Recent structural and functional imaging findings in

Recent structural and functional imaging findingsin schizophreniaMargaret A. Niznikiewicz, Marek Kubicki and Martha E. Shenton

Purpose of review

Schizophrenia is a severe mental disorder that affects nearly

1% of the general population and has long been a challenge for

both clinicians and researchers in terms of treatment and

etiology. More recently, evidence has amassed that suggests

that schizophrenia is a brain disorder, and that some aspects of

this disorder appear to be genetic. It has only been in the past

decade, however, that adequate neuroimaging tools have

become available to study brain abnormalities in schizophrenia.

These technologic advances have led to a much better

understanding of both structural and functional brain

abnormalities in schizophrenia, and allowed construction of

comprehensive theories regarding the neural underpinnings of

schizophrenia. The present review provides an account of

research activities in the fields of structural magnetic resonance

imaging (MRI), functional MRI, and diffusion tensor imaging

during the past year, dating from August 2001 to August 2002.

Recent findings

In the review we discuss MRI findings in chronic schizophrenia

and in first episode schizophrenia, and we include information

on family studies. We note that the two major hypotheses

regarding schizophrenia (neurodevelopmental and/or

neurodegenerative) provide a theoretical framework for most

studies. For the functional MRI studies, we note that questions

focus on identifying networks of brain regions that are abnormal

and contribute to functional abnormalities.

Summary

Jointly, MRI, functional MRI, and diffusion tensor imaging

research suggests that schizophrenia is a disorder that impacts

on several brain regions, leading most notably to abnormalities

in both frontal and temporal lobes, as well as to abnormal

connections between those two major structures.

Keywords

brain abnormalities, diffusion tensor imaging, functional

magnetic resonance imaging, neuroimaging, schizophrenia

Curr Opin Psychiatry 16:123–147. # 2003 Lippincott Williams & Wilkins.

Boston Veterans Affairs Healthcare System, Clinical Neuroscience Division,Laboratory of Neuroscience, Department of Psychiatry, Harvard Medical School,Boston, Massachusetts, USA

Correspondence to Margaret A. Niznikiewicz, PhD, Department of Psychiatry-116A,Boston VA Healthcare System, 940 Belmont Street, Brockton, MA 02301, USAFax: +1 508 580 0059; e-mail: [email protected]

Current Opinion in Psychiatry 2003, 16:123–147

Abbreviations

ACC anterior cingulate cortexCSP cavum septi pellucidiDLPFC dorsolateral prefrontal cortexDTI diffusion tensor imaging(f)MRI (functional) magnetic resonance imagingPTSD post-traumatic stress disorderSTG superior temporal gyrusVBM voxel-based morphometry

# 2003 Lippincott Williams & Wilkins0951-7367

IntroductionInterest in elucidating the structural and functional brain

abnormalities that occur in schizophrenia has a long

history, dating back to Kraepelin’s [1] and Bleuler’s [2]

early descriptions of schizophrenia. For Kraepelin, the

disorder, which he described as ‘dementia praecox’, or

early dementia, was defined primarily by the course or

outcome. For Bleuler the disorder was defined more by

the marked cognitive and emotional dysfunctions, and

by a split between emotions and cognition, or what he

described as ‘schizophrenia’. However, both of those

seminal thinkers believed that, ultimately, schizophrenia

would be linked to a brain disorder. Early work in this

field was thus particularly discouraging because there

were no tools available that allowed investigators to

discern subtle brain abnormalities. With the advent of

neuroimaging techniques, beginning with computer-

assisted tomography findings in 1976 [3] and the first

magnetic resonance imaging (MRI) scan of a schizo-

phrenic brain in 1984 [4], we now know more about

brain abnormalities in schizophrenia than at any other

time in the history of schizophrenia research.

In the present review we highlight important recent

structural and functional findings [i.e. MRI, functional

(f)MRI, and diffusion tensor imaging (DTI)] in schizo-

phrenia. Structurally, those findings suggest predomi-

nantly enlarged lateral ventricles and temporal lobe

abnormalities, but functionally, they suggest more

temporal–frontal connectivity abnormalities. We frame

these findings within the context of research findings

reported during the past 15 years. We highlight structural

MRI studies that address neurodevelopmental and/or

neuroprogressive hypotheses of brain abnormalities, and

functional studies that address specific hypotheses

regarding several domains of cognitive dysfunction in

schizophrenia. We end with a brief review of DTI

findings that demonstrate connectivity abnormalities in

DOI: 10.1097/01.yco.0000058610.61505.6b 123

schizophrenia, followed by a summary and discussion of

future directions in neuroimaging studies in schizophre-

nia.

It is increasingly recognized that schizophrenia is a

disease of the brain that profoundly affects most aspects

of human function. Although the exact nature of the

dysfunction and its etiology remain unknown, substan-

tial progress has been made in identifying brain

abnormalities in schizophrenia and in mapping abnormal

cognitive functions onto brain structures. One reason for

this progress is that the quality of in-vivo images using

MRI has increased dramatically over the past 15 years.

We are now able to acquire and evaluate 1 mm slices

through the entire brain, a spatial resolution that was

previously impossible [5..]. Advances in fMRI have also

made it possible to go beyond examining isolated brain

regions to examining interconnected neural networks

that are probably implicated in schizophrenia [6–9].

Additionally, the recent advent of DTI renders possible

the investigation of abnormal connectivity among brain

areas because it is well suited to examining white matter

in the brain (for review [10..]).

In this review we present the most recent findings in

schizophrenia from structural MRI, fMRI, and DTI

studies reported between 1 August 2001 and August

2002. We begin with a review of MRI structural findings

in chronic schizophrenia and in first episode schizo-

phrenia. This is then followed by a review of fMRI and

DTI findings in schizophrenia. We frame these recent

findings within the context of MRI findings over the past

15 years.

Magnetic resonance imaging: structuralfindings in chronic schizophreniaMagnetic resonance imaging has continued to provide

important information regarding the brain structure in

schizophrenia, with most studies motivated by a keen

interest in pursuing the possible causes of schizophrenia

and in identifying regions affected by the disease

process.

Overview and context

Two reviews of MRI structural findings in schizophrenia

have recently been published, one by Shenton et al. [5..]

and the other by Kasai et al. [11 .], that are quite

comprehensive. The review by Shenton et al. spans the

time period from 1988 to 2000, and reviews more than

190 MRI studies. In patients with schizophrenia, as

compared with normal control individuals, it documents

the following: lateral ventricular enlargement (80% of

studies); third ventricle enlargement (73% of studies);

medial temporal lobe volume reductions (74% of

studies), including amygdala, hippocampus, and para-

hippocampal gyrus; and neocortical superior temporal

gyrus (STG) volume reductions (100% of studies),

particularly on the left, with the percentage decreasing

to 67% of studies when STG gray and white matter are

combined. There is also moderate evidence for frontal

lobe volume reduction in schizophrenia (59% of studies),

particularly prefrontal and orbitofrontal regions, and

parietal lobe abnormalities (60% of studies), including

both supramarginal and angular gyri abnormalities; the

latter regions are important in language processing.

Finally, enlarged cavum septi pellucidi (CSP; 92% of

studies), basal ganglia abnormalities (68% of studies),

corpus callosum abnormalities (63% of studies), thalamus

abnormalities (42% of studies), and cerebellar abnorm-

alities (31% of studies) are also evident in schizophrenia.

Figure 1 [12] provides a lateral view of the brain that

depicts the locations of the frontal, parietal, temporal,

and occipital lobes, as well as major gyri in the brain,

including STG.

Previous MRI findings thus highlight the importance of

temporal lobe abnormalities in schizophrenia. However,

this is not to suggest that the temporal lobe is the only

brain region that is abnormal in schizophrenia. In fact,

the temporal lobe is highly interconnected with other

brain regions, including the frontal lobe [13–19], and

normal brain function depends on such interconnectiv-

ity. In the present review of fMRI and DTI findings in

schizophrenia, the role of neural connectivity in schizo-

phrenia is further highlighted.

Neurodegenerative hypothesis

There are two prevailing hypotheses concerning the

etiology of brain abnormalities in schizophrenia: neuro-

developmental and neurodegenerative. Shenton et al.[5..], as well as Weinberger and McClure [20 .],

discussed the merits of these two theoretical approaches,

and a review paper by Okubo et al. [21] focused primarily

on evidence for progressive changes in schizophrenia.

Although these approaches are not described in detail

here, it is important to point out that neurodevelop-

mental and neurodegenerative approaches have a long

history in schizophrenia. They are often viewed as

mutually exclusive, but are increasingly recognized as

complementary [20.], with the suggestion that schizo-

phrenia (like many neurologic diseases) may be

characterized by both neurodevelopmental and neuro-

degenerative processes. Several, if not most, of the

studies discussed here adopt those two perspectives as

their theoretical anchor points.

Evidence for progressive changes in gray matter in

chronic schizophrenia has been reported in separate

studies conducted by Velakoulis et al. [22], Hulshoff etal. [23], and Convit et al. [24]. Velakoulis et al. [22]

used a voxel-based morphometry (VBM) approach to

Schizophrenia124

study gray matter changes across all brain regions, as a

function of illness duration. This approach offers a

quick way to evaluate multiple brain regions at once,

across many individuals. Negative correlations (unre-

lated to the age of onset) with illness duration were

found for right medial temporal, medial cerebellar and

bilateral anterior cingulate, and white matter volume in

the right posterior limb of the internal capsule. Positive

correlations were noted for globus pallidus (Table 1),

suggesting the role for medication in the latter

volumetric changes. Evidence for progressive changes

was also reported by Hulshoff et al. [23]. In their cross-

sectional study of gray and white matter changes in

159 schizophrenic patients and 158 normal control

individuals (Table 1), a steeper regression for gray

matter volume changes as a function of age was found

in the schizophrenia group.

These findings support an earlier, important longitudinal

study conducted by Mathalon et al. [43..]. In patients

with schizophrenia as compared with control individuals,

those investigators reported progressive volume decline

from baseline to rescan 4 years later both in frontal and

temporal gray matter, as well as expansions in sulci and

lateral ventricles. Moreover, Mathalon et al. observed

that cortical gray matter in these brain regions showed an

accelerated decline over time in those patients with the

most severe symptoms. These observations were inter-

preted as suggesting that a progressive pathologic

process is evident in at least some patients with

schizophrenia.

A different strategy was adopted by Convit et al. [24],

who parcellated the frontal lobes into subregions and

compared the volumes of the subregions between young

normal control individuals, old normal control indivi-

duals, and young schizophrenia patients (Table 1).

Patients with schizophrenia and older normal control

individuals both showed smaller volumes in the superior

frontal gyrus and orbitofrontal regions, suggesting that

both older control individuals and younger patients with

schizophrenia exhibit frontal lobe volume reduction as

compared with younger control individuals. However,

these similarities in volume reduction do not necessarily

suggest similar mechanisms. Moreover, differences in

education between groups may have also influenced the

findings.

In another study, Lawrie et al. [44] evaluated change

over time in magnetic resonance volume of the temporal

lobe and amygdala–hippocampal complex in control

individuals and in relatives of patients with schizophre-

nia (defined as being in a family in which there were at

least two first-degree or second-degree relatives diag-

nosed with schizophrenia; Table 2). Previous results

showed a reduction in the amygdala–hippocampal

complex at baseline in relatives of patients with

schizophrenia. A subset of those people was then

followed up over time, and results revealed no changes

in temporal lobe or in the amygdala–hippocampal

complex in relatives at risk for schizophrenia (i.e. volume

reductions noted at baseline were stable and did not

change over time). However, when psychotic relatives

Inf. frontalsulcus

Sup. frontal sulcus

Percentral sulcus

Central sulcus Postcentral sulcus

Sup. parietal lobule

Intraparietal sulcus

Inf. parietal lobule

Parieto-occipitalsulcus

Preoccipital notch

Horizontal fissure

Medulla oblongataLateral sulcus

Orbital gyri

Figure 1. Lateral view of the human brain

From Carpenter and Sutin [12]; reprinted withpermission from Williams & Wilkins, New York,USA. Inf., inferior; Sup., superior.

Structural and functional imaging in schizophrenia Niznikiewicz et al. 125

Table 1. Magnetic resonance imaging structural findings in chronic schizophrenia

ReferenceMagnet/slicethickness

Participants(n)

Mean age(years)

Sex[male/female (n/n)] MRI measures and major findings

Ananth [25..] 2 Tesla/1.5 mm(contiguous)

SZ 20NC 20

SZ 37.8NC 38.6

SZ 10/10NC 10/10

Voxel-based morphometry was used to measure globaland regional gray matter. Global gray matter differenceswere observed, but more importantly regional graymatter differences were observed, particularly in the leftmediodorsal thalamus. Other differences betweengroups involved the occipitoparietal cortex; premotor,medial, and orbital prefrontal cortices; and inferolateraltemporal lobe. White matter differences were observedbetween groups in the lateral optic radiation of theoccipital cortex. Of note, abnormalities in ventral andmedial prefrontal cortices correlated with a positivefamily history of SZ. There was no proportionalreduction in gray matter with age in SZ.

Chemerinski[26]

1.5 Tesla/1.5 mmand 3–4 mm(contiguous)

SZ 45NC 45

SZ 30.0NC 30.5

Males only Total cerebral gray matter and total cerebral surfacearea, as well as ventral frontal cortex (comprised oforbitofrontal and straight gyrus) were measured. Find-ings showed no group differences for total cerebral graymatter, total cerebral surface area, or ventral frontalcortex or orbitofrontal cortex, but right straight gyrusshowed smaller volume and shape in SZ. The volume ofventral frontal cortex was negatively correlated withsocial dysfunction in SZ.

Chow [27.] 1.5 Tesla/1.5 mm(contiguous)

SZ 14NC 14(Note: 22q11deletionsyndromeand SZ)

SZ 27.5NC 28.2

SZ 7/7NC 7/7

Total gray and white matter, lateral ventricles, as well asfrontal, temporal, and parietal gray and white matterwere measured. Findings showed that total gray matter,and frontal, temporal and left parietal lobe gray matterwere significantly reduced in SZ. This was mostprominent in the frontal and temporal lobes. There wasalso an observed increase in the lateral ventricles in SZ.

