Structural Brain Imaging in Schizophrenia:
A Selective Review

Godfrey D. Pearlson and Laura Marsh

Structural neuroimaging studies have provided some of
the most consistent evidence for brain abnormalities in
schizophrenia. Since the initial computed tomography
study by Johnstone and co-workers, which reported lateral
ventricular enlargement in schizophrenia, advances in
brain imaging technology have enabled further and more
refined characterization of abnormal brain structure in
schizophrenia in vivo. This selective review discusses the
major issues and findings in structural neuroimaging
studies of schizophrenia. Among these are evidence for
generalized and regional brain volume abnormalities, the
specificity of anatomic findings to schizophrenia and to
men versus women with schizophrenia, the contribution of
genetic influences, and the timing of neuroanatomic pa-
thology in schizophrenia. The second section reviews new
approaches for examining brain structure in schizophre-
nia and their applications to studies on the pathophysiol-
ogy of schizophrenia. Biol Psychiatry 1999;46:627– 649
© 1999 Society of Biological Psychiatry

Key Words: Schizophrenia, MRI, brain, cortex, imaging,
temporal lobe

Introduction

O

f all the methods used to investigate biologic abnor-
malities in psychiatric illnesses, structural neuroim-

aging studies have provided some of the most consistent
evidence for brain abnormalities in schizophrenia. Since
the initial report by Johnstone and co-workers (1976), in
which computed tomography (CT) scans showed abnor-
mally large ventricles in schizophrenic patients, major
technologic advances in image acquisition and analysis
have added significantly to the characterization of normal
and abnormal brain structure in schizophrenia in vivo. In
particular, magnetic resonance imaging (MRI) methods
enabled more detailed and quantitative assessments of
discrete brain structures. In comparisons of schizophrenic

populations to healthy control subjects, these MRI studies
have generally shown specific deficits in gray matter
volumes, especially in frontal and temporal regions, along
with generalized increases in ventricular and sulcal size
(Marsh et al 1996; Sullivan et al 1998a). However, the
basis and clinicopathologic correlates of the identified
brain abnormalities remain unknown. Ongoing advances
in structural neuroimaging technology, as described in this
paper, promise the availability of even more refined
approaches for investigating the neuropathology of schizo-
phrenia in the living subject, allowing integration of the
neuroanatomic findings with clinical, neurocognitive,
postmortem, and functional neuroimaging and electro-
physiologic data.

The purpose of this paper is to provide a selective

review of the major issues and findings germane to
structural neuroimaging studies of schizophrenia. In the
first section, we review nonspecific abnormalities. Then,
we discuss whether certain brain regions or tissue types
(e.g., gray vs. white matter) are preferentially affected in
schizophrenia, and if such regional patterns are specific to
schizophrenia. Finally, we discuss structural neuroimaging
studies that address when brain abnormalities might de-
velop in schizophrenia. The second section reviews new
approaches for examining brain structure in schizophrenia
and their applications to studies on the pathophysiology of
schizophrenia. While it is recognized that discrepant
findings between structural neuroimaging studies can be
attributed in part to methodologic differences, including
the sophistication of image acquisition and analysis as
well as study design, the reader is referred to other reviews
for such discussions (Gur et al 1993; Marsh et al 1996;
Pearlson and Marsh 1993; Shenton et al 1997; Woodruff
and Lewis 1996).

Part I. Structural Neuroimaging Findings
in Schizophrenia

Nonspecific Structural Abnormalities

VENTRICULAR AND SULCAL ENLARGEMENT.

Lat-

eral ventricular enlargement is the best replicated ana-
tomic abnormality detected in the brains of patients with

From the Department of Psychiatry and Behavioral Science, Johns Hopkins

University School of Medicine, Baltimore, Maryland.

Address reprint requests to Godfrey D. Pearlson, MD, Division of Psychiatric

Neuroimaging, Department of Psychiatry and Behavioral Sciences, Johns
Hopkins University School of Medicine, 600 N. Wolfe St., Meyer 3-166,
Baltimore, MD 21287.

Received September 29, 1998; revised March 4, 1999; accepted March 8, 1999.

© 1999 Society of Biological Psychiatry

0006-3223/99/$20.00

PII S0006-3223(99)00071-2

schizophrenia, both in earlier CT studies and in many MRI
investigations (Shenton et al 1997). The consistency of
this finding may, in part, reflect the fact that the lateral
ventricles are easily and reliably measured. In addition, a
number of studies report disproportionately large volumes
of the temporal horns, the cortical sulci, and the third and
fourth ventricles. Together, these abnormalities provide a
context for the observation of relatively widespread vol-
ume deficits as well as focal abnormalities in schizophre-
nia (Table 1), although their significance is unclear.
Despite this, repeated demonstrations of ventricular–sulcal
enlargement have been central to the development of
hypotheses on the nature of brain dysfunction in schizo-
phrenia.

Leading explanations for the large ventricular and sulcal

spaces seen in schizophrenia revolve around whether they are
the product of an inherently aberrant developmental process

as opposed to an acquired process, yielding excessive reduc-
tions in brain tissue relative to normal development and
aging. Resolution of this controversy is confounded, in part,
because abnormally large ventricles and sulci are both non-
selective and nonspecific findings that are associated with a
variety of psychiatric conditions as well as multiple congen-
ital, developmental, acquired, and degenerative etiologies
(Pearlson and Marsh 1993; Shenton et al 1997). It is also
unclear whether ventricular–sulcal enlargement reflects
widespread anatomic abnormalities as opposed to pathology
in adjacent brain structures, or both. These issues can be
addressed through longitudinal imaging studies as well as
through examining the relationships between CSF-space
volumes and measures of discrete structures, using both
traditional morphometric methods as well as more recently
developed methods for shape analysis and diffusion imaging
(discussed later).

Table 1. Brain Structural Abnormalities in Schizophrenia Relative to Healthy Control Subjects

Observation

Positive findings

Comments/negative studies

Increased ventricular size

Johnstone et al 1976; Pearlson et al

1989; Pearlson and Marsh 1993
(review)

Most widely replicated finding

in schizophrenia research

Reduced total brain volume

Andreasen et al 1994b; Shenton et al

1997 (review)

Elkis et al 1995 (meta-analysis)

Decreased total gray matter

volume

Zipursky et al 1992, 1998; Lauriello et

al 1997; Lim et al 1996a, 1996b;
Harvey et al 1993

Effect weak and not significant;

Pearlson et al 1997b;
Buchanan et al 1993 or only
in HASC regions; Schlaepfer
et al 1994

Temporal neocortical

reductions

Barta et al 1990; Shenton et al 1992;

Zipursky et al 1994; Flaum et al
1995a; Marsh et al 1997

Nonreplication Kulynych et al

1995

Superior temporal gyrus

(STG)

Planum temporale

surface area or volume

Petty et al 1995; Barta et al 1997; Kwon

et al 1999

Imaging nonreplications–

Kulynych et al 1996;
Kleinschmidt et al 1994

Mesial temporal reductions

Barta et al 1990; Shenton et al 1992;

Pearlson et al 1997b

Imaging nonreplications–

Zipursky et al 1994; Marsh et
al 1997; Hippocampus meta-
analysis (

⫹) Nelson et al

1998

Amygdala, hippocampus,
entorhinal and
parahippocampal cortices

Frontal neocortical

reductions

Buchanan et al 1998

Imaging nonreplications Wible

et al 1995

Broca’s area and perhaps
DLPFC

Parietal neocortical

reductions

McGilchrist 1993; Donnino et al 1996;

Pearlson et al 1998

Few or no neuropathology

studies; no imaging
nonreplications

Central gray/basal ganglia

Jernigan et al 1991; Andreasen et al

1994a

Imaging nonreplications for

thalamus–Shenton et al 1997
(review); Wolkin et al 1998;
Basal ganglia abnormalities
related to neuroleptic
treatment–Chakos et al 1994

Corpus callosum

Woodruff et al 1993, 1995; Hoff et al

1994; Raine et al 1990

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A second important aspect of ventricular enlargement in

schizophrenia is that the range for ventricular–sulcal size
overlaps considerably with the normal population and
does not appear to be bimodally distributed (Daniel et al
1991). Thus, ventricular–sulcal abnormalities are present
in schizophrenic patients as a group relative to control
populations, but ventricular size in a given patient may fall
within the normal range. This observation suggests that
neuroanatomic findings in schizophrenia are graded phe-
nomena that affect all patients (Cardno and Farmer 1995;
Goldberg and Weinberger 1995). By contrast, disease
subtypes, at least based on this measure, are not apparent
(Tsuang and Faraone 1995). It is unclear whether this also
applies to focal abnormalities (Marsh et al 1999a).

Regional Brain Structural Abnormalities
in Schizophrenia

FOCAL GRAY MATTER ABNORMALITIES.

