Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346

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Progress in Neuro-Psychopharmacology & Biological

Psychiatry
journal homepage: www.elsevier.com/locate/pnp

Neural correlates of altered response inhibition and dysfunctional connectivity at rest

in obsessivecompulsive disorder
Do-Hyung Kang a, 1, Joon Hwan Jang a, 1, Ji Yeon Han b, Jae-Hun Kim c, Wi Hoon Jung b, Jung-Seok Choi a,
Chi-Hoon Choi d, Jun Soo Kwon a, b, e,
a
Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
b
Interdisciplinary Program in Neuroscience, Seoul National University, Seoul, Republic of Korea
c
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
d
Department of Diagnostic Radiology, National Medical Center, Seoul, Republic of Korea
e
Department of Brain and Cognitive Sciences, World Class University Program, College of Natural Sciences, Seoul National University, Seoul, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Objective: Functional imaging studies of obsessivecompulsive disorder (OCD) have reported altered fronto-
Received 20 August 2012 striatal activity during executive tasks. Additionally, altered connectivity of these regions during resting state
Received in revised form 30 October 2012 was found. However, the relationship between brain activity during tasks and resting state remains poorly
Accepted 5 November 2012 understood. The present study investigated neural correlates associated with abnormal response inhibition
Available online 9 November 2012
in OCD and to examine how resting state functional connectivity relates to task-related activity.
Method: Eighteen unmedicated adult OCD patients and 18 age- and sex-matched control subjects underwent
Keywords:
Default mode network
functional magnetic resonance imaging scans during both resting state and a response inhibition task. Brain
Frontalsubcortical circuit activation during response inhibition was compared between groups. Fronto-striatal regions showing altered
Functional disconnection task-related activity were used as seeds for connectivity analyses during resting state.
Obsessivecompulsive disorder Results: During the response inhibition task, OCD patients had lower activation in areas including the cingu-
Response inhibition late cortex and basal ganglia regions. Compared with control subjects, patients with OCD showed increased
functional connectivity of the caudate nucleus with the middle cingulate cortex and precentral gyrus during
rest, suggesting hyperactive striatalcortical connections.
Conclusion: This study found altered function in fronto-striatal regions during response inhibition and its re-
lation to resting state functional connectivity in OCD. Our results suggest that dysfunctional striatalcortical
connections even during rest may result in the failure of response inhibition and error monitoring observed
in OCD patients.
2012 Elsevier Inc. All rights reserved.

1. Introduction fronto-striatal circuit were reported in OCD patients during resting

Obsessivecompulsive disorder (OCD) is an anxiety disorder marked
by intrusive thoughts that produce anxiety (obsessions) and repeti-
tive behaviors to reduce anxiety (compulsions) (American Psychiatric
Association. and DSM-IV., 1994). Contemporary neurocircuitry models
of OCD, which have been contributed by functional neuroimaging stud-
ies greatly, emphasize dysfunction in fronto-striato-thalamo-cortical
(FSTC) loop, including the orbitofrontal cortex, anterior cingulate cortex
(ACC), thalamus, and basal ganglia (Kwon et al., 2009; Menzies et al.,
2008b; Rauch et al., 1994; Rauch et al., 2007; van den Heuvel et al.,
2005). However, although hyperactivity and hyperresponsiveness in
Abbreviations: rs-FC, resting state functional connectivity; SSD, stop signal delay;
SSRT, stop-signal response time.
Corresponding author at: Department of Psychiatry, Seoul National University College
of Medicine, 101 Daehak-no, Chongno-gu, Seoul 110-744, Republic of Korea. Tel.: +82 2
2072 2972; fax: +82 2 747 9063.
E-mail address: kwonjs@snu.ac.kr (J.S. Kwon).
1
Dr. Kang and Dr. Jang served as co-rst authors.
state and with symptom provocation (Baxter et al., 1988; Harrison et
al., 2009; Kwon et al., 2003; Rauch et al., 1994; Sakai et al., 2011), most
activation studies employing various cognitive tasks have suggested
hypoactivity of this circuit (Chamberlain et al., 2008; Remijnse et al.,
2006; Roth et al., 2007). To understand this inconsistency, it is essential
to investigate abnormal task-related activations and their associations
with altered functional connectivity during resting state in the same
patients.
Measurement of resting state functional connectivity (rs-FC) is
a functional magnetic resonance imaging (fMRI) technique used to
investigate neural networks by analyzing temporal correlations of
spontaneous low-frequency blood oxygen level-dependent (BOLD)
signal uctuations in different brain areas. It is believed that this uc-
tuation represents the intrinsic neuronal activity of the brain (Fox and
Raichle, 2007; Fransson, 2005). Additionally, patterns of rs-FC have di-
rect associations with the anatomical and functional architecture of
the brain (Greicius et al., 2009; Honey et al., 2007; Skudlarski et al.,
2008). In the neuropsychiatric eld, abnormal rs-FC has been reported

