Psychological Medicine (2014), 44, 14751484.

Cambridge University Press 2013 OR I G I N A L A R T I C L E

doi:10.1017/S0033291713002250

Default network connectivity as a vulnerability

marker for obsessive compulsive disorder

Z. W. Peng1,2,3, T. Xu1,4, Q. H. He3, C. Z. Shi5, Z. Wei3, G. D. Miao3, J. Jing6, K. O. Lim7, X. N. Zuo4,8*

and R. C. K. Chan1,8*
1
Neuropsychology and Applied Cognitive Neuroscience Laboratory, Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of
Sciences, Beijing, Peoples Republic of China
2
Department of Psychology, South China Normal University, Guangzhou, Peoples Republic of China
3
Guangzhou Psychiatry Hospital, Guangzhou, Peoples Republic of China
4
Key Laboratory of Behavioral Science, Laboratory for Functional Connectome and Development, Institute of Psychology, Chinese Academy of
Sciences, Beijing, Peoples Republic of China
5
Medical Imaging Center, The First Afliated Hospital of Jinan University, Guangzhou, Peoples Republic of China
6
Department of Maternal and Child Health, School of Public Health, Sun Yat-Sen University, Guangzhou, Peoples Republic of China
7
Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA
8
Magnetic Resonance Imaging Research Center, Institute of Psychology, Chinese Academy of Sciences, Beijing, Peoples Republic of China

Background. Aberrant functional connectivity within the default network is generally assumed to be involved in the
pathophysiology of obsessive compulsive disorder (OCD); however, the genetic risk of default network connectivity
in OCD remains largely unknown.

Method. Here, we systematically investigated default network connectivity in 15 OCD patients, 15 paired unaffected
siblings and 28 healthy controls. We sought to examine the proles of default network connectivity in OCD patients
and their siblings, exploring the correlation between abnormal default network connectivity and genetic risk for this
population.

Results. Compared with healthy controls, OCD patients exhibited reduced strength of default network functional
connectivity with the posterior cingulate cortex (PCC), and increased functional connectivity in the right inferior frontal
lobe, insula, superior parietal cortex and superior temporal cortex, while their unaffected rst-degree siblings only
showed reduced local connectivity in the PCC.

Conclusions. These ndings suggest that the disruptions of default network functional connectivity might be associated
with family history of OCD. The decreased default network connectivity in both OCD patients and their unaffected
siblings may serve as a potential marker of OCD.

Received 9 June 2012; Revised 7 August 2013; Accepted 8 August 2013; First published online 4 September 2013

Key words: Default network, functional connectivity, genetic risk, obsessive compulsive disorder, resting-state fMRI.

Introduction population of developing OCD (Pauls et al. 1995;