Convit [24] 1.5 Tesla/1.2 mm(contiguous)

SZ 9NC young 9NC old 9

SZ 35NC young37.4NC old 69.8

Males only Smaller volumes of superior and orbital frontal gyri wereobserved in both old NC and in SZ as compared withyounger NC. Old NC and SZ thus did not differ. Thissuggests similarities between the SZ and aging NC infrontal lobe abnormalities. (There were both age andeducation differences between groups).

Erbagci [28] 1.0 Tesla/3 mm(5-mm interslicegap)

SZ 26NC 29

SZ 34.7NC 28.6

SZ 11/15NC 11/18

Third ventricle and adhesio interthalamica were mea-sured. Results showed that the adhesio interthalamicawas more often absent in SZ than in NC. Third ventriclewas not correlated with presence or absence of adhesiointerthalamica, as predicted.

Falkai [29] 1.5 Tesla/1.2 mm(contiguous)

SZ(MA) 14SZ(U) 12NC 10

SZ(MA) 33.6SZ(U) 29.8NC 24.4(NC wereyounger)

SZ(MA) 8/6SZ(U) 8/4NC 5/5

Sylvian fissure and amygdala–hippocampal complexwere measured. Results showed that amygdala–hippo-campus volume was reduced, and there was anabnormal asymmetry in SZ(U). Sylvian fissure did notshow differences among groups. The authors sug-gested that brain abnormalities involving medial tem-poral lobe structures are not familial.

Goldstein[30..]

1.5 Tesla/3.1 mm(contiguous)

SZ 40NC 48

SZ male 46.6SZ female41.4NC male 41.6NC female39.0

SZ 27/13NC 27/13

22 regions of interest were evaluated. Relative to maleNC, male SZ were characterized by reductions infrontomedial cortex, middle frontal cortex, cingulate gyri,paracingulate gyri, Heschl’s gyrus, and Broca’s area,but with increased volume in posterior cingulate andbasal forebrain. Planum temporale was also smaller onthe right in male SZ, but larger on the right in female SZ.Relative to female NC, female SZ were characterized byreductions in fronto-orbital gyri, basal forebrain, anteriorcingulate gyri, and posterior supramarginal gyri, butexhibited increases in volume in cingulate gyri and rightplanum temporale. No differences were noted forsubcortical gray matter or for CSF.

Hagino [31] 1.5 Tesla/1 mm(contiguous)

SZ 86NC 79

SZ 29.3NC 24

SZ 46/40NC 44/35

Cavum septum pellucidum (the membrane separatingthe lateral ventricles) was measured. Findings showedno group differences in the prevalence of large cavumseptum pellucidi (74.4% in SZ; 74.7% in NC), andthere were also no sex-mediated differences. Suchlarge cavum in NC is unusual, with most other studiesreporting prevalence between 5 and 13%.

(continued opposite )

Schizophrenia126

Table 1. (continued )


Participants(n)

Mean age(years)


Hulshoff [23] 1.5 Tesla/1.2 and1.6 mm (contigu-ous)

SZ 159NC 158

SZ 35.6NC 37.7(Age range16.3–76.9)

SZ 112/47NC 106/52

Total volume of cerebral and cereballar gray and whitematter, and lateral and third ventricles were measured.Total brain volume, total cerebral gray matter, and bothprefrontal gray and white matter were reduced in SZ,and lateral ventricles and third ventricles were increasedin SZ. Results also showed steeper regression slopesfor age and gray matter volume in SZ as compared withNC.

Meisenzahl[32]

1.5 Tesla/3 mm(contiguous)

SZ 30NC 30

SZ 29.4NC 29.1

Males only 3-mm slices were reformatted and resliced into 1.5-mm.Planum temporale was measured. No volumetric orasymmetry differences were observed, regardless ofplanum temporale definitions used.

Meisenzahl[33]


SZ 44NC 48

SZ 30.2NC 30.3

Males only 3-mm slices were reformatted and resliced into 1.5-mm.Bifrontal temporal gray matter volume and generalizedwhite matter volume deficits associated with allele 2carriers.

Okugawa [34] 1.5 Tesla/1.5 mm(contiguous)

SZ 32NC 32

SZ 39.3NC 38.6

Males only Gray matter, white matter, and CSF were measured inthe frontal, temporal, parietal, and occipital lobes.Results showed gray and white matter reduction in thetemporal region in SZ, as well as white matter reductionthat was more widespread, and increased CSF inwhole brain and in the frontal and temporal lobes in SZ.

Rajarethinam[35]


SZ 20NC 20

SZ 33.5NC 33.9

Males only The amygdala–hippocampus complex (both amygdalaand hippocampus) was evaluated on 1-mm reformatted3-mm slices. Results showed no group differences forthe amygdala–hippocampal complex, but negativecorrelations were observed between left amygdala andthought disorder, between left hippocampus andnegative symptoms, and between left anterior andposterior hippocampus and both negative and positivesymptoms in SZ.

Suzuki [36.] 1.5 Tesla/1 mm(contiguous)

SZ 45NC 42

SZ 26.4NC 26.1

SZ 23/22NC 22/20

A new method, adapted from fMRI, namely statisticalprobability mapping (SPM), was used to measure graymatter and white matter of the brain.Gray matter in males: gray matter was decreased in leftsuperior temporal and middle frontal gyrus, and bilateralanterior cingulate gyrus. Gray matter in females: graymatter was decreased in right anterior cingulate gyrus,the medial part of the right superior frontal gyrus, andright middle frontal gyrus. Gray matter was increased inright precuneus, postcentral gyrus, left cuneus andprecuneus, and right cerebellumWhite matter: both males and females exhibiteddecreases in the bilateral anterior limb of the internalcapsule and superior occipitofrontal fasciculus.Females also exhibited increased bilateral parietallobes.

Takahashi [37] 1.5 Tesla/1 mm(contiguous)

SZ 40NC 40

SZ: male 26.4;female 25.9NC male 25.5;female 24.8

SZ 20/20NC 20/20

The volume of whole brain gray and white matter, andanterior cingulate gray and white matter was evaluated.Results showed that right anterior cingulate (ACG) graymatter is reduced in female SZ, and there is a lack ofright4left asymmetry in female SZ. ACG white matterin female SZ also lacked normal right4left asymmetry.

Velakoulis [22] 1.5 Tesla/3 mm(contiguous)

SZ 39(Illness dura-tion: 2–31years)

SZ 36(Range19–60)

34/5 Voxel-based morphometry was used to measuretemporal, cingulate, and cerebellar abnormalities.Findings showed that right medial temporal, cerebellar,and bilateral anterior cingulate gray matter volumescorrelated negatively with illness duration, and rightglobus pallidus volume correlated positively with illnessduration.

Velakoulis [38] 1.5 Tesla/1.5 mm(contiguous)

SZ 45NC 139

SZ 34.1NC 30.05

87.7%/59.% Both two-dimensional measure of shape (volume loss inthe head of the hippocampus) and volume distinguishedbetween the two groups.

Wang [39.] 1.5 Tesla/1.25 mm(contiguous)

SZ 15NC 15

SZ 32.9NC 30.9

Males only Principal components analysis based on left–rightasymmetry vector fields was used; group differenceswere reported in the subiculum.

(continued overleaf )


were examined separately, there was a reduction in

temporal lobe volume over time. Lawrie et al. suggested

that there are abnormalities in temporal lobe structures

in relatives at risk for schizophrenia, but that no changes

occur in those structures over time; In contrast, such

changes are seen in individuals who develop psychotic

features, further suggesting that changes over time are

observed only when psychosis is evident.

One negative finding among reports of progressive

changes was reported by Ananth et al. [25 ..], who did

not find proportional gray matter reduction with age in

patients with schizophrenia. However, they did report

left mediodorsal thalamus abnormalities using VBM, as

well as differences in occipitoparietal cortex, premotor,

medial, orbital prefrontal cortices, and inferolateral

temporal lobe in patients with schizophrenia as com-

pared with control individuals (Table 1). VBM is a

relatively new and promising technique, but it needs

further refinement, including comparison with manual

measurements of brain regions of interest (which are the

standard for comparison), before it can widely be

accepted as an accurate measure of brain regions of

interest.

Neurodevelopmental hypothesis

Support for a neurodevelopmental origin of schizophre-

nia is often sought by studying brain structures in which

perinatal maturation coincides with increased risk for

schizophrenia (i.e. second and third trimester). These

include midline structures that are proposed to mediate

attention and information processing [57], including CSP

(two thin leaflets that fuse together as the corpus

callosum and hippocampus develop; for more extensive

review [5..]). Other midline structures include the

adhesio interthalamica (single or multiple connections

between the medial surfaces of the two thalami), the

corpus callosum, and the hippocampus. Finally, other

structures that may be affected by adverse perinatal

event(s) include: the sulcal–gyral pattern of the brain, as

well as regions of the brain that are lateralized for

specialized functions such as language, including STG

and a component of that gyrus, namely the planum

temporale (for review [5..]).

Midline structures

Evidence emerging from studies of midline structures

suggests subtle neurodevelopmental abnormalities af-

fecting these brain areas. Erbagci et al. [28], for example,

examined the adhesio interthalamica to determine

whether they were present or absent (abnormal) in

schizophrenia. They found adhesio interthalamica to be

absent more often in patients with schizophrenia than in

normal control subject individuals, suggesting a neuro-

developmental abnormality in at least a subset of

patients diagnosed with schizophrenia (Table 1).

Hagino et al. [31] examined CSP, another brain anomaly

that is believed to be neurodevelopmental in origin.

They did not find group differences in the prevalence

of large CSP in a group of 86 schizophrenia patients

and 79 normal control individuals. However, this

finding is not consistent with 92% of studies showing

enlarged CSP in patients with schizophrenia (for review

[5 ..]). Moreover, those investigators reported that

74.7% of control individuals showed abnormal CSP.

This figure is much higher than the range 5–13% that

was generally reported for control individuals in

previous studies.

Narr et al. [47] examined the genetic contributions to

altered shape of the corpus callosum in a study of

dizygotic and monozygotic twins discordant for schizo-

phrenia (Table 2). No group volume differences were

found between affected and nonaffected individuals, but

both affected and unaffected monozygotic twins shared

an upward bowing of the callosum, which is suggestive

of volumetric enlargement of the ventricles and is

consistent with genetic rather than environmental

influences on corpus callosum anatomy.



Participants(n)

Mean age(years)


Wible [40] 1.5 Tesla/1.5 mm(contiguous)

SZ 17NC 17

SZ 44NC 40

Males only No group differences were observed for prefrontal graymatter, but right prefrontal white matter was reduced inSZ and this was also correlated with right hippocampalvolume.

Zuffante [41] 1.5 Tesla/1.25 mm(contiguous)

SZ 23NC 23

SZ 43.3NC 46.5

Males only No group differences were observed between groupsfor volume of area 46 (middle frontal gyrus), althoughdeficits were noted in SZ in both spatial and nonspatialworking memory tasks.

Yucel [42] 1.5 Tesla/1.5 mm(contiguous)

SZ 55NC 75

SZ 35.99NC 29.08

Males only Reduced folding of the left anterior cingulate cortex wasfound in SZ.

CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; NC, normal control; SZ, chronic schizophrenia; SZ(MA), multiply affected family (in whichthere is more than one member with SZ); SZ(U), uni-affected family (in which only one member is diagnosed with SZ).

Schizophrenia128

Table 2. Magnetic resonance imaging structural findings in childhood/adolescent onset schizophrenia or in relatives of patients diagnosedwith schizophrenia


Participants(n)

Mean age(years)


Relatives of SZ

Cannon [45.] 1.5 Tesla/5 mm(contiguous)

SZ 64SZSIBS 51NC 54

SZ 40.5SZSIBS 40.3NC 40.7(SZ = SZ orSZAFF;SZSIBS = SZor SZAFFSIB)

SZ 32/32SZSIBS 22/29NC 23/31

FH predicted gray matter volume loss in the patient andsibling groups, most strongly in the temporal lobe. Anincrease in CSF and sulcal enlargement was associatedwith hypoxia in patients only, whereas FH and sulcalenlargement in the temporal lobe were observed insiblings only. The authors concluded that FH wasassociated with increased brain abnormalities in SZ andin their nonpsychotic siblings, but not in NC.

Harris [46] 1.5 Tesla/1.5 or1.7 mm (contigu-ous)

SZ 6UP 12NC 6

SZ 38UP 69NC 38

SZ 5/1UP: positive history4/2; negativehistory 2/4NC 5/1

Whole brain and hippocampus were measured. Resultsshowed that positive history parents had a largerhippocampus volume than did SZ. The authorsspeculated that positive history parents have somecompensatory mechanisms or protective factors thatresult in larger hippocampi than in their affectedchildren.

Lawrie [44] 1.0 Tesla/1.88 mm(contiguous)

RELSZ 66NC 20

RELSZ 23.1NC 22.9(RELSZ = atleast two 1stor 2nd degreerelatives withSZ)

RELSZ 34/32NC 13/7

Previously these investigators reported reducedamygdala–hippocampal complex volume in people atrisk for SZ. In this study, a subset of these patients,along with healthy NC, were rescanned on average 2years later. Results showed that there was not areduction in temporal lobe and amygdala–hippocampalcomplex over time for all high-risk relatives. Instead,there was volume reduction in the right temporal lobe inhigh-risk individuals with psychotic features. This findingsuggests that brain structures may change over timewith psychotic symptoms, but may remain stable (i.e.reduced but no progression) in individuals at risk for SZwho do not evince psychotic symptoms.

Narr [47] 1.0 Tesla/1.2 mm(contiguous)

Discordantcotwins: MZ20; DZ 20Control cot-wins: MZ 20;DZ 20

Discordantcotwins: MZ48.3; DZ 49Control cot-wins: MZ 48.3;DZ 47.9

Discordant cotwins:MZ 10/10;DZ 10/10Control cotwins:MZ 10/10;DZ 10/10

Lateral ventricle and third ventricle volume wereevaluated, as well as corpus callosum area and verticaldisplacement (upward bowing). Results showed thatboth affected and unaffected MZ cotwins hadsignificant callosal displacements. There were nodifferences among groups in corpus callosum areameasures. Of note, lateral and third ventricle volumewere associated with corpus callosum displacement.The authors suggested that upward bowing of thecorpus callosum may be a useful developmental markerfor screening for SZ.

