Research

JAMA Psychiatry | Original Investigation

Inflammation in the Neurocircuitry

of Obsessive-Compulsive Disorder
Sophia Attwells, HBSc; Elaine Setiawan, PhD; Alan A. Wilson, PhD; Pablo M. Rusjan, PhD;
Romina Mizrahi, MD, PhD, FRCP(C); Laura Miler, HBSc; Cynthia Xu, MD; Margaret Anne Richter, MD, FRCP(C);
Alan Kahn, MD, FRCP(C); Stephen J. Kish, PhD; Sylvain Houle, MD, PhD, FRCP(C);
Lakshmi Ravindran, MD, FRCP(C); Jeffrey H. Meyer, MD, PhD, FRCP(C)

Supplemental content
IMPORTANCE For a small percentage of obsessive-compulsive disorder (OCD) cases
exhibiting additional neuropsychiatric symptoms, it was proposed that neuroinflammation
occurs in the basal ganglia as an autoimmune response to infections. However, it is possible
that elevated neuroinflammation, inducible by a diverse range of mechanisms, is important
throughout the cortico-striato-thalamo-cortical circuit of OCD. Identifying brain inflammation
is possible with the recent advance in positron emission tomography (PET) radioligands that
bind to the translocator protein (TSPO). Translocator protein density increases when
microglia are activated during neuroinflammation and the TSPO distribution volume (VT) is an
index of TSPO density.

OBJECTIVE To determine whether TSPO VT is elevated in the dorsal caudate, orbitofrontal

cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate cortex in OCD.

DESIGN, SETTING, AND PARTICIPANTS This case-control study was conducted at a tertiary care
psychiatric hospital from May 1, 2010, to November 30, 2016. Participants with OCD (n = 20)
and age-matched healthy control individuals (n = 20) underwent a fluorine F 18–labeled
N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide PET scan. It is a
high-quality second-generation TSPO-binding PET radiotracer. All participants were drug and
medication free, nonsmoking, and otherwise healthy.

MAIN OUTCOMES AND MEASURES The TSPO VT was measured in the dorsal caudate,
orbitofrontal cortex, thalamus, ventral striatum, dorsal putamen, and anterior cingulate
cortex. Compulsions were assessed with the Yale-Brown Obsessive Compulsive Scale.

RESULTS In the OCD and healthy groups, the mean (SD) ages were 27.4 (7.1) years and 27.6
(6.6) years, respectively, and 11 (55%) and 8 (40%) were women, respectively. In OCD, TSPO Author Affiliations: Research
Imaging Centre, Campbell Family
VT was significantly elevated in these brain regions (mean, 32%; range, 31%-36% except
Mental Health Research Institute,
anterior cingulate cortex, 24%; analysis of variance, effect of diagnosis: P < .001 to P = .004). Centre for Addiction and Mental
Slightly lower elevations in TSPO VT (22%-29%) were present in other gray matter regions. Health, Toronto, Ontario, Canada
The Yale-Brown Obsessive Compulsive Scale measure of distress associated with preventing (Attwells, Setiawan, Wilson, Rusjan,
Mizrahi, Miler, Xu, Kahn, Kish, Houle,
compulsive behaviors significantly correlated with TSPO VT in the orbitofrontal cortex
Meyer); Department of
(uncorrected Pearson correlation r = 0.62; P = .005). Pharmacology and Toxicology,
University of Toronto, Toronto,
CONCLUSIONS AND RELEVANCE To our knowledge, this is the first study demonstrating Ontario, Canada (Attwells, Mizrahi,
Kish, Meyer); Department of
inflammation within the neurocircuitry of OCD. The regional distribution of elevated TSPO VT Psychiatry, University of Toronto,
argues that the autoimmune/neuroinflammatory theories of OCD should extend beyond the Toronto, Ontario, Canada (Wilson,
basal ganglia to include the cortico-striato-thalamo-cortical circuit. Immunomodulatory Mizrahi, Richter, Kahn, Kish, Houle,
Ravindran, Meyer); Frederick W.
therapies should be investigated in adult OCD, rather than solely childhood OCD, particularly
Thompson Anxiety Disorders Centre,
in cases with prominent distress when preventing compulsions. Sunnybrook Health Sciences Centre,
Toronto, Ontario, Canada (Richter).
Corresponding Author: Jeffrey H.
Meyer, MD, PhD, FRCP(C), Research
Imaging Centre, Campbell Family
Mental Health Research Institute,
Centre for Addiction and Mental
Health, 250 College St, Ste B26,
JAMA Psychiatry. doi:10.1001/jamapsychiatry.2017.1567 Toronto, ON M5T 1R8, Canada
Published online June 21, 2017. (jeff.meyer@camhpet.ca).