Identified

patterns of gray matter volume abnormalities in schizo-
phrenia suggest that the entire cortex is affected (Harvey et
al 1993; Lim et al 1996a, 1996b; Shenton et al 1997;
Zipursky et al 1992, 1998), although the generally small
volume difference from normal (approximately 5%) does
not always reach statistical significance in comparisons
with healthy control populations (Pearlson 1997a). Within
the context of these widespread volume deficits, volumes
in specific frontal, temporal, and parietal cortical subre-
gions appear to be disproportionately smaller (generally
10% to 15%) (Daniel et al 1991; Shenton et al 1997;
Sullivan et al 1998a). However, like the widespread
abnormalities, the significance of focal cortical volume
deficits in schizophrenia remains unknown. Further, it is
unclear whether all patients with schizophrenia demon-
strate the same anatomic findings, if focal changes are
specific to the disease, or if there are subgroups of
schizophrenia with distinct clusters of particular volume
abnormalities that involve discrete neuroanatomic circuits.
Also unknown is whether the observed changes are the
consequence of a single disease process occurring during
a critical period, or if specific cells, regions, or compo-
nents of a distributed system (such as those sharing a
common enzyme, unusually sensitive to anoxia, or need-
ing a particular growth factor) are affected.

Temporal lobe abnormalities in schizophrenia have

been investigated in over 50 MRI studies (Shenton et al
1997), of which over 75% report differences from con-
trols. Such differences are reported in medial temporal
lobe (hippocampus, amygdala, and entorhinal or parahip-
pocampal cortex), or in various subdivisions of the supe-
rior temporal gyrus. Of nearly 10 MRI studies that
measured superior temporal gyrus volume in schizophre-
nia, the majority reported volume reductions in schizo-

phrenia (Barta et al 1990; Flaum et al 1995a; Marsh et al
1997; Menon et al 1995; Schlaepfer et al 1994; Shenton et
al 1992; Zipursky et al 1994), while two found no
differences relative to control values (Kulynych et al 1995;
Vita et al 1995). Shenton and co-workers (1997) note that
superior temporal gyrus measures in the negative reports
were comprised of combined gray and white matter
volumes, which may have obscured detection of group
differences from control subjects if the pathology is
confined to gray matter.

HETEROMODAL NEOCORTICAL VOLUME DEFICITS

IN SCHIZOPHRENIA.

Recent reviews implicate pathol-

ogy of heteromodal association cortex (HASC) in schizo-
phrenia (Pearlson et al 1996; Ross and Pearlson 1996).
HASC is a highly organized and interconnected neocorti-
cal system comprised of the planum temporale (PT), the
dorsolateral prefrontal cortex (DLPFC), Broca’s area, and
the inferior parietal lobule (IPL) (Mesulam 1985). As
discussed by Ross and Pearlson (1996), several neurode-
velopmental features of HASC suggest that its component
regions may be especially vulnerable to disruptions in
neuronal function or connectivity during brain develop-
ment, which are also implicated in schizophrenia. First,
HASC regions mature at differential rates relative to other
brain regions. For example, the late prenatal and early
postnatal phases are critical early periods in HASC devel-
opment, whereas other brain regions mature earlier in fetal
development. Therefore, a noxious process occurring dur-
ing one of these phases might affect ongoing events such
as neuronal and oligodendroglial differentiation, myelina-
tion, and astrocytic proliferation in HASC regions whereas
another area that matures relatively earlier, such as pri-
mary motor cortex, would be “protected.” Secondly, the
development of HASC regions is protracted, extending
into early adult life. For example, Brodmann area 22 has a
longer developmental process than area 17. In addition,
differentiation of HASC areas is highly dependent on
callosal fibers, i.e., corticocortical connections. This may
be related to the thicker subplate seen in HASC regions
relative to other cortical areas. Rakic (1988) postulated
that this thick subplate exists to receive developing cal-
losal fibers, and in turn, plays a critical role in gyral
formation.

Specific studies of HASC regions are few, given the

need for complex image analysis methods such as cortical
parcellation and 3D-rendering techniques to identify sul-
cal/gyral delineation boundaries. Reports of reversed nor-
mal asymmetry of PT surface area in schizophrenia (Barta
et al 1997; Petty et al 1995) are consistent with the
hypothesis of specific HASC involvement. By contrast,
there are no morphometric differences between schizo-
phrenia patients and controls on measures of anatomically

Structural Brain Imaging in Schizophrenia

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1999;46:627– 649

adjacent cortex, i.e., Heschl’s gyrus, which consists of
unimodal (primary) sensory cortex rather than HASC and
serves as an “internal control” region (Petty et al 1995).
More recently, Buchanan and colleagues (1998) tested the
HASC hypothesis using cortical sub-parcellation (Barta et
al unpublished data, 1999) and cortical “paint” techniques
(Ross and Pearlson 1996) applied to the frontal lobe.
Patients with schizophrenia showed selective gray matter
volume deficits in the right and left inferior prefrontal
cortex, which contains Broca’s area. There were no group
differences in other prefrontal regions except for a trend
for left DLPFC volume reduction. Schlaepfer and co-
workers (1994) also reported disproportionate reduction of
bilateral DLPFC regions. However, in first-episode
schizophrenic patients, Nopoulos and co-workers (1995)
reported reduced gray matter volumes only in the frontal
lobe measure. In the only frontal lobe study comparable to
Buchanan and co-workers (1998), Wible and colleagues
(1995) failed to detect group differences between patients
and control subjects.

Findings from studies on other HASC regions, e.g., the

inferior parietal lobule, are equivocal, for reasons similar
to those discussed for the frontal lobe. Generally, investi-
gators have used somewhat thick (e.g., 1 cm) slices to
examine this region, without careful delineation of parcel-
lated sub-regions or use of 3-D outlining techniques.
Schlaepfer and colleagues (1994), however, found specific
gray matter deficits in inferior parietal lobule. Two recent
abstracts add information on abnormalities in this region.
Donnino and co-workers (1996) examined 15 chronic
male schizophrenics compared to gender-matched normal
control subjects using thin (1.5 mm coronal) SPGR slices.
Like Pearlson and co-workers (1998), they reported rever-

sal in the schizophrenia group of the normal male control
pattern of left greater than right volume asymmetry.
Donnino and co-workers (1996) found this largely due to
asymmetry reversals in the IPL; Pearlson and colleagues
(1998) assessed IPL exclusively.

THALAMIC ABNORMALITIES.

The thalamus is an

important node within the neural circuits implicated in
schizophrenia. Only a few quantitative MRI investigations
have examined the thalamus, in part because of difficulties
measuring the structure reliably. For the small number of
studies conducted to date, findings are mixed. Some report
volume reductions (Andreasen et al 1994a; Buchsbaum et
al 1996; Corey-Bloom et al 1995), as have neuropatho-
logic studies (Pakkenberg 1990, 1992). Other studies
found no differences in thalamic measures between pa-
tients and control subjects (Portas et al 1998; Wolkin et al
1998). In Portas and co-workers (1998), thalamic volumes
in schizophrenic patients, but not control subjects, were
correlated with prefrontal white matter and lateral ventric-
ular volumes. Given that the thalamus is an anatomically
heterogeneous structure comprising many different nuclei,
it is possible that its abnormal regions may be difficult to
detect with available MRI methods. Parcellation of the
thalamus into its various subcomponents, if possible,
might address whether certain nuclei (e.g., the medial
dorsal nucleus, which is connected to heteromodal re-
gions) are disproportionately affected in schizophrenia.

ABNORMAL

ASYMMETRIES

IN

SCHIZOPHRENIA.

Many structures are normally lateralized in the human
brain, with surface areas or volumes being consistently
larger in one or the other hemisphere, on occasion in

Table 2. Studies of Anatomic Asymmetries in Schizophrenia

Brain region

Positive studies

Negative studies/comments

Petalia (cerebral “torque”)

Luchins et al 1979, 1982
Cowell et al 1996
Bilder et al 1994
Bullmore et al 1995

Luchins studies were with CT
Failure to replicate: Andreasen et al 1982;

Jernigan et al 1982

Early measures were linear or area; later

studies using volume measures are
more valid

Planum temporale (and

lateral sulcus)

Petty et al 1995
Barta et al 1997
Falkai et al 1995
Kwon et al 1999
Hoff et al 1992

Kulynych et al 1996; Bartley et al 1993
Review of methodologic problems in

various studies in Barta et al 1995

Anterior cingulate cortex

Albanese et al 1995

Neuropathologic study, small sample size

Assorted cortical regions

Bilder et al 1994
Tien et al 1996
Turetsky et al 1995

Occipitoparietal, premotor and prefrontal

asymmetries examined by Bilder,
heteromodal association cortex by Tien;
prefrontal and temporal by Turetsky

Inferior parietal lobule

Pearlson et al 1998

First carefully controlled documentation

of this asymmetry on MRI

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conjunction with lateralized functions such as language. A
variety of studies have demonstrated the absence or
reversal of such normal cerebral structural asymmetries in
schizophrenia (see Table 2). Such investigations are
prompted by the presence of quantitative differences
between the volumes of structures in the right versus left
cerebral hemispheres that are normally apparent as early
as the second trimester of prenatal development (Chi et al
1977b). In schizophrenia, disruptions in normal patterns of
asymmetry are thought to reflect abnormalities in fetal
brain development (see Barta et al 1997; Pearlson et al
1995b). Crow argues that such disturbed brain asymme-
tries are a “key to the etiology of schizophrenia” (Crow
1990a, 1990b, 1995a, 1995b, 1997, 1998; Crow et al
1989a, 1989b). Crow hypothesizes that one human gene
comprising an asymmetry or cerebral dominance factor
that is essential to the evolution of human language and
hand dominance also “contributes substantially to the
predisposition to psychosis.” Crow’s hypothesis also sug-
gests that processes related to asymmetries also influence
gender differences in schizophrenia by interacting with
normal differences in the rate of asymmetry development
between genders.

