Regional gray matter volume abnormalities in the at risk mental state.
ABSTRACT Individuals with an At Risk Mental State (ARMS) have a very high risk of developing a psychotic disorder but the basis of this risk is unclear. We addressed this issue by studying gray matter volume in this group with magnetic resonance imaging (MRI).
Thirty-five individuals with an ARMS, 25 patients with first episode schizophrenia, and 22 healthy volunteers were studied using a 1.5T MRI scanner. Twelve (34%) of the ARMS group developed schizophrenia in the 2 years subsequent to scanning.
There were significant volumetric differences between the three groups in the left insula, superior temporal gyrus, cingulate gyrus and precuneus. In these regions, the volume in the ARMS group was smaller than in volunteers but not significantly different from that in the first episode (FE) group. Direct comparison of the ARMS and control groups revealed additional areas of reduced volume in the left medial temporal cortex. Within the ARMS group, those subjects who later developed psychosis had less gray matter than subjects who did not in the right insula, inferior frontal and superior temporal gyrus.
The ARMS was associated with reductions in gray matter volume in areas that are also reduced in schizophrenia, suggesting that these are a correlate of an increased vulnerability to psychosis. Volumetric differences within the ARMS group may be related to the subsequent onset of schizophrenia in a subset of those at high risk.
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ABSTRACT: Motor abnormalities in individuals with schizophrenia and those at-risk for psychosis are well documented. An accumulating body of work has also highlighted motor abnormalities related to cerebellar dysfunction in schizophrenia including eye-blink conditioning, timing, postural control, and motor learning. We have also recently found evidence for motor dysfunction in individuals at ultra high-risk for psychosis (1-3). This is particularly relevant as the cerebellum is thought to be central to the cognitive dysmetria model of schizophrenia, and these overt motor signs may point to more general cerebellar dysfunction in the etiology of psychotic disorders. While studies have provided evidence indicative of motor cerebellar dysfunction in at-risk populations and in schizophrenia, findings with respect to the cerebellum have been mixed. One factor potentially contributing to these mixed results is the whole-structure approach taken when investigating the cerebellum. In non-human primates, there are distinct closed-loop circuits between the cerebellum, thalamus, and brain with motor and non-motor cortical regions. Recent human neuroimaging has supported this finding and indicates that there is a cerebellar functional topography (4), and this information is being missed with whole-structure approaches. Here, we review cerebellar-motor dysfunction in individuals with schizophrenia and those at-risk for psychosis. We also discuss cerebellar abnormalities in psychosis, and the cerebellar functional topography. Because of the segregated functional regions of the cerebellum, we propose that it is important to look at the structure regionally in order to better understand its role in motor dysfunction in these populations. This is analogous to approaches taken with the basal ganglia, where each region is considered separately. Such an approach is necessary to better understand cerebellar pathophysiology on a macro-structural level with respect to the pathogenesis of psychosis.Frontiers in Psychiatry 11/2014; 5:160.
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ABSTRACT: Psychiatric disorders such as schizophrenia and major depressive disorder were thought to be caused by neurotransmitter abnormalities. Patients with these disorders often experience relapse and remission; however the underlying molecular mechanisms of relapse and remission still remain unclear. Recent advanced immunological analyses have revealed that M1/M2 polarization of macrophages plays an important role in controlling the balance between promotion and suppression in inflammation. Microglial cells share certain characteristics with macrophages and contribute to immune-surveillance in the central nervous system (CNS). In this review, we summarize immunoregulatory functions of microglia and discuss a possible role of microglial M1/M2 polarization in relapse and remission of psychiatric disorders and diseases. M1 polarized microglia can produce pro-inflammatory cytokines, reactive oxygen species, and nitric oxide, suggesting that these molecules contribute to dysfunction of neural network in the CNS. Alternatively, M2 polarized microglia express cytokines and receptors that are implicated in inhibiting inflammation and restoring homeostasis. Based on these aspects, we propose a possibility that M1 and M2 microglia are related to relapse and remission, respectively in psychiatric disorders and diseases. Consequently, a target molecule skewing M2 polarization of microglia may provide beneficial therapies for these disorders and diseases in the CNS.Pharmaceuticals 12/2014; 7(12):1028-1048.