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 Research Original Investigation
O
bsessive-compulsive disorder (OCD) is a debilitating
neuropsychiatric disorder, significantly affecting the
function of 1% to 2% of adolescents and adults.1 A third
of OCD cases inadequately respond to pharmacotherapies with
good evidence for this condition, such as serotonin reuptake
inhibitors and clomipramine.2,3 Some directions, based on
models of striatal dopaminergic hyperactivity with stereo-
typy and abnormal glutamate uptake/regulation in the cortico-
striato-thalamo-cortical (CSTC) circuit, have led to some posi-
tive clinical trials of augmentation with antipsychotics and
N-methyl-D-aspartate receptor antagonists, respectively.4,5 Al-
though such findings are being incorporated in treatment
algorithms, 3 more consistently impactful treatment ap-
proaches are needed and the major barrier in therapeutic de-
velopment is the paucity of novel pathological targets identi-
fied in the brain of OCD.
An autoimmune pathophysiology has been proposed for
several case series of OCD characterized by prepubertal acute
onset, episodic course, and concurrent neurological abnor-
malities such as choreiform movements occurring or exacer-
bating after exposure to infection.6,7 This syndrome has been
termed pediatric autoimmune neuropsychiatric disorder asso-
ciated with group A beta-hemolytic streptococcus (GABHS)
(PANDAS) or pediatric acute neuropsychiatric syndrome (PANS).
Cross reactivity between gangliosides in basal ganglia neu-
rons with the GABHS cell wall is mechanistically implicated
in Sydenham chorea, a series of rapid and uncoordinated jerky
movements affecting the face, feet, and hands, which may oc-
cur within 6 months of the acute GABHS infection,8 and there
are some reports of antibasal ganglia antibodies in the serum
of PANDAS cases.9
Although PANDAS and PANS are relevant for only a mi-
nority of OCD cases,10,11 it is possible that the broader state of
neuroinflammation and/or autoimmunity, inducible by a more
diverse range of mechanisms, is important in OCD. Preva-
lence of anxiety disorder is strongly elevated, with rates of 30%
to 40% in medical conditions such as systemic lupus erthy-
matosis and multiple sclerosis, for which autoimmunity is an
important component of the medical disease.12,13 Also, spe-
cific prevalence rates of OCD in systemic lupus erythemato-
sus and multiple sclerosis are typically several fold higher.14,15
In addition, OCD specifically is associated with developmen-
tal disorders such as Tourette syndrome and tic disorder for
which excessive autoimmunity is also implicated.16 More-
over, induction of neuroinflammation in rodents with lipo-
polysaccharide administration is associated with anxiety be-
haviors, such as reduced exploration in the open field test, even
when accounting for changes in motor activity.17,18
Microglial activation, an important component of neuro-
inflammation, can be measured with translocator protein
(TSPO) positron emission tomography (PET) imaging
because microglia increase expression of TSPO when they
are activated. 19 In a [1-(2-chlorophenyl)-N-methyl-N-(1-
methylpropyl]-3-isoquinoline carboxamide ([11C]PK11195)
PET study of 17 children with PANDAS and 15 healthy control
adults, Kumar et al,20 using a reference tissue approach,
found elevated TSPO binding in the basal ganglia but not
thalamic regions. These findings cannot be extrapolated as
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Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder
Key Points
Question Is translocator protein distribution volume, a marker of
the microglial component of neuroinflammation, elevated in the
cortico-striato-thalamo-cortical (CSTC) circuit of
obsessive-compulsive disorder (OCD)?
Findings In this case-control study, translocator protein
distribution volume was significantly elevated in the CSTC of
participants with OCD compared with healthy control individuals.
The Yale-Brown Obsessive Compulsive Scale measure of distress
associated with preventing compulsive behaviors was positively
correlated with translocator protein distribution volume in the
orbitofrontal cortex.
Meaning The presence of neuroinflammation in the CSTC of OCD
argues for extending investigations of serum autoantibodies to the
entire CSTC and that immunomodulatory therapies should be
investigated in adult OCD.
being applicable to OCD because this study investigated
PANDAS rather than OCD. Also, this study restricted its
regional analyses to the striatum and thalamus and did not
investigate any other region implicated in the neurocircuitry
of OCD. Given that with the exception of this neuroimaging
study in PANDAS, which represents a small percentage of
cases,10,11 there are no postmortem or neuroimaging studies
of neuroinflammation in OCD, hence, it is not known as to
whether neuroinflammation occurs in OCD.
While [11C]PK11195 was the first TSPO PET radiotracer, re-
cent advances in PET radioligands for TSPO have resulted in a
second generation of radiotracers for which the specific bind-
ing signal is at least several-fold higher, such as fluorine F 18–
labeled N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-
3-yl)acetamide) ([ 18 F]FEPPA) PET. 21,22 [ 18 F]FEPPA is an
excellent radioligand for TSPO, having high and selective af-
finity, considerable brain uptake, and good reversibility.23,24
Moreover, radioactive metabolites are not detected in brain24
and the binding of [18F]FEPPA is increased during induced in-
flammation in animals as well as the positive control condi-
tion of Alzheimer disease in humans, which is associated with
microglial activation in response to amyloid deposition.25-27
The primary aim of this study is to compare TSPO distri-
bution volume (VT) in the CSTC circuit of OCD with healthy con-
trol individuals. It is hypothesized that TSPO VT, being el-
evated in neuroinflammatory states, is greater in OCD. Because
the strongest regional convergence across investigations of neu-
