A functional magnetic resonance imaging study of inhibitory control in

obsessive-compulsive disorder
Lisa A. Page
a,
, Katya Rubia
b
, Quinton Deeley
c
, Eileen Daly
c
, Fiona Toal
d
, David Mataix-Cols
a
,
Vincent Giampietro
e
, Nicole Schmitz
f
, Declan G.M. Murphy
c
a
King's College London, Division of Psychological Medicine and Psychiatry, Institute of Psychiatry, Room 3.14, Weston Education Centre, 10 Cutcombe Road, London, SE5 9RJ, UK
b
King's College London, Department of Child Psychiatry, Institute of Psychiatry, London, UK
c
King's College London, Section of Brain Maturation, Institute of Psychiatry, London, UK
d
Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital, Dublin, Ireland
e
King's College London, Biostatistics and Computing, Institute of Psychiatry, London, UK
f
Amsterdam Medical Centre, Department of Psychiatry, Amsterdam, The Netherlands
a b s t r a c t a r t i c l e i n f o
Article history:
Received 11 February 2008
Received in revised form 1 April 2009
Accepted 4 May 2009
Keywords:
OCD
Inhibition
Executive function
Functional neuroimaging
Stroop
Go/No-go
Switch
People with obsessive-compulsive disorder (OCD) have abnormalities in cognitive and motor inhibition, and it
has been proposed that these are related to dysfunction of fronto-striatal circuits. However, nobody has
investigatedneuro-functional abnormalities during a range of inhibitiontasks inadults with OCD. The aims of the
study were to compare brain activation of people with OCD and controls during three tasks of inhibitory control.
Tenunmedicatedadults with OCDand 11 healthy controls performed three different tasks of motor and cognitive
inhibitory control during event-related functional magnetic resonance imaging: a Go/No-go task (motor
inhibition), a motor Strooptask(interferenceinhibition) anda Switchtask(cognitive exibility). PeoplewithOCD
displayed signicantly different patterns of brain activation compared to controls during all three tasks. During
the Go/No-go and Switch experiments, people with OCD had underactivation in task-relevant orbitofrontal/
dorsolateral prefrontal, striatal and thalamic regions. During the motor Stroop and Switch tasks, people with OCD
also displayed underactivation in temporo-parietal areas. In the Go/No-go and motor Stroop tasks the OCDgroup
showedincreasedactivationcomparedto controls incerebellumand predominantly posterior brainregions. OCD
is associated with task-relevant fronto-striatal dysfunction during motor inhibition and cognitive switching. In
addition, parieto-temporal dysfunction was observed during tasks with a higher attentional load.
2009 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
There is increasing evidence that fronto-striatal circuits are
abnormal in people with obsessive-compulsive disorder (OCD).
Neuropsychological studies have shown that people with OCD display
abnormalities during tasks of inhibitory control (Chamberlain et al.,
2005; Penads et al., 2007), which are known to be mediated by
fronto-striatal networks. Neuroimaging studies have reported func-
tional and structural abnormalities in inhibition-relevant areas of
orbitofrontal cortex, anterior cingulate and caudate nuclei (Saxena
and Rauch, 2000; Whiteside et al., 2004). Hence it has been suggested
that abnormal inhibitory networks may be implicated in the
pathophysiology of OCD and could account for both of the disorder's
core symptoms; whereby obsessions result from a failure to inhibit
thoughts, and compulsions from a failure to inhibit behaviour
(Chamberlain et al., 2005). Specically, dysfunction of circuits that
link orbitofrontal to subcortical areas are suggested to relate to
abnormal response inhibition in OCD (Chamberlain et al., 2005;
Rosenberg and Keshaven, 1998).
Previous functional imaging studies in OCD have found reduced
activation in frontal, striatal, temporal and parietal regions during
tasks of inhibitory and cognitive control (Martinot et al., 1990; Nakao
et al., 2005; Roth et al., 2007; Woolley et al., 2008). However, results
have been inconsistent with conicting ndings of both increased
and decreased activation of anterior cingulate cortex (ACC) during
tasks of inhibition (Fitzgerald et al., 2005; Maltby et al., 2005; Nakao
et al., 2005). This may have arisen because the majority of studies
were confounded by the inclusion of medicated subjects. Also
different neuroimaging studies used different tasks of inhibitory
control, therefore limiting comparability between investigations. In
this study, therefore, we attempted to overcome these limitations by
studying brain function, using functional magnetic resonance imaging
(fMRI), during a range of tasks of inhibitory control within the same
group of medication-free patients with OCD.
We used three inhibitory tasks that were designed to be as
homogenous as possible in visualspatial presentation, motor require-
ments and length. We measured: 1) motor response inhibition with a
Go/No-go task; 2) cognitive interference inhibition with a motor
Psychiatry Research: Neuroimaging 174 (2009) 202209
Corresponding author. Tel.: +44 207848 5289; fax: +44 207848 5408.
