TITLE

Reductions in frontal, temporal and parietal volume associated with the onset of

psychosis

Stefan J Borgwardta,b,c, Philip K McGuirec, Jacqueline Astona, Ute Gschwandtnera, Marlon O

Pflügera, Rolf-Dieter Stieglitza, Ernst-Wilhelm Radueb, Anita Riecher-Rösslera

aPsychiatric Outpatient Department, University Hospital Basel, Petersgraben , CH-031 Basel,

Switzerland

bNeuroradiological Department, University Hospital Basel, Petersgraben , CH-031 Basel,

Switzerland

cInstitute of Psychiatry, Section of Neuroimaging, King’s College London, De Crespigny Park,

SE5 8AF London, UK

Corresponding author

Dr Stefan J Borgwardt

Psychiatric Outpatient Department

University Hospital Basel

Petersgraben 4

CH-4031 Basel

Switzerland

e-mail: sborgwardt@uhbs.ch

phone: 0041 61 3286126

fax: 0041 61 265 4588

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Abstract

Background: Volumetric MRI abnormalities similar to those evident in schizophrenia are

also evident in people at very high risk of psychosis. Which volumetric abnormalities are

related to psychotic illness, as opposed to vulnerability to psychosis is unclear. The aim of

the study was to compare regional gray matter volume in people before and after the onset

of psychosis using a within-subject prospective design. Methods: MRI data were acquired

from individuals when they presented with an at-risk mental state (ARMS, n=20). Over the

following 3 years, 10 subjects developed psychosis and 10 did not. Subjects were re-

scanned after the onset of psychosis or at the end of follow up if they did not become

psychotic. Images were processed and analysed using voxel-based morphometry (SPM5).

Results: In subjects who developed psychosis there were longitudinal volume reductions in

the orbitofrontal, superior frontal, inferior temporal, medial and superior parietal cortex, and in

the cerebellum. There were no longitudinal changes in subjects who did not develop

psychosis. Conclusions: The onset of psychosis was associated with a reduction in gray

matter volume in frontal, temporal and parietal cortex. These abnormalities may be

particularly associated with psychotic illness, as opposed to a vulnerability to psychosis.

Keywords: schizophrenia, at-risk mental state (ARMS), MRI, gray matter, voxel-based

morphometry (VBM), longitudinal

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1. INTRODUCTION

People at high risk of psychosis show qualitatively similar volumetric abnormalities to pa-

tients with schizophrenia. Cortical brain abnormalities have been found in genetically defined

high-risk populations such as first degree relatives and co-twins of patients with schizo-

phrenia, as well in people with an at-risk mental state (ARMS) (Baare et al., 2001;Boos et al.,

2007;Borgwardt et al., 2007c;Cannon et al., 2002;Hulshoff Pol et al., 2004;Keshavan et al.,

1997;Lawrie et al., 1999;Meisenzahl et al., 2008;Pantelis et al., 2003;Seidman et al., 1999). It

is thus unclear which MRI abnormalities are specific to psychotic illness as opposed to vul-

nerability to psychosis (DeLisi, 2008). We sought to address this issue by comparing regional

brain volume before and after the onset of psychosis in a prospective study. Subjects with an

ARMS have a 20-35% risk of developing psychosis within 2 years (Yung and McGorry,

2007). The only previous longitudinal MRI study in this group found that the subset who de-

veloped psychosis showed a longitudinal reduction in gray matter volume in the left parahip-

pocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri (Pantelis et

al., 2003). An analogous study in patients at genetic risk of psychosis reported that the onset

of psychosis in these individuals was associated with reduced gray matter in the temporal

lobes, the right frontal lobe and right parietal lobe (Job et al., 2005). These findings are con-

sistent with prospective studies in patients with established schizophrenia, which indicate

that longitudinal reductions in regional gray matter volume also occur in chronic patients

(Cahn et al., 2002;Ho et al., 2003;Kasai et al., 2003;Kubicki et al., 2002;Mathalon et al.,

2001;Sporn et al., 2003;Wood et al., 2001).