The planum temporale (PT), a brain region on the

superior surface of the temporal lobe involved in language
processing, is notable for its size differences between the
left and right sides (the normal pattern is left

⬎ right). As

PT asymmetry develops in utero, disruptions in the usual
pattern suggests a process involving abnormal neurodevel-
opment (Chi et al 1977a). In addition to serving as a
potential indicator of abnormal development, the PT is of
particular interest in schizophrenia because it is comprised
of heteromodal association cortex, as discussed earlier.
Barta and co-workers (1995) developed a novel method
for measuring the surface area of the PT that accurately
follows the surface contours of the region. Applying this
method, Petty and colleagues (1995) demonstrated a
reversal in schizophrenia of the usual PT asymmetry; a
finding not attributable to handedness differences. This
initial finding was then replicated in a second, expanded
sample (Barta et al 1997). In the second study, there was
a complete reversal of the normal PT surface area asym-
metry in both men and women schizophrenic subjects.
However, others have not detected such PT asymmetry
reversals using different MRI measurement methods, as
reviewed by Barta and co-workers (1995).

DISTURBED

CONNECTIVITY.

Recent

discussions

have focused on disturbed connectivity between different
brain regions in schizophrenia (Liddle 1997; Woodruff et
al 1997). Tien and co-workers (1996) applied factor
analysis procedures to cortical and subcortical regional
brain volume measures from MRI data in normal and

schizophrenia subjects. Basal ganglia, heteromodal corti-
cal gray, and medial temporal lobe factors were present in
both groups. The factor structure observed in normal
subjects showed a high degree of bilateral symmetry,
which was disrupted in the schizophrenia group. Across
hemispheres, the disruption was most pronounced in
medial and lateral temporal lobes structures, including
entorhinal cortex and anterior and posterior superior tem-
poral gyri. There was a significant correlation between the
basal ganglia factor and the heteromodal cortical gray
factor in the normal group that was not present in the
schizophrenia group. Within the hemispheres, left poste-
rior superior temporal gyrus did not load onto any factor in
the schizophrenic group. Thus, several brain regions seem
affected in schizophrenia, including temporolimbic and
HASC areas, with relationships between groups of regions
also being abnormal. Wible and colleagues (1995) simi-
larly found correlations between prefrontal and temporal
cortical volumes in schizophrenia that differed markedly
from volumetric associations seen in the healthy control
group.

CLINICOPATHOLOGICAL

CORRELATES

OF

RE-

GIONAL STRUCTURAL ABNORMALITIES.

Functional

brain abnormalities are also demonstrated in schizophre-
nia, (see reviews by Gur and Pearlson 1993; Liddle 1997).
Among the brain regions showing demonstratable func-
tional abnormalities in schizophrenia, e.g., DLPFC (Wein-
berger 1987), Broca’s area (McGuire et al 1993), superior
temporal gyrus (Woodruff 1997), and thalamus (Silbers-
weig et al 1996), all manifest significant structural abnor-
malities on either MRI or neuropathology (e.g., Akbarian
et al 1995; Andreasen 1997; Barta et al 1990; Buchanan et
al 1998; Pakkenberg 1992; Shenton et al 1992). It is
unknown what relationship the structural and functional
abnormalities bear to one another and which, if either, is
primary. Some hypothesize that brain abnormalities in
schizophrenia involve alterations in or altered correlations
between regional patterns of brain function (Chua et al
1995; Liddle 1997). For example, Woodruff and co-
workers (1997) reported that schizophrenics were charac-
terized by an abnormally lateralized temporal cortex re-
sponse to perception of speech. They suggested that this
change was the functional equivalent of the previously
reported structural abnormality (i.e., reversed asymmetry
of planum temporale surface area) (Barta et al 1997; Petty
et al 1995).

While none of the clinical symptoms seen in schizo-

phrenia are pathognomonic for the disease, they are
striking, and it is reasonable to ask whether they are
related to underlying brain changes. To address this
question, one needs to distinguish putative disease sub-
types (e.g., paranoid) from the severity of a specific

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symptom (e.g., thought disorder), from overall disease
severity (e.g., number of hospitalizations). Attempts to
link global brain changes of schizophrenia to specific
symptom groups have generally failed (Pearlson et al
1989), although volumes of some brain regions have been
associated with the severity of positive symptoms. For
example, several groups report that superior temporal
gyral volume reductions are related to positive symptoms
(Flaum et al 1995a; Marsh et al 1997). Reduced medial
temporal volumes have also been associated with more
severe clinical symptoms, including positive symptoms
(Bogerts et al 1993; Goldberg et al 1993) and disrupted
logical memory (Goldberg et al 1993). Reduced mesial
temporal and temporal neocortical volumes were associ-
ated in a study by Nestor and colleagues (1993) with
poorer scores on verbal memory, abstraction, and catego-
rization. More specific findings include associations be-
tween smaller anterior superior temporal gyrus volumes
and the severity of auditory hallucinations (Barta et al
1990) and smaller posterior superior temporal gyrus vol-
umes and the severity of formal thought disorder (Barta et
al 1997; Menon et al 1995; Shenton et al 1992). Mathalon
and co-workers (1997) noted that rate of MRI volume loss
over 4 years correlated with BPRS severity at baseline and
follow-up. In particular, positive symptoms predicted loss
of anterior superior temporal, frontal, and parietal (i.e.,
HASC) gray matter.

The work of Carpenter and co-workers suggests that

deficit symptoms, which are more enduring relative to
positive symptoms, may be more likely to show associa-
tions with brain structural abnormalities (e.g., Buchanan
and Gold 1996). Three CT studies found higher rates of
persistent unemployment (a presumed surrogate for sever-
ity of negative symptoms and/or cognitive impairment)
among schizophrenic patients with ventricular enlarge-
ment (Katsanis et al 1991; Pearlson et al 1985; Vita et al
1991). A fourth CT study found that increased volume of
the sylvian fissure predicted unemployment over a 4-year
follow-up (van Os et al 1995). Using MRI, Harvey and
colleagues (1993) found an association between unem-
ployment and reduced volume of the anterior cerebral
cortex and increased volume of sulcal fluid in schizophre-
nia. Others reported a relationship between negative symp-
tom severity and larger left-hemisphere and total CSF
volumes (Gur et al 1994; Mozley et al 1994).

Although many clinical and demographic variables

have been found to correlate with everyday functional
independence among patients with schizophrenia, their
relative contributions remain unclear. A presumed link of
deficit symptoms to dysfunction or structural change in the
prefrontal and parietal cortex is certainly plausible (Wein-
berger 1987). However, Buchanan and colleagues (1993),
using global gray and white matter MRI measures, found

that right and left prefrontal volumes were actually smaller
in nondeficit patients. By contrast, pilot data from Ventura
and co-workers (1997) showed that severity of the deficit
syndrome in schizophrenia correlated with lower total
frontal lobe and hippocampal volumes. In a longitudinal
analysis, Mathalon and co-workers (1997) reported an
association between reductions in prefrontal gray matter
and third ventricular expansion with negative symptoms.

Clearly, there are wide gaps in our understanding of the

links between symptoms in schizophrenia and underlying
brain changes. While it is logical that symptoms such as
hallucinated voices or disturbed language could be pro-
duced by structural or functional deficits in language
circuits, evidence for this remains suggestive rather than
conclusive. Since the original report by Barta and col-
leagues (1990), which related superior temporal gyral
volumes to psychotic symptom severity, several studies tie
positive symptoms, particularly hallucinations and thought
disorder, to structural changes in superior temporal gyrus.
The finding from Mathalon and colleagues (1997), men-
tioned previously, suggests a potential explanation for the
paradox, how can (inherently changing) positive symp-
toms be associated with (fixed) structural deficits? (Roth
and Pfefferbaum 1992). While not consistently demon-
strated, it is possible that positive symptom severity relates
to the magnitude of a dynamic process involving progres-
sive brain atrophy.

Specificity of Identified Brain Abnormalities to
Schizophrenia

ANATOMIC

DIFFERENCES

BETWEEN

MEN

AND

WOMEN WITH SCHIZOPHRENIA.

The prevalence rates

of schizophrenia in men versus women are about equal,
but there are substantial gender differences in the age of
onset, treatment response, and overall course of schizo-
phrenia (Goldstein 1995). Whether these clinical differ-
ences are reflected in anatomic differences between men
and women with schizophrenia remains unclear. Accord-
ingly, investigation of the neuropathology of schizophre-
nia requires attention to the normal gender differences in
brain anatomy (Marsh et al 1996; Pearlson and Pulver
1994).

