Cingulate gyrus neuroanatomy in schizophrenia subjects and their non-psychotic siblings.
ABSTRACT In vivo neuroimaging studies have provided evidence of decreases in the gray matter volume of the cingulate gyrus in subjects with schizophrenia as compared to healthy controls. To investigate whether these changes might be related to heritable influences, we used high-resolution magnetic resonance imaging and labeled cortical mantle distance mapping to measure gray matter volume, as well as thickness and the area of the gray/white interface, in the anterior and posterior segments of the cingulate gyrus in 28 subjects with schizophrenia and their non-psychotic siblings, and in 38 healthy control subjects and their siblings.
There was a significant effect of group status on posterior cingulate cortex (PCC) gray matter volume (p=0.02). Subjects with schizophrenia and their non-psychotic siblings showed similar reductions of gray matter volume (approximately 10%) in the PCC compared to healthy control subjects and their siblings. In turn, trend level effects of group status were found for thickness (p=0.08) and surface area (p=0.11) of the PCC. In the combined group of schizophrenia subjects and their siblings, a direct correlation was observed between PCC gray matter volume and negative symptoms. However, the reduction in PCC gray matter volume in schizophrenia subjects and their siblings was proportionate to an overall reduction in whole cerebral volume, i.e., the effect of group on the volume of the PCC became non-significant when cerebral volume was included as a covariate (p=0.4). There was no significant effect of group on anterior cingulate cortex volume, thickness, or area.
Our findings suggest that decreases in the gray matter volume of the PCC occur in schizophrenia subjects and their siblings. The presence of such decreases in the non-psychotic siblings of schizophrenia subjects suggests that heritable factors may be involved in the development of cortical abnormalities in schizophrenia.
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ABSTRACT: We examined gray- and white-matter brain volumes in first episode psychosis (FEP) at initial presentation and at two-year follow-up. We predicted that FEP subjects would show longitudinal reductions in fronto-temporal gray- and white-matter volumes compared with controls. Furthermore, we expected groups to be differentiated by diagnosis-related reductions. Twenty-five schizophrenia and 8 bipolar disorder FEP patients underwent a structural MRI scan at first presentation and 2 years later. Matched healthy subjects (n = 22) underwent a single identical scan. At initial presentation FEP subjects had significantly less gray- and white-matter than healthy subjects. Diagnostic dissociations were revealed both at first presentation and at follow-up. In schizophrenia patients, gray-matter deficits were observed in lateral and medial frontal regions and in bilateral posterior temporal lobe regions, with additional extensive losses over time in lateral fronto-temporal regions and left anterior cingulate gyrus. By contrast, gray matter deficit in bipolar patients was localized to bilateral inferior temporal gyri with additional loss over time observed only in the anterior cingulate cortex. The results are consistent with a dual process model of psychosis, in which the diagnosis-related gray matter loss is determined by neurodevelopmental gray-matter volumetric differences which predate symptom onset, and diagnosis-related neurodegenerative gray-matter loss over time.Biological Psychiatry 12/2005; 58(9):713-23. · 9.25 Impact Factor
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ABSTRACT: The view that schizophrenia is a brain disease particularly involving decrements in gray matter is supported by findings from many imaging studies. However, it is unknown whether the (progressive) loss of tissue affects the brain globally or whether tissue loss is more prominent in some areas than in others. Magnetic resonance whole brain images were acquired from 159 patients with schizophrenia or a schizophreniform disorder and 158 healthy subjects across a 55-year age span. Gray matter density maps were made and analyzed using voxel-based morphometry. Compared with healthy subjects, decreases in gray matter density were found in the left amygdala; left hippocampus; right supramarginal gyrus; thalamus; (orbito) frontal, (superior) temporal, occipitotemporal, precuneate, posterior cingulate, and insular cortices bilaterally in patients with schizophrenia or schizophreniform disorder. Compared with healthy subjects, increases in gray matter density were exclusively found in the right caudate and globus pallidus in patients with schizophrenia or schizophreniform disorder. A group-by-age interaction for density was found in the left amygdala, owing to a negative regression slope of gray matter density on age in the left amygdala in patients compared with healthy subjects. Gray matter density is decreased in distinct focal areas in the brains of patients with schizophrenia or schizophreniform disorder. The decreased density in the left amygdala is more pronounced in older patients with schizophrenia.Archives of General Psychiatry 01/2002; 58(12):1118-25. · 13.77 Impact Factor
