r Human Brain Mapping 32:601–611 (2011) r
Disorder-Specific Dysfunctions in Patients With
Compared to Patients With Obsessive-Compulsive
Disorder During Interference Inhibition and
Katya Rubia,1* Ana Cubillo,1James Woolley,2Michael J. Brammer,3
and Anna Smith1
1Department of Child Psychiatry, Institute of Psychiatry, King’s College London, London, UK
2Department of Psychological Medicine, Institute of Psychiatry, King’s College London, London, UK
3Department of Biostatistics and Computing, Institute of Psychiatry, King’s College London, London, UK
Abstract: Background: Abnormalities in inhibitory control and underlying fronto-striatal networks is
common to both attention deficit hyperactivity disorder (ADHD) and obsessive-compulsive-disorder
(OCD). The aim of this study was to investigate disorder-specific abnormalities in neural networks
mediating interference inhibition and selective attention. Method: Event-related functional magnetic res-
onance imaging (fMRI) was used to compare brain activation of boys with ADHD (18), with OCD (10),
and healthy boys during (20) during a Simon task that measures interference inhibition and controls
for and therefore comeasures attention allocation. Results: During interference inhibition, both patient
groups shared mesial frontal dysfunction compared to controls. Disorder-specific dysfunctions were
observed in OCD patients in dorsolateral prefrontal cortex during the oddball condition and in ADHD
patients in inferior parietal lobe during interference inhibition and in caudate and posterior cingulate
during the simpler oddball condition. The decreased activation in caudate and cingulate in ADHD
was furthermore negatively correlated with ADHD symptoms and positively with OCD behavioral
traits. Conclusions: The study shows that ADHD and OCD patients have shared but also disorder-spe-
cific brain dysfunctions during interference inhibition and attention allocation. Both disorders shared
dysfunction in mesial frontal cortex. Disorder-specific dysfunctions, however, were observed in dorso-
lateral prefrontal cortex in OCD patients and in caudate, cingulate, and parietal brain regions in
ADHD patients. The disorder-specific dissociation of striato-cingulate activation that was increased in
OCD compared to ADHD patients, was furthermore inversely related to the symptomatology of the
two disorders, and may potentially reflect differential dopamine modulation of striatal brain regions.
Hum Brain Mapp 32:601–611, 2011.
C 2010 Wiley-Liss, Inc.
None of the authors has any interest to declare.
Contract grant sponsor: Medical Research Council; Contract grant
numbers: G9900839, GO300155; Contract grant sponsor: The
Wellcome Trust; Contract grant number: 053272/Z/98/Z/JRS/JP/
JAT; Contract grant sponsor: PPP Healthcare Foundation; Contract
grant number: 1206/1568; Contract grant sponsor: Alicia Koplowitz.
*Correspondence to: Katya Rubia, Department of Child Psychia-
try, Institute of Psychiatry, King’s College London, London, UK.
Received for publication 3 June 2009; Revised 12 February 2010;
Accepted 14 February 2010
C 2010 Wiley-Liss, Inc.
Keywords: obsessive-compulsive disorder; attention deficit hyperactivity; disorder; fMRI; inhibition;
Attention deficit hyperactivity disorder (ADHD) is char-
acterized by symptoms of inattention, impulsiveness, and
hyperactivity [DSM IV, American Psychiatric Association,
1994]. ADHD is associated with neuropsychological defi-
cits in motor response inhibition and interference inhibi-
tion, the ability to protect a response from interference
from a predominant, distracting information [Rubia et al.,
2001b, 2007b; Sergeant et al., 2002]. Functional magnetic
resonance imaging (fMRI) studies of interference inhibition
in children with ADHD have been inconsistent, finding ei-
ther reduced frontal-striatal [Konrad et al., 2006], or tem-
poral parietal activation [Rubia et al., 2009a; Vaidya et al.,
2005], or no dysfunction [Booth et al., 2005; Smith et al.,
2006]. Electrophysiological (EEG) and fMRI studies have
further observed abnormalities in simpler selective atten-
tion tasks such as perceptual attention allocation to rare,
‘‘oddball’’ stimuli in frontal, temporal, and parietal areas
[Barry, 2003]; [Rubia et al., 2007b]; [Rubia et al., 2009a];
[Stevens et al., 2007]; [Tamm et al., 2006].
OCD is characterized by poor inhibition over intrusive,
unwanted obsessive thoughts and compulsions (DSM IV),
[American Psychiatric Association, 1994]. Patients with
OCD also have deficits in tasks of inhibitory control,
including motor response and interference
[Chamberlain et al., 2006; Menzies et al., 2008; Penades
et al., 2007]. Adults and children with OCD also have
structural [Huyser et al., 2009; Menzies et al., 2007, 2008]
and functional abnormalities in inhibitory fronto-striatal
networks and in temporo-parietal attention networks
[Menzies et al., 2008; Woolley et al., 2008].
