Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155

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Progress in Neuro-Psychopharmacology & Biological

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

Distinct functional connectivity of limbic network in the washing type

obsessive–compulsive disorder
Kyungun Jhung a,1, Jeonghun Ku b,1, Se Joo Kim c, Hyeongrae Lee d, Kyung Ran Kim c, Suk Kyoon An c, Sun I. Kim e,
Kang-Jun Yoon f, Eun Lee c,⁎
a
Department of Adolescent Psychiatry, National Center for Child and Adolescent Psychiatry, Seoul National Hospital, Seoul, South Korea
b
Department of Biomedical Engineering, Keimyung University, Daegu, South Korea
c
Institute of Behavioral Science in Medicine & Department of Psychiatry, Yonsei University College of Medicine, Seoul, South Korea
d
Department of Neurosurgery, MEG Center, Seoul National University College of Medicine, Seoul, South Korea
e
Department of Biomedical Engineering, Hanyang University, Seoul, South Korea
f
Department of Neurosurgery, St. Peter's Hospital, Seoul, South Korea

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

Article history: Neurobiological models of obsessive–compulsive disorder (OCD) emphasize disturbances of the corticostriatal
Received 28 January 2014 circuit, but it remains unclear as to how these complex network dysfunctions correspond to heterogeneous
Received in revised form 4 April 2014 OCD phenotypes. We aimed to investigate corticostriatal functional connectivity alterations distinct to OCD char-
Accepted 14 April 2014
acterized predominantly by contamination/washing symptoms.
Available online 24 April 2014
Functional connectivity strengths of the striatal seed regions with remaining brain regions during the resting con-
Keywords:
dition and the contamination symptom provocation condition were compared among 13 OCD patients with pre-
fMRI dominant contamination/washing symptoms (CON), 13 OCD patients without these symptoms (NCON), and 18
Functional neuroimaging healthy controls. The CON group showed distinctively altered functional connectivity between the ventral stria-
Obsessive–compulsive disorder tum and the insula during both the resting and symptom-provoking conditions. Also, the connectivity strength
Symptom dimensions between the ventral striatum and the insula significantly correlated with contamination/washing symptom se-
Washing type verity. As common connectivity alterations of the whole OCD subjects, corticostriatal circuits involving the
orbitofrontal and temporal cortices were again confirmed.
To our knowledge, this is the first study that examined specific abnormalities in functional connectivity of con-
tamination/washing symptom dimension OCD. The findings suggest limbic network dysfunctions to play a piv-
otal role in contamination/washing symptoms, possibly associated with emotionally salient error awareness.
Our study sample allowed us to evaluate the corticostriatal network dysfunction underlying the contamina-
tion/washing symptom dimension, which leaves other major symptom dimensions to be explored in the future.
© 2014 Elsevier Inc. All rights reserved.

1. Introduction
Neuroimaging studies have made critical advances in elucidating the
neural mechanisms that underlie obsessive–compulsive disorder
(OCD). Reports of functional neuroimaging have emphasized the
cortico–striato–thalamo–cortical (CSTC) circuit as central to the neuro-
biological model of OCD (Saxena, 2003). The development of alternative
mapping techniques to examine brain connectivity features has made it
possible to more directly demonstrate relationships between specific
Abbreviations: OCD, obsessive–compulsive disorder; CON, contamination/washing
symptoms; NCON, non-CON.
⁎ Corresponding author at: Department of Psychiatry, Yonsei University College of
Medicine, Yonsei-ro 50, Seodaemun-gu, Seoul, 120-752, South Korea. Tel.: +82 2 2228
1620; fax: +82 2 313 0891.
E-mail address: leeeun@yuhs.ac (E. Lee).
1
These authors contributed equally in the conception of the study and writing the
article.
brain regions (Fox and Raichle, 2007). In OCD, resting-state connectivity
analyses lent support to the prevailing hypothesis that abnormalities of
the CSTC circuit are apparent in a large-scale brain network level
(Harrison et al., 2009; Sakai et al., 2011). However, more recent studies
suggest the existence of broader abnormalities that involve the
temporo-parietal cortex and limbic regions in the OCD circuit (Del
Casale et al., 2011).
With regards to the heterogeneity of OCD, various phenotypes may
contribute to the discrepant neuroimaging results. Factor analytic studies
have identified stable symptom dimensions that are related to different
treatment responses (Mataix-Cols et al., 1999), comorbidities,(Mataix-
Cols et al., 2000), and genetic transmission (Alsobrook et al., 1999), as
well as distinct neural systems (van den Heuvel et al., 2009). Thus,
there may be distinct functional abnormalities of the corticostriatal net-
work that correspond to different OCD phenotypes. When exploring this
hypothesis, symptom provocation protocols have the advantage of
eliciting neural patterns more relevant to symptom emergence (Rotge

http://dx.doi.org/10.1016/j.pnpbp.2014.04.007
0278-5846/© 2014 Elsevier Inc. All rights reserved.
150 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155

