Prefrontal Structural and Functional Deficits in

Schizotypal Personality Disorder

by Adrian Raine, Todd Lencz, Pauline Yaralian, Susan Bihrle, Lori LaCasse,
Joseph Ventura, and Patrick Colletti

Structural prefrontal deficits have been reported in

patients with schizophrenia, but it is unclear if they
are also found in patients with schizophrenia spectrum personality disorders. The hypothesis that a
spectrum group will be characterized by prefrontal
structural deficits was tested by assessing prefrontal
gray and white volumes using magnetic resonance
imaging in a community sample of 16 individuals
with schizotypal/paranoid personality disorder, 27
comparisons, and 26 psychiatric controls. Frontal
neurocognitive functioning was also assessed using
the Wisconsin Card Sorting Test and the Continuous
Performance Test. The spectrum group showed
reduced prefrontal gray volumes and poorer frontal
functioning compared to both other groups.
Structural deficits were independent of functional
deficits and together correctly classified 84.2 percent
of subjects. Structural but not functional deficits
were abolished after a strict control for antisocial
personality was made. Results support the notion
that frontal deficits may be centrally involved in the
etiology of schizophrenia but also suggest that
comorbid antisocial behavior may be one factor
accounting for differences in prefrontal structural
findings across studies.
Keywords: Schizotypal, paranoid, prefrontal
gray, MRI, antisocial.
Schizophrenia Bulletin, 28(3):501-513, 2002.
Quantitative magnetic resonance imaging (MRI) studies
have found evidence for frontal structural deficits in
schizophrenia (Zakzanis and Heinrichs 1999; Yaralian
and Raine 2000). These imaging studies are about
equally divided in either showing reductions in total volume (gray and white) or area of the frontal/prefrontal
region (e.g., Andreasen et al. 1986, 1994; Raine et al.
1992*; Nopoulos et al. 1995) or failing to find these
reductions (Andreasen et al. 1990; Bilder et al. 1994;
Szeszko et al. 1999). Another study found prefrontal

Send reprint requests to Dr. A. Raine, Department of Psychology,

University of Southern California, Los Angeles, CA 90089-1061; email: raine@usc.edu.

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volume deficits in schizophrenia patients compared to

normal controls, but not when compared to chronic alcoholics (Sullivan et al. 1998), while one review reports
preliminary findings failing to observe reduced prefrontal volume in schizotypal patients (Siever et al.
2002). The significance, in part, of such frontal deficits,
if they truly exist, is that they may help account for the
functional frontal deficits repeatedly observed in schizophrenia (Buchsbaum 1990; Cannon 1996; Weinberger
and Berman 1998).
Some of these structural MRI studies have further
segmented gray from white matter within the frontal or
prefrontal region, with mixed results. Four studies found
reductions in prefrontal gray but not white matter
(Zipursky et al. 1992; Lim et al. 1995; Lim et al. 1996;
Sullivan et al. 1998), one study that assessed only gray
matter found a reduction in the dorsolateral region
(Schlaepfer et al. 1994), three studies found significant
reductions in white but not gray matter (Breier et al.
1992; Buchanan et al. 1993; Buchanan et al. 1998), and
two studies failed to find differences in gray or white
matter (Suddath et al. 1989; Wible et al. 1995). In contrast to these conflicting structural findings, at a functional level hypofrontality is one of the best replicated
imaging correlates of schizophrenia (Velakoulis and
Pantelis 1996). Compelling evidence also exists from
the neuropsychological literature for executive function
and working memory deficits in schizophrenia patients
(Park et al. 1995), with strong overall effect sizes across
studies of 0.88 for the Wisconsin Card Sorting Test
(WCST; 43 studies) and 1.16 for the Continuous Performance Test (CPT; 14 studies) (Heinrichs and Zakzanis 1998).
Further evidence for the etiologic significance of prefrontal structural deficits comes from the study of schizophrenia spectrum disorders. Spectrum disorders have traditionally encompassed the DSM "odd cluster" of

Abstract

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

A. Raine et al.

502

schizotypal personality have rarely if ever included a psychiatric control group. Similarly, despite the importance of
establishing psychiatric specificity for structural brain
deficits in schizophrenia, the majority of structural and
functional MRI studies of schizophrenia do not employ
psychiatric control groups. For example, a survey found
that of the 28 MRI studies on schizophrenia published in
the American Journal of Psychiatry between 1996 and
2000, only 3 (10.7%) employed a psychiatric control
group. Similarly, only 2 of 15 studies (13.3%) published in

Archives of General Psychiatry in this time period

employed a psychiatric control group, while for Schizophrenia Research only 2 of 14 studies (14.3%) employed
psychiatric controls. Furthermore, studies that do use psychiatric controls frequently control for only one experimental-group source of comorbidity that could confound
findings; they do not control for the full range of comorbid
disorders that are higher in the experimental group. It
remains to be seen, therefore, whether a schizophrenia
spectrum group would differ from a psychiatric control
group matched on other Axis I and II disorders.
The primary goal of the current study was to test the
hypothesis that individuals with schizophrenia spectrum
disorders would show a reduction in prefrontal gray volume compared to both comparisons and psychiatric controls. It was also predicted that the spectrum group would
show functional neurocognitive deficits as indicated by the
WCST and the CPT and that these deficits would be predicated on the structural prefrontal deficits.