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ABSTRACT: Deficits in the volume of the thalamus have been observed in both individuals with schizophrenia and their nonpsychotic relatives. However, no studies to date have examined the underlying pattern of thalamic shape change in relatives of individuals with schizophrenia. This study examined the volume and shape of the thalamus in schizophrenia subjects, their siblings, and healthy control individuals. T1-weighted magnetic resonance scans were collected in a group of young subjects with schizophrenia (mean age, 23 years) and their nonpsychotic siblings (n = 25 pairs), and control subjects and their siblings (n = 40 pairs). Thalamic surfaces were generated using high-dimensional brain mapping. A canonical weighting function was derived from the contrast between schizophrenia and control subjects and then used to generate a canonical shape score for all subjects. Maps of the estimated surface displacement between groups were also created to visualize the thalamic shape differences between groups. The thalamic canonical scores of the siblings of the schizophrenia probands were intermediate between the probands and healthy control subjects. These siblings also displayed an intermediate degree of the inward surface deformation of the anterior and posterior thalamus that was present between schizophrenia probands and controls. There was no main effect of group status on thalamic volume and no significant correlations of the structural measures with measures of psychopathology or cognitive function. Our results indicate that thalamic shape abnormalities are present in relatively young individuals with schizophrenia and their siblings. Inward deformation of the anterior and posterior regions of the thalamus represents a potential neuroanatomical endophenotype of schizophrenia.Journal of Neuroscience 01/2008; 27(50):13835-42. · 6.91 Impact Factor
Cingulate gyrus neuroanatomy in schizophrenia subjects
and their non-psychotic siblings
Daniel R. Calabresea, Lei Wangf, Michael P. Harmsa, J. Tilak Ratnanatherd,e,
Deanna M. Barcha,c, C. Robert Cloningera, Paul A. Thompsonb,
Michael I. Millerd,e, John G. Csernanskye,⁎
aDepartment of Psychiatry, Washington University School of Medicine, St. Louis, MO, United States
bDivision of Biostatistics, Washington University School of Medicine, St. Louis, MO, United States
cDepartment of Psychology, Washington University, St. Louis, MO, United States
dCenter for Imaging Science, The Johns Hopkins University, Baltimore, MD, United States
eInstitute for Computational Medicine, The Johns Hopkins University, Baltimore, MD, United States
fDepartment of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, United States
Received 5 March 2008; received in revised form 10 June 2008; accepted 16 June 2008
Available online 9 August 2008
Background and methods: In vivo neuroimaging studies have provided evidence of decreases in the gray matter volume of the
gyrus in 28 subjects with schizophrenia and their non-psychotic siblings, and in 38 healthy control subjects and their siblings.
Results: There was a significant effect of group status on posterior cingulate cortex (PCC) gray matter volume (p=0.02). Subjects with
control subjects and their siblings. In turn, trend level effects of group status were found for thickness (p=0.08) and surface area
gray matter volume and negative symptoms. However, the reduction in PCC gray matter volume in schizophrenia subjects and their
siblings was proportionate to an overall reduction in whole cerebral volume, i.e., the effect of group on the volume of the PCC became
cortex volume, thickness, or area.
Conclusions: Our findings suggest that decreases in the gray matter volume of the PCC occur in schizophrenia subjects and their
involved in the development of cortical abnormalities in schizophrenia.
© 2008 Elsevier B.V. All rights reserved.
Keywords: Cingulated; Schizophrenia; Volume; Thickness; Cortex; Sibling; Depth mapping
Available online at www.sciencedirect.com
Schizophrenia Research 104 (2008) 61–70
⁎Corresponding author. Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, 446 E.
