European Psychiatry 26 (2011) 463–469

Original article

Corticostriatal functional connectivity in non-medicated patients with

obsessive-compulsive disorder§
Y. Sakai a,*, J. Narumoto a, S. Nishida a, T. Nakamae a, K. Yamada b, T. Nishimura b, K. Fukui a
a
Department of Psychiatry, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
b
Department of Radiology, Graduate School of Medical Science Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

A R T I C L E I N F O A B S T R A C T

Article history: The basal ganglia represents a key component of the pathophysiological model for obsessive-compulsive
Received 24 August 2010 disorder (OCD). This brain region is part of several neural circuits, including the orbitofronto-striatal
Accepted 16 September 2010 circuit and dorsolateral prefronto-striatal circuit. There are, however, no published studies investigating
Available online 9 November 2010
those circuits at a network level in non-medicated patients with OCD. Resting state functional magnetic
resonance imaging scans were obtained from 20 non-medicated patients with OCD and 23 matched
Keywords: healthy volunteers. Voxelwise statistical parametric maps testing strength of functional connectivity of
Obsessive-compulsive disorder three striatal seed regions of interest (ROIs) with remaining brain regions were calculated and compared
Functional magnetic resonance imaging between groups. We performed additional correlation analyses between strength of connectivity and the
Resting state
severity scores for obsessive-compulsive symptoms, depression, and anxiety in the OCD group. Positive
Functional connectivity
functional connectivity with the ventral striatum was significantly increased (Pcorrected <.05) in the
Basal ganglia
Orbitofrontal cortex orbitofrontal cortex, ventral medial prefrontal cortex and dorsal lateral prefrontal cortex of subjects with
OCD. There was no significant correlation between measures of symptom severity and the strength of
connectivity (Puncorrected <.001). This is the first study to investigate the corticostriatal connectivity in
non-medicated patients with OCD. These findings provide the first direct evidence supporting a
pathophysiological model involving basal ganglia circuitry in OCD.
ß 2010 Elsevier Masson SAS. All rights reserved.

1. Introduction pathophysiology is not limited to those regions, but also involving

Obsessive-compulsive disorder (OCD) is a common neuropsy-
chiatric disorder with a lifetime prevalence of 2–3% [40]. OCD is
characterized by persistent intrusive thoughts (obsessions),
repetitive actions (compulsions), and excessive anxiety. A major
characteristic of obsessions and compulsions is that they are
excessive and unreasonable.
Recent advances in neuroimaging techniques have now made it
possible to provide valuable neuroanatomical data for the
assessment of pathophysiology of OCD. Menzies et al. [27]
summarized the findings from functional, metabolic, and struc-
tural imaging studies, and concluded that dysfunction in the
orbitofronto-striatal circuit and connected limbic structures
contribute to the pathophysiology of OCD. The authors also
proposed a revised model for OCD in which the underlying
§
This research received no specific grant from any funding agency in the public,
commercial, or not-for-profit sectors. All authors had full access to the data used in
this study and corresponding author Yuki Sakai takes responsibility for the integrity
of the data and the accuracy of the data analysis.
* Corresponding author. Tel.: +81 75 251 5612, fax: +81 75 251 5839.
E-mail address: yuki1209@koto.kpu-m.ac.jp (Y. Sakai).
additional brain systems, in particular the lateral frontal and
parietal regions. These latter regions form part of the dorsolateral
prefronto-striatal circuit defined by Alexander et al. [2]. Thus, the
basal ganglia circuitry is assumed to be involved in the
pathophysiology of OCD in this model. Although these studies
have proposed abnormalities in distinct brain regions in OCD
patients, there is little information regarding the abnormalities of
the circuits themselves.
Until now, the anatomical models and conceptualization of the
role of basal ganglia circuitry have relied primarily upon inference
from animal studies [16]. Recently, however, researchers have
used resting state functional magnetic resonance imaging (fMRI) to
comprehensively evaluate the functional connectivity of the basal
ganglia circuitry in humans during rest [11]. Spontaneous low-
frequency (<0.08 Hz) fluctuation of the blood oxygen level-
dependent (BOLD) signal is often used to measure resting state
functional connectivity [6,15]. The low-frequency BOLD coherence
is assumed to be related to neural activity [22]. The application of
correlation analyses to resting state fMRI data enables the
characterization of task-independent patterns of functional
connectivity [6]. This analytic approach has demonstrated that
functionally relevant patterns of activity, commonly observed