Method
Subjects. All subjects were drawn from five temporary
employment agencies in Los Angeles. This recruitment
source was chosen because pilot data showed that these
individuals had higher rates of schizotypal personality and
because the one prior study of prefrontal structural deficits
in schizotypy had also employed a community sample.
All subjects who wished to participate in the study were
allowed to do so without prior screening. Subject groups
consisted of 27 comparisons, 26 psychiatric controls, and
16 participants with a diagnosis of either schizotypal personality disorder or paranoid personality disorder
(referred to hereafter as the spectrum group). The spectrum group consisted of 10 individuals with schizotypal
personality disorder only, 4 individuals with paranoid personality disorder only, and 2 individuals with both schizotypal and paranoid personality disorder. Demographic,
cognitive, and physical measures for the three groups are
shown in table 1. Exclusion criteria were as follows: age
under 21 or over 45, nonfluency in English, history of
epilepsy, claustrophobia, pacemaker, or metal implant.
Screening of brain scans by a neuroradiologist blind to

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schizotypal, paranoid, and schizoid personality disorders

(Siever et al. 1993), although the inclusion of schizoid personality disorder has been questioned by some researchers
on the grounds that it lacks genetic relatedness with schizophrenia (Nigg and Goldsmith 1994; Torgersen 1994;
Ingraham 1995). Spectrum individuals have a stable
(schizotypal and paranoid) personality disorder with a history of disturbances in cognition, perception, and behavior
that in part mirror abnormalities found in schizophrenia
patients. Research on such individuals provides a valuable
adjunct to research on institutionalized schizophrenia
patients. To the extent that the same neurobiological correlates of schizophrenia can also be observed in individuals
with schizophrenia spectrum disorders who are free of the
confounds of institutionalization, medication, and labeling, there is increased confidence that such processes may
be of etiologic significance for schizophrenia. In contrast,
only one MRI study appears to have tested whether
schizotypal personality is related to prefrontal structural
deficits; Raine et al. (1992ft) showed that community volunteers with higher scores on self-report schizotypal personality measures had both smaller prefrontal areas and
more perseveration errors on the WCST.
Although most other imaging studies of schizotypal personality have focused on ventricular size (Cannon et al.
1994) or temporal lobe volumes (Dickey et al. 1999; Downhill et al. 2000), two additional studies of schizotypal personality disorder have relevance to the question of frontal structural deficits. Buchsbaum et al. (1997) found that patients
with schizotypal personality disorder showed an enlargement of the left anterior horn of the lateral ventricle that was
intermediate in size between that of normal controls and
schizophrenia patients. Enlargement of the anterior hom of
the lateral ventricle is suggestive of tissue loss (especially of
white matter) in the frontal lobe. Conversely, Siever et al.
(1995) failed to find significant differences between anterior
horn size in schizotypal patients, schizophrenia patients, and
controls. MRI studies of frontal volume in children with
schizophrenia spectrum symptoms (who may be viewed as
analogues of schizotypy) (Yeo et al. 1997) and childhoodonset schizophrenia (Frazier et al. 1996) have also found null
results. In contrast, frontal functional deficits represent the
best replicated correlate of schizotypal personality. Specifically, frontal functional deficits have been repeatedly and
replicably found on the WCST and the CPT with respect to
both schizotypal personality disorder and individual differences in schizotypal personality, with at least 14 studies
obtaining significant effects (e.g., Lyons et al. 1991;
Battaglia et al. 1994; Lenzenweger and Korfune 1994; Trestman et al. 1995; Roitman et al. 1997; Voglmaier et al. 1997;
Daneluzzo et al. 1998).
An important methodological issue in the literature is
that studies of structural and functional frontal deficits in

Prefrontal Structural and Functional Deficits

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

Table 1. Characteristics of the study groups

Schizophrenia
spectrum
(n = 16)

Statistics

Demographic
Sex, % male
Age, yrs, mean (SD)
Social class, mean (SD)
Ethnicity, % white
Cognitive and physical
Estimated intelligence,
mean (SD)
Handedness, mean (SD)1
Height (cm), mean (SD)
Weight (kg), mean (SD)
Head circumference (in.),
mean (SD)
History of head injury, %