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ABSTRACT: Individuals at clinical high risk (CHR) of developing psychosis present with widespread functional abnormalities in the brain. Cognitive deficits, including working memory (WM) problems, as commonly elicited by n-back tasks, are observed in CHR individuals. However, functional MRI (fMRI) studies, comprising a heterogeneous cluster of general and social cognition paradigms, have not necessarily demonstrated consistent and conclusive results in this population. Hence, a comprehensive review of fMRI studies, spanning almost one decade, was carried out to observe for general trends with respect to brain regions and cognitive systems most likely to be dysfunctional in CHR individuals. 32 studies were included for this review, out of which 22 met the criteria for quantitative analysis using activation likelihood estimation (ALE). Task related contrast activations were firstly analysed by comparing CHR and healthy control participants in the total pooled sample, followed by a comparison of general cognitive function studies (excluding social cognition paradigms), and finally by only looking at n-back working memory task based studies. Findings from the ALE implicated four key dysfunctional and distinct neural regions in the CHR group, namely the right inferior parietal lobule (rIPL), the left medial frontal gyrus (lmFG), the left superior temporal gyrus (lSTG) and the right fronto-polar cortex (rFPC) of the superior frontal gyrus (SFG). Narrowing down to relatively few significant dysfunctional neural regions is a step forward in reducing the apparent ambiguity of overall findings, which would help to target specific neural regions and pathways of interest for future research in CHR populations.Journal of Psychiatric Research 09/2014; 61. · 4.09 Impact Factor
Regional Gray Matter Volume Abnormalities in the At
Risk Mental State
Stefan J. Borgwardt, Anita Riecher-Rössler, Paola Dazzan, Xavier Chitnis, Jacqueline Aston,
Margret Drewe, Ute Gschwandtner, Sven Haller, Marlon Pflüger, Evelyne Rechsteiner, Marcus D’Souza,
Rolf-Dieter Stieglitz, Ernst-Wilhelm Radü, and Philip K. McGuire
risk is unclear. We addressed this issue by studying gray matter volume in this group with magnetic resonance imaging (MRI).
a 1.5T MRI scanner. Twelve (34%) of the ARMS group developed schizophrenia in the 2 years subsequent to scanning.
first episode (FE) group. Direct comparison of the ARMS and control groups revealed additional areas of reduced volume in the left medial
right insula, inferior frontal and superior temporal gyrus.
that these are a correlate of an increased vulnerability to psychosis. Volumetric differences within the ARMS group may be related to the
subsequent onset of schizophrenia in a subset of those at high risk.
Key Words: At risk mental state, early detection, gray matter, MRI,
schizophrenia, voxel-based morphometry
number of regions (Shenton et al. 2001; Wright et al. 2000).
However, the extent to which these findings are related to a
vulnerability to schizophrenia, as opposed to the disorder per se,
is less certain. Thus qualitatively similar abnormalities are also
evident in the siblings, offspring, and co-twins of patients with
schizophrenia, even though they are not psychotic (Baare et al.
2001; Hulshoff Pol et al. 2004; Keshavan et al. 1997; Lawrie et al.
1999; Seidman et al. 1999; Staal et al. 2000; Sharma et al. 1999).
Individuals with an ‘At Risk Mental State’ (ARMS) have an
increased vulnerability to psychosis, with the risk associated with
presence of ‘prodromal’ symptoms. Around 35% of such subjects
develop psychosis within 12 months, although the proportion
has varied between studies (Mason et al. 2004; Miller et al. 2003;
Yung et al. 2003). Relatively little is known about the nature of
neuroanatomical abnormalities in this group (Table 1). Using
magnetic resonance imaging (MRI) and a region of interest
analysis, Phillips et al. (2002) reported that hippocampal volume
in subjects with an ARMS was smaller than that in controls but not
smaller than in patients with first episode (FE) psychosis. In
addition, within the at risk group, the subset who developed a
psychotic disorder when followed up subsequent to scanning had a
euroimaging studies clearly indicate that schizophrenia is
associated with neuroanatomical abnormalities, with ro-
bust evidence of reduced gray matter volume in a
larger left hippocampal volume than the healthy subgroup. More
recently, in a voxel-based analysis of MRI data (which examined
the entire brain) from the same center, Pantelis et al. (2003)
found that within a group of subjects with the ARMS, those who
later became psychotic had smaller inferior frontal, cingulate,
superior temporal, and hippocampal volumes than those who
The aim of the present study was to use MRI to clarify the
nature of neuroanatomical abnormalities in subjects with an
ARMS by comparing them with both controls and patients with
FE psychosis. The ARMS subjects were then followed up (with-
out active treatment), and subcategorized according to whether
or not they subsequently developed psychosis so that the
baseline MRI data from these two subgroups could be compared.