Therefore it has been argued that the underlying aetio-
pathophysiology for both disorders is an abnormality in
fronto-striatal inhibitory neural networks [Huyser et al.,
2009; Menzies et al., 2008; Rubia et al., 1999, 2005b, 2008].
A shared pathophysiology, however, is at odds with a rel-
atively clear symptomatic distinction of the two disorders,
with compulsivity and impulsivity often considered as sit-
uated at opposite ends of a behavioral spectrum [Carlsson,
2000]. Only about 8% of ADHD children meet OCD crite-
ria, while up to 30% of OCD children meet criteria for
ADHD [Geller et al., 1996, 2000]. It remains to be clarified
whether there is overlap or differences in the inhibitory
networks that are affected in these two disorders. Such a
difference at the neurofunctional level would provide dis-
order-specific biomarkers that could assist with differential
diagnosis and treatment. No functional imaging study, to
our knowledge, however, has compared these two disor-
ders during inhibition or any other functions.
The aim of this study was therefore to use fMRI to
investigate the differences and commonalities in the neural
substrates of interference inhibition and simple perceptual
attention allocation in pediatric noncomorbid OCD com-
pared to pediatric noncomorbid ADHD. For this purpose
we used a Simon task—measuring interference inhibition
and selective attention—that controls for the attentional
oddball effect of low frequency appearance of incongruent
trials, and thus also comeasures simple perceptual selec-
tive attention to compare healthy children with those with
clinical ADHD and OCD. Based on previous evidence
from fMRIstudies inadolescents
hypothesized that ADHD children compared to controls
would show reduced activation in lateral fronto-striato-
cingulate and superior temporal and inferior parietal brain
regions during interference inhibition [Konrad et al., 2006;
Rubia et al., 2009a; Vaidya et al., 2005] and in inferior fron-
tal and superior temporal regions during attention alloca-
tion [Rubia et al., 2007b, 2009a,b; Stevens et al., 2007;
Tamm et al., 2006]. On the basis of our previous fMRI
study in pediatric OCD, we hypothesized that adolescents
with OCD would be characterized by different abnormal-
ities compared to controls and ADHD patients in the acti-
vation of dorsolateral and orbital frontal regions during
interference inhibition and in different parieto-temporal
brain regions during attention allocation [Woolley et al., 2008].
Patients were right-handed, male adolescents between 9
and 16 years, 10 with a clinical diagnosis of OCD (mean
age ¼ 13 years 9 months, SD ¼ 1 year) and 18 with a clini-
cal diagnosis of ADHD (mean age ¼ 14 years 3 months,
SD ¼ 2 years), recruited from clinics, parent support
groups, and advertisement. Clinical diagnosis of combined
hyperactive-impulsive subtype of ADHD without the diag-
nosis of OCD and of OCD without clinical ADHD symp-
toms (DSM IV) [American Psychiatric Association, 1994]
was established through interviews with a child psychia-
trist using the Maudsley diagnostic interview [MDI; Gold-
berg and Murray, 2002]. Exclusion criteria for both patient
groups were drug- and substance-abuse and a history of a
general or specific learning disability or comorbidity with
any other major psychiatric disorder as assessed using the
child behavior checklist [Achenbach and Edelbrook, 1983]
and the MDI. The exception was comorbidity with CD for
the ADHD group, present in one patient.
All patients with ADHD scored above threshold (over
six) on the inattention/hyperactivity scale of the parent
strength and difficulty questionnaire (SDQ) [Goodman,
1997] and above the 5th percentile on the Raven’s standard
rRubia et al. r
r 602 r
progressive matrices intelligence questionnaire (IQ), [i.e.,
converted IQ estimate over 75; Raven, 1960]. All patients
were medication-naı ¨ve.
Patients with OCD were treated and in partial remis-
sion. This group was selected as we were interested in
trait effects and wanted to minimize the confounding
impact of concurrent anxiety, ritualizing, or the potential
need to inhibit obsessions or compulsions during fMRI. A
pretreatment CY-BOCS [Children’s Yale-Brown obsessive
compulsive scale; Scahill et al., 1997], (mean total score ¼
20.5, range: 12–33) was repeated before scanning (mean
total score: 11, range: 2–21) and confirmed significant
symptomatic improvement (46% for obsessions and 49%
for compulsions). Some residual symptoms were present
in all subjects at scanning (mean total CY-BOCS score: 11,
range: 2–21). Predominant symptom subtypes were wash-
ing and checking. To avoid potential state effects of anxi-
ety and depression, additional exclusion criteria were
scores above 15 on the Birleson depression questionnaire
[Birleson, 1981] and above 19 on the Revised Children
Manifest Anxiety scale [R-CMAS; Reynolds and Rich-
mond, 1978]. They also underwent SDQ ratings for inat-
tention and restlessness at initial assessment. Two OCD
patients scored above threshold for inattention/restless-
ness on the parent SDQ questionnaire but were not
excluded on the basis the fact that inattention is common
in patients with OCD and that patients did not meet clini-
cal criteria for ADHD based on the clinical interview. The
majority of patients (n ¼ 8) were being treated with a
selective Serotonin reuptake inhibitor (SSRI), (mean: 5
months, range: 2–12). Treated patients were selected in the
OCD patient group in order to keep state effect confounds
of concurrent anxiety, depression, and ritualizing to a min-
imum during MR scanning. Five patients had completed a
course of cognitive behavioral therapy (mean, eight ses-
sions, range: 4–10). Their IQ estimates were above 75.
