Regional thinning of the cerebral cortex in schizophrenia: effects of diagnosis, age and antipsychotic medication.

Abstract

Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty remains regarding cause, mechanism and progression of the alterations. It has been suggested that antipsychotic medication reduces total gray matter volumes, but results are inconsistent. In the present study differences in regional cortical thickness between 96 patients with a DSM-IV diagnosis of schizophrenia (n=81) or schizoaffective disorder (n=15) and 107 healthy subjects (mean age 42 years, range 17-57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and antipsychotic medication on variation in global and regional cortical thickness was explored. Thinner cortex among patients than controls was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the temporal cortex in the left hemisphere. No significant interaction effect of age and diagnostic group on variation in cortical thickness was demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.

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Regional thinning of the cerebral cortex in schizophrenia:
Effects of diagnosis, age and antipsychotic medication
Ragnar Nesvåga,⁎, Glenn Lawyerb, Katarina Varnäsb, Anders M. Fjellc,
Kristine B. Walhovdc, Arnoldo Frigessid, Erik G. Jönssone, Ingrid Agartza,b,e
aDepartment of Psychiatric Research, Diakonhjemmet Hospital, P.O. Box 85, Vinderen, N-0319 Oslo, Norway
bInstitute of Psychiatry, University of Oslo, P.O. Box 85, Vinderen, N-0319 Oslo, Norway
cInstitute of Psychology, University of Oslo, P.O. Box 1094, Blindern, N-0317 Oslo, Norway
dDepartment of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, P.O. Box 1122, Blindern, N-0317 Oslo, Norway
eHuman Brain Informatics (HUBIN), Department of Clinical Neuroscience, Psychiatry Section,
Karolinska Institutet and Hospital, SE-171 76 Stockholm, Sweden
Received 31 January 2007; received in revised form 3 September 2007; accepted 12 September 2007
Available online 22 October 2007
Abstract
Morphological abnormalities of the cerebral cortex have been reported in a number of MRI-studies in schizophrenia. Uncertainty
remainsregardingcause,mechanismandprogressionofthealterations.Ithasbeensuggestedthatantipsychoticmedicationreducestotal
graymattervolumes,butresultsareinconsistent.Inthepresentstudydifferencesinregionalcorticalthicknessbetween96patientswitha
DSM-IVdiagnosisofschizophrenia(n=81)orschizoaffectivedisorder(n=15)and107healthysubjects(meanage42years,range17–
57 years) were investigated using MRI and computer image analysis. Cortical thickness was estimated as the shortest distance between
the gray/white matter border and the pial surface at numerous points across the entire cortical mantle. The influence of age and
antipsychoticmedicationonvariationinglobalandregionalcorticalthicknesswasexplored.Thinnercortexamongpatientsthancontrols
was found in prefrontal and temporal regions of both hemispheres, while parietal and occipital regions were relatively spared. Some
hemispheric specificity was noted, as regions of the prefrontal cortex were more affected in the right hemisphere, and regions of the
temporalcortexinthelefthemisphere.Nosignificantinteractioneffectofageanddiagnosticgrouponvariationincorticalthicknesswas
demonstrated. Among patients, dose or type of antipsychotic medication did not affect variation in cortical thickness. The results from
this hitherto largest study on the topic show that prefrontal and temporal cortical thinning in patients with schizophrenia compared to
controls is as pronounced in older as in younger subjects. The lack of significant influence from antipsychotic medication supports that
regional cortical thinning is an inherent feature of the neurobiological disease process in schizophrenia.
© 2007 Elsevier B.V. All rights reserved.
Keywords: Schizophrenia; Cortical thickness; Magnetic resonance imaging; Freesurfer; Antipsychotic medication
1. Introduction
The human cerebral cortex is an extensively folded
ribbon consisting of discrete layers of neurons. Studies in
macaque monkeys have shown that neurons migrate to
their destination before birth (Rakic, 1988). Recent
postmortem data suggest that new neurons are generated
in the adult human hippocampus (Eriksson et al., 1998;
Toro and Deakin, 2007), while there is conflicting
evidence regarding adult neurogenesis in the neocortex
(Abrousetal.,2005).Lessthanhalfofthecorticalsurface
Available online at www.sciencedirect.com
Schizophrenia Research 98 (2008) 16–28
www.elsevier.com/locate/schres
⁎Correspondingauthor.Tel.:+4722029952;Tel./fax:+4722029901.
E-mail address: ragnar.nesvag@medisin.uio.no (R. Nesvåg).
0920-9964/$ - see front matter © 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.schres.2007.09.015

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is visible as gyri, while the majority is buried in sulci
(Griffin, 1994). This complex three-dimensional shape of
the cortex renders it difficult to study both from a
neuropathological and neuroimaging point of view. An
automated procedure has been developed to estimate
cortical thickness using magnetic resonance imaging
(MRI) (Fischl and Dale, 2000).