rochemical abnormalities in OCD, such as 5-HT2A, 5-HTT,
5-HT1B, and mGluR5 receptor binding28-33 and fluorodeoxy-
glucose uptake,34 are in the dorsal caudate and the orbitofron-
tal cortex, these regions are given the highest priority. How-
ever, the neuropathology of OCD also implicates a broader
group of structures in the CSTC circuit, such as the thalamus,
ventral striatum, dorsal putamen, and anterior cingulate
cortex,4,5,33,34 so these regions were given the next highest pri-
ority. Also, given that neuroinflammatory pathologies of the
CSTC circuit, including vascular disease, tumors, Huntington
disease, Tourette disorder, and Sydenham chorea, are associ-
ated with disturbances of complex motor behavior, the third
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 Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder
Table 1. Demographic Characteristics of Study Participants
OCD Healthy
Characteristic (n = 20) (n = 20)
TSPO genotype, No.a
HAB 13 13
MAB 7 7
Age, mean (SD), y 27.4 (7.1) 27.6 (6.6)
Women, No. (%) 11 (55) 8 (40)
BMI, mean (SD) 22.8 (2.9) 24.4 (2.2)
Y-BOCS score, mean (SD) 23.0 (6.2) NA
Age at OCD onset, mean (SD), y 13.7 (7.1) NA
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided
by height in meters squared); HAB, high-affinity binding; MAB, mixed-affinity
binding; NA, not applicable; OCD, obsessive-compulsive disorder;
TSPO, translocator protein; Y-BOCS, Yale-Brown Obsessive Compulsive Scale.
a
Indicates single-nucleotide polymorphism rs6971 of the TSPO gene known to
influence binding of second-generation radioligands, including fluorine F
18–labeled
N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.
aim, which was exploratory, is to assess the association be-
tween TSPO VT in the dorsal caudate and orbitofrontal cortex
with severity of compulsions in OCD.
Methods
Participants
Twenty participants with OCD and 20 age-matched healthy
control individuals (within 4 years) completed the study. Par-
ticipants were recruited from the Toronto, Ontario, Canada,
area at a tertiary care psychiatric hospital (Centre for Addic-
tion and Mental Health) from May 1, 2010, to November 30,
2016. All were aged 19 to 48 years, nonsmoking, and in good
physical health (see demographic characteristics in Table 1).
None of the participants had a history of autoimmune dis-
ease, and all were free of medical illnesses for at least 4 weeks.
Fourteen healthy control individuals (70%), reported in a pre-
vious study,35 were also included in the present study. No other
healthy or OCD cases in this study were included in any other
study. The remaining control individuals have not been in-
cluded in other studies. Eleven participants (55%) had OCD
prior to age 12 years and 18 participants (90%) had OCD onset
prior to age 20 years. The presence or absence of psychiatric
disorders and OCD specifically were confirmed using the Struc-
tured Clinical Interview of DSM-IV.36 Two OCD cases had a his-
tory of a major depressive episode, a single episode occurring
4 and 5 years prior to their scan date. The severity of OCD was
measured with the Yale-Brown Obsessive Compulsive Scale
(Y-BOCS).37,38 Clinical symptoms of OCD varied and severity
of the obsessive-compulsive symptoms was moderate to se-
vere on average (eTable 1 in the Supplement). None of the OCD
cases met criteria for PANDAS or PANS.6,7
Participant diagnosis was verified by a psychiatrist (J.H.M.
or L.R.). Exclusion criteria for all participants were preg-
nancy; herbal, drug, or medication (including psychotropic)
use within the past 6 weeks, except for oral contraceptives; sub-
stance abuse (including cigarette smoking); and any history of
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Original Investigation Research
neurologic illness or injury. Other exclusion criteria con-
sisted of concurrent active Axis I disorders, current or past al-
cohol or substance dependence, bipolar I or II disorder, and
borderline or antisocial personality disorder, the latter ruled
out with the Structured Clinical Interview for DSM-IV Axis II
disorders.39 All participants underwent urine drug screen-
ing, and women received a urine pregnancy test on the screen-
ing and PET scanning days. Participants provided written in-
formed consent after all procedures were fully explained. The
protocol and informed consent forms were approved by the
research ethics board of the Centre for Addiction and Mental
Health, Toronto, Ontario, Canada.
Image Acquisition and Analysis
Each participant underwent a single [18F]FEPPA PET scan con-
ducted at the Research Imaging Centre at the Centre for Ad-
diction and Mental Health. Intravenous [18F]FEPPA24 was ad-
ministered as a bolus (mean [SD], 183.5 [10.5] MBq or 4.9 [0.3]
mCi). The [ 18 F]FEPPA was of high radiochemical purity
(>98.0%) and high specific activity (mean [SD], 133.6 [118.7]
TBq/mmol). The PET scan duration was 125 minutes after the
injection of [18F]FEPPA. Positron emission tomographic scans
were acquired using a 3-dimensional brain scanner (HRRT; CPS/
Siemens). Positron emission tomographic scans were ac-
quired and reconstructed as described previously.21,24,35,40,41
All PET images were corrected for attenuation using a single
photon point source, cesium 137 (half-life, 30.2 years; en-
ergy, 662 keV), and were reconstructed using a filtered back-
projection algorithm, with a Hann filter at Nyquist cut-off
frequency.41 Manual and automatic blood sampling (ABSS,
Model PBS-101; Veenstra Instruments) was conducted to de-
termine the input function of parent compound in plasma for
the kinetic analysis, based on the ratio of radioactivity in whole
blood to radioactivity in plasma, and the percentage of par-
ent compound in plasma.21 A biexponential function was used
to fit the blood-to-plasma ratios and a Hill function was used
to fit the percentage of unmetabolized tracer as previously
described.21,35 A 2-tissue compartment model was applied to
generate time activity curves from each region of interest (ROI)
