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Curr Psychiatry Rep (2016) 18:90

DOI 10.1007/s11920-016-0729-7


Can Neuroimaging Provide Reliable Biomarkers

for Obsessive-Compulsive Disorder? A Narrative Review
Ilana Frydman 1 & Juliana B. de Salles Andrade 1 & Paula Vigne 1 &
Leonardo F. Fontenelle 1,2,3,4

# Springer Science+Business Media New York 2016

Abstract In this integrative review, we discuss findings Keywords Obsessive-compulsive disorder . Biomarkers .
supporting the use neuroimaging biomarkers in the diagnosis Functional magnetic resonance . Voxel-based morphometry .
and treatment of obsessive-compulsive disorder (OCD). To do Diffusion tensor imaging . Proton magnetic resonance
so, we have selected the most recent studies that attempted to spectroscopy
identify the underlying pathogenic process associated with
OCD and whether they provide useful information to predict
clinical features, natural history or treatment responses. Introduction
Studies using functional magnetic resonance (fMRI), voxel-
based morphometry (VBM), diffusion tensor imaging (DTI) The core features of obsessive-compulsive disorder (OCD)
and proton magnetic resonance spectroscopy (1H MRS) in are intrusive; unwanted; recurrent and persistent thoughts,
OCD patients are generally supportive of an expanded version urges, or images (obsessions) and/or repetitive behaviours or
of the earlier cortico-striatal-thalamus-cortical (CSTC) model mental acts that are performed to reduce anxiety/distress or
of OCD. Although it is still unclear whether this information according to rigid rules [1]. This condition affects up to
will be incorporated into the daily clinical practice (due to 3.1 % of the general population, leading to decreases in virtu-
current conceptual approaches to mental illness), statistical ally all realms of quality of life and resulting in substantial
techniques, such as pattern recognition methods, appear pro- burden to the patients’ family members and to the society as
mising in identifying OCD patients and predicting their a whole [2]. Fortunately however, we have witnessed major
outcomes. advances in the management of OCD cases during the last few
decades, as serotonin reuptake inhibitors (SRIs) and exposure
and response prevention (ERP) are now able to help a sub-
stantial amount of patients that would be probably remain
symptomatic if living in another era. Advances in the way
This article is part of the Topical Collection on Anxiety Disorders
OCD cases are diagnosed have not paralleled improvements
in the way they are treated though.
* Leonardo F. Fontenelle
Until now, OCD is diagnosed purely on clinical grounds,
with neuroimaging playing only a minor role. For instance,
Obsessive, Compulsive, and Anxiety Spectrum Research Program,
neuroimaging in OCD has been only routinely recommended
Institute of Psychiatry, Federal University of Rio de Janeiro, Rio de to exclude coarse brain disease in patients firstly exhibiting
Janeiro, Brazil OCD symptoms after age 40 [3]. In fact, unoptimistic clini-
D’Or Institute for Research and Education, Rio de Janeiro, Brazil cians dispute whether neuroimaging could have any critical
Brain and Mental Health Laboratory, Monash Institute of Cognitive
role in the diagnosis of any mental disorder, including OCD.
and Clinical Neurosciences, Monash University, Clayton, Victoria, To them, if the gold standard for a psychiatric diagnosis is the
Australia identification of a specific set of signs and symptoms, it is
Rua Visconde de Pirajá, 547, 617, Ipanema, Rio de probably unreasonable to expect that neuroimaging could do
Janeiro, RJ 22410-003, Brazil any better than the clinician himself or herself. While some of
90 Page 2 of 8 Curr Psychiatry Rep (2016) 18:90

these arguments seem reasonable, neuroimaging research may Bunbalanced^ (both increased and decreased, depending on
well provide valid biomarkers for OCD in the future, i.e. char- the specific regions) [35, 36] CSTC connectivity in OCD pa-
acteristics that are both objectively measured and indicative of tients. Additional evidence of the dysfunction in the CSTC
pathogenic processes or predictive of responses to a given circuit as a potential biomarker in OCD is the intensification
therapeutic intervention [4]. [24, 31, 36] or reduction [33] in functional connectivity in
The cortico-striato-thalamo-cortical (CSTC) model of association with increase and decrease in global OCD symp-
OCD is grounded in a dysfunctional communication between tom severity, respectively. Another relevant finding is the in-
the lateral orbitofrontal-cortex (OFC) and the ventral striatum creased functional connectivity strength in the CSTC in first-
(VS) [5]. This model has been based mostly on early studies degree relatives of OCD patients [27].