Normal gender differences in brain anatomy (sexual

dimorphisms) include differences in total brain volume,
brain weight, regional brain size, and patterns of asymme-
try that are well established in both animal and human
studies (see Table 3 and reviews by Marsh and Casper
1998; Pearlson and Pulver 1994). Despite controversy
regarding their magnitude, there are also normal gender
differences in cognition that have been recognized for
many years (Heller 1993; Maccoby and Jacklin 1974).
Whether normal sexual dimorphisms in neuroanatomy

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BIOL PSYCHIATRY
1999;46:627– 649

interact with hormones to modulate differences in cogni-
tion is unknown (Schlaepfer et al 1995). In addition, how
the patterns of volumetric differences in schizophrenia are
influenced by normal gender effects, over and above
disease related effects, remains unclear.

Substantial evidence suggests that normal sexual dimor-

phisms result from different neuronal growth and pruning
patterns in male and female brains during fetal develop-
ment, in response to genetic or hormonal influences
(Dorner 1980; Gorski et al 1980; Hier and Crowley 1982;
MacLusky and Naftolin 1981; MacLusky et al 1987;
McEwen 1981; Netley 1977). Sexual differentiation con-
tinues at puberty, when neuronal pruning and remodeling
reactivate under hormonal influences (McGlone 1980).
Further evidence suggests that the rates and timing of gray
and white matter pruning, and hence longitudinal neuro-
developmental patterns, also differ among male and fe-
males (Aboitiz et al 1996; Benes et al 1994).

Using MRI in a cross-sectional study, Pfefferbaum and

co-workers (1994) demonstrated that intracranial volumes
increased between the ages of 3 to 10 years in a sample of
males and females ranging in age from 3 months to 30
years, with cortical gray matter volumes peaking in both
boys and girls around age 4 and declining thereafter.

Cortical white matter volumes increased to age 20, with
cerebrospinal fluid volume staying constant. By contrast,
Giedd and co-workers (1996) did not find age-related
brain developmental differences in corpus callosum in a
cross-sectional MRI sample of healthy 4 to 18 year-olds.
More recently, high-resolution diffusion-weighted MRI
sequences (see Part II for discussion for this technique)
have been developed to investigate white matter matura-
tion in animal models and, for example, the effects of sex
hormones on the rat brain (Prayer et al 1997). Initial data
suggest that white matter maturation accelerates with
estrogen treatment, but is delayed by testosterone. The role
of estrogen effects in brain development is corroborated
by evidence that antiestrogens inhibit myelination in
animal models (Guttinger et al 1993). In rodents, there are
also sex steroid effects on amygdala, hippocampus, and
prefrontal cortex (MacLusky et al 1987). These gender
differences occur in neocortical and limbic regions, where
they are likely associated with gender-related cognitive
dimorphisms. In addition, gender differences occur in
hypothalamic regions in association with reproductive
differences.

Given the evidence for schizophrenia as a disorder of

abnormal brain development, i.e., (Weinberger 1987), an

Table 3. Anatomic Imaging Studies Contrasting Normal Male and Female Neuroanatomy

Observation

Study

Comment

Female brain is smaller in

weight and volume

Dekaban 1978; Breedlove 1994; Schlaepfer

et al 1995

Not fully accounted for by larger

male body height

⫹ weight

Female brain is less

asymmetric, e.g., in
planum temporale (PT)
(where most males
have left

⬎ right

asymmetry)

Geschwind and Levitsky 1968; Witelson and

Kigar 1992; Diamond 1991; McGlone
1980; Kertesz et al 1990

Women have greater neuronal

density in PT; Witelson et al
1995

Female brain myelinates

and prunes earlier

Benes 1989; Geschwind and Galaburda 1985

Female brain ages

differently

Murphy et al 1996; Raz et al 1997; Cowell

et al 1994

Frontal lobe and amygdala

⫹

hippocampus differ most
markedly

Areas related to

reproductive behavior
differ

Allen et al 1989
Swaab and Fliers 1985

Sexually dimorphic nucleus of

preoptic area and bed nucleus
of the stria terminals of
hypothalamus

Language regions

(Broca’s, dorsolateral
prefrontal cortex, PT)
are proportionately
larger in females

Schlaepfer et al 1995; Harasty et al 1997

Prefrontal and lateral temporal

cortical

Visuospatial areas are

proportionately larger
in males

Pearlson et al 1998

Inferior parietal lobule

Corpus callosum (CC)

size and shape differ

Witelson 1989; Allen and Gorski 1992;

Pearlson et al 1998; Raine et al 1990;
Andreasen et al 1990

Primate gender differences in CC

closely related to development
of cerebral asymmetries; de
Lacoste and Woodward 1988

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additional unresolved issue is whether a developmental
disorder could differentially affect males and females.
Outside of the Fragile-X syndrome and other sex chromo-
some-based disorders, the answer appears to be positive.
For example, in dyslexia, Kaufmann and Galaburda
(1989) and Humphreys and colleagues (1990) found that
males showed only microdysgenesis whereas females
showed both microdysgenesis and myelinated scars. This
suggests that males with dyslexia are affected only during
neuronal migration while female brains may be “dis-
turbed” during migration as well as postmigration, includ-
ing postnatal development. In schizophrenia, structural
differences that distinguish schizophrenia from healthy
brains also appear to be regions with predictable neurode-
velopmental outcomes, i.e., normal brain asymmetries and
sexual dimorphisms. Evidence for disruption of asymme-
tries and sexually dimorphic features in schizophrenic
brains suggests that different patterns of anatomic abnor-
malities will be apparent in men versus women with
schizophrenia.

Few neuropathologic studies in schizophrenia have

explicitly examined gender differences and fewer still CT
or MRI studies comparing men and women with schizo-
phrenia have considered structures other than the ventric-
ular system (Table 4). Many studies are limited by small
and/or unequal sample sizes and additional confounds,
such as poorly matched samples. In addition, a majority of
studies have included only or mostly male subjects (No-
poulos et al 1997a). Others argue that apparent gender
differences in brain structure “evaporate if confounds such
as socioeconomic status and race are controlled” (Harvey
et al 1991; Lewis 1992). However, in a recent analysis that
accounted for these confounds (Pearlson et al 1997b),

comparisons of schizophrenic patients to healthy controls
on MRI-derived measures of superior temporal gyrus,
medial temporal structures, and global brain measures,
sex-by-diagnosis interactions were evident for tem-
porolimbic structures (right and left amygdala and a trend
for left entorhinal cortex). Thus, these data suggest dis-
ease-related gender differences in neocortical and tem-
porolimbic anatomy in schizophrenia. Whether such gen-
der differences in brain anatomic abnormalities are also
linked to the well-established gender differences in onset,
course and outcome of schizophrenia is not known.

GENETIC COMPARISONS.

A high prevalence of var-

ious biologic abnormalities and of schizophrenia spectrum
disorders in the first-degree relatives of schizophrenia
patients suggests that a proportion of clinically unaffected
first-degree relatives carry one or more pathologic genes
for the disorder (Cannon et al 1994; Kremen et al 1994;
Shedlack et al 1997; Wickham and Murray 1997). How-
ever, the identity and role of gene(s) and gene products in
schizophrenia remains unknown (Wickham and Murray
1997). One possibility is that the putative gene(s) influ-
ence cortical migration or development (Ross and Pearl-
son 1996). Thus, if structural brain abnormalities in
schizophrenia patients are genetically transmitted, they
could function as a major biologic marker for transmission
of the schizophrenia genotype, as well as reflecting envi-
ronmental etiologies (Cannon et al 1994; Wickham and
Murray 1997). As candidate genes for schizophrenia and
bipolar disorder become evident, brain imaging studies
will become extremely important for clarifying these
relationships between genotype and phenotype. Biologic
markers such as structural brain abnormalities might allow

Table 4. Brain Structural Differences in Men Versus Women with Schizophrenia

Observation

Study

Comment

Ventricular size larger in

male schizophrenics

Andreasen et al 1990; Hafner and

Gattaz 1995; Lewine et al
1995; Nopoulos et al 1997a
(reviews prior studies)

Best replicated finding challenged;

Zigun et al 1992; Vazquez-
Barquero et al 1995; Lauriello
et al 1997; Gur et al 1991,
1994; Flaum et al 1995b

Brain volume reduction

more marked in
female schizophrenics

Nasrallah et al 1990

Small sample size; Not found-

Lauriello et al 1997; Andreasen
et al 1994b

Planum temporale

volume and other
asymmetry reversals
more marked in male
schizophrenics

Falkai et al 1995 (postmortem

study); Cowell et al 1996

Not seen–Petty et al 1995

Corpus callosum

thickness greater in
female schizophrenics

Nasrallah et al 1986; Raine et al

1990

Opposite findings Hoff et al 1994;

Hauser et al 1989

More total male

abnormalities

Lewine et al 1990; Hafner and

Gattaz 1995; Nopoulos et al
1997a

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identification of phenocopies and homogeneous subtypes
and clarification of the relationship of the genotype to the
neural phenotype. Such data, which highlight genetic
influences, are a useful counterpoint to discordant
monozygotic twin studies, which emphasize environmen-
tal factors (Suddath et al 1990). Finally, studies focusing
on a single generation (e.g., sib-pair designs) control better
for possible age and family environment confounds.