et al., 2008). Investigation of functional networks using a symptom prov-
ocation paradigm targeted to elicit a certain OC symptom dimension
may provide important information relevant to identifying specific ab-
normalities in OCD circuits. However, there is a paucity of studies that
have examined distinct pattern of OCD circuit by symptom dimension.
The contamination/washing symptom dimension is one of the most
common symptom dimensions in individuals with OCD (Rasmussen
and Eisen, 1992). Patients with predominantly contamination/washing
symptoms are characterized by strong avoidance and elevated disgust
sensitivity, suggesting that this dimension of OCD may be closer to a
“limbic spectrum disorder” (Mataix-Cols and van den Heuvel, 2006).
Previous studies on the contamination/washing dimension of OCD
using a symptom provocation paradigm reported greater activations
in limbic areas, such as the insula and the parahippocampal gyrus, as
well as the ventral part of the prefrontal cortex during symptom provo-
cation (Mataix-Cols et al., 2003, 2004; Phillips et al., 2000; Shapira et al.,
2003). Although these findings are still inconclusive, they suggest that
distinct neural systems mediate different symptom dimensions, in con-
trast to the common neurobiological changes found in OCD patients as a
whole, such as alterations of the orbitofrontal cortex (Pujol et al., 2004;
van den Heuvel et al., 2009) and ventral striatum (Pujol et al., 2004). Di-
rect evidence is still scarce at a network level in regards to the heteroge-
neity of the disorder. Based on prior knowledge of the CSTC circuit and
symptom provocation studies, we hypothesized that the limbic circuit
may be involved in the pathophysiology of the contamination/washing
dimension of OCD.
In the present study, we aimed to explore functional connectivity al-
terations specific to the contamination/washing dimension of OCD. For
comparison, we included both OCD patients without contamination/
washing symptoms and healthy controls (HC). An augmented reality
paradigm (Ku et al., 2008) that simulates visual illusory stimuli in an
ecologically valid manner to provide subjects with the experience of vir-
tual stimuli mixed with a real image was used to effectively provoke
contamination symptoms in MRI device. We hypothesized that OCD pa-
tients with predominant contamination fears and washing rituals
would demonstrate distinct functional connectivity patterns while pro-
cessing the symptom-provoking stimuli compared to patients without
these symptoms and healthy controls. We expected that the identified
functional connectivity abnormalities in the contamination-based OCD
would be associated with the limbic network. We also predicted that
the distinct functional connectivity alterations would be associated
with the contamination/washing symptom severity.
2. Methods
“symmetry obsessions,” “ordering compulsions,” “repeating compul-
sions,” and “counting compulsions” divided by 4. The practice of dividing
by the number of items in each dimension ensured comparable score
ranges across dimensions. Because only two patients in our sample ex-
hibited hoarding or sexual/religious symptoms ≥2, these dimensions
were not analyzed in this study. We considered patients to be in the con-
tamination/washing (CON) group if contamination obsessions or
cleaning compulsions were currently present and were major problems
for the patient, with a score of at least 2 for at least one of these symp-
toms. Patients without contamination/washing symptoms (NCON
group) did not exhibit any current contamination obsessions, cleaning
compulsions, or any past principal symptom under this category. With
regard to psychiatric comorbidity, one subject each from the CON
group and NCON group presented with social anxiety disorder. Three
subjects in the CON group and 2 in the NCON group had depressive dis-
order not otherwise classified as comorbidity. All OCD participants were
taking a stable dose of medication for at least 3 months before the MRI
scan, except for one patient in the CON group who was medication-
free for more than a month before the scan (Table 1).
We recruited 19 age- and gender-matched HC via postings in the
hospital and local newspaper advertisements. Any participants with a
past or current diagnosis for any Axis I disorder, past or current drug
abuse/dependence (except nicotine and caffeine), or neurological disor-
ders were excluded. Depression and anxiety severities were measured
using the Beck Depression Inventory (Beck et al., 1961) and the Beck
Anxiety Inventory (Beck and Steer, 1990), respectively. In addition, all
participants completed the Disgust Scale—Revised to measure disgust
sensitivity (Olatunji et al., 2007). We also excluded any participants
with contraindications for a general functional magnetic resonance im-
aging (fMRI) experiment. One of the patients withdrew from the exper-
iment before fMRI scanning, and data from one HC was excluded from
analysis due to noise from movements. Thus, a total of 13 patients in
the CON group, 13 patients in the NCON group, and 18 in the HC
group were included in the final analysis. After complete description
of the study to the subjects, written informed consent was obtained.
All the process of this study was carried out in accordance with the lat-
est version of the Declaration of Helsinki.
Table 1
Demographics and clinical characteristics of participants.
CON group NCON group HC group

(N = 13) (N = 13) (N = 18)