with positron emission tomography (PET) and single photon A recent fMRI pattern recognition study investigated
emission computed tomography (SPECT) showing hyperme- whether generic fear-inducing, disgust-inducing and neutral
tabolism of the head of the caudate nucleus and the orbital stimuli could be decoded from brain patterns of single
gyrus [6]. Recently, the CSTC model of OCD has been ex- fMRIs of individual OCD patients and healthy controls and
panded to accommodate other brain areas that also appear to whether these differences could provide information to cor-
be involved in the pathophysiology of OCD, including the rectly guess subjects’ diagnostic status [37]. The authors ob-
hippocampus, the amygdala and the parietal cortex circuitry tained 100 % (p < 10−6) diagnostic accuracy by using two
[7–11]. In this article, we will discuss recent imaging studies coordinates of right OFC and one of the left caudate nucleus
that attempted to better delineate the pathogenic processes for the discrimination between groups based on volumes cal-
associated with OCD (including the CSTC model) and/or to culated for fear-inducing vs. neutral pictures. Lastly, using a
predict treatment response. qualitative approach, Peterson and coworkers investigated the
diagnostic specificity of resting-state connectivity findings re-
Functional Magnetic Resonance Imaging ported in several DSM-IV-TR anxiety disorders (including
OCD, posttraumatic stress disorder, social anxiety disorder,
Latest reviews and meta-analysis on functional imaging of specific phobia, panic and generalized anxiety disorder).
OCD include functional magnetic resonance imaging Among these conditions, OCD was the one most reliably as-
(fMRI), PET and SPECT studies. They generally converge sociated with abnormalities in the corticostriatal networks, as
to show hyperactivity within the OFC [6, 12], the caudate well as in the default mode network [38].
nucleus [6, 12] and the thalamus [12] of OCD patients as
compared to healthy controls. These areas become more ac- Voxel-Based Morphometry
tive during symptom provocation and less active after
effective treatment, either with medication or with cognitive The reports of functional abnormalities of the CSTC in OCD
behaviour therapy (CBT) [6, 12–14]. Studies with cognitive was paralleled by increased interest in the possibility of struc-
tasks during functional imaging further support the involve- tural brain abnormalities in the same regions. Initial studies
ment of those areas in the pathophysiology of OCD [8, 14]. employed case-control region-of-interest (ROI) methods.
Some early pre/posttreatment studies focused in predicting Their most consistent finding was reduced volume of OFC,
response to treatment of OCD patients, including medication, but there were also significant abnormalities in the striatum,
CBT and even neurosurgery. While decreased regional cere- thalamus, amygdala, anterior cingulate cortex (ACC) and hip-
bral blood flow (rCBF) in the OFC was associated with better pocampus [8]. The ROI method has several limitations, in-
response to SRIs [15–18], increased rCBF in the posterior cluding the manual delineation of brain regions and the need
cingulate gyrus predicted increased response both to of an a priori hypothesis [8]. In contrast, structural analysis
cingulotomy and to fluvoxamine [16, 19]. Also, greater with voxel-based morphometry (VBM) allows the investiga-
rCBF in the right caudate nucleus was associated with better tion of both grey and white matter volumes in the whole brain
response to paroxetine [20] and increased rCBF in the right in an automated and unbiased way, without the need of
cerebellum and left superior temporal gyrus predicted re- prespecified regions for investigation [8, 39]. The majority
sponse to fluvoxamine [21]. In contrast, CBT studies in of VBM studies only report grey matter results [39].
