Brain Structural Abnormalities In Behavior Therapy-Resistant Obsessive-Compulsive Disorder

Background: Although several neuroimaging studies have demonstrated that behavior therapy (BT) modifies the neural circuits involved in the pathogenesis of obsessive-compulsive disorders (OCD), the structural abnormalities underlying BT-resistant OCD remain unknown.
Methods: In this study, we examined the existence of regional structural abnormalities in both the gray matter (GM) and the white matter (WM) of patients with OCD at baseline using voxel-based morphometry (VBM) in responders (n=24) and non-responders (n=15) to subsequent BT. Three-dimensional T1-weighted magnetic resonance imaging was performed before the completion of 12 weeks of BT.
Results: Relative to the responders, the non-responders exhibited significantly smaller GM volumes in the right ventromedial prefrontal cortex, the right orbitofrontal cortex (OFC), the right precentral gyrus, and the right anterior cingulate cortex (ACC). In addition, relative to the responders, the non-responders exhibited significantly smaller WM volumes in the left cingulate bundle, the left superior frontal WM, the left external capsule, and bilateral anterior cingulate bundles.
Conclusions: These results suggest that brain structures in several areas including the OFC, ACC, and cingulate bundles are related to the lack of a response to BT in patients with OCD. The use of a VBM approach may be advantageous to understanding differences in brain abnormalities between responders and non-responders to BT.

[Keywords]
obsessive-compulsive disorders, behavior therapy, voxel-based morphometry, treatment resistance, orbitofrontal cortex

Introduction

Orbitofrontal-cortex (OFC)'striatal brain circuits are known to be involved in the pathogenesis of obsessive-compulsive disorder (OCD). A large number of functional neuroimaging studies have suggested that several regions including the basal ganglia, the OFC, and the anterior cingulate cortex (ACC) play major roles in the processing that underlies the emergence of OCD symptoms.
Structural neuroimaging studies in patients with OCD can provide information for structural basis of pathophysiology of OCD. However, so far the results of structural neuroimaging studies have been inconsistent. A recent meta-analysis of gray matter (GM) changes in OCD using voxel-based morphometry (VBM), a widely used, automated whole brain analysis method, provided evidence of bilateral regional GM volume increase in the lenticular nucleus and bilateral regional GM volume decrease in the dorsal medial frontal/anterior cingulate gyri in patients with OCD, relative to healthy controls.1 In contrast, another meta-analysis of GM changes in OCD using VBM demonstrated that OCD patients have many smaller volumes in the parieto-frontal cortical regions, and larger volumes in the putamen and OFC, relative to normal controls. 2 Yet another meta-analysis based on a region-of interest (ROI) method has reported that, compared with healthy controls, reduced volumes in the left ACC and right OFC are mainly observed in OCD patients, and the bilateral thalamic volumes are increased. 3 Finally, a recent mega-analysis of large sample of OCD patients using VBM revealed the significantly smaller volumes associated with OFC'striatal brain circuits in OCD compared with healthy subjects. 4The major reasons for the discrepancies among previous studies may be attributed to both methodological differences and the heterogeneity of the clinical samples. On the other hand, recent studies have demonstrated that white matter (WM) abnormalities may exist in OCD patients. 5,6,7
Several neuroimaging studies of behavior therapy (BT) for OCD patients have also contributed to understanding the neural effect of BT in OCD patients. Most of these imaging studies were performed while the patients were in a resting state. In positron emission tomography (PET) studies performed after successful BT, decreased right caudate metabolic rate8,9and decreased bilateral thalamic activity were observed, while increased activity in the ACC was observed in OCD patients after intensive cognitive behavior therapy (CBT). 10In functional magnetic resonance imaging (fMRI) studies, three studies11,12,13 used cognitive provocation paradigms before and after CBT, and demonstrated activation changes in broad areas associated with prefrontal-subcortical cerebellar connections . In terms of identifying predictors of response to BT, a previous PET study14 observed that a higher pretreatment metabolic activity in the left OFC was associated with a better response to BT. Recently, our study15 examined the neural effect of BT using single photon emission computed tomography (SPECT), and demonstrated that the baseline regional cerebral blood flow (rCBF) in bilateral OFC was significantly correlated with the change in the score of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) among responders.
However, even after the combination of CBT and pharmacological treatment, half of the OCD patients remain treatment resistant. 16Thus, the neural mechanisms responsible for treatment resistance should be clarified using not only functional imaging, but also structural imaging. To date, only two studies17,18 have used VBM to examine structural changes in OCD patients after CBT, and Lazaro et al17 demonstrated a significant increase in the GM volume in all OCD patients (both children and adolescents) after treatment. However, no study has ever revealed the structural abnormalities that predict BT-resistance.
In this study, using VBM approach, we examined the existence of regional GM and WM abnormalities at baseline in patients with OCD, who responded or did not respond to subsequent BT. We hypothesized that structural differences may exist in brain regions comprising the cortico-subcortical circuits between OCD patients who respond or do not respond to BT.