0278-5846/$ see front matter 2012 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.pnpbp.2012.11.001
 D.-H. Kang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346 341

in disorders including schizophrenia (Bluhm et al., 2007; Garrity et Table 1

al., 2007), depression (Greicius et al., 2007; Lui et al., 2011), and OCD Demographic characteristics and symptom rating scales of patients with obsessive
compulsive disorder and control subjects.
(Fitzgerald et al., 2010; Harrison et al., 2009; Jang et al., 2010; Sakai
et al., 2011). Patients with Control
Impairment in response inhibition (i.e., cognitive processes that OCD subjects
(N = 18) (N = 18) Statistics P-value
enable executive control in accordance with changing situational
demands) is implicated in underlying intrusive ideas and ritualistic Demographic characteristics
Sex (male/female) 12/6 12/6 2 = 0.00 1.00
behaviors (Bannon et al., 2002; Chamberlain et al., 2006), and also
Handedness (right/left) 17/1 18/0 2 = 1.03 0.31
regarded as an endophenotypic marker (Chamberlain et al., 2005). Age (years) 24.9 5.9 24.7 2.7 t = 0.18 0.86
Previous studies investigating response inhibition in OCD patients Estimated IQ 107.8 13.0 111.7 9.3 t = 1.05 0.30
have reported discrepant ndings (Maltby et al., 2005; Roth et al., Illness duration (years) 6.5 5.5
2007; Woolley et al., 2008). Hypoactivation of brain areas such as Clinical rating scales
Y-BOCS score
orbitofrontal and medial frontal cortices, pre- and postcentral gyri,
Obsessive score 11.9 4.0
superior temporal cortex, fusiform cortex, and basal ganglia was ob- Compulsive score 10.7 5.6
served during response inhibition in OCD patients (Roth et al., 2007; Total score 22.1 7.6
Woolley et al., 2008). In contrast, Maltby et al. (2005) reported hyper- BAI score 17.7 15.1 4.5 4.8 t = 3.55 b0.01
BDI score 15.4 9.5 3.3 4.5 t = 4.91 b0.01
activation of the ACC, lateral orbitofrontal cortex, caudate, and thala-
mus during the go/no-go task. Discrepancies among these studies Values are presented as mean SD.
may be attributable to differences in task design, selection of patients, Abbreviations: OCD, obsessivecompulsive disorder; Y-BOCS, YaleBrown Obsessive
Compulsive Scale; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory.
or medication effects. Two studies used the go/no-go task with adult
OCD patients (Maltby et al., 2005; Roth et al., 2007) and another
used the stop-signal task with adolescent OCD patients (Woolley et
al., 2008). Medication effects in previous studies may also reduce sta-
tistical power or bias the results.
In the current study, we used both task-related and resting state 2.2. The task
fMRI to explore direct associations between these two functional net-
works in unmedicated adult patients with OCD. The stop-signal task, In the current study, we used a modied version of the stop-signal
which robustly activates the frontalsubcortical circuit (Aron and task to evaluate response inhibition ability (Supplementary Fig. 1)
Poldrack, 2006; Li et al., 2006), was used to evaluate response inhibi- (Aron and Poldrack, 2006; Band et al., 2003). The stop-signal para-
tion ability. OCD patients were hypothesized to show abnormal acti- digm consisted of a go task and a stop task. For each trial, a neutral
vations in components of FSTC circuitry during the stop-signal task. male or female face stimulus was displayed on a computer screen.
We also investigated how the status of the rs-FC is related to brain ac- For the go task, subjects were required to discriminate between
tivation during performance of the response inhibition task. male and female faces as fast as possible using the index and middle
ngers of the right hand, respectively. For the stop task (30% of trials),
2. Methods subjects attempted to stop their responses when a stop signal (Hz:
750, duration: 100 ms) sounded following a particular stop signal
2.1. Participants delay (SSD) subsequent to the face stimulus. The SSD changed dynam-
ically throughout the experiment, depending on the subject's behav-