2.1. Participants
Mean SD Mean SD Mean SD

The study was approved by the Institutional Review Board of Sever- Age (years) 28.2 7.4 26.3 4.8 28.2 6.6
ance Hospital, Yonsei University Health System. We recruited 27 OCD pa- Education (years)a 15.2 1.8 14.6 2.2 16.6 1.1
Onset age (years) 16.9 6.2 14.7 4.0
tients from the psychiatric outpatient clinic of Severance Hospital, Yonsei
Duration of illness (years) 10.9 7.6 11.8 6.5
University College of Medicine. Diagnosis of OCD and screening of Y-BOCS total 20.1 6.9 24.2 5.1
healthy controls (HC) were performed using the Mini-International Neu- Y-BOCS contamination/washingb 3.6 0.7 0.9 1.0
ropsychiatric Interview (Sheehan et al., 1998). For OCD participants, any BDIc 17.4 11.3 16.7 10.6 3.4 3.0
BAIc 22.7 9.7 21.1 15.9 4.8 5.4
cases with current diagnoses of Axis I disorders other than OCD, minor
Disgust scale totalc 54.7 9.3 59.1 11.1 45.2 8.4
depression, and social phobia were excluded. The Yale–Brown Obses-
sive–Compulsive Scale and Symptom Checklist (Y-BOCS) (Goodman N % N %
et al., 1989) was used to assess OC symptom severity and dimensions. Medication at study time
Each of the major categories of the Y-BOCS symptom checklist was Medication-free (N1 month) 1 7.7 0 0
assigned a score of 0 (absent symptom), 1 (symptom present but not a SSRI 6 46.2 7 53.8
major reason for concern), or 2 (prominent symptom). The major symp- SSRI combinations 2 15.4 2 15.4
Antipsychotic augmentations 4 30.8 4 30.8
tom dimension scores were then computed using the algorithm de-
scribed by Mataix-Cols et al. (1999). Briefly, the “contamination/ CON, contamination; NCON, non-contamination; HC, healthy control; SD, standard devia-
washing” score was the sum of “contamination obsessions” and “wash- tion; Y-BOCS, Yale–Brown Obsessive–Compulsive Scale; BDI, Beck Depression Inventory;
BAI, Beck Anxiety Inventory; SSRI, selective serotonin reuptake inhibitor.
ing/cleaning compulsions” divided by 2; the “harm/checking” score a
Indicates significant difference between NCON group and HC group (P b 0.05).
was the sum of “aggressive obsessions” and “checking compulsions” di- b
Indicates significant difference between CON and NCON group (P b 0.001).
vided by 2; and the “symmetry/ordering” score was the sum of c
Indicates significant difference between OCD patients and HC group (P b 0.001).
 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155
2.2. Task paradigm
All participants underwent fMRI scanning under the augmented-
reality environment composed of a combination of real-world and
computer-generated data. During the scan, participants experienced
the contamination/washing symptom provocation condition, in which
a virtual image of dirty feces was overlaid on both hands of the real-
time superimposed image of the participant's body (Fig. 1). During the
control resting condition, participants passively viewed the crosshair.
The symptom provocation condition (3 min) and control condition
(5 min) were sequentially conducted in a counterbalanced order.
2.3. fMRI acquisition/preprocessing
We conducted fMRI experiments on a research-dedicated whole-
body 1.5-Tesla MRI system (Signa Eclipse; GE Medical Systems, Wau-
watosa, WI, USA) using a standard quadrature birdcage head coil. Func-
tional images were obtained using an echo planar imaging (EPI)
sequence (gradient echo). Thirty slices (5-mm thickness) were ac-
quired during each acquisition period (FOV = 240 mm, TE/TR/θ =
22 ms/2000 ms/90°). A series of high-resolution anatomical images
was also acquired with a fast-spoiled gradient echo sequence (FOV =
240 mm, TE/TR/θ = 18 ms/85 ms/12°) before the functional scans for
spatial normalization.
The fMRI data were separately preprocessed in each condition using
Analysis of Functional Neuroimage (AFNI) software (Cox, 1996). The
first 10 time points in the symptom provocation condition of the time
series data sets and first 15 time points in the control condition of the
time-series data sets were discarded. Slice timing correction, motion
correction, and mean-based intensity normalization were performed
for all slices within a volume. Spatial normalization was performed to
transform data into the Talairach space using the Montreal Neurological
Institute avg152T1 template provided by the AFNI. All voxels were
resampled as 2 × 2 × 2-mm size by linear interpolation. Spatial smooth-
ing was done using a Gaussian filter with 6-mm full-width at half-
maximum (FWHM), and the data were temporally band-pass filtered
(0.01–0.08 Hz) to reduce low-frequency fluctuation of the blood oxygen
level-dependent signal for functional connectivity analyses (Biswal
et al., 1995; Greicius et al., 2003).
2.4. fMRI data analysis
2.4.1. Defining regions of interest
In order to assess different cortical functional connectivity patterns
with specific striatal subdivisions of the basal ganglia (caudate nucleus
and putamen) between OCD patients and controls, we defined four
Fig. 1. Augmented reality virtual dirty stimuli-presenting system. A participant can see his/her body and the superimposed animation of dirty feces on both hands through a head-mounted
display (HMD).
151
striatal seed regions in the following locations based on a previous
study of the human striatum (Harrison et al., 2009): (1) the dorsal cau-
date (DC) (x = ±13, y = 15, z = 9), (2) the ventral caudate/nucleus ac-
cumbens (NA) (x = ±9, y = 9, z = −8), (3) the dorsal caudal putamen
(DP) (x = ±28, y = 1, z = 3), and (4) the ventral rostral putamen (VP)
(x = ±20, y = 12, z = −3). The regions of interest (ROIs) were defined
as a 3.5-mm radial sphere for each striatal location.
2.4.2. Functional connectivity analysis
Seed reference time series were calculated by extracting and averag-
ing time series data from the specific defined seeds. Correlation maps of
the left and right DCs were obtained via correlation analysis between the
seed reference time series and the time series from the rest of the whole
brain in a voxel-wise manner for each scan. For nuisance signals, individ-
ual T1 images with segmented white matter and cerebrospinal fluid
were thresholded at 50% tissue probability type and binarized to create
nuisance variable masks, together with a binary mask of the global
brain volume. Nuisance signals were then extracted for each mask by cal-
culating the mean ROI value across the time series. The six head move-
ment parameters, white matter signal changes, cerebrospinal fluid
signal changes, and global signal changes were covariated in the correla-
tion analysis. Then, the functional connectivity map was generated by
converting the correlation coefficients to z-values representing function-
al connectivity strength using Fisher's r-to-z transformation (z = 1/2 ln
((1 + r)/(1 − r))), where r is the correlation coefficient at each voxel,
to make the distribution of correlation coefficient normal (Zhou et al.,
2007). After functional connectivity maps were obtained for each seed,
separately for each hemisphere, one-way ANOVA was performed to in-
vestigate hemisphere by group interaction. As no significant interactions
were found, we obtained the individual functional connectivity map of
the DC for group analysis by averaging functional connectivity maps of
the left and right DCs. We performed the same process for other seeds.
2.4.3. Statistical analysis
To assess within-group functional connectivity patterns, we per-
formed one sample t-tests with an individual functional connectivity
map for each seed. One-way analysis of variance (ANOVA) was used
to examine differences among the CON, NCON, and HC groups. For inter-
pretation, we took a voxel-wise height threshold of P b 0.001 within a
cluster extent threshold of 37 voxels, which corresponds to the
family-wise error correction for the corrected P b 0.05. Correlation anal-
yses were performed to test how functional connectivity strength was
related to symptom severity (Y-BOCS contamination/washing score).
For this analysis, the individual connectivity strength was extracted
based on the survived clusters in the group analysis.
152 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155