E-mail address: l.page@iop.kcl.ac.uk (L.A. Page).
0925-4927/$ see front matter 2009 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.pscychresns.2009.05.002
Contents lists available at ScienceDirect
Psychiatry Research: Neuroimaging
j our nal homepage: www. el sevi er. com/ l ocat e/ psychr esns
Stroop task; and 3) inhibition of irrelevant stimulusresponse asso-
ciations in order to switch to new relevant ones during a Switch task.
Patients withOCDhave beenreported to be impairedinsimilar tasks of
motor and cognitive inhibition (Chamberlain et al., 2005; Chamberlain
et al., 2006; Menzies et al., 2008; Penads et al., 2007). Furthermore, all
of these tasks activate task-relevant fronto-cingulo-striatal neural
networks ingeneral adult samples; predominantly right fronto-striatal
regions in the Go/No-go task (Rubia et al., 2005a; Rubia et al., 2001;
Rubia et al., 2006), bilateral fronto-striatal and parieto-temporal
regions in the Switch task (Rubia et al., 2006; Smith et al., 2004) and
predominantly left-hemispheric fronto-striatal and parieto-temporal
regions during the motor Stroop task (Rubia et al., 2006). We hypothe-
sized that people with OCD would show abnormal brain activation
in task-relevant prefrontal, striatal and cingulate regions when com-
pared to controls.
2. Methods
2.1. Participants
Ten right-handed menwith OCD(aged over 18 but less than 60 years)
were recruited by advertisement from within OCD local support groups.
They all fullled DSM-IV criteria for OCDas determined by the Structured
Clinical Interview for DSM-IV (SCID-P) (First et al., 1997). Six of the OCD
subjects had predominantly doubting obsessions with checking compul-
sions, three had predominantly contamination obsessions with washing
compulsions, andone hadpredominantly hoarding behaviours. Most OCD
subjects also had obsessive-compulsive symptoms from domains other
thantheir predominant domain. Elevenhealthymalecontrols matchedfor
age, IQ and handedness were recruited locally by advertisement.
Individuals were excluded if they had a history of tic disorder or any
neurological disease. No OCD or control participant was taking psycho-
tropic medication, and all had been medication free for a minimum of
6 weeks prior to MRI scanning (6 OCD participants were medication
nave).
OCDsymptomseveritywas assessedusingtheYale-BrownObsessive
Compulsive Scale (Y-BOCS) (Goodman et al., 1989) and the revised
Obsessive Compulsive Inventory (OCI-R) (Foa et al., 2002). Depressive
symptom severity was assessed with the Beck Depression Inventory
(BDI) (Beck et al., 1961). Anxiety was assessed in two ways; 1) by the
Beck Anxiety Inventory (BAI) (Beck et al., 1988) to assess general state
anxiety, and 2) using a visual analogue scale to measure anxiety about
the scan immediately prior to scanning. Two patients with OCD had a
current co-morbid diagnosis of dysthymic disorder (but no other past or
present Axis-I disorder), three had a past history of major depressive
disorder and one of past alcohol dependence. Full-scale intelligence
quotient (FSIQ) was determined using the abbreviated Wechsler Adult
Intelligence Scale (Wechsler, 1981). Controls scored below clinical
threshold on the Y-BOCS, OCI-R, BDI and BAI. After complete description
of the study to the subjects, written informed consent was obtained. The
study was approved by the local research ethics committee.
As expected, groups did not differ in age and IQ, but OCD
participants had more obsessive-compulsive symptoms and were
signicantly more depressed and anxious than controls. The visual
analogue scale revealed that OCD subjects were signicantly more
anxious about having the scan than controls (see Table 1).
2.2. Functional neuroimaging paradigms
2.2.1. Details of paradigms
Rapid, mixed trial, event-related fMRI designs were used for all tasks
with jittered inter-stimulus intervals (ISI) and randomised events to
optimise statistical efciency. Events were jittered of between 1.6 and
2.0 s for the Go/No-go and motor Stroop tasks. Subjects were trained
onceoneachof the tasks prior toscanningtomakesure theyunderstood
the task instructions. All tasks were presented on a mirror within the
MRI scanner during the scan, and response data were recorded on a
personal computer. Each task lasted about 6 min. Only activations that
were associated with successful trials were included in the analyses.
The Go/No-go and motor Stroop fMRI paradigms have been
described in detail elsewhere (Rubia et al., 2005a; Rubia et al., 2006).