0924-9338/$ – see front matter ß 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.eurpsy.2010.09.005
464 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469
during task performance, are intrinsically represented by sponta-
neous brain activity [10,15]. Di Martino et al. confirmed the
hypothesized motor, cognitive, and affective divisions among
striatal subregions using this approach. Their results were
consistent with the hypothesized arrangement of the human
basal ganglia circuitry [11], including the orbitofronto-striatal and
dorsolateral prefronto-striatal circuits, that was based on anatom-
ical studies of the macaque [2]. In addition to using this technique
to investigate brain activity within various functional systems in
healthy subjects, the methodology has also been applied to
diseased subjects to characterize the pathophysiological changes
associated with diseases [7]. Harrison et al. reported altered
functional connectivity of basal ganglia circuitry in patients with
OCD, while most of their patients were under medication (e.g.,
selective serotonin reuptake inhibitors [SSRIs]) [20]. The drug
administration could be one of the major confounding factors that
modulate the neural condition, and SSRIs are known to have great
influence on functional connectivity [3,36].
Our study extends this approach to detect abnormalities in the
basal ganglia circuitries of non-medicated patients with OCD. First,
we evaluated the ability of the technique in depicting distinct
functional connections within the basal ganglia circuitry. We then
compared the level of connectivity with the basal ganglia between
non-medicated OCD patients and healthy controls.
2. Patients and methods
2.1. Subjects
Twenty patients diagnosed with OCD (based on the DSM-IV
criteria) and 23 healthy controls matched for age, sex, and
handedness participated in this study (see Table 1 for sample
characteristics, two subjects were excluded at a preprocessing
step). Trained and experienced clinical psychiatrists and psychol-
ogists assessed all patients and healthy controls. Patients were
recruited at the Kyoto Prefectural University of Medicine Hospital,
Kyoto, Japan. All patients were primarily diagnosed using the
Structured Clinical Interview for DSM-IV Axis I Disorders-Patient
Edition (SCID) [12].
The exclusion criteria for patients and healthy controls were:
(1) cardiac pacemakers or other metallic implants or artifacts; (2)
significant disease, including neurological diseases, disorders of
the pulmonary, cardiac, renal, hepatic, or endocrine systems, or
metabolic disorders; (3) prior psychosurgery; (4) current or past
DSM-IV axis I diagnosis of any psychiatric illness except OCD; (5)
DSM-IV diagnosis of mental retardation and pervasive develop-
mental disorders based on a clinical interview and psychosocial
history; (6) pregnancy; and (7) the use of any kind of psychotropic
medication. None of the subjects had been taking any kind of
psychotropic medication for at least 8 weeks.
Table 1
Demographic and clinical characteristics of subjects in the OCD and control groupsa.
Characteristic
Sex, M/F, No.
Handedness, right/left, No.
Age, y
Psychotropic Medication naı̈ve/free patients, No.
Total Y-BOCS score
HDRS score
HARS score
HARS: Hamilton Anxiety Rating Scale; HDRS: Hamilton Depression Rating Scale; NA: not applicable; OCD: obsessive-compulsive disorder; Y-BOCS: Yale-Brown Obsessive-
Compulsive Scale.
a
Values represent the mean  SD score unless otherwise specified. For all scales, high scores denote greater severity.
b
x2 test.
c
Independent sample t test.
There was no history of psychiatric illness in the healthy
controls as determined by the Structured Clinical Interview for
DSM-IV Axis I Disorders-Non-patient Edition (SCID-NP) [13]. In
addition, we confirmed them that there was no psychiatric
treatment history in any of their first-degree relatives. Classifica-
tion of handedness was based on a modified 25-item version of the
Edinburgh Inventory. The Medical Committee on Human Studies at
the Kyoto Prefectural University of Medicine approved all the
procedures in this study. All participants gave written, informed
consent after receiving a complete description of the study.
2.2. Task
All subjects underwent an approximately 8 min resting-state
scan. They were instructed simply to keep their eyes closed, not to
think of anything particular, and not to fall asleep. We interviewed
all subjects just after the scan and confirmed that they did not fall
asleep during the scan. In addition, we asked patients whether they
had any kind of OCD symptoms during the scan; none experienced
symptoms of OCD or excessive anxiety.
2.3. Clinical assessments
All patients were surveyed for obsessive-compulsive symp-
toms, depression, and anxiety using the Japanese version of the
Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) symptom
checklist [30], the 17-item Hamilton Depression Rating Scale
[18], and the Hamilton Anxiety Rating Scale [17], respectively.
2.4. MR image acquisition
We used a whole-body 1.5 Tesla MR system (Gyroscan Intera;
Philips Medical Systems, Best, The Netherlands) with a six-
channel phased-array head coil to generate magnetic resonance
images. Foam pads were used to reduce head motion and scanner
noise. Functional data were collected using gradient echo Echo
Planar Imaging (EPI) sequences (echo time/repetition time, 40/
2411 ms; flip angle, 808; field of view, 192 mm2; imaging matrix,
64  64, 35 slices; slice thickness, 3.6 mm, no gaps) during an
about 8 min period, resulting in a total of 200 volumes. The first
five functional scans were discarded before subsequent analysis.
High-resolution (1  1  1.5 mm3) T1-weighted magnetization-
prepared rapid gradient echo images were acquired before each
resting image.
2.5. Data processing
The functional MRI data were preprocessed using the Oxford
Centre for Functional Magnetic Resonance Imaging of the Brain
Software Library (FMRIB; FSL version 4.1.2), statistical parametric
mapping (Wellcome Department of Cognitive Neurology; SPM5),
Patients with OCD (n = 20) Controls (n = 23) P-value
8/12 10/13 .82b
19/1 21/2 .64b
30.9  9.3 30.8  7.7 .96c
7/13 No medication NA
24.6  5.71 NA NA
6.1  4.6 NA NA
7.6  5.5 NA NA
 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469
and RESTing-state fMRI data analysis toolkit (REST version 1.3, by
Song Xiaowei, http://resting-fmri.sourceforge.net).
First, non-brain structures were removed from the echo planar
imaging volumes using the Brain Extraction Tool in the FSL
software package. Data were then corrected for motion and slice
timing, spatially normalized into the stereotactic space of the
Montreal Neurological Institute (MNI), and resampled at
