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Focal Gray Matter Density Changes in Schizophrenia
Hilleke E. Hulshoff Pol, PhD;
Hugo G. Schnack, PhD;
René C. W. Mandl, MS;
Neeltje E. M. van Haren, MS;
Hilde Koning, MS;
D. Louis Collins, PhD;
Alan C. Evans, PhD;
René S. Kahn, MD, PhD
Arch Gen Psychiatry. 2001;58:1118-1125.
ABSTRACT
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Background The view that schizophrenia is a brain disease particularly involving
decrements in gray matter is supported by findings from many imaging studies.
However, it is unknown whether the (progressive) loss of tissue affects the
brain globally or whether tissue loss is more prominent in some areas than
in others.
Methods Magnetic resonance whole brain images were acquired from 159 patients
with schizophrenia or a schizophreniform disorder and 158 healthy subjects
across a 55-year age span. Gray matter density maps were made and analyzed
using voxel-based morphometry.
Results Compared with healthy subjects, decreases in gray matter density were
found in the left amygdala; left hippocampus; right supramarginal gyrus; thalamus;
(orbito) frontal, (superior) temporal, occipitotemporal, precuneate, posterior
cingulate, and insular cortices bilaterally in patients with schizophrenia
or schizophreniform disorder. Compared with healthy subjects, increases in
gray matter density were exclusively found in the right caudate and globus
pallidus in patients with schizophrenia or schizophreniform disorder. A group-by-age
interaction for density was found in the left amygdala, owing to a negative
regression slope of gray matter density on age in the left amygdala in patients
compared with healthy subjects.
Conclusions Gray matter density is decreased in distinct focal areas in the brains
of patients with schizophrenia or schizophreniform disorder. The decreased
density in the left amygdala is more pronounced in older patients with schizophrenia.
INTRODUCTION
THE VIEW THAT schizophrenia is a brain disease particularly involving
decrements in gray matter is supported by findings from many imaging studies.1, 2, 3, 4, 5, 6, 7, 8, 9
Global gray matter volume decreases of approximately 2% were reported in a
recent meta-analysis of volumetric magnetic resonance imaging (MRI) studies
in schizophrenia.3 However, results from this
meta-analysis also suggest that changes may be more prominent in some brain
areas than in others.3 Indeed, relative to
the cerebral volume differences, volume decreases were found in the anterior
superior temporal gyrus (7%), amygdala and hippocampal complex (6%), thalamus
(4%), and frontal lobes (2%). Increases relative to the cerebral volume differences
were found in the globus pallidus (24%), putamen (6%), and caudate nucleus
(4%). Global temporal lobe volume differences, on the other hand, were proportionate
to the overall cerebral volume decreases in schizophrenia. Findings from studies
using statistical analysis of images on a voxel-by-voxel basis predominantly
suggest involvement of the thalamus and prefrontal-thalamic-cerebellar circuitry,10, 11 and structural changes in the temporal
pole, insula, amygdala, and dorsolateral prefrontal cortex in schizophrenia.12 However, diffuse gray (and white) matter abnormalities
have also been found.13
Recent evidence from longitudinal studies suggests that the decreases
in brain volume may be progressive over the course of the illness in schizophrenia,14, 15 and this may also be the case for
gray matter changes. A 4-fold greater decrease in cortical gray matter volume
and the thalamus area was reported in patients with childhood-onset schizophrenia
in a 2-year longitudinal study.16, 17
Synaptic degeneration in the left thalamus with increasing duration of disease
was suggested in a neuropathological study in schizophrenia.18
However, it is unknown whether progressive gray matter loss in schizophrenia
affects gray matter globally or whether some areas show more decreases than
other areas.