3. Results different compared to the other two groups. Functional connectivity

3.1. Participants
Table 1 describes the demographic and clinical characteristics of the
participants. The proportions of females among the CON (n = 2),
NCON (n = 4), and HC group (n = 3) were not significantly different
(χ2 = 1.21, P = 0.55). The educational level of the NCON group was
lower than that of HC group. Depression, anxiety, and disgust symptoms
were higher in the two OCD groups compared to the HC group. Y-BOCS
total scores did not differ significantly between the CON group and the
NCON group, but Y-BOCS contamination/washing scores differed be-
tween the two groups (t = 8.4, P b 0.001). Also, there were no differ-
ences in the medication status between the two OCD groups.
3.2. Functional connectivity
3.2.1. Functional connectivity during resting state
Within-group functional connectivity results are shown in Supple-
mental Table 1. Fig. 2 shows the results of the between-group analysis.
The CON group demonstrated significantly lower functional connectivity
of the VP seed with the insula (x, y, z = −38, 0, 10; F = 9.01; BA 13;
Fig. 2a). In the NCON group, functional connectivity between the VP
and the dorsolateral prefrontal cortex (DLPFC) (NCON b CON and
NCON b HC; x, y, z = 46, 12, 46; F = 11.04; BA 6; Fig. 2b) and that be-
tween the DP and the orbitofrontal cortex (OFC) (NCON N CON and
NCON N HC; x, y, z = 58, 20, 2; F = 9.81; BA 47) were significantly
in the DP with the left superior temporal cortex (x, y, z = − 38, 6,
− 26; F = 10.09; BA 38; Fig. 2c) and the connectivity in the DC with
the superior temporal cortex (x, y, z = 40, −26, 2; F = 10.01; BA 22;
Fig. 2c) were significantly different between the OCD groups and the HC
group.
3.2.2. Functional connectivity during contamination symptom provocation
The within-group functional connectivity analysis results obtained
while participants experienced the augmented reality of dirty feces on
their hands are shown in Supplemental Table 2.
In the group comparison analysis, the CON group showed significantly
increased functional connectivity between the ventral striatum and the
right insula (x, y, z = 44, 2, −10; F = 9.06; BA13; Fig. 3a). In the NCON
group, functional connectivity between the VP and the medial prefrontal
cortex (x, y, z = −8, 24, 50; F = 10.31; BA8; Fig. 3b) was significantly de-
creased compared to the other two groups. In comparing HCs and the
two OCD groups, significantly different connectivity patterns were seen
in the VP seed region with the OFC (x, y, z = 54, 30, −8; F = 10.87;
BA47; Fig. 3c) and the lateral temporal cortex (x, y, z = −56, − 16,
−10; F = 11.38; BA21; Fig. 3c) and in the DP seed region with right
white matter (x, y, z = 28, −40, 20; F = 9.69; BA 13; Fig. 3c).
3.2.3. Relationship between functional connectivity strength and symptom
severity
Individual functional connectivity strengths were extracted for re-
gions that showed significant differences in the group analysis, and

