in the antecubital fossa and kept patent with a slow drip
images (60 slices, 0.3 mm gap between slices) were                  of isotonic saline. At 9:50 a.m., two baseline venous
acquired and angled parallel to the clivus, covering the            blood samples were taken 10 min and 0 min prior to
entire brain. Proton density (PD) weighted and T2-                  infusion. At 0 min, 2DG or placebo was infused over a
weighted images were acquired simultaneously (echo                  period of 20 min. Four more blood samples were taken
time (TE)1 = 20 ms, TE2 = 100 ms, TR = 4000 ms, echo                at 60 min, 90 min, 120 min and 150 min after the
train length: 6, total acquisition time: 10 min 12 s). The          infusion was started.
matrix size and field of view was set at 256 × 205 and                  Blood was collected in tubes containing 0.5 ml of
22 cm, respectively. The number of signal averages                  an EDTA (40 mg/ml) and Na2S2O5 (20 mg/ml)
was 1.                                                              solution. Plasma was obtained by centrifugation
                                                                    (15 min at 3000 rpm) in a refrigerated centrifuge
2.3.2. Image processing                                             (5 °C) and was then stored at − 80 °C until assaying. A
   Image processing and computations were done on a                 515 WATERS isocratic HPLC was used for assaying
SUN Ultra10 (Sun MicroSystems Inc., Mountain View,                  HVA, with a Symmetryshield RP18 25 cm column for
CA, USA) workstation with the BAMM software (Brain                  the separation of the compounds. Intra-assay variability
Activation and Morphological Mapping, University of                 was 5% for HVA. Inter-assay variability was 9% for
Cambridge, UK). Initially, a mask of parenchymal tissue             HVA.
48                                M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53


2.5. Statistical analyses

   The data were analyzed with the STATA computer
program, version 8 (StataCorp., 2001). The variable
“condition” had two levels: the placebo condition
(reference) and the 2DG condition. HVA was sampled
on six occasions (time 1–6). Time points 1–6 were
divided into the variables timeA (time 1–2) and timeB
(time 3–6) reflecting the two pre- and the four post-
infusion measurement occasions. TimeB served as the
independent variable of interest, with timeA as covariate
to control for baseline values. The mean HVA level of              Fig. 1. Effects of 2-deoxy-glucose and placebo on plasma HVA (ng/
                                                                   ml) in 31 patients with psychosis. Data points represent mean plasma
the two pre-infusion samples for each person and each
                                                                   HVA levels. Time 1 and 2 reflect the two pre-infusion (baseline)
condition was used to construct a baseline HVA variable            occasions on which plasma HVA was measured (i.e., 10 min and 0 min
(HVA_base) (Marcelis et al., 2004).                                prior infusion). Times 3–6 reflect the four post-infusion sampling
   To investigate the effect of global tissue volume on            occasions: respectively, 60 min, 90 min, 120 min, and 150 min post-
HVA during metabolic stress, multilevel linear regres-             infusion. The increase in HVA over time in the 2DG condition
                                                                   compared to the placebo condition was statistically significant
sion analyses (see below) were conducted with HVA as
                                                                   (condition × timeB interaction term, Likelihood Ratio Statistic (LRS)
the dependent variable and tissue volume, condition,               = 84.93, p < 0.001).
timeB, as well as their interactions, as independent
variables. In addition, HVA-baseline, timeA, age, sex
and total brain volume were added as covariates to adjust          (SD: 63.4); for CSF: 169.2 cm3 (SD: 32.0). Total cere-
for their a priori hypothesized confounding effects.               bral brain volume (grey + white + CSF volume) was
   As the average measure of HVA is assumed to vary                1274.1 cm3 (SD: 127.2). Mean levels of HVA (ng/ml) at
across persons, two observations will be more similar if           the six measurement points during the stress and
they are from the same person. Our design of repeated              placebo condition are presented in Fig. 1.
measures within the same person therefore compro-                     There was no evidence for an effect of antipsychotic
mised statistical independence of the observations. In             medication dosage (expressed as standard haloperidol
order to deal with this issue, multilevel random                   equivalents) on brain tissue volume (β for grey matter:
regression models were fitted (Goldstein, 1987) with               1.01, 95% CI: − 3.19–5.21; β for white matter:− 3.52,
the XTREG module in STATA. The β is the fixed                      95% CI:− 7.9–0.86; β for CSF: 2.5, 95% CI:− 1.08–
regression coefficient of the predictor in the multilevel          6.10).
model and can be interpreted identically to the estimate
in a unilevel regression analysis. Interaction terms were          3.2. Association between global tissue volumes and
evaluated by Likelihood Ratio test.                                HVA level changes during metabolic stress