In the present study, we used magnetic resonance imaging (MRI) to assess regional gray

matter volume in people with an ARMS. Subjects were scanned when they first presented

with ‘prodromal’ symptoms and were then followed clinically for 3 years. Those who de-

veloped psychosis during this period were scanned again after its onset. The other subjects

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were scanned at the end of the 3-year follow up period. On the basis of previous longitudinal

MRI studies of the ARMS and of other groups at high risk of psychosis (i.e. genetic risk)

(Table 1), we tested the hypothesis that transition to psychosis would be associated with lon-

gitudinal reductions in gray matter volume in the frontal, cingulate and temporal cortex. Addi-

tionally, as the only previous longitudinal MRI study in subjects with an ARMS (Pantelis et al.,

2003) had been published in a major general medical journal and is very influential in re-

search, it needs to be replicated in a similar population. Our intention was to replicate that

study with a comparable sample size but a longer follow up period.

TABLE 1

2. MATERIAL AND METHODS

2.1 Participants

Subjects were recruited from a service area covering 200.000 habitants in and around Basel,

Switzerland, in the framework of the FEPSY project (Früherkennung von Psychosen), a

multi-domain study on the early detection of psychosis. The study-design and criteria for

identification of the ARMS subjects has been described in detail elsewhere (Pflueger et al.,

2007;Riecher-Rossler et al., 2007). The study was approved by the local ethics committee of

the University of Basel and has been carried out in accordance with The Code of Ethics of

the World Medical Association (Declaration of Helsinki). Written informed consent was

obtained from each participant.

For this study, we included 20 subjects with an ARMS that agreed to participate in the

imaging arm of the study. 10 developed psychosis in the follow-up period (converters) and 10

did not (non-converters). Subjects were included in the current study if they agreed to an MRI

scan and if the MRI sequences were of adequate quality.

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2.1.1 Screening procedure

For screening purposes, we used the Basel Screening Instrument for Psychosis, BSIP

(Riecher-Rossler et al., 2008), a 46-item checklist based on variables which have been

shown to be risk factors of psychosis (Riecher-Rossler et al., 2006;Riecher-Rossler et al.,

2007) such as DSM-III-R – ‘prodromal’ symptoms, social decline, drug abuse, previous

psychiatric disorders or genetic liability for psychosis. The severity of (pre-) psychotic

phenomena was assessed with the Brief Psychiatric Rating Scale (BPRS), which was used

in combination with the BSIP. The BSIP was constructed as a screening checklist to identify

those at risk and is followed by a more extensive early detection interview in a next step. To

assess the IQ we used the MWT (Lehrl, 1991), an established measure in German-speaking

subjects. All assessments were conducted by experienced psychiatrists who underwent

regular training.

2.1.2 Inclusion criteria for individuals with an at-risk mental state (ARMS)

The ARMS group was defined using criteria closely corresponding to the PACE criteria

(Yung et al., 1998) employed in previous MRI studies of subjects with an ARMS (Borgwardt

et al., 2006;Borgwardt et al., 2007b;Garner et al., 2005;Pantelis et al., 2003;Phillips et al.,

2002;Velakoulis et al., 2006;Borgwardt et al., 2007c;Yung et al., 1998). Inclusion thus

required one or more of the following a) "attenuated" psychotic symptoms b) brief limited

intermittent psychotic 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 symptoms 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 Brief Limited Intermittent Psychotic Symptoms (BLIPS)

required scores of 4 or above on the hallucination item, or 5 or above on the unusual thought

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content, suspiciousness or conceptual disorganisation items of the BPRS, with each

symptom lasting less than one week before resolving spontaneously.

2.1.3 Exclusion criteria

Age below 18 years, insufficient knowledge of German, IQ < 70, previous episode of

schizophrenic psychosis (treated with major tranquillisers for more than 3 weeks), psychosis

due to organic reasons or substance dependency, or psychotic symptoms within a clearly

diagnosed depression, or borderline personality disorder.

2.1.4 Clinical follow-up and transition to psychosis

All subjects were offered supportive counseling and clinical management. Transition to

psychosis was monitored using the BPRS transition criteria according to Yung et al. (Yung et

al., 1998). During the first year of follow-up, high-risk individuals were assessed monthly.

During the second and third years, all individuals were assessed 3-monthly and thereafter

once a year. 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 OPCRIT (Operational Criteria OPCRIT checklist for psychotic and

affective illness) (McGuffin et al., 1991).

2.2 Structural MRI

2.2.1 Acquisition of MRI data

All subjects were scanned twice using a SIEMENS (Erlangen, Germany) MAGNETOM

VISION 1.5 T scanner at the University Hospital Basel. The first scan was done at study

intake. Those subjects who developed psychosis during the follow up period were scanned

again after its onset. The other subjects were scanned at the end of the 3-year follow up

period. Head movement was minimised by foam padding and velcro straps across the

forehead and chin. A three-dimensional volumetric spoiled gradient recalled echo sequence

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generated 176 contiguous, 1 mm thick sagittal slices. Imaging parameters were: time-to-

echo, 4 msec; time-to-repetition, 9.7 msec; flip angle, 12; matrix size, 200x256; field of view,

25.6x25.6 cm matrix; voxel dimensions, 1.28x1x1 mm.