Twin studies of healthy control populations emphasize

the role of heritability of total brain and sulcal volumes,
and show similar, but smaller, effects for ventricular
volumes (Pfefferbaum et al 1997; Reveley et al 1982).
Studies of nonschizophrenic siblings of patients with
schizophrenia show ventricular volumes intermediate be-
tween those of patients and control subjects (DeLisi et al
1986; Weinberger et al 1981). In monozygotic twins
discordant for schizophrenia, the schizophrenic twin has
larger ventricles while ventricular size is intermediate
between that of the schizophrenia patients and normal
controls in the unaffected twin (Reveley et al 1982, 1984).
Shihabuddin and co-workers (1996) assessed lateral ven-
tricular enlargement and frontoparietal atrophy on CT in
one large family containing multiple cases of schizophre-
nia. Shihabuddin hypothesized that these changes may be
associated with a schizophrenia-related gene and denote a
susceptibility to schizophrenia-related conditions. Frangou
and co-workers (1997) initially suggested that planum
temporale volume asymmetry in patients with schizophre-
nia, and their first-degree relatives, did not differ from
those of normal control subjects. However, a later study
(Barta et al 1997) showed that schizophrenia patients
differ in asymmetry of the planum temporale surface area
but not in the volume of the underlying gray matter.
Cannon and colleagues (1997) contrasted MRI measures
from schizophrenia patients and their unaffected siblings;
the schizophrenia patients had increased CSF, especially
in the frontal lobes and left hemisphere. In a small pilot
study (Seidman et al 1997), there was increased ventricu-
lar size and reduced volumes of gray matter and right
amygdala in the nonschizophrenic sisters of schizophrenia
patients relative to female control subjects. Sharma and
co-workers (1998) examined families multiply affected
with schizophrenia. Ventricular volume in the MRI scans
of schizophrenia patients was larger than those of first-
degree relatives and control subjects.

Wickham and Murray (1997) argue that questions of

biologic vulnerability markers can be usefully addressed
via sibling comparisons. Presumed obligate genetic carri-
ers (e.g., nonschizophrenic individuals who have parents
and children with schizophrenia) are of particular interest
to researchers. Sharma and co-workers (1998) compared
MRI scans of patients from families multiply affected with
schizophrenia to many of their first-degree relatives and to

group-matched normal control subjects. Male schizo-
phrenics had larger lateral ventricles than normal control
subjects, but the schizophrenia patients had smaller total
brain volumes and larger lateral ventricles compared to
nonaffected age- and gender-matched siblings. Structural
brain measures in siblings were no different than those in
the healthy control subjects, but presumed obligate carriers
showed similar lateral ventricular enlargement to schizo-
phrenia patients. Sharma argued that nonschizophrenic
relatives could manifest similar brain changes to schizo-
phrenia patients, especially relatives who are presumed
carriers of the schizophrenia gene.

Other than the ventricles, relatively few anatomic

regions have been investigated in this context. Dauphi-
nais and co-workers (1990) reported smaller temporal
lobe size in nonschizophrenic siblings. Dickey and
colleagues (1997) preliminarily explored structural
brain abnormalities in schizotypal personality disorder
(SPD). Although SPD commonly appears in family
members of schizophrenics, the Dickey sample was
recruited through local advertisements. Many of the
same structural abnormalities previously reported to
occur in the brains of patients with schizophrenia (for
example, reduced gray matter volume of the posterior
superior temporal gyrus and whole-brain gray matter),
though, were also found by Dickey in SPD. Silverman
and co-workers (1998) found that the ventricular-brain
ratio in the schizophrenic patients was similar to that of
their siblings with SPD, but differed from family
members without schizophrenia-related disorders.

COMPARISON DISORDERS.

In the absence of a defin-

itive pathologic feature, none of the reported structural
abnormalities is pathognomonic for schizophrenia. Com-
parison of brain abnormalities in schizophrenia to those
present in other neuropsychiatric conditions that also
exhibit brain structural abnormalities provides one ap-
proach for discerning normal patterns as well as those that
are unique to schizophrenia versus some other condition,
e.g., Alzheimer’s disease, epilepsy, mood disorders, alco-
holism, or Parkinson’s disease (Marsh et al unpublished
data, 1999; Sullivan et al 1998b). Potentially more reveal-
ing are comparisons of schizophrenia to disorders that
share clinical phenomena with schizophrenia, as these may
reveal clinicopathologic correlations that are either spe-
cific to schizophrenia or merely common to the presence
of certain clinical signs. Neurologic disorders with schizo-
phrenia-like illness and more overt neuropathology than
idiopathic schizophrenia may further improve the likeli-
hood of detecting abnormalities and clinicopathologic
relationships, which are salient to the schizophrenic syn-
drome. Here, we discuss two candidate disorders for such
comparisons: bipolar disorder and epilepsy.

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Bipolar Disorder.

Bipolar disorder (BP) is a common

disorder with a lifetime prevalence of 1.5%. Psychotic
symptoms frequently occur, and, in the absence of addi-
tional history, the clinical syndrome of acute mania can be
indistinguishable from an acute schizophrenic episode
(Carlson and Goodwin 1973). In addition, many patients
with schizophrenia experience depression or other affec-
tive symptoms. These shared clinical features of schizo-
phrenia and bipolar disorder have led some to suggest that
there is a continuum of pathology between bipolar disor-
der and schizophrenia (see Crow 1990b; Taylor 1992).

Separate structural and functional imaging studies com-

paring control subjects to bipolar disorder or to schizo-
phrenia subjects implicate many of the same brain regions
in both conditions, including the frontal lobe, basal gan-
glia, and temporolimbic structures (see reviews and com-
ments by Pearlson and Schlaepfer 1995a, 1997c; Soares
and Mann 1997). However, it is also important to note that
many earlier neuroimaging studies on bipolar disorder
included mixed samples of patients with bipolar type I and
type II syndromes, major depression, early as well as late
onset syndromes, and psychotic versus nonpsychotic fea-
tures, for example. By contrast, the study criteria for
studies on schizophrenia have tended to be more selective
(see Pearlson and Schlaepfer 1997). Nonetheless, despite
the clinical heterogeneity of studies on bipolar disorder,
certain anatomic findings have emerged. Like schizophre-
nia, these include generalized changes such as increased
ventricle size and sulcal widening, and localized volume
abnormalities such as reduced amygdala and/or anterior
temporal lobe volumes (Altshuler et al 1991; Hauser et al
1989; Pearlson et al 1997b; Strakowski et al 1993), and
subgenual cingulate volumes (Drevets et al 1997). A more
recent MRI study suggests amygdalar enlargement in
bipolar disorder (Altshuler et al 1998). In contrast to
studies of schizophrenia, MRI studies of bipolar disorder
also reveal an increased frequency of subcortical white
matter hyperintensities (Aylward et al 1994; Brown et al
1992; Dupont et al 1990; reviewed by Marsh et al 1996).

Few studies have directly compared brain abnormalities

in schizophrenia to those in bipolar disorder. Those carried
out so far seem to suggest that regional changes in
schizophrenia consist of disturbances in normal asymme-
tries and changes in entorhinal cortex volumes, whereas
bipolar disorder subjects show an increased frequency of
subcortical white matter hyperintensities and perhaps cin-
gulate changes (Aylward 1994; Drevets et al 1997; Noga
et al 1995). Recently, Lim and colleagues (unpublished
data, 1999) showed that global cerebral gray matter
reductions in patients with bipolar disorder were interme-
diate between those of schizophrenia and controls, along
with a similar pattern of cortical deficits to schizophrenia,
i.e., maximal reductions in prefrontal cortex and superior

temporal regions. These findings support the hypothesis
that HASC regions are preferentially affected in schizo-
phrenia.

Epilepsy.

The occurrence of transient psychotic symp-

toms or prolonged interictal schizophrenia-like syndrome
in some patients with epilepsy has led to hypotheses that
epilepsy may serve as a useful model for investigating the
neuropathology of schizophrenia (Engel and Rocha 1992;
Scheibel 1991; Slater et al 1963). Although epilepsy and
ictal psychotic phenomena are related to recurrent parox-
ysmal electrophysiologic events, this hypothesis suggests
that the occurrence of chronic interictal schizophrenia-like
illness represents additional brain disease, i.e., structural
pathology, not directly related to seizure generation. In
particular, brain abnormalities specific to psychosis or
negative symptoms should be over and above the abnor-
malities seen in epilepsy without these symptoms. Accord-
ingly, comparisons of patients with epilepsy plus schizo-
phrenia-like

syndromes

(E

⫹SCZ) to patients with

idiopathic schizophrenia enables identification of converg-
ing brain abnormalities or critical nodes that are specific to
the schizophrenic syndrome, rather than epiphenomena.