Bothtasks consistedof 208 trials including 24No-go/incongruent trials
(12%) with a mean inter-trial-interval (ITI) of 1.8 s. In the Go/No-go
task, arrows in the centre of the screen pointed either left or right
for 300 ms and the subject had to press the left or right button,
respectively, during the remaining 1.5 s of blank screen. Pseudo-
randomly, No-go arrows pointing upwards (300 ms duration)
appeared on the screen (not at the same time as the Go arrows) and
the subject was instructed not to respond to these. In the motor Stroop
task, the congruent stimuli consistedof arrows placedeither onthe left
of the screen pointing left or the right of the screen pointing right,
appearing for 300 ms, and the subject was required to press the left or
right button respectively. The incongruent (motor Stroop) stimuli
(300 ms duration) consisted of arrows pointing left but appearing on
the right of the screen, or arrows pointing right and appearing on the
left of the screen. The subject was told to press the button according
to the direction of the arrow, and to inhibit the pre-potent tendency to
respond to the predominant spatial information of the side of the
screen upon which it appeared. The event-related analysis for the
Go/No-go and motor Stroop tasks contrasted activation associated
withNo-go/incongruent trials withthat of baseline go/congruent trials
(for details, see Rubia et al., 2006).
The Meiran Switch task (Meiran, 1996) was adapted for fMRI so
that working memory requirements were kept minimal in order to
elicit pure cognitive exibility functions; the task has been described
in detail elsewhere (Rubia et al., 2006; Smith et al., 2004). A target
appeared in one of four corners of a grid with a central arrow. If the
central arrowwas horizontal, the subject indicated whether the target
was on the left or right side of the grid (left or right button) or if the
central arrow was vertical, indicated whether the target was in the
lower or upper half of the grid (up or down button). Every four to six
repeat trials (128 trials in total) there followed a switch trial (19%; 24
trials in total) where the arrow changed position (from horizontal to
vertical or vice-versa) requiring a visualspatial switch. The ITI was
2.4 s. The event-related analysis contrasted activation associated with
switch trials with that of repeat trials see Rubia et al. (2006).
2.2.2. fMRI acquisition
Gradient-echo echo-planar MR imaging (EPI) data were acquired on a
GE Signa 1.5 T Neuro-optimised MR system(General Electric, Milwaukee,
WI, USA) at the Maudsley Hospital, London. Consistent image quality was
ensured by a daily semi-automated quality control procedure. A
quadrature birdcage headcoil was used for RF transmission and reception.
In each of 16 non-contiguous planes parallel to the anteriorposterior
commissure, 208(152for Switchtask) T
2
-weightedMRimages depicting
Table 1
Subject demographic and questionnaire data.
OCD subjects
(n=10)
Control subjects
(n=11)
t-test df P-value
Mean (S.D.) Mean (S.D.)
Age 39.1 years (10.2) 34.1 years (10.1) 1.1 19 0.27
Full scale IQ
a
114 (16) 117 (21) 0.3 15 0.76
Beck Depression Inventory 18.7 (9.8) 2.3 (5.2) 3.7 14 b0.01
Beck Anxiety Inventory 18.2 (14.5) 1.4 (1.3) 3.3 16 b0.01
VAS of anxiety about scan 30% (31) 5% (6) 2.1 14 0.05
Y-BOCS 23.5 (3.9) 0 (0.7) 16.6 16 b0.01
Obsessive Compulsive
Inventory
26.4 (9.7) 3.1 (2.3) 6.2 14 b0.01
VAS = visual analogue scale.
Y-BOCS = Yale-Brown Obsessive Compulsive Scale.
a
As assessed by the WAIS-R (Wechsler, 1981).
203 L.A. Page et al. / Psychiatry Research: Neuroimaging 174 (2009) 202209
BOLD(Blood Oxygen Level Dependent) contrast covering the whole brain
were acquired with TE=40 ms, TR=1.8 s (2.4 s for Switch task), ip
angle=90, in-plane resolution=3.1 mm, slice thickness=7 mm, and
slice-skip=0.7 mm. At the same time, a high resolution inversion
recovery echo-planar image of the whole brain was acquired in the inter-
commissural plane with TE=40 ms, TI =180 ms, TR=16,000 ms, in-
plane resolution=1.5 mm, slice thickness =3 mm, and slice-
skip=0.3 mm. This echo-planar imaging dataset provided almost
complete brain coverage.
2.3. Analysis
In fMRI analysis, most commonly used assessments of the signicance
of the t of the resulting model use normal theory and the validity of the
normality assumption is rarely tested. The method of analysis used in this
study, XBAM(Brammer et al., 1997; Bullmore et al., 1999), makes no such
assumptions. Instead, it uses medianstatistics tocontrol outlier effects and
permutation rather than normal theory based inference. Furthermore the
most common test statistic is computed by standardising for individual
difference in residual noise before embarking on second level, multi-
subject, testing using robust permutation-based methods. This allows a
mixed effects approach to analysis an approach that has recently been
recommended following a detailed analysis of the validity and impact of
normal theory based inference in fMRI in large number of subjects
(Thirion et al., 2007).