This study analyzed focal gray matter density across a 55-year age span
in brain MRI of 159 patients with schizophrenia or a schizophreniform disorder
and 158 healthy subjects using voxel-based morphometry. Voxel-based morphometry
has several advantages over the standard volume measurements. Using this technique,
several studies have demonstrated structural brain abnormalities among different
patient populations.19, 20, 21, 22
Voxel-based morphometry is not biased to one particular structure, includes
structures that are difficult to quantify by the standard volume measurements,
and provides a comprehensive assessment of anatomical differences throughout
the brain.23 The aim of this study was to examine
the presence of focal changes in gray matter density in schizophrenia and,
if present, whether these become more pronounced with age.
SUBJECTS AND METHODS
SUBJECTS
One hundred fifty-nine patients with schizophrenia or schizophreniform
disorders and 158 healthy comparison subjects from the Utrecht Schizophrenia
Project, Utrecht, the Netherlands, participated after written informed consent
was obtained. All subjects were between the ages of 16 and 70 years. Subjects
with a major medical or neurological illness including migraine, epilepsy,
hypertension, cardiac disease, diabetes mellitus, endocrine disorders, cerebrovascular
disease, alcohol or other drug dependence, head trauma in the past, or an
IQ below 80 were excluded. To allow for unbiased estimates of gray matter
density changes with age in patients, care was taken that the severity of
illness was evenly distributed across the age range in patients. The number
of patients who were recruited from various outpatient and inpatient clinics
was evenly distributed across the age range. Patient outcome (defined by the
logarithmically transformed ratio of the cumulative months of hospitalization
and the cumulative months of illness since first symptoms) was not statistically
significantly correlated with their age (r = 0.01, P = .88).
The presence or absence of psychopathological abnormality was established
in all subjects using the Comprehensive Assessment of Symptoms and History24 and Schedule for Affective Disorders and Schizophrenia
Lifetime Version25 assessed by trained and
experienced psychologists and psychiatrists (H.E.H., N.E.M.H., H.K., and colleagues)
in the Department of Psychiatry, University Medical Center, Utrecht. Diagnostic
consensus was achieved in the presence of a senior psychiatrist (R.S.K. and
colleagues). All patients met DSM-IV diagnoses of
schizophrenia or schizophreniform disorder; those with schizophreniform disorder
met the criteria for the diagnosis of schizophrenia after 1 year of illness.
All healthy comparison subjects met Research Diagnostic Criteria26
of "never [being] mentally ill."
Age at onset of illness was defined as the first time patients had been
seeking medical or psychological help for their psychotic symptoms. All patients
had received antipsychotic medication in the past and all but 4 patients received
antipsychotic medications at the time of the MRI scan. Medication included
typical and atypical (clozapine, risperidone, olanzapine, or sertindole) antipsychotic
agents. Medication dose was expressed as haloperidol-dose equivalents. Subjects
were matched for age, sex, and height, and for the socioeconomic status of
their parents expressed as the highest completed level of education by one
of their parents. There were no interaction effects of age by sex for patients
compared with controls or for age at onset by sex within the patient cohort
(Table 1).
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Table 1. Demographic Data*
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Brain MRI scans from all subjects were evaluated by 2 independent clinical
neuroradiologists. No gross abnormalities were reported in any of the subjects.
MRI ACQUISITION AND PROCESSING
Magnetic resonance images were acquired using a scanner (Philips Gyroscan;
Philips Medical Systems, Best, the Netherlands) operating at 1.5 T in all
subjects. T1-weighted, 3-dimensional, fast field echo scans with 160 to 180
1.2-mm contiguous coronal slices (echo time [TE], 4.6 milliseconds; repetition
time, 30 milliseconds; flip angle, 30°; field of view, 256 mm; and in-plane
voxel sizes, 1 x 1 mm2) and T2-weighted, dual echo turbo
spin echo scans with 120 1.6-mm contiguous coronal slices (TE1, 14 milliseconds;
TE2, 80 milliseconds; repetition time, 6350 milliseconds; flip angle, 90°;
field of view, 256 mm; and in-plane voxel sizes, 1 x 1 mm2)
of the whole head were used for quantitative measurements. In addition, T2-weighted,
dual echo turbo spin echo scans with 17 axial 5-mm slices and a 1.2-mm gap
(TE1, 9 milliseconds; TE2, 100 milliseconds; flip angle, 90°; field of
view, 250 mm; and in-plane voxel sizes, 0.98 x 0.98 mm2)
were used for clinical neurodiagnostic evaluation. Processing was done on
the neuroimaging computer network of the Department of Psychiatry, which includes
workstations (Unix 9000; Hewlett Packard, Palo Alto, Calif), a computer server,
and Pentium III–equipped personal computers. Prior to quantitative assessments
10 MRIs were randomly chosen and cloned for intrarater reliability determined
by the intraclass correlation coefficient. All MRIs were coded to ensure masking
for subject identification and diagnosis, scans were put into a Talairach
frame (no scaling), and corrected for inhomogeneities in the magnetic field.27 Binary masks of gray matter were made based on histogram
analyses and a series of mathematical morphological operators to connect all
voxels of interest within the cranium, as validated previously.28
The binary gray matter masks were then analyzed using voxel-based morphometry.