Control subjects were 20 right-handed male healthy ado-
lescents between 10 and 17 years (mean age ¼ 14 years,
5 months, SD ¼ 1) with an IQ estimate of over 75 and no
history of any mental or neurological disorder, or of
neuro-tropic medication or drug- and substance-abuse.
Written informed consent/assent was given for all par-
ticipants and the study was approved by the local Ethical
One-way ANOVA with group as factor showed that, as
expected, ADHD patients scored significantly higher than
OCD patients on the SDQ ratings for inattention/hyperac-
tivity [Mean SDQ (SD) ADHD: 9 (1); OCD: 5 (3); t ¼ 5,
df ¼ 26, P < 0.0001]. Groups did not differ significantly in
age. However, there was a significant effect for IQ estimate
[Controls: IQ estimate mean (SD) ¼ 104 (15); range: 81–
125; ADHD ¼ 93 (9) range: 75–114; OCD ¼ 102 (20); range:
81–140; F(2, 45) ¼ 3, P < 0.045]. Post-hoc test (Bonferroni
corrected) showed that ADHD children had a significantly
lower IQ compared to healthy controls (P < 0.045). Conse-
quently, all behavioral and fMRI analysis were conducted
covarying for IQ.
fMRI Paradigm: Simon Task
Subjects practiced the Simon task once prior to scanning.
The 6-min fMRI adaptation of the Simon task involves a
stimulus-response incompatibility effect and measures in-
terference inhibition and selective attention and controls
for the attentional oddball effect [Rubia et al., 2006, 2007b,
2009a; Smith et al., 2006].
Subjects have to press a left/right button depending on
whether an arrow stimulus of 300-ms duration points ei-
ther to the left or right side of the screen. The mean ITI
was 1.8 s, but jittered between 1.6 and 2 s for optimal sta-
tistical efficiency of fast event-related FMRI data analysis
[Dale, 1999]. In congruent trials (160 trials), the arrow
pointing left (right) appears on the left (right) side of the
screen. In 12% of trials (24 trials), arrows appear on the
opposite side of where they point and subjects have to in-
hibit responding according to the interfering, predominant
spatial information while continue to respond to the iconic
information (arrow direction). To control for the atten-
tional oddball effect of the low frequency appearance of
the incongruent trials, slightly slanted ‘‘oddball’’ but con-
gruent stimuli appeared in another 12% of trials (24 trials),
to which subjects have to respond to as to the congruent
stimuli (see Fig. 1).
Response times are typically slower and more erratic to
incongruent compared to congruent trials, called the con-
flict reaction time and conflict error effects, respectively
(conflict RT/error effect: MRT/error incongruent – MRT/
The event-related analysis compares successfully per-
formed incongruent with successfully performed oddball
trials to measure the neural correlates of interference inhi-
bition, controlling for the attentional oddball effect (incon-
gruent-oddball trials). The attentional oddball effect is
measured in the comparison of oddball with congruent tri-
als (oddball-congruent trials).
Analysis of Performance Data
Repeated measure ANCOVA with group as factor with
three levels and IQ as covariate were used to compare the
main performance variables of the Simon and the oddball
conditions between the three groups. Post-hoc compari-
sons were conducted for significant group effects using
fMRI Image Acquisition
Gradient-echo echoplanar MR imaging (EPI) data were
acquired on a GE Signa 1.5T Horizon LX System (General;
Electric, Milwaukee, WI) at the Maudsley Hospital, Lon-
don. Consistent image quality was ensured by a semiauto-
mated quality control procedure. A quadrature birdcage
head coil was used for RF transmission and reception. In
each of 16 noncontiguous planes parallel to the anterior–
rDisorder-specific dysfunctions in ADHD and OCD r
r 603 r
depicting BOLD (blood oxygen level dependent) contrast
covering the whole brain were acquired with TE ¼ 40 ms,
TR ¼ 1.8 s, flip angle ¼ 90?, in-plane resolution ¼ 3.1 mm,
slice thickness ¼ 7 mm, slice-skip ¼ 0.7 mm.