85.2
30.9 (6.9)
35.3(10.3)
57.1

88.5
29.0 (6.6)
36.6(11.5)
38.5

87.5
32.1 (5.4)
33.9(10.9)
43.8

X2 = 0.9, df=2, p=0.95

F (2,67) = 1.2, p = 0.31
F (2,67) = 0.3, p = 0.72
X2 = 2.0, df=2, p=0.37

101.7(14.9)

97.8(13.1)

94.5(13.1)

F (2,67) = 0.4, p = 0.68

33.8 (9.8)
175.9(7.9)
80.8(15.0)
57.6(2.1)

33.5 (10.5)
179.7(9.1)
80.9(15.7)
57.2(1.7)

35.2 (9.6)
176.5(10.8)
78.7(11.6)
57.1 (2.3)

F
F
F
F

39.3

38.5

37.5

X2 = 0.01,ctf=2, p = 0.99

(2,67)
(2,67)
(2,67)
(2,67)

= 0.2, p = 0.86
= 1.3, p = 0.27
= 0.15, p = 0.86
= 1.5, p = 0.39

Note.SD = standard deviation.

1
High scores indicate greater degree of right-handedness.

group membership resulted in one subject being excluded

from analyses because of encephalomalasia, consisting of
significant atrophy to the right temporal and frontal cortex. Subjects were paid $5.50 per hour for participation
and were informed that the study concerned the biological
basis of personality and behavior problems, including
criminal behavior. After subjects were given complete
descriptions of the study, written informed consent was
obtained in accordance with Institution Review Board
procedures at the University of Southern California.
The comparison group consisted of participants without a diagnosis of schizophrenia, psychotic disorders,
schizophrenia spectrum disorders, or substance or alcohol
dependence. A psychiatric control group was formed from
a total of 63 other volunteers to obtain as close a match as
possible for the comorbid conditions found in the spectrum group. Results of this matching are shown in table 2
for affective and anxiety disorders, conduct and antisocial
personality disorders, and Cluster B and C personality disorders. There were no significant differences between
groups, using %2 (p > 0-35 in all cases), with the only trend
for significance being the psychiatric controls having
slightly higher rates of Cluster C personality disorders
than the spectrum group. However, there was a nonsignificantly higher rate of comorbidity for antisocial personality
disorder in the spectrum group (50.0%) than in the psychiatric controls (38.5%). Furthermore, the spectrum group
(mean [M] = 9.4, standard deviation [SD] = 4.1) had significantly higher scores on a dimensional measure of antisocial personality disorder (see below) compared to both
psychiatric controls (M = 6.7, SD = 3.5; / = 2.2, df= 40, p

503

= 0.033) and comparisons (M = 3.7, SD = 2.4; t = 5.7, df=

41, p = 0.0001).
Because substance and alcohol use could be a confound in structural brain imaging correlates of schizophrenia spectrum disorders, details of rates of alcohol and substance abuse/dependence, together with past month usage,
are given for the psychiatric control and spectrum groups
in table 3. Similarly, quantity and frequency of alcohol
usage for these groups are given in table 4. There were no
significant group differences.

Diagnostic, Cognitive, Physical, and Psychosocial

Assessment. Diagnoses were made using DSM-IV criteria (American Psychiatric Association 1994) and ascertained using the Structured Clinical Interview for
DSM-IV Axis I Disorders (First et al. 1994a) and the
Structured Clinical Interview for DSM-IV Axis II
Personality Disorders (SCID-II, First et al. 1994fc).
Diagnoses were made by advanced clinical psychology
Ph.D. students who had undergone a standardized training
and quality assurance program for diagnostic assessment
(Ventura et al. 1998). Prior to diagnostic assessments on
the study sample, diagnostic procedures were piloted on
subjects also drawn from temporary employment agencies
and interview tapes assessed jointly by J.V., A.R., and
T.L. In addition to diagnostic testing, an alcohol use questionnaire to assess frequency of alcohol consumption was
completed by participants. A dimensional measure of antisocial personality disorder was created by summing
scores of the seven DSM-IV criterion C symptoms of the
SCID-n.

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C = 27)

Psychiatric
control
(n = 26)

Comparison

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

A. Raine et al.

Table 2. Rates of psychiatric disorder in the psychiatric control and schizophrenia spectrum groups,
together with %2 analyses
Psychiatric
control
(n = 26)
1

Schizophrenia
spectrum
(n=16)

x2

df

0.88

53.8

56.3

0.02

Anxiety2

19.2

18.8

0.00

0.97

Conduct disorder

53.8

50.0

0.06

0.81

Antisocial personality disorder

38.5

50.0

0.54

0.46

15.4

25.5

0.59

0.44

Cluster C 4

15.4

0.0

2.70

0.10

Affective

Cluster B

3
4

Major depression, bipolar depression, other depressive disorders.

Phobia, panic, generalized anxiety.
Borderline, histrionic, obsessive-compulsive.
Avoidant, dependent, narcissistic.