to quantitate TSPO VT with [18F]FEPPA PET, as this was pre-
viously demonstrated to be the optimal model for [18F]FEPPA
PET.21
Regions of interest were automatically generated using
the semiautomated software (ROMI; Research Imaging Cen-
tre, Centre for Addiction and Mental Health). ROMI is based
on the individualization of a set of standard ROIs using mag-
netic resonance imaging (MRI) coregistered with the PET
image, followed by a step of gray matter voxel selection, which
incorporates the probability of gray matter based on the seg-
mentation of the individual MRI as previously described.42,43
For the anatomical delineation of ROIs, the first 13 partici-
pants (OCD: n = 8; healthy: n = 5) underwent 2-dimensional
axial proton density MRI acquired with a General Electric Signa
1.5-T MRI scanner (section thickness, 2 mm; repetition time,
>5300 milliseconds; echo time, 13 milliseconds; flip angle, 90°;
number of excitations, 2; acquisition matrix, 256 × 256; and
field of view, 22 mm). The remaining 27 participants (OCD:
n = 12; healthy: n = 15) underwent 2-dimensional axial proton
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 Research Original Investigation
Figure 1. Elevated Translocator Protein Distribution Volume in Obsessive-Compulsive Disorder
25
Translocator Protein Distribution Volume
20
15
10
0
Dorsal Orbitofrontal
Caudate Cortex
Translocator protein distribution volume was significantly greater across brain
regions assessed in participants with obsessive-compulsive disorder (n = 20)
compared with healthy control individuals (n = 20). The single-nucleotide
polymorphism rs6971 of the TSPO gene, which influences binding of
second-generation translocator protein positron emission tomography
radioligands, was included as a nuisance factor in the analyses of variance.
density MRI acquired with a General Electric Signa 3-T MRI
scanner (section thickness, 2 mm; repetition time, 6000 mil-
liseconds; echo time, 8 milliseconds; flip angle, 90°; number
of excitations, 1; acquisition matrix, 256 × 192; and field of
view, 16.5 mm). A subset of participants were scanned with
both MRI machines to rule out bias due to delineation with
ROMI. The differences in MRI acquisitions resulted in near
identical TSPO VT values and regional volumes in a sample
undergoing both MRI (n = 12; r > 0.97; P < .001; J.H.M.,
unpublished data, May 2010-February 2014).
DNA Extraction and Polymorphism Genotyping
The binding affinity of [18F]FEPPA for TSPO is affected by a
single-nucleotide polymorphism (rs6971; C→T) in exon 4 of
the TSPO gene (NCBI Entrez Gene 706).41,44 Individuals with
high-affinity binding (Ala147/Ala147) and mixed-affinity bind-
ing (Ala147/Thr147) account for more than 95% of the popu-
lation in the greater Toronto area.35,45 The polymorphism
rs6971was genotyped as described previously.41 Homozy-
gotes for the low binding gene (Thr147/Thr147) were ex-
cluded from data analysis.
Statistical Analysis
To test the primary hypothesis, a multivariate analysis of vari-
ance (MANOVA) was applied with TSPO VT in the dorsal cau-
date, orbitofrontal cortex, thalamus, ventral striatum, dorsal
putamen, and anterior cingulate cortex as the dependent vari-
ables, with diagnosis as the key independent predictor vari-
able and genotype (rs6971 polymorphism) as an additional in-
dependent variable. Main effects were considered significant
at the conventional P ≤ .05. Effects in each region, analyzed
by univariate analysis of variance (ANOVA), were considered
significant after Bonferroni correction at P ≤ .009.
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Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder
Healthy HAB
Healthy MAB
Obsessive-compulsive disorder HAB
Obsessive-compulsive disorder MAB
Thalamus Ventral Dorsal Anterior
Striatum Putamen Cingulate Cortex
Region
Translocator protein distribution volume values represent raw values
unadjusted for genotype. For this polymorphism, high-affinity homozygotes
are denoted as HAB (high-affinity binding) and heterozygotes are denoted as
MAB (mixed-affinity binding). The dark horizontal bars indicate the mean for
each group.
To assess whether there was a global difference in TSPO
VT between participants with OCD and healthy control indi-
viduals, a MANOVA was also applied with TSPO VT from all re-
gions sampled included as the dependent variables, with di-
agnosis and genotype as independent predictor factors. The
association of TSPO VT in the dorsal caudate and orbitofron-
tal cortex with time occupied, interference, distress, resis-
tance, and control over obsessions and compulsions was as-
sessed applying a partial correlation coefficient controlling for
genotype. This was treated as a posthoc analysis. Statistical
analyses were performed using IBM SPSS version 22.0.46
To investigate whether there was evidence for a pattern
of TSPO VT elevation in OCD that differs as compared with the
elevations found in major depressive disorder,35 a post hoc
analysis was done comparing the relative TSPO VT values in
the dorsal caudate and orbitofrontal cortex, regions most im-
plicated in OCD, in relation to TSPO VT in the anterior cingu-
late cortex, a region implicated in major depressive disorder
(eAppendix in the Supplement).
Results
Translocator protein VT was significantly greater in the OCD
cases within the dorsal caudate, orbitofrontal cortex, thala-
mus, ventral striatum, dorsal putamen, and anterior cingu-
late cortex (MANOVA; main effect of diagnosis: F6,32 = 2.8,
P = .03; main effect of genotype: F 6,32 = 6.2, P < .001)
(Figure 1). Differences in individual regions were robust
(ANOVAs: dorsal caudate: F1,37 = 15.5, P < .001; orbitofrontal
cortex: F1,37 = 13.5, P = .001; thalamus: F1,37 = 13.2, P = .001;
ventral striatum: F 1,37 = 14.4, P = .001; dorsal putamen:
F1,37 = 12.8, P = .001; and anterior cingulate cortex: F1,37 = 9.5,
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 Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder Original Investigation Research