fMRI Image Analysis
We used the software package of XBAM (http://
www.brainmap.co.uk) [Brammer et al., 1997] that makes
no normality assumptions, which are usually violated in
fMRI data, but instead uses median statistics to control for
outlier effects and robust permutation rather than normal
theory-based inference. Furthermore the most common
test statistic is computed by standardizing 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 analy-
sis—an approach that has recently been recommended fol-
lowing a detailed analysis of the validity and impact of
normal theory-based inference in fMRI in large number of
subjects [Thirion et al., 2007].
fMRI data were realigned to minimize motion-related
artifacts [Bullmore et al., 1999], and smoothed using a
Gaussian filter (full-width half maximum, 7.2 mm). Time-
series analysis of individual subject activation was per-
formed using XBAM, with a wavelet-based resampling
method previously described [Bullmore et al., 2001].
Briefly, we first convolved each experimental condition
with two Poisson model functions (delays of 4 and 8 s).
We then calculated the weighted sum of these two convo-
lutions that gave the best fit (least-squares) to the time se-
ries at each voxel. A goodness-of-fit statistic (the SSQ-
ratio) was then computed at each voxel consisting of the
ratio of the sum of squares of deviations from the mean
intensity value due to the model (fitted time series) di-
vided by the sum of squares due to the residuals (original
time series minus model time series). The appropriate null
distribution for assessing significance of any given SSQ-ra-
tio was established using the wavelet-based data resam-
pling method [Bullmore et al., 2001] and applying the
model-fitting process to the resampled data. This process
was repeated 20 times at each voxel and the data com-
bined over all voxels, resulting in 20 null parametric maps
of SSQ-ratio for each subject, which were combined to
give the overall null distribution of SSQ-ratio. The same
permutation strategy was applied at each voxel to pre-
serve spatial correlation structure in the data. Activated
voxels, at a <1 level of Type I error, were identified
through the appropriate critical value of the SSQ-ratio
from the null distribution. For the fMRI analysis of the
Simon condition, activation associated with congruent tri-
als was subtracted from activation associated with oddball
trials. For the analysis of the oddball condition, activation
associated with congruent trials was subtracted from acti-
vation related to oddball trials. Individual maps were reg-
istered into standard Talairach space using rigid-body and
Generic group activation maps were then produced for
the two task conditions. Individual SSQ-ratio maps were
transformed into standard space, first by rigid body trans-
formation of the fMRI data into a high-resolution inversion
recovery image of the same subject, and then by affine
transformation onto a Talairach template. Instead of rely-
ing on asymptotic distributions such as t or F that assume
data normality, we use data-driven, permutation-based
methods with minimal distributional assumptions that are
more suitable for fMRI data analysis in this kind of sizes
[Zhang et al., 2009]. A generic activation group map was
produced for each experimental condition by calculating
the median observed SSQ-ratio over all subjects at each
voxel in standard space and testing them against the null
distribution of median SSQ-ratios computed from the iden-
tically transformed wavelet resampled data [Brammer
Schematic representation of the fMRI Simon task. Subjects
respond to the iconic information (direction of arrow) and have
to inhibit the predominant tendency to respond to the spatial
information in incongruent trials (side of arrow appearance). In
oddball trials the stimulus is congruent but slightly slanted.
rRubia et al. r
r 604 r
et al., 1997]. Then thresholding at any required level of sig-
nificance proceeds exactly as for normal t or F tests where
the observed statistic is tested against the appropriate criti-
cal value from a theoretical rather than a data-derived dis-
tribution. The voxel-level threshold was first set to 0.05 to
give maximum sensitivity and to avoid Type II errors.
Next, a cluster-level threshold was computed for the
resulting 3D voxel clusters such that the final expected
number of Type I error clusters was <1 per whole brain.
The necessary combination of voxel and cluster level
thresholds was not assumed from theory but rather was
determined by direct permutation for each dataset, giving
excellent Type II error control [Bullmore et al., 1999]. Clus-
ter mass rather than a cluster extent threshold was used,
to minimize discrimination against possible small, strongly
responding foci of activation [Bullmore et al., 1999, 2001].
Briefly, a voxel-wide significance threshold was set (P <
0.05), and surviving voxels were assembled into 3D clus-
ters using a contiguity criterion. The mass of each cluster
was calculated by adding the statistical values of all clus-
ter members and thresholded at P < 0.01. Less than one
false positive activation locus was expected for P < 0.05 at
voxel level and P < 0.01 at cluster level.