3. Results                                                             There was a significant effect of condition on HVA
                                                                   (β = 1.54, p < 0.001). In addition, a significant condi-
3.1. Subjects and descriptives                                     tion × timeB interaction was found (Likelihood Ratio
                                                                   Statistic (LRS) = 84.93, p < 0.001), indicating an in-
    The sample consisted of 15 men and 16 women. The               crease in HVA over time in the 2DG condition compared
mean age was 30.7 years (S.D.: 7.4) and mean age of                to the placebo condition.
first psychotic symptoms was 22.1 years (S.D.: 5.8).                   In Fig. 2A, HVA level differences between the stress
The mean duration of illness was 8.6 years (S.D.: 5.7).            and placebo condition at the six measurement points
Twenty-eight patients were receiving antipsychotic                 are depicted for three grey matter volume groups,
medication (atypical: n = 15; typical: n = 13). Mean               suggestive of interaction. This hypothesis was exam-
current dosage in terms of standard haloperidol                    ined statistically by fitting a three-way interaction
equivalents was 4.99 (S.D.: 3.06). Of the 28 patients,             between grey matter volume, condition, and time B,
12 patients also used a benzodiazepine, and 4 used an              which yielded a significant negative grey matter × con-
antidepressant.                                                    dition × timeB interaction (β = − 0.0036, p < 0.021). This
    Mean tissue volumes were, for grey matter:                     negative interaction indicates that the increase in HVA
559.5 cm3 (SD: 64.0); for white matter: 545.4 cm3                  in the stress condition was stronger in patients with
                                             M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53                                49


                                                                               HVA during stress was measured in the group with the
                                                                               highest white matter volumes, plotting of HVA level
                                                                               differences between 2DG and placebo conditions over
                                                                               time separately for each tertile of white matter did not
                                                                               reveal a dose–response relationship (Fig. 2B).
                                                                                  For the measure of CSF volume, no significant
                                                                               CSF × condition × timeB interaction was apparent, al-
                                                                               though the direction of the effect was similar (β =
                                                                               − 0.0008, p < 0.80).
                                                                                  In order to examine whether the effect of grey matter
                                                                               volume was independent of white matter volume and
                                                                               vice versa, both interaction terms were entered in the
                                                                               analyses, which reduced both the effect size and
                                                                               statistical significance of the interaction with grey
                                                                               matter volume, as well as of the interaction with white
                                                                               matter volume (grey matter × condition × timeB: β =
                                                                               − 0.0027, p < 0.19; white matter × condition × timeB:
                                                                               β = −0.00149, p < 0.47). This suggests that the effects
                                                                               of grey and white matter volume on HVA reactivity are
                                                                               correlated.