Ontario, 7-200, Chicago, IL 60611, United States. Tel.: +1 312 926-2323; fax: +1 312 926 8080.
E-mail address: email@example.com (J.G. Csernansky).
0920-9964/$ - see front matter © 2008 Elsevier B.V. All rights reserved.
Post-mortem studies of the brains of individuals with
schizophrenia have provided evidence of abnormalities
in the neuroanatomical architecture of the cortex, espe-
cially the cingulate gyrus (Benes et al., 1991; Benes
1991; Benes and Bird 1987; Benes et al., 2001; Chana
et al., 2003; Dolan et al., 1995; Todtenkopf et al., 2005).
In turn, in vivo neuroimaging studies comparing indi-
viduals with schizophrenia to healthy controls have
shown evidence of decreased gray matter volume in the
anterior cingulate gyrus (Ha et al., 2004; Job et al., 2002;
Shapleske et al., 2002; Sigmundsson et al., 2001), the
posterior cingulate gyrus (Hulshoff Pol et al., 2001;
(Mitelman et al., 2003; Narr et al., 2005; Wang et al.,
2007). These abnormalities may be relevant to the cog-
nitive disturbances associated with schizophrenia, as the
cingulate gyrus is involved in a variety of cognitive
functions, including error detection (anterior cingulate
gyrus) and spatial memory (posterior cingulate gyrus),
which are known to be disturbed in schizophrenia (Ga-
However, the causes of such changes, more specifically
whether they are due to heritable or environmental in-
fluences associated with the disorder, are unknown.
a neurobiological abnormality associated with schizophre-
nia may be examined by studying relatives of individuals
is heritable in the general population and related to a
heritable vulnerability to develop the disorder, one would
expect it to be present in an attenuated form in the siblings
of schizophrenia subjects (Cardno et al., 1999). For ex-
ample, the non-psychotic siblings of individuals with schi-
zophrenia demonstrate attenuated impairments in several
elements of neurocognitive function (Cannon et al., 1994;
Delawalla et al., 2006; Karlsgodt et al., 2007), and studies
of brain structures among the first-degree relatives of
schizophrenia subjects are also consistent with this hypo-
2003; Harms et al., 2007; Staal et al., 1998).
In the present study, we examined the gray matter
volume, thickness and area of the anterior and posterior
psychotic siblings. We selected the cingulate gyrus as a
cortical region of interest for this study because we pre-
associated cortical thinning in schizophrenia subjects
(Wang et al., 2007). Moreover, neurocognitive functions
relevant to the cingulate gyrus (e.g., attention) have been
observed to be impaired in the relatives of patients with
schizophrenia (Cannon et al., 1994). Finally, measures of
cortical structure have been found to be heritable in the
general population (Lenroot et al., 2007). Therefore,
given these prior observations, we hypothesized that the
non-psychotic siblings of individuals with schizophrenia
would demonstrate cingulate gyrus gray matter volumes
and thicknesses intermediate between their affected sib-
lings and the healthy control subjects.
The subjects included in this study were drawn from a
larger population of 216 subjects who volunteered for
studies ofbrain structure andfunctionatthe Conte Center
for the Neuroscience of Mental Disorders at Washington
University School of Medicine in St. Louis. The study
University School of Medicine. Subjects consisted of
non-psychotic siblings (n=28 pairs), and healthy control
subjects and their siblings (n=38 pairs), matched for age,
race, and parental socioeconomic status (Table 1). This
common) with the cohort used in our previous reports on
the thalamus (Harms et al., 2007) and basal ganglia
(Mamah et al., 2008).