The cerebral cortex constitutes the major part of gray
matter tissue within the brain. Changes in gray matter
volumes could therefore imply alterations in either cortical
surfaceareaorcorticalthickness.Alternatively,variationin
regional folding patterns of the cortex may explain
alterations in gray matter volumes. MRI-studies have
shown smaller volumes of global, frontal, and temporal
gray matter as well as smaller volumes of hippocampus,
cerebellum,thalamus,corpuscallosum,andlargervolumes
of the lateral ventricles among patients with schizophrenia
compared to controls (Honea et al., 2005; Shenton et al.,
2001; Wright et al., 2000). A number of studies have also
foundthinnercortexinfrontalandtemporalregionsbothin
childhood-onset (White et al., 2003), first-episode (Narr
etal.,2005a,b)andchronicschizophrenia(Kuperbergetal.,
2003)patientswhencomparedtocontrols,thoughnegative
findings have been reported (Wiegand et al., 2004). Brain
abnormalities have been shown to occur in persons with a
high risk of developing schizophrenia (Job et al., 2003;
Pantelisetal.,2003)andamongpatientswithafirstepisode
ofschizophrenia(Keshavanetal.,2005;Steenetal.,2006).
This indicates that at least some of the brain alterations in
schizophrenia are present in the early phase of the illness.
The underlying pathological process as well as the clinical
importance of the gray matter loss is at present poorly
understood (DeLisi et al., 2006). Postmortem studies have
found lower brain weight (Harrison et al., 2003) and
smallergray matter volume (Pakkenberg, 1987) in patients
relativetocontrols.Thedifferencemayrepresentreduction
ofneuropil(SelemonandGoldman-Rakic,1999)orlossof
glia cells (Stark et al., 2004), rather than loss of neuronal
cells (Pakkenberg, 1992, 1993; Harrison, 1999a; Thune
et al., 2001).
Longitudinal MRI-studies of normal aging have
demonstrated a heterogeneous pattern of cortical matura-
tion in the developing brain (Thompson et al., 2005)
which at least partly is related to cognitive measures
(Shaw et al., 2006). Frontal and occipital regions have
thinnercortexwithincreasingage,whilethishasnotbeen
shown for temporal regions (Salat et al., 2004). In a
longitudinal study of childhood-onset schizophrenia
spanning over five years, the patients showed reduction
of gray matter volume first in parietal, and later in
temporal and prefrontal cortical areas compared to the
healthy children (Thompson et al., 2001). Some cross-
sectional studies of patients with schizophrenia have
found an interaction effect of age and diagnosis on gray
matter volumes (Hulshoff Pol et al., 2002; Velakoulis
et al., 2002), indicating an accelerated loss of gray matter
in schizophrenia with increasing age. With regard to
cortical thickness, a negative correlation was found
between age and prefrontal cortical thickness in patients
with first-episode schizophrenia, but not in patients with
first-episode affective psychosis or controls (Wiegand
etal.,2004).Incontrast,othercross-sectionalstudieshave
foundnointeractioneffectofageanddiagnosticgroupon
variation in cortical thickness among patients with first-
episode (Narr et al., 2005a,b) or chronic schizophrenia
(Kuperberg et al., 2003). At present there is no published
study assessing longitudinal data on cortical thickness in
schizophrenia.
There is some evidence for an effect of antipsychotic
medication on volumes of basal ganglia, particularly of
the caudate nucleus, and total brain gray matter volume
(Scherk and Falkai, 2006). The effect also appears to be
influenced by gender (Heitmiller et al., 2004) and type
of medication (Kopelman et al., 2005). A recent study
reported reduction in frontal and total gray matter
volumes among first-episode patients receiving halo-
peridol for two years, while no change was observed
among patients receiving olanzapine (Lieberman et al.,
2005). A smaller study of patients receiving treatment
for an acute exacerbation of psychosis observed increase
in gray matter volume in response to risperidone and
ziprasidone, while no change was found in response to
haloperidol treatment (Garver et al., 2005).
The aims of this hithertolargest studyonthe topic were
to investigate differences in cortical thickness between
patients with schizophrenia and healthy controls, and
further investigate effects of antipsychotic medication and
interaction effects between age and diagnostic group. A
two-step analysis was performed: First, cortical thickness
was measured at numerous points across the entire cortical
mantle. Second, mean cortical thickness within selected
regions of the prefrontal and temporal cortex in both
hemispheres was calculated and compared between
groups. Interactions between age and diagnostic group on
variationincorticalthicknesswerealsoinvestigatedintwo
steps: First, group differences in age regression slopes at
numerous points across the cortical mantle were investi-
gated. Second, group differences in age regression slopes
of mean cortical thickness within regions where patients
had thinner cortex than controls were explored. The
potential effect of antipsychotic medication on variation in
cortical thickness was investigated by including current
andestimatedlifetimeexposureofmedicationascovariates
in separate analyses among patients only.
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2. Materials and methods
2.1. Subject characterization
2.1.1. Recruitment and clinical assessment
Subjects were unrelated Caucasian individuals
recruited in Stockholm, Sweden, between 1999 and
2003, and have been previously described (Jönsson et al.,
2006).Aftercompletedescriptionofthestudy,allsubjects
gave written informed consent to participate. The study
was approved by the Research Ethics Committee at
Karolinska Institutet.