Table 2. TSPO Density Measured By VT Across Multiple Brain Regions in Obsessive-Compulsive Disorder

TSPO VT, Mean (SD)a Effect

Obsessive-Compulsive Disorder Healthy Diagnosis Genotype
HAB MAB Total HAB MAB Total Difference,
Region of Interest (n = 13) (n = 7) (n = 20) (n = 13) (n = 7) (n = 20) % F1,37 P Value F1,37 P Value
Dorsal caudate 10.7 (2.3) 6.9 (1.4) 9.4 (2.7) 7.8 (2.1) 5.2 (1.7) 6.9 (2.3) 35.6 15.5 <.001 23.9 <.001
OFC 13.4 (2.8) 9.3 (2.1) 12.0 (3.2) 10.1 (2.5) 7.5 (2.0) 9.2 (2.6) 30.9 13.5 .001 17.5 <.001
Thalamus 16.2 (3.2) 8.9 (2.4) 13.7 (4.6) 11.3 (3.0) 8.3 (2.0) 10.2 (3.0) 33.5 13.2 .001 26.5 <.001
Ventral striatum 12.1 (2.2) 6.8 (1.3) 10.2 (3.2) 8.3 (2.1) 6.4 (1.8) 7.6 (2.2) 33.8 14.4 .001 25.6 <.001
Dorsal putamen 11.8 (2.4) 6.6 (1.7) 10.0 (3.3) 8.3 (2.1) 6.1 (1.5) 7.5 (2.1) 32.6 12.8 .001 26.2 <.001
ACC 12.4 (2.3) 6.9 (1.7) 10.5 (3.4) 9.5 (2.0) 6.5 (1.4) 8.5 (2.3) 23.5 9.5 .004 40.3 <.001
MPFC 12.8 (2.4) 7.1 (1.7) 10.8 (3.5) 9.4 (2.1) 6.7 (1.3) 8.4 (2.2) 27.5 11.9 .001 34.8 <.001
DLPFC 13.0 (2.1) 7.3 (1.9) 11.0 (3.4) 10.0 (2.0) 7.1 (1.8) 9.0 (2.3) 22.0 9.1 .005 38.5 <.001
VLPFC 13.9 (2.6) 8.2 (1.8) 11.9 (3.6) 10.7 (2.2) 7.7 (2.0) 9.6 (2.5) 23.9 10.0 .003 31.8 <.001
Insula 13.3 (2.6) 7.5 (1.8) 11.3 (3.6) 9.9 (2.3) 6.9 (1.5) 8.8 (2.5) 27.7 11.4 .002 33.0 <.001
Temporal cortex 13.5 (2.5) 7.8 (2.1) 11.5 (3.6) 10.4 (2.3) 7.2 (1.8) 9.3 (2.6) 24.3 9.5 .004 33.5 <.001
Inferior parietal cortex 14.1 (3.1) 8.1 (1.8) 12.0 (4.0) 10.9 (2.2) 7.9 (1.9) 9.8 (2.6) 22.2 7.5 .009 29.8 <.001
Occipital cortex 13.9 (2.6) 7.8 (2.1) 11.8 (3.8) 10.6 (2.4) 7.4 (1.9) 9.5 (2.7) 23.8 8.9 .005 33.9 <.001
Hippocampus 12.2 (2.3) 6.9 (2.0) 10.3 (3.3) 8.7 (2.5) 6.8 (2.0) 8.0 (2.5) 28.9 9.4 .004 20.3 <.001
a
Abbreviations: ACC, anterior cingulate cortex; ANOVA, analysis of variance; Indicates binding to the single-nucleotide polymorphism rs6971 of the TSPO
DLPFC, dorsolateral prefrontal cortex; HAB, high-affinity binding; gene known to influence binding of second-generation TSPO radioligands,
MAB, mixed-affinity binding; MPFC, medial prefrontal cortex; including fluorine F 18–labeled
OFC, orbitofrontal cortex; TSPO, translocator protein; VLPFC, ventrolateral N-(2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide.
prefrontal cortex; VT, distribution volume.