We recruited 18 patients (12 men, 6 women) from the OCD clinic ior, to make the subject successfully inhibit the response in 50% of
at the Seoul National University Hospital. All patients fullled the trials and fail to inhibit in the other 50% of trials. If the subject inhibited
DSM-IV criteria for OCD, diagnosed using the Structured Clinical Inter- successfully on a stop trial, inhibition was made more difcult on a
view for DSM-IV Axis I Disorders (SCID-I) (First et al., 1996). Using an subsequent trial by increasing the SSD by 50 ms; if the subject failed
internet advertisement, we also recruited 18 volunteer control sub- to inhibit successfully, the SSD was decreased by 50 ms. This design
jects, who were matched with the patient group for age, sex, and IQ ensured that every subject was working at the edge of his or her inhib-
as assessed by the Korean version of the Wechsler Adult Intelligence itory capacity, thus keeping the difculty level high and, at the same
Scale (Kim and Lee, 1995). The Structured Clinical Interview for time, homogenous across subjects.
DSM-IV, Non-patient Version (SCID-NP) was used in assessing Axis I After 15 min of training, subjects performed three sessions of the
psychiatric disorders in control subjects. The exclusion criteria includ- experiment; each session consisted of 84 go trials and 36 stop trials.
ed any lifetime history of psychosis, bipolar disorder, major depressive At the beginning of each trial, a xation stimulus was presented for
disorder, substance abuse or dependence, Tourette's disorder, signi- 340 ms, and then the male face or female face appeared for 500 ms.
cant head injury, seizure disorder, or mental retardation. At the time On randomly determined stop trials, a tone occurred at a particular
of inclusion, no patient with OCD had a comorbid axis I disorder. The SSD after the face stimulus. After a go or a stop trial, a xation stimulus
demographic characteristics of the participants are presented in was presented again. Randomly distributed null time was also added
Table 1. When the patients were recruited, 12 were drug-naive and to the xation period to prevent automatic responses based on expec-
the remaining six had been unmedicated for at least 4 weeks. tancy; this varied from 1170 to 7020 ms. We used the Optseq program
To assess the severity of OC symptoms, we tested all of the partici- (http://surfer.nmr.mgh.harvard.edu/optseq/) to obtain an efcient
pants using the YaleBrown Obsessive Compulsive Scale (Y-BOCS) trial sequence and intervals aligned with the event-related fMRI.
(Goodman et al., 1989). We used the Beck Depression Inventory (BDI) Behavioral analyses were conducted to determine representative per-
(Beck et al., 1961) and the Beck Anxiety Inventory (BAI) (Beck et al., formance values. Based on the race model, stop-signal response time
1988) to measure the severity of depression and anxiety, respectively. (SSRT) was calculated by subtracting average SSD from the median
Patients with prominent hoarding symptoms were excluded because correct go response time (Aron and Poldrack, 2006; Band et al., 2003).
their symptoms might have been associated with neural involvement Average SSD was assessed in each session for every subject, using the
different from that of non-hoarding patients (Lochner et al., 2005). values right after the successful inhibition probability reached 50%.
The study was thoroughly explained to the subjects and written Other measures computed were median correct go response time, me-
informed consent was obtained. This study was approved by the insti- dian stop response time, error rates for go discrimination, and average
tutional review board at the Seoul National University Hospital. rate of successful inhibition.
342 D.-H. Kang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346
2.3. Functional data acquisition and preprocessing
All imaging was performed using a 1.5-Tesla whole-body scanner
(Siemens AVANTO, Erlangen, Germany). Functional images were