Time series analysis for each individual subject was based on a
previously published wavelet-based data resampling method for func-
tional MRI data (Bullmore et al., 1999). Using rigid and afne transforma-
tions, the fMRI data were rst co-registered and subsequently the
individual statistical maps that were obtained were normalised into
Talairach space (Brammer et al., 1997). A generic brain activation map
(GBAM) was then produced for each experimental condition and
hypothesis testing was carried out at the cluster level, shown to give
excellent cluster-wise type I error control instructural andfunctional fMRI
analysis (Bullmore et al., 1999). For eachtask, b1 false positive cluster over
the whole brain was expected at a P-value of b0.05 at the voxel-level and
b0.0025 at the cluster level. ANOVA analysis for between-group
differences was conducted using randomisation-based tests for voxel or
cluster-wise differences as described in detail by (Bullmore et al., 1999).
For this particular groupcomparison, less than1falseactivatedcluster was
expected at a P-value of b0.05 for voxel- and b0.0075 for cluster
comparisons (Bullmore et al., 1999).
2.3.1. Correlations between brain activation and performance/symptoms
Scalar measure of BOLD response (SSQ) for each participant was
extracted in each of the signicant clusters of between-group
activation differences. Pearson correlations were then calculated
between these and performance measures in healthy controls and in
OCD patients separately for each task. In patients, brain activation in
these clusters was correlated with symptom measures on the OCI-R
and Y-BOCS scores and the mood scales (BDI, BAI, VAS). P-values were
corrected for multiple testing using the False Discovery Rate.
3. Results
3.1. Performance data
There were no signicant differences between people with OCD
and controls on any measures of accuracy or response time during
Table 2
Reaction time and accuracy variables for OCD subjects and controls across the tasks.
Task variable Mean (S.D.) t-test P
df =19
Go/No-go task OCD (n=10) Controls (n=11)
Probability of inhibition 96.3% (4.6) 97.3% (3.4) 0.6 0.54
MRT go response/ms 465 (99) 443 (87) 0.5 0.60
Stroop task OCD (n=10) Controls (n=11)
Stroop errors 19.6% (18.8) 15.2% (13.1) 0.6 0.54
MRT congruent trials/ms 642.5 (138.7) 585.4 (156.7) 0.9 0.40
Stroop effect/ms 128.7 (58.4) 120.1 (58.0) 0.3 0.74
Switch task OCD (n=10) Controls (n=10) df =18
Switch errors 8.8% (10.5) 4.6% (4.7) 1.1 0.27
MRT/ms repeat trials 654.6 (146.5) 600.7 (153.7) 0.8 0.43
Switch cost/ms 224.5 (154.6) 194.5 (136.5) 0.5 0.65
MRT = Mean reaction time; Stroop effect: MRT incongruentMRT congruent; Switch
cost: MRT switch trialMRT repeat trial.
Table 3
ANOVA differences in brain activation between the healthy control group and the OCD group for the three tasks.
Task Contrast Brain region Laterality Brodmann
area
Talairach
coordinates
No. of
voxels in
cluster
P-value
of cluster
x y z
Go/No-go (No-goNGo) Control
groupNOCD
group
Cerebellum (vermis) L and R 4 41 24 251 b0.0001
Ventromedial orbitofrontal/anterior cingulate (extending to L
caudate/putamen/thalamus)
L and R 25/32/47/
45
4 7 7 165 0.0010
Anterior cingulate/caudate/putamen/thalamus/hippocampus R 25 36 22 7 107 0.0024
OCD
groupNcontrol
group
Posterior cingulate/middle temporal/lingual gyrus/precuneus R 30/31/39 25 52 9 99 0.0005
Posterior cingulate L 30/31 18 37 20 66 0.0043
Cerebellum (anterior and posterior lobes) L 43 63 24 56 0.0008
Ventromedial frontal cortex R 10 29 44 4 51 0.0059
Middle/superior temporal gyrus R 38/21 47 4 13 48 0.0055
Premotor cortex R 6/4 29 11 48 32 0.0067
Stroop
(incongruent Ncongruent)
Control
groupNOCD
group
Middle temporal gyrus (extending to precuneus/posterior
cingulate
R 39/31 29 59 26 96 0.0017
Middle/superior temporal gyrus R 39/22 51 56 9 78 0.0067
Inferior parietal lobule/superior temporal gyrus L 40/22 40 30 26 47 0.0033
Superior parietal lobule/precuneus L 7/40 11 70 31 40 0.0035
OCD
groupNcontrol
group
Cerebellum/posterior cingulate L 22 63 18 43 0.0061
Switch (switchNrepeat) Control
groupNOCD
group
Dorsolateral prefrontal gyrus (extending to/premotor cortex /
anterior cingulate/caudate/thalamus)
L 9/6/24/32 33 7 42 94 0.0031
Precuneus/posterior cingulate L 7/31 7 44 48 45 0.0074
OCD
groupNcontrol
group

ANOVAs at Pb0.05 for voxel activation. P-values were selected to yield less than one false positive cluster per brain map.
