Anatomically related grey and white matter
abnormalities in adolescent-onset schizophrenia
Gwenae «lle Douaud,1Stephen Smith,1Mark Jenkinson,1Timothy Behrens,1Heidi Johansen-Berg,1
JohnVickers,1Susan James,2NatalieVoets,1,3Kate Watkins,1,4Paul M. Matthews1,3and Anthony James2
1FMRIB Centre, Department of Clinical Neurology,University of Oxford, John Radcliffe Hospital,Oxford,
2Highfield Adolescent Unit,Warneford Hospital,Oxford,3GlaxoSmithKline Clinical Imaging Centre,
Hammersmith Hospital and Department of Clinical Neurosciences, Imperial College, London and4Department of
Experimental Psychology,University of Oxford,UK
Corresponding to: Dr Gwenae «lle Douaud, FMRIB Centre,University of Oxford, John Radcliffe Hospital, Headington,
Adolescent-onset schizophrenia provides an exceptional opportunity to explore the neuropathology of
schizophrenia free from the potential confounds of prolonged periods of medication and disease interactions
with age-relatedneurodegeneration.Our aimwas toinvestigate structuralgrey and white matter abnormalities
in adolescent-onset schizophrenia. Whole-brain voxel-wise investigation of both grey matter topography and
white matter integrity (Fractional Anisotropy) were carried out on 25 adolescent-onset schizophrenic patients
and 25 healthy adolescents.We employed a refined voxel-based morphometry-like approach for grey matter
analysis and the recently introduced method of tract-based spatial statistics (TBSS) for white matter analysis.
Both kinds of studies revealed widespread abnormalities characterized by a lower fractional anisotropy neuro-
anatomically associated with localizedreduced grey matterin the schizophrenic group.The grey matterchanges
can either be interpreted as the result of a locally reduced cortical thickness or as a manifestation of different
patterns of gyrification.There was a widespread reduction of anisotropy in the white matter, especially in the
corpus callosum.We speculate that the anisotropy changes relate to the functional changes in brain connectivity
that are thought to play a central role in the clinical expression of the disease.The distribution of grey matter
changes was consistent with clinical features of the disease. For example, grey and white matter abnormalities
found in the Heschl’s gyrus, the parietal operculum, left Broca’s area and the left arcuate fasciculus (similar to
previous findings in adult-onset schizophrenia) are likely to relate to functional impairments of language and
auditory perception. In addition, in contrast to earlier studies, we found striking abnormalities in the primary
sensorimotor and premotor cortices and in white matter tracts susbserving motor control (mainly the pyrami-
dal tract). This novel finding suggests a new potential marker of altered white matter maturation specific to
adolescent-onset schizophrenia. T ogether, our observations suggest that the neuropathology of adolescent-
onset schizophrenia involves larger and widespread changes than in the adult form, consistent with the greater
Keywords: schizophrenia; age of onset; voxel-based morphometry; diffusion tensor imaging; pyramidal tract
Abbreviations: DLPFC=dorso-lateral prefrontal cortex; DTI=diffusion tensor imaging; FA=fractional anisotropy;
FEF=frontal eye field; FSL=FMRIB (functional magnetic resonance imaging of the brain centre) software library;
IRTK=image registration toolkit; MD=mean diffusivity; ROI=region of interest; SMA=supplementary motor area;
SPM=statistical parametric mapping;TBSS=tract-based spatial statistics; VBM=voxel-based morphometry;
Received April 4, 2007 . Revised July 3, 2007 . Accepted July10, 2007
Various models of the pathophysiological process in
schizophrenia are still debated. Although a neurodevelop-
mental hypothesis for schizophrenia is now well established
(Rapoport et al., 2005), some observations still suggest
that a contribution from a degenerative process following
the onset of psychosis is superimposed on the develop-
mental impairments (Lieberman, 1999; Church et al., 2002;
doi:10.1093/brain/awm184Brain (2007) Page1of12
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Perez-Neri et al., 2006). Other reports suggest that altered
plasticity may also play a pathogenic role in the disease
(Feinberg, 1982; Sporn et al., 2003; Vidal et al., 2006).
Early-onset schizophrenia offers a unique opportunity
to explore the aetiology of this major mental disorder.