Methods

Participants
Japanese patients with OCD were recruited at Nagoya City University Hospital. Diagnoses were made based on structured interviews conducted by trained psychiatrists using the Structured Clinical Interview for DSM-IV Patient Version (SCID-P). Before enrollment in this study, all the OCD patients had been taking serotonin reuptake inhibitors (SRIs) for at least 3 months. During these 3 months, the OCD patients had not responded to at least one course of full-dose SRI therapy at our hospital (minimum doses: clomipramine, 150 mg/day; fluvoxamine, 200 mg/day; paroxetine, 40 mg/day). 19 Therefore, these OCD patients were regarded as treatment-resistant to SRIs because they had failed to respond to one adequate trial of an SRI. 20 The SRI dose administered to each patient was not altered during the entire course of the BT. The OCD patients were not permitted to use any psychotropic medication other than an SRI during the study. The equivalence of each drug was calculated according to a previously described method, 21 in which the recommended therapeutic dose was standardized with respect to the recommended dose of clomipramine (150 mg/day).
The exclusion criteria were the presence of a current or past neurological or other significant medical illness, substance dependence, mental retardation, or pregnancy. Patients with other axis I disorders were excluded. Thirty healthy volunteers with demographic characteristics similar to those of the treatment group were also recruited. None of the volunteers had a history of neurologic or psychiatric disorders or were taking any medication.
The study protocol was approved by the Ethics Committee of Nagoya City University Graduate School of Medical Sciences, and all the subjects provided their written informed consent.

Clinical Assessments
OCD severity was assessed using the clinician-rated 10-item Y-BOCS.22,23 An improvement in the global Y-BOCS score of 40% or greater was considered to represent a clinical response, because a recent study suggested that patients whose Y-BOCS scores decreased by 39% or less were still rated as moderately ill at post-treatment. 24Two trained psychiatrists assessed the Y-BOCS independently. The intraclass correlation was 0.87 (95% IC: 0.75 to 0.93) for the pretreatment Y-BOCS scores and 0.85 (95% IC: 0.70 to 0.92) for the post-treatment Y-BOCS scores, suggesting an excellent inter-rater reliability. The clinical subtypes of OCD were identified using the Y-BOCS symptom checklist. 25 In addition, the severity of depression was assessed using the Beck Depression Inventory-II (BDI-II), 26 while the severity of anxiety was assessed using the State-Trait Anxiety Inventory (STAI). 27These clinical ratings were assessed at baseline and at the completion of BT.
Differences in the demographic and clinical variables among the three groups were examined using an analysis of variance (ANOVA). The male/female ratio was compared using a chi-square test. In addition, we compared the changes in the clinical treatment effects before and after BT among both the responders and the non-responders using paired t-tests.

Treatment
Individual BT led by experienced psychiatrists was performed using a detailed treatment manual. 28The treatments consisted of 45-minute sessions once a week for 12 consecutive weeks. All the patients who participated in this study were treated by at least two psychiatrists under the supervision by an expertof the exposure and response prevention (ERP) technique, to monitor the quality of therapy. The BT consisted of the following sessions. The first session included psycho-education about the nature of OCD and the BT model for the treatment of OCD. The second session began with treatment planning based on both a behavior analysis and an exposure hierarchy of anxiety-evoking situations. Following the planning sessions, the ERP sessions began. Exposure exercises were arranged hierarchically, beginning with mild or moderately distressing ones. Patients were encouraged to persist with each exposure until their distress decreased noticeably. All the patients received therapist-guided BT sessions once a week.

MRI image acquisition
All the brain images were acquired at baseline using a 1.5-T MRI system (Gyoro Scan Interu; Philips Medical Systems, Best, The Netherlands). The scanning parameters for the three-dimensional -T1-turbo filed echo (3D-T1-TFE) sequences were as follows: echo time = 3.90 ms; repetition time =8.4 ms; inversion time = 1000ms ;flip angle, 7 degrees; acquision matrix, 256 x 256; field of view (FOV) = 256mm, section thickness, 1mm; voxel size = 1.0 x 1.0 x 1.0 mm. All the MRI acquisiton was performed in the Department of Radiology of Nagoya City University Hospital. The baseline MRI was conducted within the 14-day period prior to the start of BT.