2.2.2 Analysis of gray matter volume

2.2.2.1 Image pre-processing

We analyzed MR images for all subjects on a commercially available (Intel based

workstations running Debian Linux 3.1) using voxel-based morphometry (VBM). Images were

processed with Statistical Parametric Mapping software (SPM5, Wellcome Department of

Imaging Neurosciences, University College London; [http://www.fil.ion.ucl.ac.uk/spm])

running under the MATLAB 7.00 (R14) environment. The image processing steps have been

described in detail elsewhere (Good et al., 2001;Ashburner and Friston, 2000).

In the segmentation step, images were spatially normalized into the same stereotactic space.

In SPM5, prior probability maps that are relevant to tissue segmentation are warped to the

individual brains, making the creation of a customized template unnecessary. The

normalization was performed by first estimating the optimum 12-variable affine

transformation for matching images and then optimizing the normalization using 16 nonlinear

iterations. To preserve the total within-voxel volume, which may have been affected by the

nonlinear transformation, every voxel’s signal intensity in the segmented GM images was

multiplied by the Jacobian determinants derived from the spatial normalization. The analysis

of these modulated datasets was used to detect regional differences in absolute tissue

volume. Finally, all images were smoothed using a 5mm full-width-at half-maximum

Gaussian kernel, as done before in other voxel-based morphometry studies (Honea et al.,

2005). We have chosen a small smoothing kernel, because it allows detecting a greater

number of regions with small structures such as the medial temporal lobes and cingulate.

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Also, according to the matched filter theorem, the width of the smoothing kernel determines

the scale at which morphological changes are most sensitively detected (White et al., 2001).

2.2.2.2 Statistical analysis of MRI data

Between-group differences (baseline vs. follow up) in gray matter volume were estimated by

fitting an analysis of covariance (ANCOVA) model at each intracerebral voxel in standard

space. For each subject follow-up minus baseline difference images were created, and then

analyzed with a regression model with an intercept (parameter of interest) and centered

covariates of age and total gray matter volume. A cluster-defining threshold of p = .001

uncorrected was used, and clusters were considered significant at p < .05 cluster level,

corrected for a whole-brain search. Finally, significant clusters were anatomically localised

using the atlas of (Talairach and Tournoux, 1988), except for foci in and close to the

cerebellum, which were localised using the atlas of (Schmahmann et al., 1999).

2.3 Statistical analysis of clinical and demographic data

Clinical and socio-demographic differences between groups were examined using one-way

analysis of variance (ANOVA), t-test, or chi-square test. Statistical analyses were performed

with the Statistical Package for the Social Sciences (SPSS 12.0).

3. RESULTS

3.1 Sample characteristics

The mean duration between baseline and follow up scan of all ARMS subjects was between

3 and 4 years (Table 2). Nine of the 10 transitions to psychosis occurred during the first year

of follow up and one in the second year. All the subjects who developed psychosis met

OPCRIT criteria for schizophrenia when re-assessed 12 months post transition. Subjects

who developed psychosis were scanned after transition to psychosis. The mean period

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between transition and the follow up scan was 802 days (Table 2). During this period, five

subjects were treated with low doses of atypical antipsychotic medication. A large proportion

of the converters group were scanned within 1-3 days, therefore 5/10 were also

antipsychotic-naive. All subjects were receiving non-specific psychological support or

antidepressive/sedative medication on an outpatient basis. The 10 non-converters did not

differ significantly from the converters with respect to ethnicity, age, gender, handedness,

educational level, and IQ. There was a trend for more severe psychopathology already at

baseline in the converters (Table 2).

TABLE 2

3.2 Gray matter abnormalities during transition to psychosis

Progressive changes in the converters

Comparing baseline and follow up scans, converters showed decreases in gray matter

volume (p<0.05 corrected for multiple comparisons) in the orbitofrontal cortex that included

the right orbital and left rectal gyrus as well as in the right inferior temporal, superior frontal,

and superior parietal lobule, the left precuneus, and the right hemisphere of the cerebellum

(Figure 1).