In particular, an understanding of the interplay of the
disease-associated pathology and normal brain develop-
ment may offer crucial insights into the pathophysiological
process of the disease. Age-related changes in grey matter
throughout normal adolescence are dynamic, with sub-
stantial thinning of cortical grey matter starting initially in
primary areas and occurring later in the secondary cortices
of the frontal and parietal lobes and finally in the temporal
lobes (Giedd et al., 1999; Sowell et al., 2001; Gogtay et al.,
2004; Paus, 2005). In early-onset schizophrenia, the rate
of grey matter loss appears greater, with larger changes
found in parietal brain regions extending anteriorly into
temporal lobes, involving also the sensorimotor and dorso-
lateral prefrontal cortices, as well as frontal eye fields
(Thompson et al., 2001) and with a superior medial
frontal grey matter loss later reaching the cingulate gyrus
(Vidal et al., 2006).
Fractional anisotropy (FA), a proxy measure of white
matter integrity, normally increases from the neonatal
period to adulthood (Schneider et al., 2004; Barnea-Goraly
et al., 2005; Ben Bashat et al., 2005; Ashtari et al., 2007).
Two diffusion tensor imaging (DTI) studies of adolescent-
onset schizophrenia have revealed reduced FA in the frontal
and in the right occipital white matter, and in the left
posterior hippocampus (Kumra et al., 2004; Kumra et al.,
2005; White et al., 2007). Current theories of schizo-
phrenia highlight the potential role of altered brain
connectivity that may be manifest at a macro-anatomical
level through structural changes of white matter tracts
(Stephan et al., 2006).
However, as most cases are first diagnosed between the
age of 20 and 25 years, the majority of structural brain
imaging studies in schizophrenia thus far has been confined
to adult subjects. We are aware of only a few studies that
have explored whole-brain changes in early-onset schizo-
phrenia on a voxel-by-voxel basis (Sowell et al., 2000;
Thompson et al., 2001; Vidal et al., 2006). Moreover,
despite a prolific literature, the structural cerebral changes
revealed in adult-onset schizophrenia have previously
shown great inconsistencies, partly due to the heterogeneity
of the methods applied and to special methodological
problems in working with this disease population, such
as appropriately handling the enlargement of ventricles
(Shenton et al., 2001; Honea et al., 2005; Kanaan et al.,
2005; Kubicki et al., 2005; Walterfang et al., 2006; Kubicki
et al., 2007). In performing the work described here,
we took advantage of recent advances in voxel-based grey
matter morphometry and white matter integrity analyses,
as well as more appropriate statistical inferences.
The first aim of our study was to investigate differences
in the topographic distribution of grey matter between
adolescent-onset schizophrenic patients and healthy adoles-
cent subjects, making no a priori assumptions about the
location of possible abnormalities. Second, using diffusion-
weighted images, we tested for alterations in the white
matter integrity that could be related to grey matter
changes, to work towards building a more comprehensive
neuroanatomical characterisation of the disease.
The study was undertaken in accordance with the guidance of
the Oxford Psychiatric Research Ethics Committee and written
consent was obtained from all participants (and their parents if
under the age of 16 years).
Twenty-five adolescent-onset schizophrenic participants (18 men,
7 women, aged 13 to 18 years) were recruited from the Oxford
diagnosed as having DSM IV (APA, 1994) schizophrenia, using
the Kiddie Schedule for Affective Disorders and Schizophrenia
(Kaufman et al., 1997). In addition, the participants were
administered the Positive and Negative Syndrome Scale (PANSS)
(Kay et al., 1989). Age at onset of symptoms ranged from 11 to
17 years. All schizophrenic patients were receiving atypical
antipsychotics (Table 1).
Twenty-five healthy control participants, matched for age and
sex to the patient group, were included in this study. These
adolescent control participants were recruited from the commu-
nity through their general practitioners and were screened for
any history of emotional, behavioural or medical problems.
Questionnaire (Oldfield, 1971). All participants attended normal
schools. Exclusion criteria included moderate mental impairment
(IQ560), a history of substance abuse or pervasive developmental
disorder, significant head injury, neurological disorder or major
medical disorder (Table 1). Three schizophrenic patients and one
control fulfilled criteria for mild learning disability according to
DSM-IV (IQ 470) but showed no brain lesion on their respective
The 50 participants underwent the same imaging protocol with
a whole-brain T1-weighted and diffusion-weighted scanning
using a 1.5T Sonata MR imager (Siemens, Erlangen, Germany)
with a standard quadrature head coil and maximum 40mT.m?1
The 3D T1-weighted FLASH sequence was performed with
the following parameters: coronal orientation, matrix 256?256,
208slices, 1?1mm2in-plane resolution, slice thickness 1mm,
TE/TR=5.6/12ms, flip angle ?=19?.
Diffusion-weighted images were obtained using echo-planar
bandwidth=1860Hz/vx, voxel size 2.5?2.5?2.5mm3) with 60
isotropically distributed orientations for the diffusion-sensitising
gradients at a b-value of 1000s.mm?2and 5 b=0 images.