acquired using an echo-planar imaging sequence (TR = 2.34 s, TE =
52 ms, FOV = 220 mm, FA = 9, 3.44 3.44 5 mm 3, no interslice
gap, 25 axial slices). Task-related functional images were acquired in
three runs of 362 s each, and 486 volumes in total were acquired for
each subject. We presented task stimuli using a presentation program
(http://www.neurobs.com) installed on a Windows-based PC; stimuli
were projected on a screen that was made visible to the subjects using
a mirror mounted above the subjects' heads. Participants responded to
the target by pressing an MRI-compatible mouse button with the
index and middle ngers of their right hands. For acquisition of resting
state functional images, all subjects received 4.68-min scans (120 vol-
umes) during which they were explicitly asked to close their eyes,
relax, and refrain from focusing on any particular thought.
Imaging data were preprocessed using Statistical Parametric Map-
ping (SPM8; http://www.l.ion.ucl.ac.uk/spm). The rst four images
in each run were discarded to eliminate the nonequilibrium effects
of magnetization. The functional images were corrected for differ-
ences in slice acquisition timing followed by motion correction, such
as adjusting to the middle image of the second session. Spatial normal-
ization into standard MNI (Montreal Neurologic Institute) space was
performed, and spatial smoothing using a 6-mm full-width at half-
maximum Gaussian blur was applied to all images. Data during the
stop-signal task were then analyzed using a canonical hemodynamic
response function in SPM8. Low-frequency signal drifts were removed
using a 128-s high-pass lter, and temporal autocorrelation in the fMRI
time series was corrected using a rst-order autoregressive model. Four
main types of trial outcome were rst distinguished: go success (G), go
error, stop success (SS; stop trials without a button press), and stop
error (failed stop trials with a button press). We chose the SS minus G
contrast to determine response inhibition-related brain activation.
2.4. Statistical analyses: functional imaging data and clinical variables
Individual demographic measures were compared across groups
using chi-square analysis and t-tests. Independent t-tests were also
performed to examine signicant differences in behavioral variables
between patients with OCD and control subjects.
Within-group analyses were performed with a second-level
one-sample t-test (P b 0.05, corrected using topological peak-false dis-
covery rate (FDR) as implemented in SPM8) (Chumbley et al., 2010). A
between-group comparison was performed using two-sample t-tests.
The results were reported at P b 0.005 (uncorrected) with a cluster
size of greater than 27 for whole-brain multiple comparison, which
corresponds to a corrected threshold of P b 0.05 as determined by the
AlphaSim program, or a small volume correction (SVC) of P b 0.05,
family-wise error corrected in a 5-mm-radius sphere centered on
the peak coordinates for regions of a priori interest (i.e., caudate nu-
cleus, putamen, and parahippocampal cortex) as mentioned in the
Introduction (Worsley et al., 1996). For further analysis, we dened
the functional regions of interest (ROIs) from each cluster including
the peak-activated voxel in the result of the between-group analysis.
Each ROI was created using a 5-mm-radius sphere surrounding the
peak-activated voxel in each cluster. We then extracted mean param-
eter estimates from each ROI using MarsBaR software (http://marsbar.
sourceforge.net/) in normalized images.
To conduct ROI-wise rs-FC analysis, the following additional steps in
the smoothed fMRI data were performed using the Resting-state fMRI
Data Analyze Toolkit (REST version 1.6 by SONG Xiao-Wei et al.: http://
www.restfmri.net). Temporal band-pass ltering (0.009 Hzb fb 0.08 Hz)
was performed to isolate low-frequency BOLD uctuations of interest.
Signals from the regions of no interest and the rst temporal deriva-