Many commentaries and investigations on the relation-

ship between E

⫹SCZ and schizophrenia have focused on

the role of temporal lobe pathology and temporal lobe
epilepsy (TLE) in the occurrence of the schizophrenic
syndrome (Mace 1993; Sachdev 1998; Trimble 1991). In
part, this bias is because E

⫹SCZ occurs most commonly

(though not exclusively) in patients with localization-
related epilepsy of temporal lobe origin (the most common
site for localized seizure foci). Furthermore, samples were
limited to patients with TLE, the clinical characterizations
of patients with E

⫹SCZ tended to focus on the presence of

psychotic symptoms (which, as above, may be clinico-
pathologically related to temporal lobe processes), and
brain regions outside the temporal lobe were not exam-
ined. However, the hypotheses on the relationship between
epilepsy and schizophrenia are important historically in
that they influenced the theoretical basis for focusing
anatomic investigations of schizophrenia on specific brain
regions, namely the lateral and medial temporal lobe (e.g.,
Barta et al 1990; Suddath et al 1990). Yet, the prevailing
hypotheses on relationships between epilepsy and schizo-
phrenia did not evolve along with advances in imaging
technology and evidence from MRI of widespread cortical
abnormalities in schizophrenia.

Despite speculation on the importance of left temporal

pathology in E

⫹SCZ, the neuroimaging data, albeit lim-

ited, has not been compelling in this regard. At the least,
neuroimaging and neuropathologic studies comparing
E

⫹SCZ to schizophrenia tend to implicate extratemporal,

and possibly, subcortical abnormalities as common factors

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(Bruton et al 1994). One CT study found no group
differences between E

⫹SCZ on linear measures of ven-

tricular regions or qualitative assessments of cerebral
sulci, although ventricular measures were enlarged in both
groups relative to published norms (Perez et al 1985). A
more recent MRI study comparing patients with E

⫹SCZ

to patients with schizophrenia, and TLE patients without
psychosis (Marsh et al unpublished data, 1999) showed
temporal and frontoparietal gray matter deficits in all three
patient groups relative to healthy control subjects, with the
extent of these deficits greatest in the E

⫹SCZ group.

Hippocampal volume abnormalities were significantly
smaller in the TLE relative to the control subjects and the
schizophrenic patients, but there were no differences in
hippocampal volumes between E

⫹SCZ, the schizophrenic

patients, and the control subjects. In another MRI study,
patients with nonpsychotic TLE and first-episode schizo-
phrenic patients showed similarly enlarged ventricular
volumes relative to control subjects, with larger temporal
horns in the schizophrenic group and larger frontal horns
in the TLE group (Barr et al 1997). In addition, left
hippocampal volumes were relatively smaller in the
schizophrenic patients and were comparable in size to
patients with left TLE.

The Timing of Neuroanatomic Pathology
in Schizophrenia

EVIDENCE FOR ABERRANT NEURODEVELOPMENT

IN SCHIZOPHRENIA.

Despite the usual onset of schizo-

phrenia in adolescence or early adulthood, a prevailing
hypothesis suggests that schizophrenia develops as a result
of a disruption in normal early brain development that is
then clinically manifest later in life when inter-related
neural systems mature (Jakob and Beckmann 1986; Jones
and Lewis 1992; Weinberger 1987; Weinberger et al
1988). Support for this hypothesis is derived from epide-
miologic evidence of an increased incidence of perinatal
insults and obstetrical complications in the schizophrenic
population (Jones et al 1998; Kendell et al 1996), the
presence of mild somatic defects suggestive of an ecto-
dermal developmental etiology (Green et al 1994), and
documentation of premorbid neurobehavioral abnormali-
ties during infancy and childhood in individuals who go on
to develop schizophrenia (Cannon et al 1997; Pilowsky et
al 1993; Weinberger et al 1988).

Several MRI studies report an excess of gross structural

abnormalities in schizophrenia, such as cavum septum
pellucidum and callosal agenesis, that reflect abnormal
brain development (e.g., Nopoulos et al 1997b; Nopoulos
et al 1995). Quantitative MRI studies also provide data
that is consistent with abnormal brain development in
schizophrenia, such as reversed cerebral asymmetries or

aberrant sulcal/gyral morphology (Barta et al 1997; Bull-
more et al 1995; Kikinis et al 1994). The neuropathologic
evidence of abnormal cytoarchitecture, gyral patterns, and
neural migratory patterns in postmortem brains of schizo-
phrenic patients is also compelling (Akbarian et al 1995;
Arnold et al 1997; Jakob and Beckmann 1986), although
these findings have not been consistently replicated. Fur-
ther supporting the hypothesis that anatomic abnormalities
are present before the clinical onset of illness are cross-
sectional MRI studies that, in general, fail to demonstrate
correlations of brain abnormalities with duration of illness
and age of illness onset (see Marsh et al 1996).

MRI studies on patients with childhood-onset schizo-

phrenia (first psychotic symptoms before age 12 years)
provide an opportunity to test whether there are different
anatomic abnormalities associated with psychotic phe-
nomenology in a population that has not yet undergone
adolescent cerebral maturational processes. Recent MRI
studies on such cases by the NIMH Child Psychiatry
Group provide insights in this regard. Frazier and col-
leagues (1996) reported that basal ganglia were larger,
attributable to prior treatment with conventional neurolep-
tics and that lateral ventricles were (nonsignificantly)
larger compared to normal age-matched controls. The
same group reported that these early-onset patients did not
differ from controls in whole-brain adjusted temporal lobe
volumes, except for larger superior temporal gyri (Jacob-
sen et al 1998). At 2-year follow-up, schizophrenic sub-
jects showed significantly greater decreases in bilateral
superior temporal gyrus and left hippocampus volumes
than did healthy subjects. Decline in right posterior supe-
rior temporal gyrus volume was associated with worse
positive symptoms at both baseline and follow-up. Thus,
at initial assessment, portions of the superior temporal
gyrus were larger in patients relative to control subjects,
but progressive tissue loss was seen with ongoing illness
(Jacobsen et al 1998). Also, ongoing ventricular increases
were seen in schizophrenics compared to control subjects
(Rapoport et al 1997). In a subset of these patients, no
differences were observed between controls and schizo-
phrenics in planum temporale area or asymmetry (Jacob-
sen et al 1998). However, the method used had not
previously distinguished adult-onset schizophrenics from
control subjects on this measure. The frequency of an
enlarged cavum septum pellucidum was higher in the
patient group compared to control subjects (Nopoulos et al
1998).

It may be hard to generalize from these findings, as

childhood onset schizophrenia is rather rare with an
atypical presentation of the disorder, much as in the case
of childhood-onset Huntington’s disease, which may in-
volve a variant neuropathology. In addition, the NIMH
sample is itself a treatment-resistant subset from within

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childhood-onset schizophrenia, again suggesting that gen-
eralizability from this sample may be limited. However,
these interesting findings offer some support for (perhaps
ongoing) developmental anomalies.

Other studies have examined brain abnormalities in

adults with chronic schizophrenia who had an early age of
illness onset (i.e., preadolescent and adolescent) (Lim et al
1996a; Marsh et al 1997) and compared these findings to
schizophrenic patients with a more typical age onset of
schizophrenia in young adulthood (Marsh et al 1999).
These MRI studies show similar patterns of brain abnor-
malities (widespread reductions in cortical gray matter and
temporolimbic abnormalities) in both patient groups, de-
spite their clinical differences in onset age, clinical course,
and response to neuroleptic medications. Thus, these data
in adults are suggestive of similar processes in early onset
versus later onset groups, although such cross-sectional
analyses cannot address whether disparate processes were
present earlier.

EVIDENCE

FOR

NEURODEGENERATIVE

DISEASE

PROCESSES IN SCHIZOPHRENIA.

A competing hy-

pothesis on the nature of schizophrenia (see DeLisi
1997) is that the clinical onset of schizophrenia is
followed by an active and ongoing neurodegenerative
process. If a progressive process in schizophrenia per-
sists into adulthood, identification of the underlying
pathophysiology, and whether it is restricted to a subset
of patients, is extremely important; an appealing aspect
of this hypothesis is that it more readily offers the
potential for therapeutic interventions that stave off or
even abort the disease process.

Several brain imaging studies have addressed the issue

of progressive brain changes in schizophrenia, but there
are conflicting findings in both longitudinal and cross-
sectional studies. Longitudinal CT (Illowsky et al 1988)
and MRI (Vita et al 1988) studies showed no accelerated
atrophy compared to control subjects. Lim and co-workers
(1996a), in a cross-sectional study using an age-regression
model, found no evidence for accelerated brain change in
schizophrenia. However, other MRI studies (DeLisi et al
1995; Hoffman et al 1991; Kemali et al 1989; Mathalon et
al 1997; Turetsky et al 1995; Woods et al 1990) show
small decreases in brain volume in schizophrenic patients
over time. By contrast, progressive changes have not been
detected in follow-up studies of first-episode cases (Jaskiw
et al 1994; Vita et al 1994).