To increase signal-to-noise ratio, scanning was repeated three
times and all scans were corrected for head motion and eddy
currents using successive affine registrations before being averaged.
Page 2 of12Brain (2007)G. Douaud et al.
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As we wanted to investigate voxel-wise changes between schizo-
phrenic patients and control participants across the whole brain,
it was important that the use of non-linear deformations to
register native scans into a common space was carried out with
appropriate accuracy. The details of non-linear transformations
may considerably influence the results, depending on the nature
of the spatial registration itself or the dimensionality of the
underlying model (Ashburner and Friston, 2001; Bookstein, 2001;
Crum et al., 2003). Thus, two voxel-based analyses using different
practical methodologies for the automated segmentation and
registration of the brains were carried out for the investigation of
the grey matter morphometry:
I. We conducted an ‘optimized’ VBM-style protocol (Good
et al., 2001) using FSL tools (Smith et al., 2004, www.fmrib.
ox.ac.uk/fsl) for brain extraction (Smith, 2002) and segmenta-
tion (Zhang et al., 2001) and the IRTK tool for non-rigid
(Rueckert et al., 1999) to spatially register the native images.
II. We then verified that we were able to reproduce similar
patterns of grey matter change with the optimized VBM
protocol using the standard segmentation and registration tools
available in the statistical parametric mapping software (SPM2,
www.fil.ion.ucl.ac.uk/spm) (Ashburner et al., 2000; Ashburner
and Friston, 2000).
using spline-basedfree-form deformation
Thecommon optimizedprotocol carried out toassess
differences in the topographic distribution of grey matter between
adolescent-onset schizophrenic patients and controls was the
following: first, a left–right symmetric study-specific grey matter
template was built from the 50 grey matter-segmented native
images and their respective mirror images that were all affine-
registered to the ICBM-152 grey matter template. The 50 native
grey matter volume images were then non-linearly normalized
onto this template (Fig. 1). The optimized protocol also intro-
duces a compensation (or ‘modulation’) for the contraction/
enlargement dueto the non-linearcomponent of the
T able1 Demographics data of adolescent-onset schizophrenic patients and controls
Age M (mean?SD)
Age F (mean?SD)
Full scale intelligence quotient (range, mean?SD)
Socio-economic status (The national statistics socio-economicclassification.
Age at onset of symptoms (range, mean?SD)
Disease duration (mean?SD)
PANSS: positive scores (mean?SD)
PANSS: negative scores (mean?SD)
Chlorpromazine equivalents (mean?SD)
Details of the treatment in mg.
Rd=risperidone depot (injectable)
R1; R3; R4+Rd37 .5;
Fig.1 Reduced grey matter in patients in Heschl’s gyri (left; z=10), the SMA (middle; x=4) and the parietal operculi (right; z=22)
obtained with the FSL-VBM approach overlaid on the average of the non-linearly registered T1-weighted images.
Imaging adolescent-onset schizophreniaBrain (2007)Page 3 of12
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transformation: each voxel of each registered grey matter image
was divided by the Jacobian of the warp field. Finally, all 50
modulated normalised grey matter volume images were smoothed
with an isotropic Gaussian kernel with a sigma of 3.5mm (?8mm
White matter preprocessing
FA, mean diffusivity (MD), ?//(first eigenvalue) and ??(average
of the second and third eigenvalues) maps were generated using
DTIFit within the FMRIB Diffusion Toolbox (part of FSL; Smith
et al., 2004).
Voxel-wise differences in DTI indices were assessed using
Tract-Based Spatial Statistics (TBSS, also part of FSL), a recent
approach which increases the sensitivity and the interpretability of
the results compared with voxel-based approaches based purely
on non-linear registration (Smith et al., 2006). Ventricular
enlargement caused by the pathophysiological process may for
instance considerably mislead the interpretation of the voxel-based
results. TBSS aims to solve the problematic issues of standard
voxel-wise methods via the use of a carefully tuned non-linear
registration (the same as was used for the grey matter analysis
earlier), followed by the projection of the nearest maximum
FA values onto a skeleton derived from a mean FA image. This
projection step aims to remove the effect of cross-subject spatial
variability that remains after the non-linear registration.
Finally, special care has also been given to the statistical method
employed to investigate changes in the grey matter distribution
and white matter integrity. To achieve accurate inference includ-
ing full correction for multiple comparisons over space, we used
permutation-based non-parametric inference within the frame-
work of the general linear model (Nichols and Holmes, 2002)
to investigate changes in the distribution of grey matter, FA and
MD between both groups (5000 permutations). Results were all
considered significant for P50.01 (after initial cluster-forming
thresholding at P-uncorrected=0.05), fully corrected for multiple
comparisons. We also carried out exactly the same analyses with a
subset of 15 right-handed schizophrenic males (mean age?SD:
16.4?1.4) and 15 age-matched right-handed control males (mean
age?SD: 16.3?1.6) to account for any possible gender?disease,
handedness?disease or gender?handedness?disease interaction
in our grey and white matter results.