Estimated intelligence was based on the five subtests

(vocabulary, arithmetic, digit span, digit symbol, block
design) of the Wechsler Adult Intelligence Scale-Revised
(Wechsler 1981). Degree of right versus left hand preference
was assessed using the abbreviated Oldfield Inventory (Bryden 1977). History of head injury was defined as head
trauma resulting in hospitalization. Social class was measured using the Hollingshead classification system (Hollingshead 1975). A physical examination was conducted to
derive measures of height, weight, and head circumference.

categories completed, and trials to achieve the first category were computed.
MRI. Full details of MRI assessments are given in Raine
et al. (2000). Structural MRIs were conducted on a Philips
S15/ACS (Selton/Conn) scanner with a magnet of 1.5
Tesla field strength. Following an initial alignment
sequence of one midsagittal and four parasagittal scans
(spin-echo Tl-weighted image acquisition, repetition time
[TR] = 600 ms, time to echo [TE] = 20 ms) to identify the
anterior commissure-posterior commissure (AC-PC)
plane, 128 three-dimensional Tl-weighted gradient-echo
coronal images (TR 34 ms, TE 12.4 ms, flip angle 35, 1.7
mm over contiguous slices, 256 X 256 matrix, field of
view [FOV] = 23 cm) were taken in the plane directly
orthogonal to the AC-PC line.
Brain images were reconstructed in three dimensions
using a SPARC workstation and semiautomated CAMRA
S200 ALLEGRO software used for gray/white/cerebrospinal fluid (CSF) segmentation. Segmentation of gray
and white matter was performed using a thresholding
algorithm, with the operator blind to group membership
applying a cutoff value to the signal intensity histogram to
optimally differentiate white from gray, areas of which
were defined using an automated seeding algorithm on
each slice. Further details of the algorithm are reported in
Raine et al. (2000).
Following our earlier study (Raine et al. 1992a), the
frontal region was defined as all cortex anterior to the genu
of the corpus callosum and divided into left and right
hemispheres along the longitudinal fissure. Interrater reliability (intraclass correlation coefficient) based on 23 scans
(raters blind to each other's ratings and group member-

Neurocognitive Measures of Frontal Functioning

CPT. Version 4.08 of the degraded stimulus version
of the CPT (Nuechterlein et al. 1983) was administered
according to author guidelines. Visually degraded numbers ranging from 0 to 9 were flashed on a computer
screen (placed 1 meter from the subjects in the subjects'
line of vision) for 40 ms at the rate of one per second. The
subjects' task was to press a response button on a Gravis
joystick every time they saw the figure "0" but to not
respond to all other stimuli. Targets had a 0.25 probability
of occurrence. After 10 presentations of the target stimulus only, subjects were given 120 practice trials after
which 480 test stimuli (lasting 8 minutes) were presented.
Hits, false alarms, sensitivity, and response bias scores
were computed.
WCST. A computerized version of the WCST (Grant
and Berg 1948) was administered in which subjects sorted
a pack of 64 cards according to color, shape, and number.
Visual feedback (right or wrong) was provided after each
card placement. This task reflects abstract reasoning, cognitive flexibility, and the ability to maintain and change
set. Total errors, percent perseverative errors, number of

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1
2

Prefrontal Structural and Functional Deficits

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

Table 3. Lifetime rates of alcohol and substance abuse/dependence in the psychiatric control and
schizophrenia spectrum groups, together with usage in the past month
Schizophrenia
spectrum
(n = 16)

23.1
38.5
7.7

31.3
50.0
0.0

3.8
3.8
0.0
19.2
31.3
15.4
11.5
7.7
0.0

6.3
0.0
4.8
38.1
37.5
12.5

7.7
30.8
0.0
23.1
7.7
0.0

6.3
0.0
0.0
6.3
50.0
6.30
23.1
6.3
0.0

0.0
0.0
0.0
7.7
0.0
0.0

0.0
6.3
0.0
0.0
6.3
0.0

df

1.80

0.46

1.29
0.74

0.26
0.69

1.3
0.80

0.07
1.76

25.0
12.5
0.0

0.0
3.8
0.0

x2

2
2

2.25

1.6

0.26
0.67

0.80
0.41

0.32

0.45

1.67
0.45

0.19

0.98

1.66

2.86

0.20

0.24

Note.x2 analyses were conducted on psychiatric disorder categorization (absent-abuse-dependence) and on substance use in past
month (yes/no). PCP = Phencyclidine.

ship) was as follows: left prefrontal gray 0.99, right prefrontal gray 0.99, left prefrontal white 0.93, right prefrontal white 0.94, total brain volume 0.99.

right hemisphere) design for gray and white matter separately. The ability of measures to predict group membership independent of confounds was assessed using logistic
regression and the Wald %2 statistic using a classification
cutoff of 0.5, with the Nagelkerke statistic used for variance estimation. Brain and neurocognitive variables were
entered using a stepwise forward procedure (Wald) with
an entry probability of 0.05 and a removal probability of