Nestadt et al. 2000; Hanna et al. 2002). The concordance
Obsessive compulsive disorder (OCD) is a neuro-
rate for OCD is also greater among monozygotic twins
psychiatric disorder associating with persistent intru-
(8087%) than dizygotic twins (4750%) (Inouye, 1965;
sive thoughts (obsessions) and/or repetitive behaviors
ODonnell, 1970).
(compulsions), and the lifetime prevalence is estimated
There is increasing evidence to suggest that OCD is
to be 23% worldwide (Weissman et al. 1994). Em-
associated with altered connectivity within the default
pirical ndings from family studies have suggested
mode network (DMN) (Harrison et al. 2009; Fitzgerald
that the rst-degree relatives of patients with OCD
et al. 2010; Jang et al. 2010; Sakai et al. 2010; Stern et al.
have almost 312 times more risk than the general
2012), which is thought to be the backbone of the
intrinsic functional architecture (Vincent et al. 2007;
Hagmann et al. 2008; Biswal et al. 2010; Zuo et al.
* Address for correspondence: R. C. K. Chan, Ph.D. and Xi-Nian 2012) and relevant to brain development (Dosenbach
Zuo, Institute of Psychology, Chinese Academy of Sciences, 16 Lincui
et al. 2010; Power et al. 2010) and disorders (Broyd
Road, Beijing 100101, Peoples Republic of China.
(Email: rckchan@psych.ac.cn) [R.C.K.C.]
et al. 2009). This network is more active when the
(Email: zuoxn@psych.ac.cn) [X.N.Z.] brain is at a resting state and has been implicated in
These authors contributed equally to this work. the cognitive functions associated with self-referential
1476 Z. W. Peng et al.
mental activity (Gusnard et al. 2001), the extraction of
episodic memory (Cabeza et al. 2002), imagining the
future (Schacter et al. 2007) and mind wandering
(Mason et al. 2007). DMN regions include the posterior
cingulate cortex (PCC), precuneus, medial prefrontal
cortex, ventral anterior cingulate cortex and lateral
parietal cortex (Raichle et al. 2001). Several studies
have shown that OCD patients demonstrate abnormal
DMN functional connectivity (Harrison et al. 2009;
Fitzgerald et al. 2010, 2011; Jang et al. 2010; Sakai
et al. 2010; Hou et al. 2012; Stern et al. 2012). For
instance, Harrison et al. (2009) reported that OCD
patients had increased functional connectivity along
a ventral corticostriatal axis within the DMN and
decreased functional connectivity in the dorsal stria-
tum within the lateral prefrontal cortex and the ventral
striatum within the midbrain ventral tegmental area by
using the striatum seed regions. Jang et al. (2010) found
that OCD patients had less functional connectivity
with the PCC in the anterior cingulate cortex, middle
frontal gyrus, and putamen. Taken together, these
ndings suggest that abnormal functional connectivity
of the DMN exists in OCD patients. However, the
heritability property of functional connectivity within
the DMN in OCD remains unclear.
Due to their high risk of developing OCD, un-
affected siblings of patients with OCD can provide
rich genetic information for OCD research, thus help-
ing to disentangle state and trait characteristic of the ill-
ness. Thus an important next step in the identication
of DMN connectivity as a putative biological marker is
to examine the functional connectivity of the DMN in
unaffected siblings of OCD patients, providing new
insights into genetic risk factors for OCD.
The purpose of this study was to examine the
proles of functional connectivity of the DMN in
patients with OCD, their unaffected siblings, and
healthy controls. Given the high familial risk of OCD,
we expected to observe in unaffected siblings a pattern
of functional connectivity within the DMN intermedi-
ate between OCD patients and healthy controls.
Method
Participants
The subjects (see Table 1 for details) were recruited
through the Guangzhou Psychiatry Hospital and
included: (1) patients who met Diagnostic and
Statistical Manual of Mental Disorders, fourth edition
(DSM-IV) criteria for OCD [OCD group; n = 15,
10 males; age (S.D.) 26.7 4.8 years]; (2) the unaffected
siblings of individuals with OCD (SIB group; n = 15,
seven males; age 30.0 9.0 years); and (3) healthy con-
trol subjects (CON group; n = 28, 21 males; age
27.5 8.4 years). All participants were from the Chinese
Han population. Each unaffected sibling was com-
pared with one OCD patient and they came from the
same family. The individuals with OCD were all out-
patients and had been stabilized on selective serotonin
reuptake inhibitors for at least 4 weeks (see online
Supplementary Material). Siblings were full siblings,
based on self-report. The institutional research and
ethics committee of Guangzhou Psychiatry Hospital
approved all study protocols. All subjects gave written
informed consent before participation.
All subjects were diagnosed with DSM-IV criteria for
OCD by using the Structured Clinical Interview (SCID)
for DSM-IV-TR Axis I disorders (First et al. 1996). The
patients had no history of neurological disorder,
Tourettes syndrome, head injury, serious medical con-
dition, or history of drug or alcohol addiction. The SIB
and CON subjects were screened by using the SCID for
the DSM-IV-TR Axis I disorders, Research Version,
Non-Patient edition (SCID-I/NP; First et al. 2002).
Healthy controls with a family history of Axis I or II
psychiatric disorders were excluded.
Measures
Clinical and neurocognitive assessments
Estimated intelligence quotient (IQ) was assessed
with the Wechsler Adult Intelligence Scale-Revised
(Wechsler, 1981), and subjects with a total score of less
than 80 were excluded. The YaleBrown Obsessive
Compulsive Scale (YBOCS) was used to assess illness
severity (Goodman et al. 1989). The Obsessive
Compulsive Inventory Revised (OCI-R) was used to
characterize obsessive and compulsive phenomena,
including obsessing, washing, checking, neutralizing,
ordering and hoarding (Foa et al. 2002; Peng et al.
2011). The Beck Depression Inventory (BDI; Beck &
Steer, 1984) was used to assess depressive symptoms,
and the State-Trait Anxiety Inventory (STAI;
Spielberger, 1983) was used to measure anxiety symp-
toms. The Annett Handedness Inventory measured
handedness information (Spreen & Strauss, 1991).
An experienced psychiatrist administered all clinical
ratings.
Magnetic resonance imaging acquisition
All scans were performed on a Signa HDe 1.5-T GE
Signa scanner (GE Medical Systems, USA) equipped
with an eight-channel phased-array head coil at the
First Afliated Hospital of Jinan University. For each
subject, 141 resting-state functional images (blood oxy-
genation level-dependent) were acquired with a single-
shot echo-planar imaging sequence [repetition time
(TR) = 2000 ms, echo time (TE) = 60 ms, matrix = 64 64,
 Vulnerability marker for OCD 1477