In addition, we performed a simple regression analysis with
the antipsychotic dosage (chlorpromazine equivalent) within the
patient group, to explore whether the therapy interacts with trait-
related structural abnormalities.
Significant differences between patients and control participants
in ?// and ?? (within the clusters showing significant changes
of anisotropy between both groups) were investigated by averag-
ing the relevant eigenvalue data across ROIs identified by the
Finally, we tested the potential for changes identified at the
group level to distinguish cases from controls at an individual
level. We therefore applied a simple multivariate discriminant
analysis on the 50 smoothed and modulated grey matter images,
using leave-one-out testing to form a discriminant vector from
N-1 participants and testing this on the subject left out. This gives
an unbiased estimation of discrimination ability between the
groups of participants. We used the group-mean-difference
t-statistic (from the two groups of participants within the N-1
subset) as the discriminant function.
Grey matter results
adolescent-onset schizophrenic patients revealed a highly
significant bilateral difference in grey matter volume
distribution (patients5controls) in Heschl’s gyrus, the
parietal operculum and the supplementary motor area
(SMA). It also showed significant bilateral differences
(patients5controls) in the primary sensory and in the
primary motor cortices. Significant reduced grey matter in
the patients was also demonstrated in the left premotor
cortex [including regions in Broca’s area 44 and in the
frontal eye field (FEF)] and in the right anterior cingulate
gyrus, the right dorso-lateral prefrontal cortex (DLPFC),
the precuneus and the temporal lobes (Figs 1, 2 and 5)
(Table 2). When possible, these results were checked using
a toolbox providing probabilistic cytoarchitectonic maps in
the MNI standard space (Eickhoff et al., 2005).
No significant differences were found when testing the
opposite contrast (patients4controls).
Though it no longer survived the correction for multiple
comparisons due to a reduction of the statistical power,
the pattern of grey matter results found with the VBM
analysis on the two subsets of right-handed males only was
very similar to the one obtained with the gender and
handedness mixed (but matched) populations.
The pattern of grey matter results found with the SPM2-
based VBM analysis was also similar to that obtained with
the FSL software (Fig. 3). The difference was that we found
slightly fewer significant clusters with SPM2-VBM than
with FSL-VBM (see Supplementary Material, Table S1).
The spatial map resulting from the simple regression
analysis of grey matter volume loss with dosage of
antipsychotics in the patient group did not show any
similarity to the patients–controls difference map (see
Supplementary Material, Figure S1).
The discriminant analysis on the smoothed modulated
grey matter images was able to detect adolescent-onset
schizophrenic participants with 88% sensitivity and 80%
specificity. Classification of the participants into one of the
two groups demonstrated 84% accuracy (42/50 participants
were correctly classified according to their diagnosis).
comparison of controlparticipants and
White matter results
TBSS mapping of anisotropy differences between the
adolescent-onset schizophrenic patients and the healthy
controls demonstrated a highly significant bilateral decrease
of FA in the pyramidal and the corticopontine tracts,
the superior thalamic radiations and the medial lemniscus
in patients (Figs 4 and 5) and reduced anisotropy in the
corpus callosum (from the splenium to the genu), the left
Page 4 of12Brain (2007) G. Douaud et al.
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Fig. 2 3D representation of the significant grey matter loss found in patients overlaid on an inflated cortical surface (FSL-VBM).
T able 2 Local peaks of the significant clusters (corrected P-value50.01) showing reduced grey matter in the patient group
(FSL-VBM) contrasted with the controls (secondary local maxima within a cluster are also presented when required)
Cortical region (BA)Side MNI (mm) Local maximum
Parietal operculum (BA40)
Parietal operculum (BA40)
Pars opercularis (BA44)
! Pars opercularis (BA44)
Post-central gyrus (BA2)
Pre-central gyrus (BA4)
Post-central gyrus (BA1)
Pre-central gyrus (BA4)
Anterior cingulate gyrus (BA24/32)
! Anterior cingulate gyrus (BA32)
! Anterior cingulate gyrus (BA24/32)
! DLPFC (BA9)
Calcarine fissure (BA17)
Inferior temporal gyrus (BA20)
Middle temporal gyrus (BA20/21)
Imaging adolescent-onset schizophrenia Brain (2007) Page 5 of12
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arcuate fasciculus and the left optic radiations (Figs 4
and 5). The pyramidal and corticopontine tracts could be
differentiated from the medial lemniscus in the brainstem
There were no relative increases in FA or MD in the
The pattern of reduced anisotropy found with the TBSS
analysis on the two subsets of right-handed males only was
similar to the one obtained with the gender and handedness
mixed populations, but did not survive the correction for
The spatial map resulting from the simple regression
analysis of reduced FA with dosage of antipsychotics in the
patient group did not show any significant result.