We had previously examined the MRI data from the same
subjects for macroscopic radiological abnormalities and found
that these were more common among the ARMS subjects than
controls, but equally prevalent in ARMS and FE subjects (Borg-
wardt et al. 2006). In the present study, we examined regional
gray matter volume using a voxel-based morphometric (VBM)
approach. By surveying the whole brain, VBM provides a
nonbiased measure of regional differences in volumes of gray
matter (Ashburner and Friston 2000). On the basis of previous
MRI studies of the ARMS and of other groups at high risk of
schizophrenia, we predicted that subjects with an ARMS would
show volumetric deficits relative to controls that were qualita-
tively similar to those in patients with FE schizophrenia. Our
second hypothesis, based on the study by Pantelis et al. (2003),
was that ARMS subjects who later developed psychosis would
show reduced gray matter volume relative to ARMS subjects who
did not in the inferior frontal, cingulate, superior temporal cortex,
and the hippocampus.
Methods and Materials
The MRI data were collected as part of a research program
(Prediction and early detection of schizophrenia - a prospective
MD’S, R-DS) and the Neuroradiological Department (SH, E-WR), Univer-
and the Department of Biostatistics and Computer (XC), Institute of
Psychiatry, King’s College London, United Kingdom.
Department, University Hospital Basel, Petersgraben 4, CH-4031 Basel,
Switzerland; E-mail: email@example.com.
Received June 2, 2006; revised July 11, 2006; accepted August 4, 2006.
BIOL PSYCHIATRY 2007;61:1148–1156
© 2007 Society of Biological Psychiatry
multilevel approach), supported by the Swiss National Science
Foundation (No. 3200-057216-99; 3200-057216/3) that has been
described in detail elsewhere (Riecher-Rössler et al, in press).
Subjects with an ARMS and patients experiencing their FE of
psychosis were recruited through a specialized clinic for the early
detection of psychosis at the Psychiatric Outpatient Department,
University Hospital in Basel, Switzerland. The following exclu-
sion criteria applied to both these groups: history of previous
psychotic disorder (treated with major tranquilizers for ? 3
weeks); psychotic symptomatology clearly due to ‘organic’ dis-
order or substance abuse according to ICD-10 research criteria;
psychotic symptomatology clearly associated with an affective
psychosis or a borderline personality disorder; age under 18
years; inadequate knowledge of the German language; and IQ
less than 70. After these exclusion criteria were applied, subjects
were assessed using the ‘Basel Screening Instrument for Psycho-
sis’ (BSIP) (Riecher-Rössler et al, in press), the Brief Psychiatric
Rating Scale (BPRS) (Lukoff et al. 1986; Ventura et al. 1993), and
the Scale for the Assessment of Negative Symptoms (SANS)
(Andreasen 1989). The BSIP was used to evaluate ‘prodromal’
symptoms (defined according to DSM-III-R) occurring in the last
5 years; nonspecific ‘prodromal’ signs (Riecher et al. 1991; Hafner
et al. 1991) in the last 2 years; previous or current psychotic
symptoms, psychosocial functioning over the last 5 years, sub-
stance dependency; and psychotic disorders among first and
second degree relatives (Riecher-Rössler et al. 2006).
The family history of psychosis was obtained using a semi-
structured interview from the subject and, whenever possible, a
first-degree relative. The frequency of current and previous
alcohol use was estimated using a semi-structured interview. To
assess the premorbid IQ we used the MWT, an established
measure in German-speaking subjects (Lehrl 1991).
The ARMS group (n ? 35) was defined using criteria corre-
sponding to the Personal Assessment and Crisis Evaluation
(PACE) criteria (Yung et al. 1998) employed in the two previous
MRI studies of the ARMS (Pantelis et al. 2003; Phillips et al. 2002).
Inclusion thus required one or more of the following: a) “atten-
uated” psychotic symptoms, b) brief limited intermittent psy-
chotic symptoms (BLIPS), or c) a first degree relative with a
psychotic disorder plus at least two indicators of a clinical
change, such as a marked decline in social or occupational
functioning. Inclusion because of “attenuated” psychotic symp-
toms required scores of 2 or 3 on the hallucination item, 3 or 4 on
the unusual thought content or suspiciousness items of the BPRS
for at least several times a week and persisting for more than 1
week. Inclusion because of BLIPS required scores of 4 or above
on the hallucination item, or 5 or above on the unusual thought
content, suspiciousness or conceptual disorganization items of
the BPRS, with each symptom lasting less than 1 week before
The FE group (n ? 25) was defined as subjects who met the
operational criteria for first episode psychosis described by Yung
et al. (1998), again as used to define first episode psychosis in the
previous MRI studies of the ARMS (Pantelis et al. 2003; Phillips et
al. 2002). Inclusion required scores of 4 or above on the
hallucination item, or 5 or above on the unusual thought content,
suspiciousness or conceptual disorganization items of the BPRS.