FIGURE 1

No significant gray matter increases over time in regional gray matter volume were found

(p<0.05 corrected for multiple comparisons). Comparing converter who were neuroleptic

naive at the follow up scan (n=5) with those who were not (n=5) showed no statistically

significant gray matter differences.

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Progressive changes in the non-converters

The non-converters did not show any significant gray matter loss or increases over time in

regional gray matter volume (p<0.05 corrected for multiple comparisons).

A brief review of previous results

At baseline those subjects who later developed psychosis (n=12) had less gray matter than

subjects who did not (n=23) in the right insula, inferior frontal and superior frontal gyrus

(Borgwardt et al., 2007c). Compared to controls, converters had less gray matter in the

posterior cingulate gyrus, precuneus, and paracentral lobule bilaterally which extended into

the left superior parietal lobule already before transition to psychosis (Borgwardt et al.,

2007b), but more gray matter volume in some areas of the left parietal/posterior temporal

region.

4. DISCUSSION

This is one of the first studies to show gray matter volume change around the transition

phase of psychosis using neuroimaging methods. In this longitudinal voxel-based

morphometry study regional gray matter volumes were analysed in 10 subjects with an

ARMS before and after transition to psychosis (converters) and in 10 comparable control

ARMS subjects without transition to psychosis (non-converters). The main findings of this

study were a decrease of cortical volumes in converters in the orbitofrontal cortex that

included the right orbital and left rectal gyrus as well as in the right inferior temporal, superior

frontal, and superior parietal lobule, the left precuneus, and the right hemisphere of the

cerebellum. These findings suggest that at least some of the cortical gray matter

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abnormalities known in schizophrenia patients, occur during the acute process of transition to

psychosis.

Despite a large body of neuroimaging studies in schizophrenia showing multiple subtle brain

abnormalities in this disease, we do not know the exact time course of their occurrence.

Meta-analytic reviews on studies so far primarily conducted on samples of chronic

schizophrenic patients indicate that these patients compared to healthy controls show

reduced brain size, enlarged lateral and third ventricles, reduced frontal lobe volume,

reduced volumes of temporo-limbic structures and of corpus callosum, and increased volume

of basal ganglia (Vita et al., 2006). Neuroimaging studies from first episode schizophrenia

subjects find small reductions in brain volumes at initial presentation (Steen et al., 2006), and

volume loss over time in those patients who have a deteriorating clinical course (DeLisi et al.,

1997;Ho et al., 2003;Lieberman et al., 2001).

In this situation it seems fundamental for the understanding of the pathogenesis of these

brain changes to establish the timing when they occur, in particular to find out whether they

are already present prior to the occurrence of a first psychotic episode. Recent studies

demonstrate that neuroanatomical abnormalities are already evident in first-degree relatives

and co-twins of patients with schizophrenia (Baare et al., 2001;Boos et al., 2007;Cannon et

al., 2002;Hulshoff Pol et al., 2004;Keshavan et al., 1997;Lawrie et al., 1999;Seidman et al.,

1999). In a prior cross-sectional study, we had compared baseline MRI data of the ARMS

sample (n=35) as a whole (independent of subsequent clinical outcome) with healthy controls

and first-episode patients (Borgwardt et al., 2007c). Compared with healthy controls, both

first-episode patients and ARMS subjects showed significantly less gray matter volume in the

posterior part of the left superior temporal gyrus and the adjacent part of the left insula, and

in a second region involving the posterior cingulate gyrus and precuneus (Borgwardt et al.,

2007c;Borgwardt et al., 2008). However, the ARMS group was heterogenous including both,

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patients who later developed psychosis and those who did not. Within the ARMS group,

those subjects who developed psychosis (ARMS-T; n=12) had less grey matter than subjects

who did not (ARMS-NT; n=23) in the right insula, inferior frontal and superior frontal gyrus

(Borgwardt et al., 2007c).

In another study, we found that the subgroup of ARMS subjects who subsequently became

psychotic, had regional gray matter reductions relative to healthy controls in the posterior

cingulate gyrus, precuneus, and paracentral lobule bilaterally which extended into the left

superior parietal lobule before transition to psychosis (Borgwardt et al., 2007b), but more

gray matter volume in some areas of the left parietal/posterior temporal region. This was

consistent with previous reports of relatively increased hippocampal volume (Phillips et al.,

2002) in subjects with an ARMS who later develop psychosis. We discussed that these

differences might be related to an active pathological process that underlies the transition to

psychosis. However, due to the cross-sectional design of these studies these findings could

also have been explained by longstanding differences that predate the onset of ‘prodromal’

symptoms.