O’Driscoll[48.]


RELSZ 20NC 14

RELSZ 35.4NC 36.2

RELSZ 9/11NC 5/ 9

Amygdala–anterior hippocampus and posteriorhippocampus were evaluated. Results showed reducedvolume of amydgala–anterior hippocampal volume aswell as poor delayed verbal memory in RELSZ ascompared with NC. Across all participants there was acorrelation between delayed verbal memory andamygdala–anterior hippocampus. The data provide anempiric link between verbal memory deficits andvolumetric abnormalities in the amygdala–anteriorhippocampus in RELSZ.

Seidman[49..]


RELSZ 45SZ 18NC 48(RELSZ =families withone or two1st degreerelatives withSZ)

RELSZ 44.6SZ 43.2NC 40.1(Group differ-ences in sex,education, andIQ)

RELSZ 17/28SZ 10/8NC 27/21

Volumes of total cerebrum and of hippocampi weremeasured. Results showed significantly smaller lefthippocampus volumes in RELSZ, particularly formultiplex families (i.e. those with more than one personwith SZ), but no differences were found in hippocampalvolumes between SZ and their relatives. Additionally,verbal memory and left hippocampal volume werepositively correlated, particularly in the multiplex RELSZ.The authors suggested that reduced hippocampalvolumes and verbal declarative memory deficits reflect avulnerability to SZ.





Participants(n)

Mean age(years)


Steel [50] 1.0 Tesla/1.5 mm(contiguous)Some sectionstested onanother 1.0 Teslascanner/1.5 mm(contiguous)

6 sibships(n = 18)[SIBSHIP = 1patient withSZ, oneobligate carrier(inheritedgenetic risk, noSZ), one non-carrier and noSZ]

SZ sibships46.2Obligate 49Noncarrier45.2

7/11 Whole brain, prefrontal and temporal lobes, caudate,lentiform and thalamic nuclei, as well as amygdala–hippocampal complex, lateral, third and fourth ventricleswere measured. Results showed overall reduction incortical gray matter in SZ siblings (5%) withpronounced loss in the amygdala–hippocampus (12%).Obligate carriers were similar to SZ siblings in exhibitingamygdala–hippocampal complex volume reduction, andwere similar to unaffected noncarriers in exhibitingwhole brain gray matter volume reduction. Obligatecarriers had smaller ventricles than did SZ siblings. Theauthors concluded that reduced cortical gray matterwas associated with phenotypic SZ, whereasreductions in medial temporal lobe structures such asthe amygdala–hippocampus were associated with agenetic risk for SZ.

Van Erp [51.] 1.5 Tesla/1.3 mm(contiguous)

SZ 72 (60 SZ/12 SZAFF)US 58NC 53

SZ 40.2US 40.7NC 40.9

Males only Hippocampus was measured and smaller hippocampusvolume was found in SZ with FH, followed by SZwithout hypoxia, their siblings, and NC. There was noassociation between hypoxia and hippocampal volumein NC. Of note, smaller hippocampus correlated withearlier age of onset in SZ.

Childhood/adolescent onset of SZ

James [52] 1.5 Tesla/5 mm(contiguous)

AOSZ 16NC 16

AOSZ 16.6NC 16.0(Mean age atbaseline MRIscan differedbetweengroups)

AOSZ 9/7NC 9/7

Whole brain, lateral ventricles, third ventricle, temporallobe, and medial temporal lobe structures (amygdalaand hippocampus) were measured in adolescents withSZ and in NC. SZ had follow-up scans on average 2.7years later, and NC had follow-up scans on average 1.7years later. Results showed generalized ventricularenlargement (lateral and third ventricle), particularly inmale SZ, which was most prominent on the left, as wellas left amygdala volume reduction in SZ, and a trendtoward left hippocampal volume reduction in SZ. Therewas no progression of tissue loss in brain volumes or inlateral and third ventricular volumes over time.

Levitt [53] 1.5 Tesla/1.4 mm(contiguous)

COSZ 13NC 20

COSZ 14.2NC 12.0 (IQdifferencesbetweenCOSZand NC)

Children Total brain, temporal lobe volume, amygdala, andhippocampus volume were measured. Results showedthat amygdala volume, especially on the left, was largerin the COSZ group than in NC. There was also a trendfinding for a reversal of the normal right4left amygdalaasymmetry in COSZ.

Matsumoto[54]


AOSZ 40NC 40

AOSZ 15.5NC 15.7

AOSZ 20/20NC 20/20

Total gray and white matter of the superior temporalgyrus was measured in early onset SZ. Total brainvolume was also measured. Results showed that totalgray and white matter volume of the right superiortemporal gyrus was smaller in AOSZ than in NC.Bilateral volumes in AOSZ were correlated with age atonset of psychosis, whereas severity of thoughtdisorder and hallucinations were inversely related toright superior temporal gyrus volume. The authorssuggested that these findings may reflect aneurodevelopmental disruption.

Thompson[55..]


COSZ 12NC 12

COSZ 13.9NC 13.5(Onset byage 12)

COSZ 6/6NC 6/6

This study followed individuals over 5 years with threeseparate MRI scans. Results showed that deficitsprogress from parietal areas, to temporal lobes, andsensorimotor and dorsolateral prefrontal cortices inpatients with COSZ.


Schizophrenia130

Amygdala–hippocampal complex

Three recent studies examined the amygdala–hippo-

campal complex in schizophrenia. Velakoulis et al. [38]

used both traditional volumetric measures and shape

measures to evaluate the hippocampus in schizophrenia.

Both shape-based and volume-based analyses suggested

reduced hippocampal volume in the patient group.

Specifically, the shape-based analysis indicated volu-

metric loss in the posterior portion of the hippocampus

(Table 1). Those researchers suggested that abnormal

receptor distribution in early development could lead to

altered hippocampal development in terms both of

shape and connectivity. Figure 2 provides MRI images

that depict the amygdala–hippocampal complex, as well

as the temporal lobe, frontal lobe, lateral ventricles, and

STG.

Although amygdala and hippocampal volume reductions

in schizophrenia are among the more robust findings, not

all studies report volume reductions. For example, in a

recent study conducted by Rajarethinam et al. [35], no

group differences were found in hippocampus and

amygdala volumes, although left amygdala volume

correlated negatively with the severity of thought

disorder in the patient group, and left hippocampal

volume was correlated with negative symptoms in the

patient group. Of note, in that study 3-mm slices were

used, as compared with use of 1.5-mm slices by

Velakoulis et al. [38]. This difference in spatial resolution

may explain the negative finding because differences in

spatial resolution can adversely effect the ability to

detect differences between groups. Of further note, that

reductions in left amygdala volume were correlated with

increased formal thought disorder confirms several

earlier studies that showed similar correlations (for

review [5..]).

Falkai et al. [29] were interested in evaluating families in

which only the proband had schizophrenia versus

families in which multiple family members were affected

with schizophrenia. They found more reduction as well

as abnormal asymmetry in the amygdala–hippocampal

complex in families in which only the proband was

diagnosed with schizophrenia, as compared with control

individuals and with probands from families with mul-

tiple diagnoses of schizophrenia. Those investigators

interpreted this finding as suggesting that brain abnorm-

alities in medial temporal lobe regions are not familial.

The question of how genetic transmission might impact

on reduction in hippocampal volume was also addressed

in a familial MRI study conducted by Harris et al. [46].

Hippocampal volumes were studied in patients with

schizophrenia, in their parents (families in which only

one parent had an ancestral history of schizophrenia),

and in normal control individuals. Unaffected parents

with an ancestral history of schizophrenia had larger

hippocampal volumes than did their affected offspring

(Table 2). Those authors concluded that reduced

hippocampal volume is not a genetically transmitted

risk factor. In addition, the unaffected parents with

ancestral history of schizophrenia had the largest

hippocampal volumes among the three groups, suggest-

ing that such increases in volume may represent a

protective or compensatory factor in a person at genetic

risk for schizophrenia. Of note, however, the proportion

of males and females in the positive and negative history

groups and in the control group was not equal, and this

in itself might have affected the findings.

The findings reported by Harris et al. [46] are not

consistent with findings from a study conducted by

Seidman et al. [49..]. Those investigators examined



Participants(n)

Mean age(years)


Other

McCreadie[56]


SZDYS 31SZNDYS 31NC 31

SZDYS 43SZNDYS 44NC 43(Nevermedicated SZfrom SouthIndia, with andwithout DYS)

SZDYS 18/13SZNDYS 18/13NC 18/13

Cerebral hemisphere and lateral ventricles were mea-sured on two contiguous slices. Caudate and lentiformnucleus were measured. Results showed that leftlentiform gyrus was larger in SZDYS whereas rightventricle : hemisphere ratio was larger in SZNDYS thanin NC. When volume of lentiform nucleus was correctedfor hemisphere in a smaller group of patients, volumedifferences between groups were not present. Theauthors suggested that SZDYS may have striatalpathology that may represent a subset of SZ.

AOSZ, adolescent onset schizophrenia; COSZ, childhood onset schizophrenia; CSF, cerebrospinal fluid; DYS, dyskinesia; DZ, dyzygotic twin; FH,fetal hypoxia; IQ, intelligence quotient; MRI, magnetic resonance imaging; MZ, monozygotic twin; NC, normal control; RELSZ, relative ofschizophrenia; SZ, schizophrenia; SZAFF, schizoaffective disorder; SZDYS, schizophrenia with dyskinesia; SZNDYS, schizophrenia withoutdyskinesia; UP, unaffected parents; US, unaffected siblings.


hippocampal volume as a marker of vulnerability for

schizophrenia in both simplex (one person in the family

with schizophrenia) and multiplex (two people in the

family with schizophrenia) unaffected relatives of

schizophrenic patients, patients with schizophrenia, and

normal control individuals (Table 2). Using this genetic

sampling approach, left hippocampus was found to be

reduced in the unaffected relatives, especially those

from the multiplex families. Moreover, the volume

found in the unaffected relatives was not significantly

different from that found in patients with schizophrenia.

Seidman et al. also reported a correlation between

deficits in verbal memory performance and reduced left

hippocampal volume. This association is similar to that

reported in previous structural MRI studies (for review

[5..]) and to that reported by O’Driscoll et al. [48.], who

found reduced anterior amygdala–hippocampus in rela-

tives of patients with schizophrenia as compared with

control individuals, which was correlated with impair-

ments in verbal memory. These data thus provide an

empiric link between verbal memory deficits and brain

abnormalities in the amygdala–hippocampal complex

both in schizophrenia and in relatives of patients with

schizophrenia.

Similar findings were also reported by Van Erp et al.[51 .]. They found the smallest hippocampal volume in

patients with schizophrenia, followed by their full

siblings, and normal control individuals. In addition,

the smallest hippocampal volumes were observed in

schizophrenic patients with fetal hypoxia, a relationship

not noted in any other group.

The effect of fetal hypoxia on cortical gray matter loss

and on volume of cerebrospinal fluid was also assessed

in a study conducted by Cannon et al. [45 .] in a group

of patients with schizophrenia, full siblings of schizo-

phrenic patients, and matched normal control indivi-

duals (Table 2). Fetal hypoxia predicted reductions in

gray matter volume and increased levels of cerebro-

spinal fluid in patients and their siblings, but not in

control individuals. Of note, hypoxia did not correlate

with white matter changes in any group. These findings

point to a scenario in which genetic vulnerability and

environmental factors may interact in the development

of schizophrenia, because brain regions particularly

vulnerable to hypoxia, such as the hippocampus, were

especially impacted in at least a subset of patients

diagnosed with schizophrenia.

Finally, Steel et al. [50] compared volumes of specific

brain regions, including the amygdala–hippocampal

complex, in sibships with either one patient with

schizophrenia, one obligate carrier without the disorder

but with affected offspring, and one nonaffected

‘noncarrier’. Obligate carriers shared reduced amygda-

la–hippocampal volumes with schizophrenic patients,

but not the whole brain, or frontal or temporal lobe

reductions found in schizophrenic patients. Those

findings suggest that reduced cortical structures are

associated with the phenotype of schizophrenia, whereas

the reduction in the amygdala–hippocampal complex is

associated with genetic risk for schizophrenia in the

absence of the disorder. Of note in this regard, a recent

twin study was conducted in post-traumatic stress

Figure 2. Coronal 1.5 mm view of the brain

Coronal view

Right Left

Sagittal view

Anterior Posterior

Sagittal view

Front Back

Frontallobe

Lateralventricle

Superiortenporalgyrus

Amygdala-hippocampalcomplex

Temporallobe

Coronal 1.5 mm view of the brain shows the temporal lobe, frontal lobe,superior temporal gyrus, amygdala–hippocampal complex, and thelateral ventricles. The location of the coronal slice is depicted in thesagittal view. (Courtesy of Susan Demeo, Magdalena Hale Spencer,and Anders Brun.)

Schizophrenia132

disorder (PTSD) monozygotic twins discordant for

PTSD [58]. It found that the unaffected twin also

showed reduced amygdala–hippocampal volume as

compared with monozygotic twins without PTSD,

suggesting that such volume reduction may reflect a

genetic vulnerability or predisposition to PTSD.

Cortical and subcortical sex differences

The role of sex differences in mediating gene expres-

sion in schizophrenia was examined by Goldstein et al.[30 ..]. They assessed a range of cortical and subcortical

brain volumes, and hypothesized that sex-mediated

brain differences in men and women with schizophrenia

are present in cortical but not in subcortical regions.

Indeed, differential patterns of cortical brain abnormal-

ities were found in schizophrenic men and women

relative to their control groups (Table 1). No sex

differences were found in asymmetry, with the excep-

tion of the planum temporale, in which male patients

exhibited smaller planum temporale on the right and

female patients showed larger planum temporale on the

right, resulting in greater planum temporale symmetry

in women. This finding is not consistent with that of

Meisenzahl et al. [32], who reported no asymmetry

differences in males using three different methods of

planum temporale definition. As expected, however,

Goldstein et al. found no sex-mediated group differ-

ences in subcortical regions, despite normally existing

sex dimorphisms in these areas. The authors inter-

preted their findings as supporting the role of

neurodevelopmental factors in schizophrenia, especially

because they relate to timing of the release of gonadal

hormones and their relative distribution between

cortical and subcortical brain regions.