All subjects gave informed consent after the risks and
benefits of participation were explained. Using the Diag-
nostic and Statistical Manual for Mental Disorders —
tion 1994), all subjects were diagnosed on the basis of the
consensus of a psychiatrist who conducted a semi-struc-
tured interview and a specially-trained research assistant
who used the Structured Clinical Interview for the DSM-
DSM-IV criteria for schizophrenia, while the healthy
comparison subjects had no lifetime history of DSM-IV
psychotic or major mood disorders (i.e., major depressive
clinically stable for at least two weeks prior to their
participation. Subjects in any group were excluded if they
met DSM-IV criteria for substance abuse or dependence
within the month preceding assessment, met DSM-IV
criteria for mental retardation, had a severe or unstable
medical disorder, or had a head injury with neurological
sequelae or loss of consciousness.
The siblings of the schizophrenia subjects were exclu-
ded if they had a lifetime history of a DSM-IV psychotic
62D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
disorder, but not other DSM-IV disorders. Therefore, the
comparison group to control for possible effects on brain
structure arising from psychiatric disorders other than
schizophrenia. The siblings of healthy comparison sub-
jects were enrolled in an identical manner to the siblings
of the schizophrenia subjects, and met the same inclusion
and exclusion criteria.
2.2. Clinical and cognitive assessments
as previously described (Delawalla et al., 2006; Harms
et al., 2007) so that we could examine the correlation
between these measures and the neuroanatomical mea-
sures in the schizophrenia subjects and their siblings.
Briefly, psychopathology was measured using the Scale
for the Assessment of Negative Symptoms (SANS) (An-
dreasen 1983), the Scale for the Assessment of Positive
Symptoms (SAPS) (Andreasen 1984), the Structured In-
terview for Prodromal Syndromes (SIPS) (Miller et al.,
1999), and the Chapman Psychosis Proneness Scales
(Chapman et al., 1995). Cognitive function was assessed
using a battery of neuropsychological tests (Delawalla
et al., 2006; Harms et al., 2007). The raw scores from the
individual psychopathological and neuropsychological
tests were first converted to z-scores using the mean and
domain were then averaged to yield three domains of
clinical symptoms – positive symptoms, negative symp-
toms, and thought disorganization – and four broad cog-
nitive domains – working memory, episodic memory,
executive function, and attention. The mean scores of
these domains by subject group were nearly identical to
those reported in Harms et al. (2007), as expected given
the highly overlapping subject pools.
2.3. MR scanning and image analysis
All MR scans were collected on a 1.5-Tesla VISION
system (Siemens Medical Systems). The MR scanning
protocol included the collection of multiple (2–4) high-
resolution, 3D T1-weighted MPRAGE volumes: voxel
resolution: 1 mm×1 mm×1.25 mm, TR: 9.7 ms, TE:
4.0 ms, flip angle: 10o10°, scan time: 6.5 min per acqui-
sition. The MPRAGE scans for each subject were aligned
volume (Buckner et al., 2004), which was then trilinearly
interpolated into 0.5 mm×0.5 mm×0.5 mm isotropic
voxels to produce smoother intensity histograms for more
were defined as previously reported (Ratnanather et al.,
2004; Wang et al., 2007). The paracingulate gyrus bet-
ween the cingulate sulcus and any paracingulate sulcus
in the presence of the paracingulate sulcus influences
measures of ACC morphometry (Fornito et al., 2008a)
paracingulate sulcus was coded using a 3 tiered rating
system (0 for absent, 1 for present, 2 for prominent),
used as a covariate in the analyses of the ACC measures.
We used Labeled Cortical Mantle Distance Map
and thickness (Miller et al., 2003; Miller et al., 2000;
Priebe et al., 2006; Ratnanather et al., 2004; Wang et al.,
2007). First, a region of interest (ROI) containing the
cingulate gyrus and its surrounding voxels was first
2004) was used to segment the ROI into gray matter
(GM), white matter (WM) and cerebral-spinal fluid
Demographic characteristics of subjects with schizophrenia (SCZ) and their siblings (SCZ–SIB), and control subjects (CON) and their siblings
Demographic profiles of subjects
N SCZSCZ–SIB CON–SIBCONχ2or F, p
Age: mean (std)
Race (Caucasian/African American
Parental SES: mean (std)
χ2(3) =3.5, p=0.3
Minor differences in how the siblings reported their parental information account for the small differences in SES between the siblings of a sib-pair.