OCD patients have found that increased rCBF in the left There are a few meta-analyses of VBM studies that com-
OFC [15], higher activation in the temporal pole and amyg- pared OCD patients to healthy controls. Radua et al. found
dala during symptom provocation [22] and the degree of con- increased bilateral regional grey matter volumes in the ventral
nectivity of the right basolateral nuclei group of the amygdala anterior part of the putamen (lenticular nucleus) and in the
[23] were all associated with a good therapeutic outcome. caudate nucleus and decreased volumes in the dorsal medial
More recent resting-state fMRI studies have focused on the frontal/anterior cingulate gyrus [40]. According to this meta-
analysis of the functional connectivity of the brain. They have analysis, studies that enrolled more severe OCD patients were
found increased [24–31], decreased [32–34] and more likely to report increased grey matter in these regions
Curr Psychiatry Rep (2016) 18:90 Page 3 of 8 90

[40]. In another meta-analysis, Rotge et al reported smaller attempts to categorize OCD patients according to treatment
grey matter density in the supramarginal gyrus, the dorsolateral response were performed by Hoexter et al., who found that
prefrontal cortex and the OFC and greater densities in the basal left and right medial OFC thicknesses were a strong predictor
ganglia (putamen) and the anterior prefrontal cortex of OCD of treatment response in treatment of naive patients with an
patients [41]. Finally, Peng et al. found OCD patients to show accuracy of approximately 80 %, sensitivity of 77 % and
smaller grey matter volume in the frontal eye fields, medial specificity of 81 % [46].
frontal gyrus and ACC and increased volumes in the lenticular
nucleus, caudate nucleus and right parietal lobules [42]. Diffusion Tensor Imaging
A recent and comprehensive non-meta-analytical review
investigated the consistency and replicability of findings from Diffusion tensor imaging (DTI) is an MRI procedure that can
VBM studies in OCD samples. This review also addressed the measure water diffusion inside the brain [47]. Diffusivity is an
relationship between clinical variables and OCD anatomy, indirect marker of tissue integrity and fibre directions that
which was Ba potentially crucial factor that has been system- made the study the microstructure of the white matter
atically examined only in a limited number of studies^. The in vivo possible [48]. The most used parameters to study
authors found defects in the Baffective^ frontostriatal loop of DTI are mean diffusivity (MD) and fractional anisotropy
OCD patients, including the OFC, ACC, striatum, thalamus (FA). MD measures the average diffusivity in all directions
and temporolimbic regions (with volume reductions in the and is linked to tissue density. FA reflects diffusion direction
cortex and relative expansions of tissue at the deep grey matter and is related to fibre orientation. Other parameters less often
structures and limbic levels). There were also alterations of the used are the axial diffusivity (AD) and the radial diffusivity
Bexecutive^ circuits, including reductions in the dorsomedial, (RD). The former reflects diffusion parallel to the white matter
dorsolateral, ventrolateral and frontopolar prefrontal cortices tracts and allows the identification of axonal alterations, while
and the associative temporo-parieto-occipital areas. White the latter reflects diffusion perpendicular to the white matter
matter findings showed increased volume of internal capsule tracts and reveals myelination issues. The FA values are based
and reduced frontal and parietal volume [43•]. both on AD and RD [48, 49].
Piras et al. suggested that increased volume in the medial In a meta-analysis [42], DTI studies revealed that OCD
OFC and internal capsule may contribute more prominently to patients had significantly lower FA in the cingulum bundles,
the severity of OCD symptoms, whereas morphometric altera- inferior fronto-occipital fasciculus (IFOF), superior longitudi-
tions in the prefrontal, parietal and temporo-occipital regions nal fasciculus (SLF) and increased FA in the left uncinate
could be regarded as markers of clinical status and disease pro- fasciculus (UF). Regression analysis showed that OCD symp-
gression (e.g. being related to age/duration of illness). Similar tom severity was associated with decreased FA in the right
attempts to study the relationship between brain volumes and cingulum bundles. While these findings are not inconsistent
age were also performed by the international OCD Brain with the CSTC model of OCD, reductions of FA values within
Imaging Consortium, which performed a multicenter VBM the IFOF and the SLF also indicate the involvement of the
mega-analysis with 412 adult OCD patients and 368 healthy parietal lobes [50–53]. A subsequent review [48] reported
subjects in 2014. In this study, OCD patients had smaller decreased FA in the corpus callosum (CC), the cingulum
volumes of frontal grey and white matter bilaterally, including and the left anterior limb of the internal capsule (ALIC), the
the ACC and the inferior frontal gyrus extending to the anterior latter both in unmedicated [54] and medicated OCD patients
insula and greater cerebellar grey matter bilaterally. A group by [55]. Symptom severity was positively correlated with MD in
age analysis was performed and found relative volume preser- the corpus callosum (genu), the bilateral ALIC and bilateral
vation in the putamen, insula and OFC and volume loss in the SLF [56] and with FA in the left middle temporal gyrus [57],
temporal cortex bilaterally in OCD with increasing age [39]. as well as decreased FA within the uncinate and the cingulum
One study discriminated OCD patients from healthy con- bundle [58].