Cingulate cortex and schizophrenia

The anterior cingulate cortex (ACC) was examined in

three studies. Yucel et al. [42] studied the morphology of

the ACC in a group of 55 male patients and 75 normal

control individuals. The surface morphology of the ACC

was used to classify paracingulate sulcus either as

prominent, present, or absent. The results suggest that

patients had less leftward folding of the anterior

cingulate than did control individuals, and these

differences existed over and above those found in the

entire left hemisphere. The results were viewed as

supporting evidence for the role of neurodevelopmental

factors in the etiology of schizophrenia because cortical

folding is established in the second and third trimesters

of pregnancy, remains stable throughout life, and is not

influenced by environmental factors such as alcohol

abuse, neuroleptic exposure, or age.

In contrast to Yucel et al. [42], two other studies [30..,37]

found group differences in ACC to be sex related (i.e.,

observed only in women). Additionally, Takahashi et al.

[37] found reduced gray and white matter in the ACC,

along with reduced asymmetry in women, in a study that

examined ACC gray and white matter using high-

resolution three dimensional MRI.

Frontal cortex and schizophrenia

Three studies evaluated the role of frontal cortex in

schizophrenia. In the first of those, Chemerinski et al.[26] looked at the relationship between social function in

male patients with schizophrenia and the morphology of

the ventral frontal cortex, parcellated into orbitofrontal

gyrus and straight gyrus. Both volume and surface

measures were completed (Table 1). Only the volume

of the straight gyrus was found to be smaller in the

patient group and, in agreement with the study

hypothesis, was correlated with measures of social

adjustment, both before and after illness onset. This

relationship became especially clear when negative

symptoms were controlled for, suggesting that negative

symptomatology and poor social function may represent

two distinct features of the illness. These data are

consistent with previous findings suggesting that pre-

morbid functioning, particularly poor premorbid social

functioning, may be related to more frontal lobe

abnormalities in schizophrenia (for review [5..]).

In the second study, Wible et al. [40] analyzed the

relative volumes of gray and white matter of the

prefrontal cortex and its correlations with clinical

variables. Although no differences were found in gray

matter, white matter was reduced in the right hemi-

sphere in the patient group, and it correlated with

volume of the right hippocampus in the patients only.

Also, patients with high negative symptom scores had

lower white matter volumes than did those with low

negative scores. The fact that the patients in the study

were characterized by more negative symptoms suggests

the importance of evaluating more homogeneous patient

groups, because this may make a large difference with

respect to which brain regions are most affected.

Differences in genetic loading may also be important

because there is some indication that patients with more

negative symptoms may have more neurodevelopmental

abnormalities and an earlier age of onset (for review

[5 ..]).

Finally, in the third study, that conducted by Zuffante etal. [41], a lack of volumetric changes in the frontal lobes

(area 46) was noted, despite the presence of deficits on

tasks of both spatial and nonspatial working memory.

Schizophrenia and gene expression

More direct studies of genetic factors that might be

associated with schizophrenia include those by Chow etal. [27 .] and Meisenzahl et al. [33]. The latter

investigators [33] examined the relationship between


brain volumetric measures and individual genotypes.

Specifically, because higher plasma levels of interleukin-

1b are found in blood samples of schizophrenic patients,

they examined the relationship between interleukin-1ballele 2 carriers and volumetric brain abnormalities.

Schizophrenic patients who were carriers had smaller

volumes in the frontal and temporal gray matter and a

generalized deficit in white matter volume. There was

no association between the interleukin-1b polymorphism

at position –511 and schizophrenia.

Chow et al. [27.], in a preliminary study of 14 adults with

schizophrenia who also suffered from 22q deletion

syndrome (a disorder associated with increased risk for

schizophrenia) and 14 age-matched and sex-matched

control individuals, found that the patient group

exhibited smaller total gray matter volumes in the

temporal and frontal lobes. White matter did not show

volumetric differences between groups.

Taken together, these results suggest a scenario of how

genetically mediated risk for schizophrenia might inter-

act with other genetic and environmental vulnerability

factors to result in schizophrenia.

Summary

MRI structural findings in schizophrenia over the past

year are generally in agreement with previous structural

MRI findings in schizophrenia. Multiple brain regions

appear to be affected in schizophrenia, although rather

than generalized deficits these abnormalities are pre-

dominantly in temporal lobe, including medial temporal

lobe (e.g. amygdala–hippocampal complex) and neocor-

tical temporal lobe (i.e. STG, which includes planum

temporale and Heschl’s gyrus; see Goldstein et al.[30 ..]), followed by frontal, parietal [27 .,30..], and

occipital lobe abnormalities [34]. In addition, family

members of patients with schizophrenia appear also to

evince brain abnormalities, including amygdala–hippo-

campal volume anomalies [44,46,48.,49..] and corpus

callosum anomalies [47].

The recent and growing interest in studies of families

and relatives is particularly important; such investiga-

tions provide crucial information because brain abnorm-

alities observed in nonpsychotic relatives of patients with

schizophrenia provide the best indicator of potential

vulnerability markers of schizophrenia, independent of

psychosis. Such studies also provide important clues to

possible early neurodevelopmental anomalies that reflect

both liability or vulnerability to schizophrenia, and relate

to the expression of schizophrenia.

Finally, we note new methodologic advances, such as

the use of VBM [22,25..,36.], which offer a quick way

to evaluate multiple brain areas across many indivi-

duals, in contrast to the usual labor intensive manual

tracing of brain regions of interest. Additionally, a more

sophisticated method of asymmetry definition based on

a vector field [39 .] offers what may represent a better

assessment of asymmetry in such structures as hippo-

campus. These methods, which need further refine-

ment, will probably offer new possibilities for

generating hypotheses that can then be followed up

in more carefully delineated manual region of interest

investigations.

Magnetic resonance imaging studies: firstepisode schizophreniaThe extent to which brain abnormalities found in

chronic schizophrenia are also present in first episode

schizophrenia is the focus of a number of MRI studies.

Individuals with a first episode of schizophrenia provide

a unique opportunity to examine the effects of a

psychiatric process without the confounding factors of

chronicity and exposure to chronic neuroleptic medica-

tions. Additionally, studying first episode schizophrenia

patients, as well as childhood and adolescent onset

schizophrenia, and at-risk populations such as relatives of

schizophrenic patients (see previous section) and in-

dividuals with schizotypal personality disorder is a

fruitful strategy to elucidate the etiology of schizophre-

nia and its cognitive correlates [5..,59,60]. Again, as with

the MRI studies of chronic schizophrenia, both neuro-

developmental and neurodegenerative models of schizo-

phrenia provide a theoretical framework for many of the

studies.

Initial abnormalities

The majority of studies document that brain abnormal-

ities exist at the onset of the illness.

Multiple brain areas approach

Two studies examined multiple brain areas to look for

evidence of an initial insult [61,62]. Cahn et al. [61] (see

Table 3 for brain regions studied) found enlargement of

the third ventricle only, suggesting to these investigators

that other brain abnormalities reported in schizophrenia

may appear later in the course of illness and also may be

medication related.

Using the strategy of comparing volumetric changes

across different clinical populations, Salokangas et al. [62]

examined differences in several brain areas (Table 3) in

first episode schizophrenia, and in depression, with and

without psychotic features. First episode patients

evinced reduced left frontal lobe volumes, whereas

depressive patients with psychosis evinced enlarged

ventricular and posterior sulcal cerebrospinal fluid

volumes. Patients with depression without psychotic

features only evinced larger white matter volumes than

other clinical groups.

Schizophrenia134

Table 3. Magnetic resonance imaging structural findings in first episode schizophrenia

ReferenceMagnet/slicethickness Participants (n)

Mean age(years)


Cahn [61] 1.5 Tesla/1.6 mm(contiguous)

SZ 20NC 20

SZ 27.63NC 27.24(Neurolepticnaı̈ve)

SZ 16/4NC 16/4

ICC, total brain, frontal lobe (gray and white matter),cerebellum, hippocampus, parahippocampal gyrus,thalamus, caudate nucleus, and lateral and third ventricleswere measured. Only third ventricle differed in SZ ascompared with NC, with enlarged third ventricle in SZ.The investigators concluded that this paucity of findings infirst episode SZ suggests that brain abnormalities developover time as seen in chronic SZ, which may therefore berelated to a progression of the illness or to the effects ofneuroleptic medications over time. (There weredifferences in education between groups).

Frumin [63] 1.5 Tesla/1.5 mm(contiguous)

SZ 14AFF 19NC 18

SZ 28.1AFF 25.8NC 24.5(Minimal neuro-leptic expo-sure)

SZ 11/3AFF 14/5NC 16/2

Corpus callosum area and shape measures werecompleted. Group differences were noted in shape for SZversus NC, but no differences between groups wereobserved for area measures of the corpus callosum.

Gunduz [64] 1.5 Tesla/5 mm (contigu-ous), 1 mm inplane resolution

SZ = 51(SZAFF 4,SZPHRE13)NC 28

SZ 24.5NC 25.8(Neurolepticnaı̈ve and mini-mal exposure)

SZ 37/14NC 17/11

Total brain volume, caudate nucleus, putamen, nucleusaccumbens volume, and subcommissural limbic forebrainvolume were measured. Findings showed no groupdifferences in volumes of the basal ganglia, although agewas correlated with volumes of caudate and putamen inNC. (There were differences in education and parentalsocioeconomic status between groups).

Joyal [65] 1.5 Tesla/1.5 mm(contiguous)

SZ 18NC 22

SZ 28NC 30(Neurolepticnaı̈ve)

SZ 11/7NC 14/8

Entorhinal cortex and whole brain volume were measured.Findings showed smaller entorhinal cortex volume in SZversus NC.

Keshavan [66] 1.5 Tesla/5 mm(1-mm inter-slice gap)

SZ 31Non-SZP 12NC 31

SZ 24.20Non-SZP22.83NC 25.09

SZ 20/11Non-SZP 6/6NC 20/11

Area measures of the corpus callosum were completed.Findings showed smaller area of corpus callosum, itsanterior genu, anterior body, isthmus, and anteriorsplenium in SZ as compared with NC and non-SZP. Age-related increases in corpus callosum size observed in NCwere not seen in patients, suggesting neuro-developmental abnormalities.

McCarley[67..]


SZ 15AFF 18NC 18

SZ 27.6AFF 23.5NC 24.9

SZ 12/3AFF 15/3NC 15/3

ICC, total gray and white matter, planum temporale, andHeschl’s gyrus were measured. Findings showed smallergray matter volume of the left planum temporale andsmaller Heschl’s total gray matter volume in SZ, whichdiffered from AFF and NC.

Salokangas[62]


SZ 11PD 20Non-PD 17NC 19

SZ 36.6PD 34.0Non-PD 38.4NC 30.5

SZ 3/8PD 8/12Non-PD 8/9NC 12/7

Frontal and temporal lobe gray and white matter weremeasured, as well as lateral ventricles and sulci. Findingsshowed reduced gray matter volume in left frontal lobe inSZ group as well as larger ventricular and posterior sulcalcerebrospinal fluid volumes in the PD group, and largerwhite matter volumes in the non-PD group.

Sumich [68] 1.5 Tesla/1.5 mm(contiguous)

SZ 25NC 16

SZ 24.0NC 27.0(Minimallytreated withneuroleptics)

All male Whole brain, Heschl’s gyrus, planum temporale,hippocampus, and amygdala were measured. Findingsshowed smaller hippocampus volumes and smaller leftplanum temporale volumes in the SZ group.

Szesko [69] 1.0 Tesla/3.1 mm(contiguous)

SZ 75NC 36

SZ 24.7SZ 27.3NC = 25.3

SZ 43/32NC 24/12

Hippocampal volume and ICC were measured. Findingsshowed that anterior hippocampal volume was correlatedwith motor and executive functions in men with SZ.

Lee [70.] 1.5 Tesla/1.5 mm(contiguous)

SZ 22AFF 20NC 24

SZ 26.0AFF 22.6NC 24.0

SZ 17/5AFF 15/5NC 21/3

Whole brain gray and white matter and CSF weremeasured. Findings showed smaller volume of leftfusiform gyrus in SZ versus NC and AFF. Right fusiformgyrus volume was also smaller in SZ as compared withthe NC group only.

Wood [71] 1.5 Tesla/1.5 mm(contiguous)

SZ 30CHRSZ 12NC 26

SZ 21.8CHRSZ 33.6NC 23.8

SZ 19/11CHRSZ 11/1NC 14/12

ICC, temporal lobe, hippocampus, and whole brain weremeasured in a follow-up study averaging 2.2 yearsfollowing the first MRI scan. Findings showed whole brainvolume loss in both chronic and first episode SZ at followup.

AFF, affective disorder with psychosis; CHRSZ, chronic schizophrenia; CSF, cerebrospinal fluid; ICC, intracranial contents (brain, ventricular system,and subarachnoidal CSF); MRI, magnetic resonance imaging; NC, normal control; non-SZP, nonschizophrenic psychotic; PD, psychotic depression;SZ, first episode schizophrenia; SZAFF, schizoaffective; SZPHRE, schizophreniform.


Temporal lobe structures (amygdala–hippocampal complex,

entorhinal cortex, and superior temporal gyrus)

Four studies looked directly at STG volumetric

abnormalities [53,54,67..,68]. [The study conducted

by Levitt et al. [53] is discussed in detail under Change

over time (see below).] A study conducted by

McCarley et al. [67 ..] focused on gray matter in STG,

amygdala–hippocampal complex, and parahippocampal

gyrus in first episode schizophrenia, patients with a first

episode of affective psychosis (mainly manic), and in

normal control subject individuals (Fig. 2). Patients

with first episode schizophrenia had smaller gray matter

volumes of left posterior STG, left planum temporale,

and total Heschl’s gyrus volume relative to control

individuals and to affective patients. Similar conclusions

were drawn in a study conducted by Sumich et al. [68],

in which first episode schizophrenic patients were

found to have smaller volumes of hippocampus

bilaterally and smaller left planum temporale relative

to control individuals.

