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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
Abstract
Structural prefrontal deficits have been reported in
patients with schizophrenia, but it is unclear if they
are also found in patients with schizophrenia spec-
trum 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 vol-
ume (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
volume deficits in schizophrenia patients compared to
normal controls, but not when compared to chronic alco-
holics (Sullivan et al. 1998), while one review reports
preliminary findings failing to observe reduced pre-
frontal 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 schizo-
phrenia (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 con-
trast to these conflicting structural findings, at a func-
tional 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 Per-
formance Test (CPT; 14 studies) (Heinrichs and Zakza-
nis 1998).
Further evidence for the etiologic significance of pre-
frontal structural deficits comes from the study of schizo-
phrenia spectrum disorders. Spectrum disorders have tra-
ditionally encompassed the DSM "odd cluster" of
Send reprint requests to Dr. A. Raine, Department of Psychology,
University of Southern California, Los Angeles, CA 90089-1061; e-
mail: raine@usc.edu.
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Schizophrenia Bulletin, Vol. 28, No. 3, 2002 A. Raine et al.
schizotypal, paranoid, and schizoid personality disorders
(Siever et al. 1993), although the inclusion of schizoid per-
sonality disorder has been questioned by some researchers
on the grounds that it lacks genetic relatedness with schiz-
ophrenia (Nigg and Goldsmith 1994; Torgersen 1994;
Ingraham 1995). Spectrum individuals have a stable
(schizotypal and paranoid) personality disorder with a his-
tory 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 corre-
lates of schizophrenia can also be observed in individuals
with schizophrenia spectrum disorders who are free of the
confounds of institutionalization, medication, and label-
ing, 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 vol-
unteers with higher scores on self-report schizotypal per-
sonality measures had both smaller prefrontal areas and
more perseveration errors on the WCST.
Although most other imaging studies of schizotypal per-
sonality have focused on ventricular size (Cannon et al.
1994) or temporal lobe volumes (Dickey et al. 1999; Down-
hill et al. 2000), two additional studies of schizotypal person-
ality disorder have relevance to the question of frontal struc-
tural deficits. Buchsbaum et al. (1997) found that patients
with schizotypal personality disorder showed an enlarge-
ment 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 childhood-
onset schizophrenia (Frazier et al. 1996) have also found null
results. In contrast, frontal functional deficits represent the
best replicated correlate of schizotypal personality. Specifi-
cally, frontal functional deficits have been repeatedly and
replicably found on the WCST and the CPT with respect to
both schizotypal personality disorder and individual differ-
ences 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; Trest-
man 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
schizotypal personality have rarely if ever included a psy-
chiatric 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 Schizo-
phrenia Research only 2 of 14 studies (14.3%) employed
psychiatric controls. Furthermore, studies that do use psy-
chiatric controls frequently control for only one experi-
mental-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 vol-
ume compared to both comparisons and psychiatric con-
trols. 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 predi-
cated 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 per-
sonality disorder or paranoid personality disorder
(referred to hereafter as the spectrum group). The spec-
trum group consisted of 10 individuals with schizotypal
personality disorder only, 4 individuals with paranoid per-
sonality disorder only, and 2 individuals with both schizo-