For the between-group comparisons, one-way ANCOVA
analysis with IQ as covariate and group as factor with
three levels was conducted using randomization-based test
for voxel or cluster-wise differences as described above
[Bullmore et al., 1999, 2001]. For these between-group com-
parisons, less than 1 false activated cluster was expected at
a P-value of P < 0.05 for voxel and P < 0.01 for cluster
comparisons. Then scalar
response for each participant were extracted in each of the
significant clusters of the one way ANCOVA analysis and
post-hoc t-tests (using Bonferroni correction) were con-
ducted on these measures to identify comparisons between
the different groups.
Correlation Between Brain Activation,
Performance, and Symptoms
Scalar measure of mean BOLD response for each partici-
pant was extracted in each of the significant clusters of
between-group activation differences. Pearson correlations
(two-tailed) were then calculated between brain activation
and eitherSDQ inattention/hyperactivity
ADHD patients or CY-BOCS obsession and compulsion
scores in OCD patients.
Repeated measures ANCOVA with group as factor and
trial-type as within-subject levels (congruent, incongruent,
and oddball) was conducted for reaction times and errors.
There was a significant within-subjects effect on reaction
times (F ¼ 3, df ¼ 2, P < 0.05) which was due to a within-
subject linear effect (F ¼ 5, df ¼ 1, P < 0.03) where all sub-
jects had the slowest reaction times in the Simon condition,
followed by the oddball condition, with the fastest reaction
times for the congruent trials. There was also a significant
reaction time by group effect (F ¼ 4, df ¼ 3, P < 0.02). Post-
hoc group comparisons showed that this was due to a larger
Simon RT effect in patients with OCD when compared to
ADHD patients (P < 0.027) (see Table I).
For errors, there was a significant effect of trial type on
errors within subjects (F ¼ 13, df ¼ 2, P < 0.0001), which
was due to all subjects making more errors to incongruent
compared to congruent or oddball trials (see Table I).
Multivariate test, however, showed no group by error
effect (F ¼ 1, df ¼ 4, P ¼ n.s.).
ANOVA showed no significant between-group differen-
ces in the extent of 3D motion during task performance.
Oddball—Congruent trials. Within-group activations are
shown in Figure 2a. Controls activated medial and dorso-
lateral prefrontal cortex, posterior cingulate/precuneus,
superior temporal gyri, inferior parietal lobe, visual cortex,
TABLE I. Performance variables of the Simon task by group
(N ¼ 20)
ADHD (N ¼ 18)
OCD (N ¼ 10)
MRT ¼ mean reaction time (ms); SD ¼ intra-subject standard deviation.
rDisorder-specific dysfunctions in ADHD and OCD r
r 605 r
and cerebellum. ADHD children activated posterior cingu-
late and precuneus. OCD patients activated posterior cin-
gulate, precuneus, and hippocampal gyrus.
ANCOVA with group as factor showed a significant
group effect in the activation of right dorsolateral prefron-
tal cortex and of bilateral posterior cingulate (Table II,
Fig. 3a). Post hoc t-tests (peak; Bonferroni corrected)
response in right dorsolateral prefrontal cortex compared
to controls (P < 0.001) and compared to ADHD patients (P
< 0.001). ADHD patients did not differ from controls in
this measure. ADHD patients, however, showed under-
activation in the posterior cingulate gyrus activation clus-
ter compared to controls (P < 0.029) and compared to
OCD patients (P < 0.012), both of which did not differ
from each other.
In patients with OCD, BOLD response in the posterior
cingulate activation cluster was positively correlated with
the CY-BOCS obsession scores (r ¼ 0.7, P < 0.015) but not
the compulsion score. In patients with ADHD, SDQ scores
of inattention/hyperactivity were significantly negatively
correlated with brain activation in this region (r ¼ ?0.5,
P < 0.03). No other correlations were observed.
Incongruent—Oddball trials. Group activations for each
group are shown in Figure 2b. In line with previous find-
ings in healthy adults and children using the same inter-
ference inhibition task [Rubia et al., 2006; Smith et al.,
2006], controls activated bilateral ventrolateral and dorso-
lateral prefrontal cortex, putamen and thalamus, middle
temporal gyrus, inferior parietal gyri, and anterior cingu-
ADHD activated right lateral prefrontal cortex, mesial
frontal cortex and anterior and posterior cingulate, caudate
and putamen. OCD patients activated left inferior prefrontal
cortex, and right inferior parietal/middle temporal gyri.
ANCOVA showed two significant group effect clusters
in right anterior cingulate/SMA and right inferior parietal
lobe. Post-hoc comparisons showed that the cluster in pari-
etal lobe was significantly reduced in ADHD patients com-
pared to controls and OCD patients (P < 0.01) who did
not differ from each other. The cluster in SMA was reduced
in both patient groups compared to controls (P < 0.05).
Patients did not differ from each other in this measure.