204 L.A. Page et al. / Psychiatry Research: Neuroimaging 174 (2009) 202209
scanning (Table 2). These included measures of Stroop effect and
Switch cost for the motor Stroop and Switch tasks respectively,
representing the mean additional time that a subject took to
successfully respond to the motor Stroop or Switch condition com-
pared to the baseline congruent/repeat conditions.
3.2. Go/No-go task
3.2.1. Within-group comparisons
For the contrast between No-go vs. Go trials, controls signicantly
activated right inferior and orbital frontal areas and left middle frontal
gyrus. In addition there was signicant activation bilaterally in the
fusiform, cerebellum, and inferior parietal lobes. The OCD group had
signicant activation in right medial frontal gyrus and bilaterally in
superior frontal gyri, precentral areas, precuneus and temporal gyri;
and in left cerebellum (Table in Appendix 1).
3.2.2. Between-group comparisons
Controls had signicantly increased activation compared to
people with OCD in a bilateral, but predominantly left-hemispheric
cluster comprising ventromedial orbitofrontal cortex, anterior cin-
gulate gyrus, caudate, putamen and thalamus; in a right hemispheric
cluster comprising caudate, putamen, thalamus and hippocampus;
and in the vermis of the cerebellum. In contrast, individuals with OCD
had signicantly greater activation than controls bilaterally in
posterior cingulate; in right ventromedial frontal cortex, premotor
cortex, temporal gyrus; and in left cerebellar hemispheres (Table 3
and Fig. 1).
3.3. Motor Stroop task
3.3.1. Within-group comparisons
For the contrast between incongruent and congruent trials, the
control group showed widespreadactivationbilaterally ininfero-medial
frontal, right parieto-temporal regions andinleft occipito-parietal areas,
premotor cortex and cerebellum. The OCD group showed bilateral
activation in the inferior/middle frontal gyri, and in the left tempo-
parieto-occipital areas and cerebellum (Table in Appendix 1).
3.3.2. Between-group comparisons
The control group had signicantly greater activation than the
OCD group bilaterally in precuneus, in the right middle and superior
temporal gyri, and in left superior temporo/inferior parietal junction
and superior parietal lobe/precuneus. The OCD group showed
signicantly greater activation than controls only in a left-hemi-
spheric cluster comprising lateral cerebellumand posterior cingulate
gyrus (Table 3 and Fig. 1).
3.4. Switch task
3.4.1. Within-group comparisons
For the contrast of switch-repeat trials, the control group had
signicantly greater activation in the left post-central gyrus, superior
temporal gyrus, bilateral inferior parietal lobe and right anterior and
middle cingulate. In the OCD group, activation for this contrast was
signicantly greater bilaterally in the inferior parietal lobes and post-
central gyri (Table in Appendix 1).
Fig. 1. Between-group differences (orange represents control NOCD; blue represents OCDNcontrol).
205 L.A. Page et al. / Psychiatry Research: Neuroimaging 174 (2009) 202209
3.4.2. Between-group comparisons
The control group showed signicantly greater activation than the
OCD group in a cluster comprising the left middle frontal gyrus,
premotor cortex, anterior cingulate, caudate and thalamus. There was
also increased activation in a cluster including left posterior cingulate
and precuneus. No clusters of increased activation were observed for
the OCD group compared to the control group (Table 3 and Fig. 1).
3.5. The relationship between task performance and differences in brain
function
In the control group for the motor Stroop task, a signicant
negative correlationwas found between the Stroop error score and the
standardised power of BOLD response (SSQ) in the left superior
parietal lobule/left precuneus cluster that was increased in activation
compared to the OCD group (BA 7/40; Pearson correlation r =0.74;
Pb0.01). In the Switch task, a signicant negative correlation was
found within the control group between the Switch cost and
standardised power of BOLD response in the left precuneus/left
posterior cingulate cluster that was increased in activation compared
to the OCD group (BA 7/31; Pearson correlation r=0.81; Pb0.04).
No signicant correlations were observed within the OCD group
between areas of underactivation and performance. In the OCD group,
no signicant correlations were found between symptom severity (as
assessed by either the OCI-R or the Y-BOCS) or between mood scales
(BDI, BAI, VAS) and standardised power of BOLDresponse in any of the
signicantly underactivated clusters for any of the tasks.