typal 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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Prefrontal Structural and Functional Deficits Schizophrenia Bulletin, Vol. 28, No. 3, 2002
Table 1. Characteristics of the study groups
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, %
Comparison
C = 27)
85.2
30.9 (6.9)
35.3(10.3)
57.1
101.7(14.9)
33.8 (9.8)
175.9(7.9)
80.8(15.0)
57.6(2.1)
39.3
Psychiatric
control
(n = 26)
88.5
29.0 (6.6)
36.6(11.5)
38.5
97.8(13.1)
33.5 (10.5)
179.7(9.1)
80.9(15.7)
57.2(1.7)
38.5
Schizophrenia
spectrum
(n = 16)
87.5
32.1 (5.4)
33.9(10.9)
43.8
94.5(13.1)
35.2 (9.6)
176.5(10.8)
78.7(11.6)
57.1 (2.3)
37.5
Statistics
X
2
= 0.9, df=2, p=0. 95
F (2,67) = 1.2, p = 0.31
F (2,67) = 0.3, p = 0.72
X
2
= 2.0, df=2, p=0. 37
F (2,67) = 0.4, p = 0.68
F (2,67) = 0.2, p = 0.86
F (2,67) = 1.3, p = 0.27
F (2,67) = 0.15, p = 0.86
F (2,67) = 1.5, p = 0.39
X
2
= 0.01,ctf=2, p = 0.99
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 cor-
tex. 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 with-
out 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 spec-
trum 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 dis-
orders. 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 nonsignifi-
cantly higher rate of comorbidity for antisocial personality
disorder in the spectrum group (50.0%) than in the psychi-
atric controls (38.5%). Furthermore, the spectrum group
(mean [M] = 9.4, standard deviation [SD] = 4.1) had sig-
nificantly higher scores on a dimensional measure of anti-
social personality disorder (see below) compared to both
psychiatric controls (M = 6.7, SD = 3.5; / = 2.2, df= 40, p
= 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 con-
found in structural brain imaging correlates of schizophre-
nia spectrum disorders, details of rates of alcohol and sub-
stance 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 crite-
ria (American Psychiatric Association 1994) and ascer-
tained 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 ques-
tionnaire to assess frequency of alcohol consumption was
completed by participants. A dimensional measure of anti-
social personality disorder was created by summing
scores of the seven DSM-IV criterion C symptoms of the
SCID-n.
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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
Affective
1
Anxiety
2
Conduct disorder
Antisocial personality disorder
Cluster B
3
Cluster C
4
Psychiatric
control
(n = 26)
53.8
19.2
53.8
38.5
15.4
15.4
Schizophrenia
spectrum
(n=16)
56.3
18.8
50.0
50.0
25.5
0.0
x
2
0.02
0.00
0.06
0.54
0.59
2.70
df
1
1
1
1
1
1
P
0.88
0.97
0.81
0.46
0.44
0.10
1
Major depression, bipolar depression, other depressive disorders.
2
Phobia, panic, generalized anxiety.
3
Borderline, histrionic, obsessive-compulsive.
4
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 (Bry-
den 1977). History of head injury was defined as head
trauma resulting in hospitalization. Social class was mea-
sured using the Hollingshead classification system (Holling-
shead 1975). A physical examination was conducted to
derive measures of height, weight, and head circumference.
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 num-
bers 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 stimu-
lus 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, cog-
nitive flexibility, and the ability to maintain and change
set. Total errors, percent perseverative errors, number of
categories completed, and trials to achieve the first cate-
gory 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/cere-
brospinal 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 relia-
bility (intraclass correlation coefficient) based on 23 scans
(raters blind to each other's ratings and group member-
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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
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)
23.1
38.5
7.7
3.8
3.8
0.0
19.2
31.3
15.4
11.5
7.7
0.0
0.0
3.8
0.0
7.7
30.8
0.0
23.1
7.7
0.0
0.0
0.0
0.0
7.7
0.0
0.0
Schizophrenia
spectrum
(n = 16)
31.3
50.0
0.0
6.3
0.0
4.8
38.1
37.5
12.5
25.0
12.5
0.0
6.3
0.0
0.0
6.3
50.0
6.30
23.1
6.3
0.0
0.0
6.3
0.0
0.0
6.3
0.0
x
2
1.80
1.29
0.74
1.3
0.80
0.07
1.76