Both the mean ?// and mean ??, averaged across
the clusters ofsignificantly
patients comparedwith controls,
different between the two groups: ?//(?10?3mm2.s?1) was
relatively reducedin the
1.218?0.008; patients: 1.186?0.008, P50.03), while ??
Fig. 4 Significant reduction of FA in the corticospinal/
corticopontine tracts, the superior thalamic radiations, the
left optic radiations, the corpus callosum, the left arcuate
fasciculus and in the brainstem (distinction of the corticospinal/
corticopontine tracts and the medial lemniscus) of the
adolescent-onset schizophrenic patients overlaid on the mean
FA map.The skeletonized results have been thickened for
better visibility. A red^green^blue rendering of the orientation
of the white matter tracts (red=x-axis; green=y-axis;
blue=z-axis) has been overlaid to help identifying the
corticospinal tract (blue).
Fig. 3 FSL-VBM results (red) and SPM-VBM results (blue)
represented for the same range oft-values (42.8).Results are very
similar for instance in Brodmann area 44, the parietal operculi
and the occipital lobe.
Fig. 5 Examples demonstrating the correspondence between grey
and white matter results: decrease of FA in the corticospinal/cor-
ticopontine tracts (green) and grey matter loss in the SMA (red) in
the top row on an axial view; decrease of FA in the left arcuate
fasciculus (green) and grey matter loss in Brodmann area 44 (red)
in the middle row on a sagittal view and in the bottom row on a
coronalview.Results were overlaid on a single control subject for a
better identification of the regions involved.
Page 6 of12Brain (2007) G. Douaud et al.
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(?10?3mm2.s?1) was increased (controls: 0.570?0.006;
patients: 0.587?0.006, P50.04).
Correspondence between grey and white
There was good concordance between the reduced grey
matter and the decrease of anisotropy found in the left
Brodmann area 44 and the left arcuate fasciculus of the
patients (Fig. 5). The primary sensori-motor, premotor
and supplementary motor cortex changes are related
anatomically with reduced FA in the pyramidal and the
corticopontine tracts, the posterior superior thalamic
radiations and the medial lemniscus (see example in
Fig. 5). Both a region in the left primary visual cortex
abnormalities in the patients.
Patients with early-onset schizophrenia present with more
severe symptoms and signs than adult-onset patients
(Rapoport et al., 2005; White et al., 2006). Our study
allows us to relate the clinical pattern of deficits to trait-
associated differences in grey matter distribution and in
white matter microstructure. A comparison between this
study and previous imaging investigations of adult-onset
schizophrenia suggests qualitatively similar patterns of
change relative to age-matched healthy controls, consistent
with the hypothesis that there is a continuum of disease
with a common neuropathological substrate. However, an
unexpected observation in our study of the adolescent
population was the remarkably large grey matter changes
consistent with altered white matter integrity in motor
control regions. These have not traditionally been con-
sidered as major sites of pathological change. They might
possibly representa surrogate
dynamicsof white matter
Grey matter morphological changes in
The topography of grey matter changes in the adolescent-
onset schizophrenic subjects suggests a structural substrate
for the relatively severe functional impairments in language
and working memory for early-onset schizophrenic patients
(White et al., 2006). The VBM-style analysis revealed
differences in the grey matter topographic distribution
bilaterally in Heschl’s gyri, the parietal operculum and in
the left Brodmann area 44 in Broca’s area of adolescent-
onset patients. The different patterns of grey matter
distribution found in the Heschl’s gyri are consistent with
previous ROI approaches showing a bilateral decrease of
volume in male patients with paranoid schizophrenia
(Rojas et al., 1997) and in both female and male first-
episode schizophrenic patients (Hirayasu et al., 2000).
A voxel-wise approach using deformation-based morphom-
etry also suggested that there may be a correlation of local
volume decrease in left Heschl’s gyrus and severity of
auditory hallucinations (Gaser et al., 2004). Remarkably,
concomitant with the increased activation in Heschl’s gyri
of patients having verbal auditory hallucinations, significant
correlations between BOLD signal and temporal hallucina-
tion pattern were also found in the left parietal operculum
and Broca’s area (Dierks et al., 1999). The left parietal
operculum, sometimes referred as the anterior supramar-
ginal gyrus, was also found involved in greater rate of
clinical improvement for subjects with auditory/verbal
hallucinations when targeted by transcranial magnetic
stimulation (Hoffman et al., 2007).