In a study of adolescent persons with early onset

schizophrenia, Matsumoto et al. [54] found reduced

right rather than left superior temporal gyrus, and

severity of thought disorder and hallucinations were

inversely correlated with volume of the right superior

temporal gyrus, suggesting that this pattern of

abnormalities may be characteristic of early onset

schizophrenia. Of note, this asymmetry finding is the

reverse of that reported in adult onset schizophrenia,

in which left STG is frequently reported to be

reduced [67 ..].

The relationship between hippocampal volume and

neuropsychological function was evaluated by Szeszko

et al. [69] in 43 men and 32 women with first episode

schizophrenia. Anterior hippocampus was correlated

with both executive and motor functions in men,

although no significant correlations emerged for

women. These results further suggest that medial

temporal lobe abnormalities are present at first

episode and that such abnormalities are associated

with what are considered frontal lobe functions,

therefore further suggesting an abnormality in fron-

to–temporal neural circuitry in schizophrenia. These

findings also suggest a role for sex in mediating both

structural and functional abnormalities in schizophre-

nia.

Joyal et al. [65] measured the entorhinal cortex in

neuroleptic naı̈ve patients with schizophrenia and

control individuals. Those investigators reported re-

duced entorhinal cortical volume in the patient group.

This finding is consistent with previous reports of

entorhinal cortical volume reduction in schizophrenia

(for review [5 ..]).

Fusiform gyrus

Lee et al. [70.] reported reduced left fusiform gyrus in

first episode patients with schizophrenia relative to first

episode patients with affective psychosis (mainly manic)

and normal control individuals. The fusiform gyrus

volume on the right was smaller in schizophrenic

patients as compared with controls but not smaller than

in the affective group. This gyrus is important in the

identification of human faces, and volume reduction here

may be relevant to problems that patients with schizo-

phrenia experience with respect to social cues.

Midline structures

Keshavan et al. [66] measured the area of the corpus

callosum in neuroleptic naı̈ve first episode patients,

nonpsychotic patients, and normal control individuals.

Reduced area was found in the anterior genu, body,

isthmus, and splenium subdivisions of the corpus

callosum, which connect heteromodal association areas,

but not in those areas that connect primary cortices, in

first episode schizophrenia patients, followed by non-

schizophrenic, and psychotic patients. In addition, age-

related growth in the size of the corpus callosum was

present in normal persons but not in first episode

schizophrenia patients. The authors viewed these results

as supporting a neurodevelopmental abnormality, which

impacts primarily on association cortices. Frumin et al.[63] also reported abnormal shape but not volume in first

episode schizophrenia patients, but not in affective

psychosis patients.

Subcortical structures

Gunduz et al. [64] examined the integrity of parts of

the basal ganglia (caudate nucleus, nucleus accum-

bens, putamen, subcommissural limbic forebrain) in

first episode, medication naı̈ve schizophrenia patients.

No volumetric differences were found in basal ganglia

structures between neuroleptic naı̈ve first episode

schizophrenic patients (n = 53) and normal controls

(n = 28). Of note also is the study conducted by

McCreadie et al. [56], in which gray matter volume in

components of the basal ganglia (putamen and caudate

nucleus), as well as volume of the lateral ventricles,

were measured in never medicated patients in rural

India, who were estimated to have been ill for

approximately 10 years. One group of patients

suffered from dyskinesia whereas the other did not.

Results showed larger left putamen in the dyskinesia

patients; the patients without dyskinesia evinced a

higher lateral ventricle : hemisphere ratio, especially on

the right side. The authors concluded that schizo-

phrenic pathology may interfere with normal, age-

related changes in the basal ganglia, which are

independent of medication effects (Table 2). Several

methodologic limitations preclude clear-cut interpreta-

tion of the findings.

Schizophrenia136

Change over time

Change over time was explicitly addressed in four

studies [52,53,55..,71]. In the study conducted by Levitt

et al. [53], volumetric changes in medial temporal lobe

regions were evaluated in a group of early psychosis

schizophrenic patients (mean age 14 years; mean time of

onset to scan time 4.2 years). Although childhood onset

schizophrenia patients are different from first episode

populations, in this group no volumetric changes were

observed in the hippocampus, but the amygdala was

enlarged in the patient group, with the group difference

more pronounced on the left side. There was also a trend

toward left greater than right asymmetry in the amygdala

volume in the patient group (Table 2).

Both the study by Thompson et al. [55..] and that by

Wood et al. [71] found evidence of ongoing neuro-

degenerative processes, whereas James et al. [52] did

not. Using a new method for evaluating the brain,

Thompson et al. [55..] tracked the rate of progression

of gray matter loss in children with childhood onset

schizophrenia (aged 13–18 years). Results suggest an

age-dependent loss of gray matter, which is progressive

and most pervasive in the parietal lobe early, with

progression to superior frontal and motor areas, and

lateral temporal and dorsolateral prefrontal cortex. Of

particular note, the rate of progression in this group

surpassed normal gray matter loss observed in normal

control individuals.

Furthermore, to examine progressive changes over time,

Wood et al. [71] conducted a study of first episode and

chronic patients with a 2.2-year time interval between

MRI scans. No time-related changes were observed in

the hippocampus or in the temporal lobe in the first

episode group. However, whole brain volumetric loss

was observed in both first episode and chronic groups,

and the rates did not differ between the two patient

groups.

In contrast, James et al. [52], in their study of

adolescent onset schizophrenia cases, demonstrated

enlarged lateral and third ventricles and reduced left

amygdala, and a trend toward left hippocampal volume

reduction at baseline as compared with control

individuals (Table 2). Scans taken at an average of

1.7 years later for control individuals and 2.7 years later

for the adolescent onset group revealed no reduction

over time. The authors interpreted these findings as

suggesting a nonprogressive neurodevelopmental dis-

order that impacts on brain structures before the onset

of clinical symptoms. However, the small sample, the

different time intervals between scans for patient and

control groups, and the relatively thick 3-mm slices all

limit the generalizability of these findings. It is also

quite likely that early onset schizophrenia constitutes a

subtype of schizophrenia that is unrelated to adult

onset schizophrenia.

Summary

First episode patients evince brain abnormalities, most

notably in medial temporal lobe (amygdala–hippocampal

complex, entorhinal cortex), STG, corpus callosum, left

planum temporale and left Heschl’s gyrus, left frontal

gray matter, and left fusiform gyrus. They also generally

have larger lateral ventricles than do control individuals.

These findings are similar to those reported in chronic

schizophrenia. In addition, there is some indication that

initial brain abnormalities are present at the onset of

illness, suggesting neurodevelopmental influences.

Furthermore, there is some indication that certain brain

regions may show progressive changes over time,

although far more research work following a large

number of first episode patients over time is needed

before conclusions can be drawn regarding brain changes

over time.

Functional brain imaging studiesfMRI has been increasingly used to study abnormal

cognitive processes in schizophrenia because it is less

invasive and costly than positron emission tomography

and because it promises better localization of function

than does positron emission tomography. Because the

fMRI signal reflects, indirectly, the relationship between

neural activity in response to a stimulus and blood flow

levels within brain regions, it can, at least in principle,

aid in identifying brain regions that exhibit abnormal

response to cognitive task requirements. As such, fMRI

can complement other imaging techniques such as

structural MRI, which offers an excellent spatial resolu-

tion, and event-related potentials, which offer excellent

temporal resolution, to provide information on where in

the brain cognitive operations are disturbed. However,

its ultimate success crucially depends upon appropriate

experimental designs and data analysis techniques

[72,73].

Most recent fMRI studies focused on deficits identified

by neuropsychologic and clinical research as central to

schizophrenia, including working memory, language

function, and thought disorder and auditory hallucina-

tions, as well as social cognition and correlates of

abnormal saccadic eye movements. More recently, fMRI

has also been used to ascertain the impact of medication

and behavioral therapy treatments. In addition, studies

have examined abnormal motor function [74,75] and

some have focused on face and affect processing [76,77].

In most studies, the focus has been on identifying a

network of brain regions that exhibit abnormal activation

and that are involved in the cognitive processes under

investigation. Figure 3 provides an illustration of fMRI

activation differences between normal control indivi-


duals and patients with schizophrenia, in the inferior

frontal lobe as a result of semantic encoding operations.

Of note, the activation observed in control individuals

was lacking in patients with schizophrenia. Below, we

review relevant fMRI studies conducted over the past

year; the studies are grouped according to the type of

cognitive operation investigated.

Executive function

Prefrontal cortex is involved in various aspects of

executive functioning and has been studied extensively

in schizophrenia. Weinberger et al. [78 ..], for example,

viewed prefrontal dysfunction and its association with

impaired working memory function as central to the

pathophysiology of schizophrenia. Those investigators

suggested that the catechol-O-methyl-transferase gene is

involved in regulation of frontal lobe function, especially

with respect to working memory tasks, and as such may

represent a candidate genetic risk factor for schizophre-

nia.

Two central objectives regarding the role of prefrontal

cortex in schizophrenia are to identify whether the

conditions that lead to abnormal dorsolateral prefrontal

cortex (DLPFC) response are manifested as either

hypoactivation or hyperactivation, and to identify the

network of functional connections between brain areas

that are involved in supporting specific cognitive

operations. With regard to the latter, the connections

between DLPFC and temporal cortex are especially

relevant to our understanding of functional abnormalities

in schizophrenia.

Barch et al. [79..] looked at the role of prefrontal

cortex in working and long-term memory deficits in

schizophrenia during the processing of verbal and

nonverbal stimuli. Those investigators found that right

DLPFC showed decreased activation in both working

memory and long-term memory tasks in patients with

schizophrenia (Table 4), as well as decreased activa-

tion in hippocampal regions, basal ganglia, thalamus,

and parietal cortex. This suggests that in schizophre-

nia there are impairments in the neural circuits that

are necessary to perform cognitive routines common

to both working memory and long-term memory

tasks, rather than impairments in discrete functional

areas.

However, in a study of logical reasoning conducted by

Ramsey et al. [81], prefrontal activation was normal in

medicated patients, after correcting for performance

between patients and normal control individuals. This

result is consistent with some previous studies [96,97]

that did not find ‘hypofrontality’ in patients, when

both patients and control individuals performed equally

well on a task (Table 4). In the same design,

nonmedicated patients showed activation levels that

were higher than those in normal control individuals.

These results suggest that performance levels across

groups may be an important factor in interpreting the

results of activation studies. Additionally, the result

found in unmedicated patients suggests that efficiency

of neural communication may be compromised in

schizophrenia.

Similarly, no group differences in the DLPFC were

found by Paulus et al. [82] in a study of decision making

(Table 4). However, abnormal activation was found

within the fronto-parietal network in patients with

schizophrenia (i.e. less activation in the inferior, medial

prefrontal, and right superior temporal cortex, and more

activation in the postcentral and inferior parietal cortex).

However, interpretation of these results is difficult

because, in addition to the complexity of the process

studied, nonmedicated patients as well as patients

medicated with typical and atypical neuroleptics were

included in the study.

An indication of abnormal fronto-parietal connection in

schizophrenia was also found by Honey et al. [83]. In the

working memory study, in which no group differences

were found in performance accuracy, a correlation was

found between increased reaction time and activation in

parietal cortex in the normal control group, whereas no

such correlation was detected in the patient group

(Table 4).

The functional integrity of prefrontal brain regions in

mediating inhibitory function was investigated by Rubia

et al. [84] using stop and ‘go/no go’ inhibitory motor

tasks. In the stop task there was less activation in the left

dorsolateral superior frontal gyrus and an increase in

subcortical areas in the schizophrenia group, with

equivalent behavioral performances in the patient and

normal control groups, suggesting involvement of an

abnormal neural network in inhibitory function.

The role of ACC in mediating error monitoring was

examined in normal control individuals and schizophre-

nic patients using an event-related fMRI design during a

continuous performance task [85.]. When the target

detection was made more challenging by degrading the

quality of the visual display, more errors were committed

by both groups. Healthy individuals showed a response-

related increase in activation in the anterior cingulate

gyrus related to error detection. Such an increase in

anterior cingulate gyrus activation was not observed in

schizophrenic patients. Moreover, anterior cingulate

gyrus activation was associated with impairments in

performance adjustment, suggesting that abnormal

internal error monitoring in schizophrenia may be related

to functional abnormalities in the cingulate cortex. A

Schizophrenia138

caveat to these results is that all patients were

medicated, which might have contributed to the limited

response in the cingulate.

Kumari et al. [86] examined functional correlates of

procedural learning often found to be abnormal in

schizophrenia. In normal control individuals there was

increased activity in brain regions associated with

procedural learning, including striatum, thalamus, cere-

bellum, precuneus, medial frontal lobe, and cingulate

gyrus. In schizophrenic patients, however, the only

structure activated was the anterior portion of the

inferior gyrus. Importantly, patients with schizophrenia

did not exhibit evidence of procedural learning. Again,

the results indicate a possible role of activated structures

in procedural learning, and abnormal procedural learning

in patients, which may stem from the inadequate

engagement of these structures.

Overall, results of many of the studies involving different

aspects of memory and executive function indicate that

functional abnormalities in schizophrenia are not only a

matter of reduced activation in the same brain region as

in normal control individuals (as demonstrated in some

studies) but also a matter of engaging different regions

or, alternatively, using different strategies mediated by

the same region, as demonstrated by other studies. For

example, Zorrilla et al. [80], using a picture recognition

paradigm, showed that in the patients there was a

positive correlation between recognition memory and

activation in the parahippocampal and hippocampus gyri

during encoding, whereas in normal control individuals

there was a negative correlation between these two

variables.

Saccadic eye movements

Two recent papers discussed neural substrates of

saccadic inhibition deficits in schizophrenia, which are

believed to represent a vulnerability marker for schizo-

phrenia and have been associated with a dysfunction in

the dorsolateral prefrontal cortex [98–100]. However, the

neural bases of the antisaccadic deficit are not well

understood [101,102]. The two studies also provide

nonconvergent results, probably due to different meth-

odologies (Table 4). In one of them, McDowell et al. [87]

analyzed blood oxygenation level dependent signal

change between refixation (fixation baseline) and anti-

saccades (refixation saccade baseline). Under these

conditions, only DLPFC was found to exhibit less

activation in patients with schizophrenia during anti-

saccade generation (Table 4).