Statistical Analyses. Repeated measures analyses of

variance (ANOVAs) using the multivariate approach
(Vasey and Thayer 1987) were conducted on left and right
hemisphere volume measures in a 3 (groups) X 2 (left and

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Alcohol
Abuse
Dependence
Past month
Sedatives-hypnotics-anxiolytics
Abuse
Dependence
Past month
Cannabis
Abuse
Dependence
Past month
Stimulants
Abuse
Dependence
Past month
Opioids
Abuse
Dependence
Past month
Cocaine
Abuse
Dependence
Past month
Hallucinogens/PCP
Abuse
Dependence
Past month
Poly
Abuse
Dependence
Past month
Other
Abuse
Dependence
Past month

Psychiatric
control
(n = 26)

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

A. Raine et al.

Table 4. Means (standard deviations) and results of f test comparisons for alcohol usage in the
psychiatric control and schizophrenia spectrum groups
Psychiatric
control
(n = 26)
mean (SD)

Schizophrenia
spectrum

Times used, past week

0.78(1.28)

1.63 (2.06)

1.67

40

0.11

Times used, past month

3.50 (5.03)

5.94 (7.02)

1.27

40

0.21

No. of drinks when drinking

2.70 (2.63)

2.56 (3.05)

0.16

40

0.87

Largest no. of drinks on

one occasion

5.85(5.61)

7.00 (8.24)

0.54

40

0.59

(n = 16)
mean (SD)

Prefrontal gray was expressed as a function of whole

brain volume. A repeated measures multivariate ANOVA
confirmed the main effect for group, F(2,66) = 4.50, p =
0.015. A breakdown of this effect showed that the spectrum group had smaller prefrontal/whole brain volumes
than both comparisons, t = 2.1, df= A\,p = 0.044, and psychiatric controls, t = 2.76, df= 39, p = 0.009. There was no
significant group X hemisphere interaction, F(2,66) =
0.09, /? = 0.91, but the main effect for hemisphere, F(l,66)
= 89.0, p = 0.000, again indicated relatively greater gray
volume in the right hemisphere. There was no significant
group difference in overall brain volume, F(2,66) = 1.54, p
= 0.22.

Results
Prefrontal Structure. There was a main effect for group
on prefrontal gray volumes, F(2,66) = 3.5, p = 0.037. The
spectrum group had smaller prefrontal gray volumes than
both comparisons, t = 2.6, df =41, p = 0.011, and psychiatric controls, / = 2.3 , df= 40, p = 0.028 (figure 1). The
spectrum group showed a 12.4 percent reduction in the
volume of prefrontal gray matter compared to the comparison group, and a 13.2 percent reduction compared to psychiatric controls. 1 Corresponding effect sizes (d) were
0.84 and 0.73, respectively, and are in the large range
(Cohen 1988). There was no interaction between group
and hemisphere, F(2,66) = 0.1, p = 0.91, but there was a
main effect for hemisphere, F(l,88) = 94.4, p = 0.001,
with the right hemisphere having higher gray volume than
the left. In contrast, there was no group difference in prefrontal white matter, F(2,66) = 0.14, p = 0.87 (figure 1),
and no group X hemisphere interaction, F(2,66) = 0.54, p
= 0.58. There was a main effect for hemisphere, F(l,66)
= 31.5, p = 0.0001, indicating a larger volume of white
matter in the left hemisphere.

Frontal Neurocognitive Functioning. The principal

component analysis of the eight subtests from the WCST
and CPT produced a first factor that accounted for 47.9
percent of the total unrotated variance. Percent perseverative errors was the highest loading WCST variable on
this factor, while false alarm rate was the highest loading
CPT variable. Loadings on this factor for the eight subtests were as follows: WCST percent perseverative error
0.86, total errors 0.85, number of categories -0.79, trials
to first category 0.69; CPT false alarm rate 0.75, hit rate
-0.45, response bias -0.34, sensitivity -0.62. Given that
all the loadings were greater than 0.30 and loaded in a
theoretically meaningful fashion, the factor was labeled
"frontal functioning," with higher scores indicating poorer
frontal functioning.
Groups differed significantly on the frontal factor score,
F(2,59) = 4.69, p = 0.013 (table 5). The spectrum group performed significantly more poorly on this global factor than
did both the comparisons, t = 2.55, df= 37, p = 0.015, and
the psychiatric controls, t = 2.51, df= 36, p = 0.017.
With respect to specific subtests of frontal functioning
(table 5), groups differed significantly on WCST trials to
complete first trial, F(2,62) = 5.01, p = 0.010, and CPT
false alarms, F(2,63) = 4.85, p = 0.011; and there was a
trend for CPT response bias, F(2,63) = 3.09, p = 0.053.