Patients diagnosed with schizophrenia by their
treating physician were recruited from outpatient clinics
specialised in the treatment of psychoses. All centres
were managed by the Stockholm County healthcare
organisation and responsible for different specific
geographical catchments areas in the North-Western
Stockholm County. Control subjects were drawn from a
population register or recruited among hospital staff
members who had previously participated in clinical
studies at Karolinska Institutet. Premorbid IQ was
estimated using a proxy, the Wechsler Adult Intelligence
Scale (WAIS) vocabulary subtest, which measures
lexical knowledge (Wechsler, 1981). Highest achieved
educational level was setas the totalnumber of complete
years spentinschool.Subjectswereassessedforlifetime
psychiatric diagnoses according to Diagnostic and
Statistical Manual of Mental Disorders, version III-R
(American Psychiatric Association, 1987) and IV
(American Psychiatric Association, 1994) using reviews
of hospital case notes and semistructured interviews
(Spitzer et al., 1986, 1988) performed by psychiatrists.
The diagnostic procedures have been thoroughly
evaluated (Ekholm et al., 2005; Vares et al., 2006).
Age at onset of illness was defined as onset of psychotic
symptomsaccordingtoanyavailablesource.Durationof
illnesswasdefinedasthedifferenceinyearsbetweenage
at onset and age at investigation. Patients' current use of
antipsychotic medication was calculated on the basis of
an interview and medical records. Current doses of
antipsychotic medication were converted to equivalent
doses of haloperidol (Kane et al., 2003). A proxy for
lifetime load of antipsychotic medication was derived as
theproduct ofcurrentmedication and duration ofillness.
Handedness was assessed by questioning subjects about
their preferred hand when using a pair of scissors. All
subjects were healthy according to physical examination
and biochemical screening. Exclusion criteria were a
history of head trauma with loss of consciousness for
more than 5 min, or somatic disorders affecting brain
function.
2.1.2. Demographic and clinical data
A total of 96 patients were included, 81 fulfilling
DSM-IV criteria for schizophrenia and 15 for schizoaf-
fective disorder. The control group consisted of 107
subjects (30 from a population register and 77 among
hospital staff) with no history of psychiatric illness and
no psychotic illness among first-degree relatives. Mean
age of all subjects was 42 years (range 17–57 years).
Eighty-two patients and 90 controls were right-handed,
constituting 85% in each group. Demographic and
clinical data are presented in Table 1.
Inthestructureddiagnosticinterview,eightpatientsand
two controls met DSM-IV criteria for a lifetime diagnosis
ofalcoholdependence,whilefivepatientsandfivecontrols
met criteria for a lifetime diagnosis of alcohol abuse.None
of the participants were recruited as or receiving any
treatmentforalcoholorillicitdrugusedisordersatthetime
of investigation. Last years consumption of alcohol was
not found to significantly influence the variation in gray
matter volumes measured in a subset of the subjects in the
present study (Nesvåg et al., 2007).
At the time of investigation 89 patients received
psychopharmacological treatment. Of these, 41 received
atypical(clozapine,olanzapine,orrisperidone),40typical
(haloperidol, perfenazine, zuclopenthixole, or fluanxol)
and seven patients received both atypical and typical
antipsychotic medication. Three patients received a
combination of antipsychotic medication and lithium,
and one patient received a combination of antipsychotic
medication and carbamazepine. One patient received
Table 1
Demographic and clinical data
Patients
(n=96)
Healthy subjects
(n=107)
Men (%)72.9
Mean SD
42.1
12.5
43.3
24.6
68.2
Range Mean SD
25–57 41.6
8–2014.1
13.3 9–66
5.914–45
Range
19–56
9–22
Age, years
Education, yearsa
WAIS vocabularyb
Age at onset of illness,
years
Duration of illness, years 17.3
Medication, mg/dayc
7.3
2.7
9.0
2.9
11.0 16–6951.2
8.6
3.3
0–41
0–164.0
t-tests showed no significant differences (pb0.05) in age between
patients and controls. Among patients, no significantdifferences in age
at onset, duration of illness, or medication were found between men
and women.
aData available for 92 patients and 100 controls. Significant group
difference (pb0.01).
bData available for 58 patients and 70 controls. Significant group
difference (pb0.01).
cCurrent antipsychotic medication converted to equivalent doses of
haloperidol.
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lithium only. Eight patients received antidepressant in
addition to antipsychotic medication. Seven patients
received no psychopharmacological treatment at the
time of investigation.
2.2. Brain measures
2.2.1. MR scan acquisition
All subjects were examined in a 1.5 T General
Electronics Signa system at the MR Research Center,
Karolinska Hospital, Stockholm, Sweden. T1-weighted
images were acquired using a three-dimensional spoiled
gradient recalled (SPGR) pulse sequence with the
following parameters: 1.5 mm coronal slices, no gap,
35° flip angle, repetition time 24 ms, echo time 6.0 ms,
number of excitations 2, field of view 24 cm, acquisition
matrix 256×192. From visual inspection, all scans were
judged to be excellent without obvious motion artifacts.
All scans were found to lack gross pathology when
evaluated by a neuroradiologist.