tives (head motion parameters, global signal, white-matter signal,
and cerebrospinal uid signal) were regressed out to reduce spurious
correlations due to cardiac and respiratory uctuations. The residual
signal from the regression analysis was used for the rs-FC analysis. As
functional studies in OCD have revealed regional decits in FSTC circuit,
we selected seven areas as ROIs that constitute the circuit from among
regions showing group differences in activation during response inhibi-
tion, which were the bilateral caudate nucleus, right putamen, left fron-
tal cortex, right ACC, right middle cingulate cortex (MCC), and right
parahippocampal cortex. Each ROI was created using a 5-mm-radius
sphere surrounding the peak-activated voxel for each cluster. Time-
series voxel values were extracted from these selected ROIs. We dened
functional connections as statistical associations between ROIs in the
functional time series. An interregional functional correlation matrix
(N N, where N is the number of ROI) was constructed for each indi-
vidual. Thirty-six square functional correlation matrices (7 7) were
acquired from the OCD patients and the control subjects. Finally,
correlation coefcients were normalized with the Fisher's r-to-z trans-
form. Between-group connectivity differences were determined by
two-sample t-tests. To correct for inated type I error, signicance cor-
rections for multiple comparisons were done using FDR (Pb 0.05). The
relationship between behavioral performances during the stop-signal
task and the strength of functional connectivity was evaluated with
Pearson's correlation coefcients.
3. Results
3.1. Behavioral performance
No signicant differences in age, sex, or mean IQ were detected
between patients with OCD and controls (Table 1). The correct re-
sponse rate on go trials was more than 80% for all subjects. The OCD
patients showed signicantly increased SSRT compared with control
subjects [325.1 ms (SD = 54.3) vs. 275.0 ms (SD = 47.0); t-test t =
2.95, df = 34, P = 0.01]. No signicant differences were observed be-
tween OCD patients and control subjects for other behavioral measures
such as the median correct go response time [672.1 ms (SD = 161.7)
vs. 601.6 ms (SD = 88.6); t-test t = 1.62, df= 34, P =0.11], median
stop response time [617.3 ms (SD = 125.3) vs. 561.7 ms (SD = 73.2);
t-test t = 1.62, df= 34, P = 0.11], or go discrimination error rates [9.3%
(SD =5.6) vs. 6.3% (SD = 4.5); t-test t = 1.80, df= 34, P =0.08].
3.2. Brain activation during the response inhibition task
During performance of the stop-signal task, both the OCD patients
and control subjects showed bilateral brain activation within the infe-
rior, middle, and superior frontal cortices, as well as the supramarginal
cortex, superior parietal cortex, and cerebellum. Activation was also
observed within the superior medial frontal cortex (Fig. 1). Healthy
controls also showed brain activation in the ACC, middle cingulate cor-
tex and striatum, including the caudate and putamen, whereas these
regions didn't show a signicant activation in the OCD patients.
Compared with the controls, the OCD patients had lesser activation
of brain areas including the left precentral gyrus, bilateral caudate nu-
cleus, right putamen, right ACC, right MCC, right occipital cortex, left
angular cortex, and bilateral superior/middle temporal cortex. The pa-
tients with OCD, however, showed greater activation than the controls
in the bilateral superior parietal cortex (Table 2 and Fig. 2).
3.3. Functional connectivity during the resting state
We found signicant differences in functional connectivity during
the resting state between OCD patients and controls (Fig. 3). Com-
pared with the controls, the patients showed signicantly greater
functional connectivity between the right MCC and the left caudate
nucleus and between the right MCC and the right PHC. Additionally,
the strength of functional connectivity between the MCC and the
 D.-H. Kang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346 343