2  2  2 mm3. The data were then spatially smoothed using a
Gaussian kernel of 6 mm full width at half-maximum (FWHM) in
SPM5. Correlation analysis is sensitive to the effects of gross head
motion. Therefore, we excluded two healthy controls who had
excessive head motions, more than 1 mm of maximum displace-
ment in x, y or z and more than 18 of angular rotation about each
axis based on the record of head motions within each scan [42].
We removed any linear trends from the BOLD signal data, then
filtered the signal through a temporal band-pass filter (0.01–
0.08 Hz) using REST (version 1.3). [15,23] We identified the time
series for nine nuisance signals for inclusion in our analyses: global
signal, white matter (WM), cerebrospinal fluid (CSF), and six
motion parameters. The global signal is thought to reflect a
combination of physiological processes (such as cardiac and
respiratory fluctuations) and scanner drift. Therefore, it was
included as a nuisance signal to minimize the influence of such
factors [5,24]. To extract the mean time series within WM and CSF,
we used masks created by setting a threshold at 90 and 70%,
respectively, in SPM5’s a priori mask settings. We confirmed that
each mask was accurately included within each brain region for
every subject.
2.6. Regions of Interest section and seed generation
We used spherical seed ROIs (diameter = 7 mm), as described
by Di Martino et al. [11]. We first distinguished between the
ventral striatum and dorsal caudate (DC). Second, we divided the
ventral striatum into inferior and superior regions (VSi and VSs,
respectively) corresponding to the nucleus accumbens and ventral
caudate, respectively. Consequently, we generated three seed ROIs
in each hemisphere: DC, VSs, and VSi (dorsal to ventral) in which
the MNI coordinates were centered at x = () 13, y = 15, z = 9;
x = () 10, y = 15, z = 0; and x = () 9, y = 9, z = 8, respectively. We
confirmed that all seed coordinates were centered within the gray
matter (using the 152 brain standard MNI gray matter provided by
FSL). One set of seeds was created for each hemisphere.
2.7. Functional connectivity map
We performed a voxel-wise functional connectivity analysis for
each ROI [42]. The seed reference time series of each ROI was
obtained by averaging the time series of all voxels within the ROI.
We conducted a correlation analysis between the seed reference
and the remaining whole brain in a voxel-wise manner. The
correlation coefficients were then transformed to z-values using
the Fisher r-to-z transformation to improve normality. This yielded
spatial maps in which the voxel values represented the strength of
the correlation with the ROIs.
The individual z-values were entered into one-sample t tests in
a voxel-wise manner to determine the brain regions that had
significant positive connectivity with each ROI within each group.
We set the significance threshold at Pcorrected <.05 based on Monte
Carlo simulations [39]. The corrected threshold corresponds to
Puncorrected <.001 with a minimum cluster size of 560 mm3. For
each seed ROI, thresholded functional connectivity from both
groups were combined by means of an ‘OR’ operation. We were
interested only in brain regions with positive correlation because
the interpretation of negative correlation remains controversial
when using global signal regression during the initial processing
465
step [28]. Therefore, we used this as a mask in between-group two-
sample t tests.
To confirm the difference in distribution of each seed ROI, we
entered the individual z-values from every two of three ROIs (DC
versus VSi, DC versus VSs, and VSs versus VSi) into paired-sample t
tests in a voxel-wise manner. In this analysis, we intended to confirm
that our analysis showed the features of distinct basal ganglia
circuits. Therefore, we used only the healthy control group in this
analysis. As before, we set a threshold at Pcorrected <.05 based on
Monte Carlo simulations [39]. The corrected threshold corresponds
to Puncorrected <.001 with a minimum cluster size of 480 mm3.
2.8. Group-level analysis
To compare the functional connectivity of each striatal seed
between groups, the z-values were entered into a two-sample t test
in a voxel-wise manner. This analysis was masked using the
combined positive functional connectivity maps for each striatal
seed, as discussed above. The threshold was again set at
Pcorrected <.05 based on Monte Carlo simulations [39]. The
corrected threshold corresponds to Puncorrected <.001 with a
minimum cluster size of 184–280 mm3. The different cluster size
thresholds reflect different number of comparisons to be corrected
for connectivity maps of different striatal seed ROIs.
2.9. Correlation analyses
We performed additional correlation analyses between indi-
vidual z-values and the severity scores for obsessive-compulsive
symptoms, depression, and anxiety (see above for survey
methodology) in the OCD group. We used a Pearson product-
moment correlation to examine the relationship between individ-
ual z-values and each clinical measure. We set a threshold at
Puncorrected <.001 at a voxel-level. We conducted these analyses
only in the regions identified in the group-level analysis.
3. Results
3.1. Sample characteristics
Group differences in demographic variables were examined
using independent group t tests. The x2 tests were used to examine
differences in joint classifications of discrete variables. The
distribution of age, sex, or handedness did not differ between
patients with OCD and healthy controls (Table 1). With respect to the
psychotropic medication, seven patients were drug naive while the
remainders were drug-free for at least 8 weeks prior to the study.
3.2. Functional connectivity map
The connectivity maps of each seed ROI (Pcorrected <.05,
corresponding to Puncorrected <.001 and a cluster size of
560 mm3) were combined between groups (Fig. 1). In general,
the strongest functional connectivity in each ROI occurred around
each seed and in the contralateral homologous region. Other
distinct regions also exhibited significant connectivity with each
ROI. More specifically, the DC seed exhibited significant positive
connectivity with the bilateral dorsolateral prefrontal cortex
(DLPFC), bilateral ventral lateral prefrontal cortex (VLPFC), and
bilateral mediodorsal thalamus. The VSs seed predicted activity
bilaterally in the orbitofrontal cortex (OFC), ventral medial
prefrontal cortex (VMPFC), and mediodorsal thalamus. The VSi
seed exhibited connectivity with the bilateral OFC, bilateral middle
cingulate cortex, bilateral amygdala, and bilateral hippocampi.
There were no substantial hemispheric differences among all ROIs.
466 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469