2.2.2. MR scan postprocessing
TheMRimageswereusedtocalculatethicknessofthe
cerebral cortex (Dale et al., 1999; Fischl et al., 1999a,
2001) using automated procedures (FreeSurfer, http://
surfer.nmr.mgh.harvard.edu/)thathavebeenvalidatedvia
histological (Rosas et al., 2002) as well as manual
measurements(Kuperbergetal.,2003).Corticalthickness
measureswereobtainedbyreconstructingrepresentations
of the gray/white matter boundary and the pial surface
(DaleandSereno,1993;Daleetal.,1999)andcalculating
the distance between those surfaces at numerous points
(vertices) across the cortical mantle (Fischl and Dale,
2000). Vertices were arranged in a triangular grid with
approximately 1mm spacing, allowing for measures of
cortical thickness at up to 160000 points in each
hemisphere. Topological defects in the gray/white matter
boundary were manually fixed by laboratory assistants
(listed under Acknowledgements) who were instructed
and supervised by senior researchers (AMF and KBW).
All analyses were performed without knowledge of
subject identity. This method of estimating cortical
thickness uses both intensity and continuity information
from the entire three-dimensional MR volume in
segmentation and deformation procedures to construct
representations of the gray/white matter boundary and
pial surface. The maps produced are not restricted to the
voxel resolution of the original images and are thus
capable of detecting submillimeter differences between
groups (Fischl and Dale, 2000). Thickness measures may
be mapped on the ‘inflated’ surface of each participant's
reconstructed brain (Dale and Sereno, 1993; Fischl et al.,
1999b), allowing visualization of data across the entire
corticalsurfacewithoutinterferencefromcorticalfolding.
Maps were smoothed using a circularly symmetric
Gaussian kernel across the surface with a standard
deviation of 12.6 mm and averaged across participants
using a non-rigid high-dimensional spherical averaging
method to align cortical folding patterns (Fischl et al.,
1999b). This procedure provides accurate matching of
morphologically homologous cortical locations across
subjects on the basis of each individual's anatomy while
minimizingmetricdistortion,resultinginameanmeasure
of cortical thickness for each group at each point on the
reconstructed surface. In addition, the software tools
provide automatic parcellation of the cortex into 84
regions, based on anatomical landmarks and a manually
labeled training set (Fischl et al., 2004).
2.3. Statistical analysis
2.3.1. Demographic and clinical data
Two-tailed t-tests were applied to analyze diagnostic
groupdifferencesinage,educationandWAISvocabulary
score,andgenderdifferencesamongpatientswithrespect
to age at onset, duration of illness and antipsychotic
medication.
2.3.2. Entire cortex analysis
Statistical maps were created, showing significant
differences in cortical thickness between patients and
controls with age and gender as covariates (Fig. 1).
Statistical comparisons of global data and surface maps
weregeneratedbycomputingagenerallinearmodelofthe
effects of each predictor variable on cortical thickness at
each vertex. Various covariates were contrasted to test for
significant effects of gender, handedness, duration of
illness, current and estimated lifetime dose and type, i.e.
typical or atypical, of antipsychotic medication. All
analyses were done while controlling for the effect of
age, and supplementary analyses were done with age and
WAIS vocabulary score as covariates. To adjust for multi-
ple comparisons, False Discovery Rate (FDR) (Genovese
et al., 2002) was applied. FDR provides posthoc
calibration of p-values from large numbers of statistical
tests. The exact threshold of significance is dependent on
the data. For an FDR of 5%, our data implied an appro-
priate threshold of significance at p=0.015 for left and
p=0.017 for right hemisphere. A conservative threshold
for both hemispheres was set at p=0.010.
2.3.3. Region-of-interest analysis
Based on previous data (Kuperberg et al., 2003; Narr
et al., 2005a; Shenton et al., 2001; White et al., 2003;
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Wright et al., 2000), a number of cortical regions
frequently reported to be affected in schizophrenia were
a priori chosen in the prefrontal (superior and medial
frontal gyrus) and temporal (superior temporal gyrus
and temporal pole) cortex. Control regions with weaker
association to schizophrenia were chosen in the parietal
(postcentral gyrus and sulcus, angular gyrus and sulcus)
and occipital (cuneus and occipital pole) cortex. These
regions are among the 84 parcellations which are
automatically obtained in FreeSurfer (Fischl et al.,
2004). Two-tailed t-tests were applied to compare
measures of mean cortical thickness within selected
labels between groups. For regions where a significant
difference in mean cortical thickness between patients
and controls was found, the percentage difference from
highest value was computed.
2.3.4. Interactions between age and diagnostic group
Tocomparetheinfluenceofageonvariationincortical
thickness between diagnostic groups, we first applied a
general linear model on each vertex of the entire cortical
mantle, allowing for difference in age regression slopes
between groups. Then, a comparison of age regression
slopes for patients and controls within areas of the cortex
which in Fig. 1 were shown to be significantly thinner in
patients than controls was performed. This was done by
manually drawing labels along the edge of each area with
significant group differences in cortical thickness (Fig. 2,
upper panel). Two-tailed t-tests were applied to compare
z-transformed correlation coefficients of age and mean
cortical thickness within each label between patients and
controls.
3. Results
3.1. Demographic and clinical data
There were no significant differences with respect to
age between patients and controls (Table 1). Patients had
significantly less education (t=3.91, df=190, pb0.01)
and lower score on WAIS vocabulary (t=3.63; df=126;
pb0.01) than controls. Among patients, there were no
significant gender differences in age at onset, duration of
illness or dose of current medication. Among controls
there were significant differences in age between subjects
recruitedfroma populationregisterandsubjectsrecruited
among hospital staff (mean (±SD) age 47.1 (±3.4) and
39.4 (±9.6) years, respectively; t=4.30; df=105;
pb0.01), while these groups did not differ with respect
to education or WAIS vocabulary score.