No correlations were observed in patients between be-
havioral scores and clusters of significant group effect
Axial slices for the group activation maps for the three groups
at P < 0.05 for voxel and P < 0.01 for cluster levels for the (a)
Oddball condition (oddball—congruent trials) (b) Simon condi-
tion (incongruent—oddball trials). Red ¼ Controls; Green ¼
ADHD; Blue ¼ CD. Overlapping brain regions: Yellow: overlap
between ADHD and Controls; Magenta: overlap between CD
and Controls. Cyan: overlap between ADHD and CD. White:
overlap between all groups. Talairach z-coordinates are indicated
for slice distance (in mm) from the inter-commissural line. The
right side of the picture corresponds to the right side of the
brain. For the ADHD group in the oddball-congruent contrast a
cluster p value of P < 0.025 is shown as they showed no activa-
tion at P < 0.01.
TABLE II. ANCOVA differences in brain activation between healthy adolescents and those with ADHD and OCD
Subject contrastBrain regions of activation (Brodman area; BA)
OCD, C > ADHD
C, ADHD > OCD
C > ADHD, OCD
C, OCD > ADHD
R posterior cingulate/caudate (BA 31/23)
R superior/middle frontal gyrus (BA 8/9/6)
R SMA/anterior cingulate/superior parietal (6/32/7)
R inferior parietal lobe (BA 39/40)
N voxels ¼ number of voxels. P-value for ANCOVAs at P < 0.05 for voxel activation and P < 0.01 for cluster activation. Those P-values
were selected to yield less than one false positive cluster per brain map. SMA ¼ supplementary motor area.
rRubia et al. r
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Discriminant Analysis to Test the Ability of
Brain Activation Difference Clusters to
Predict Group Membership
To explore whether the brain activation clusters that dif-
fered between groups were sensitive enough to predict
group membership, we computed separate discriminant
analysis from group sizes using leave-one-out classification
using the scalar measures of mean BOLD response for
each participant for each of the significant clusters of
between-group activation differences. For the parietal acti-
vation cluster that was decreased in ADHD patients com-
pared to both controls and OCD patients (who had the
highest activation) during the interference inhibition con-
dition, the specificity was relatively moderate with 60%
ADHD patients, however, was very high with 89.9% cor-
rect group classification, but moderate for OCD with 60%
For the oddball condition, two clusters differed between
groups, the posterior cingulate/caudate cluster that was
decreased in activation in ADHD compared to OCD and
controls and a frontal lobe cluster that was disorder-specif-
ically reduced in OCD compared to the other two groups.
Specificity as well as sensitivity for the posterior cingu-
late/caudate cluster was relatively moderate with 55% cor-
rect classification of controls, and 60% sensitivity to
classify ADHD and OCD patients. The prefrontal lobe
cluster was the least sensitive, with 50% correct classifica-
tion of controls and 33% sensitivity to classify OCD
patients and 22% sensitivity to classify ADHD patients.
For all subjects, the Simon condition was the most diffi-
cult condition as shown in higher error rates and slower
reaction times for this condition compared to the oddball
or congruent conditions. Reaction times to oddball trials
were also slower for all subjects compared to the congru-
ent condition, suggesting that attention allocation to infre-
quent trials led to a slowing of reaction time, presumably
reflecting the attentional oddball effect. No group differen-
ces, however, were observed during performance of the
simple selective attention (oddball) condition. There were
significant group differences, however, for the Simon inter-
ference effect on reaction times, which was significantly
Axial sections showing the ANCOVA results for the between-
group differences in brain activation at P < 0.05 for voxel and
P < 0.01 for cluster levels for the contrast of (a) Oddball condi-
tion (Oddball—congruent trials). The activation cluster in right
dorsolateral prefrontal cortex was disorder-specifically reduced
in patients with OCD when compared to healthy controls and
ADHD patients, while the activation cluster in posterior cingu-
late and caudate was disorder-specifically reduced in ADHD
compared to both OCD and controls. (b) Simon condition
(Incongruent - oddball trials). The cluster in SMA/anterior cingu-
late was reduced in both patient groups compared to healthy
controls. The right inferior parietal activation, however, was spe-
cifically reduced in ADHD patients compared to both healthy
controls and OCD patients. Talairach z-coordinates are indicated
for slice distance (in mm) from the inter-commissural line. The
right side of the picture corresponds to the right side of the brain.
rDisorder-specific dysfunctions in ADHD and OCD r
r 607 r
higher for OCD compared to ADHD patients. The fMRI
data showed that during the interference inhibition condi-
tion, boys with ADHD and with OCD shared under-acti-
vation compared to controls in anterior cingulate, the SMA
and in the dorsal superior parietal lobe. Disorder-specific
dysfunctions were observed in OCD patients in right dor-
solateral prefrontal cortex during the oddball condition.