Fig. 1. Areas of brain activation in response to response inhibition. We reported brain regions surviving a signicance threshold of P b 0.05, corrected for whole-brain multiple com-
parisons using topological false discovery rate (FDR) for peak height (P b 0.001, uncorrected).

PHC in OCD patients was positively correlated with SSRT (r = 0.512, In the stop-signal paradigm, a signicant between-group differ-
P = 0.030) and go discrimination error rates (r = 0.486, P = 0.041) ence in SSRT was observed. The ndings showing impaired perfor-
(Fig. 4). The patients showed a trend toward increased connectivity mance on tasks requiring response inhibition function are consistent
between the left precentral gyrus and the left caudate nucleus (FDR with the ndings from behavioral studies reporting decits in response
corrected P = 0.07). inhibition in patients with OCD (Chamberlain et al., 2006; Penades et al.,
2007) and suggest that these patients require a longer delay to stop the
4. Discussion prepotent response.
Response inhibition refers to cognitive processes that enable exec-
To our knowledge, this is the rst fMRI study in OCD to combine utive control over prepotent motor response in accordance with
neural activity during the resting state and response inhibition task changing situational demands. Previous studies have established the
performance. In the current study, patients with OCD, as compared critical importance of the frontal cortex and subcortical structures,
with control subjects, had reductions in task-related brain activation such as the caudate and subthalamic nucleus, for stop-signal response
in areas including the ACC, MCC, and basal ganglia regions, which inhibition (Aron and Poldrack, 2006; Li et al., 2006; Li et al., 2008). In
constitute the frontalsubcortical circuitry. Furthermore, the caudate terms of fMRI results, we specically investigated differences in the
nucleus exhibited increased connectivity with the precentral gyrus neural correlates of the inhibitory control between patients with
and MCC during resting state in OCD patients. OCD and the control group. When required to inhibit responding,
OCD patients showed underactivation of basal ganglia, such as the pu-
Table 2 tamen and caudate nucleus, and of cingulate cortex regions. Addition-
Regional differences in brain activations during the stop-signal task between patients ally, hyperactivation in the parietal cortex and cerebellum was also
with obsessivecompulsive disorder and control subjects. observed. Our results are consistent with previous event-related fMRI
Anatomical region Side BA Peak coordinate Cluster Z-value studies on OCD using response inhibition tasks, which have proposed
(MNI) size a dysregulation of the striatalcortical pathway mediating the response
x y z inhibition function (Maltby et al., 2005; Roth et al., 2007; Woolley et al.,
2008). Those studies reported altered activation in the prefrontal cor-
Control > OCD
Precentral gyrus L 4 56 4 34 41 4.10 tex, precentral gyrus, and basal ganglia regions in OCD patients. The in-
Fusiform cortex R 37 22 38 22 42 4.07 volvement of parietalcerebellar functional alteration, combined with
Middle temporal cortex L 21 62 36 8 32 3.79 frontalsubcortical dysfunction, has been suggested in the pathophysi-
Middle occipital cortex R 18 34 90 0 60 3.75 ology of OCD (Chamberlain et al., 2008; Kang et al., 2003; Menzies
Superior temporal cortex R 22 62 10 8 118 3.68
Angular cortex L 39 50 64 40 53 3.59
et al., 2008a). The parietalcerebellar dysfunction may be related to
Putamena R 28 12 4 20 3.48 visuospatial decits and dysfunction in coordinating complex mental
Caudate nucleusa R 14 10 16 20 3.28 and cognitive functions.
Anterior cingulate cortexa R 32 12 50 12 17 3.28 Increased connectivity between the caudate nucleus and the corti-
Calcarine cortex R 18 22 82 4 74 3.25
cal regions (the precentral gyrus and MCC) during resting state in
Middle cingulate cortex R 23 18 34 36 31 3.21
Cerebellum L 14 76 16 29 3.10 patients with OCD was also observed in this study. Basal ganglia struc-
Caudate nucleusa L 14 18 24 16 3.00 tures are implicated in the regulation of both simple and complex
motor acts (Li et al., 2008). Among them, the caudate nucleus has
OCD > control long been a central target for investigation into the pathophysiology of
Superior parietal cortex R 7 20 52 76 43 3.84
Cerebellum L 18 46 36 33 3.59
OCD. Activity of the caudate nucleus is involved in the modication of
Superior parietal cortex L 7 18 62 70 35 3.51 striatalcortical projections. Increased functional connectivity observed
Parahippocampal cortexa R 30 26 20 22 16 3.18 in the current study may be associated with alterations of thalamic-
Superior parietal cortex L 7 22 62 54 29 3.01 cortical glutamatergic neurotransmission resulting from increased acti-
Abbreviations: BA, Brodmann area; MNI, Montreal Neurological Institute; OCD, obsessive vation of the direct GABAergic striatal-thalamic pathway (Kwon et al.,
compulsive disorder; R, right; L, left. 2009; Rotge et al., 2010).
Statistical signicances were set to P b 0.005 (uncorrected) and cluster size greater than Successful performance in the stop-signal task requires sustained
27 for multiple comparison, which corresponds to a corrected threshold of P b 0.05 as
determined by the AlphaSim program.
attention and constant monitoring of the stop signal (Li et al., 2006).
a
A small volume correction for regions of a priori interest (P b 0.05, family-wise Exaggerated or false error signals are suggested to be related to a
error corrected). wide range of OC symptoms in OCD (Endrass et al., 2008; Ursu et al.,
344 D.-H. Kang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346