Fig. 2. Significant between-group differences in functional connectivity with striatal seeds during the resting state. a) Regions demonstrating differences between CON vs. HC and NCON;
b) regions demonstrating differences between NCON vs. HC and CON; c) regions demonstrating differences between HC vs. CON and NCON. VP, ventral putamen; L, left; BA, Brodmann
area; DP, dorsal caudate; OFC, orbito-frontal cortex; R, right; DLPFC, dorsolateral prefrontal gyrus; STG, superior temporal gyrus; DC, dorsal caudate; HC, healthy control group; CON, con-
tamination group; NCON, non-contamination group. Results are displayed at corrected P b 0.05.
 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155 153

Fig. 3. Significant between-group differences in functional connectivity with striatal seeds during the symptom provocation paradigm. a) Regions demonstrating differences between CON vs.
HC and NCON; b) regions demonstrating differences between NCON vs. HC and CON; c) regions demonstrating differences between HC vs. CON and NCON. NA, nucleus accumbens; R, right;
BA, Brodmann area; VP, ventral putamen; L, left; MPFC, medial prefrontal cortex; DP, dorsal putamen; WM, white matter; IFG, inferior frontal gyrus; MTG, middle temporal gyrus; HC, healthy
control group; CON, contamination group; NCON, non-contamination group. Results are displayed at corrected P b 0.05.

correlation analyses were performed with contamination/washing symptom severity (r = −0.616, P = 0.001; Fig. 4a). During the symp-
symptom severity as measured by the Y-BOCS checklist. We determined tom provocation condition, functional connectivity between the NA
that the resting state functional connectivity of the VP seed region with and the insula also exhibited a significant correlation with contamina-
the insula was negatively correlated with contamination/washing tion/washing severity (r = 0.478, P = 0.013; Fig. 4b).