Fig. 1. Positive functional connectivity maps with each ROIs in the right hemisphere (shown as blue circles in the left column). Maps for the healthy control group and OCD
group were generated separately and combined to display the brain regions included in the group-level analyses. DC, VSs, and VSi indicate the dorsal caudate, superior ventral
striatum, and inferior ventral striatum, respectively. Images are displayed in the neurological orientation. Numbers at the top of each row indicate the section number in MNI
space.

3.3. Direct comparison between the functional connectivity maps for
each seed ROI within the Healthy Control Group
There was a significant difference in the distribution of each
striatal seed (Pcorrected <.05, corresponding to Puncorrected <.001 and
a cluster size of 480 mm3) based on voxel-wise paired-sample t
tests (Fig. 2). When compared with the VSs and VSi, the DC had
significantly greater connectivity with DLPFC and insula. In
addition, the VSs exhibited significantly greater connectivity with
DLPFC compared with VSi. Both the VSs and VSi were highly
associated with limbic structures, including the amygdala and
hippocampus, in comparison with the DC. With regard to the OFC,

Fig. 2. Direct comparison between the functional connectivity maps for each striatal seeds in the right hemisphere within the healthy control group. The upper row shows the
brain regions in which the first seed has significantly greater connectivity than the second seed and the lower shows the reverse comparison. Images are displayed in the
neurological orientation. Numbers at the top of each row indicate the section number in MNI space. Color bars indicate the z score ranges. See the legend to the Fig. 1 for an
explanation of the abbreviations.
 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469 467

Fig. 3. Brain regions showing significantly greater positive connectivity with the right (red) and left (green) VSs seed ROIs in the OCD group compared with the healthy control
group. Those regions are (A) projected to the surface, (B) overlaid on sagittal slices, and (C) overlaid on coronal slices. The red circle on the sagittal slice of x = 10 and coronal
slice of y = 15, and the green circle on the sagittal slice of x = 10 and coronal slice of y = 15 represents the right and left VSs seed ROIs, respectively. Images are displayed in the
neurological orientation. Numbers at the top of each row indicate the section number in MNI space. Color bars indicate the z score ranges. See the legend to the Fig. 1 for an
explanation of the abbreviations.

the VSi exhibited significantly greater connectivity with the medial 3.5. Correlation analyses
portion of OFC than the other two ROIs. There were no substantial
hemispheric differences. We found no evidence that individual z-values from each
striatal seed ROI and the clinical severity scores of obsessive-
3.4. Group-level analysis compulsive symptom, depression and anxiety were correlated.