Fig. 2. Brain regions showing group differences in response to response inhibition. Abbreviations: AC, angular cortex; ACC, anterior cingulate cortex; FFC, fusiform cortex; MTC, mid-
dle temporal cortex; OC, occipital cortex; PHC, parahippocampal cortex; PreCG, precentral gyrus; SPC, superior parietal cortex; STC, superior temporal cortex.

Fig. 3. Strengths of resting state functional connectivity in OCD patients and control subjects. The functional connectivity is illustrated by lines of two width according to the two signicant
levels (thin line: Pb 0.05, uncorrected; thick line: Pb 0.05, FDR corrected). Abbreviations: ACC, anterior cingulate cortex; MCC, middle cingulate cortex; PHC, parahippocampal cortex;
PreCG, precentral gyrus.

2003). Recently, Guehl et al.(2008) claimed that caudate hyperactivity
in OCD is related to overfunctioning of the error-monitoring system
and the development of obsessive phenomenology. Another study
posited that the caudate nucleus becomes more active when sub-
jects respond in a controlled manner to prevent an action from being
automatically executed (Vink et al., 2006). These ndings indicate
alterations in information processing in pathways involving the cau-
date nucleus in OCD. Additionally, OC symptom improvement with
deep brain stimulation in the caudate nucleus has been reported
(Aouizerate et al., 2005). Taken together, results from the current
and previous studies support the notion that patients with OCD have
functional alterations in cortical and basal ganglia regions during
both resting states and response inhibition tasks. Consequently, dis-
ruptions of functional connections may mediate repetitive, compul-
sive behaviors and the failure of response inhibition (Gu et al., 2008;
Saxena and Rauch, 2000).

Fig. 4. Correlations between behavioral performances and strength of functional connectivity between the MCC and the PHC. Abbreviations: MCC, middle cingulate cortex; PHC,
parahippocampal cortex.
 D.-H. Kang et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 340346
This study has several limitations. First, depression symptoms in
OCD patients could have had confounding effects, although OCD pa-
tients who had comorbid depressive disorder were excluded from
this study. Second, our patient group was heterogeneous in terms of
symptom clusters, and thus the results could have been inuenced
by the variety of symptoms among the patients.
5. Conclusion
This study provides evidence for neural correlates of functional al-
terations in patients with OCD during both resting state and perfor-
mance of a response inhibition task. The results of the current study
also suggest that increased functional connectivity between the cingu-
late cortex and the PHC may be responsible for the response inhibition
impairment observed in patients with OCD.
Further research to clarify the effects of treatment on the functional
disconnections found in this study should help advance the under-
standing of the pathophysiology of OCD.
Supplementary data to this article can be found online at http://
dx.doi.org/10.1016/j.pnpbp.2012.11.001.
Acknowledgments
This research was supported by a grant (2009K001270) from the
Brain Research Center of the 21st Century Frontier Research Program
funded by the Ministry of Science and Technology, Republic of Korea,
and grant from the Seoul National University Hospital Research Fund
(No: 04-2008-104). None of the authors have any conicts of interests
to this study.
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