The binary gray matter masks were resampled to a voxel size of 2 x 2
x 2.4 mm3, blurred using an isotropic Gaussian kernel (full
width at half maximum of 8 mm) to generate gray matter "density maps." The
density maps represent the local concentration of gray matter (between 0 and
1) per voxel. Each of the MRIs was transformed into a standardized coordinate
system in a 2-stage process using the ANIMAL algorithm.29
In the first step, a linear transformation was found by minimizing a mutual
information joint entropy objective function computed on the gray level images.30 A nonlinear transformation was computed in the second
step by maximizing the correlation of the subject's image with that of a standardized
brain. The nonlinear transformation is run up to a scale (full width at half
maximum of 4 mm) that aligns global anatomical regions while minimally affecting
local volume changes. The standardized brain was selected earlier among 200
brain MRIs of healthy subjects between the ages of 16 and 70 years. To select
the standardized brain, all 200 brain MRIs were registered to the Montreal
standard brain31 and averaged, yielding one
average brain image. The mean square error on the normalized intensity values
was computed between each of the brain MRIs and the average brain image. The
standardized brain was the brain image with the smallest mean square error.
Transformations were then applied to the gray matter density maps to remove
global differences in the size and shape of individual brains.
STATISTICAL ANALYSIS
Linear regression analysis was performed through all brains for each
voxel separately in the gray matter density maps (other examples of this procedure32, 33, 34). Group (schizophrenia
and healthy comparison subjects), sex (male and female), and handedness (right,
left, or ambidextrous) entered the analysis as predictor variables; age served
as a covariant. To evaluate the changes with age in schizophrenia, a similar
linear regression analysis was performed, adding the interaction between age
and schizophrenia as predictor variable. Given the number of subjects, data
resolution, voxel size, and volume of the search region, the critical threshold t value for a 2-tailed  significance level of P<.05 after correcting for multiple comparisons is |t|>5.0, according to random field theory.35
For the main effects of schizophrenia, effects at |t|>5.0
were provided in Table 2 and Figure 1. Note that for interaction effects
with age, effects at |t|>4.5 were provided in
Table 3, Figure 2, and Figure 3 to show that significant (at |t|>5.0)
age-related changes represented a cluster of voxels.
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Table 2. Focal Gray Matter Density Decreases and Increases in Schizophrenia*
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Figure 1. Focal decreases (A-C) and increases
(D) in gray matter density in patients with schizophrenia compared with healthy
comparison control subjects. The thresholded map of t
statistic values (|t|>5.0) is superimposed on axial
(A at Z = -14; B at Z = 8), sagittal
(C at X = -17), and coronal (D
at Y = 1) sections through the magnetic resonance
image of the standardized reference brain. The X, Y, and Z values indicate the distance
(in millimeters) of a given section from the sagittal, coronal, and axial
plane, respectively, passing through the anterior commissure.