Fig. 4. Correlation between connectivity strengths and symptom severity. (a) Strength of the functional connectivity between the ventral putamen (VP) and insula during the resting state
predicted Yale–Brown Obsessive–Compulsive Scale (Y-BOCS) contamination/washing scores (P = 0.001). (b) Strength of the functional connectivity between the nucleus accumbens
(NA) and insula during symptom provocation condition predicted Y-BOCS contamination/washing scores (P = 0.013).
154 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155
4. Discussion
The present study employed an MR-compatible augmented reality
system in which dirty material was superimposed on the real-time
image of the participants' hands to investigate distinct corticostriatal
network abnormalities associated with contamination/washing symp-
toms. Subjects exhibiting contamination/washing dimension of OCD
demonstrated functional connectivity alterations between the ventral
striatum and the insula during both the resting state and the symptom
provocation condition compared to OCD patients without predominant
contamination/washing symptoms and controls. These connectivity
strengths between the ventral striatum and the insula were found to
specifically correlate with contamination/washing symptom severity,
supporting the hypothesis of distinct corticostriatal network dysfunc-
tions to underlie the contamination/washing symptom dimension. To
our knowledge, this is the first study that examined specific abnormal-
ities in functional connectivity of contamination/washing symptom di-
mension OCD.
In primates, anterior insula, containing amygdala inputs, projects to
the ventral striatum, which includes the nucleus accumbens, ventral cau-
date and ventral putamen (Chikama et al., 1997; Fudge et al., 2005). Rest-
ing state functional connectivity between the ventral striatum and the
insula has also been demonstrated in healthy adults (Cauda et al.,
2011a,b), which is known to be involved in emotional salience detection
and attention control, integrating external elements about the stimuli
and internal information about individual cognitive, homeostatic and
emotional states to organize behavior (Cauda et al., 2011b; Cho et al.,
2012), as well as error awareness processes (Cauda et al., 2012; Klein
et al., 2013). Our study demonstrated decreased functional connectivity
of the ventral putamen with the insula in OCD patients with predomi-
nantly contamination/washing symptoms during the resting state. Dur-
ing symptom provocation, functional connectivity of the ventral
striatum with the insula was altered in the opposite direction from the
resting state, with increased connectivity strength in the contamina-
tion/washing group. Abnormal insular hyperactivation has been demon-
strated in previous symptom provocation fMRI studies of OCD patients
with contamination/washing symptoms (Phillips et al., 2000; Shapira
et al., 2003). Taken together, deficits in the functional system of the ven-
tral striatum and the insula at rest may serve vulnerability to emotionally
salient stimuli detection and attention control in contamination-based
OCD patients, which may become aberrantly increased in face of contam-
ination symptom provoking stimuli that is distinctively emotionally sa-
lient to this population of OCD patients. In addition to the above
findings, functional connectivity strength between the ventral striatum
and the insula significantly correlated with contamination/washing
symptom severity. This is in strong agreement with previous reports of
association between insular activation and washing symptom severity
(Mataix-Cols et al., 2004). These findings provide additional evidence,
at a functional network level, to support the notion that contamina-
tion/washing symptom dimension is mediated by distinct neural corre-
lates. More specifically, the limbic network, especially including the
ventral striatum with the insula, seems to play a key role in the contam-
ination/washing phenotype of OCD, possibly through the dysfunctional
control of emotionally salient error awareness.
Alternatively, a substantial body of data identifies the insular cortex
as a potential site for recognizing and experiencing disgust (Olatunji
et al., 2010). The heightened connectivity of the ventral striatum with
the insula during contamination symptom provocation may be
interpreted as heightened disgust processing in contamination/
washing-type OCD patients. However, there was no difference in disgust
between CON and NCON OCD patients in the present study. Further-
more, connectivity strength did not correlate with disgust scores. Thus,
it may be difficult to explain all the results by the mechanism of disgust.
In the OCD group without prominent contamination/washing symp-
toms, functional connectivity disturbances were observed in the stria-
tum with distributed regions of the prefrontal cortex. This finding is
consistent with the previous resting-state functional connectivity
study whose OCD patient samples were not characterized by prominent
contamination/washing symptoms but more so by aggressive/checking
symptoms (Harrison et al., 2009). Taken together with distinct findings
of the contamination-based OCD patients, current results seem to sup-
port the neurobiological model that hypothesizes contamination/wash-
ing symptom dimensions to be a limbic spectrum disorder and the
symmetry/order and checking symptom dimensions as a disturbance
of the fronto-striatal network.
Consistent with past studies, corticostriatal network alterations com-
mon to all OCD patients were demonstrated in the present study. During
the resting state, alterations involving the dorsal striatum and temporal
cortices appear to be common pathophysiological changes in OCD. Ab-
normal activities of the temporal regions in OCD have been identified
in recent functional neuroimaging reviews (Rotge et al., 2008), and asso-
