Dysfunction of dorsolateral prefrontal cortex in antipsychotic-naïve
Ben J. Harrisona,⁎, Murat Yücela,b,⁎, Marnie Shawc, Warrick J. Brewera,b,
Pradeep J. Nathand, Stephen C. Strothere, James S. Olverf, Gary F. Egang,
Dennis Velakoulisa, Patrick D. McGorryb, Christos Pantelisa,g
aMelbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne, Australia
bORYGEN Research Centre and the Early Psychosis Prevention and Intervention Centre (EPPIC), Department of Psychiatry,
The University of Melbourne, and NorthWestern Mental Health Program, Melbourne Health, Australia
cCognitive Neuroscience Laboratory, School of Psychology, Flinders University, Australia
dBehavioural Neuroscience Laboratory, Department of Physiology, Monash Centrefor Brain and Behavior, Monash University, Australia
eThe Rotman Research Institute, University of Toronto, Ontario, Canada
fCentre for Positron Emission Tomography, Austin Hospital, The University of Melbourne, Australia
gHoward Florey Institute, The University of Melbourne, Australia
Received 6 December 2005; received in revised form 31 January 2006; accepted 13 February 2006
Reports of abnormal activation of the dorsolateral prefrontal cortex (dlPFC) are common in functional neuroimaging studies of
schizophrenia, although very few have examined brain activity in patients close to the onset of illness. In this H2
eight young male patients with first-episode schizophreniform psychosis and age-matched control subjects performed a version of
the Stroop task that we have previously shown to engage the middle-frontal gyrus. At the time of testing, patients were
antipsychotic-naïve and were scanned within 1 week of initial contact with our clinical program. All patients received a later
diagnosis of schizophrenia 6 months after participating in the study. Whole-brain (within-group) and region-of-interest (between-
group) analyses were carried out and data underwent spatial reproducibility testing. Compared with healthy subjects, patients
showed significantly greater reaction-time (RT) interference but normal RT accuracy on the Stroop task. This pattern correlated
with significant under-activation of the posterior left middle-frontal gyri in the patient versus control group. These findings support
an emerging model of impaired cognitive control in schizophrenia and suggest that there is significant dysfunction of the dlPFC
close to the onset of illness that may coincide with, or be modulated by, the transition-to-illness phase.
© 2006 Elsevier Ireland Ltd. All rights reserved.
15O PET study,
Keywords: Schizophrenia; Dorsolateral prefrontal cortex; Cognitive control; First-episode psychosis
Extending early observations of reduced frontal lobe
metabolism and blood flow changes in schizophrenia
(i.e. resting “hypofrontality”; Ingvar and Franzén, 1974;
Buchsbaum et al., 1982), the most reproducible finding
Psychiatry Research: Neuroimaging 148 (2006) 23–31
⁎Corresponding authors. Ben Harrison (electronic). Murat Yücel
(postal) Melbourne Neuropsychiatry Centre, Department of Psychia-
try, The University of Melbourne, Level 3, National Neuroscience
Facility, 161 Barry Street, Carlton, Melbourne, Australia. Tel.: +61 3
8344 1877; fax: +61 3 8345 0599.
E-mail address: firstname.lastname@example.org (B.J. Harrison).
0925-4927/$ - see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
magnetic resonance imaging (fMRI) studies of this
disorder has been that patients show decreased task-
related activation of the dorsolateral prefrontal cortex
(dlPFC) (Andreasen et al., 1992; Weinberger et al., 1986;
see also meta-analyses by Davidson and Heinrichs, 2003;
Glahn et al., 2005). Although a more complex picture of
this abnormality has emerged with studies using fMRI
(Callicott et al., 2003; Manoach, 2003), the relationship
between impaired dlPFC activity and impaired higher
cognition inschizophrenia remains compelling.Recently,
middle-frontal gyrus (Brodmann's area 9/46) in mediat-
ing cognitive control (CC) deficits in patients with
schizophrenia — the ability to coordinate one's
thoughts/actions in line with specific goals or task-
oriented behaviors (Barch et al., 2001; MacDonald and
Carter, 2003; MacDonald et al., 2005; Perlstein et al.,
2003). This pattern has been observed most readily in
fMRI studies of stimulus-response compatibility para-
digms, where patients show a reduced capacity to sustain
task-relevant (i.e. correct) responses, in the face of
distraction from task-irrelevant (i.e. incorrect) items —
a phenomenon that has been linked to impaired context
processing in schizophrenia (Cohen et al., 1999).