                                                                               4. Discussion

                                                                                   Total grey and white matter volume in patients with
                                                                               psychotic disorder were negatively associated with HVA
                                                                               reactivity during metabolic stress, suggesting that
                                                                               reduced grey and white matter volume lead to an
                                                                               enhanced DA/NA-mediated stress response. CSF was
                                                                               not significantly associated with HVA reactivity,
Fig. 2. These figures reflect the differences in mean plasma HVA levels
(ng/ml) between the two conditions (i.e., 2DG and placebo condition),
                                                                               suggesting that altered CSF volume does not affect the
stratified by brain volume group. The lines in the figure in (A) indicate      DA/NA-mediated stress response.
three grey matter tertiles and the lines in the figure in (B) indicate three       The metabolic stress paradigm has been used
white matter tertiles: lowest volume group (open squares), middle              previously in preclinical and clinical studies. For
volume group (closed squares), and highest volume group (closed                example, studies in rats and healthy volunteers have
triangle). Time 1 and time 2 reflect the two pre-infusion (baseline)
sampling occasions (i.e., 10 min and 0 min prior infusion). Times 3–6
                                                                               shown a 2DG-induced increase in cerebral blood flow to
reflect the four post-infusion measurement points at, respectively,            multiple cortical and subcortical regions (Breier et al.,
60 min, 90 min, 120 min, and 150 min post-infusion.                            1993a; Elman et al., 1999), as well as a 2DG-induced
                                                                               increase in striatal dopamine release using [11C] PET in
                                                                               healthy subjects (Adler et al., 2000). The paradigm was
lower grey matter volume than in patients with higher                          first applied to patients with schizophrenia by Breier et
grey matter volume. Adjustment for age, sex, total                             al. (Breier, 1989; Breier et al., 1993b), and their findings
brain volume, and medication dosage did not affect the                         of altered HVA reactivity in this patient group have
results (β = − 0.0041, p < 0.005).                                             recently been replicated in a larger sample (Marcelis et
   For white matter volume, a significant negative white                       al., 2004).
matter × condition × timeB interaction was found (β =                              The association between grey matter volume and
− 0.0032, p < 0.046), indicating that the increase in HVA                      HVA reactivity to metabolic stress is consistent with a
during metabolic stress was stronger in patients with                          prior report on the relationship between decreased grey
lower white matter volume than in patients with higher                         matter volume in the prefrontal cortex and excessive
white matter volume. Adjustment for age, sex, total                            HVA release in patients with schizophrenia, measured
brain volume and medication dosage did not change                              during similar stress conditions (Breier et al., 1993b). In
effect size and associated significance level (β =                             a sample of three times as many patients, and for the first
− 0.0031, p < 0.039). Although the smallest increase in                        time since the publication of Breier more than 10 years
50                                 M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53


ago, these findings have now been independently                     dopamine release by loss of cortical control). This
replicated by the present study, in that reduced cerebral           mechanism is thought to be more pronounced during
grey matter alterations were associated with increased              perturbing than during resting conditions (Breier et al.,
plasma HVA levels during 2DG administration. Al-                    1993b).
though subregions of grey matter such as the prefrontal                 However, as the present study yielded only indirect
cortex were not examined, the present investigation                 evidence by examining global tissue volumes in
extends the earlier findings (Breier et al., 1993b) by              relation to the DA/NA mediated stress response, this
investigating not only grey matter in relation to the               hypothesized dysfunctional neurocircuit involved in
stress measure, but also white matter and CSF.                      stress regulation needs to be more directly tested using
    White matter provides the physiological basis for               techniques such as positron emission tomography
cortico-cortical and subcortico-cortical connections                (PET) and single photon emission tomography
and there is accumulating evidence for abnormal                     (SPECT). Dopamine receptor imaging studies have
connectivity in schizophrenia (Friston and Frith, 1995;             already produced direct evidence for a cortical origin
Hubl et al., 2004). Recent investigations into the                  of the upregulated striatal dopamine function in
organization of cerebral white matter are indicative of             schizophrenia (Kapur and Lecrubier, 2003). Whether
deficient intra- and interhemispheric connectivity in               the hypothesized DA dysregulation is reflective of a
patients with schizophrenia (Burns et al., 2003;                    state, of a trait, or the combination of trait/state also
Hulshoff Pol et al., 2004; Kubicki et al., 2003; Zhou               warrants further investigation. Recent evidence sug-
et al., 2003). The present results showed that                      gests that both components are involved: a state
decreased white matter volume was associated with                   component associated with psychotic exacerbations
an enhanced DA/NA mediated stress response,                         and a trait component present in remitted patients and
although the evidence was less strong than for grey                 in schizophrenia spectrum disorder (Abi-Dargham et
matter and might plausibly be attributed to the                     al., 2004).
correlation between grey and white matter. Despite                      CSF volume, in contrast to grey and white matter
the lack of clarity concerning the exact relationship               volume, was not associated with altered HVA reactivity.
between grey and white matter, reductions in these                  This suggests that altered CSF volume is not part of the
tissue volumes were associated with excessive DA/NA                 same neurobiological substrate that leads to an enhanced
release following metabolic stress.                                 central stress response.
    Reduced grey matter may reflect widespread (in-
cluding prefrontal) cortical volume loss. White matter              4.1. Methodological considerations
reduction may indicate impairments in the connections
between the (prefrontal) cortex and subcortical struc-                  Much of the plasma HVA originates from central and
tures. The present findings may fit the model postulating           peripheral noradrenaline (NA) systems. Even under
that stress-induced increases in mesocortical prefrontal            fasting conditions, around 75% of plasma HVA derives
dopamine activity are involved in regulating subcortical            from NA neuronal metabolism (Kopin et al., 1988).
dopamine activity, by exerting an inhibitory influence              Nevertheless, plasma HVA changes also reflects central
on striatal dopamine. Indeed, reduced grey matter                   dopamine (DA) activity (Amin et al., 1992), or can at
volume in schizophrenia may impact on cortical                      least be regarded as a central response to stress (Marcelis
dopamine function and diminish its “brake” function                 et al., 2004).
on the striatal dopamine system, resulting in excessive                 Global tissue volumes, and not specific brain areas,
release of striatal dopamine following even mild stress             were investigated in relation to stress reactivity. In a
(Laruelle, 2000). The aberrant stress regulation system             meta-analysis, decreases in grey matter of around 2%
in schizophrenia may be the consequence of primary                  and in white matter of around 1% have been found in
deficits of the prefrontal cortex, but could be the result          patients versus controls (Wright et al., 2000). Although
of abnormal inputs due to alterations in other regions              these grey and white matter changes are not equally
such as mesotemporal structures, which are often found              distributed but are more pronounced in certain areas
to be affected in schizophrenia (Breier et al., 1992a;              than in others, they are not specific to any particular
Heinz et al., 2003).                                                brain area, and findings regarding sub-areas of the brain
    Thus, grey and white matter deficits may mediate the            are not as consistent as the findings regarding global
altered HVA response to stress, assuming that these                 grey and white matter changes. Thus, changes in global
global tissue alterations reflect dysfunctional cortico-            tissue volumes are among the most robust in the
subcortical circuitry (i.e., dysinhibition of striatal              literature and are arguably most suitable in the search for
                                   M. Marcelis et al. / Schizophrenia Research 86 (2006) 45–53                                           51