P = .004, with elevations of 35.6%, 30.9%, 33.5%, 33.8%,

32.6%, and 23.5% magnitudes, respectively) (Figure 1 and
Table 2). In addition, generally lesser but significant eleva-
tions of TSPO VT were observed in all gray matter regions
sampled (Table 2). There was no effect of age or sex on TSPO
Figure 2. Greater Translocator Protein (TSPO) Distribution Volume (VT)
in Orbitofrontal Cortex Is Correlated With Distress Associated With
Preventing Compulsive Behaviors
20

VT in any region (MANOVA; main effect of age: F6,31 = 0.69,

P = .66; main effect of sex: F6,31 = 0.85, P = .54).
Orbitofrontal Cortex TSPO VT

Greater TSPO VT in the orbitofrontal cortex was signifi-
cantly correlated with greater distress associated with pre-
venting compulsive behaviors as reported on the Y-BOCS (un-
corrected Pearson partial correlation coefficient controlling for
genotype; r = 0.62; P = .005) (Figure 2 and Table 3).
Reanalysis of the data set omitting the 2 patients who had
a history of a major depressive episode demonstrated the results
were similarly significant (MANOVA; main effect of diagnosis:
F6,30 = 2.5, P = .04; main effect of genotype: F6,30 = 5.5, P = .001).
Differences in individual regions were robust (ANOVAs; dorsal
caudate: F1,35 = 13.3, P = .001; orbitofrontal cortex: F1,35 = 13.8,
P = .001; thalamus: F1,35 = 13.8, P = .001; ventral striatum:
F1,35 = 14.0, P = .001; dorsal putamen: F1,35 = 13.8, P = .001; and
anterior cingulate cortex: F1,35 = 9.3, P = .004). The eFigure and
eTable 2 in the Supplement show further results comparing the
relative TSPO VT values across the dorsal caudate and anterior
cingulate cortex between those with OCD and those with ma-
jor depressive episode, as well as an itemized list of Hamilton
Depression Rating Scale score results in these samples.
Discussion
To our knowledge, this is the first study to investigate inflam-
mation in the brain of OCD. The most prominent finding is
15
10
5
HAB
MAB
0
0 1 2 3 4
Y-BOCS Distress Associated With Preventing Compulsions
Greater TSPO VT was significantly correlated with greater distress associated
with preventing compulsive behaviors as reported on the Yale-Brown Obsessive
Compulsive Scale (Y-BOCS). The single-nucleotide polymorphism rs6971 of the
TSPO gene influences binding of second-generation TSPO positron emission
tomography radioligands, including fluorine F 18–labeled N-(2-(2-fluoroethoxy)
benzyl)-N-(4-phenoxypyridin-3-yl)acetamide. For the purposes of the display,
corrected TSPO VT values for genotype are shown. For this, a linear model of
TSPO VT = b0+b1*genotype was applied and b1 = 4.158 in the
obsessive-compulsive disorder data set. Because the effect of genotype
corresponded to a b1 value of 4.158, mixed-affinity binding (MAB) TSPO VT
values were raised by 4.158 to visually correct them to high-affinity binding
(HAB) TSPO VT values. Note, for this data set, this approach provided visually
similar TSPO VT value corrections as are found with the other approach of
multiplying TSPO VT from MAB cases by 1.4. For this polymorphism,
high-affinity homozygotes are denoted as HAB and heterozygotes are denoted
as MAB.