Table 1. Demographic and clinical characteristics of study subjects

Patients with
Measure OCD (n = 15) SIB (n = 15) CON (n = 28) p

Age, years 26.7 (4.8) 30.0 (9.0) 27.5 (8.4) 0.47

Sex, n 0.14
Male 10 7 21
Female 5 8 7
Education, years 14.0 (2.5) 14.5 (2.6) 12.9 (3.4) 0.25
IQ estimate 106.9 (14.9) 102.9 (15.1) 106.3 (15.8) 0.73
Age at onset of OCD, years 19.6 (5.9)
Duration of illness, years 7.4 (4.8)
YBOCS total 25.7 (6.0) 2.3 (2.3) 1.9 (2.8) <0.01
YBOCS obsessions 15.6 (3.7) 1.0 (1.4) 0.9 (1.2) <0.01
YBOCS compulsions 13.7 (3.8) 1.3 (1.6) 1.0 (2.0) <0.01
OCI-R 21.0 (10.2) 8.4 (7.3) 10.5 (9.6) <0.01
BDI 20.5 (13.7) 3.7 (8.4) 7.1 (8.2) <0.01
STAI state 55.1 (20.2) 24.9 (14.3) 33.5 (18.4) <0.01
STAI trait 57.9 (18.7) 24.9 (17.1) 33.1 (18.1) <0.01

Data are given as mean (standard deviation).

OCD, Obsessive compulsive disorder; SIB, siblings of individuals with OCD; CON, healthy control subjects; IQ, intelligence
quotient; YBOCS, YaleBrown Obsessive Compulsive Scale; OCI-R, Obsessive Compulsive Inventory Revised; BDI, Beck
Depression Inventory; STAI, State-Trait Anxiety Inventory.