We found loss of grey matter in the right anterior
cingulate gyrus. This finding is in line with two previous
reports using ROI analysis that demonstrated a reduced
volume in the right anterior cingulate cortex in schizo-
phrenia (Zhou et al., 2005) and in first-episode schizo-
phrenia (Lopez-Garcia et al., 2006). Interestingly, using
dynamic causal modelling in schizophrenic patients relative
to healthy subjects, Mechelli and coworkers showed a
bilateral reduction in the functional intrinsic connectivity
between Heschl’s gyrus and the anterior cingulate cortex
(Mechelli et al., 2007). This suggests functional interactions
between these regions, which we speculate may be related to
the core symptoms of auditory hallucinations.
We also provide evidence for reduced grey matter
volume in the right dorso-lateral prefrontal cortex. This
result extends observations from two earlier studies investi-
gating insight in first-episode antipsychotic-naive schizo-
phrenic patients, in which a volume reduction in the right
DLPFC was reported for patients presenting with poor
insight compared with those who had good insight and
there was a negative correlation of this volume with
awareness of symptoms (Shad et al., 2004, 2006).
However, functional deficits in schizophrenia are not
confined to cognitive domains of language and auditory
perception. White and coworkers have highlighted greater
relative motor performance deficits in adolescent patients
compared with adult-onset patients (White et al., 2006).
More severe impairments of motor control have been
related to an earlier age of diagnosis (Manschreck et al.,
2004). Consistent with these clinical findings, we found
striking differences in the distribution of grey matter
in sensorimotor and premotor areas (S1, M1, SMA,
Brodmann area 44 and FEF). These findings are consistent
with the results of an earlier deformation-based approach
which showed accelerated loss of grey matter in early-onset
schizophrenic patients in the sensorimotor, supplementary
motor and frontal eye fields relative to matched healthy
controls (Thompson et al., 2001). In our study, we found
also a lower fractional anisotropy in the corticospinal
tract (and in a white matter region that we presume to be
in the corticopontine tract) and in the superior thalamic
Imaging adolescent-onset schizophreniaBrain (2007)Page 7 of12
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Although sensorimotor and premotor areas appear not
to have been a major focus of attention for a long time
in structural analyses of schizophrenia, some studies have
recently reported a bilateral reduction of grey matter
volume in line with our findings in the SMA (Suzuki
et al., 2005; Exner et al., 2006; Lopez-Garcia et al., 2006)
and in the pre-central and the post-central gyri (Zhou
et al., 2005, 2007). Loss of grey matter in the primary
motor area and the SMA might be related to the impaired
psychomotor performance, extrapyramidal symptoms and
the presence of neurological soft signs (Dazzan and Murray,
2002; Bachmann et al., 2005) that have been detected in
schizophrenic patients (Jahn et al., 2006; Putzhammer and
Klein, 2006). Interestingly, these disturbances have been
also found in never-medicated patients and in adolescents
who later developed schizophreniform disorders (Gupta
et al., 1995; Chatterjee et al., 1995; Flyckt et al., 1999;
Cannon et al., 2006).
It is notable that most of the premotor and motor
regions revealed by the grey matter analysis can be related
to speech production. In addition to our finding in
Brodmann area 44, we have provided evidence for a signifi-
cantly reduced grey matter in the SMA, a region that plays
a role in word production (Ziegler et al., 1997; Blank et al.,
2002; Alario et al., 2006; Tremblay and Gracco, 2006).
Finally, the bilateral local peaks of grey matter volume
reduction in the primary motor cortex are localized in the
middle of the functional representation of the mouth based
on a meta-analysis of PET studies (Fox et al., 2001).
Interestingly, parietal operculum at its junction with the
temporal lobe is considered to act as an interface between
posterior temporal cortex (speech perception) and motor
cortex (speech production) (Wise et al., 2001).
Interpretation of grey matter changes
defined by voxel-wise analysis
The similar pattern of the grey matter abnormalities
found with two different practical methodologies reinforce
our confidence in these results. We found a few more
significant clusters with FSL-VBM than with SPM2-VBM,
analysing the data with the same statistical model. Because
there could be a continuum of results, dependent on the
degrees of freedom of the non-rigid registration (Crum
et al., 2003), this small divergence may be due to the
slightly more accurate non-linear registration used within
the FSL-VBM preprocessing (free-form deformation with
20mm initial control point spacing in this analysis,
Rueckert et al., 1999) than in the SPM2-VBM (discrete
a 25mm cutoff in our study, Ashburner et al., 2000).