Mean duration of illness for the schizophrenia subjects was 4.3 (SD 4.3) years.
63D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
(CSF) (Fig. 1B). A topologically correct isosurface was
then generated at the GM/WM interface (Han et al.,
2001; Han et al., 2002). We then used dynamic pro-
gramming to delineate the boundary of the anterior and
posterior cingulate gyrus subsurfaces (Khaneja et al.,
1998) (Fig. 1C,D). All of these neuroanatomical algo-
rithms were implemented by one of the authors (DC),
who was blind to diagnosis and subject information.
Finally, LCMDM was used to compute the gray matter
volume and thickness, while area of the GM/WM inter-
ACC and PCC as detailed in Wang et al. (2007).
Mean whole-brain cortical gray matter thickness and
total cerebral brain volume were calculated using Free-
Surfer (Dale et al., 1999; Desikan et al., 2006; Fischl
et al., 2004; Fischl et al., 1999; Segonne et al., 2007).
Total cerebral volume included cortical and subcortical
gray matter plus white matter and was specifically de-
fined as the volume (L+R) enclosed interior to the
FreeSurfer pial surfaces (i.e., interface of gray matter
with cerebrospinal fluid) minus the volume of the lateral
ventricles (L+R) from the FreeSurfer volumetric seg-
mentation. These measures were used as covariates in
Fig. 1. Outline ofcingulate gyrus procedure. A. Paneldepicts the rough region ofinterest(yellow) surroundingthe cingulategyrus ina sagittal view. The
red line shows the division between ACC and PCC. B. The alternating kernel method was used to segment gray matter (blue), white matter (white), and
cerebral-spinal fluid (red) in a local region of interest, in coronal view. As the cingulate gyrus follows a “C” shape (in sagittal view), a coronal section
sometimescontains a top and bottom region,asdepictedhere.Herethetop regioncorresponds toa section through thedorsalportionofthe PCC,and the
to the cingulate gyrus ROI, from which the cingulate subsurface was extracted. The top part of the panel shows the ROI-surface with the sulcal boundary
interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article).
64D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
2.4. Statistical analysis
Group comparisons of gray matter volume were per-
formed using a mixed-model with group, hemisphere,
and group⁎hemisphere as fixed effect predictors.
of thickness and area, we also performed group
comparisons of these measures. The mixed-model
estimated the covariance (correlation) in the residuals
due to both the sibling and across hemisphere rela-
tionships. Gender was included as a covariate in all
analyses since our groups differed in their gender
distribution. Scores for the prominence of the paracingu-
late sulcus were also included as a covariate in the
analyses of the ACC. The cingulate volume and area
measures were analyzed both without and with total
cerebral volume as an additional covariate, while
cingulate thickness was analyzed without and with
mean overall cortical thickness (from FreeSurfer) as an
additional covariate. The significance of the predictor
variables was assessed using Type III sums-of-squares.
All statistical analyses were performed in SAS 9.1 (SAS
Institute Inc., Cary, NC).
Correlations between neuroanatomical measures
and the clinical and cognitive domain scores were
computed on an exploratory basis, using Spearman's
rho and without correction for multiple comparisons.
The correlation analysis was confined to the cingulate
measures that demonstrated a main effect of group
status, and was conducted using the combined group
of schizophrenia subjects and their siblings while con-
trolling for group status. For any correlated measures
with pb0.01, we also computed the correlations within
the schizophrenia subjects and their siblings separately.
3.1. Anterior cingulate cortex
The volume, thickness, and surface area of the
ACC showed main effects of hemisphere (all pb0.002),
but no main effect of group (pN0.4), and no group-by-
hemisphere interaction (pN0.2). Based on the estimated
marginal means for the hemisphere effect, volume
and area were respectively 11% and 9% larger in the
right than left ACC, while thickness was 9% smaller
in the right than left ACC. The effect of group status
on ACC volume, thickness, and area remained non-
significant (pN0.2) when (1) total cerebral volume
was added as a covariate to the analysis of volume
and area and (2) mean cortical thickness was added as a
covariate to the analysis of anterior cingulate thickness.