Fig. 1. Statistical maps illustrating significant differences (pb0.01) in cortical thickness between patients with schizophrenia and healthy subjects.
Maps are produced from general linear models of cortical thickness at each vertex covarying for age and gender.
20 R. Nesvåg et al. / Schizophrenia Research 98 (2008) 16–28

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3.2. Entire cortex analysis
Statistical maps of group differences in cortical
thickness are shown in Fig. 1. These maps show a pattern
of thinner cortex among patients than controls in
widespread areas of the prefrontal and temporal cortex
in both hemispheres, while cortical thickness in parietal
and occipital areas were not significantly different
between groups. Highly significant differences were
found in the dorsolateral prefrontal and orbitofrontal
cortex in both hemispheres, whereas no significant group
difference was found for the most anterior part of the
frontal pole. In the right hemisphere, patients had thinner
cortex in the ventromedial prefrontal (anterior cingulate
andstraightgyrus)andinsularcortex.Intemporalregions,
patients had significantly thinner cortex of the temporal
pole and anterior part of superior temporal gyrus in both
hemispheres. In the right hemisphere, the difference was
confinedtothesuperiortemporalgyrus,whereasintheleft
hemisphere patients also had thinner cortex in the medial
andinferiortemporalgyrus.Significantlythickercortexin
patients thancontrolswas found in thesuperiorpart ofthe
right precentral gyrus.
When controlling for the effect of WAIS vocabulary
score (available for 58 patients and 70 controls), a similar
pattern of thinner cortex in patients within prefrontal and
temporalregionsofbothhemisphereswasfound(pictures
not shown). Group differences were restricted to the
anterior part of the inferior and middle frontal gyrus,
orbitofrontalgyrus,andtheanteriorandmedialpartofthe
Fig. 2. Scatterplots and age regression slopes of mean cortical thickness (mm) with increasing age within selected regions of the cortex for patients
with schizophrenia (red) and healthy subjects (blue). Significant correlations of age and mean cortical thickness within each region for patients and
controls are marked (⁎). Regions are manually labeled along the edges of areas with significant group differences in cortical thickness (see upper
panel).
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middle temporal gyrus in both hemispheres. In separate
regression analyses, subjects' gender, handedness and
durationsofillnessdidnotsignificantlyaffectvariationin
cortical thickness.
3.3. Region-of-interest analysis
Mean cortical thickness measures within selected
parcellated regions are shown in Table 2. The pattern of
thinner cortex among patients compared to controls in
prefrontal and temporal, but not parietal and occipital
regions in both hemispheres, remained. The difference
was largest in the left superior temporal gyrus and the left
temporalpole.Thep-valuesforgroupdifferencesinmean
corticalthickness (Table2) werenot adjusted for multiple
comparisons. However, when applying the conservative
Bonferroni correction, all reported differences in prefron-
tal and temporal parcellated regions remained significant
(pb0.05), except left middle frontal gyrus and right
superior temporal gyrus (p=0.12 for both).
3.4. Influence of antipsychotic medication
Current dose or type of antipsychotic medication did
not significantly affect variation in cortical thickness. The
derivedproxyforlifetimeloadofantipsychoticmedication
did not affect cortical thickness when controlling for age.
3.5. Interactions between age and diagnostic group
The initial vertex-wise analysis revealed no group
differences in age regression slopes between patients
and controls when adjusting for FDR. Results from the
comparison of correlation coefficients of mean cortical
thickness and age in areas of the cortex that were thinner
among patients than controls are shown as scatterplots
in Fig. 2. A significant group difference was found in the
left prefrontal cortex (Fig. 2, panel G) with a steeper
downward directed age regression slope among controls
compared to patients (z=2.43; p=0.008). For other
regions, the age regression slopes were not significantly
different between diagnostic groups.
4. Discussion
The main finding of this study was reduced cortical
thickness in widespread areas of the prefrontal and
temporal brain regions of both hemispheres among
patients with schizophrenia compared to a group of age
and gender matched control subjects. These results are
in concordance with findings from a previous study
using the same methodology on a smaller subject group
(Kuperberg et al., 2003), and a series of volumetric
studies showing involvement of frontal and temporal
cortical regions in schizophrenia (Honea et al., 2005;
Table 2
Regional cortical thickness measures in patients and controls
RegionStructureSide Patients (n=96) Controls (n=107)t (df=1, 201)pa
%b
FrontalMiddle f. gyrusRight
Left
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
Right
Left
2.32 (0.22)
2.42 (0.21)
2.65 (0.24)
2.80 (0.22)
2.68 (0.31)
3.21 (0.30)
3.31 (0.35)
3.25 (0.37)
2.19 (0.24)
1.96 (0.19)
1.79 (0.18)
2.02 (0.18)
2.49 (0.22)
2.48 (0.19)
2.42 (0.22)
2.45 (0.19)
1.95 (0.17)
1.96 (0.18)
1.87 (0.16)
1.86 (0.20)
2.45 (0.22)
2.50 (0.23)
2.83 (0.26)
2.94 (0.27)
2.80 (0.31)
3.49 (0.28)
3.57 (0.32)
3.56 (0.31)
2.21 (0.21)
2.00 (0.19)
1.80 (0.18)
2.06 (0.21)
2.55 (0.21)
2.50 (0.19)
2.43 (0.21)
2.48 (0.18)
2.00 (0.17)
1.95 (0.18)
1.88 (0.17)
1.90 (0.20)
4.24
2.77
5.04
3.93
2.79
6.78
5.52
6.39
0.43
1.41
0.14
1.36
1.87
0.57
0.64
1.28
0.16
1.65
0.57
1.20
.000
.006
.000
.000
.006
.000
.000
.000
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
n.s.