4. Discussion
We demonstrated that, despite comparable task performance,
relative to healthy controls, medication-free people with OCD had
dysfunction of task-relevant fronto-striatal and/or parieto-temporal
brain regions during tasks of inhibition. Reduced activation was
observed in task-relevant orbital and dorsolateral fronto-striatal
regions in OCD subjects during the Go/No-go and the Switch tasks,
respectively, while motor Stroop task performance elicited reduced
activation in patients in parieto-temporal brain regions.
We found task-relevant underactivation in task-relevant prefrontal
brain regions; that is the orbitofrontal cortex during the Go/No-go task
and the dorsolateral prefrontal cortex during the Switch task. The
underactivation of orbitofrontal areas is consistent with the nding
that these brain regions are structurally, biochemically and function-
ally abnormal in people with OCD (Busatto et al., 2000; Fitzgerald
et al., 2000; Menzies et al., 2008; Saxena and Rauch, 2000; Whiteside
et al., 2004). The left dorsolateral prefrontal underactivation during
the Switch task is in line with ndings of a correlation between
abnormal blood owin left inferior prefrontal cortex and errors on the
Wisconsin Card Sorting Switching Task in adult OCD (Lucey et al.,
1997). Furthermore, dorsolateral prefrontal cortical activation has
previously been found to be reduced during a ColourWord Stroop
task (Nakao et al., 2005) and during planning (Van den Heuvel et al.,
2005). We have recently reported decits in orbitofrontal cortex
during motor response inhibition and in dorsolateral prefrontal cortex
during the same Switch task in partly remitted adolescent patients
with OCD (Woolley et al., 2008).
In addition we also observed underactivation of subcortical, striatal
and paralimbic brain regions, including caudate, putamen, thalamus and
anterior cingulate gyrus during the Go/No-go and Switch tasks. Caudate
abnormalities have beenidentiedinprevious functional studies at rest in
OCD (Whiteside et al., 2004), but underactivation has also been noted
during tasks of executive functioning; for example during an implicit
learning task (Rauch et al., 1997), a planning task (Van den Heuvel et al.,
2005), anda ColourWordStrooptasks (Martinot et al., 1990; Nakao et al.,
2005). We have also observed caudate underactivation during motor
inhibition in adolescents with OCD (Woolley et al., 2008). Our results
therefore add further evidence that in people with OCD there is
underactivation of fronto-striato-thalamic areas during tasks of motor
inhibition (e.g. the Go/No-go task) and cognitive switching (e.g. the
Switch task). This is consistent with the suggestion that fronto-striatal
function during inhibition is abnormal in OCD and might underpin poor
inhibitory control over intrusive obsessions and compulsions (Chamber-
lain et al., 2005). In the resting state and on symptom provocation
however, previous functional neuroimaging studies have more often
found orbitofrontal areas to be overactive (Saxena and Rauch, 2000).
Graybiel and Rauch proposed that dysfunction of the projections fromthe
orbitofrontal and anterior cingulate cortices to ventral striatum and
caudate may be responsible for symptoms in OCD (Graybiel and Rauch,
2000), which explains why overactivation of these brain regions is found
during symptom provocation in those with the disorder (Adler et al.,
2000; Mataix-Cols et al., 2004). It has been argued that if fronto-striato-
thalamic pathways are chronically over-activated during obsessive and
compulsive symptoms, they may be less recruitable during cognitive
challenge (Evans et al., 2004). Our ndings of fronto-striatal under-
activation during inhibitory performance in OCD are in line with this
theory.
Several previous studies that tested inhibition in OCD have reported
overactivation of anterior cingulate gyrus in a Stroop-like task
(Fitzgerald et al., 2005), a Go/No-go task (Maltby et al., 2005) and in a
continuous monitoring task (Ursu et al., 2003). This is in contrast to our
ndings in the Go/No-go and the Switch tasks, where we found
underactivation. This apparent discrepancy with our results may have
arisen because these previous studies assessed brain activation during
the commissioning of errors (i.e. only when errors occur), whereas we
deliberately considered only successful inhibition of a pre-potent
response. Activity in brain regions involved in inhibitory control may
be reduced in people with OCD, while activity in performance
monitoring areas may be increased. Also, unlike in our study, medicated
participants were included in the studies mentioned above, and both
chronic and acute use of SSRIs has been shown to alter brain activation
(Gerdelat-Mas et al., 2005). Another factor that may have playeda role is
the relatively lower frequency of the No-go and incongruent trials inour
task design compared to those of previous studies. It is possible that
apart from inhibitory mechanisms the attentional oddball effect of the
low frequency of targets could have contributed to the brain under-
activation ndings of this study.