We compared the positive functional connectivity between 4. Discussion

each striatal seed ROI and other regions of the brain between
groups. We observed a significantly greater positive functional
connectivity between bilateral VSs seed ROIs and other brain
regions in individuals in the OCD group (Pcorrected <.05, corre-
sponding to Puncorrected <.001 and a cluster size of 184 to 280 mm3)
(Fig. 3, Table 2). Conversely, we found no evidence for decreased
connectivity in any of the regions.
The right VSs seed ROI exhibited a significantly greater positive
connectivity with the bilateral OFC, ipsilateral rectal gyrus, and
bilateral VMPFC in the OCD group. In the left VSs seed ROI, we
observed a significantly greater positive connectivity with the
ipsilateral OFC, ipsilateral DLPFC, and ipsilateral superior frontal
gyrus in the OCD group.
There was no difference in the functional connectivity of the DC
and VSi seed ROIs between the healthy control and OCD groups.
To the best of our knowledge, this is the first study to detect
abnormalities in distinct basal ganglia circuitries, at a network
level, in non-medicated patients with OCD. Our resting state fMRI
study of 20 OCD patients with no medication and 23 healthy
controls revealed significantly greater positive functional connec-
tivity between the ventral striatum and brain regions including the
OFC, DLPFC, and VMPFC in patients with OCD. This is consistent
with the recently proposed revised model for OCD [27].
We depicted and compared the brain regions which exhibited
significantly high positive functional connectivity with each ROI in
the DC, superior ventral striatum, and inferior ventral striatum [11]
(Figs. 1 and 2). The ventral striatum and DC had positive functional
connections with the OFC and DLPFC, respectively (Fig. 1). This is
consistent with previous anatomical studies of primates that have

Table 2
Brain regions exhibiting a significant increase in positive connectivity with the bilateral VSs in the OCD groupa.

ROI Anatomical region BA Side Cluster-level Voxel-level MNI Coordinates at center of the cluster
P value (FWE corrected) Cluster Sizeb Z value x (+Right) y (+Anterior) z (+Superior)

Right VSs Rectal gyrus 11 R .002 68 3.93 12 48 16

Orbital gyrus 10 R 3.70 10 58 6
Orbital gyrus 11 L .002 68 3.77 14 40 24
Orbital gyrus 11 L 3.68 4 42 22
Ventral medial prefrontal cortex 10 L .005 59 3.68 2 66 2
Ventral medial prefrontal cortex 10 R 3.20 1 66 6

Left VSs Dorsolateral prefrontal cortex 9 L .017 45 4.26 40 16 46

Superior frontal gyrus 6 L 3.57 34 10 42
Orbital gyrus 11 L .045 35 4.25 14 44 24
Orbital gyrus 11 L 3.37 6 46 22