3.2. Posterior cingulate cortex
There was a significant effect of group status on PCC
volume (F(3,56)=3.6, p=0.02). Post-hoc pair-wise
group comparisons indicated that both the subjects
with schizophrenia and their siblings had significantly
smaller PCC volumes than the healthy control subjects
(11%, t88=−2.9, p=0.005, and 9%, t73=−2.4, p=0.02,
respectively; Table 2). Subjects with schizophrenia
and their siblings had similar PCC volumes (t30=
−0.5, p=0.6), as did the healthy control subjects and
their siblings (t37=0.25, p=0.8). There was a trend
toward a main effect of group on the thickness of the
PCC (F(3,57)=2.4, p=0.08), with the siblings of the
schizophrenia subjects having the smallest thickness
(6% smaller than the controls and siblings of controls,
t72=−2.3, p=0.02 for both comparisons). However,
schizophrenia subjects and controls did not differ signi-
ficantly in PCC thickness (p=0.26). There was also a
trend for an effect of group on PCC area (F(3,58)=2.1,
p=0.11). The schizophrenia subjects had an 8% smaller
area than controls (t90=−2.5, p=0.01), although the
area in the siblings of the schizophrenia subjects was not
statistically different from either the control subjects
(p=0.33) or their siblings (p=0.70). There was a main
effect of hemisphere on PCC thickness (4% greater in
left hemisphere) and area (6% larger in left hemisphere,
pb0.0001 for both), but not on volume (p=0.6). None
of the three measures showed a hemisphere-by-group
When we included total cerebral volume as a
covariate, the effect of group on PCC volume became
non-significant (p=0.40). The effect of group on PCC
area and thickness remained non-significant upon
inclusion of total cerebral volume and mean cortical
thickness as covariates, respectively (p=0.15, p=0.26).
There were no group differences in the prominence
of the paracingulate sulcus in either hemisphere
(left: χ2= 6.4 df=6, p=0.4; right: χ2= 4.7, df=6,
p=0.6). Across the 132 total subjects, the percentage of
subjects with a paracingulate sulcus rated as absent,
present, and prominent was 54%, 17%, and 29%,
respectively, for the left hemisphere, and 73%, 8%, and
18%, respectively, for the right hemisphere. The pro-
minence of the paracingulate sulcus had a strong effect
on volume, thickness, and area of the ACC (pb0.0001
for all three measures), with each step-wise increase in
its prominence predicting a decrease in each of the three
65D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
Mixed-model analysis with group and gender as fixed
effects indicated an effect of group on both total cerebral
volume and mean cortical thickness (F(3,50)=4.9, p=
0.004; F(3,51)=4.7, p=0.006, respectively). Post-hoc
pair-wise comparisons showed that the schizophrenia
subjects had smaller total brain volumes than their sib-
lings (schizophrenia subjects: least square mean cerebral
volume=934 cm3, SE=19.1; their siblings: 967 cm3,
SE=14.4; t31=−2.0, p=0.06), who in turn had smaller
brain volumes than the control subjects (1008 cm3, SE=
14.0; t62=−2.1,p=0.04). However, the cerebral volumes
of the control subjects and their siblings (1033 cm3,
SE=15.6) were not different (t39=−1.5, p=0.14). Mean
cortical thickness of the schizophrenia subjects was thin-
ner than the controls (schizophrenia subjects: 2.42 mm,
SE=0.015; controls: 2.47 mm, SE=0.015; t66=−2.4,
p=0.02). Mean cortical thickness of the siblings of the
schizophrenia subjects (2.43 mm, SE=0.015) trended
toward a reduction compared to controls (t63=−1.7, p=
0.10) and was significantly reduced compared to control
siblings (2.50 mm, SE=0.014; t62=−3.1, p=0.003).