ADHD patients showed disorder-specific dysfunctions in
posterior cingulate and caudate during the oddball condi-
tion and in right inferior parietal lobe during interference
inhibition. Furthermore, the activation cluster in posterior
cingulate and caudate showed a disorder-specific dissocia-
tion with respect to disorder symptomatology: it correlated
negatively with ADHD symptoms and positively with
During the attentional oddball condition, both disorders
showed disorder-specific under-activations. Right dorsolat-
eral prefrontal cortex (DLPFC) was exclusively under-acti-
vated in OCD patients, while ADHD patients showed
exclusive posterior cingulate and caudate under-activation.
Dysfunction in right DLPFC is a consistent finding in
adults with OCD during higher executive selective atten-
tion and planning tasks [Menzies et al., 2008] and has pre-
viously been observed in children with OCD during
inhibition failures [Woolley et al., 2008]. The findings
show that patients with OCD recruit the DLPFC activation
to a lesser extent not only during higher-level executive
function tasks but already during simple perceptual func-
tions of attention allocation and, furthermore, that this is
disorder-specific when compared to ADHD.
This activation cluster in caudate and posterior cingulate
was significantly decreased in ADHD compared to con-
trols and OCD patients, who had a nonsignificantly ele-
vated BOLD response compared to controls (see Fig. 3a).
There was furthermore an interesting dissociation in the
relationship between the activation cluster and disorder-
specific symptomatology. Activation in this region corre-
lated positively with OCD symptoms, but negatively with
ADHD symptoms. Underactivation of the posterior cingu-
late and caudate is a key finding in fMRI studies of
ADHD and has been observed during several cognitive
functions including the same attention allocation task
[Rubia et al., 2007b, 2009a], as well as other functions of
response inhibition [Durston et al., 2003; Rubia et al., 1999,
2005b, 2008; Vaidya et al., 1998], reward [Rubia et al.,
2009b], and timing [Rubia et al., 1999, 2001a, 2009c]. Fur-
thermore, in two of these studies we also observed a nega-
tive correlation between cingulate activation and ADHD
symptoms [Rubia et al., 2005b, 2007b]. The posterior cingu-
late is connected to the limbic system and visuo-motor
pathways and is relevant for the dynamic allocation of vis-
ual-spatial attention, in particular to visually salient events
such as oddball trials [Mohanty et al., 2008; Small et al.,
2003]. The caudate likewise is an important area for atten-
tion to saliency [Davidson et al., 2004; Zink et al., 2004,
2006] and is known to be mediated by dopamine that pre-
dominantly innervates the basal ganglia [Volkow et al.,
2006]. The reduced activation in ADHD patients in dopa-
minergically innervated brain regions that are important
for visual spatial attention to saliency is in line with evi-
dence for reduced levels of dopamine in ADHD patients
[Krause, 2008] which is known to modulate the attentional
response to saliency [Volkow et al., 2006]. By analogy, one
could argue that the increased caudate and posterior cin-
gulate activation in OCD patients and its positive correla-
tion with OCD symptoms could be related to enhanced
dopamine levels in this patient group as indicated by
reduced DAT levels and D2 receptor abnormalities [Denys
et al., 2004; Hesse et al., 2005; Kim et al., 2003, 2007] that
could lead to enhanced activation of brain regions that
mediate salience [Volkow et al., 2006]. Several fMRI stud-
ies have found posterior cingulate (together with anterior
cingulate) and caudate to be increased in adult patients
with OCD during rest, symptom provocation and tasks of
cognitive control and to correlate positively with OCD
symptoms [Menzies et al., 2008; Page et al., 2009]. It thus
appears that these two disorders that are antagonistic with
respect to documented dopamine receptor and transporter
binding in the basal ganglia—indicative of enhanced dopa-
mine levels in OCD [Denys et al., 2004; Hesse et al., 2005;
Kim et al., 2003, 2007] and reduced dopamine levels in
ADHD [Krause, 2008]—are also antagonistic with respect
to the activation of dopamine-innervated brain regions that are
involved in the processing of saliency [Volkow et al., 2006].
Interference Inhibition Condition
During the interference inhibition condition, both patient
groups shared dysfunction in the SMA and anterior cingu-
late, typical areas for interference inhibition [Botvinick
et al., 1999; Ridderinkhof et al., 2004; Rubia et al., 2006;
Ullsperger and von Cramon, 2001]. In ADHD children,
under-activation of the SMA and anterior cingulate has
frequently been observed during tasks of cognitive control
and selective attention [Dickstein et al., 2006; Rubia et al.,
2009a; Smith et al., 2006]. A study in adult OCD also
found the SMA to be under-activated during a similar in-
terference inhibition task [Fitzgerald et al., 2005]. The
under-activation finding in anterior cingulate is in line
with previous fMRI studies in OCD children and adults dur-
ing similar cognitive control tasks [Page et al., 2009; Woolley
et al., 2008], although there have also been reports of
increased activation, in the context of error processing [Fitz-
gerald et al., 2005; Maltby et al., 2005; Menzies et al., 2008].