Interpretation of such voxel-wise analyses in the grey
matter has inherent limitations, however. Indeed, although
consistent with some previous volumetric findings, it is
not possible to clearly determine if the results we found
are the consequenceof
developmentally reduced thickness or atrophy or rather
an indirect reflection of a different gyrification pattern
associated with this disease. It might be possible that a
misalignment of the gyri/sulci or even different folding
patterns may lead to the difference of grey matter
distribution that we found between healthy and patient
groups. White and colleagues have found significant
changes of the sulco-gyral morphology in adolescent-onset
schizophrenia (White et al., 2003). Many other studies have
found either a localised increase of the gyrification index
(GI) (Vogeley et al., 2000, 2001; Harris et al., 2004;
Narr et al., 2004; Falkai et al., 2006) or a decrease of the
gyrification complexity (Kulynych et al., 1997; Sallet et al.,
2003; Jou et al., 2005; Wheeler and Harper, 2007; Bonnici
et al., 2007). Among these different analyses, one study
has explored whole-brain cortical folding in the largest
population of schizophrenic patients (N=40), confirming
the increase of GI in the prefrontal cortex identified
by Vogeley and colleagues and also showing a decrease of
GI in the rest of the cortex (Sallet et al., 2003). Study of
cortical thickness (and cortical area labelling) in these
participants should allow the confound of potential sulci
misalignment to be overcome to identify among our results
those representing an effective loss of grey matter from
those characterising difference in sulco-gyral patterns
(Voets et al., in preparation).
Changes in white matter integrity are related
anatomically to the grey matter pathology
We believe that our approach to defining the white matter
pathology represents an advance over previously applied
strategies (Smith et al., 2006). This may contribute to the
greater extent and clinico-pathologically more consistent
changes that we have observed relative to earlier DTI
studies in early-onset schizophrenia (Kumra et al., 2004,
2005; White et al., 2007). In addition, the combined
application of diffusion- and T1-weighted imaging has
allowed us to directly relate grey and white matter
pathology (Fig. 5).
Associated with reduced grey matter found in the caudal
end of superior temporal and inferior parietal parts of
the Sylvian fissure (Heschl’s gyri and parietal operculum)
and in the left pars opercularis of Broca’s area, we found
thata partof thesuperior
presumably the arcuate fasciculus, showed a left-lateralized
reduced degree of anisotropy. This white matter change is
consistent with two reports in adult-onset schizophrenia
(Burns et al., 2003; Pugliese et al., 2007). The arcuate
fasciculus has been investigated recently in detail in vivo by
DTI tractography studies in human brains (Catani et al.,
2005; Makris et al., 2005; Parker et al., 2005; Powell et al.,
2006; Schmahmann et al., 2007) and confirmed to
connect Wernicke’s area (rostrally bordered by Heschl’s
gyrus) and Broca’s area through the parietal operculum
(or supramarginal gyrus) more extensively on the left than
Page 8 of12Brain (2007)G. Douaud et al.
by guest on June 6, 2013
et al., 2006).
In correspondence with the grey matter abnormalities
found bilaterally in the primary motor, the premotor and
the supplementary motor cortices, TBSS analysis of FA
shows a reduced anisotropy in the pyramidal tract of
adolescent-onset schizophrenic patients. A third of the
pyramidal tract neurons originate from M1, the rest of
them arising from premotor area and SMA (Nolte, 1999).
The corticospinal tract changes may be specifically related
to the early age at symptom onset (Manschreck et al.,
2004). The changes may be especially prominent as they
occur in brains that are still developing during adolescence,
especially in the (sensori)motor-related areas (Sowell et al.,
2001; Paus, 2005; Toga et al., 2006). Particularly, the
posterior limb of the internal capsule is thought to be one
major area of white matter development during childhood
and adolescence (Paus et al., 1999; Schmithorst et al., 2002;
Barnea-Goraly et al., 2005; Ashtari et al., 2007). Hence, it is
likely that this exceptional finding in the corticospinal tract
may be the marker of a delay in white matter maturation
specific to adolescent-onset schizophrenia, as none of the
DTI studies investigating adult-onset schizophrenia have
found a change of anisotropy in this tract or, even more
generally, in any tract present in the posterior limb of
the internal capsule (Kanaan et al., 2005; Kubicki et al.,
We indeedalso found
of anisotropy in the corticopontine tract, the superior
thalamic radiations and the medial lemniscus, together
the functional disconnection
considered as a fundamental abnormality in schizophrenia
(Andreasen et al., 1996; Honey et al., 2005). The posterior
part of the superior thalamic radiations together with the
medial lemniscus (the ‘posterior column-medial lemniscus
system’ in Mettler, 1948) and the posterior part of the
corticopontine tract are the two major ascending and
descending pathways of the primary somatosensory cortex.