The nding of underactivation in people with OCD in parieto-
temporal brain regions during the motor Stroop task was not predicted,
but is in agreement with a recent study using a Chinese version of the
Stroop task (Nakao et al., 2005) where OCD subjects displayed
underactivation in right temporal areas. Nakao et al. also found hypo-
activation of anterior cingulate and caudate in the OCDgroup, whichwe
did not observe in this task, but did in our other two tasks of inhibition
(Nakao et al., 2005). This latter nding may be accounted for by
differences between task versions. Our motor version of the Stroop is
easier than the ColourWord Stroop, and elicits greater parieto-
temporal activation with relatively less fronto-striatal activation (Liu
et al., 2004; Rubia et al., 2006), presumably due to its high load on
visualspatial selective attentionmechanisms (Rubia et al., 2006; Simon
and Berbaum, 1990) that are mediated by temporal and parietal brain
regions. The importance of parieto-temporal regions for task perfor-
mance is further conrmed in our study by the negative correlation
between Stroop errors and parieto-temporal activation in the control
group. The motor Stroop task measures a cognitive form of inhibition
(inhibition of distraction by interfering information) but does not
require the motor inhibition of the Go/No-go and Switch tasks. The
parieto-temporal underactivationduringtheStrooptaskinOCDpatients
may therefore reect problems with attentional rather than inhibitory
networks per se, in line with neuropsychological evidence for poor
performance in selective attention as well as motor inhibition in OCD
patients (Chamberlain et al., 2005; Nakao et al., 2005; Okasha et al.,
2000; Penads et al., 2007). The Switch task was associated with
206 L.A. Page et al. / Psychiatry Research: Neuroimaging 174 (2009) 202209
underactivation of the precuneus in people with OCD; also there was a
negative correlationbetweenprecuneus activityandthe Switcheffect in
controls but not in OCD, suggesting that this area contributes
importantly to cognitive exibility in controls. There is some previous
evidence in OCDfor structural and functional abnormalities in temporal
and parietal brainregions (Kimet al., 2001; Menzies et al., 2008) andwe
have found these areas to be underactivated in partly remitted
adolescents with OCD during the same Switch and motor Stroop tasks
(Woolley et al., 2008). Our ndings suggest that neural dysfunction in
OCD is not limited to fronto-striatal pathways during motor inhibition,
but is also present in the parieto-temporal attentional networks that are
important for more cognitive forms of inhibition, such as interference
inhibition (keeping irrelevant information out of mind), which is an
important component of cognitive exibility.
Finally, in the Go/No-go and motor Stroop tasks we also found
increased activation in posterior brain regions in people with OCD; in
posterior cingulate, temporal lobe in the Go/No-go task and in left
cerebellum/posterior cingulate during the motor Stroop task. This
suggests that people with OCD may utilise alternative, posterior brain
regions to achieve the same task performance, perhaps compensating for
the reduced activation in task-relevant orbitofronto-cingulo-striatal
regions in the Go/No-go task, and in parieto-temporal networks during
the motor Stroop task.
The ndings of unimpaired performance on tasks of inhibitory
control in adults with OCDare not in line with ndings of decits during
similar tasks of motor inhibition, interference inhibition and cognitive
switching (Chamberlain et al., 2005; Chamberlain et al., 2006; Menzies
et al., 2008; Penads et al., 2007). The subject numbers of this study are
relatively small for neuropsychological analyses, and group differences
may have emerged with larger sample sizes. Furthermore, fMRI
adaptations of cognitive tasks lose behavioural sensitivity and the
tasks were purposely designed to be easy in order to prevent a large
number of errors in patients. Reduced brain activation despite normal
task performance has previously been observed in OCD (Nakao et al.,
2005) and other psychiatric patient groups (Rubia et al., 2005b; Schmitz
et al., 2006) suggesting that reduced brain activation during task
performance may be a sensitive index of neurocognitive dysfunction
even in the absence of differences in behavioural performance.
We did not nd any correlations between the severity of OCD
symptoms and brain activation changes. Although the correlation
ndings need to be considered preliminarily given the low subject
numbers of this study, this could suggest that the observed brain
dysfunctions are trait rather than state effects. This would be further
supported by the similarities between the observed abnormalities in
prefrontal, striatal and parietal brain regions in this patient group
compared to those we have previously observed in a treated and
partially remitted adolescent OCD group (Woolley et al., 2008).