ciated resting-state functional connectivity alterations have also been
demonstrated (Harrison et al., 2009). The superior and middle temporal
gyri have dense connections to the OFC, anterior cingulate cortex, amyg-
dala and hypothalamus and are suggested to be involved in coupling vis-
ceral emotional responses and complex visual stimuli, as may occur
during OC symptom provocation (Olson et al., 2007). Several other stud-
ies have suggested that the temporal cortex is involved in mediating anx-
iety manifestations as part of the limbic network (Choi et al., 2006;
Maihofner et al., 2007). Further studies are needed to more clearly iden-
tify the roles of the temporal cortex in OCD pathophysiology.
During symptom provocation, general functional connectivity alter-
ations of the ventral striatum with the OFC were again confirmed. The
OFC is one of the most consistently activated regions in OCD symptom
provocation studies (Rotge et al., 2008), as well as being emphasized in
previous resting state functional connectivity studies of OCD (Harrison
et al., 2009; Sakai et al., 2011). More specifically, current finding is also
consistent with a recent resting-state study that demonstrated common
connectivity alterations of the ventral striatum and the OFC, independent
of the effect of particular symptom dimensions (Harrison et al., 2013).
The current study extends to show the general role of this functional net-
work alteration during symptom provocation. The OFC is one of the key
limbic network components in detecting error signals (Noonan et al.,
2012). As sensory information is projected to the OFC for evaluation of
error signals, heightened connectivity of the cognitive network involving
the OFC may lead to stimuli misinterpretation as a signal for danger.
When coupled with limbic system hyperconnectivity mediated by the
ventral striatum, OC symptoms may emerge. This hypothesis should be
evaluated further in future research.
Certain limitations should be considered for future research, as most
patients were on medications, and their confounding effects cannot be
completely excluded. However, previous symptom provocation studies
have reported similar results in medicated and non-medicated patients
(Adler et al., 2000). Also, normalizing effects of pretreatment functional
abnormalities have been demonstrated in several studies, including nor-
malization of heightened resting-state activity in ventral corticostriatal
regions (Saxena et al., 1999). These suggest that medication effects, if
any, may attenuate differences between patients and controls. Secondly,
OCD patients were subgrouped into those with and without prominent
contamination/washing symptoms. As OCD patients generally present
with more than one type of OC symptom, a dimensional approach that
explores other major symptom dimensions will be important in subse-
quent research. Considering that functional connectivity studies have
not yet been able to address this multi-symptomatic nature of OCD in
specific detail due to factors such as sample size, the current symptom
provocation functional connectivity study using subgroups may be a use-
ful starting point for future research.
5. Conclusion
In conclusion, the current study explored functional brain network
disturbances, some of which are general to OCD and some distinct to
 K. Jhung et al. / Progress in Neuro-Psychopharmacology & Biological Psychiatry 53 (2014) 149–155
the contamination/washing dimension. The findings suggest limbic net-
work dysfunctions to play a pivotal role in contamination/washing
symptoms, possibly associated with emotionally salient error aware-
ness. Circuits involving the striatum, OFC, and temporal cortices were
again confirmed to be common neural substrates of OCD. These results
suggest that the combination of general orbitofronto-striatal circuit dys-
functions and some distinct network alterations may lead to emergence
of OCD with different symptom phenotypes.
Acknowledgements
This work was supported by a faculty research grant from the Yonsei
University College of Medicine (6-2010-0019).
Appendix A. Supplementary data
Supplementary data to this article can be found online at http://dx.
doi.org/10.1016/j.pnpbp.2014.04.007.
References
Adler CM, McDonough-Ryan P, Sax KW, Holland SK, Arndt S, Strakowski SM. fMRI of neu-
ronal activation with symptom provocation in unmedicated patients with obsessive
compulsive disorder. J Psychiatr Res 2000;34:317–24.
Alsobrook IJ, Leckman JF, Goodman WK, Rasmussen SA, Pauls DL. Segregation analysis of
obsessive–compulsive disorder using symptom-based factor scores. Am J Med Genet
1999;88:669–75.
Beck AT, Steer RA. Manual for the Beck Anxiety Inventory. San Antonio: Psychological
Corporation; 1990.
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depres-
sion. Arch Gen Psychiatry 1961;4:561–71.
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;34:537–41.
Cauda F, Cavanna AE, D'Agata F, Sacco K, Duca S, Geminiani GC. Functional connectivity
and coactivation of the nucleus accumbens: a combined functional connectivity and
structure-based meta-analysis. J Cogn Neurosci 2011a;23:2864–77.
Cauda F, Costa T, Torta DM, Sacco K, D'Agata F, Duca S, et al. Meta-analytic clustering of
the insular cortex: characterizing the meta-analytic connectivity of the insula when
involved in active tasks. Neuroimage 2012;62:343–55.
Cauda F, D'Agata F, Sacco K, Duca S, Geminiani G, Vercelli A. Functional connectivity of the
insula in the resting brain. Neuroimage 2011b;55:8–23.
Chikama M, McFarland NR, Amaral DG, Haber SN. Insular cortical projections to functional
regions of the striatum correlate with cortical cytoarchitectonic organization in the
primate. J Neurosci 1997;17:9686–705.
Cho YT, Fromm S, Guyer AE, Detloff A, Pine DS, Fudge JL, et al. Nucleus accumbens, thal-
amus and insula connectivity during incentive anticipation in typical adults and ado-
lescents. Neuroimage 2012;66C:508–21.