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Table 3. Focal Gray Matter Density Changes With Age*
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Figure 2. Excessive age-related focal decreases
in gray matter density in patients with schizophrenia compared with healthy
comparison control subjects. The thresholded map of t
statistic values (|t|>4.5) is superimposed on axial
sections (A at Z = -17, B at Z = -13,
C at Z = -8,
D at Z = 13)
through the magnetic resonance image of the standardized
reference brain. Z value indicates the distance
(in millimeters) of a given section from axial plane passing through the anterior
commissure.
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Figure 3. Age-related decrease in gray matter
density in the amygdala in patients with schizophrenia compared with healthy
comparison control subjects. A, The thresholded map of t statistic values (|t|>4.5) superimposed
on a detail from a sagittal (X = -20) section
of the amygdala-hippocampal region of the standardized reference brain. B,
The regression of gray matter density—varying between 0 and 1—on
age in a left amygdala voxel (X = -20,
Y = -7, and
Z = -17)
in schizophrenia and comparison subjects. The X, Y, and
Z values indicate the distance
(in millimeters) of a given section from the sagittal, coronal, and axial
plane, respectively, passing through the anterior commissure.
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In case of a significant main or interaction effect between age and
schizophrenia, post hoc analyses were done on local minima and maxima—these
were voxels that represented the local minimum or maximum (of a cluster of
significant voxels) in the t-map: (1) adding antipsychotic
medication dose or outcome as predictor variable to the regression analysis
in the patients; (2) (for interaction effects with age only) adding the SD
of the unstandardized residual of the dependent variable per age decade as
weight in weighted linear regression analysis to exclude cohort biasing effects
of the cross-sectional design; and (3) adding time of the scan to the analysis
and calculating partial Pearson product moment correlation coefficients correcting
for age to exclude time of measurement artifacts.
RESULTS
Linear regression analysis revealed significant decreases in gray matter
density in patients with schizophrenia compared with healthy comparison subjects
in the left amygdala; left hippocampus; thalamus; (orbito) frontal, temporal,
occipitotemporal, precuneate, posterior cingulate, and insular gyri bilaterally
(Figure 1A-C and
Table 2). In patients with
schizophrenia significant increases in gray matter density were found exclusively
in the right caudate nucleus and globus pallidus (Figure 1D and Table 2).
A significant interaction with age was found for gray matter density
in the left amygdala in patients with schizophrenia (t
= -5.01, unstandardized regression coefficient b = -0.078 density
change over 55 years, reflecting approximately 8% density loss); the density
of the left amygdala did not decrease significantly with age in healthy comparison
subjects (Figure 2, Figure 3, and Table 3).
Age at onset, outcome, antipsychotic medication at the time of the MRI
scan acquisition, and interactions with sex and age or age at onset did not
explain these gray matter density changes in patients with schizophrenia.
Moreover, the SD of the unstandardized residual of gray matter density per
age decade and time of the MRI scan did not explain the findings.
COMMENT
This cross-sectional study compared gray matter density in 159 patients
with schizophrenia or a schizophreniform disorder and 158 healthy comparison
subjects across a 55-year age span. Its main finding is that distinct focal
areas in the brains of patients with schizophrenia or a schizophreniform disorder
display decreased gray matter density, including the left amygdala; left hippocampus;
right supramarginal gyrus; thalamus; (superior) temporal, occipitotemporal,
precuneate, posterior cingulate, and insular gyri bilaterally. Moreover, the
left amygdala density decrease was more pronounced in the older than in the
younger patients with schizophrenia. These findings could not be explained
by outcome, age at onset, antipsychotic medication at the time of the MRI
scan, interactions of sex with age or age at onset, changes in gray matter
density variation with age, or by time of measurement effects.