1
Groups were balanced for sex, but to assess for any interactions
between group and sex, sex was entered as a second factor in all analyses. No group x sex, F(2,62) = 0.78, p = 0.46, or group x sex x hemisphere, F(2,62) = 0.79, p = 0.46, interactions were observed.

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0.10. Other hypotheses were tested using ANOVA and t

tests. All tests of significance are 2-tailed with an alpha of
0.05.
The two neuropsychological measures of frontal functioning (WCST and CPT) each yielded four performance
scores reflecting different aspects of test performance. To
reduce the number of variables for analysis, these eight
subscores were subjected to principal component analysis,
and factor scores from the first principal component were
calculated using the regression method.

df

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

Prefrontal Structural and Functional Deficits

Figure 1. Prefrontal gray and white matter volumes in the three groups

Prefrontal Volume
Controls
Psychiatric Controls
Schizotypals
85

75

65

55

45

GRAY

WHITE

Table 5. Group comparisons on the frontal factor (first principal component) and subtests of the WCST
and CPT

Frontal factor

Comparison
(n = 27),
mean (SD)

Psychiatric
control
(n = 26),
mean (SD)

Schizophrenia
spectrum
(n = 16),
mean (SD)

at

-0.27 (0.89)

-0.16(0.64)

0.60 (1.22)

4.69

2,59

0.013

17.68(8.53)
13.40(9.04)
22.12(9.64)
2.65 (1.44)

19.36(10.21)
15.21 (10.96)
24.62 (9.52)
2.27(1.25)

31.47(23.80)
20.80(12.09)
28.69(10.69)
1.81 (1.33)

5.01
2.37
2.21
1.96

2,62
2,65
2,65
2,65

0.010
0.102
0.118
0.149

0.035 (0.065)
0.58 (0.39)
0.78 (0.26)
0.91 (0.14)

0.019(0.020)
0.66 (0.25)
0.78 (0.25)
0.93 (0.08)

0.071 (0.062)
0.39 (0.40)
0.70 (0.29)
0.87(0.18)

4.85
3.09
0.56
1.25

2,63
2,63
2,63
2,63

0.011
0.053
0.572
0.294

WCST
Trials to first category
% perseverative errors
Total errors
No. of categories
CPT
False alarms
Response bias
Hit rate
Sensitivity

Note.CPT = Continuous Performance Test; SD = standard deviation; WCST = Wisconsin Card Sorting Test.

comparisons was only marginally significant in the predicted direction, / = 1.77, df= 40, p = 0.084. The spectrum
group had a poorer response bias compared to psychiatric
controls, / = 2.69, df= 38, p = 0.01, but the contrast with
comparisons, while in the predicted direction, was statistically nonsignificant, t = 1.57, df= 40, p = 0.125.

The spectrum group had a significantly higher percentage

of perseveration errors on the WCST than did both comparisons, / = 2.65, df= 38, p = 0.012, and psychiatric controls, t = 2.23, df= 38, p = 0.031. The spectrum group also
had a higher CPT false alarm rate than did psychiatric controls, / = 3.86, df = 38, p = 0.000, but the contrast with

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cc

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

A. Raine et al.

the possible effects of these confounds on structural and

functional brain differences, these four variables were
simultaneously entered as covariates and the above analyses were repeated. After this control, group differences
still remained for prefrontal gray volume, F(2,62) = 4.29,
p = 0.018. For frontal functioning, group differences were
marginally significant, F(2,61) = 2.34, p = 0.066. The
absolute group difference between spectrum and comparison groups was reduced only 9.7 percent after the substance abuse control, and this difference still remained
significant, F(l,33) = 4.46, p = 0.042.
Possible Confounding Effect of Antisocial Behavior.
The significantly higher scores on antisocial personality in
the spectrum group relative to the two other groups raised
the question of whether prefrontal structural deficits are
an artifact of the increased antisocial behavior in the spectrum group. To test this possibility, a logistic regression
analysis was conducted in which prefrontal gray volume
was used to predict spectrum versus comparison group
membership after controlling for the dimensional measure
of antisocial personality disorder. The schizotypy-prefrontal gray relationship was abolished, %2 = 0.001, df= 1,
p = 0.98, after controlling for antisocial personality disorder.2 In contrast, group differences on frontal neurocognitive functioning remained after controlling for antisocial
personality, %2 = 7-23, df=\,p = 0.007.
Because the spectrum group had nonsignificantly
higher rates of antisocial personality disorder and significantly higher scores on the dimensional measure of antisocial personality than psychiatric controls did, a complete
statistical control was made on the dimensional measure
of antisocial personality disorder in logistic regressions

2
Our previous findings of reductions in prefrontal gray volume in
individuals with antisocial personality disorder (Raine et al. 2000) are
not a function of increased schizotypai personality in this group because
(1) the antisocial personality disorder group showed reduced prefrontal
volume compared to a psychiatric control group matched on schizophrenia spectrum disorder, and (2) reduced prefrontal gray differentiated the
antisocial personality disorder group from the control group after initial
entry of schizotypai personality in a logistic regression, x2 = 5.08, df= 1,
p = 0.024.