The symptoms must have occurred at least several times a week
and persisted for more than 1 week.
Healthy volunteers (n ? 22) were recruited from the same
geographical area as the other groups, through local advertise-
ments. These individuals had no current psychiatric disorder, no
history of psychiatric illness, head trauma, neurological illness,
serious medical or surgical illness, substance abuse, and no
family history of any psychiatric disorder as assessed by an
experienced psychiatrist in a detailed clinical interview.
After complete description of the study to the subjects, written
informed consent was obtained.
All the participants were Caucasian. Most (32/35; 91%) of the
ARMS group had never taken antipsychotics or mood stabilizers,
and were receiving nonspecific psychological support or antide-
pressive/sedative medication on an outpatient basis. Three ARMS
subjects were receiving low doses of an atypical antipsychotic.
A large proportion of FE patients were scanned within 1-3
days of first contact, therefore most of the FE patients (15/25;
60%) were also antipsychotic-naive. Six had been taking antip-
sychotics for ? 1 month and 4 had been taking them for 1-3
months. None of the controls (C) had previously received
antipsychotic medication. The ARMS, FE and C groups did not
differ significantly in ethnicity, gender, handedness, current and
previous alcohol intake, or total intracranial brain volume. The
groups were matched for premorbid IQ: ARMS: 109 (14), FE: 103
Table 1. MRI Findings in the At Risk Mental State (ARMS)
Baseline MRI Findings
n MRI Method
ARMS Versus Healthy
ControlsConverters Versus Non-converters
Phillips et al. 2002 60 ARMS (20 ARMS-T vs. 40
ARMS-NT); 139 healthy
Region of interest (ROI) analysis
of hippocampal and whole
Smaller left and right
to healthy controls
-[No control group]
Larger left hippocampus in
converters compared to non
Pantelis et al. 2003 75 ARMS (23 ARMS-T vs. 52
Converters had smaller gray matter
volume in the right medial
temporal, lateral temporal,
inferior frontal cortex, and in the
Converters had a significantly
larger (12%) pituitary volume
Garner et al. 2005 31 ARMS-T vs. 63 ARMS-NT ROI analysis of pituitary volume -[No control group]
Velakoulis et al. 2006 135 ARMS (39 ARMS-T vs.
96 ARMS-NT); 87 healthy
ROI analysis of hippocampal,
amygdala, whole brain and
of interest; VBM, voxel-based morphometry; MRI, magnetic resonance imaging.
S.J. Borgwardt et al.
BIOL PSYCHIATRY 2007;61:1148–1156 1149
(15), C: 108 (5). The ARMS and FE groups had a similar
proportion of patients with a family history of psychosis. The FE
group was older than the ARMS and C groups and the ARMS and
FE groups had achieved a lower educational level at school than
the C group. The FE group had higher total BPRS scores than the
ARMS group (Table 2).
The ARMS subjects were followed up at monthly intervals
during the first year, at 3 month intervals during the second and
third years and annually thereafter. At each assessment subjects
were examined using the BPRS. The criteria for transition to
psychosis were those defined by Yung et al. (1998). In subjects
who met these criteria, the diagnosis was determined by a
diagnostic interview using ICD-10 research criteria at the time of
transition, corroborated by a subsequent assessment at least one
year post transition using Operational Criteria (OPCRIT) checklist
for psychotic and affective illness (McGuffin et al. 1991).
Image Acquisition. Subjects were scanned using a Siemens
(Erlangen, Germany) Magnetom Vision 1.5 T scanner at the
University Hospital Basel. Head movement was minimized by
foam padding and velcro straps across the forehead and chin. A
three-dimensional volumetric spoiled gradient recalled echo
sequence generated 176 contiguous, 1 mm thick sagittal slices.
Imaging parameters were: time-to-echo, 4 msec; time-to-repeti-
tion, 9.7 msec; flip angle, 12; matrix size, 200 x 256; field of view,
25.6 x 25.6 cm matrix; voxel dimensions, 1.28 x 1 x 1 mm.