4.1. Study limitations
We only included males, and so generalisability of our ndings is
limited. It is also possible that our results are confounded by
symptoms of depression in the OCD group as, although none met
the criteria for a current diagnosis of major depressive disorder, and
two met the criteria for dysthymic disorder. Moreover, the OCD group
scored signicantly higher on the Beck Depression Inventory than
controls. Likewise, anxiety ratings were signicantly higher in the
OCD group, which could potentially have confounded our ndings,
albeit that there is a strong case for considering both depression and
anxiety to be a core component of the disorder (Tynes et al., 1990).
Due to unequality of the variances of mood scores between patients
and controls, it was not appropriate to covary for mood ratings in the
between-group fMRI analyses. However the correlational analyses
suggest that anxiety/depression levels were not related to the
observed changes in BOLD response.
The diagnostic specicity of the ndings remains to be established
as it is possible that decits in inhibitory processes are not specic to
OCD but to a variety of neuropsychiatric disorders, such as ADHD
(Rubia et al., 2005b). The patient sample was too small to perform
correlation analyses between specic symptom dimensions and brain
activation during these tasks. This will be important in future studies
because it is plausible that different symptomdimensions of OCDhave
distinct neural correlates e.g. Mataix-Cols et al., 2004.
4.2. Conclusions
In summary, using 3 different tasks of inhibitory control we demon-
strate that people with OCD have signicantly reduced activation in task-
relevant brainregions, despitehavingnoclinicallydetectableperformance
differences. In addition, our ndings suggest an important role for
abnormalities in attentional networks mediated by parieto-temporal
networks. These results are congruent withtheories that peoplewithOCD
have functional abnormalities in fronto-striato-thalamic pathways during
motor and cognitive inhibition. Whether these ndings are specic to
OCD, whether there are particular subtypes of OCD who display these
abnormalities to a greater extent and whether the abnormalities are
reversible with treatment remain to be investigated. We propose that
inadequate control over the obsessions andcompulsions that characterize
OCDmayrelatetoabnormalities intheneural substrates for inhibitoryand
attentional control.
Acknowledgements
This work was supported by the South London and Maudsley NHS
Foundation Trust, and the MRC UK A.I.M.S. programme.
Appendix A
Table
Brain activation for each of the two groups for the three tasks.

Task Group Brain region Laterality Brodmann

area
Talairach
coordinates
No. of
voxels in cluster
P-value
of cluster
x y z
Go/No-go
(No-goNBaseline)
Controls Fusiform gyrus R 37 36 52 7 195 0.0002
Cerebellum (anterior and posterior lobes) L and R 4 41 24 148 0.0005
Fusiform gyrus/inferior temporal gyrus L 37/19 47 52 13 110 0.0005
Cuneus/middle occipital gyrus L 18 22 81 20 82 0.0017
Inferior parietal lobe/supramarginal gyrus L 40/39 36 41 42 81 0.0049
Lingual gyrus/middle temporal gyrus R 17/18/22 7 85 4 76 0.0032
Inferior/superior parietal lobe R 40/7 40 56 48 56 0.0076
Orbitofrontal cortex R 11 29 52 13 29 0.0246
Middle frontal gyrus L 10 33 52 2 27 0.0224
Inferior frontal gyrus R 44 47 19 26 25 0.0148
Middle temporal gyrus R 21 47 63 4 21 0.0246
(continued on next page) (continued on next page)
207 L.A. Page et al. / Psychiatry Research: Neuroimaging 174 (2009) 202209
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Task Group Brain region Laterality Brodmann
area
Talairach
coordinates
No. of
voxels in cluster
P-value
of cluster
x y z
OCD
patients
Cerebellum (posterior lobe) L 43 63 24 210 0.0003
Precuneus/inferior occipital gyrus/middle/inferior temporal gyrus L 7/19/32 33 56 48 138 0.0006
Posterior cingulate/cuneus/lingual gyrus R 30/18/19 22 63 9 134 0.0006
Superior/medial frontal gyrus R 10/11 7 59 13 82 0.0040
Inferior/middle temporal gyrus/ precuneus/superior parietal lobule R 37/7 54 56 2 80 0.0051
Precentral gyrus R 4 29 7 48 73 0.0062
Cerebellum (vermis) L 4 67 13 36 0.0190
Precentral gyrus L 4 29 11 48 32 0.0136
Medial frontal gyrus R 46 33 33 26 28 0.0105
Superior frontal gyrus L 10 25 56 2 25 0.0105
Cuneus L 18 25 74 9 23 0.0204
Stroop
(StroopNBaseline)
Controls Middle temporal gyrus/fusiform gyrus/ inferior parietal gyrus/
middle/superior temporal gyrus
R 39/37/22/
40/19
29 59 26 540 0.0003
Precuneus/fusiform gyrus/middle occipital gyrus/inferior parietal
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L 7/19/40 14 70 37 526 0.0003
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OCD
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31
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Switch
(SwitchNBaseline)
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OCD
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