It is possible that deterioration occurs only in a sub-

group of schizophrenic patients. Historically, pneumoen-
cephalography studies found progressive ventricular en-
largement in schizophrenic patients with a deteriorating
course (Haug 1962). In schizophrenic patients rescanned 2
to 3 years after initial assessment, approximately 50% of

patients resembled healthy control subjects, but the re-
mainder had more than 5 times the rate of total ventricular
enlargement of the control subjects (Nair et al 1997).
Recently, an analysis of CT-derived measures of ventric-
ular size from 53 schizophrenic patients scanned an
average of 5 years apart (Davis et al 1998) showed marked
longitudinal increases in ventricular size in the “Kraeplin-
ian” patients (about 40% of the sample), compared both to
non-Kraepelinian schizophrenic patients and to elderly
normal control subjects. These data suggest that neurode-
generative processes are specific to the Kraeplinian sub-
group, which was defined on the basis of chronic dependence
on others for life necessities, chronic unemployment, and
symptom chronicity. Another promising lead is the observa-
tion that elderly, chronic institutionalized schizophrenic pa-
tients develop a non-Alzheimer type dementia (Barak et al
1997; Purohit et al 1993). Examination of such individuals
using quantitative anatomic measures is important to deter-
mine if this is the rule in schizophrenia, when the process
begins, and whether those with prominent deficit symptoms
are at high risk.

The largest study to date addressing this question is that

of DeLisi (1997), which reported on 50 young, first-
episode schizophrenic patients who were followed since
first clinical onset and 20 control subjects. Annual scans
where obtained from 4 or more years and slopes of change
in measured brain regions were calculated. No differences
were found for total temporal lobe or hippocampus/
amygdala volumes. Schizophrenic patients were charac-
terized by decreased hemisphere sizes, right cerebellum
area, isthmus of the corpus callosum area, and of left
lateral ventricle (on coronal but not axial slices). Gur and
co-workers (1998) rescanned 40 schizophrenics (20 first-
episode) at a mean of 30 months. Patients were distin-
guished by frontal lobe volume decreases. Various volume
reductions correlated with positive and negative symptoms
in a complex manner, differing between first-episode and
previously-treated schizophrenia and further complicated
by medication effects.

There are well-documented precedents for neurode-

velopmental conditions with an adult neurodegenerative
outcome, e.g., Alzheimer disease in Down syndrome
(Raz et al 1995). If schizophrenia exemplifies this type
of condition, then this awareness would be an important
advance in our understanding of the disorder. Existing
evidence suggests that at least a subset of patients with
schizophrenia manifest degenerative changes, but there
are problems with such studies. These include generally
small patients and control samples, mainly cross-sec-
tional design, relatively brief follow-up times, inclusion
of substance abusers, and selection of unrepresentative
age spans of schizophrenic subjects relative to the
lifetime span of the illness.

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Part II. Advances in Structural
Neuroimaging Methodology

MRI continues to provide the best methodology for
examining the anatomic details of the brain in the living
subject. Most of the structural imaging studies on schizo-
phrenia described in Part I examined abnormalities in the
size (either area or volume) of the total brain, or of various
brain regions, or structures such as specific lobes, ventri-
cles, gyri, or nuclei. The computerized approaches for
obtaining these measures have become quite advanced,
with improved image acquisition and image contrast, and
3-dimensional surface rendering enabling the refined mea-
surement of very specific structures or regions, e.g.,
entorhinal cortex or the inferior parietal lobule. Other
computerized methods are used to obtain separate esti-
mates of the volumes of gray matter, white matter, and
CSF for a given region (Reiss et al 1998). While these
investigations of the relative sizes of different brain
structures in schizophrenia have been unequivocally infor-
mative, the data provided are limited to the global char-
acteristics of a structure and the methods have overall been
extremely labor intensive. In addition, even in disease
states, the extent of normal variation attributable to aging,
gender, total brain size, handedness, race, body size, and
perhaps, socioeconomic status (Gur and Pearlson 1993;
Marsh et al 1996) may obscure the recognition of pathol-
ogy. Thus, additional morphometric methods that provide
biologically meaningful information are necessary to com-
plement the traditional measures of structural size and for
integration with clinical and functional studies.

Advances in Image Analysis Approaches

STEREOLOGY.

Stereological techniques, based on the

Cavalieri principle, have traditionally been used in histo-
logic and pathologic studies to obtain accurate and unbi-
ased measures of the number of objects (e.g., neurons) in
an anatomically defined volume (Howard and Reed 1998).
These techniques form the usual basis for estimating
volumes for regions of interest (ROIs) from structural
neuroimaging data. The Cavalieri principle is based on a
theory that the volume of any structure can be estimated
by cutting it into thin parallel slices, measuring the
cross-sectional area of the structure in each slice, summing
these areas, and multiplying the sum by the slice thickness.
The accuracy of the measurement is thus a function of the
thinness of the slices: thick slices yield less precise
estimates than thinner ones. In earlier imaging studies,
thicker image slices, variable orientation of the head in the
scanner, reduced image contrast (and hence the clarity of
brain structural margins), and scanning sequences that
imaged only a limited portion of the brain all profoundly
affected volume estimates. Gradual improvements in im-

aging technology now enable collection of MRI data that
samples the entire brain in very thin slices and can be
reoriented in a standardized fashion along the 3-D axis,
thereby minimizing these confounding influences. More
sophisticated imaging hardware has also facilitated the
efficient acquisition of small isotropic voxels (e.g., 1 mm

3

)

that reduce error when image data are reoriented and
resliced against standardized landmarks (Stievenart et al
1993).

POINT COUNTING.

Many volumetric measurements

of brain structures from MRI data typically involve tracing
the edges of region of interest (ROI) on a series of images.
This edge-tracing approach is extremely laborious, espe-
cially with newer acquisition sequences that include an
increased number of thinner slices. To reduce the effort
involved in volumetric measurements but still maintain
anatomic accuracy, several studies have substituted point
counting methods as opposed to edge tracing for delineat-
ing ROIs. Point counting refers to a method in which a 3-D
grid is superimposed on the image data (Hyman et al
1998). Specialized software can be used to display a series
of cross-sectional images of the brain that are overlaid
with the regular, 3-D grid of points. After denoting
whether grid points intersect the ROI, software algorithms
calculate the true volume of the structure in physical units
and substantially reduce the time devoted to image analysis.

CORTICAL “PAINT” TECHNIQUES.

Many morpho-

metric imaging studies have been limited by the inability
to measure accurately and reliably structures in which
gyral patterns are highly convoluted or variable when
viewed from a single 2-D orientation. Earlier MRI studies
subdivided, or parcellated, the brain into its functional or
anatomic subregions using standardized geometrically de-
fined algorithms, (e.g., Zipursky et al 1992). More re-
cently, novel software tools have been developed to enable
3-D tracing of complex cortical regions, such as the
prefrontal cortex and its superior, middle, inferior, and
orbital subregions (Ross and Pearlson 1996). These meth-
ods for parcellating brain regions may also enhance our
ability to detect specific structure–function relationships.
One approach uses a “paint” method (Ross and Pearlson
1996), which allows for demarcation of specific gyri by
“painting” the region of interest on a 3-D rendering of the
cortical surface. With this method, the rater views a 3-D
surface rendered image of the brain along with the three
orthogonal views (coronal, axial, and sagittal). Such a
method enables visualization of entire lobes or brain
regions as well as subregions. After identifying the sulcal
landmarks for a given region and their course over the
brain’s curvature, the sulcal landmarks for each demar-
cated region are each “painted” a different color on the

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3-D representation of the brain. These colors are then
depicted on each set of orthogonal views and define the set
of voxels used to calculate the gray and white matter
components of the region of interest. When applied to
analyses of frontal lobe structures in schizophrenia com-
pared to control subjects (Buchanan et al 1998), schizo-
phrenic patients, showed significant reductions in total
prefrontal volume, as well as selective volume reductions
in inferior prefrontal gray matter bilaterally and total
prefrontal white matter. The greater anatomic precision
provided by the “paint” technique may account for the
inconsistent results from earlier MRI studies using ana-
tomic landmarks on a 2-D image slices to define prefrontal
cortical regions (see Marsh et al 1996; Wible et al 1995).

IMAGE AVERAGING AND AUTOMATED PARCELLA-

TION.

Image averaging and automated parcellation tech-

niques (Andreasen et al 1996) provide an alternative to
traditional manually based morphometric techniques or
the “paint” techniques described above. Image averaging
techniques, which have been adapted from functional
neuroimaging approaches, rely on the standardized stereo-
taxic coordinate system proposed originally by Talairach
and Tournoux (1988) to define, or parcellate, brain re-
gions. Using specialized computer software and specific
anatomic anchor points, the raw image data are mapped
onto the standardized coordinate space so that all images
are coregistered in the 3-D grid. In effect, the brain image
data are “normalized” to the grid, which defines over 1000
3-D volumes that theoretically map to the same neuroana-
tomic regions across subjects. Comparisons can be either
pixel-wise or across parcellated regions. A main advantage
of these techniques is that the entire brain can be evaluated
simultaneously. In addition, the method is more automated
and thus more efficient than manual morphometric mea-
surements. By contrast, the manual sulcal-based methods
delineate brain subdivisions more accurately, require ad-
vanced knowledge of neuroanatomy, and can be associ-
ated with reduced reliability over time. Thus, the auto-
mated methods may be more appropriate for estimating
volumes of larger structures, such as cerebral lobes, the
cerebellum, and ventricles, or in combination with a
limited degree of nonautomated image processing.