Choi JS, Kim HS, Yoo SY, Ha TH, Chang JH, Kim YY, et al. Morphometric alterations of an-
terior superior temporal cortex in obsessive–compulsive disorder. Depress Anxiety
2006;23:290–6.
Cox RW. AFNI: software for analysis and visualization of functional magnetic resonance
neuroimages. Comput Biomed Res 1996;29:162–73.
Del Casale A, Kotzalidis GD, Rapinesi C, Serata D, Ambrosi E, Simonetti A, et al. Functional
neuroimaging in obsessive–compulsive disorder. Neuropsychobiology 2011;64:
61–85.
Fox MD, Raichle ME. Spontaneous fluctuations in brain activity observed with functional
magnetic resonance imaging. Nat Rev Neurosci 2007;8:700–11.
Fudge JL, Breitbart MA, Danish M, Pannoni V. Insular and gustatory inputs to the caudal
ventral striatum in primates. J Comp Neurol 2005;490:101–18.
Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale–
Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen
Psychiatry 1989;46:1006–11.
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:
253–8.
155
Harrison BJ, Pujol J, Cardoner N, Deus J, Alonso P, Lopez-Sola M, et al. Brain corticostriatal
systems and the major clinical symptom dimensions of obsessive–compulsive disor-
der. Biol Psychiatry 2013;73:321–8.
Harrison BJ, Soriano-Mas C, Pujol J, Ortiz H, Lopez-Sola M, Hernandez-Ribas R, et al. Al-
tered corticostriatal functional connectivity in obsessive–compulsive disorder. Arch
Gen Psychiatry 2009;66:1189–200.
Klein TA, Ullsperger M, Danielmeier C. Error awareness and the insula: links to neurolog-
ical and psychiatric diseases. Front Hum Neurosci 2013;7:14.
Ku J, Kim JJ, Jung YC, Park IH, Lee H, Han K, et al. Brain mechanisms involved in processing
unreal perceptions. Neuroimage 2008;43:793–800.
Maihofner C, Sperling W, Kaltenhauser M, Bleich S, de Zwaan M, Wiltfang J, et al. Sponta-
neous magnetoencephalographic activity in patients with obsessive–compulsive dis-
order. Brain Res 2007;1129:200–5.
Mataix-Cols D, Baer L, Rauch SL, Jenike MA. Relation of factor-analyzed symptom dimen-
sions of obsessive–compulsive disorder to personality disorders. Acta Psychiatr Scand
2000;102:199–202.
Mataix-Cols D, Cullen S, Lange K, Zelaya F, Andrew C, Amaro E, et al. Neural correlates of
anxiety associated with obsessive–compulsive symptom dimensions in normal vol-
unteers. Biol Psychiatry 2003;53:482–93.
Mataix-Cols D, Rauch SL, Manzo PA, Jenike MA, Baer L. Use of factor-analyzed symptom
dimensions to predict outcome with serotonin reuptake inhibitors and placebo in
the treatment of obsessive–compulsive disorder. Am J Psychiatry 1999;156:1409–16.
Mataix-Cols D, van den Heuvel OA. Common and distinct neural correlates of obsessive–
compulsive and related disorders. Psychiatr Clin North Am 2006;29:391–410. [viii].
Mataix-Cols D, Wooderson S, Lawrence N, Brammer MJ, Speckens A, Phillips ML. Distinct
neural correlates of washing, checking, and hoarding symptom dimensions in obses-
sive–compulsive disorder. Arch Gen Psychiatry 2004;61:564–76.
Noonan MP, Kolling N, Walton ME, Rushworth MF. Re-evaluating the role of the
orbitofrontal cortex in reward and reinforcement. Eur J Neurosci 2012;35:997–1010.
Olatunji BO, Cisler J, McKay D, Phillips ML. Is disgust associated with psychopathology?
Emerging research in the anxiety disorders. Psychiatry Res 2010;175:1–10.
Olatunji BO, Williams NL, Tolin DF, Abramowitz JS, Sawchuk CN, Lohr JM, et al. The Dis-
gust Scale: item analysis, factor structure, and suggestions for refinement. Psychol As-
sess 2007;19:281–97.
Olson IR, Plotzker A, Ezzyat Y. The Enigmatic temporal pole: a review of findings on social
and emotional processing. Brain 2007;130:1718–31.
Phillips ML, Marks IM, Senior C, Lythgoe D, O'Dwyer AM, Meehan O, et al. A differential
neural response in obsessive–compulsive disorder patients with washing compared
with checking symptoms to disgust. Psychol Med 2000;30:1037–50.
Pujol J, Soriano-Mas C, Alonso P, Cardoner N, Menchon JM, Deus J, et al. Mapping structur-
al brain alterations in obsessive–compulsive disorder. Arch Gen Psychiatry 2004;61:
720–30.
Rasmussen SA, Eisen JL. The epidemiology and clinical features of obsessive compulsive
disorder. Psychiatr Clin North Am 1992;15:743–58.
Rotge JY, Guehl D, Dilharreguy B, Cuny E, Tignol J, Bioulac B, et al. Provocation of obses-
sive–compulsive symptoms: a quantitative voxel-based meta-analysis of functional
neuroimaging studies. J Psychiatry Neurosci 2008;33:405–12.
Sakai Y, Narumoto J, Nishida S, Nakamae T, Yamada K, Nishimura T, et al. Corticostriatal
functional connectivity in non-medicated patients with obsessive–compulsive disor-
der. Eur Psychiatry 2011;26:463–9.
Saxena S. Neuroimaging and the pathophysiology of obsessive compulsive disorder. In: Fu
C, Senior C, Russell TA, Weinberger DR, Murray R, editors. Neuroimaging in Psychia-
try. London, England: Martin Dunitz; 2003. p. 191–224.
Saxena S, Brody AL, Maidment KM, Dunkin JJ, Colgan M, Alborzian S, et al. Localized
orbitofrontal and subcortical metabolic changes and predictors of response to parox-
etine treatment in obsessive–compulsive disorder. Neuropsychopharmacology 1999;
21:683–93.
Shapira NA, Liu Y, He AG, Bradley MM, Lessig MC, James GA, et al. Brain activation by
disgust-inducing pictures in obsessive–compulsive disorder. Biol Psychiatry 2003;
54:751–6.
Sheehan DV, Lecrubier Y, Sheehan KH, Amorim P, Janavs J, Weiller E, et al. The Mini-
International Neuropsychiatric Interview (M.I.N.I.): the development and validation
of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychi-
atry 1998;59(Suppl. 20):22–33. [quiz 4–57].
van den Heuvel OA, Remijnse PL, Mataix-Cols D, Vrenken H, Groenewegen HJ, Uylings HB,
et al. The major symptom dimensions of obsessive–compulsive disorder are mediat-
ed by partially distinct neural systems. Brain 2009;132:853–68.
Zhou Y, Liang M, Tian L, Wang K, Hao Y, Liu H, et al. Functional disintegration in paranoid
schizophrenia using resting-state fMRI. Schizophr Res 2007;97:194–205.