Image Preprocessing. Optimized voxel-based morphometry
preprocessing was performed with Statistical Parametric Map-
ping software (SPM2, Wellcome Department of Imaging Neuro-
sciences, University College London, United Kingdom). The
image processing steps have been described in detail elsewhere
(Ashburner and Friston 2000; Good et al. 2001). The segmenta-
tion algorithm implemented in SPM incorporates an a priori
knowledge of the likely spatial distribution of tissue types in the
brain with prior probability tissue maps derived from a large
number of subjects. To ensure the most accurate segmentation
possible, we created study-specific customized prior probability
maps based on all 82 subjects. The preprocessing stages were as
follows: 1) scans were segmented into probabilistic maps of gray
and white matter and cerebrospinal fluid with a modified mixture
model clustering algorithm; 2) the segmented gray matter map
was mapped to a gray matter template, and the derived warping
parameters were applied to the original T1-weighted image to
map it into standard space (this procedure prevents skull and
other nonbrain voxels from contributing to the registration, while
avoiding the need for explicit skull-stripping); 3) the registered
image was then re-segmented, which is necessary because the a
priori knowledge incorporated into the SPM2 segmentation
algorithm means that it works optimally on images in standard
space. The segmented maps were then modulated through
multiplying voxel values by the Jacobian determinants from the
spatial normalization to correct for volume changes. Finally, all
normalized, segmented, modulated gray matter tissue maps were
smoothed with a Gaussian filter of 5 mm full width at half
Statistical Analysis of MRI Data. Using x-BAMM (Brain Acti-
vation and Morphological Mapping, version 2.5, http://www-bmu.
psychiatry.cam.ac.uk/software/), between-group differences in
gray matter volume were estimated by fitting an analysis of
covariance (ANCOVA) model at each intracerebral voxel in
standard space, covarying for total gray matter volume and age at
scan. Given that structural brain changes are likely to extend over
a number of contiguous voxels, test statistics incorporating
spatial information, such as 3D cluster mass (the sum of supra-
threshold voxel statistics), are generally more powerful than
other possible test statistics, which are informed only by data at
a single voxel. Therefore, our approach was to initially set a
relatively lenient p value (p ? .05) to detect voxels putatively
demonstrating differences between groups. We then searched
for spatial clusters of such voxels and tested the cluster mass of
each cluster. Permutation testing was used to assess statistical
significance at both the voxel and cluster levels (Bullmore et al.
1999; Sigmundsson et al. 2001). At the cluster level, we set the
Table 2. Demographic and Clinical Characteristics
Age at Baseline (years)
Handedness (mixed or left)a
Patients with a First Degree Relative with Schizophrenia
BPRS at Intake
SANS at Intake
Patients with Antipsychotics at MRI Scan
Intracranial Brain Volume
Days between MRI and Onset of Psychosis
Duration of Clinical Follow-Up After MRI (months)33 (mean)
C, control group; BPRS, Brief Psychiatric Rating Scale; SANS, Scale for the Assessment of Negative Symptoms; MRI, magnetic resonance imaging.
aOne value (handedness) each is missing in the ARMS, ARMS-T and the C group.
1150 BIOL PSYCHIATRY 2007;61:1148–1156
S.J. Borgwardt et al.
statistical threshold for cluster significance for each analysis such
that the expected number of false positive clusters was ? 1, and
quote the p value at which this occurred. The principal advan-
tages of cluster-level testing are that it confers greater sensitivity
by incorporating information from more than one voxel in the
test statistic, and also substantially reduces the search volume or
number of tests required for a whole brain analysis, thereby
mitigating the multiple comparisons problem.
Significant clusters were anatomically localized using the atlas
of Talairach and Tournoux (1988), except for foci in and close to
the cerebellum, which were localized using the atlas of Schmah-
mann et al. (2000).
Between Group Comparisons of Demographic Data
Clinical and sociodemographic differences between groups
were examined using one-way analysis of variance (ANOVA),
t-test, or chi-square test (Table 2). Statistical analyses were
performed with the Statistical Package for the Social Sciences
(SPSS for Windows, Rel, 12.0, SPSS Inc., Chicago, Illinois).
Clinical Follow-up of High Risk Subjects
The mean duration of follow-up of all ARMS subjects was 25
months (median 23 months). Twelve of the 35 ARMS subjects (34%)
developed a psychosis subsequent to being scanned (ARMS-T). The
mean duration of follow up in this subgroup was 306 days (range,
25–1137 days). Ten of the transitions to psychosis occurred during
the first year of follow-up, with one in the second year and one in
the fourth. All the subjects who developed a psychosis met OPCRIT
criteria for schizophrenia when re-assessed 12 months post transi-
tion. The 23 individuals who did not develop a psychosis (ARMS-
NT) during follow-up (66%) did not differ significantly from the
ARMS-T group with respect to ethnicity, age, gender, educational
level, premorbid IQ, family history of psychosis, BPRS, SANS,
exposure to antipsychotic medication, current and previous alcohol
intake, or total intracranial brain volume. The median duration of
follow-up in this subgroup was 41 months. Left or mixed handed-
ness was more common in the ARMS-T group compared to the
ARMS-NT group (Table 2).