trols using grey and white matter data analysed with support Recent DTI studies reporting original data from adults with
vector machine (SVM) and Gaussian process classifier (GPC) OCD addressed the value of white matter integrity as an
techniques [44]. The accuracies were all above 75 %. Regions endophenotype for OCD [59] and the ability of DTI to cor-
with higher discriminative power were the frontostriatal cir- rectly identify OCD patients as so [60]. Fan and coworkers
cuit, the temporo-parieto-occipital junction and the cerebel- compared FA, AD, RD and MD values within the corpus
lum [44]. These findings are consistent with the results from callosum, the cingulum bundle, the IFOF and the SLF across
a transdiagnostic meta-analysis of VBM studies that enrolled unmedicated OCD patients, their unaffected siblings and un-
patients with DSM-IV-TR anxiety disorders, which found that related healthy controls. They found lower FA values in the
patients with OCD had increased bilateral grey matter vol- left cingulum bundle of OCD patients compared to healthy
umes (vs. healthy controls and vs. individuals with other anx- controls, with the unaffected siblings staying midway between
iety disorders) in the lenticular/caudate nuclei [45]. Finally, OCD patients and healthy controls, thus suggesting that white
90 Page 4 of 8 Curr Psychiatry Rep (2016) 18:90

matter integrity within the CSTC circuit may be an body [66] and genu [65, 66, 68] of corpus callosum; the right
endophenotype for OCD [59]. At least one study investigated [66] and left cingulum [65–67]; the right [65, 66] and left
the diagnostic utility of DTI findings in OCD. By employing uncinate fasciculus [66]; the ALIC bilaterally [66] and the left
SVM to FA images from 28 OCD patients and 28 healthy posterior limb of the internal capsule [66], among others.
controls, Li and colleagues found that a distributed network In the study by Fitzgerald et al. [35], patients with OCD
including bilateral prefrontal and temporal regions, inferior showed more pronounced age-related increases in FA than did
fronto-occipital fasciculus, superior fronto-parietal fasciculus, the healthy controls in the anterior corpus callosum, anterior
splenium of corpus callosum and left middle cingulum bundle cingulum bundle and the ALIC. Greater FA in anterior cingu-
was able to correctly identify OCD patients with a sensitivity lum bundle also correlated with more severe symptoms after
of 86 % and a specificity of 82 %, leading to an accuracy of controlling for age. This interesting finding was interpreted as
84 % [60]. a reflection of delayed and/or protracted white matter devel-
Other recent and original studies reported the clinical im- opment in paediatric OCD. It was also consistent with other
pact of DTI abnormalities in OCD patients, more specifically studies showing OCD symptom severity to correlate positive-
the relationships between white matter integrity and both cog- ly with increased FA in many other white matter tracts, includ-
nition [61] and treatment responses [62, 63]. In one study ing the ALIC [65] and the splenium of the corpus callosum in
comparing 20 OCD patients to 20 paired healthy controls, paediatric samples [67] and the left middle temporal gyrus in
white matter integrity was decreased in the OCD patients’ an adult sample [57]. Interestingly, one study found an asso-
orbitofrontal-striatal loop, lateral frontal and posterior associa- ciation between greater FA in the dorsal cingulum bundle and
tive cortices, left SLF and the body of corpus callosum. In this better performance on measures of response inhibition and
study, semantic fluency (an ability that was found to predict cognitive control in the absence of differences between
OCD diagnosis with an accuracy of 90 %) correlated with OCD and healthy individuals, thus suggesting that some white
increased MD in the left temporal and bilateral parietal regions matter abnormalities are compensatory, allowing OCD pa-
and decreased FA in the right posterior corona radiata and the tients to perform well in the face of competing and conflicting
left corticospinal tract [61]. Interestingly, as the white matter information [67].
integrity in these latter regions did not differ between OCD The issue of white matter integrity in paediatric OCD is far
and healthy controls, semantic fluency impairment was not from settled though. For instance, in the study by Rosso et al.