In the other study, Raemaekers et al. [88] used an event-

related fMRI design. Brain activity generated during

saccade and antisaccade tasks were compared across

brain regions involved both in the generation of saccades

and in structures involved in the transmission of an

inhibitory signal to brainstem regions. In this design,

group difference existed in the striatum but not in the

DLPFC, suggesting that striatum structures are part of a

network that governs saccadic eye movement.

Language function in schizophrenia

Abnormal language function, in its many manifestations,

including thought disordered speech and verbal halluci-

nations, is a hallmark symptom of schizophrenia. It has

been proposed that abnormal lateralization of language

areas may be an underlying factor.

Functional lateralization for language was examined by

Sommer et al. [89 .]. Those investigators used a

lateralization index that was calculated for several areas

supporting language function (Table 4). Lower scores

on the lateralization index were found in schizophrenic

patients, which was due to increased activation in the

right hemisphere rather than to reduced activation in

the left hemisphere, suggesting an inefficiency in

inhibiting the nondominant hemisphere. The laterali-

zation index was also correlated with the severity of

hallucinations.

Figure 3. Semantic processing functional magnetic resonanceimaging study

z = 8 mm T value

4

3.5

3

2.5

2

1.5

1

0.5

0

Results are shown for a semantic processing functional magneticresonance imaging study. The axial image shows difference in activationin the left inferior prefrontal cortex (area in yellow) between nine controlindividuals and nine schizophrenia patients, which reflects groupdifferences in semantic encoding in a levels of processing paradigm.(Courtesy of Marek Kubicki.)


Table 4. Functional magnetic resonance imaging findings in schizophrenia

ReferenceParticipants(n)

Mean age(years)

Sex[male/female(n/n)] Task design Major findings

Executive and memory function studies

Barch [79..] SZ 38NC 48

SZ 36.3NC 36.5

SZ 24/14NC 23/25

WM and LTM tasks. Bothverbal and nonverbal stimuliwere presented within threetasks: WM-n-back task;encoding task; and recognitiontask. Block design; whole braincoverage

Impaired activation was found in SZ in theright DLPFC and the medial temporal lobefor both WM and LTM tasks. Otherregions found to have impaired activationduring both WM and LTM included basalganglia, thalamus, and parietal cortex.

Zorilla [80] SZ 8NC 10

SZ 54.2NC 61.9

SZ 3/5NC 8/2

Picture encoding andrecognition task

In NC, a negative correlation was foundbetween level of activation inparahippocampal gyrus and hippocampusfor the recognition task. In SZ, a positivecorrelation between the same variableswas found.

Ramsey [81] Exp 1: SZ 10;NC 10Exp 2: SZ (medi-cationnaı̈ve)11; NC 10

Exp 1: SZ 28.9;NC 24.1Exp 2: SZ 27.7;NC 28.4

Exp 1: SZ 9/1;NC 7/3Exp 2: SZ 8/3;NC 7/3

Logical reasoning, a version ofXT-task. Block design; wholebrain coverage

After correcting for performance, brainactivation was not different between NCand medicated SZ. In unmedicated SZ,brain activity was elevated relative to NC.

Paulus [82] SZ 15NC 15

SZ 41.7NC 41.0

All male Two-choice prediction task.Block design; whole braincoverage

No differences in activation were noted inthe right prefrontal cortex in SZ and NC.Less activation was found in inferior,medial prefrontal, and right superiortemporal gyrus in SZ. More activation wasalso found in right prefrontal and bilateralparietal cortex in medicated SZ relative tounmedicated SZ.

Honey [83] SZ 20NC 20

SZ 34.6NC 39.3

All male Verbal n-back task. Blockedperiodic BA design; whole braincoverage

No group difference was found inactivation levels in the prefrontal and parietalregions. A lack of correlation betweenreaction time and level of activation inparietal regions was found in SZ.

Rubia [84] SZ 6NC 7

SZ 40.0NC 40.0

All male Motor response inhibition stopand go/no-go tasks. Blockdesign; whole brain coverage

In both the stop and go/no-go tasks,reduced activation was observed in the leftanterior cingulate in SZ. During the stoptask, increased signal was observed in theright and left dorsomedial andventromedial thalamus, and right putamenin SZ.

Carter [85.] SZ 17NC 16

SZ 33.5NC 34.1

SZ 12/5NC 11/5

Error monitoring task. Subjectsdetected visual cues in eitherclear or degraded displayconditions in alternating blocks.Event-related design; wholebrain coverage

NC activated anterior cingulate, rightmedial frontal, and left posterior parietalcortex during error commission. No error-related increase in brain activity was foundin SZ.

Kumari [86] SZ 6NC 6

SZ 34.67NC 31.38

All male Procedural, sequence learningtask. Block design; whole braincoverage

Procedural learning was associated withactivation in the striatum, thalamus,cerebellum, precuneus, medial frontallobe, and cingulate gyrus in NC. In SZ,only anterior inferior gyrus was activated.

Saccadic eye movement studies

McDowell[87]

SZ 14NC 13

SZ 37.0NC 35.0

SZ 10/4NC 12/1

Refixation saccade and anti-saccade tasks. Block design;whole brain coverage

SZ patients did not show increasedDLPFC activation during the antisaccadetask as was observed in NC.

Raemaekers[88]

SZ 16NC 17

SZ 27.9NC 25.9

SZ 13/3NC 10/7

Occulomotor task: prosaccade,antisaccade, and active fixation.Event-related design; wholebrain coverage

Overall, activation was reduced in SZrelative to NC in all regions. The interactionbetween level of activation during theinhibitory task and illness was significantfor striatum only. SZ did not show theactivity in the striatum, which was presentin NC during antisaccade (inhibitoryactivity).

(continued opposite )

Schizophrenia140



Mean age(years)


Language studies

Sommer[89.]

SZ 12NC 12

SZ 27.0NC 28.0

All male Verb generation and semanticdecision reverse read task.Block design; whole braincoverage

Reduced language-laterality activation inthe SZ group was related to increasedactivation in the right hemisphere ratherthan to decreased activity in the lefthemisphere.

Kircher [90] SZ 6NC 6

SZ 34.3NC 34.0

All male Speech generation task.Seven Rorschach cards werepresented on the screenduring scanning and subjectswere asked to describe them.Event-related design; wholebrain coverage

In SZ, severity of thought disorder wascorrelated positively with activity in thecerebellar vermis, right body of caudate,and right precentral gyrus. Severity ofthought disorder was negativelycorrelated with left superior temporalgyrus, and the posterior part of middletemporal gyrus.

Kircher [91.] SZ 6NC 6

SZ 34.3NC 34.0

All male Speech generation task.Seven Rorschach cards werepresented on the screenduring scanning and subjectswere asked to describe them.Event-related design; wholebrain coverage

NC activated more the left, whereas SZactivated more the right middle temporalgyrus.

Lawrie [44] SZ 8NC 10

SZ 28.6NC 26.4

SZ 3/5NC 5/5

Sentence completion task.Block design; whole braincoverage

Bilateral activation of DLPFC and leftmiddle/superior temporal gyrus wasobserved in both groups. Functionalfrontotemporal connectivity wasdiminished in SZ.

Bentaleb [92] SZ 1NC 1

SZ 36NC 36

Female casestudy

Patient with auditoryhallucinations scanned duringhallucinations and whilelistening to external speech.Block design; whole braincoverage

Auditory verbal hallucinations wereassociated with increased activity in theleft primary auditory cortex and the rightmiddle temporal gyrus.

Shegrill [93] SZ 1 SZ 36 Male singlecase study

Single patient imaged duringsomatic and auditory verbalhallucinations. Event-related-likedesign; whole brain coverage

Somatic hallucinations were associatedwith activation in the primarysomatosensory and posterior parietalcortex, and auditory hallucinations wereassociated with middle and superiortemporal cortex activation.

Motor function studies

Kodama [74] SZ 9NC 10

SZ 23.2NC 24.9

SZ 6/3NC 6/4

Finger tapping task. Blockdesign. Slices coveringprefrontal cortex (axial slicesabove the corpus callosum)

Less activation was found in the premotorareas in SZ; after training, the activationlevel increased in the left premotor area inSZ and decreased in NC.

Muller [75] SZ(HA) 10SZ(OL) 10SZ(UN) 10NC 10

SZ(HA) 32.0SZ(OL) 30.2SZ(UN) 32.7NC 32.8

SZ(HA) 10SZ(OL) 10SZ(UN) 7/3NC 10

Finger tapping task. Blockdesign; whole brain coverage

Right premotor cortex, putamen, and leftcerebellum had higher activation inSZ(UN) than in NC. SZ(UN) exhibitedhigher level of activation than other treatedSZ patients across all regions studied.

Face and emotion processing studies

Kosaka [76] SZ 12NC 12

SZ 26.0NC 24.4

SZ 6/6NC 6/6

Facial emotional intensityjudgment task and the size of ageometric shape judgment task.Block design; coronal slicescovering amygdala only

Positive facial emotion identificationactivated the amygdala bilaterally in bothgroups, but greater activation of the rightamygdala was found in SZ relative to NC.Negative face emotion identification didnot produce group differences, butbilateral amygdala activation was found inSZ whereas only right amygdala activationwas found in NC.

Quintana [77] SZ 8NC 8

SZ 35.22NC 29.25

SZ 6/2NC 6/2

Visual-motor task of cue andstimulus matching with either acircle or a facial diagram. Blockdesign; axial slices superior tothe middle temporal lobe

Motor cortical areas involved in therepresentation and execution of facialmovement were activated in SZ onlyduring processing of facial expressions.



Two fMRI studies conducted by Kirscher and coworkers

[90,91 .] focused on thought disorder and its relationship

to brain activation. fMRI was performed while thought

disordered and normal control individuals talked about

Rorschach cards. In the control individuals the amount of

words articulated was positively correlated with activa-

tion in the left STG, whereas in the patients it was

correlated with activation in the right STG. Those

authors interpreted these results as evidence for

abnormal lateralization of areas involved in word retrieval

and speech planning and monitoring. They proposed

that relatively greater activation of the right STG in the

patients may directly contribute to loosening of associa-

tions, because the right STG is presumably involved in

generating broad semantic fields [103,104] whereas the

left STG is involved in maintaining narrow semantic

fields so that contextually inappropriate meanings are

suppressed early.

Functional correlates of auditory hallucinations

The relationship between auditory hallucinations and

functional connectivity between frontal and temporal

structures was examined in an fMRI study conducted by

Lawrie et al. [105 .]. Both patients and control individuals

showed equivalent levels of DLPFC activation in the

sentence completion task, but the functional correlation

coefficient between activity in left DLPFC and left

medial/superior temporal cortex was lower in the patient

group, and this correlation connectivity coefficient was

lower still in patients with hallucinations (Table 4). This

finding of abnormal connectivity between frontal and

temporal areas is in agreement with the findings of a

study conducted by Ford et al. [106].

A direct approach of mapping auditory hallucinations

onto brain regions was taken by Bentaleb et al. [92] in a

single case study. In that study a female patient with

schizophrenia was scanned while experiencing auditory

verbal hallucinations, and while listening to external

speech that eliminated the subjective experience of

auditory hallucinations. Experiencing auditory hallucina-

tions was associated with increased activity in the

primary auditory cortex and medial temporal gyrus.

Another single case was reported by Shegrill et al. [93],

who acquired fMRI signal during somatosensory and

auditory hallucinations. Somatosensory hallucinations

activated primary somatosensory and parietal cortices,

whereas auditory hallucinations activated the middle and

superior temporal cortex. Both of these studies sug-

gested that experiencing hallucinations in a given

modality (auditory or somatosensory) involves activation

of sensory areas that are normally involved in processing

sensory information in that modality.

Functional magnetic resonance imaging: a tool to study

the efficacy of clinical interventions

Wykes et al. [94.] used fMRI to study functional brain

changes after cognitive remediation therapy aimed at

improving information processing during working mem-

ory tasks. All individuals were scanned twice. Decreased

activation was found in normal individuals on repeat

scans, whereas increased activation of the right inferior

frontal gyrus was observed in schizophrenic patients,

especially those who underwent cognitive remediation

therapy (Table 4). Because no other measures such as

medication or symptom severity changed across the two

scanning sessions, the authors suggested that these



Mean age(years)


Drug and behavioral therapy efficacy studies

Wykes [94.] SZ(CRT) 6SZ(CT) 6NC 6

SZ(CRT) 35.0SZ(CT) 36.0NC 36.0

All male Two back, working memorytask, a vigilance task. Blockdesign; 10 axial slices in theanterior commissure-posteriorcommissure plane

As a result of cognitive remediationtherapy, increased values of FPQ werefound in SZ in right inferior frontal gyrus,and bilateral occipital cortex, and de-creased values of FPQ were found in NCin the left inferior/middle frontal gyrus, rightfrontal cortex, and right inferior frontalcortex.

Stephan [95.] SZ 6NC 6

SZ 25.8NC 27.5

SZ 5/1NC 5/1

Alternating finger tapping taskof the right and left hand.Subjects were scanned twice,3 weeks apart, with SZ beingmedicated at the 2nd scan.Block design; whole brain cov-erage

This study examined CFC as a function ofolanzapine treatment with seed voxelcorrelational analysis. Results suggest thatthere is a normalization of CFC afterolanzapine treatment.

CFC, cerebellum functional connectivity; DLPFC, dorsolateral prefrontal cortex; Exp, experiment; FPQ, fundamental power quotient; LTM, long-termmemory; NC, Normal control; SZ, schizophrenia; SZ(CT), SZ receiving cognitive therapy; SZ(CRT), SZ receiving cognitive remedial therapy; SZ(HA),SZ receiving haldol; SZ(OL), SZ receiving olanzapine; SZ(UN), untreated SZ; WM, working memory.

Schizophrenia142

results were attributable to practice and remediation

therapy benefits.