Abnormalities in the ARMS Group Independent of
Subsequent Clinical Outcome
To test the hypothesis that the ARMS group would show
qualitatively similar volumetric abnormalities to the FE group, we
compared the ARMS sample as a whole (independent of subse-
quent clinical outcome) with the controls and the FE patients.
ARMS versus C versus FE. There were significant between
group differences in gray matter volume in two regions. The first
included the posterior part of left superior temporal gyrus and
the adjacent part of the left insula, while the second involved the
posterior cingulate gyrus and precuneus (Figure 1) (p ? .002).
Post-hoc testing revealed that in both these regions, the volume
Figure 1. Gray matter probability maps for comparison of all subjects with an At-Risk Mental State (ARMS), first-episode patients and healthy controls.
S.J. Borgwardt et al.
BIOL PSYCHIATRY 2007;61:1148–1156 1151
in the ARMS group was significantly smaller than that in controls
(p ? .002) but was not significantly different from that in the FE
group (Figure 2).
At a less stringent statistical threshold (p ? .01), there were
additional differences in a region spanning the left parahip-
pocampal gyrus (coordinates of cluster centroids x ? -22.2, y ?
-21.6, z ? -16), hippocampus (-28.8, -10.5, -15.8) and amygdala
(-30.6, -7.4, -20), a region spanning the right insula (46, -28, 17.6)
and superior temporal gyrus (48.6, -28.4, 8), and in the posterior
aspect of the cerebellar hemispheres bilaterally (41, -57.9, -24
and -36.7, -67.7, -24). In all these regions the ARMS subjects had
smaller gray matter volumes than controls but were not different
from the FE group.
The same set of regions showed significant group differences
when the analysis was repeated after excluding the subjects on
ARMS versus C. To further clarify the nature of the abnor-
malities in the ARMS group we then compared them with
controls directly. There were areas of reduced gray matter
volume in the posterior cingulate gyrus and precuneus (p ?
.002). At a less stringent statistical threshold (p ? .01), there were
three additional areas of reduced volume in the left insula and
superior temporal gyrus, the left parahippocampal gyrus, hip-
pocampus, amygdala, and the right anterior superior temporal
gyrus and amygdala (Figure 3).
These differences remained when the analysis was repeated
without the subjects on antipsychotic medication.
MRI Differences Within the ARMS Group
To test the hypothesis that ARMS subjects who later became
psychotic would show reduced inferior frontal, cingulate,
temporal and hippocampal volume compared to those who
did not, we compared the MRI data from ARMS subjects who
had (ARMS - Transition; ARMS-T, n ? 12) and had not (ARMS
- No Transition; ARMS-NT, n ? 23) developed psychosis in the
ARMS-T versus ARMS-NT. Relative to the ARMS-NT group,
the ARMS-T group had smaller gray matter volumes in a region
which included the right insula and the adjacent part of the right
anterior superior temporal gyrus (Figure 4) (p ? .002). At a less
stringent statistical threshold (p ? .01), there was an additional
region of smaller volume in the ARMS-T group in the anterior
cingulate gyrus (.5, 23.1, 36.3).
There were 3 regions where there was relatively more gray
matter volume in the ARMS-T than the ARMS-NT group: a large
bilateral region which included the parahippocampal, fusiform,
and medial occipital gyri, plus the posterior temporal, inferior
parietal and postcentral cortex (-54.8, -45.9, 16.5), and two
smaller regions, one involving the red nucleus and thalamus (-.4,
-28.2, 5.5), and the other the right supramarginal gyrus (52.3,
Again, when the analysis was repeated after excluding the
subjects on antipsychotic medication, the same regions showed
Our first prediction, that individuals with an ARMS would
show volumetric deficits qualitatively similar to those seen in first
episode psychosis was confirmed. The ARMS group had smaller
gray matter volumes in a cluster that included the left insula and
adjacent parts of the superior temporal gyrus and in a midline
region that included the posterior cingulate gyrus and precuneus.