2.25

1.6
1.67
0.45

1.66

2.86

df
2
2
2
2
2
2
2

2
1
2

P
0.46
0.26
0.69
0.26
0.67
0.80
0.41

0.32

0.45
0.19
0.98

0.20

0.24

Note.x
2
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 pre-
frontal gray 0.99, left prefrontal white 0.93, right pre-
frontal white 0.94, total brain volume 0.99.
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
right hemisphere) design for gray and white matter sepa-
rately. The ability of measures to predict group member-
ship 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 vari-
ance 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
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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
(n = 16)
mean (SD) df
Times used, past week
Times used, past month
No. of drinks when drinking
Largest no. of drinks on
one occasion
0.78(1.28)
3.50 (5.03)
2.70 (2.63)
5.85(5.61)
1.63 (2.06)
5.94 (7.02)
2.56 (3.05)
7.00 (8.24)
1.67
1.27
0.16
0.54
40
40
40
40
0.11
0.21
0.87
0.59
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 func-
tioning (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.
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 psychi-
atric 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 compar-
ison group, and a 13.2 percent reduction compared to psy-
chiatric 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 pre-
frontal 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.
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 analy-
ses. No group x sex, F(2,62) = 0.78, p = 0.46, or group x sex x hemi-
sphere, F(2,62) = 0.79, p = 0.46, interactions were observed.
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 spec-
trum group had smaller prefrontal/whole brain volumes
than both comparisons, t = 2.1, df= A\,p = 0.044, and psy-
chiatric 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.
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 persev-
erative 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 sub-
tests 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 per-
formed 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.
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Prefrontal Structural and Functional Deficits Schizophrenia Bulletin, Vol. 28, No. 3, 2002
Figure 1. Prefrontal gray and white matter volumes in the three groups
Prefrontal Volume
Controls Psychiatric Controls
Schizotypals
cc
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
WCST
Trials to first category
% perseverative errors
Total errors
No. of categories
CPT
False alarms
Response bias
Hit rate
Sensitivity
Comparison
(n = 27),
mean (SD)
-0.27 (0.89)
17.68(8.53)
13.40(9.04)
22.12(9.64)
2.65 (1.44)
0.035 (0.065)
0.58 (0.39)
0.78 (0.26)
0.91 (0.14)
Psychiatric
control
(n = 26),
mean (SD)
-0.16(0.64)
19.36(10.21)
15.21 (10.96)
24.62 (9.52)
2.27(1.25)
0.019(0.020)
0.66 (0.25)
0.78 (0.25)
0.93 (0.08)
Schizophrenia
spectrum
(n = 16),
mean (SD)
0.60 (1.22)
31.47(23.80)
20.80(12.09)
28.69(10.69)
1.81 (1.33)
0.071 (0.062)
0.39 (0.40)
0.70 (0.29)
0.87(0.18)
F
4.69
5.01
2.37
2.21
1.96
4.85
3.09
0.56
1.25
at
2,59
2,62
2,65
2,65
2,65
2,63
2,63
2,63
2,63
P
0.013
0.010
0.102
0.118
0.149
0.011
0.053
0.572
0.294
Note.CPT = Continuous Performance Test; SD = standard deviation; WCST = Wisconsin Card Sorting Test.
The spectrum group had a significantly higher percentage
of perseveration errors on the WCST than did both com-
parisons, / = 2.65, df= 38, p = 0.012, and psychiatric con-
trols, t = 2.23, df= 38, p = 0.031. The spectrum group also
had a higher CPT false alarm rate than did psychiatric con-
trols, / = 3.86, df = 38, p = 0.000, but the contrast with
comparisons was only marginally significant in the pre-
dicted 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 statisti-
cally nonsignificant, t = 1.57, df= 40, p = 0.125.
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Schizophrenia Bulletin, Vol. 28, No. 3, 2002 A. Raine et al.
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 cor-
tex 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 func-
tional 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 dif-
ferences in frontal functional deficits remained significant,
X
2
= 6.86, df=\,p = 0.0088, indicating independence of
structural and functional deficits. Independence of struc-
tural and functional deficits was confirmed by the lack of
significant correlations between the frontal functional fac-
tor 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 pre-
dicted 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.
Further Control for Substance Use. Although psychi-
atric 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
the possible effects of these confounds on structural and
functional brain differences, these four variables were
simultaneously entered as covariates and the above analy-
ses 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 compari-
son groups was reduced only 9.7 percent after the sub-
stance 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 spec-
trum 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-pre-
frontal gray relationship was abolished, %
2
= 0.001, df= 1,
p = 0.98, after controlling for antisocial personality disor-
der.
2
In contrast, group differences on frontal neurocogni-
tive 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 signifi-
cantly higher scores on the dimensional measure of antiso-
cial 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 schizophre-
nia 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, x
2
= 5.08, df= 1,
p = 0.024.
Table 6. Logistic regression predicting schizotypai versus comparison group membership using pre-
frontal gray and frontal functioning as predictor variables
Wald x
2
entry
Step 1: prefrontal gray
Step 2: frontal functioning
X
2
6.60
6.86
df
1
1
P
0.010
0.009
Nagelkerke R
2
0.218
0.408
Correct classification
73.68
84.21
Note.Nagelkerke R
2
refers to total variance account for; correct classification refers to the percentage of cases correctly classified into
groups.
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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 non-