eld of view (FOV) = 240 mm 240 mm, 6 mm slice
thickness, 22 axial slices, no gap, ip angle = 90].
All subjects were instructed to relax, stay awake, lie
still, keep their eyes closed and not to think of anything
in particular. In order to assess the stability of the
resting-state scans and the reproducibility of ndings,
the second resting-state scan (REST2) was obtained fol-
lowing the rst resting-state scan (REST1) with the
same parameters after 1-min break. We also acquired
a high-resolution T1-weighted anatomical image for
each subject using a three-dimensional fast spoiled
gradient-recalled sequence with 128 contiguous slices
(TR = 8 ms, TE = 1.7 ms, ip angle = 20, FOV = 240 mm
240 mm, matrix = 256 256, slice thickness = 1.0 mm).
Subject-level data pre-processing and connectivity analyses
Both structural and functional data pre-processing
were conducted with the Connectome Computation
System (http://lfcd.psych.ac.cn/ccs.html) developed
by the Laboratory for Functional Connectome and
Development (Zuo et al. 2013) based on the 1000
Functional Connectomes Project scripts (Biswal et al.
2010), producing the resultant four-dimensional (4D)
residual time series for subsequent subject-level func-
tional connectivity analyses. All details of the data
pre-processing can be found in our recent work (Wei
et al. 2013; Zuo et al. 2013). Of note, the Friston-24
model was employed to correct for individual
in-scanner head motion (Yan et al. 2013). We examined
resting-state functional connectivity (RSFC) associated
with the hub of the default network (i.e. seed region
of a sphere with 6 mm radius): the PCC (x = 8,
y = 56, z = 26) in MNI152 standard space (Andrews-
Hanna et al. 2010). For each subject, we rst transferred
individual residual 4D data to the Montreal Neuro-
logical Institute (MNI152) 2 mm space and extracted
the mean time series by averaging across all voxels in
each seed region. Using this mean time series, we
performed a whole-brain seed correlation analysis for
each subject using the AFNI program 3dm+, carried
out in each individuals native space. This analysis
produced subject-level correlation maps of all voxels
in the brain that were positively or negatively corre-
lated with the seeds time series. Finally, these corre-
lation maps were converted into z value maps using
Fishers r-to-z transformation to improve the data
normality.
Group-level default network connectivity analyses
Group-level analyses were implemented as a two-way
(factors: group, scan) repeated-measure (scan) analysis
of covariance using the Linear Mixed Effect (LME)
Matlab toolbox in FreeSurfer 5.1 (Bernal-Rusiel et al.
2012). Cluster-based statistical corrections for multiple
comparisons were performed using Gaussian random
eld theory (z > 2.3; corrected p < 0.05). This group-level
analysis produced thresholded z statistic maps show-
ing brain regions with signicantly detectable RSFC
1478 Z. W. Peng et al.
with the PCC seed regions for OCD, SIB and CON
groups, respectively, as well as differences in default
network RSFC (i.e. group difference maps indicating
OCD versus SIB, SIB versus CON and OCD versus CON
comparisons). Of note, according to previous studies
showing age, sex, IQ and head micromovement-related
changes of default network connectivity (Biswal et al.
2010; Tomasi & Volkow, 2012; Zuo et al. 2012; Yan
et al. 2013) and the wide age range of OCD patients
in the present study, we modeled age, sex, IQ, and
mean framewise displacement (Yan et al. 2013) as
covariates in the group-level LME model.
Testretest reliability and reproducibility
Despite the reasonable testretest reliability of the
resting-state functional magnetic resonance imaging
(R-fMRI) measures reported (Zuo et al. 2010a,b, 2012),
previous studies have shown the dynamic and uncon-
strained nature of R-fMRI (Yan et al. 2009; Chang &
Glover, 2010). We conducted careful stability analysis
to evaluate the testretest reliability of default network
mapping across the two resting-state scans (see online
Supplementary Material).
Relationship with clinical and neurocognitive variables
To examine whether default network connectivity can
predict neurocognitive function and clinical symptom
severity in OCD, we conducted partial correlation
analysis by controlling for the effects of age, sex and
estimated IQ. Across subjects in the patient group,
RSFC in the regions showing high testretest reliabil-
ity and reproducibility (see online Supplementary
material), OCD versus CON or SIB versus CON differ-
ences were averaged to correlate with YBOCS, BDI
and STAI scores.
Results
Demographic data
One-way analysis of variance was used to examine
if there were any differences in behavior measures
among the three groups. The results are summarized
in Table 1. Briey, the three groups did not differ signi-
cantly in age, sex, and education or estimated IQ. All
subjects were right handed. As a group, our OCD
patients were mildly impaired [total YBOCS: 25.7
(S.D. = 6.0); OCI-R: 21.0 (S.D. = 10.2); BDI: 20.5 (S.D. = 13.7);
state STAI: 55.1 (S.D. = 20.2); trait STAI: 57.9 (S.D. = 18.7)]
compared with SIB and normal CON subjects.
Default network connectivity: OCD versus CON
Compared with healthy controls, OCD patients were
found to have signicantly decreased RSFC within
the PCC. We also observed signicantly increased
RSFC in the right inferior frontal lobe, insula and
superior temporal lobe. Of note, the right superior par-
ietal cortex also showed increased RSFC. We employed
the threshold of z > 2.3, corrected p < 0.05 for cluster
level statistic in FSL (Oxford University, UK). The
signicant cluster was still there with the threshold
at z > 3.1. These results are shown in Fig. 1.
Default network connectivity: OCD versus SIB
Compared with SIB subjects, OCD patients exhibited
decreased RSFC in the right middle temporal gyrus
(Fig. 2).
Default network connectivity: SIB versus CON
With the PCC seed (Fig. 3), compared with CON sub-
jects, SIB participants only showed a lower RSFC in the
PCC and no increased RSFC was found.
Testretest reliable and reproducible ndings
For PCC seeded RSFC maps, we measured the test
retest reliability of the default network connectivity
across REST1 and REST2 with the intraclass correlation
coefcient (ICC). There was fair (ICC = 0.4) to excellent
(ICC = 0.9) reproducibility for RSFC within default net-
work regions (online Supplementary Fig. S1).
Default network connectivity predicts clinical scores
To assess if the reduction of short-distance default
network connectivity in both OCD patients and their
siblings is associated with various clinical or neurocog-
nitive measures, we extracted the mean RSFC within
the overlap region for PCC seeds and correlated
them with clinical scores. Our RSFC-symptom correla-
tional analyses found that there was a signicant nega-
tive correlation between RSFC in the overlap region
for the PCC and YBOCS obsessive subscale scores
(Pearson r = 0.49, p = 0.008).
Discussion
The goal of the present study was to examine differ-
ences in functional connectivity within the DMN in
OCD patients, their unaffected siblings and matched
controls to test the hypothesis that the disruptive con-
nectivity of the DMN in OCD may be a putative mar-
ker for this disease. We observed reduced functional
connectivity in the PCC within the DMN not only in
patients with OCD but also in their unaffected siblings.
These disrupted connectivity patterns were present in
the two sequential scans with a 1-min interval, imply-
ing their testretest reliability. The presence of abnorm-
alities of the DMN in unaffected siblings suggests that