There was also a trend for smaller volumes in the left parahip-
pocampal gyrus, hippocampus and amygdala, and a region
spanning the right insula and superior temporal gyrus, and in the
posterior aspect of the cerebellar hemispheres bilaterally.
Reductions in left superior temporal gyral and insular volume
are well established findings in structural neuroimaging studies
of schizophrenia, and these areas have also been implicated in
functional neuroimaging studies of the disorder (Curtis et al.
1998; Fu et al. 2005; Garner et al. 2005; Kircher et al. 2000;
McDonald et al. 2000; McGuire et al. 1995, 1998; Seidman et al.
2003; Shenton et al. 1992; Velakoulis et al. 2006; Wible et al.
1995; Wright et al. 1995; Wright et al. 1999). Similarly, the
cingulate gyrus has consistently been implicated in structural and
functional imaging studies of schizophrenia, although findings
have been more frequent in its anterior than its posterior part
(Falkai et al. 1988; Shenton et al. 2001; Wright et al. 2000). Medial
temporal lobe, especially hippocampal volume alterations, are
among the most robust brain vulnerabilities for schizophrenia
(DeLisi et al. 1997b, 2004; DeLisi and Hoff 2005; Hirayasu et al.
1999; Seidman et al. 2002; van Erp et al. 2004; Velakoulis et al.
1999). Patients with schizophrenia and nonpsychotic relatives
from families with multiple persons with schizophrenia had
significantly smaller right parahippocampal anterior volumes
than controls (Seidman et al. 2003; Velakoulis et al. 2006).
Abnormalities in the cerebellum and precuneus have been less
frequently described in schizophrenia, but reduced volume and
differential activation have been reported in both these regions
(Jacobsen et al. 1997; Levitt et al. 1999; Loeber et al. 2001;
Nopoulos et al. 1999; Shenton et al. 2001; Wright et al. 2000).
The finding that subjects with an ARMS showed MRI abnor-
malities that are qualitatively similar to those associated with
schizophrenia is consistent with MRI data from studies of other
groups at high risk of psychosis. Thus, compared to controls, the
nonpsychotic relatives (Job et al. 2003, 2005; Lawrie et al. 1999;
Figure 2. Between group differences in gray matter volume in a region
spanning the anterior part of the left superior temporal gyrus and the
adjacent part of the left insula.
1152 BIOL PSYCHIATRY 2007;61:1148–1156
S.J. Borgwardt et al.
Pantelis et al. 2003) and co-twins of patients with schizophrenia
(Cannon et al. 2002; Hulshoff Pol et al. 2004; Suddath et al. 1990),
and individuals with a schizotypal personality (Dickey et al.
1999; Kawasaki et al. 2004) all show reduced regional gray
matter volumes in areas that are also sites of volume reduction in
Previous structural MRI studies that have compared ARMS
subjects and controls, have used a region of interest approach
(Table 1). Phillips et al. (2002) found smaller hippocampal
volumes in the ARMS group, but a more recent study from the
same center did not find medial temporal volume differences in
a larger sample (Velakoulis et al. 2006). A recent functional
imaging study has reported that subjects with an ARMS displayed
differential activation relative to controls and patients with
psychosis in the anterior cingulate cortex during a visual oddball
continuous performance task (Morey et al. 2005).
Our second hypothesis was that within the ARMS group,
those who became psychotic subsequent to scanning would
show reduced gray matter volume relative to those who did not
in the inferior frontal, cingulate, superior temporal cortex and the
hippocampus, as described in previous comparisons of these
subgroups (Table 1). Consistent with this prediction, we found
that those who later developed schizophrenia had a smaller gray
matter volume in a region spanning the right insula, inferior
frontal gyrus and superior temporal gyrus. These differences
were located in similar parts of the right inferior frontal and
anterior superior temporal cortex to those identified by Pantelis
et al. (2003).
Although these were not predicted, we also identified areas
where the ARMS subjects who later became psychotic had
relatively more gray matter volume than those who did not.
These differences were evident in the parahippocampal gyri, the
parietal and posterior temporal cortex, and the thalamus. The
differences in the parahippocampal gyri are of particular interest,
as Phillips et al. (2002) found that ARMS subjects who later
became psychotic had a larger left hippocampal volume than
those who did not, and longitudinal MRI studies of both subjects
with an ARMS and of the relatives of patients with schizophrenia
indicate that transition to psychosis is associated with a progres-
sive reduction in medial temporal volume (Job et al. 2005;
Pantelis et al. 2003). However, we did not find significant
volumetric differences between the ARMS subgroups in the
hippocampus and amygdala, which is consistent with a region of
interest (ROI) study in ARMS subjects (Velakoulis et al. 2006).