significant, x
2
= 3.0, df= 1, p = 0.083, but the group differ-
ence in frontal neurocognitive functioning remained sig-
nificant, X
2
= 5.56, df=\,p = 0.018.
Discussion
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 per-
cent reduction compared to psychiatric controls. Corre-
sponding 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 psychi-
atric controls. These functional frontal findings are consis-
tent 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 fail-
ure 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 neu-
rocognitive measures, which have been traditionally asso-
ciated 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 neu-
rocognitive measures of "frontal" functioning used in this
study are complex measures of executive/attentional func-
tions that involve neural networks outside of this brain
region. For example, the CPT is known to activate bilat-
eral frontal and occipital regions, together with right tem-
poral and parietal regions (Buchsbaum et al. 1990). Fur-
thermore, 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 pre-
frontal-subcortical circuits (Bilder et al. 1995). Future
imaging studies that both segment prefrontal gray volume
into structural subregions and assess prefrontal and sub-
cortical functioning using imaging techniques with high
spatial resolution (e.g., fMRI) are needed to elucidate the
complex interplay between prefrontal structure and func-
tion.
As noted above, only 10.7-14.9 percent of structural
MRI studies of schizophrenia have employed a psychi-
atric 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 comor-
bid 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 symp-
toms in this noninstitutionalized sample), we have previ-
ously 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 consis-
tent with one prior community study showing an associa-
tion 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 dis-
order that do not differ statistically from controls'. Fur-
thermore, 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 schizo-
typal patients may be spared prefrontal structural deficits
and have greater prefrontal reserves compared to schizo-
phrenia patients. One possible explanation for the contra-
diction is that samples may differ in comorbidity with anti-
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Schizophrenia Bulletin, Vol. 28, No. 3, 2002 A. Raine et al.
social personality. In the present community-derived spec-
trum sample with relatively high base rates of antisocial
behavior, controlling for group differences in antisocial
personality disorder abolished the prefrontal gray volume
difference between the spectrum and comparison groups
(p = 0.98) and reduced the difference between the spec-
trum and psychiatric control groups to a nonsignificant
level (p = 0.083). Although significant comorbidity has
been reported between schizophrenia and violent criminal
behavior (Belfrage 1998; Raesaenen et al. 1998; Volavka
1999), control for antisocial behavior has rarely, if ever,
been included in studies of schizophrenia and spectrum
disorders. On the other hand, group differences in frontal
functioning remained intact after controlling for antisocial
personality and attest to the robustness of functional
frontal deficits in spectrum disorders. Ultimately, patients
with both schizotypal and antisocial/impulsive features
may have a somewhat different etiology compared to
schizotypal patients lacking these features. Consequently,
controlling for antisocial comorbidity in future studies of
schizophrenia and schizophrenia spectrum disorders may
help clarify conflicting findings and produce a clearer pic-
ture of the unique risk factors for spectrum disorders.
The effect size (d) of 0.84 for the structural prefrontal
gray volume reduction in the spectrum group compared to
the comparison group is relatively large (Cohen 1988).
Although one limitation of the current study is that a
schizophrenia patient group with which to compare effect
sizes was not included, a recent meta-analysis (Yaralian
and Raine 2000) observed an overall effect size of 0.42 for
frontal gray loss in schizophrenia patients compared to
controls. In comparison, the doubling of the effect size in
spectrum individuals could be interpreted as highlighting
the advantage of studying noninstitutionalized spectrum
individuals from the community who do not share the
methodological confounds that apply to institutionalized
schizophrenia patients. Alternatively, comorbid antisocial
behavior may contribute to the effect size obtained for pre-
frontal structure, although this argument cannot explain
the large effect size of 0.8 found for functional prefrontal
deficits.
In conclusion, schizophrenia spectrum disorder is
characterized by reduced prefrontal gray volumes and
reduced frontal functioning compared to both comparison
and psychiatric control groups. Though these results sup-
port the potential etiologic significance of prefrontal struc-
tural deficits in schizophrenia, the possibility exists that
these effects are abolished by careful control for antisocial
personality, comorbidity that may account for discrepant
findings in the literature. In contrast, in the spectrum group
we observed functional deficits of equal magnitude that
cannot be accounted for by either structural deficits or
comorbid antisocial behavior.
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Acknowledgments
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 Nuechter-
lein 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).
The Authors
Adrian Raine, D.Phil., is Robert G. Wright Professor of Psy-
chology, 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 Pro-
fessor, Department of Psychiatry and Biobehavioral Sci-
ences, University of California Los Angeles, Los Angeles,
CA. Patrick Colletti, M.D., is Chief of Magnetic Resonance
Imaging and Professor of Radiology, Department of Radiol-
ogy, USC School of Medicine.
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