An interesting report from Stephan et al. [95 .] discussed

the role of olanzapine in ‘normalizing’ the functional

connectivity between cerebellar activity and thalamic

cortical circuitry during finger tapping in patients with

schizophrenia. Using seed voxel correlation analysis,

which was introduced by Horwitz and coworkers

[107,108], the study explored cerebellar functional

connectivity, and it was concluded that olanzapine

improved cerebellar functional connectivity for the right

but not for the left cerebellum (Table 4).

Summary

Continuing the tradition of more recent reports [109],

most studies reported during the past year used

activation paradigms that employed experimental de-

signs traditionally used in neuropsychology such as the

n-back task, verb generation or finger tapping, along with

clinical tools such as Rorschach cards. The experiments

were designed to identify which brain regions show

abnormal activation in tasks probing executive and

memory processes, language processes, and motor

function. The overwhelming number of studies suggests

that for any given task there is not a single abnormal

brain region that is related to abnormal function, but

instead there is a network of brain regions that are

affected and that, together, contribute to functional

abnormalities in schizophrenia. Abnormal connectivity

between temporal and frontal brain regions continues to

figure prominently in functional abnormalities in schizo-

phrenia. Importantly, some studies indicated that

patients with schizophrenia not only show a nonoptimal

activation in brain regions used by normal control

individuals in a given task, but they also might use

different brain regions, either as part of compensatory

mechanisms or faulty neural connections. Finally, as a

new development, a handful of studies used fMRI as a

tool to look at the efficacy of both medication and

behavior therapy interventions. This latter application of

fMRI will probably figure more prominently in future

studies, particularly in studies testing the efficacy of new

medications in targeting cognitive and clinical symptoms

in schizophrenia.

Diffusion tensor imagingDTI is another promising tool that permits further

examination of abnormal functional connectivity in

schizophrenia, and thus brings us closer to under-

standing schizophrenia as a disease of disconnections,

or disruptions, in important brain areas that work in

concert, and not in isolation, in cognition and behavior.

DTI is a relatively new technique that can be used to

visualize and measure the diffusion of water in brain

tissue, and it is particularly useful for evaluating white

matter abnormalities in the brain. Thus far seven DTI

studies have been conducted in schizophrenia [110–

115,116 ..] to investigate white matter abnormalities in

multiple brain regions, including prefrontal and temporal

white matter, corpus callosum, and uncinate fasciculus

(for review [10 ..]). Figure 4 shows a single coronal slice

of a tensor map (see left image; this map is primarily

used for visualization purposes) and an anisotropy map

(see right image; this map is used for diffusion

quantification), both of which were derived from DTI

data. Figure 5 shows the newest application of DTI,

namely in-vivo white matter fiber tractography, a

method that will render possible both dissection and

quantification of major white matter pathways in the

human brain in vivo.

In a recent study, Kubicki et al. [116..] used DTI to

examine the structural integrity of white matter tracks

(b)(a)

Figure 4. Diffusion tensor imaging

Coronal slices (4-mm thick) are shown that wereacquired on a 3 Tesla magnet using diffusiontensor imaging. These images are from a normalcontrol individual. (a) A diffusion tensor map, inwhich the blue lines represent the in-planecomponent of the diffusion (i.e. white matter fibertracts are traveling parallel to the acquisitionplane). The out-of-plane components of diffusionare color coded (from yellow to dark orange),and represent fibers that are perpendicular to theacquisition plane (i.e. the darker the color, thestronger the out-of-plane diffusion). (b) Afractional anisotropy map – a rotationallyindependent measure that is frequently used forquantifying diffusion. (Courtesy of MarekKubicki.)


of the uncinate fasciculus, the most prominent fiber

track that connects the frontal and temporal lobes.

Those investigators found a lack of normal left4right

asymmetry in a fractional anisotropy measure (a

measure of water diffusion within the fibers, and thus

an indirect measure of the integrity of the fibers) in

patients with schizophrenia as compared with normal

control individuals. Findings from that study are but

another piece of evidence in support of abnormal

connectivity patterns between the frontal and temporal

lobes in schizophrenia.

ConclusionThe picture emerging from current MRI and fMRI

research, as well as from the small number of DTI

studies thus far conducted, is that schizophrenia is a

brain disorder in which multiple areas are affected not in

a random manner but along the lines of functional

connectivity, with prominent roles played by both frontal

and temporal cortical structures, but also with involve-

ment of relevant subcortical brain regions. As new

experimental designs are informed by advances in

cognitive neuroscience, and new analytic techniques

optimize information that can be gleaned from fMRI

designs and from new advances in structural MRI and

DTI, the field of schizophrenia will be enriched with a

more comprehensive understanding of this devastating

disease. In the domain of fMRI research, advances in

analyzing fMRI data are important for meaningful

interpretation of results. Accordingly, future directions

should include careful experimental designs that afford a

better understanding of the neural connectivity involved

in supporting cognitive tasks. It is also becoming

apparent that medication status of patients is an

important factor, both as a potential confounding factor

and as a variable of interest with respect to the efficacy of

medication on cognitive tasks evaluated by fMRI, as

well as on possible neuroprotective effects with respect

to ameliorating possible changes in brain structure over

time as evaluated by structural MRI and DTI. Finally,

more studies are needed that evaluate relatives of

patients with schizophrenia in order to elucidate further

Figure 5. In-vivo three-dimensional fiber tractography of the human brain

An in-vivo three-dimensional fiber tractography ofthe human brain is shown, which was createdusing diffusion tensor imaging data. The dataused to create this three-dimensional modelwere acquired on a 3 Tesla magnet. (Courtesy ofHae Jong Park.)

Schizophrenia144

markers or genetic risk factors associated with brain

abnormalities in schizophrenia.

AcknowledgementsResearch by the authors and cited in the present review was supportedin part by the National Institute of Mental Health MH R01 50740 (MES),MH K02 01110 (MES), MH 63360 (MAN), by two VeteransAdministration Merit Awards (MES and MAN-Co-PI), and by aNARSAD Young Investigator Award (MK). The authors also wish toacknowledge Lisa Lucia for her assistance in getting the bibliographyand tables together, and Marie Fairbanks for her administrative support.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:. of special interest.. of outstanding interest

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These investigators apply VBM measures to elucidating cortical and subcorticalgray matter abnormalities in schizophrenia. This method will probably be importantin future structural and fMRI studies because it can be completed quickly in a largenumber of cases, in contrast with manual measurements, which are timeconsuming and restrict the number of cases that can be evaluated at any onetime. Moreover, multiple brain regions can be evaluated at once.

26 Chemerinski E, Nopoulos PC, Crespo-Facorro B, et al. Morphology of theventral frontal cortex in schizophrenia: relationship with social dysfunction.Biol Psychiatry 2002; 52:1–8.

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Chow EW, Zipursky RB, Mikulis DJ, Bassett AS. Structural brainabnormalities in patients with schizophrenia and 22q11 deletion syndrome.Biol Psychiatry 2002; 51:208–215.

This paper presents a study of patients with schizophrenia and 22q11 deletionsyndrome. By investigating known genetic disorders in which one outcome isschizophrenia-like symptoms, we may learn more about the genetic determinantsof schizophrenia.

28 Erbagci H, Yildirim H, Herken H, Gumusburun E. A magnetic resonanceimaging study of the adhesio interthalamica in schizophrenia. Schizophr Res2002; 55:89–92.

29 Falkai P, Honer WG, Alfter D, et al. The temporal lobe in schizophrenia fromuni- and multiply affected families. Neurosci Lett 2002; 325:25–28.

30. .

Goldstein JM, Seidman LJ, O’Brien LM, et al. Impact of normal sexualdimorphisms on sex differences in structural brain abnormalitiesin schizo-phrenia assessed by magnetic resonance imaging. Arch Gen Psychiatry2002; 59:154–164.

This paper investigates more than 22 brain regions using MRI, and it is a carefuland thoughtful study of the impact of normal sexual dimorphisms on sexdifferences in structural brain abnormalities in schizophrenia.

31 Hagino H, Suzuki M, Kurokawa K, et al. Magnetic resonance imaging studyof the cavum septi pellucidi in patients with schizophrenia. Am J Psychiatry2001; 158:1717–1719.

32 Meisenzahl EM, Zetzsche T, Preuss U, et al. Does the definition of borders ofthe planum temporale influence the results in schizophrenia? Am J Psychiatry2002; 159:1198–1200.

33 Meisenzahl EM, Rujescu D, Kimer A, et al. Association of an interleukin-1beta genetic polymorphism with altered brain structure in patients withschizophrenia. Am J Psychiatry 2001; 158:1316–1319.

34 Okugawa G, Sedvall GC, Agartz I. Reduced grey and white matter volumesin the temporal lobe of male patients with chronic schizophrenia. Eur ArchPsychiatry Clin Neurosci 2002; 252:120–123.

35 Rajarethinam R, DeQuardo JR, Miedler J, et al. Hippocampus and amygdalain schizophrenia: assessment of the relationship of neuroanatomy topsychopathology. Psychiatry Res 2001; 108:79–87.

36.

Suzuki M, Nohara S, Hagino H, et al. Regional changes in brain gray andwhite matter in patients with schizophrenia demonstrated with voxel-basedanalysis of MRI. Schizophr Res 2002; 55:41–54.

This paper uses VBM to evaluate regional changes in the brain in schizophrenia.Such methods will probably become more commonplace in future structural MRIstudies of schizophrenia.

37 Takahashi T, Kawasaki Y, Kurokawa K, et al. Lack of normal structuralasymmetry of the anterior cingulate gyrus in female patients with schizo-phrenia: a volumetric magnetic resonance imaging study. Schizophr Res2002; 55:69–81.


38 Velakoulis D, Stuart GW, Wood SI, et al. Selective bilateral hippocampalvolume loss in chronic schizophrenia. Biol Psychiatry 2001; 50:531–539.

39.

Wang L, Sarang C, Miller MI, Csernansky JG. Statistical analysis ofhippocampal asymmetry in schizophrenia. Neuroimage 2001; 14:531–545.

This paper uses a principal components analysis based on left–right asymmetryvector fields. It is a method that will probably become more commonplace in futurestructural MRI studies of schizophrenia.

40 Wible CG, Anderson J, Shenton ME, et al. Prefrontal cortex, negativesymptoms, and schizophrenia: an MRI study. Psychiatry Res 2001; 108:65–78.

41 Zuffante P, Leonard CM, Kuldau JM, et al. Working memory deficits inschizophrenia are not necessarily specific or associated with MRI-basedestimates of area 46 volumes. Psychiatry Res 2001; 108:187–209.

42 Yucel M, Stuart GW, Maruff P, et al. Paracingulate morphologic differencesin males with established schizophrenia: a magnetic resonance imagingmorphometric study. Biol Psychiatry 2002; 52:15–23.

43. .

Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A. Progressive brain volumechanges and the clinical course of schizophrenia in men: a longitudinalmagnetic resonance imaging study. Arch Gen Psychiatry 2001; 58:148–157.

This paper, published in February of 2001 and thus covering earlier data thanthose included in the present review (August 2001 to August 2002), presents acompelling finding of accelerated frontotemporal cortical gray matter decline andcortical sulcal and lateral ventricle enlargement in schizophrenia. Of note, severityof illness was associated with more accelerated changes over time. The latter maysuggest neurotoxicity of medication because higher doses of medication are oftenused in patients with more severe symptoms, or it might reflect the neurotoxicity ofpsychosis itself.

44 Lawrie SM, Whalley HC, Abukmeil SS, et al. Temporal lobe volume changesin people at high risk of schizophrenia with psychotic symptoms. Br JPsychiatry 2002; 181:138–143.

45.

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This study provides information concerning the possible effects of fetal hypoxia onstructural abnormalities in schizophrenia, in the siblings of patients withschizophrenia, and control individuals.

46 Harris JG, Young DA, Rojas DC, et al. Increased hippocampal volume inschizophrenics’ parents with ancestral history of schizophrenia. SchizophrRes 2002; 55:11–17.

47 Narr KL, Cannon TD, Woods RP, et al. Genetic contributions to alteredcallosal morphology in schizophrenia. J Neurosci 2002; 22:3720–3729.

48.

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This paper, similar to that of Seidman et al. [49..], provides important newinformation regarding amygdala–hippocampal volume and deficits in verbalmemory in the first-degree relatives of patients with schizophrenia.

49. .

Seidman LJ, Faraone SV, Goldstein JM, et al. Left hippocampal volume as avulnerability indicator for schizophrenia: a magnetic resonance imagingmorphometric study of nonpsychotic first-degree relatives. Arch GenPsychiatry 2002; 59:839–849.

This paper focuses on MRI findings in the nonpsychotic first-degree relatives ofpatients with schizophrenia. It is one of the first studies to use high spatialresolution MRI to investigate a very understudied but important group of individuals– the relatives of patients with schizophrenia. Of note, the investigators foundreduced hippocampal volume in the relatives, suggesting that hippocampal volumemay be a vulnerability indicator for schizophrenia.

50 Steel RM Whalley HC, Miller P, et al. Structural MRI of the brain in presumedcarriers of genes for schizophrenia, their affected and unaffected siblings. JNeurol Neurosurg Psychiatry 2002; 72:455–458.

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Van Erp TGM, Saleh PA, Rosso IM, et al. Contributions of genetic risk andfetal hypoxia to hippocampal volume in patients with schizophrenia orschizoaffective disorder, their unaffected siblings, and healthy unrelatedvolunteers. Am J Psychiatry 2002; 159:1514–1520.

This paper provides important information about genetic risk and fetal hypoxia andits association with hippocampal volume reduction in patients with schizophreniaand their unaffected siblings.

52 James AC, Iavaloyes A, James S, Smith DM. Evidence for non-progressivechanges in adolescent-onset schizophrenia: follow-up magnetic resonanceimaging study. Br J Psychiatry 2002; 180:339–344.

53 Levitt JG, Blanton RE, Rochelle C, et al. Medial temporal lobe in childhood-onset schizophrenia. Psychiatry Res 2001; 108:17–27.

54 Matsumoto H, Simmons A, Williams S, et al. Superior temporal gyrusabnormalities in early-onset schizophrenia: similarities and differences withadult-onset schizophrenia. Am J Psychiatry 2001; 158:1299–1304.