Fig. 1. Group-level default network functional connectivity differences between obsessive compulsive disorder patients and
healthy controls. LH, Left hemisphere; PCC, posterior cingulate cortex; RSFC, resting-state functional connectivity; RH, right
hemisphere.
these abnormalities are mainly due to genetic factors
rather than to treatment or other secondary environ-
mental factors. Taken together, these ndings suggest
that OCD is associated with disrupted functional
connectivity within the DMN, and may provide new
insights into the understanding of the pathophysiology
of this disorder.
The present study demonstrates that OCD patients
are associated with abnormal functional connectivity
in the PCC within the DMN. These ndings are con-
sistent with previous studies about resting-state func-
tional connectivity in OCD. Fitzgerald et al. (2010)
found that pediatric OCD patients exhibited less func-
tional connectivity within the PCC during the resting
state. In addition, previous studies have identied
structural and functional abnormalities of the PCC
in OCD patients. Neuroanatomically, recent studies
demonstrated that OCD patients had reductions of
gray matter volume in the PCC (Matsumoto et al.
2010), as well as white matter reduction in the PCC
(Cannistraro et al. 2007). Functionally, the PCC is
important for cognitive inhibition (Rubia et al. 2005;
Simmonds et al. 2008) and exibility (Fox et al. 2003;
Chamberlain et al. 2008; Pearson et al. 2011), which
are the core cognitive dysfunctions in OCD and
Vulnerability marker for OCD 1479
suggested as cognitive biological markers for OCD
(Chamberlain et al. 2007; Menzies et al. 2007). Most
recently, two resting-state studies both found that
OCD patients showed decreased functional connec-
tivity within the DMN when using the PCC as seed,
which is similar to our results (Jang et al. 2010; Stern
et al. 2012). However, their results did not nd that
OCD patients had reduced connectivity in the PCC.
This difference might be due to the differences of
sample heterogeneity or seed selection. Specically,
one study included medicated and unmedicated
patient samples (Stern et al. 2012), and another study
dened the PCC seed region using a different labeled
template (Jang et al. 2010). Relative to healthy controls,
OCD patients also showed increased functional
connectivity in the inferior frontal lobe and insula,
which are core regions of the salience network
involved in implementing and maintaining attention
to external task demands and detecting salient events
(Dosenbach et al. 2007). Particularly, the insula may
act as an integral hub in mediating dynamic inter-
actions between externally oriented attentional net-
works and internally oriented self-related networks.
In other words, this region is important for switching
attention away from an internal focus toward the
1480 Z. W. Peng et al.
Fig. 2. Group-level default network functional connectivity differences between obsessive compulsive disorder patients and
their rst-degree siblings. LH, Left hemisphere; PCC, posterior cingulate cortex; RSFC, resting-state functional connectivity;
RH, right hemisphere.
external environment after detecting potentially harm-
ful situations (Menon & Uddin, 2010). Our results
found that OCD patients had decreased functional
connectivity in the DMN, but increased connectivity
in the salient network. Based on the causal relationship
between the salience network and the DMN (Chiong
et al. 2013), it is natural to speculate that OCD patients
have difculties in disengaging from internal mental
processes when needing to respond more appropri-
ately to salient external information related to potential
risk.
Intriguingly, our ndings also demonstrated that
the unaffected siblings exhibited impairments in func-
tional connectivity within the PCC similar to OCD
patients. Given that the unaffected siblings have not
received any medication for the treatment of OCD
symptoms, the similar functional connectivity patterns
shown in them suggests that such a disrupted func-
tional connection in their OCD probands was not sec-
ondary to medication or the effects of the illness. This
nding is consistent with the ndings of disrupted
functional connectivity when the rst-degree relatives
of OCD patients were asked to perform a functional
task. For instance, Chamberlain et al. (2007, 2008)
demonstrated that relatives and OCD patients both
showed impaired cognitive exibility and motor inhi-
bition, which were related to the PCC (Rubia et al.
2005; Pearson et al. 2011). However, future research is
needed to elucidate the precise function and connec-
tivity of the PCC in rst-degree relatives. These
ndings may ultimately contribute to brain-based mar-
kers for OCD and aid in determining risk genes.
The observed decreased functional connectivity
within the DMN may contribute to the core cognitive
symptoms of OCD. The DMN has been implicated in
cognitive functions associated with internal thought
in contrast to stimulus-based perception (Buckner
et al. 2008). The reduced RSFC of the DMN in OCD
patients may blur the normal boundary between
internal thoughts and external perceptions. Based on
difculty in inhibiting the external stimuli (uncon-
trolled and recurrent thoughts, impulses or images),
OCD patients might pay more attention to the distres-
sing stimuli and attend less on internal thoughts. This
may result in an ambiguous integration between ones
own thoughts and feeling with external events.
Furthermore, OCD patients would seem to be imbued
with exaggerated perceptions of external stimuli for
attempting to avoid or control the uncontrolled and
recurrent thoughts. Indeed, the preoccupations were
 Vulnerability marker for OCD 1481