considered a consequence of primary pathogenic processes. [69], FA, AD, RD and MD maps were obtained from 17
Fan et al. compared the FA, AD, RD and MD maps from 15 children and adolescents with OCD and 19 matched healthy
OCD patients before and after 12 weeks of treatment with controls. The authors reported significantly lower FA in sev-
different SRIs, including fluvoxamine (6 patients), fluoxetine eral white matter clusters of OCD patients, with over 84 % of
(4 patients), sertraline (3 patients) and paroxetine (2 patients). significant voxels localized in a single cluster that
Drug treatment resulted in a reduction in RD of the left encompassed a large expanse of bilateral frontal cortex and
striatum and right midbrain and in MD of the right midbrain extended into the corpus callosum. In contrast to the literature
[62]. Further, the observation that some white matter reviewed above, there were no regions of significantly higher
abnormalities seen in OCD patients may not be rectifiable FA in OCD children and adolescents compared with the con-
by adequate treatment was confirmed in a cross-sectional trols. Patients also had significantly higher RD in areas that
study reporting significant decreases in the FA values of the overlapped with the largest cluster of FA reduction. Earlier age
nucleus accumbens among 11 OCD patients who failed to at onset of OCD correlated significantly with higher RD in the
show response to drugs as compared to 11 OCD patients right corpus callosum and lower FA in the right thalamus, the
who were not deemed to be resistant to drugs [63]. While latter area already implicated in the pathophysiology of early-
the definition of treatment resistance in this latter study was onset OCD. Finally, Gassó and colleagues discovered positive
not completely clear, its findings suggest that impairments in correlations between MD in cerebellar lobes and six genetic
reward processing may contribute to lack of appropriate polymorphisms related to glutamatergic and dopaminergic
response to treatment in OCD patients [63]. pathways in OCD children and adolescents [70].
Although it would be interesting to clarify whether white
matter integrity findings would be able to differentiate early- Proton Magnetic Resonance Spectroscopy
from late-onset OCD cases (with potential implications for
treatment and outcome), we were unable to identify studies Proton magnetic resonance spectroscopy (1H MRS) is a non-
addressing this topic. In fact, recent studies found paediatric or invasive technique that allows the quantification of certain
adolescent OCD patients to exhibit abnormalities of white neurochemical concentrations in many brain regions in vivo.
matter integrity that were heterogeneous as those exhibited These neurochemicals includes N-acetyl aspartate (NAA),
in the adult literature [64], including defects in the SLF [65, measured as the total of NAA + N-acetyl aspartyl glutamate
66]; the corticospinal tracts [65, 67]; the splenium [65–68], (tNAA); creatine (Cre); choline (Cho); myo-inositol (mI) and
Curr Psychiatry Rep (2016) 18:90 Page 5 of 8 90

Glx, which is composed by glutamate (Glu) and glutamine compared with controls. In this latter study, the NAA/Cr ratios
(Gln). So, MRS can be used to characterize metabolic abnor- in this region were negatively correlated with the total score
malities in many conditions, such Alzheimer ’s and on the Y-BOCS [78]. However, newer studies did not replicate
Huntington’s diseases. Since it is a completely non-invasive previous ones or at least minimized the role of glutamate in the
method, it has the advantage that the same subject can be pathophysiology of OCD. For instance, using an MRS tech-
analyzed multiple times, allowing longitudinal studies and nique capable of measuring minimally contaminated gluta-
pretreatment and posttreatment [71]. Therefore, MRS is wide- mate levels in three striatal subregions, Simpson et al. did
ly used to investigate neurological and psychiatric disorders, not show differences between patients and controls [79]. In a
enabling neurobiological models of disease pathology and recent study, the rostral subdivision of the ACC has been
providing potential biomarkers [72]. examined by means of MRS and fMRI performed during an
Glutamatergic neurotransmission and homeostasis may be emotional counting Stroop task. While the values of Gln/Glu,
altered in OCD, mainly in the CSTC circuit. There is evidence Glu and Gln did not differ between patients and controls, there
of these changes coming from animal models, genetic, phar- was also no association between the deactivation of the rACC
macological and biochemical studies [73]. There is also inter- during the Stroop task and the metabolic levels measured by
est in the role of glutamate across many conditions character- MRS, thus suggesting that a dysfunctional rACC in OCD is
ized by repetitive behaviours other than compulsions, such as not related to impaired glutamatergic neurotransmission [80•].