Further Control for Substance Use. Although psychiatric controls and the spectrum group were matched on
substance abuse, the spectrum group had nonsignificantly
higher rates of cocaine, cannabis, stimulant, and sedative
use than did psychiatric controls. To further control for

Table 6. Logistic regression predicting schizotypai versus comparison group membership using prefrontal gray and frontal functioning as predictor variables
X2

df

Nagelkerke R2

Correct classification

Step 1: prefrontal gray

6.60

0.010

0.218

73.68

Step 2: frontal functioning

6.86

0.009

0.408

84.21

Wald x 2 entry

Note.Nagelkerke R2 refers to total variance account for; correct classification refers to the percentage of cases correctly classified into
groups.

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Independence of Structural and Functional Prefrontal

Deficits. The spectrum group was characterized by both
structural and functional prefrontal deficits. It has been
hypothesized that structural deficits to the prefrontal cortex give rise to the frontal functional deficits in this group.
If this were the case, then equating the three groups on
prefrontal gray volume would abolish the frontal functional deficits in the spectrum group. This hypothesis was
tested by entering prefrontal gray volumes in the first
block predicting spectrum group versus comparison group
membership in the logistic regression, and then entering
the frontal functional factor in a second block. After
equating the differences in prefrontal structure, group differences in frontal functional deficits remained significant,
X2 = 6.86, df=\,p
= 0.0088, indicating independence of
structural and functional deficits. Independence of structural and functional deficits was confirmed by the lack of
significant correlations between the frontal functional factor and prefrontal gray volumes in the entire sample and
in each of the three samples (all r < 0.27, p> 0.21).
This independence of structural and functional
deficits suggests that these factors account for independent
proportions of variance in the group difference between
the spectrum and comparison groups. This hypothesis was
tested in a logistic regression analysis with spectrum
group versus comparison group as the grouping variable
and prefrontal gray and the frontal factor as two predictor
variables entered on the same block. Results are shown in
table 6. Prefrontal gray had the strongest relation to groups
and was entered first, accounting for 21.8 percent of the
variance in group membership. After entry of prefrontal
gray, the frontal functioning factor still significantly predicted group membership, almost doubling the percentage
of variance accounted for, from about 22 percent to about
41 percent. The variables together correctly classified 84.2
percent of subjects.

Prefrontal Structural and Functional Deficits

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

predicting group differences on structural and functional

frontal measures. Full control for antisocial personality
rendered the previously significant group difference nonsignificant, x 2 = 3.0, df= 1, p = 0.083, but the group difference in frontal neurocognitive functioning remained significant, X2 = 5.56, df=\,p = 0.018.

Discussion

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Findings support the hypothesis that schizotypal/paranoid

personality disorder is characterized by structural and
functional prefrontal deficits. The spectrum group showed
a 12.4 percent reduction in the volume of prefrontal gray
matter compared to the comparison group, and a 13.2 percent reduction compared to psychiatric controls. Corresponding effect sizes (d) were 0.84 and 0.73, respectively,
and are in the large range (Cohen 1988). These findings
could not be accounted for by differences in whole brain
volume, alcohol and drug use, history of head injury, or
comorbidity for affective and anxiety disorders. Similar
group differences in functional frontal deficits were found,
with effect sizes of 0.80 for both comparisons and psychiatric controls. These functional frontal findings are consistent with the previous literature showing robust WCST
and CPT deficits in schizotypals, as noted earlier. Given
that the spectrum group also showed poorer prefrontal
functioning compared to matched psychiatric controls, the
current findings provide support for the centrality of
frontal structural and functional deficits in schizophrenia
spectrum disorders.
Structural prefrontal deficits were independent of
functional deficits in schizophrenia spectrum patients.
Though not predicted, this result is consistent with the failure of all three prior cross-sectional studies that compared
schizophrenia patients to controls and assessed prefrontal
structural deficits together with frontal neurocognitive
functioning (Andreasen et al. 1986; DeMyer et al. 1988;
DeLisi et al. 1991). Set against these three failures, one
longitudinal study observed that frontal volume reductions
predicted decline in executive functions over a 31-month
period (Gur et al. 1998), while one cross-sectional study of
only chronic schizophrenia patients showed that reduced
dorsolateral prefrontal area was associated with impaired
performance on both the WCST and the CPT (Seidman et
al. 1994). There are at least two possible explanations for
this lack of structure-function association. First, if the
structural deficit was localized to the orbitofrontal cortex,
such damage might be less likely to affect frontal neurocognitive measures, which have been traditionally associated with dorsolateral prefrontal regions. In support of
this explanation, frontal neurocognitive measures have
been found within schizophrenia patients to correlate with