Importantly, and supporting the specificity of such
findings in schizophrenia, CC-related hypofunction of the
dlPFC has been characterized in chronically ill, medicated
and medication-naïve patients (Javitt et al., 2000; MacDo-
nald and Carter, 2003; Perlstein et al., 2003) and has been
distinguished quantitatively from other psychiatric dis-
orders (Holmes et al., 2005). However, questions still
remain about the timing and stability of dlPFC-CC deficits
expression across different stages of illness. For instance,
stage of illness where there is evidence for significant tem-
poral fluxinthe anatomyandphysiological integrityof the
dlPFC(Pantelis et al.,2005).Tothisend,we have reported
significant progressive changes (atrophy) in dlPFC grey
matter over the initial few years of illness that are apparent
before illness onset (Pantelis et al., 2003a), while a recent
fMRI study suggested a progressive worsening of dlPFC
hypofunction on a putative CC task between first-episode
and chronically ill patients versus relative normality in
people identified at ultra-high risk (UHR) for psychosis
(Morey et al., 2005). Hence, these findings suggest that
inferences of a static or trait-invariant dlPFC-CC dysfunc-
tion in schizophrenia may be misleading.
In this H2
with schizophreniform psychosis, who each later transi-
15O PET study, we examined dlPFC-CC
tioned to schizophrenia and who, at the time of testing,
were within a week of initial contact with our early inter-
vention program after experiencing a first episode of
psychotic symptoms. The critical difference between this
group of first-episode patients and those of previous
studies (Barch et al., 2001; MacDonald et al., 2005)
relates to the duration of untreated psychosis (DUP). In
earlier studies, patients were potentially untreated for up
to 5 years longer than the current sample and may have
been a more severely affected group given the negative
correlation of DUP and cognitive outcome in schizophre-
nia (Amminger et al., 2002; Harrigan et al., 2003).
Therefore, we considered it useful to study a sample of
is more appropriate to test the null hypothesis of “no trait
deficit” of dlPFC-CC in schizophrenia.
In this study, subjects performed a classic stimulus-
response compatibility paradigm, the Stroop task, that
in previous studies including our own has been shown
to engage the middle-frontal gyrus in healthy subjects
(Banich et al., 2000; Erickson et al., 2004; Harrison et al.,
2005;Kerns etal.,2004; MacDonald et al., 2000;Milham
et al., 2003b). Under this paradigm, CC is estimated from
the behavioral performance of subjects asked to name the
printed color of incongruent color word nouns (i.e. RED)
where thewordnounservesasa potentdistractiontotask-
irrelevant word reading. For a dlPFC-CC deficit to exist,
under-activity of the middle-frontal gyrus compared with
healthy subjects as well as a corresponding impairment of
reaction time (RT) and/or task accuracy (error) scores.
Eight male patients with first-episode schizophreni-
form psychosis (mean age 21.2±3 years) were recruited
during initial treatment at the Early Psychosis Preven-
tion and Intervention Centre (EPPIC), a program of
ORYGEN Youth Health, Melbourne. All patients held a
current diagnosis based on the Structured Diagnostic
Interview for DSM-IV (SCID-I; First et al., 1998) and a
confirmed diagnosis of schizophrenia assessed at least 6
months after their participation in the study. Patients
were scanned within 1 week following contact with the
EPPIC; program admission criteria, as described else-
where (McGorry et al., 1996), were age of onset be-
tween 16 and 30 years and the presence of active
psychosis as reflected by at least one of the following: (i)
delusions; (ii) hallucinations; (iii) disorder of thinking/
speech, other than simple acceleration or retardation;
24 B.J. Harrison et al. / Psychiatry Research: Neuroimaging 148 (2006) 23–31
and (iv) disorganized, bizarre, or markedly inappropri-
ate behavior. Scores on the Positive and Negative
Syndrome Scale (PANSS; Kay et al., 1991) were
total=50.3±7.5; positive symptoms=29.7±2.5; and
negative symptoms=20.5±6.9. Exclusion criteria in-
cluded a significant current history of alcohol or illicit
drug dependence and a recent history of psychoactive
medication use, including steroids, or any other contra-
indication to PET scanning.