5.3
3.2
6.4
4.8
4.3
8.0
7.3
8.7
Superior f. gyrus
TemporalSuperior t. gyrus
Temporal pole
ParietalPostcentral gyrus
Postcentral sulcus
Angular gyrus
Angular sulcus
OccipitalGyrus cuneus
Occipital pole
Mean cortical thickness in mm (SD) within selected brain regions automatically parcellated by FreeSurfer.
aSignificant group differences (pb0.05) based on t-tests, not adjusted for multiple comparisons.
bSignificant group differences shown as percentage difference from highest value.
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Narr et al., 2005a; Shenton et al., 2001; White et al.,
2003; Wright et al., 2000).
4.1. Putative pathological mechanisms
The underlying pathophysiological mechanism of the
observed cortical thinning is at present poorly understood.
Postmortem data points to reduced neuronal size and
arborization of dendrites in prefrontal cortical regions as
key findings in schizophrenia (Harrison, 1999a; Selemon
and Goldman-Rakic, 1999), while no reduction in number
ofneuronsinprefrontalcortexhasbeenfound(Thuneetal.,
2001). A meta-analysis of brain weight in schizophrenia
found a slight, but significant, reduction of 2% in 540
patientsascomparedto794controls(Harrisonetal.,2003).
Absence of gliosis in postmortem brain tissue (Arnold
et al., 1998) argues against a view of schizophrenia as a
neurodegenerative disease. Impaired connectivity between
frontal and temporal cortical areas has been a suggested
pathological mechanism for the disorder (Davis et al.,
2003; Friston and Frith, 1995). Findings from diffusion
tensorimaging(DTI)studieshaveprovidedsupportforthis
theory (Kubicki et al., 2002; Wang et al., 2004), while
postmortemstudieshavefoundnodifferenceinmyelinated
fiber length in prefrontal cortex (Marner and Pakkenberg,
2003) or area, fibre density or number in the uncinate
fasciculi(Highleyetal.,2002).Atthispoint,itisnotclearif
abnormal development of white matter fiber bundles may
explain the cortical abnormalities in the brain of patients
withschizophrenia.The onlypublishedstudyof combined
DTI and structural MRI data in schizophrenia showed
significantly reduced fractional anisotropy (FA) in the
entorhinal cortex among patients, while volume of the
entorhinal cortex was not significantly reduced (Kalus
et al., 2005). Studies combining DTI with functional MRI
(Schlösser et al., 2007) and proton magnetic resonance
spectroscopy(Steeletal.,2001)havenotshownfunctional
changesinregionswithFA,orviceversa,indicatingaweak
relationship between structure and function. A thinner
cortex in prefrontal and temporal regions may reflect
disruptionsinthewhitematterbundlesconnectingthem,or
impaired connectivity may be a consequence of an
abnormal maturation of the cortex. Regionally thinner
cortex and impaired connectivity may also be independent
features of the disorder.
4.2. Regional specificity
Mechanisms underlying the selective vulnerability of
prefrontal and temporal cortex and the relative preser-
vation of parietal and occipital cortex in schizophrenia
remain to be clarified. According to the neurodevelop-
mental model of schizophrenia, early pre- or perinatal
insults mayinterfere withnormalbrain development and
entail subtle brain abnormalities (Rapoport et al., 2005).
As symptoms of schizophrenia in general do not
manifest themselves until early adulthood it has been
proposed that additional events taking place in the later
stages of brain maturation may be superimposed upon
theseearlyinsults(Pantelisetal.,2005).Inthisrespect,it
is of interest to note that in the developmental trajectory
of the cerebral cortex prefrontal and temporal regions
mature later than parietal and occipital regions (Thomp-
son et al., 2005). The observed regional thinning of the
cortexinschizophreniamaythusreflectadisruptioninthe
later stages of cortical maturation, such as excessive
synaptic pruning. Although the evidence for adult
neurogenesisinthehumancerebralcortexiscontroversial
(Abrous et al., 2005) aberrant expression of developmen-
tal genes in the adult cortex may play a role in the
neuropathological process of schizophrenia (Toro and
Deakin, 2007).