Significant changes in gray matter density were found in brain regions
that were previously reported to be altered in volume in schizophrenia.1, 2, 3, 4, 5, 6, 7, 8, 9, 36, 37, 38, 39, 40, 41, 42
The primarily left-sided involvement of the medial temporal area is in agreement
with suggested decreased hemispheric dominance with predominantly left-sided
brain involvement in schizophrenia,43 although
the thalamic and other (cortical) decreases were bilateral. Thalamic decreases
have been reported in several studies.10, 36
Close inspection of the local minimum of the t-map
of the left and right thalamus in Table
2 and of Figure 1B further
suggests that the decreases may be particularly pronounced in the dorsomedial
nucleus, which is consistent with recent evidence of a volume reduction in
this nucleus in (first-episode) schizophrenia44, 45
and with a loss of neurons in this nucleus in the brains of schizophrenic
patients in postmortem studies.46, 47
Interestingly, the mediodorsal nucleus of the thalamus has prominent anatomical
connections with the frontal cortex, including the orbitofrontal cortex,48 where highly significant gray matter density decreases
were found in our study. These density decreases are in agreement with the
decreased orbitofrontal gray matter volume reported earlier in schizophrenia.6, 38 Decreased orbitofrontal gray matter
has been related to increased negative symptoms in male49
and female38 patients with schizophrenia. Also,
in a postmortem study decreases of D3 and D4 dopamine
receptor transcripts, suggestive for a disruption of cortical dopaminergic
neurotransmission at the level of receptor expression, were found to be restricted
to the orbitofrontal cortex of patients with schizophrenia.50
The gray matter density decreases in the middle and medial superior frontal
areas are in concordance with decreased volumes in these areas of the frontal
cortex found previously (although only in male patients).37
They furthermore support functional MRI studies suggesting aberrant frontal
cortex activation during working memory tasks in schizophrenia.51, 52
Temporal lobe involvement in our study was predominantly found in the (anterior)
superior temporal gyri bilaterally, which is consistent with findings from
volumetric studies.3 Increases in gray matter
density were exclusively found in the (right) caudate and globus pallidus
nuclei that are part of the basal ganglia. These nuclei were found to be increased
in volume in several earlier studies in patients with schizophrenia who were
taking (typical) antipsychotic medication.39, 40, 41
Additional areas with significant decreases in gray matter density in
schizophrenia were the insula, posterior cingulate, precuneate, supramarginal
gyrus, and occipitotemporal gyri. These structures have not been extensively
reported on in volumetric studies in schizophrenia. Involvement of the insula
in schizophrenia was suggested earlier in a few volumetric studies6, 53 and in a study using voxel-based morphometry.12 Anatomically, connections between the insula and
the amygdala; thalamus; and (orbito) frontal, (superior) temporal, and cingulate
gyri have been described.54 Functionally, the
insula is implicated in somatosensory processing, showing increased activation
during pleasant and aversive taste stimuli.55
It is part of a pain perception network56 that
may also include a (separate) area that activates during the anticipation
of pain.57 Interestingly, sensitivity to pain
appears diminished in patients with schizophrenia58
and in a few of their relatives.59 In addition,
the insula may be involved in conveying a cortical representation of fear
to the amygdala.60 The posterior cingulate
also deserves further study in schizophrenia. It is part of the retrosplenial
cortex which, on the basis of functional imaging studies, is considered to
play a prominent role in the processing of emotionally salient stimuli.61 The gray matter density decreases in the precuneus,
or medial parietal cortex, may be associated with the aberrant activation
pattern in this area in the brains of patients with schizophrenia during verbal
fluency62 and long-term memory recognition.63 Involvement of the supramarginal gyrus has been reported
before and may be related to attentional abnormalities in patients. The small
areas of decreased gray matter density in the medial occipitotemporal gyrus,
or lingual gyrus, were reported earlier in a voxel-based morphometric study.11 This area has been associated with spatial information
processing,64 which may be impaired in schizophrenia.65 In a volumetric MRI study the posterior cingulate,
precuneate, and occipitotemporal gyri were not significantly decreased in
schizophrenia.6 This may not be in contrast
to our findings, however, since the areas of decreased gray matter density
in these brain regions were rather small and may, therefore, not have reached
significance in the larger parcellation units of the cortex as defined in
the volumetric study.