Eight control subjects (7 male; 1 female) were also
recruited by approaching ancillary hospital staff and
their families or via local advertisements (mean age
22.6±2 yrs). Control subjects were matched with the
patients 101.1±7) with the National Adult Reading Test
(NART; Nelson and O'Connell, 1978). All participants
that entered the study were screened for co-morbid
and by physical and neurological examination. All
participants spoke English as a first language and pre-
sented with adequate visual and auditory functioning.
Five subjects in each group were smokers and three were
non-smokers. All participants gave written informed
by the Behavioral Research and Ethics Committees for
the North Western Mental Health Care Network,
Melbourne and the Austin Hospital Human Research
2.2. Stroop task and behavioral analysis
Subjects completed a version of the Stroop color-
word paradigm (Stroop, 1935) that has been previously
reportedby ourgroup (Harrisonetal., 2005; Yücel etal.,
2002). It consisted of sequential congruent (A) and
incongruent (B) trials where each trial corresponded to a
continuous 6-s PETscan. Eight trials were presented in a
4AB design on a computer monitor located approxi-
mately 6 cm from the subject in the PET scanner. For
each trial, 36 stimulus words were presented consecu-
tively 3 mm above a fixation point (white cross) for
1300 ms with an inter-stimulus interval (ISI) of 350 ms.
Instructions specified that subjects attend to and name as
quickly as possible the color of the print in which the
word was written, without reading the word.
Voice onset latencies were recorded with a micro-
phone that was fixed to the subject's mask, although it
was not visible to the subject. We determined the mean
latency of responses for each of the four congruent and
four incongruent conditions. Responses that were not
clearly recorded, were abnormally fast (b100 ms) or that
were abnormally slow (N1200 ms) were excluded from
for both groups and accounted for less than approxi-
mately 10% of all responses made. We alsocalculatedthe
number of errors made during the eight Stroop scan trials.
errors due to incorrect verbalizations (commissions).
or patient) differences in vocalized reaction times (RTs)
and commission error scores were examined using
repeated measures analyses of variance (ANOVAs) and
post hoc comparisons in the Statistical Package for the
Social Sciences (SPSS) Version 11.
2.3. Image acquisition, preprocessing and analysis
Image acquisition andpreprocessingparameters were
identical to those previously published (Harrison et al.,
2005; Yücel et al., 2002). For each subject, eight H2
PET scans (i.e. 4AB task pairs) were acquired using a
Siemens/CT1 951R ECAT PET scanner, which gen-
erates 31 transaxial slices across an axial field of view of
10.8 cm. PET images were reconstructed resulting in
data volumes with 128*128*31 voxels (each of
2.43*2.43*3.375 mm3). A high-resolution T1-weight-
ed MRI was also acquired for each subject (GE Signa
1.5T scanner, voxel size 0.9*0.9*1.4 mm3). Spatial
in SPM2. Data were smoothed with a 12-mm FWHM
Gaussian filter. Normalization to standard space was
performed using FSL (http://www.fmrib.ox.ac.uk/fsl/
Functional data were analyzed using NPAIRS 1.0. For
umn.edu/incweb/npairs_info.html or see Strother et al.