The reduced integrity found in these tracts may thus be
closely related to the bilateral grey matter loss demonstrated
in theprimary somatosensory
result, in line with the first recent report of a grey matter
atrophy in the post-central gyrus (Zhou et al., 2007), gives
a probable structural substrate for the subtle somatosensory
disturbances observed in schizophrenic patients (Ritzler
et al., 1977; Javitt et al., 1999; Tanno et al., 1999).
right hemisphere (Parkeretal., 2005;Powell
a bilaterallower degree
of which is generally
cortex. This latter
Functional consequences of loss
of white matter integrity
Inter- and intra-hemispheric connectivity disturbances have
been suggested to play a major role in schizophrenia
(McGlashan and Hoffman, 2000; Stephan et al., 2006). Our
findings of a widespread reduction of anisotropy in the
white matter seem to further support the hypoconnectivity
hypothesis, which suggests that neuronal interactions could
be altered by subtle microstructural abnormalities in the
spatial distribution of synapses, length or calibre of axons
or the geometry of axonal branches (Beaumont and
Dimond, 1973; Friston and Frith, 1995; Innocenti et al.,
2003). The decrease of anisotropy revealed in the white
matter can be interpreted either as a loss of organization
of the fibres (which is expected to be associated with
a reduction of the longitudinal diffusivity ?//) or as an
alteration of the myelin (which should be associated with
an increase of the transverse diffusivity ??) (Beaulieu, 2002;
Song et al., 2002; Concha et al., 2006). Both types of change
were found in the adolescent-onset schizophrenia group.
Previous work has demonstrated impairments of myelina-
tion in chronic schizophrenia and a lack of a significant
relationship between myelin water fraction and age,
suggesting the absence or the delay in ongoing brain
maturation (Davis et al., 2003; Flynn et al., 2003).
Particularly, in line with the observation of a substantial
reduction of myelin water fraction in the corpus callosum
in adult-onset schizophrenia, we also found altered white
matter integrity distributed from the splenium to the genu
in our schizophrenic adolescents (Foong et al., 2000; Agartz
et al., 2001; Ardekani et al., 2003; Kanaan et al., 2006).
The corpus callosum undergoes major microstructural
changes during healthy adolescence (Barnea-Goraly et al.,
2005; Ben Bashat et al., 2005; Snook et al., 2005; Ashtari
et al., 2007) and disruption of its development is expected
to have consequences for brain connectivity and plasticity
(Innocenti et al., 2003).
In summary, with study of adolescent-onset schizophrenia,
we have been able to characterize widespread neuropatho-
logical changes that can plausibly be related to symptoms
and signs of the disease. Care was taken to optimise the
methodology to allow investigation of both grey matter
distribution and white matter integrity and to relate them
at the level of whole brain structure. The changes suggest
both pathology affecting grey matter morphology and inter/
intra-hemispheric white matter connections and would be
consistent with molecular pathogenesis involving myelin.
A post hoc analysis suggested that 42/50 participants could
be correctly classified as schizophrenic patients or healthy
controls on the basis of the nature and extent of changes
seen in the grey matter.
At present, we cannot distinguish whether the greater
changes found in our study compared with the previous
literature arise from the good sensitivity of the methods
employed here (Sowell et al., 2000) or from the greater
severity of disease with the early age of symptom onset
(Manschreck et al., 2004). We therefore aim in future work
to explore adult-onset schizophrenia with the same metho-
dological approaches. Another issue will be to determine
with a longitudinal study whether the brain abnormalities
Imaging adolescent-onset schizophrenia Brain (2007)Page 9 of12
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demonstrated in these schizophrenic adolescents will show
dynamic evolution (Thompson et al., 2001; Vidal et al.,
2006) towards the less marked changes previously observed
in adult-onset schizophrenia, particularly in the sensor-
imotor-related grey and white matter.
Supplementary material is available at Brain online.
We would like to thank the participants and their families,
referring psychiatrists and the Donnington Health Centre,
Oxford. We would also like to thank Dr Clare MacKay
at the University of Oxford Centre for Clinical Magnetic
Resonance Research for providing helpful comments on
this manuscript. This study is supported by the MRC,
OHSRC, UK EPSRC, BBSRC and Wellcome Trust.
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