The more prominent decrease in left amygdala density in older compared
with younger patients with schizophrenia suggests a loss of gray matter in
this limbic brain region over the course of the illness. This finding is consistent
with the theory that neurodegenerative brain changes such as progressive dysplasia
at the synaptic or cellular level may be involved in schizophrenia,66 possibly in addition to neurodevelopmental processes.
In healthy subjects no changes with age were found in the amygdala, which
is consistent with earlier findings suggesting that the volume of the amygdala
starts to decrease only after the age of 60 years.67
However, a cohort effect might also explain the interaction between age and
diagnosis. Since the amygdala has particularly widespread anatomical projections
to the lateral orbitofrontal gyri68 and hippocampus—as
well as to the medial orbitofrontal gyri, insula, temporal pole, and mediodorsal
nucleus of the thalamus,69 while receiving
extensive sensory input from the neocortex70—our
findings may suggest that a circuit involving the amygdala and its projection
areas show (progressive) changes in schizophrenia. Interestingly, meta-analysis
of hippocampal complex studies in schizophrenia found that inclusion of the
amygdala in the region of interest significantly increased effect sizes across
studies,42 providing indirect evidence for
decreased amygdala volume in schizophrenia. Neuropathological studies revealed
extensive loss of tissue71 and an increase
in dopamine72 and its metabolite homovanillic
acid73 in the left amygdala in schizophrenia.
Moreover, patients with schizophrenia showed aberrant activation of the left
amygdala during exposure to pictures of happy and sad facial expressions.74 Indeed, involvement of the amygdala in schizophrenia
would be consistent with its central role in emotional and social behavior75—both of which are disturbed in schizophrenia.
It would also be consistent with a functional disconnection syndrome in schizophrenia,
induced by aberrant modulation of synaptic plasticity in the context of emotional
and social learning, as has been suggested previously.76
This study was based on in vivo MRIs of 159 brains of patients with
schizophrenia or a schizophreniform disorder and 158 healthy comparison subjects
using voxel-based morphometry. These measurements do not allow for inferences
into the mechanisms that may be involved in this process, which remain to
be elucidated in future (postmortem) studies. Moreover, the patients' medication
may have influenced findings.77 Although antipsychotic
medication taken at the time of the MRI scan was unrelated to the age-associated
decrease in left amygdala density, effects of cumulative medication cannot
be ruled out. Effects from cohort or time of measurement cannot be excluded
completely.78 Yet, it seems unlikely that they
explained the findings, as possible confounding effects of outcome, age at
onset of the disease, changes in variance with age, and time of the scan did
not influence the results. In future studies, more refined analyses may relate
the focal gray matter density changes to the heterogeneity of the disease
symptoms in these patients,79 as was suggested
before.80
CONCLUSIONS
This study found distinct focal areas in the brains of patients with
schizophrenia with decreased gray matter density, including the left amygdala;
left hippocampus; right supramarginal gyrus; thalamus; and the (orbito) frontal,
(superior) temporal, and occipitotemporal precuneate, posterior cingulate,
and insular gyri bilaterally. Moreover, the decreased density in the left
amygdala was more prominent in older patients with schizophrenia or a schizophreniform
disorder.
AUTHOR INFORMATION
Accepted for publication June 26, 2001.
This research was supported by grant 7F99.(2).37 from the HersenStichting
Nederland (Dutch Brain Foundation), The Hague, the Netherlands (Dr Hulshoff
Pol).
From the Department of Psychiatry, University Medical Center, Utrecht,
the Netherlands (Drs Hulshoff Pol, Schnack, and Kahn, Mr Mandl, and Mss van
Haren and Koning); and the Montreal Neurological Institute, McGill University,
Montreal, Quebec (Drs Collins and Evans).
Correponding author and reprints: Hilleke E. Hulshoff Pol, PhD, Department
of Psychiatry, A01.126 University Medical Center, Utrecht, 3584 CX Utrecht,
the Netherlands (e-mail: h.e.hulshoff{at}psych.azu.nl).
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