Since there was a trend for a small age difference
between groups (Table 1), we also conducted supple-
mentary analyses using age as an additional covariate in
the mixed-models that tested for group differences in
(Total cerebral volume or mean cortical thickness were
not included as covariates in these models). The effect of
and PCC (F(1,122)=6.6, p=0.01, and F(1,123),
p=0.01, respectively). However, the significance of the
main effect of group was unaffected by the inclusion of
group on volume, thickness, and area of the PCC, res-
pectively, upon inclusion of age as a covariate).
3.4. Correlations of clinical and cognitive variables
with PCC volume
Based on the premise that the schizophrenia subjects
and their siblings shared a common neurobiological
we computed partial correlations between PCC volume
(right and left separately) and the clinical and cognitive
domain scores within this combined group of subjects,
controlling for group status. The only significant corre-
lation was an inverse correlation between left PCC
volume and negative symptoms (Spearman's r=−0.36,
p=0.007), such that a larger left PCC volume was
associated with fewer negative symptoms. An analysis
of each group separately showed that this relationship
was driven by the sibling group more than the group of
Table 2 Least square means (standard errors) in each hemisphere and segment of the cingulate gyrus, from a mixed-model with group, hemisphere, and group⁎hemisphere as fixed effect predictors,
controlling for gender in the posterior cingulate (PCC), and gender and prominence of the paracingulate sulcus in the anterior cingulate (ACC)
Adjusted morphometric measures in anterior and posterior cingulate cortex
Surface area (cm2)
There was a significant effect of group status on PCC volume (F(3,56)=3.6, p=0.02).
66 D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
schizophrenia subjects (siblings: r=−0.43, p=0.02;
schizophrenia subjects: r=−0.28, p=0.15), though
both correlations were in the same direction.
The results of this study demonstrate the presence of
reduced gray matter volumes of the posterior segment of
the cingulate gyrus in schizophrenia subjects and their
non-psychotic siblings relative to healthy control subjects
siblings did not differ from their affected siblings. In
addition, smaller PCC volumes were correlated with the
intensity of negative symptoms in the combined group of
schizophrenia subjects and their non-psychotic siblings.
While this relationship was not hypothesized, it does
suggest that the difference in PCC volume observed in
association with schizophrenia may have clinical con-
sequences. Interestingly, we have previously observed an
increase in negative symptoms in the non-psychotic
siblings of schizophrenia subjects as compared to healthy
controls and their siblings (Delawalla, et al., 2006).
Our analysis of area and cortical thickness suggested
that the observed gray matter volume reductions in the
posterior cingulate most likely arose from some combi-
nation of decreases in both area and thickness. Previous
studies of the cingulate gyrus in schizophrenia subjects
have attributed gray matter volume decreases to cortical
thinning (Bouras et al., 2001; Chana et al., 2003; Ongur et
density (Benes et al., 2001; Todtenkopf et al., 2005) and
reductions in the density of pyramidal and nonpyramidal
cells (Olney and Farber 1995) are also plausible explana-
tions. Unfortunately, the methods available for in vivo
neuroimaging studies cannot yet discern among these
Decreased ACC and PCC volumes have been pre-
viously reported in subjects with schizophrenia as com-
pared to healthy controls (Ha et al., 2004; Hulshoff Pol
et al., 2001; Job et al., 2002; Shapleske et al., 2002;
Sigmundsson et al., 2001; Sowell et al., 2000). The ab-
sence of ACC effects in this study may be related to the
relatively young age of the schizophrenia subjects, as
most of the cited studies employed subjects with at least
10 years of illness. Consistent with this hypothesis,
Fornito et al (2008b) found no difference in gray matter
volume of “limbic” ACC in first-episode schizophrenia
patients relative to controls. That we detected a decrease
in ACC volume in a previous study of more chronic
schizophrenia subjects suggests that deficits in ACC
(Farrow et al., 2005; Vidal et al., 2006).