4.3. Age
In the present study, a significantly steeper downward
directedageregressionslopeinhealthysubjectscompared
to patients with schizophrenia was found in the left
prefrontal cortex. Examination of the regression slopes,
however, revealed that the intercept is lower for patients
thancontrols,andthattheregressionlinesalmostintersect
inthehigheragerange(Fig.2,panelG),indicatingthatthe
differenceinageregressionslopeisduetoaloweroffsetin
patients than controls. For other regions, the decrease in
meancorticalthicknesswith increasingage wassimilar in
patients and controls. This is in concordance with the
cross-sectional study using the same method on a smaller
sample (Kuperberg et al., 2003), but not with the larger
study showing a slightly steeper regression slope of gray
matter volume with increasing age among patients than
controls (Hulshoff Pol et al., 2002). In accordance,
progressive loss of gray matter volume with increasing
age in patients relative to controls has been reported in a
number of longitudinal studies of first-episode (Cahn
etal.,2002;Farrowetal.,2005;Whitfordetal.,2006)and
chronic schizophrenia patients (Mathalon et al., 2001),
whilesomestudieshavenotfoundsuchaprogression(Ho
et al., 2003; Lieberman et al., 2001). So far, the results on
possible loss of gray matter (typically measured as
volumes or cortical thickness) with increasing age and
duration of illness are inconsistent (Weinberger and
McClure, 2002). Some of the discrepancies may be due
toclinicalsubjectheterogeneity,reflectedinthefindingof
a more pronounced volume loss in patients with a severe
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Page 9

outcome than in patients with a better outcome of the
disease (Ho et al.,2003; Lieberman et al.,2001). Notably,
since patients have a thinner cortex even in their first
episode of psychosis (Keshavan et al., 2005; Steen et al.,
2006) a direct comparison of longitudinal brain changes
between patients and controls may not be appropriate.
4.4. Antipsychotic medication
In the present study, neither type, nor dose of current
or estimated lifetime load of antipsychotic medication
significantly influenced the variation in cortical thick-
ness. In a previous study we reported only a trend level
association between smaller volumes of frontal lobe
gray matter and antipsychotic medication using a
different segmentation method on a subset of the present
subject material (Nesvåg et al., 2007). Lieberman et al.
(2005) have reported reduction of total and frontal gray
matter volumes, and increase in ventricular and caudate
volumes, in response to treatment with haloperidol, but
not olanzapine, from a randomized controlled study of
161 first-episode patients repeatedly investigated over
two years. Most of the reduction had occurred after
12 weeks of treatment. In accordance a cross-sectional
voxel-based morphometry study comparing 32 patients
receiving typical, 30 patients receiving atypical anti-
psychotic medication and 22 drug-free patients showed
significant differences in brain volumes between
medicated and non-medicated patients (Dazzan et al.,
2005). Typical antipsychotic medication was related to
larger volume of putamen and reduced volume of
discrete parts of the prefrontal and temporal cortex,
while atypical medication was related to larger volume
of thalamus. However, when comparing the two groups
of medicated patients, only one cluster (left middle
temporal gyrus) showed grey matter deficit among
patients receiving typical as compared to patients
receiving atypical medication. A study of 19 acutely
admitted patients reported an increase in gray matter
volumes in response to four weeks of treatment with
risperidone and ziprasidone, but not haloperidol (Garver
et al., 2005). Furthermore, in a study of healthy macaque
monkeys given olanzapine or haloperidol with serum
levels equal to treatment of patients with schizophrenia,
both types of medication were associated with reduction
in postmortem weight and volume of the brain when
compared to monkeys given placebo (Dorph-Petersen
et al., 2005). Concurring with results from the present
study, antipsychotic medication has not previously been
found to influence cortical thickness (Kuperberg et al.,
2003; Narr et al., 2005a,b; Wiegand et al., 2004). Thus
the effect of antipsychotic medication on cerebral cortex
morphology remains elusive. While there is consistent
evidence for an association between typical antipsy-
chotic medication and larger volumes of basal ganglia,
foremost the caudate (Dazzan et al., 2005; Keshavan
et al., 1994; Lieberman et al., 2005), more conflicting
results have come from studies of associations between
basal ganglia volumes and atypical antipsychotic
medication (Dazzan et al., 2005; Heitmiller et al.,
2004; Lang et al., 2001). A recently published review
concluded that different effects of typical and atypical
medication on variation in cortical and subcortical
volumes may be explained by different mechanisms of
action (Scherk and Falkai, 2006). Preclinical and
postmortem studies have shown associations between
antipsychotic medication and ultrastructural morpho-
logical changes, indicative of synaptic plasticity, in the
caudate and prefrontal cortex, while there is no evidence
for gliosis or neurotoxic effects of antipsychotic
medication (Dean, 2006; Harrison, 1999b). Some of
the MRI-based studies showing morphological change
in response to antipsychotic medication have been
performed in patients with first-episode schizophrenia
(Lieberman et al., 2005) or in patients with an acute
exacerbation of psychosis (Garver et al., 2005). The
effect of medication may be confined to the early phase
or acute psychotic state of the disorder, and possibly is
of less importance among patients with chronic, stable
schizophrenia, as was the case for patients in the present
study.
4.5. Gender
The present study showed no significant effect of
gender on variation incorticalthickness. Amonghealthy
subjects larger intracranial volume in men and gender-
specific differences in the degree of lateralization have
been reported (Good et al., 2001; Nopoulos et al., 2000).