The role and biologic significance of image averaging

methods in structural imaging analyses of schizophrenia
remains unclear. This is because interpretations of signal
intensity values from MRI data are based on their ana-
tomic location (e.g., white versus gray matter), as opposed
to functional imaging studies that measure cerebral activ-
ity throughout the brain. Another issue is that coregistra-
tion (normalization) of structural MRI data to a uniform
grid may actually obscure disease-related structural abnor-
malities or even normal anatomic variability under inves-

tigation. This issue is particularly germane to studies on
schizophrenia. Nonetheless, as with other approaches,
image averaging techniques appear to provide a novel and
useful tool for the study of brain morphology in schizo-
phrenia provided the limitations of the method are also
taken into account. Recent reports using image averaging
techniques to compare schizophrenic subjects to control
subjects support evidence for widespread abnormalities
involving cortical volume reductions and ventricular en-
largement as well as major white matter tracts (Wolkin et
al 1998). An earlier study using this method highlighted
evidence for signal intensity reductions in the thalamus
and its white matter connections (Andreasen et al 1994a).

SHAPE ANALYSIS.

The objective of shape analysis is

to examine and quantify focal characteristics (or descrip-
tors) of a structure that are independent of variations in
size, which reflects more global features of a structure. In
shape analysis, mathematical models of image analysis are
used to evaluate evidence of neuropathologic change, such
as morphological distortion of a boundary, a feature that
would not be apparent in a volumetric measure. For the
hippocampal boundary, comparisons might include mea-
sures of the number and size of concavities within the
boundary, the length of the boundary, the shape of
contours within the boundary, or the topological relation-
ships between various regions on the boundary to one
another or to a neighboring structure (Gonzalez and Wintz
1987). The internal characteristics of a structure, repre-
sented by pixels within the defined boundary, can also be
analyzed for changes in texture (variations in signal
intensities) or compactness (pixel density for a given
region), along with the usual measures of area or volume.
In combination, this information can be used to test
specific models of disease pathology. For example, if the
neuropathology of schizophrenia is related to a distur-
bance in neuronal migration, there would be a decrease in
the size of a structure without concomitant change in
shape characteristics if the migratory disturbance is gen-
eralized. However, if abnormal development were selec-
tive to specific regions of the hippocampus, for example,
such focal changes would affect the configuration or shape
of the hippocampus on MRI. Earlier MRI studies using
quantitative shape analysis techniques (Casanova et al
1990a, 1990b) suggested nonspecific disease-related dis-
tortions of the temporal and prefrontal lobes in schizophre-
nia. However, these studies did not use high-resolution
MRI acquisition techniques, which reduce the confound-
ing effects of MRI partial voluming on shape analysis. The
newer image acquisition and analytic techniques, which
enable consistent 3-D realignment of the brain data against
specified anatomic landmarks, should also permit more
meaningful analyses of corpus callosum abnormalities in

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1999;46:627– 649

schizophrenia, as prior analyses of the shape and size of
this structure have produced inconsistent results (Tibbo
1998).

SURFACE AREA, THICKNESS, AND MEAN CURVA-

TURE.

Surface area measurements provide another ap-

proach for obtaining information on brain structure that
may have greater biologic relevance than size measure-
ments alone and will also be useful for integration with
functional neuroimaging data. In the case of cortical
structures, separate estimates of cortical thickness and
surface area, which both contribute to estimates of cortical
volume, may provide information that has different impli-
cations. Specifically, measures of surface area devoted to
a particular function, e.g., motor activity, may be indica-
tive of the relative portion of the brain devoted to the
related task. Using a tessellation approach for deriving
surface area of the planum temporale, Petty and co-
workers (1995) and Barta and colleagues (1997) showed
reversal of the usual pattern of left greater than right
hemispheric asymmetry in schizophrenia. Disturbances in
measures of cortical thickness, which normally vary re-
gionally, would indirectly reflect disruptions in the cortical
columns. Differences in surface areas, but similar thick-
ness, suggest that fewer cortical columns are devoted to
the region in the patients with less surface area. Con-
versely, similar surface areas for a given region, along
with differences in the degree of thickness, suggest that
similar amounts of the brain are devoted to a region, but
that the development within the cortex between the groups
was perhaps different. Measures of mean curvature of the
brain surface may provide method for assessing the extent
and character of convolutions on the brain’s surface,
thereby serving as an index of normal versus abnormal
brain development (van Essen 1997).

Diffusion Tensor Imaging

MR diffusion imaging, a recently developed extension of
MRI technology, provides an approach for mapping and
quantifying white matter connections between brain re-
gions (Mori and van Zijl 1995; Prichard 1998; van Zijl et
al 1994; Westin et al 1997). MR diffusion measures on
solutions were first described by Stejskal and Tanner
(1965) and imaging was first performed in vivo by Le
Bihan (1990). The basic principles of diffusion imaging
involve setting MRI parameters to use the net flow of
water to generate image contrast. Under circumstances
where the mobility of water is unrestricted, e.g., a still
bowl of water, there is no directional preference and water
displacement in the x-, y-, and z-directions is equal, a
condition of isotropic diffusion. Anisotropic diffusion
occurs when there are structural limitations, e.g., as

imposed by organized fibers (such as axonal fibrils) that
are arrayed predominantly in one direction (Beaulieu and
Allen 1994).

Quantification in diffusion imaging is based on the

diffusion constant, referred to as the apparent diffusion
coefficient (ADC). The ADC, calculated for each image
voxel, is based on the gradient amplitude and duration of
the magnetic field used during image acquisition. When
ADCs are orientation-dependent, as for brain tissue and
white matter in particular, in vivo diffusion is described
with six different diffusion constants, which are generally
ordered in a tensor. A tensor is an array of numbers. In
order to get information on directionality in three dimen-
sions, tensors are measured for each voxel using six
different magnetic field orientations. Linear algebraic
operations are then performed on the tensors to derive
anisotropy indices. Differences in anisotropy represent
relative differences in diffusional amplitude or rate,
thereby providing information on axonal density and the
directionality of neural structures. Thus, differences in
anisotropy may correspond to variation in the number or
coherence of fibers within regions, and may be used to
contrast subjects in healthy versus diseased states.

Initial studies on healthy control subjects using dimen-

sional diffusion imaging studies demonstrate greater align-
ment of fiber tracts in the right hemispheric anterior
internal capsule as compared to this same region on the
left (Peled et al 1997). Initial analyses using diffusion
tensor images for studies on schizophrenia report lower
diffusion anisotropy in the white matter of the prefrontal
cortex in patients relative to controls subjects (Buchsbaum
et al 1998). Using 18-FDG PET in the same subjects, there
was also evidence for lower correlation coefficients be-
tween metabolic rates in the prefrontal cortex and the
striatum in the patients relative to control subjects, sug-
gesting convergent evidence for aberrant frontostriatal
connectivity in schizophrenia. A more recent report using
diffusion tensor imaging showed reduced white matter
anisotropy, particularly in the corpus callosum, in schizo-
phrenic men relative to age-matched healthy control men
(Lim et al 1998). These findings might be explained by
disordered fibers within the bundles or reduced bundle
number in the corpus callosum.

Summary

In this review, we discussed the general neuroanatomic
findings from structural neuroimaging studies of schizo-
phrenia. We also addressed issues related to the specificity
of these findings in terms of gender differences in brain
abnormalities in schizophrenia, observations in clinically
unaffected relatives, and comparisons with other neuro-
psychiatric disorders. The relationships of these structural

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1999;46:627– 649

neuroimaging findings to the neurodevelopmental and
neurodegenerative hypotheses of schizophrenia were also
discussed. Finally, we reviewed newer methods of struc-
tural image acquisition, processing, display, and analysis,
and their applications in research on schizophrenia.

Structural imaging methodologies have proven to be

powerful tools enabling the recognition of fundamental
brain abnormalities in schizophrenia. To date, these in-
clude evidence for widespread deficits in cortical gray
matter volumes, regional reductions in heteromodal asso-
ciation cortex and temporolimbic structures, and nonspe-
cific increases in ventricular size, thereby implicating
dysfunction of neural circuits involving cortical, thalamic,
basal ganglia, and limbic structures in the pathogenesis of
the illness. Presumably, the identified patterns of regional
change are related to characteristic symptoms of the
disorder, although there are still no consistently demon-
strated clinicopathologic correlates. The emerging evi-
dence that affected neocortical regions comprise compo-
nents of the heteromodal neocortical association network
may provide a framework for further investigating the
otherwise elusive brain structure–function relationships.
Furthermore, the converging role of heteromodal regions
in both the expression of neuroanatomic gender differ-
ences and in normal cerebral asymmetries suggests that
disruption of these cortical areas in schizophrenia may be
important to the clinical expression of the disease, includ-
ing clinical differences between men and women with
schizophrenia. The continued development of techniques
for investigating the brain will ensure that structural
neuroimaging will remain a strong contender in helping to
address questions related to the origin and mechanism of
brain alterations in schizophrenia.

Supported by NIH (MH53485, RR00722, MH43326, MH43775,
NS28115).

This work was presented at the conference, Schizophrenia: From

Molecule to Public Policy, held in Santa Fe, New Mexico in October
1998. The conference was sponsored by the Society of Biological
Psychiatry through an unrestricted educational grant provided by Eli
Lilly and Company.

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