associations between brain measures and clinical                    4.2. Conclusion
variables.
    A possible shortcoming of the current study is the                  This investigation explored whether changes in brain
absence of a control group which precludes definite                 structure in schizophrenia may affect central nervous
conclusions as regards the relevance of the findings for            system functioning through a dysregulated dopaminer-
schizophrenia. However, investigating the functional                gic stress response. The robust measures of grey and
correlate of a structural brain abnormality is relevant             white matter volume, but not CSF volume, were
and biologically plausible in a population that is known            negatively associated with the central stress response.
to exhibit the abnormality in question (i.e., individuals           The findings support the hypothesis that compromised
with schizophrenia). This was our rationale for                     neurocircuits, in terms of dysfunctional cortico-subcor-
examining the association between tissue volumes and                tical connections, may provide the anatomical basis for
stress-induced plasma HVA in patients only, similar to              stress-induced increases in striatal dopamine, which
the approach used in a previous report on the                       may consequently affect psychosis susceptibility. Neu-
association between prefrontal cortex volume and                    roreceptor imaging techniques, such as PET and SPECT,
2DG-induced HVA increase in patients with schizo-                   which can be used to more directly assess regional
phrenia (Breier et al., 1993b). Moreover, the present               cerebral dopamine concentrations and fluctuations
findings have face validity, in that they replicate and             therein provide the tools to further test this hypothetical
support findings and hypotheses previously described in             pathway mediating the central stress response.
the literature (Breier et al., 1993b; Kapur and Lecrubier,
2003).                                                              Acknowledgements
    Almost all patients were taking an antipsychotic
medication that influences dopamine levels. However,                   This study was supported by the Dutch Brain Society
patients with schizophrenia have a much stronger HVA                and the Dutch Prevention Fund.
increase than controls during 2-DG exposure, indicating                We thank Truda Driesen for her assistance in data
that (chronic) antipsychotic treatment does not preclude            collection.
stress-induced increases in dopamine function (Breier et
al., 1993b; Marcelis et al., 2004). Moreover, antipsy-              References
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