Relatively little is known about the nature of the brain abnormalities in this high-risk group

close to the actual process of transition to psychosis (Wood et al., 2008). The transition from

prodromal phase into frank psychosis (Job et al., 2005;Pantelis et al., 2003) and the first two

years of the first-episode (Farrow et al., 2005) has been associated with frontal and temporal

decreases in gray matter. Using a similar voxel-based approach in subjects with an ARMS,

Pantelis et al (Pantelis et al., 2003) found that subjects with ‘prodromal’ symptoms who de-

veloped psychosis showed a longitudinal reduction in gray matter volume in the left parahip-

pocampal, fusiform, orbitofrontal and cerebellar cortices, and the cingulate gyri. In another

longitudinal study with largely the same subjects (Sun et al., 2008), greater brain contraction

was found in the right prefrontal region in people with transition to psychosis compared with

ARMS subjects who did not develop psychosis. The present study confirmed previous re-

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ports on emerging psychosis and suggests that there may be subtle alterations in brain struc-

ture associated with vulnerability to psychosis, but other brain structural changes found in

schizophrenia may emerge as psychosis develops (Job et al., 2005;Lawrie et al., 2002;Pan-

telis et al., 2003;Sun et al., 2008). However, we could not confirm longitudinal changes in an-

terior cingulate found in the Melbourne sample (Sun et al., 2008;Velakoulis et al., 2006); this

might be caused by mixed diagnosis in the converters group of the Melbourne sample while

in contrast, in the present study, all patients with subsequent psychosis developed schizo-

phrenia. It should also also be noted, that the inter-scan interval in the present study was 3-4

years compared to only one year in the (Pantelis et al., 2003) study. Furthermore, the partly

different brain regions could also be due to methodological differences, including the use of

relatively thick slices in the (Pantelis et al., 2003) study.

The changes in gray matter volume that we observed are unlikely to simply be an effect of

treatment with antipsychotic drugs or mood stabilizers, as all of non-converters and half of

the converters were naïve to these medications at the time of second scanning. All of those

who received antipsychotics were treated with atypical compounds in very low doses and

over very short time periods. Furthermore, despite the smallness of numbers, we compared

those converter who were neuroleptic naive at the follow up scan with those who were not

and could not find any gray matter differences. Effects of antipsychotics on gray matter

volume may be less likely with atypicals than typical compounds (Lieberman et al., 2001).

Furthermore, medication effects have been identified in brain regions (such as the caudate)

other than those where group differences were evident in the present study (Dazzan et al.,

2005).

4.1 Limitations

Some limitations of our study should be considered. As in previous neuroimaging studies of

individuals with an At Risk Mental State, our group sizes were modest as these subjects are

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relatively difficult to recruit. As a result we cannot exclude the possibility that we were unable

to detect some group differences because of limited statistical power. However, the sample

is comparable in size to the only other longitudinal VBM study of ARMS (Pantelis et al.,

2003). The only solution to overcome this sample size problem is a multi-centre study using

voxel-based morphometric analyses.

Since our sample was too small to stratify by gender, we cannot comment on the potential ef-

fects of gender on progressive gray matter change during the transition phase. However, we

are aware of gender-differences in our ARMS sample at baseline. In a cross-sectional VBM

analysis of 35 baseline MRI scans of subjects with an ARMS we found that some gray matter

abnormalities were specific for males, whereas others were specific for females (Borgwardt

et al., 2007a).

Furthermore, there was a trend towards a longer inter-scan interval in the non-converters

and follow-up scans were not always acquired immediately after transition to psychosis;

therefore effects secondary to progression of illness subsequent to the onset of psychosis

may have contributed to the observed brain changes in the transition group. However, the

mean period between onset of psychosis and follow up scanning was relatively short. Finally,

although voxel-based morphometric methods are widely used in research in psychiatry and

neuroscience, it would be useful to confirm the present findings with an independent method

of image analysis, such as a region of interest technique (Velakoulis et al., 2006).

4.2 Conclusions

Overall, by using advanced neuroimaging methods optimized for detecting regional

volumetric changes, the results of this study suggest distinct state and trait imaging markers

of psychosis. Gray matter volume loss in orbito-frontal and fronto-temporal areas are

associated with the immediate development of psychosis. These brain areas may be of

particular importance in understanding the neurobiology of the progression towards

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psychosis. These findings are of considerable clinical significance given the proposed use of

brain volume change as intermediate phenotypes.