Figure 3. Areas of reduced gray matter volume in subjects with an At-Risk Mental State (ARMS) relative to controls.
S.J. Borgwardt et al.
BIOL PSYCHIATRY 2007;61:1148–1156 1153
The finding that there are volumetric differences between ARMS
subjects who do and do not later develop schizophrenia is consis-
tent with evidence that the transition to psychosis is associated with
changes in regional gray matter volumes, particularly in the inferior
frontal, cingulate and medial temporal cortex (Job et al. 2005;
Pantelis et al. 2003). The cross-sectional differences we identified
within the ARMS group may thus be related to pathological pro-
cesses associated with the subsequent onset of psychosis.
As in previous neuroimaging studies of individuals with an
ARMS, our group sizes were modest as these subjects are
relatively difficult to recruit. We cannot therefore exclude the
possibility that we were unable to detect some group differences
because of limited statistical power. The differences in gray
matter volume that we observed are unlikely to be related to
treatment with antipsychotic drugs or mood stabilizers, as the
majority of the ARMS and the FE subjects were naive to these
medications at the time of scanning. Also, when repeating the
analyses without the subjects on antipsychotic medication,
the results did not change. Similarly, although the FE group was
slightly older and had less formal education than the other
groups, this could not account for the differences between the
ARMS and control groups who were matched in these respects.
We defined the At-Risk Mental State using the PACE criteria
(Yung et al. 1998) because these had been used in the previous
volumetric MRI studies of subjects with prodromal symptoms
(Pantelis et al. 2003; Phillips et al. 2002) and are widely used in
this field. Nevertheless, there are other ways of defining subjects
with prodromal symptoms, and our ARMS sample and results
may have been different had we employed different diagnostic
criteria (Cornblatt 2002; Klosterkotter et al. 2001; McGlashan et
al. 2001). It should be acknowledged that the subgroup of ARMS
subjects who subsequently developed schizophrenia could also
be regarded as patients in the very early stage of the FE, that were
identified earlier than if they had presented to standard psychi-
atric services. However, this would not apply to the majority of
the ARMS group, as they did not go on to develop psychosis.
who did not (ARMS-NT).
1154 BIOL PSYCHIATRY 2007;61:1148–1156
S.J. Borgwardt et al.
We used VBM, a technique that permits comparisons of the
entire brain volume at the single voxel level. We used the ‘opti-
mized’ VBM method (Good et al. 2001) to minimize the potentially
confounding effects of errors in stereotactic normalization. Addi-
tionally, to identify regional differences in gray matter volume
instead of gray matter concentration, we used a ‘modulated’ version
of VBM, which involves the multiplication of the spatially normal-
ized gray matter by its relative volume before and after warping.
Nevertheless, it is important to validate our findings using another
method of analysis, such as a region of interest approach.
An unexpected observation was that a trend for left or
mixed-handedness was more common in the ARMS subjects who
developed a psychosis than in those who did not, although the
actual number of subjects with mixed/left handedness was small.
Nevertheless, this is consistent with an increased prevalence of
left or mixed handedness and abnormalities of cerebral asymme-
try in patients with schizophrenia (DeLisi et al. 1997a) and their
relatives (Orr et al. 1999) and merits further investigation in larger
Subjects with an ARMS showed reduced gray matter volume
relative to controls in areas that were also sites of volume reduction
in schizophrenia. These findings may reflect their increased vulner-
ability to psychosis. There were also volumetric differences within
the ARMS group associated with the subsequent development of
psychosis. These could be related to a process which underlies a
progression from a high risk state toward a psychotic illness. Further
longitudinal neuroimaging studies of subjects with an ARMS should
clarify the significance of these findings.
Parts of this work were presented at the 13thBiennal Winter
Workshop on Schizophrenia Research (Davos, Switzerland, Feb-
ruary, 2006) and at the conference on the Early Phase of
Psychosis (London, April, 2006).
This research was supported by project grants from the Swiss
National Science Foundation (No. 3200-057216-99; 3200-
057216/3), Eli Lilly (Switzerland), AstraZeneca (Switzerland),
Janssen-Cilag (Switzerland) and Bristol-Myers Squibb (Switzer-
land). Furthermore, a personal grant was provided by the Swiss
National Science Foundation (PBBSB-106936) and the Novartis
Foundation. The sponsors of this study had no role in study
design, collection, analysis, interpretation of data, writing of this
report, and in the decision to submit the paper for publication.
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