Fig. 3. Group-level default network functional connectivity differences between obsessive compulsive disorder rst-degree
siblings and healthy controls. LH, Left hemisphere; PCC, posterior cingulate cortex; RSFC, resting-state functional
connectivity; RH, right hemisphere.

speculated on contributing to many symptoms of OCD Conclusion

for less sense of self-relevance (Fitzgerald et al. 2010).
In the present study, we used the resting-state func-
Thus, abnormal functional connectivity of the DMN
tional connectivity approach to show the default net-
may be involved in the psychopathological symptoms
works in OCD patients and their unaffected siblings
of OCD.
during rest. The current study provides a unique
opportunity to understand the pathophysiology of,
and the susceptibility to, OCD. Our ndings support
Limitations and future work the hypothesis that OCD is associated with abnormal
functional connectivity of the DMN. The similar abnor-
Given different OCD symptom dimensions relating to
mal connectivity in the PCC with the DMN in both
distinct neural mechanisms (Mataix-Cols et al. 2004),
OCD patients and their unaffected siblings may serve
we were unable to divide the OCD patient sample
as a neuroimaging marker for the development of
into different subtypes because of the relatively small
OCD. Future studies combining R-fMRI with struc-
sample. Second, OCD patients in this study were
tural MRI techniques will be vital to explore how the
mostly treated with antidepressants and had long
functional alterations shown in this study are related
average illness duration, so the effects of the illness
to structural changes, and whether these changes
duration and medication cannot completely be ruled
could be used for early screening markers, or detecting
out in our results. Further studies using different sub-
disease progression and medication effects in OCD
types and drug-naive cohorts are required to conrm
patients.
our preliminary results. Finally, from a methodological
perspective, the current study only focused on the
examination of the default network connectivity and
Supplementary material
may be enhanced with high-resolution full-brain net-
work explorations to gain more insights of brain func- For supplementary material accompanying this paper
tion under such a psychiatric condition. visit http://dx.doi.org/10.1017/S0033291713002250.
1482 Z. W. Peng et al.
Declaration of Interest
None.
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