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Figure 1: Progressive gray matter volume loss during transition to psychosis

In the ARMS who developed psychosis there were progressive gray matter volumes

reductions (blue; p=0.05 corrected for multiple comparisons) in the right superior frontal

gyrus (Talairach coordinates: 24 46 31), orbital gyrus (14 28 -23), inferior temporal gyrus (48

-24 22), superior parietal lobule (32 -56 53) and cerebellum (8 -56 -24) as well as in the left

precuneus (-16 -80 39) and rectal gyrus (-4 28 -25).

Images are presented in standard neurological fashion, with the right hemisphere shown on

the right of the figure, and vice versa. Coordinates (x, y and z) refer to the point of maximal

change in each cluster in stereotactic space as defined in the atlas of Talairach and

Tournoux (1998). Red regions denote areas of gray matter volume reduction during transition

to psychosis.

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Table 1: Longitudinal MRI findings in people at high-risk of psychosis

Center Study group Follow

up

period

MRI method MRI findings

1. At baseline

2. Progressive changes

Edinburgh

High Risk

Study4

Lawrie et al. 2002

19 genetic high risk

subjects with

subthreshold

psychotic symptoms

(12 at first scan)

2 years ROI1

analyses

1) No baseline comparison between

converters and controls.

2) Reductions in temporal lobes (relative

change: 2.3-2.5 %), caudate (0.7-1.1

%), and prefrontal cortex (0.3-0.4 %)

bilaterally

Job et al. 2005

a) 18 genetic high risk

subjects with

subthreshold

psychotic symptoms

b) 8 genetic high risk

subjects who have

developed

schizophrenia

2 years VBM

analysis of

GM3 density

1) No gray matter differences between

converters and non-converters.

2a) Reductions in the right cerebellum

and amygdala as well as in the, left

fusiform gyrus, uncus, superior and

inferior temporal gyrus, and in the

parahippocampal gyrus bilaterally.

2b) Reductions in the left inferior

temporal gyrus, left uncus and the right

cerebellum

Ultrahigh-

Risk (UHR)

Studies

from

Melbourne4

Pantelis et al. 2003

a) 10 ARMS

converters

b) 11 ARMS non-

converters

1 year VBM2

analysis of

GM3 volume

1) At baseline, converters had smaller

grey matter volume in the right medial

temporal, lateral temporal, inferior

frontal cortex, and in the cingulate

bilaterally

2a) Converters had gray matter volume

reductions in the left parahippocampal,

fusiform, orbitofrontal and cerebellar

cortices, and the cingulate gyri.

2b) In non-converters, GM reductions

were restricted to the cerebellum

Sun et al. 2008

12 ARMS converters

1 year Cortical

surface

1) No control group.

- 25 -

vs.

23 ARMS non-

converters

motion

analysis

2) Compared to non-converters,

converters had greater brain surface

contraction in the right prefrontal region,

and with a non-significant trend in the

left prefrontal region and bilateral

occipital poles1 ROI = Region-of-Interest

2 VBM = Voxel-based morphometry

3 GM = Gray matter

4 Samples from the same center are largely overlapping.

- 26 -

Table 2: Demographic characteristics of the individuals with an at-risk mental state

who developed psychosis (Converters) and those who did not (Non-Converters)

Characteristic Converters

(n=10)

Non-

Converters

(n=10)

P

Age at baseline (mean years, SD) 25.2 (6.7) 24.2. (6.1) ns

Age at follow-up scan (mean years, SD) 28.1 (6.5) 28.3 (6.4) ns

Gender (male/female) 7/3 5/5 ns

Handedness (mixed or left) 1) 2 0 ns

Educational level

<9 yrs

9-11 yrs

12-13 yrs

>13 yrs

2

4

4

0

3

4

1

2

ns

IQ (MWT) 2) 110.1 (10.8) 109.5 (13.5) ns

BPRS total score at intake 41.6 (9.7) 35.4 (4.6) ns °

SANS score at intake 9.5 (5.8) 5.1 (3.9) ns °

Subjects with antipsychotics at baseline scan 1 0 ns

Subjects with antipsychotics at follow up scan 5 0 0.01

Intracranial brain volume .761 (.06) .756 (.08) ns

Days between scans 1034 (648) 1495 (252) ns °

Days between baseline scan and onset of psychosis 232 (203)

Days between onset of psychosis and follow up scan 802 (722)

ns ° = p<0.1

1) One value is missing in the Converters

2) Two values are missing in the Non-Converters