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 Research Original Investigation
Table 3. Positive Correlation Between Regional Translocator Protein Distribution Volume in Dorsal Caudate
and Orbitofrontal Cortex and Distress Associated With Compulsive Behaviors
Dorsal Caudate
Y-BOCS Subscale Correlations Controlling
for rs6971 Genotypea r P Valueb
Time spent performing compulsions 0.30 .17
Interference due to compulsions 0.21 .38
Distress associated with compulsions 0.48 .04
Resistance against compulsions 0.06 .80
Degree of control over compulsions −0.04 .88
Total compulsion severity 0.28 .25
Total obsession severity 0.20 .41
Overall severity 0.25 .30
greater TSPO VT throughout the CSTC circuit implicated in OCD
including the orbitofrontal cortex, dorsal caudate, thalamus,
dorsal putamen, ventral striatum, and, albeit to a slightly lesser
extent, the anterior cingulate cortex. This finding was also pres-
ent in the other gray matter regions of brain at a slightly lower
level of magnitude and this regional distribution is consis-
tent with a neuroinflammatory phenotype. These results have
important implications for the pathophysiology of OCD and
novel therapeutic treatment directions.
The best explanation for elevated TSPO V T is that it
reflects neuroinflammation consequent to microglial activa-
tion. Across diverse models of cerebral artery occlusion,
toxin exposure, and lipopolysaccharide administration, it is
consistently demonstrated that the temporal course of
elevations in TSPO levels are highly correlated with markers
of microglial activation.47-49 The widespread distribution of
elevated TSPO VT throughout gray matter is consistent with
investigations of TSPO VT with more sensitive radioligands
in diseases with microglial activation and more focal
pathologies such as Alzheimer disease and stroke, which
tend to find that no gray matter region is fully spared from
an elevation of TSPO VT.26,27,50 This could be accounted for
by diffuseness of initiating disease pathology; spread of
microglial activating disease–associated molecular patterns
and/or pathogen-associated molecular patterns; and most
plausibly, paracrine effects of activated microglia.51 Even so,
it is interesting that TSPO V T was elevated by more than
30% within the orbitofrontal cortex, dorsal caudate, thala-
mus, dorsal putamen, and ventral striatum. The involve-
ment of the CSTC has important implications for the auto-
immune etiology of OCD. Traditionally, investigations of
autoantibodies in serum of OCD cases mostly focus on stria-
tum, presumably because GABHS is associated with Syden-
ham chorea and the PANDAS mechanism is based on the
epitope cross reactivity of the striatum with GABHS. 6,7
Some investigators are beginning to evaluate serum autoan-
tibodies to other parts of the CSTC circuit such as the
thalamus,52 but our study argues that it is critical that such
studies consistently pursue autoantibodies for the dorsal
caudate and orbitofrontal cortex as well as the remainder of
the CSTC circuit.
This study demonstrates that microglial activation
occurs well beyond the initial, frequently childhood, onset
of OCD, and the presence of activated microglia provides a
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Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder
Abbreviation: Y-BOCS, Yale-Brown
Obsessive Compulsive Scale.
Orbitofrontal Cortex a
Indicates binding to the
r P Value b single-nucleotide polymorphism
rs6971 of the TSPO gene known to
0.38 .11
influence binding of
0.32 .18 second-generation TSPO
0.62 .005 radioligands, including fluorine F
18–labeled N-(2-(2-fluoroethoxy)
0.03 .90
benzyl)-N-(4-phenoxypyridin-3-yl)
−0.09 .71 acetamide.
0.33 .17 b
P value derived from uncorrected
0.23 .35 Pearson partial correlation
coefficient controlling for rs6971
0.29 .23
genotype.
useful opportunity to modulate their function as a therapeu-
tic strategy. Although pharmaceutical development does not
traditionally prioritize OCD, neuromodulatory treatments
under development for other diseases associated with
microglial activation, such as Alzheimer disease,53,54 might
be repurposed toward OCD. Microglial activation may
include components harmful to neurons and glia (termed M1
responses), such as creating reactive oxygen and nitrogen
species and producing proinflammatory cytokines, but also
include helpful components (termed M2 responses) such as
clearing cellular debris, inducing angiogenesis, and promot-
ing tissue repair. 55 More specifically, the current study
would suggest that medications under investigation for
shifting activated microglia from an M1 to M2 state, such as
azithromycin, minocycline, and bexarotene, 56 should be
investigated in OCD, particularly in samples in which the
severity of distress associated with preventing compulsive
behaviors is highly prevalent. Consistent with consideration
of an immunomodulatory approach, minocycline, an antibi-
otic that, among its effects, inhibits major histocompatibility