(2002). Initial preprocessing involved volume mean nor-
malization of scans (i.e. proportional scaling) and dimen-
sionality reduction with principal components analysis
(PCA), retaining20 principalcomponents (Harrisonetal.,
2005; Shaw et al., 2002). To characterize within-group
differences in task-related rCBF, each scan was classified
as either congruent or incongruent, and the primary
difference in task-related variance between them was
determined. To do so, NPAIRS combines analyses with
split-half resampling, which takes the specified data and
randomly divides it into two disjoint halves. Each half is
this case, canonical variate analysis (CVA) with 35 splits,
and the two results are compared. Among other metrics,
patterns produced by the split analyses. Reproducibility is
derived from the Pearson product correlation coefficient
25 B.J. Harrison et al. / Psychiatry Research: Neuroimaging 148 (2006) 23–31
(r) of the scatter plots of resulting pairs of independent
statistical parametric maps (i.e. 35 pairs). The r-values
from the data splits are then displayed as a histogram,
which is further summarized by its median, avoiding
potential outlying r-values from influential subjects in
individual splits. These summarized patterns are then
expressed as canonical variates (CVs) and associated
canonical eigenimages (CEs) and the latter converted to
multivariate statistical parametric maps (for a detailed
description of NPAIRS spatial reproducibility testing, see
Strother et al., 2002). Probability values corresponding to
CEs are equivalent to an empirical correction for random
subject effects. We classified results as significant if
reaching peak height probability of Puncorrectedb0.001 and
N20 contiguous voxels.
To test for group differences in functional activation
between controls and patients, we also performed a
confirmatory region-of-interest (ROI) analysis of the
middle-frontal gyrus. This ROI approach was chosen
because our primary hypothesis involved this brain re-
gion, but also to reduce the risk of false-positive activa-
tion (Type 1 error) when comparing small groups of
subjects across whole-brain volumes. The actual se-
lection of the ROI was based on within-group results
(Table1), which indicated that bothpatients and controls
engaged anoverlapping areaofthemiddle-frontalgyrus.
The inclusive ROI dimensions were; x=−40/−56 mm;
y=−6/+14 mm; z=+16/+46 mm). The analysis itself
involved identical procedures to that described above,
with the addition of a dependent variable distinguishing
Within-group pattern of brain activity associated with performance of the Stroop task
Patients Healthy subjects
Superior occipital gyrus
Superior frontal gyrus
3.17Pre/post central gyrus
−16Orbital frontal gyrus10148
Superior temporal gyrus
Medial temporal gyrus
Inferior frontal gyrus
Orbital frontal gyrus
Superior frontal gyrus
Inferior temporal gyrus
Superior parietal cortex
Superior occipital gyrus
Activities are reported if exceeding a minimum cluster extent of at least 30 contiguous voxels at a probability thresholding of Puncorrectedb0.001. The
x, y, z co-ordinates are reported in MNI-to-Talairach space. The NPAIRS (split-half) reproducibility values of these brain activity patterns
corresponded to canonical correlations of 0.93 and 0.92 for patients and controls, respectively.
26B.J. Harrison et al. / Psychiatry Research: Neuroimaging 148 (2006) 23–31
the two study groups. This tested for any significant
difference in (Stroop) task-related activation of the
and N20 contiguous voxels).
Meanreaction-time (RT) scores forthecongruentand
incongruent conditions were 585/775 ms (S.D.=86/
62 ms) for controls and 571/871 ms (S.D.=75/102 ms)
for patients (Fig. 1). Repeated measures ANOVA
revealed a significant main effect of task condition
for RT performance (F(1, 14)=4.77, Pb0.04). Patients
showed proportionally greater slowing only in the
incongruent condition, signifying a greater RTinterference
effect (190versus 300ms; F(1,14)=5.36,Pb0.03).There
were no main effects of task condition (F(1, 14)=3.0,
Pb0.17) or task-by-group interaction (F(1, 13)=1.81,
be noted that rates of error were very low across the 4AB
trials, accounting for less than 2% of the total responses
3.2. PET rCBF
Task-related rCBF activations corresponding to with-
in-group canonical eigenimage (CE) results for patients
and control subjects are given in Table 1. These CEs
corresponded to canonical correlations of 0.93 and 0.92
for patients and controls, respectively, indicating within-
group reproducibility. For patients, significant rCBF acti-
in the cerebellum, thalamus, dorsal anterior-cingulate
left primary motor area and left middle-frontal gyri. For
control subjects, significant rCBF activation was ob-
served bilaterally in the cerebellum, left primary and
supplementary motor areas, brainstem and middle-frontal
gyri and right orbital prefrontal cortex.
Confirmatory ROI analysis of task-related rCBF
activity of left middle-frontal gyri between patients and
controls revealed significantly greater activity in the con-
trolgroup (Z=3.77, Pb0.001;x, y, z=−48, 13, 32; BA9/
46) (Fig. 2).