the dorsolateral but not the orbitofrontal area (Seidman et

al. 1994). Second, it must be remembered that the neurocognitive measures of "frontal" functioning used in this
study are complex measures of executive/attentional functions that involve neural networks outside of this brain
region. For example, the CPT is known to activate bilateral frontal and occipital regions, together with right temporal and parietal regions (Buchsbaum et al. 1990). Furthermore, damage to subcortical structuresincluding the
thalamus, hippocampus, and amygdalawould be
expected to interfere with tasks, such as the CPT and
WCST, that are dependent on the integrity of these prefrontal-subcortical circuits (Bilder et al. 1995). Future
imaging studies that both segment prefrontal gray volume
into structural subregions and assess prefrontal and subcortical functioning using imaging techniques with high
spatial resolution (e.g., fMRI) are needed to elucidate the
complex interplay between prefrontal structure and function.
As noted above, only 10.7-14.9 percent of structural
MRI studies of schizophrenia have employed a psychiatric control group. A strength of the present study is the
use of a psychiatric control group that controls for all Axis
I and II disorders, unlike the few studies that employ a
psychiatric control group but control for only one comorbid disorder. As such, the structural and functional deficits
found in the spectrum group cannot be readily attributed to
most comorbidity. Specifically, although rates of drug and
alcohol abuse/dependence in the spectrum group were
quite high (possibly reflecting self-medication for symptoms in this noninstitutionalized sample), we have previously shown for this sample that individuals dependent on
drugs or alcohol have prefrontal gray volumes identical to
controls (Raine et al. 2000). Furthermore, the spectrum
group was reasonably well matched to psychiatric controls
on substance use, and additional control for nonsignificant
group differences on cannabis, sedatives, cocaine, and
stimulant use left results essentially unchanged.
Findings on prefrontal structural deficits are consistent with one prior community study showing an association between reduced prefrontal volume and increased
schizotypy (Raine et al. 1992fc), but the findings conflict
with those of a recent study by Downhill et al. (2001)
showing prefrontal volumes in schizotypal personality disorder that do not differ statistically from controls'. Furthermore, Buchsbaum et al. (2002) have found higher, not
lower, glucose metabolic rates in Brodmann area 10 in 13
patients with schizotypy personality disorder, while a
review by Siever et al. (2002) similarly argues that schizotypal patients may be spared prefrontal structural deficits
and have greater prefrontal reserves compared to schizophrenia patients. One possible explanation for the contradiction is that samples may differ in comorbidity with anti-

Schizophrenia Bulletin, Vol. 28, No. 3, 2002

A. Raine et al.

510

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comorbid antisocial behavior.

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The Authors

Wible, C.G.; Shenton, M.E.; Hokama, H.; Kikinis, R.;

Jolesz, F.A.; Metcalf, D.; and McCarley, R.W. Prefrontal
cortex and schizophrenia: A quantitative magnetic resonance imaging study. Archives of General Psychiatry,
52:279-288, 1995.

Adrian Raine, D.Phil., is Robert G. Wright Professor of Psychology, Department of Psychology, University of Southern
California (USC), Los Angeles, CA. Todd Lencz, Ph.D., is
Research Psychologist, Department of Research, Hillside
Hospital (North Shore-Long Island Jewish Health System),
Glen Oaks, New York. Pauline Yaralian, M.A., is Research
Assistant; Susan Bihrle, Ph.D., is Research Associate; and
Lori LaCasse, B.A., is Research Coordinator, Department of
Psychology, USC. Joseph Ventura, Ph.D., is Assistant Professor, Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles,
CA. Patrick Colletti, M.D., is Chief of Magnetic Resonance
Imaging and Professor of Radiology, Department of Radiology, USC School of Medicine.

Yaralian, P.S., and Raine, A. "Meta-Analysis of Frontal

Lobe Size in Schizophrenia as Assessed by Magnetic Resonance Imaging." Poster presented at the Society for
Research in Psychopathology annual meeting, Boulder,
CO, November-December 2000.
Yeo, R.A.; Hodde-Vargas, J.; Hendren, R.L.; Vargas, L.A.;
Brooks, W.M.; Ford, C.C.; Gangestad, S.W.; and Hart,
B.L. Brain abnormalities in schizophrenia-spectrum children: Implications for a neurodevelopmental perspective.
Psychiatry Research: Neuroimaging, 76:113, 1997.

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The authors wish to thank Jennifer Bobier, Nicole Diamond,

Kevin Ho, Blane Horvath, Shari Mills, and Kristen Taylor for
assistance in data collection and scoring, and Keith Nuechterlein for providing the Continuous Performance Test. This
study was supported by grants to the first author from the
National Institute of Mental Health (RO3 MH50940-O1A2,
and an Independent Scientist Award K02 MH01114-01).