complex II expression and reduces M1 type markers,57 sig-
nificantly reduced Y-BOCS scores in a recent randomized,
double-blind, placebo-controlled study of add-on to fluvox-
amine in 102 patients with OCD.58
Limitations
This study has several limitations, most of which are attrib-
utable to the interpretation of TSPO VT and the application
of PET imaging. Elevated TSPO VT is well-established as a
marker of microglial activation; however, given that TSPO
has roles in translocating cholesterol from outer to inner cell
membranes and may form an oligomer with the mitochon-
drial permeability transition pore,59 it is theoretically pos-
sible that as knowledge regarding TSPO increases, other fac-
tors will be identified that may influence TSPO binding in
the brain. Also, binding of the PET radiotracer can be
affected by changes in density and affinity of the target. In
addition, the association between elevated TSPO and OCD,
as well as greater distress associated with preventing com-
pulsive behaviors, indicates significant associations among
these phenomena but does not establish a causal one as this
issue will require future study through a combination of
longitudinal studies and assessment of immunomodulatory
interventions.
jamapsychiatry.com
 Inflammation in the Neurocircuitry of Obsessive-Compulsive Disorder
Conclusions
In summary, to our knowledge, this study is the strongest evi-
dence to date for inflammation in the brain in OCD. The dem-
onstration of elevated TSPO VT in the CSTC circuit addresses
ARTICLE INFORMATION
Accepted for Publication: May 3, 2017.
Published Online: June 21, 2017.
doi:10.1001/jamapsychiatry.2017.1567
Author Contributions: Dr Meyer had full access to
all the data in the study and takes responsibility for
the integrity of the data and the accuracy of the
data analysis.
Study concept and design: Meyer.
Acquisition, analysis, or interpretation of data: All
authors.
Drafting of the manuscript: Attwells, Setiawan,
Rusjan, Mizrahi, Meyer.
Critical revision of the manuscript for important
intellectual content: Attwells, Setiawan, Wilson, Miler,
Xu, Richter, Kahn, Kish, Houle, Ravindran, Meyer.
Statistical analysis: Attwells, Setiawan, Miler, Meyer.
Obtained funding: Houle, Meyer.
Administrative, technical, or material support:
Wilson, Xu, Kahn, Houle, Meyer.
Study supervision: Wilson, Mizrahi, Houle, Meyer.
Conflict of Interest Disclosures: Drs Wilson,
Houle, and Meyer have received operating grant
funds for other studies from Janssen, Bristol-Myers
Squibb, Eli Lilly and Company, GlaxoSmithKline,
Lundbeck, and SK Life Sciences in the past 5 years.
Dr Meyer has been a consultant to Mylan,
Lundbeck, Takeda, Teva, and Trius in the past 5
years. None of these companies participated in the
design or execution of this study or in the writing of
the manuscript. Dr Meyer is an inventor on 4
patents of blood markers to predict brain
inflammation and/or to diagnose affective disorders
and a dietary supplement to reduce depressed
mood in the postpartum period. Dr Meyer is
arranging collaborations with nutraceutical
companies for the dietary supplement. No other
disclosures were reported.
Funding/Support: This study was supported by a
Canada Research Chair from the Canadian Institutes
of Health Research (Dr Meyer), an operating grant
from the Grant Family, and funding from the
Canadian Foundation for Innovation and the Ontario
Ministry for Research and Innovation (infrastructure).
Role of the Funder/Sponsor: The funding sources
had no role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; or decision to submit
the manuscript for publication.
Meeting Presentations: This study was presented
in part at the Society of Biological Psychiatry Annual
Meeting; May 18, 2016; Atlanta, Georgia; and the
American College of Neuropsychopharmacology
Annual Meeting; December 6, 2016; Hollywood,
Florida.
Additional Contributions: James L. Kennedy, MD
(Tanenbaum Centre for Pharmacogenetics),
assisted with genotyping; Nathan Kolla, MD, PhD
(Research Imaging Centre, Institute of Medical
Science, University of Toronto), assisted with
jamapsychiatry.com
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a critical gap in the autoimmune/neuroinflammatory theory
of OCD. The regional distribution of greater TSPO VT through-
out the CSTC circuit argues for consideration of autoimmune
mechanisms beyond the basal ganglia and suggests a new op-
portunity for repurposing immunomodulatory therapies to
treat OCD.
medical coverage; Alvina Ng, BSc, and Laura
Nguyen, BSc, worked as study technicians; and Jun
Parkes, MSc, Armando Garcia, BSc, Winston
Stableford, BSc, and Min Wong, BSc (Research
Imaging Centre), served as chemistry staff. Also,
Terry Bell, BSc, and Ted Harris-Brandts, BSc
(Research Imaging Centre), provided engineering
support. All contributors are paid employees of the
Centre for Addiction and Mental Health.
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