ADHD patients showed a disorder-specific under-activa-
tion in the inferior parietal lobes. The inferior parietal
lobes have previously been found to be dysfunctional in
ADHD children during similar tasks of interference inhibi-
tion [Konrad et al., 2006] and related inhibition and atten-
tion tasks [Dickstein et al., 2006; Rubia et al., 2007b, 2008,
2009c; Smith et al., 2006]. The finding of disorder-
rRubia et al. r
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specificity of parietal dysfunction during the higher-level
selective attention task together with the finding of disor-
der-specific posterior cingulate and caudate under-activa-
tion during the simpler, perceptive selective attention
(oddball) condition, suggests that ADHD patients may
have more pronounced neuro-functional problems with
the recruitment of posterior parietal visual-spatial attention
areas than patients with OCD. The activation cluster in the
parietal lobes was the most sensitive to distinguish ADHD
patients from OCD patients and controls, as shown in the
discrimination analysis, where the BOLD response in this
region was able to correctly classify ADHD patients with
about 90% sensitivity. This suggests that inferior parietal
activity may potentially be a diagnostic neuro-functional
biomarker for ADHD, at least when compared to controls
and OCD patients.
Behaviorally, only OCD patients showed a higher inter-
ference effect in the Simon task compared to ADHD
patients. The findings are in line with similar findings of
performance deficits in OCD, but not ADHD patients in
the same task of interference inhibition [Penades et al.,
2007; Rubia et al., 2007a). Nevertheless, ADHD patients
had both shared and disorder-specific brain activation def-
icits with respect to OCD patients. It has consistently been
shown that brain activation is more sensitive than behav-
ioral performance and thus reduced brain activation de-
spite comparable task performance is a common finding in
ADHD patients [Rubia et al., 1999, 2005b, 2007b, 2008,
2009a,b,c; Smith et al., 2006].
A limitation of this study is the relatively small sample
size of the OCD group, although the sample sizes for the
other two groups were relatively large for fMRI studies.
The relatively lower sample size for OCD patients com-
pared to that of ADHD patients may have biased the posi-
tive findings towards the group with higher statistical
power. Another limitation is the fact that the two disor-
ders differed in their clinical severity and medication sta-
medication-naı ¨ve, while most of the patients with OCD
were medicated with SSRIs and in partial remission. While
this has the advantage of keeping confounding state symp-
toms of anxiety, depression, and ritualizing in the OCD
group minimal, a comparison with fully symptomatic
OCD patients may potentially elicit more severe and disor-
der-specific brain dysfunctions in patients with OCD. Rela-
tively little is known on the effects of SSRIs on functional
brain activation patterns. There is evidence that SSRIs
increase specific regional relative metabolic rate in healthy
subjects and impulsive aggression, with differing effects
depending on treatment duration [Gerdelat-Mas et al.,
2005; New et al., 2004]. Acute SSRI administration has
been shown to upregulate prefrontal brain regions during
cognitive control tasks [Del-Ben et al., 2005; Vollm et al.,
2005]. Tryptophan depletion that reduces brain serotonin
levels by about 60% has been shown to reduce dorsolateral
and inferior prefrontal brain activation during tasks of
cognitive control [Rubia et al., 2005a, Evers et al., 2006]. In
adult OCD, acute SSRI medication has been shown to
reduce symptom related overactivation in frontal and
striatal brain regions, but to increase task-relevant brain
2005a,b]. Overall, the available evidence therefore implies
that medication may have had a mitigating effect on brain
dysfunction that might have been more pronounced in
medication-naı ¨ve adolescents with OCD.
In conclusion, this study is a first step toward delineat-
ing the underlying neuro-functional differences between
these two diagnostic disorders in relation to a commonly
affected behavioral and neuropsychological phenotype
that is inhibitory and attention dyscontrol. The study
shows shared mesial frontal dysfunctions during higher
cognitive selective attention/interference inhibition, but
also disorder-specific deficits in both patient groups. OCD
patients showed disorder-specific dysfunction in dorsolat-
eral prefrontal activation while ADHD patients showed
disorder-specific under-activation of parietal lobes, cau-
date, and posterior cingulate, the latter of which was
inversely correlated with OCD and ADHD symptoms and
could potentially be related to the documented inverse
striatal dopamine abnormalities in the two disorders. The
disorder-specific parietal dysfunction in ADHD was the
most sensitive to correctly classify ADHD patients with
about 90% sensitivity. Disentangling the specificity of the
underlying pathophysiology of these two disorders will
ultimately help towards establishing disorder-specific bio-
markers that can provide an important aid to a more
objective diagnosis and help with the development of dis-
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