55. .

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This paper presents a new method for mapping brain changes over time andreveals a quite dynamic change of accelerated gray matter loss in very earlyschizophrenia.

56 McCreadie RG, Thara R, Padmavati R, et al. Structural brain differencesbetween never-treated patients with schizophrenia, with and withoutdyskinesia, and normal control subjects: a magnetic resonance imagingstudy. Arch Gen Psychiatry 2002; 59:332–336.

57 Andreasen NC, Arndt S, Swayze V, et al. Thalamic abnormalities inschizophrenia visualized through magnetic resonance image averaging.Science 1994; 266:294–298.

58 Gilbertson MW, Shenton ME, Ciszewski A, et al. Smaller hippocampalvolume predicts pathologic vulnerability to psychological trauma. NatNeurosci 2002; 5:1242–1247.

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60 Mehler C, Warnke A. Structural brain abnormalities specific to childhood-onset schizophrenia identified by neuroimaging techniques. J Neural Transm2002; 109:219–234.

61 Cahn W, Hulshoff Pol HE, Bongers M, et al. Brain morphology inantipsychotic-naive schizophrenia: a study of multiple brain structures. Br JPsychiatry Suppl 2002; 43:S66–S72.

62 Salokangas RKR, Cannon T, Van Erp T, et al. Structural magnetic resonanceimaging in patients with first-episode schizophrenia, psychotic and severenon-psychotic depression and healthy controls: Results of the Schizophreniaand Affective Psychoses (SAP) project. Br J Psychiatry 2002; 181 (suppl43):S58–S65.

63 Frumin M, Golland P, Kikinis R, et al. Shape differences in the corpuscallosum in first-episode schizophrenia and first-episode psychotic affectivedisorder. Am J Psychiatry 2002; 159:866–868.

64 Gunduz H, Wu H, Ashtari M, et al. Basal ganglia volumes in first-episodeschizophrenia and healthy comparison subjects. Biol J Psychiatry 2002;51:801–808.

65 Joyal CC, Laakso MP, Tiihonen J, et al. A volumetric MRI study of theentorhinal cortex in first episode neuroleptic-naive schizophrenia. BiolPsychiatry 2002; 51:1005–1007.

66 Keshavan MS, Diwadkar VA, Harenski K, et al. Abnormalities of the corpuscallosum in first episode, treatment naive schizophrenia. J Neurol NeurosurgPsychiatry 2002; 72:757–760.

67. .

McCarley RW, Salisbury DF, Hirayasu Y, et al. Association between smallerleft posterior superior temporal gyrus volume on magnetic resonance imagingand smaller left temporal P300 amplitude in first-episode schizophrenia. ArchGen Psychiatry 2002; 59:321–331.

This study documents smaller posterior STG volume and smaller left temporalP300 in first episode patients with schizophrenia, which is not evident in firstepisode affective psychotic patients, suggesting that these anomalies are presentat first episode of illness and may be quite specific to schizophrenia.

68 Sumich A, Chitnis XA, Fannon DG, et al. Temporal lobe abnormalities in first-episode psychosis. Am J Psychiatry 2002; 159:1232–1235.

69 Szeszko PR, Strous RD, Goldman RS, et al. Neuropsychological correlatesof hippocampal volumes in patients experiencing a first episode ofschizophrenia. Am J Psychiatry 2002; 159:217–226.

70.

Lee CU, Shenton ME, Salisbury DF, et al. Fusiform gyrus volume reduction infirst-episode schizophrenia: a magnetic resonance imaging study. Arch GenPsychiatry 2002; 59:775–781.

This study is among the first to show fusiform gyrus volume reduction in firstepisode schizophrenia. Because fusiform is related to human face perception, thisfinding may underlie problems that patients with schizophrenia experience withsocial cues and interpreting facial emotions.

71 Wood SJ, Velakoulis D, Smith DJ, et al. A longitudinal study of hippocampalvolume in first episode psychosis and chronic schizophrenia. Schizophr Res2001; 52:37–46.

72 Cohen MS. Parametric analysis of fMRI data using linear systems methods.Neuroimage 1997; 6:93–103.

73 Cohen MS, DuBois RM. Stability, repeatability, and the expression of signalmagnitude in functional magnetic resonance imaging. J Magn Reson Imaging1999; 10:33–40.

74 Kodama S, Fukuzako H, Fukuzako T, et al. Aberrant brain activation followingmotor skill learning in schizophrenic patients as shown by functional magneticresonance imaging. Psychol Med 2001; 31:1079–1088.

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75 Muller JL, Roder C, Schuierer G, Klein HE. Subcortical overactivation inuntreated schizophrenic patients: a functional magnetic resonance imagefinger-tapping study. Psychiatry Clin Neurosci 2002; 56:77–84.

76 Kosaka H, Omori M, Murata T, et al. Differential amygdala response duringfacial recognition in patients with schizophrenia: an fMRI study. SchizophrRes 2002; 57:87–96.

77 Quintana J, Davidson T, Kovalik E, et al. A compensatory mirror corticalmechanism for facial affect processing in schizophrenia. Neuropsychophar-macology 2001; 25:915–924.

78. .

Weinberger DR, Egan MF, Bertolino A, et al. Prefrontal neurons and thegenetics of schizophrenia. Biol Psychiatry 2001; 50:825–844.

This paper presents a thorough and persuasive argument for the role of prefrontalcortex, and the role of catechol-O-methyl-transferase val allele in increasing the riskfor schizophrenia.

79. .

Barch DM, Csernansky JG, Conturo T, Snyder AZ. Working and long-termmemory deficits in schizophrenia: Is there a common prefrontal mechanism? JAbnorm Psychol 2002; 111:478–494.

This is a very good study conducted in a large number of individuals that carefullylooked at the contributions of prefrontal and temporal structures in workingmemory and long-term memory task, concluding that both of those structures areinvolved in supporting cognitive subroutines.

80 Zorrilla LTE, Jeste DV, Brown GG. Functional MRI and novel picture-learningamong older patients with chronic schizophrenia: abnormal correlationsbetween recognition memory and medial temporal brain response. Am JGeriatr Psychiatry 2002; 10:52–61.

81 Ramsey NF, Koning HA, Welles P, et al. Excessive recruitment of neuralsystems subserving logical reasoning in schizophrenia. Brain 2002;125:1793–1807.

82 Paulus MP, Hozack NE, Zauscher BE, et al. Parietal dysfunction isassociated with increased outcome-related decision-making in schizophreniapatients. Biol J Psychiatry 2002; 51:995–1004.

83 Honey GD, Bullmore ET, Sharma T. De-coupling of cognitive performanceand cerebral functional response during working memory in schizophrenia.Schizophr Res 2002; 53:45–56.

84 Rubia K, Russell T, Bullmore ET, et al. An fMRI study of reduced leftprefrontal activation in schizophrenia during normal inhibitory function.Schizophr Res 2001; 52:47–55.

85.

Carter CS, MacDonald AW, Ross LL, et al. Anterior cingulate cortex activityand impaired self-monitoring of performance in patients with schizophrenia:an event-related fMRI study. Am J Psychiatry 2001; 158:1423–1428.

This interesting study examined the role of ACC in error monitoring and relatedreduced activation in the ACC to reduced error sensitivity in schizophrenia.

86 Kumari V, Gray JA, Honey GD, et al. Procedural learning in schizophrenia: afunctional magnetic resonance imaging investigation. Schizophr Res 2002;57:97–108.

87 McDowell JE, Brown GG, Paulus M, et al. Neural correlates of refixationsaccades and antisaccades in normal and schizophrenia subjects. BiolPsychiatry 2002; 51:216–223.

88 Raemaekers M, Iansma JM, Cahn W, et al. Neuronal substrate of thesaccadic inhibition deficit in schizophrenia investigated with 3-dimensionalevent-related functional magnetic resonance imaging. Arch Gen Psychiatry2002; 59:313–320.

89.

Sommer IE, Ramsey NF, Kahn RS. Language lateralization in schizophrenia,an fMRI study. Schizophr Res 2001; 52:57–67.

This interesting study addressed the issue of functional laterality in schizophrenia.

90 Kircher TT, Liddle PF, Brammer MJ, et al. Neural correlates of formal thoughtdisorder in schizophrenia: preliminary findings from a functional magneticresonance imaging study. Arch Gen Psychiatry 2001; 58:769–774.

91.

Kircher TT, Liddle PF, Brammer MJ, et al. Reversed lateralization of temporalactivation during speech production in thought disordered patients withschizophrenia. Psychol Med 2002; 32:439–449.

This study, in spite of the small number of individuals studied, offers an interestingexplanation for language associative dysfunction in schizophrenia.

92 Bentaleb LA, Beauregard M, Liddle P, Stip E. Cerebral activity associatedwith auditory verbal hallucinations: a functional magnetic resonance imagingcase study. J Psychiatry Neurosci 2002; 27:110—115.

93 Shegrill SS, Cameron LA, Brammer MI, et al. Modality specific neuralcorrelates of auditory and somatic hallucinations. J Neurol NeurosurgPsychiatry 2001; 71:688–690.

94.

Wykes T, Brammer M, Mellers J, et al. Effects on the brain of a psychologicaltreatment: cognitive remediation therapy: functional magnetic resonanceimaging in schizophrenia. Br J Psychiatry 2002; 181:144–152.

This is an interesting example of using fMRI to study the effects of behavioralcognitive therapy.

95.

Stephan KE, Magnotta VA, White T, et al. Effects of olanzapine on cerebellarfunctional connectivity in schizophrenia measured by fMRI during a simplemotor task. Psychol Med 2001; 31:1065–1078.

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96 Fletcher PC, McKenna PJ, Frith CD, et al. Brain activations in schizophreniaduring a graded memory task studied with functional neuroimaging. Arch GenPsychiatry 1998; 55:1001–1008.

97 Manoach DS, Press DZ, Thangaraj V, et al. Schizophrenic subjects activatedorsolateral prefrontal cortex during a working memory task, as measured byfMRI. Biol Psychiatry 1999; 45:1128–1137.

98 Weinberger DR, Berman KF, Zec RF. Physiological dysfunction ofdorsolateral prefrontal cortex in schizophrenia, 1: regional cerebral bloodflow evidence. Arch Gen Psychiatry 1986; 43:114–124.

99 Nieman DH, Bour LJ, Linszen DH, et al. Neuropsychological and clinicalcorrelates of antisaccade task performance in schizophrenia. Neurology2000; 54:866–871.

100 Park S, Holzman PS. Association of working memory deficit and eye trackingdysfunction in schizophrenia. Schizophr Res 1993; 11:55–61.

101 Nakashima Y, Momose T, Sano I, et al. Cortical control of saccade in normaland schizophrenic subjects: a PET study using a task-evoked rCBFparadigm. Schizophr Res 1994; 12:259–264.

102 Crawford TJ, Puri BK, Nijran KS, et al. Abnormal saccadic distractability inpatients with schizophrenia: a 99mTc-HMPAO SPET study. Psychol Med1996; 155:1703–1710.

103 Faust M. Chiarello C. Sentence context and lexical ambiguity resolution bythe two hemispheres. Neuropsychologia 1998; 36:827–835.

104 Beeman M, Friedman RB, Grafman J, et al. Summation priming and coarsesemantic coding in the right hemisphere. J Cogn Neurosci 1994; 6:26–45.

105.

Lawrie SM, Buechel C, Whalley HC, et al. Reduced frontotemporalfunctional connectivity in schizophrenia associated with auditory hallucina-tions. Biol Psychiatry 2002; 51:1008–1011.

In spite of the limited number of individuals assessed, this interesting study showsboth lack of hypofrontality in a task in which both groups performed at acomparable level, and evidence for abnormal fronto-temporal connectivity in thepatients, especially in those who were hallucinating.

106 Ford JD, Mathalon DH, Whitfield S, et al. Reduced communication betweenfrontal and temporal lobes during talking in schizophrenia. Biol Psychiatry2002; 51:485–492.

107 Horwitz B, Duara R, Rapoport SI. Inter-correlations of glucose metabolicrates between brain regions: application to healthy males in the state ofreduced sensory input. J Cereb Blood Flow Metab 1984; 4:484–499.

108 Horwitz B, Rumsey JM, Donohue BC. Functional connectivity of angulargyrus in normal reading and dyslexia. Proc Natl Acad Sci USA 1998;95:8939–8944.

109 Hofer A, Weiss EM. Advances in the neuroimaging of cognitive functions inschizophrenia. Curr Opin Psychiatry 2002; 15:3–7.

110 Buchsbaum MS, Tang CY, Peled S, et al. MRI white matter diffusionanisotropy and PET metabolic rate in schizophrenia. NeuroReport 1998;9:425–430.

111 Lim KO, Hedehus M, Moseley M, et al. Compromised white matter tractintegrity in schizophrenia inferred from diffusion tensor imaging. Arch GenPsychiatry 1999; 56:367–374.

112 Foong J, Maier M, Clark CA, et al. Neuropathological abnormalities of thecorpus callosum in schizophrenia: a diffusion tensor imaging study. J NeurolNeurosurg Psychiatry 2000; 68:242–244.

113 Foong MR, Symms GJ, Barker M, et al. Investigating regional white matter inschizophrenia using diffusion tensor imaging. NeuroReport 2002; 13:333–336.

114 Agartz I, Andersson JL, Skare S. Abnormal brain white matter inschizophrenia: a diffusion tensor imaging study. NeuroReport 2001;12:2251–2254.

115 Steel RM, Bastin ME, McConnell S, et al. Diffusion tensor imaging (DTI) andproton magnetic resonance spectroscopy (1H MRS) in schizophrenicsubjects and normal controls. Psychiatry Res 2001; 106:161–170.

116. .

Kubicki M, Westin CF, Maier S, et al. Uncinate fasciculus findings inschizophrenia: a magnetic resonance diffusion tensor imaging study. Am JPsychiatry 2002; 159:813–820.

This interesting study used DTI to examine the largest white matter fiber tractconnecting the frontal and temporal lobe, namely the uncinate fasciculus. Findingsof abnormal asymmetry suggest that fronto-temporal connections may bedisrupted in schizophrenia.


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