BA: Brodmann’s Area(s); FWE: family-wise error; L: left; MNI: Montreal Neurological Institute; OCD: obsessive-compulsive disorder; R: right; VSi: inferior ventral striatum;
VSs: superior ventral striatum.
a
All results at Pcorrected <.05, corresponding to Puncorrected <.001 and a cluster size of 184 to 280 mm3.
b
Number of voxels.
468 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469
shown that focal projections from OFC terminate in the rostral,
medial, and ventral parts of the striatum, and that the DLPFC
projects primarily to the head of caudate [16]. Our data have also
shown that the inferior ventral striatum has strong connectivity
with limbic structures, such as the amygdala, hippocampus, and
cingulate cortex (Fig. 1). Anatomical and electrophysiological
studies in animals have shown that afferents from the prefrontal
cortex and limbic structures converge onto the nucleus accumbens
[14,32], which corresponds to the ROI in the inferior ventral
striatum in our study. With respect to the thalamus, the
mediodorsal thalamus, included in the schema defined by
Alexander et al. [2], had a high degree of connectivity with both
the DC and ventral striatum (Fig. 1).
Direct comparisons between seed ROIs within the healthy
control group also indicated that the dorsal most caudate seed was
primarily associated with the DLPFC, and that the ventral seed was
primarily associated with the limbic areas. This dorsal/ventral
distinction in caudate connectivity had gradual transition (Fig. 2),
and is consistent with the models of a cognitive/affective division
between the dorsal and ventral striatum [16,31]. Thus, we were
able to successfully visualize both the orbitofronto-striatal circuit
and associated limbic structures as well as the dorsolateral
prefronto-striatal circuit.
In the group level analysis, non-medicated patients with OCD
exhibited significantly greater functional connectivity between the
bilateral ventral striatum and the OFC, DLPFC, and VMPFC (Table 2,
Fig. 3). Among these regions, the OFC is central to our
understanding of the pathology of OCD [27]. Saxena et al.
suggested the OCD model of dysfunction of the orbitofronto-
striato-thalamic circuitry with a particular emphasis on hyperac-
tivity of the circuitry among the OFC, striatum and thalamus [35].
Our finding of increased functional connectivity between the
bilateral OFC and ventral striatum is consistent with this model.
Many previous studies have focused on the brain regions included
in this model. Functional metabolic studies using positron
emission tomography (PET), predominantly to investigate glucose
utilization across the brain either at rest or during symptom
provocation, suggest that patients with OCD have increased
metabolic activity in the bilateral OFC and in striatal regions
[4,34]. Whiteside et al. [41] performed a meta-analysis of PET and
single photon emission computed tomography (SPECT) studies and
suggested that differences between patients with OCD and healthy
controls occur consistently in the OFC and the head of caudate
nucleus. FMRI studies using symptom provocation paradigms have
also shown that OCD sufferers exhibit abnormal activation of brain
regions in the orbitofronto-striatal circuit and connected limbic
structures [1,26,27]. Although these studies identified abnormali-
ties of the brain regions included in the model proposed by Saxena,
none of them have directly investigated these circuits themselves.
Thus, our results are the first direct evidence that supports the
orbitofronto-striatal model of OCD excluding the effect of any kind
of psychotropic medication.
A number of studies that utilize cognitive paradigms suggest
that large-scale neurocognitive abnormalities in several brain
regions outside the OFC, including the DLPFC, are involved in the
development of OCD. For example, fMRI studies of planning and
response inhibition have reported differential activation of brain
regions in the dorsolateral prefrontal circuits [25,38]. Moreover,
deficits in cognitive set shifting are also evident in patients with
OCD [8,27]. This is thought to be more dependent upon the DLPFC
and VLPFC than the OFC [19,29]. These data suggest that cognitive
deficits in OCD are not underpinned exclusively by OFC pathology.
In our study, the left ventral striatum exhibited significantly
greater connectivity with the DLPFC in patients with OCD. Thus,
our results provide additional support for the larger-scale revised
model of OCD [27].
The increases in functional connectivity seen in the OCD group
converged exclusively in that with the ventral striatum. Tanaka
et al. measured activity in the striatum using fMRI in healthy
subjects. The authors altered serotonin levels by manipulating
tryptophan and found that activity in the ventral striatum was
correlated with reward prediction at shorter time scales. Further-
more, the relationship was significant at low, but not high,
serotonin levels [37]. Serotonin is thought to play an important
role in the pathophysiology of OCD based on the effectiveness of
SSRIs [33], although the mechanism by which this occurs remains
unclear. In our study, we detected an increase in functional
connectivity only with the ventral striatum among the patients
taking no medication, including SSRIs. This may be related to
alterations in the serotonergic system associated with OCD.
Recently, there have been two studies of OCD patients using
resting state fMRI [20,21]. One of these studies recruited similar
approach to our study although most of their patients were under
medication. In that literature, Harrison et al. showed the increased
connectivity of the ventral striatum to the OFC and anterior
cingulate cortex (ACC) in patients with OCD [20]. Our main finding
of the increased connectivity between the bilateral OFC and ventral