3.3. Omnibus brain–behavioral correlation
Pearson's product-moment correlations (one-tailed,
simple regression) were carried out between subjects'
within-group CV scores (i.e. omnibus whole-brain acti-
numbers in this study, additional correlations between
subjects' functional, behavioral and demographic/clinical
variables were limited due to the issue of multiple com-
parisons. For both groups, there were significant overall
positive correlations between the CV and RT measures
These correlations reflect a certain degree of functional-
specificity with the current paradigm, with higher CV
scores covarying with higher RT scores (i.e. indexing
incongruent task activity) and vice versa, thus reflecting
the relative cognitive demands of the two Stroop
conditions on rCBF activity.
Disturbance of cognitive control (CC), the ability to
coordinate one's thoughts and actions in line with
to a range of phenomenological features of schi-
zophrenia, including disorganization symptoms and
working memory deficits and, in recent fMRI studies,
has been ascribed to a primary dysfunction of the dlPFC
(Barch et al., 2001; MacDonald and Carter, 2003;
Perlstein et al., 2001). In this study, we tested the dlPFC-
Fig. 1. Mean and standard deviation of reaction-time performance on
the Stroop task.
27B.J. Harrison et al. / Psychiatry Research: Neuroimaging 148 (2006) 23–31
naïve patients with schizophreniform psychosis who
were later diagnosed with schizophrenia and, at the time
of testing, had only recently experienced their first
episode of psychotic symptoms. Specifically, we sought
to test whether these patients would show a less severe
pattern of dlPFC-CC dysfunction compared with exist-
ing recent studies of first episode patients with
presumably longer durations of untreated psychosis
(Barch et al., 2001; MacDonald et al., 2005). However,
contrary to the null hypothesis of ‘no trait deficit’ of
dlPFC-CCin patients at an early stage of illness,patients
in this study did show significant under-activation of the
left middle-frontal gyri relative to healthy subjects as
well as evidence for a behavioral CC deficit. Together,
these findings support the CC model of schizophrenia
and suggest that there is significant physiological
dysfunction of the dlPFC close to the onset of illness.
Consistent with our previous findings (Harrison et
al., 2005) and also other functional imaging studies of
healthy subjects (Erickson et al., 2004; Milham et al.,
2003b), both groups showed significant task-related
activation of the dlPFC during Stroop task performance.
These activations, which occurred in a region of the left
posterior middle-frontal gyrus, were almost identical for
both groups and, as reflected by a brain-wide activity
estimate (i.e. CV scores), showed a positive correlation
with subjects' RT performance. Overall, these findings
appear to be consistent with multiple studies now that
implicate this brain region as responsible for generating
CC on the Stroop task (Banich et al., 2000; Erickson et
al., 2004; Kerns et al., 2004; MacDonald et al., 2000;
Milham et al., 2003b). Specifically, the dlPFC may
contribute to Stroop performance by maintaining a
context for the task in working memory over time (i.e.
color naming versus word reading), and/or by biasing
the top-down processing of stimuli towards a correct
color-naming response (Miller and Cohen, 2001).
However, the primary implication of this study is that
despite activating an almost identical region of the
dlPFC during task performance, patients also showed
significant under-activity of this region when compared
to healthy subjects.
Importantly, the pattern of reduced dlPFC activity in
first-episode patients was accompanied by a relative
impairment in the speed of RT performance on the
Stroop task, where patients showed significantly greater
task accuracy. Although we suggest that this latter
finding should be considered with regards to more
sophisticated studies of this paradigm in schizophrenia
patients' reduced dlPFC activity contributed to their
reduced capacity for CC on the Stroop task, given that
both dimensions were found to be correlated in this
study. It is also worth noting here that in studies of the
Stroop task in healthy subjects, the strength or efficiency
of dlPFC-CC has been inferred from the pattern of
decreased activity in posterior brain regions (e.g.
fusiform gyrus) due to their role in processing word
stimulus features, i.e., more deactivation, more inhibi-
tion of task-irrelevant processing (Banich et al., 2001;
Carter et al., 1995; Milham et al., 2003a,b, 2002). While
not a specific focus of our study, patients' did show less
and impaired CC at this early stage of illness.