No differences, however, have been found with respect
to cortical surface anatomy in long-term treated patients
(Nopoulos et al., 2000). When investigating gender
differences of brain morphology among first-episode
schizophrenia patients, thicker cortex in right ventrome-
dial frontal regions has been reported among men, and
higher concentration of gray matter in posterior parietal
cortical regions among women (Narr et al., 2005a). In
a study of patients with chronic schizophrenia, larger
ventricular volumes were found only among male
patients relative to controls (Nopoulos et al., 1997).
The male patients also had a longer duration of illness
and greater load of medication than female patients, but
neither of these variables significantly correlated with
ventricular size.
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4.6. Lateralization
Certainbrainfunctionsarelateralized.PierrePaulBroca
first identified a functional asymmetry related to language
inthelefthemisphere(Broca,1861),andmorerecentwork
hasshownthatlanguageisgeneratedinthelefthemisphere
in about 95% of the population, and even so in 70% of
subjects with a dominant left hand (Capozzoli, 1999).
Recent MRI-studies have shown leftward asymmetry in
frontalandtemporalregions,andarightwardasymmetryin
occipital regions of the healthy brain (Barrick et al., 2005;
Luders et al., 2006), also referred to as the cerebral torque.
Morphological studies of the brain in schizophrenia have
shown a reduced and even reversed asymmetry of the
planum temporale among patients relative to healthy
subjects (Sommer et al., 2001). This has been held as
evidence for a genetically disturbed lateralization during
neurodevelopment in schizophrenia (Crow, 1999, 2004;
Esiri and Crow, 2002; Mitchell and Crow, 2005). In the
present study, in which 85% of both patients and controls
were right-handed, no significant effect of handedness on
variation in cortical thickness was found. Furthermore, a
left-larger-than right pattern in mean cortical thickness of
inferior frontal gyrus and superior temporal gyrus was
found both among patients and healthy subjects (Table 2).
The distribution of significant difference in cortical
thickness showed some hemispheric specificity when
evaluated qualitatively (Fig. 1). Patients had thinner cortex
in parts of the insula, anterior cingulate, precentral and
straight gyrus in the right hemisphere, and in parts of the
medial and inferior temporal gyrus in the left hemisphere.
4.7. Strengths and limitations
The major strength of this study was the comparatively
large group of participants who were subjected to careful
clinical characterization. MR measures were obtained
using methods that have been thoroughly validated.
Potentialeffectsofalcoholconsumptiononthegraymatter
had been carefully ruled out. The same calibrated MR
systemwasusedforallinvestigationswithoutupgradingor
other uncontrolled changes throughout the study period.
The issue of false positive findings resulting from
multiple comparisons in the vertex-wise general linear
model analyses was considered using a conservative
threshold of significance (p=0.01) with an expected rate
of false positive findings of less than 5%.
Given the aim of investigating effects of antipsychotic
medication on brain cortical thickness, the study would
have benefited from detailed data on lifetime load of
antipsychotic medication. A full history of antipsychotic
medication was, however, not available for all patients
and the derived proxy for lifetime load of antipsychotic
medication provides only a rough estimate.
Years of education and WAIS vocabulary score were
significantly lower in patients than controls (Table 1).
Among the subjects for whom data on WAIS vocabulary
were available, group differences in cortical thickness
were still present, though less widespread than in the
entire group analysis. Information on parental education
would have been helpful to further control for socio-
demographic group differences.
A cross-sectional design is an obvious limitation for
detecting effects of age on variation in morphological
brain measures. Cross-sectional data may reveal inter-
action effects, but caution is warranted when inferring
any conclusions regarding longitudinal changes.
5. Conclusion
The cortex is significantly thinner in prefrontal and
temporalbrainregionsinbothhemispheresamongpatients
with schizophrenia compared to age and gender matched
control subjects, while parietal and occipital regions are
relatively spared. The influence of age on variation in
regional cortical thickness is similar in patients and
controls. Dose or type of antipsychotic medication has no
significant effect on variation in cortical thickness among
the patients. The results suggest that regional cortical
thinning is an inherent feature of the disease process in
schizophrenia.
Role of funding source
This study was financially supported by the Wallenberg Founda-
tion and the Swedish Medical Research Council (K2004-21X-15078-
01A 45, K2007-62X-15077-04-1, and K2007-62X-15078-04-3) and
the University of Oslo. The funding organizations had no further role
in study design; in the collection, analysis and interpretation of data; in
the writing of the report; and in the decision to submit the paper for
publication.
Contributors
RN, GL, AF and IA designed the study. IA organized magnetic
resonance imaging and EGJ performed clinical assessment of study
participants.RN,GL,KV,AMFandKBWperformedstatisticalanalyses
of the data. AF supervised the statistical analyses. RN performed
literature searchandwrotethemanuscript.Allauthorscontributedtoand
have approved the final manuscript.
Conflict of interest
All authors declare that they have no conflict of interest.
Acknowledgements
We thank Monica Hellberg, Emma Bonnet and Lilian Frygnell for
their effort in recruitment and handling of patients at the Karolinska
Hospital throughout the study period. We also thank Ylva Østby,
Christian Tamnes, and Lars Tjelta Westlye who have performed
25 R. Nesvåg et al. / Schizophrenia Research 98 (2008) 16–28

Page 11

preprocessing and quality assessments of MR images at the Institute of
Psychology, University of Oslo.
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