striatum is similar to their results. Although we cannot compare
those results directly because they did not put the VSs seed ROIs,
the increased connectivity between the OFC and ventral striatum
seems to be a robust finding. With regard to the ACC, we did not
find the evidence of changes in functional connectivity with the
striatum. In the earlier study, most of their patients were taking
some kinds of antidepressants (e.g., SSRIs), while all of our patients
were non-medicated [20]. Those drugs have great influence on
functional connectivity and could be one of the main confounding
factors [3,36]. Especially, antidepressant treatment could increase
corticolimbic connectivity, including the one between the ACC and
striatum [3]. Thus, the previous finding of the increased
connectivity between the ACC and ventral striatum might reflect
the influence of the drug administration. In addition, the earlier
study adopted the more liberal threshold than that we adopted.
This fact might contribute differences between results.
While Harrison et al. showed that the specific strength of
connectivity between the OFC and ventral striatum predicted
patients’ obsessive-compulsive symptoms severity, we found no
correlation between strength of connectivity and the clinical
severity scores. Chamberlain et al. detected abnormal activation
of the OFC in their clinically unaffected close relatives as well as in
OCD patients, suggesting that those abnormalities reflect an
underlying vulnerability but not symptom severity [9]. Although
this study shows that abnormalities in the OFC might not
represent the OCD symptom severity, this question remains
controversial.
Our study has several limitations. First, the potential confound
of respiratory and cardiac cycle artifacts could be aliased into the
spontaneous low-frequency fluctuations and may have reduced
the specificity of the connectivity effect [23]. However, Birn et al.
[5] confirmed that the contributions of aliased cardiac and
respiratory signals to resting-state functional connectivity are
relatively minor. Second, seed-based approaches to map functional
connectivity require a priori selection of ROIs. We limited our
analyses to three striatal subregions in each hemisphere, based on
the model for OCD [27]. Moreover, we had to limit our ROIs, due to
spatial resolution limitations. However, in the future, higher
resolution fMRI techniques will allow researchers to examine
other brain regions, including subregions of the basal ganglia, such
as the substantia nigra and pallidum. Last, Mataix-Cols et al. [26]
suggested that there are distinct neural correlates under symptom
dimensions in OCD. To address these last issues and determine the
common and distinct neural correlates for OCD, we require a larger
sample size.
 Y. Sakai et al. / European Psychiatry 26 (2011) 463–469
5. Conclusion
In conclusion, this is the first study to investigate the
orbitofronto-striatal circuits, associated limbic structures, and
dorsolateral prefronto-striatal circuits at a network level in non-
medicated patients with OCD using resting state fMRI. We detected
a significant increase in positive functional connectivity between
the bilateral ventral striatum and several brain regions, including
the OFC, DLPFC, and VMPFC. Abnormalities in the serotonergic
system might contribute to the fact that all abnormalities converge
on functional connectivity with the ventral striatum. Application of
this method, combined with other modalities, will be useful for
investigations into the pathophysiology of OCD.
Conflict of interest statement
None of the authors has an actual or perceived conflict of
interest.
References
[1] Adler CM, McDonough-Ryan P, Sax KW, Holland SK, Arndt S, Strakowski SM.
fMRI of neuronal activation with symptom provocation in unmedicated
patients with obsessive compulsive disorder. J Psychiatr Res 2000;34(4–
5):317–24.
[2] Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally
segregated circuits linking basal ganglia and cortex. Annu Rev Neurosci
1986;9:357–81.
[3] Anand A, Li Y, Wang Y, Wu J, Gao S, Bukhari L, et al. Antidepressant effect on
connectivity of the mood-regulating circuit: an FMRI study. Neuropsycho-
pharmacology 2005;30(7):1334–44.
[4] Baxter Jr LR, Phelps ME, Mazziotta JC, Guze BH, Schwartz JM, Selin CE. Local
cerebral glucose metabolic rates in obsessive-compulsive disorder. A compar-
ison with rates in unipolar depression and in normal controls. Arch Gen
Psychiatry 1987;44(3):211–8.
[5] Birn RM, Diamond JB, Smith MA, Bandettini PA. Separating respiratory-varia-
tion-related fluctuations from neuronal-activity-related fluctuations in fMRI.
Neuroimage 2006;31(4):1536–48.
[6] Biswal B, Yetkin FZ, Haughton VM, Hyde JS. Functional connectivity in the
motor cortex of resting human brain using echo-planar MRI. Magn Reson Med
1995;34(4):537–41.
[7] Broyd SJ, Demanuele C, Debener S, Helps SK, James CJ, Sonuga-Barke EJ.
Default-mode brain dysfunction in mental disorders: a systematic review.
Neurosci Biobehav Rev 2009;33(3):279–96.
[8] Chamberlain SR, Fineberg NA, Menzies LA, Blackwell AD, Bullmore ET, Robbins
TW, et al. Impaired cognitive flexibility and motor inhibition in unaffected
first-degree relatives of patients with obsessive-compulsive disorder. Am J
Psychiatry 2007;164(2):335–8.
[9] Chamberlain SR, Menzies L, Hampshire A, Suckling J, Fineberg NA, del Campo
N, et al. Orbitofrontal dysfunction in patients with obsessive-compulsive
disorder and their unaffected relatives. Science 2008;321(5887):421–2.
[10] Damoiseaux JS, Rombouts SA, Barkhof F, Scheltens P, Stam CJ, Smith SM, et al.
Consistent resting-state networks across healthy subjects. Proc Natl Acad Sci U
S A 2006;103(37):13848–53.
[11] Di Martino A, Scheres A, Margulies DS, Kelly AM, Uddin LQ, Shehzad Z, et al.
Functional connectivity of human striatum: a resting state FMRI study. Cereb