stereotypies and impulsivity. Naaijen et al. performed a review In order to identify endophenotypic biomarkers for OCD,
including 59 studies investigating frontostriatal glutamatergic one study compared the neurochemistry in caudate nucleus,
profile with 1H MRS in autism spectrum disorder (ASD), ACC and medial thalamus among OCD patients, non-ill first-
attention deficit hyperactivity disorder (ADHD) and OCD degree family members (also termed vulnerability group) and
[74]. Despite the disparity of the reviewed studies, the authors healthy controls [81]. The absolute levels of total tNAA were
were able to report interesting findings, like increased Glx in lower and levels of tCholine, Glx and myo-inositol were
the striatum across ADHD, OCD and ASD groups and in- higher in the caudate nucleus and in the ACC of OCD patients
creased Glx in the ACC of paediatric and adolescent ADHD as compared to the family controls. In contrast, the latter group
and ASD groups. They also reported decreased Glx in the displayed a similar yet attenuated OCD profile, with lower
ACC of adults with ASD and ADHD. Thus, glutamatergic levels of tNAA and higher levels of tCholine, Glx and myo-
abnormalities occur not only in OCD but also in other disor- inositol in the same regions as compared to normal controls. A
ders characterized by an inability to inhibit behaviours. recent study has also highlighted the role of glutamate in early
In a critical review of the literature on OCD patients’ MRS stages of OCD. For instance, Ortiz found no differences in the
profile, Brennan et al. analyzed 28 studies comparing neuro- concentration of Glx in the ACC between OCD children and
chemical levels in OCD patients versus healthy controls and adolescents and healthy controls, but the concentrations of
the changes in patients after treatment with SSRIs or CBT Glx were significantly lower in OCD patients with a long
[75]. Although many heterogeneous findings were revealed, duration of the condition (more than 24 months) as compared
the authors were able to find a somewhat consistent MRS to patients with a shorter duration [82].
profile among OCD patients, including reduced tNAA in the
ACC and caudate; reduced Glx in the ACC; increased Glx in
caudate and increased tCho in the thalamus, parietal white
matter and hippocampus. Rather than suggesting irreversible Conclusion
neuronal loss, reduced tNAA levels in OCD might be poten-
tially reversible, as suggested by the normalization of tNAA The studies included in this review confirmed and expanded
levels after treatment with citalopram or CBT. The evidence the key role of the CSTC circuit and its limbic connections in
supporting an effect of CBT over NAA levels were further the pathogenesis of OCD [83]. Accordingly, structures
supported by more recent studies. Atmaca et al. compared pertaining to the CSTC circuits have been identified as regions
the neurochemistry of hippocampus in OCD patients before discriminating OCD cases from healthy controls and other
and after treatment with CBT. The results revealed that NAA anxiety disorder cases in studies using either quantitative
levels, which were reduced in patients compared to controls at (e.g. Bclassifiers^) or qualitative strategies, respectively. In
baseline, increased after treatment [76]. Similar results were terms of treatment response, thicknesses of the left and right
also reported by O’Neill et al. who observed lower levels of medial OFC have already differentiated responders from non-
NAA in pACC OCD patients which increased after CBT [77]. responders, with an overall classification accuracy of around
A recent study investigating the ACC, the caudate and the 80 % [46]. Perhaps in the future, pattern recognition methods
putamen, areas involved in the CSTC circuit, endorsed the (such as SVM) will have the potential to be used in the clinical
previous findings of Brennan’s group review by showing low- practice. Maybe the classification accuracies will be optimized
er NAA/Cr in the ACC of unmedicated OCD patients by combining single or multimodal imaging methods with
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Conflict of Interest Ilana Frydman, Juliana B. de Salles Andrade and compulsive disorder. Neuropsychobiology. 2011;64(2):61–85.
Paula Vigne declare that they have no conflict of interest. 14. Maia TV, Cooney RE, Peterson BS. The neural bases of obsessive–
Leonardo F. Fontenelle reports personal fees from D’Or Institute for compulsive disorder in children and adults. Develop Psychopathol.
Research and Education. 2008;20(04):1251–43.
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Human and Animal Rights and Informed Consent This article does sponse to behaviour therapy and pharmacotherapy in obsessive
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of the authors.
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