A broader implication of the current study's findings
beyond disturbances of CC is that physiological dysfunc-
tion of the dlPFC appears to exist soon after the onset of
Fig. 2. Posterior left middle-frontal gyri activation during Stroop task performance in antipsychotic-naïve patients with schizophreniform psychosis
(left) and age/IQ matched healthy control subjects (right). Reproducible Z-score activations are displayed at a range 2.33 to 5.0 to aid visualization of
clusters within dlPFC region exceeding a probability threshold of Puncorrectedb0.001.
28 B.J. Harrison et al. / Psychiatry Research: Neuroimaging 148 (2006) 23–31
schizophrenia. This finding is supported by a handful of
other studies that have also characterized significant in-
activation of the dlPFC during higher cognitive perfor-
mance in first-episode patients (Boksman et al., 2005;
MacDonald et al., 2005; Morey et al., 2005). However, a
unique feature of our patient group compared with prior
studies is that they were likely to have been recruited at
closer proximity to illness onset given the specific early
intervention focus of the EPPIC/ORYGEN program
(McGorry et al., 1996). Such patients typically have a
first contact, with a median of 49 days of untreated psy-
chosis (Harrigan et al., 2003). Compared with other
studies (e.g. Morey et al., 2005), this is reflected by the
mid-twenties) and shorter duration of illness (6 versus
20 months). Nevertheless, the study by Morey et al.
(2005) remains particularly relevant to our findings
because, in addition, they reported relatively intact
dlPFC function in a group of individuals classified at
ultra-high risk (UHR) for psychosis. If it can be assumed
that this UHR group included a percentage of cases
ultimately to develop schizophrenia, then the dlPFC
dysfunction that has been characterized in first-episode
patients would seem to coincide with or be modulated by
the transition-to-illness phase. While this requires further
clarification, a primary insult to higher cognition around
the time of illness onset fits with our previous notion that
those behavioral processes, namely executive functions,
which normally optimize developmentally during the late
risk for psychosis), are accordingly, the most often
compromised in a patient with schizophrenia (Pantelis
studies to focus on the functional pathophysiology of this
stage of illness and its links to normal brain maturation,
and moreover, whether functional correlates during this
stage can be used as a guide to prognosis, treatment
response or prediction of outcome.
In closing, there are some limitations to this study that
to examine brain activity in patient and control subjects.
Although we argue that this method was sufficiently
suited to address our study aims, the use of fMRI,
particularly event-related fMRI, offers better spatio-
temporal resolution and seems the method of choice for
future studies. While studies of antipsychotic-naïve first-
episode patients often and understandably involve small
patient numbers, this may limit their generalisability and
ideally should be extended. On the other hand, and in
contrast to most functional imaging studies of schizo-
phrenia, our results were derived through testing the spa-
tial reproducibility of data, which strengthens the
generalisability of findings. This issue of reproducibility
in brain-activation studies of schizophrenia is particularly
relevant for the dlPFC, where large differences in the
spatial locations of activity have been reported among
individual patients (see Manoach, 2003). However, our
findings indicate that in a group of young, schizophreni-
form patients there was a spatially reliable reduction of
dlPFC activity. Lastly, we consider dlPFC dysfunction to
represent only one, albeit a crucial aspect of impaired
cognitive control in schizophrenia. Other studies of such
patients that focus on more dynamic aspects of cognitive
control, in particular involving anterior-cingulate cortex
(e.g. Kerns et al., 2005), may lead to a broader
understanding of schizophrenia's neural basis and
specific implications for this stage of illness.
This work was supported by National Health and
Medical Research Council (NHMRC) grant 970599, the
NHMRC Brain Research Network and Janssen-Cilag. It
was undertaken to fulfill part of the requirement of a
Doctor of Philosophy (PhD) to BJH funded by an
Australian Post-graduate Award (APA). The authors
thank colleagues and staff from the Department of
Nuclear Medicine, Centre for PET, Austin Hospital.
Murat Yücel is supported by an NH&MRC Program
Grant (ID: 350241) and Melbourne Neuropsychiatry
Centre is supported by the Department of Psychiatry,
University of Melbourne and Melbourne Health.
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