Cortex 2008;18(12):2735–47.
[12] First MB, Spizer RL, Gibbon M, Williams JBW. Structures Clinical Interview for
Axis I DSM-IV Disorders-Patient Edition (CID-I/P). New York: Biometrics
Research Department, New York State Psychiatric Institute; 1994.
[13] First MB, Spizer RL, Gibbon M, Williams JBW. Structures Clinical Interview for
DSM IV TR Axis I Disorders-Non-patient Edition (SCID-I/NP). New York:
Biometrics
. Research Department, New York State Psychiatric Institute; 2001
[14] Friedman DP, Aggleton JP, Saunders RC. Comparison of hippocampal, amyg-
dala, and perirhinal projections to the nucleus accumbens: combined antero-
grade and retrograde tracing study in the Macaque brain. J Comp Neurol
2002;450(4):345–65.
[15] Greicius MD, Krasnow B, Reiss AL, Menon V. Functional connectivity in the
resting brain: a network analysis of the default mode hypothesis. Proc Natl
Acad Sci U S A 2003;100(1):253–8.
469
[16] Haber SN. The primate basal ganglia: parallel and integrative networks. J Chem
Neuroanat 2003;26(4):317–30.
[17] Hamilton M. The assessment of anxiety states by rating. Br J Med Psychol
1959;32(1):50–5.
[18] Hamilton M. Development of a rating scale for primary depressive illness. Br J
Soc Clin Psychol 1967;6(4):278–96.
[19] Hampshire A, Owen AM. Fractionating attentional control using event-related
fMRI. Cereb Cortex 2006;16(12):1679–89.
[20] Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R,
et al. Altered corticostriatal functional connectivity in obsessive-compulsive
disorder. Arch Gen Psychiatry 2009;66(11):1189–200.
[21] Jang JH, Kim JH, Jung WH, Choi JS, Jung MH, Lee JM, et al. Functional
connectivity in fronto-subcortical circuitry during the resting state in obses-
sive-compulsive disorder. Neurosci Lett 2010;474(3):158–62.
[22] Leopold DA, Murayama Y, Logothetis NK. Very slow activity fluctuations in
monkey visual cortex: implications for functional brain imaging. Cereb Cortex
2003;13(4):422–33.
[23] Lowe MJ, Mock BJ, Sorenson JA. Functional connectivity in single and multi-
slice echoplanar imaging using resting-state fluctuations. Neuroimage
1998;7(2):119–32.
[24] Macey PM, Macey KE, Kumar R, Harper RM. A method for removal of global
effects from fMRI time series. Neuroimage 2004;22(1):360–6.
[25] Maltby N, Tolin DF, Worhunsky P, O’Keefe TM, Kiehl KA. Dysfunctional action
monitoring hyperactivates frontal-striatal circuits in obsessive-compulsive
disorder: an event-related fMRI study. Neuroimage 2005;24(2):495–503.
[26] Mataix-Cols D, Wooderson S, Lawrence N, Brammer MJ, Speckens A, Phillips
ML. Distinct neural correlates of washing, checking, and hoarding symptom
dimensions in obsessive-compulsive disorder. Arch Gen Psychiatry
2004;61(6):564–76.
[27] Menzies L, Chamberlain SR, Laird AR, Thelen SM, Sahakian BJ, Bullmore ET.
Integrating evidence from neuroimaging and neuropsychological studies of
obsessive-compulsive disorder: the orbitofronto-striatal model revisited.
Neurosci Biobehav Rev 2008;32(3):525–49.
[28] Murphy K, Birn RM, Handwerker DA, Jones TB, Bandettini PA. The impact of
global signal regression on resting state correlations: are anti-correlated
networks introduced? Neuroimage 2009;44(3):893–905.
[29] Nagahama Y, Okada T, Katsumi Y, Hayashi T, Yamauchi H, Oyanagi C, et al.
Dissociable mechanisms of attentional control within the human prefrontal
cortex. Cereb Cortex 2001;11(1):85–92.
[30] Nakajima T, Nakamura M, Taga C, Yamagami S, Kiriike N, Nagata T, et al.
Reliability and validity of the Japanese version of the Yale-Brown Obsessive-
Compulsive Scale. Psychiatry Clin Neurosci 1995;49(2):121–6.
[31] O’Doherty J, Dayan P, Schultz J, Deichmann R, Friston K, Dolan RJ. Dissociable
roles of ventral and dorsal striatum in instrumental conditioning. Science
2004;304(5669):452–4.
[32] O’Donnell P, Grace AA. Synaptic interactions among excitatory afferents to
nucleus accumbens neurons: hippocampal gating of prefrontal cortical input. J
Neurosci 1995;15(5 Pt 1):3622–39.
[33] Pigott TA, Seay SM. A review of the efficacy of selective serotonin reuptake
inhibitors in obsessive-compulsive disorder. J Clin Psychiatry 1999;60(2):
101–6.
[34] Rauch SL, Jenike MA, Alpert NM, Baer L, Breiter HC, Savage CR, et al. Regional
cerebral blood flow measured during symptom provocation in obsessive-
compulsive disorder using oxygen 15-labeled carbon dioxide and positron
emission tomography. Arch Gen Psychiatry 1994;51(1):62–70.
[35] Saxena S, Brody AL, Schwartz JM, Baxter LR. Neuroimaging and frontal-
subcortical circuitry in obsessive-compulsive disorder. Br J Psychiatry Suppl
1998;35:26–37.
[36] Schwarz AJ, Gozzi A, Reese T, Bifone A. In vivo mapping of functional connec-
tivity in neurotransmitter systems using pharmacological MRI. Neuroimage
2007;34(4):1627–36.
[37] Tanaka SC, Schweighofer N, Asahi S, Shishida K, Okamoto Y, Yamawaki S, et al.
Serotonin differentially regulates short- and long-term prediction of rewards
in the ventral and dorsal striatum. PLoS One 2007;2(12):e1333.
[38] van den Heuvel OA, Veltman DJ, Groenewegen HJ, Cath DC, van Balkom AJ, van
Hartskamp J, et al. Frontal-striatal dysfunction during planning in obsessive-
compulsive disorder. Arch Gen Psychiatry 2005;62(3):301–9.
[39] Ward BD. Simultaneous inference for FMRI data. 2000. http://afni.nimh.nih.-
gov/afni/doc/manual/AlphaSim.
[40] Weissman MM, Bland RC, Canino GJ, Greenwald S, Hwu HG, Lee CK, et al. The
cross national epidemiology of obsessive compulsive disorder. J Clin Psychia-
try 1994;55(Suppl.):5–10.
[41] Whiteside SP, Port JD, Abramowitz JS. A meta-analysis of functional neuroim-
aging in obsessive-compulsive disorder. Psychiatry Res 2004;132(1):69–79.
[42] Zhou Y, Shu N, Liu Y, Song M, Hao Y, Liu H, et al. Altered resting-state functional
connectivity and anatomical connectivity of hippocampus in schizophrenia.
Schizophr Res 2008;100(1–3):120–32.