In the PCC, we found that the effect of group on PCC
volume became non-significant after inclusion of total
cerebral volume as a covariate. This indicates that the
PCC volume reduction in these schizophrenia subjects
and their siblings was proportionate to changes in
overall cerebral volume. Notably, in our previous study
of a more chronic cohort of schizophrenia subjects
(mean illness duration of 12 years) (Wang et al., 2007),
we found that the deficit in PCC volume between
schizophrenia subjects and controls was significant even
after accounting for total brain volume. This suggests
that deficits in PCC volume may increase as the disease
progresses, and to a greater degree than any further
changes in total brain volume. Taken together, it can be
suggested that the disease process of schizophrenia may
have progressive effects on both the ACC and PCC over
the course of the illness.
We hypothesized that the non-psychotic siblings
would have intermediate changes because they share ap-
proximately half of their genes. Thus, the reduction in
PCC volume in schizophrenia subjects and their non-
psychotic siblings is consistent with the hypothesis that
abnormalities of brain structure occur in schizophrenia
because of heritable influences. However, we cannot
exclude the possible effect of common environmental
factors. Several studies have correlated adverse social
factors with the development of psychotic disorders
(Cantor-Graae 2007; Harrison et al., 2001; Wicks et al.,
2005). Unfortunately, it is difficult to collect reliable in-
formation on the presence and severity of adverse envi-
ronmental events that may contribute to the pathogenesis
of disease (Cantor-Graae 2007).
The effects of antipsychotic drug treatment must
be considered when examining neuroanatomical changes
in patients with schizophrenia. Antipsychotic drugs have
been shown to effect gray matter volume in patients with
schizophrenia (Lieberman et al., 2005). Exposure to
typical neuroleptics has been associated with increased
correlated to decreased ACC volume (Kopelman et al.,
2005; McCormick et al. 2005). However, antipsychotic
drug effects would not be involved in findings of
neuroanatomical abnormalities in the untreated siblings
of the schizophrenia subjects. Thus, our finding of re-
duced PCC volume in the siblings of schizophrenia
subjects strongly suggests that the reduction of PCC
volume in their affected siblings cannot be solely ex-
plainedasa consequence ofantipsychoticdrugtreatment.
The list of genes implicated in the pathogenesis
of schizophrenia is steadily growing (Arnold et al.
67 D.R. Calabrese et al. / Schizophrenia Research 104 (2008) 61–70
a role in neurodevelopment. For example, Neuregulin 1
has been shown to moderate migration of neuronal
precursors, aid in glial development and survival, and
act as a neurotrophic factor (Anton et al., 1997; Rio et al.,
also been hypothesized to play a role in neuronal
migration, axonal guidance and outgrowth (Bellon,
2007; Miyoshi et al., 2003). However, the influence
of such genes would be expected to exert more general
effects on cortical architecture. Notably, the PCC changes
proportionate to overall changes in cerebral volume.
Therefore, it is possible that our findings are related to
genes that influence general aspects of cortical develop-
ment. Alternately, genes with general effects on cortical
development could have greater or lesser effects on
particular cortical regions because of a relationship
between the timing of their expression and the timing of
maturation of particular cortical regions, become active
Further studies of neuroanatomical irregularities in
patients with schizophrenia and their family members in
conjunction with studies of genetic polymorphisms
known to alter the risk of developing schizophrenia are
needed to shed light on the role of genetic influences on
Role of funding source
Funding for this study was provided by NIH grants P50
MH071616, R01 MH056584, and P41-RR15241; the NIH had no
of data; in the writing of the report; and in the decision to submit the
paper for publication.
John G. Csernansky and Lei Wang designed the study and
wrote the protocol. Daniel R. Calabrese and Michael P. Harms
managed the literature searches and analyses, and undertook the
statistical analysis, and Daniel R. Calabrese wrote the first draft of the
manuscript. All authors contributed to and have approved the final
Conflict of interest
All authors declare that they have no conflicts of interest.
The authors would like to thank the Conte Center Clinical and
Administration Core for subject assessments, the Biostatistics and
Data Management Core for data management and archiving, and
Dr. Murat Yucel for helpful discussions on the paracingulate gyrus.
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