VBM protocol
VBM was performed using the VBM 8 'toolbox (http://dbm.neuro.uni-jena.de/vbm) implemented in SPM8 (http://www.fil.ion.ucl.ac.uk/spm) running on Matlab 7.5 (Mathworks Inv., Sherborn, MA, USA), with default parameters. Each 3D-MRI T1-weighted image was segmented into GM, WM, and cerebrospinal fluid (CSF). Then, the segmented images were spatially normalized to the same stereotaxic space by using the diffeomorphic anatomical registration through exponentiated Lie algebra (DARTEL) algorithm. 29 The voxel values were modulated by Jacobian determinants for the nonlinear components, and smoothed with a Gaussian kernel of 8-mm full width at half maximum (FWHM).

Statistical analysis
Three two-sample t-tests (responders vs. non-responders, responders vs. healthy participants, and non-responders vs. healthy participants) were performed to detect regional differences in GM or WM volumes using SPM 8. In addition, a multiple regression analysis was performed to test the relationship between regional GM or WM volumes at baseline and the change in the Y-BOCS score among not only the responders, but also among the non-responders. For all the analyses, patients' age was used as nuisance covariate. In this analysis, the statistical significance level was thresholded for correction of multiple comparisons using a false discovery rate (FDR) 30of 0.05. Cluster extent threshold was set at 100 voxels to reduce possible noise. The cluster locations were converted from coordinates related to the Montreal Neurologic Institute (MNI) atlas system to coordinates related to the Talairach atlas.

Results

Clinical characteristics of participants
Forty-five patients were enrolled in this study. Two patients dropped out during the waiting-list period because they were transferred to another clinic. Four patients did not undergo MRI because of their unwillingness. As a result, 39 patients completed the BT. All the OCD patients and healthy participants were right-handed. Among the 39 patients with OCD, 24 were regarded as responders and 15 were regarded as non-responders, according to the above-mentioned criteria. Table 1 shows the mean scores and the standard deviations of the clinical and demographic characteristics for the responders and the non-responders with OCD and the healthy participants. No significant differences in the baseline clinical or demographic characteristics were observed between the two OCD groups. Also, other than the BDI-II score and the STAI score, no significant differences in the clinical or demographic characteristics were observed among the two OCD groups and the healthy participants. In addition, no significant differences in the total intracranial volume, global GM volume, or global WM volume were observed among the three groups.
We identified the following types of OCD symptoms: among the responders with OCD, contamination/cleaning was the major symptom in 16 patients, aggressive/checking was the major symptom in 5 patients, and symmetry/ordering was the major symptom in 3 patients. Among the non-responders with OCD, contamination/cleaning was the major symptom in 8patients, aggressive/checking was the major symptom in 4 patients, and symmetry/ordering was the major symptom in 3 patients. No significant differences in any symptom dimension were observed between the two OCD groups (contamination/cleaning t (37)=1.135, p=0.183;'aggressive/checking t (37)=1.415, p=0.165; symmetry/ordering t (37)=1.896, p=0067). The sexual/religious symptoms or hoarding symptoms was not identified in either OCD groups.

Clinical findings before and after treatment
As shown in Table 2, the mean Y-BOCS score drastically decreased after 12 weeks of BT among the responders (p < 0.001), and the mean percent reduction in the Y-BOCS score was 52.2% ?? 7.4%. Among the non-responders, on the other hand, although the mean Y-BOCS score significantly decreased after 12 weeks of BT (p <0.01), the mean percent reduction in the Y-BOCS score was only 10.5% ?? 8.4%.
Furthermore, the mean STAI score also decreased significantly after BT, but only among the responders. The mean BDI-II score, however, did not change significantly before and after BT among either the responders or the non-responders.

Results of VBM analysis
Table 3 (Fig. 1) shows both the GM and the WM volume differences between responders and non-responders with OCD. At the time of the baseline assessments, the non-responders exhibited significantly smaller GM volumes in the right ventromedial prefrontal cortex (Brodmann 25), the right OFC (Brodmann 11), the right precentral gyrus (Brodmann 6), and the right ACC (Brodmann 24), compared with the responders. No significantly larger GM volumes were observed in any brain region among the non-responders, compared with the responders. Also at the time of the baseline assessments, the non-responders exhibited significantly smaller WM volumes in the left cingulate bundle, the left superior WM, the left external capsule, and bilateral anterior cingulate bundles, compared with the responders. No significantly larger WM volumes were observed in any brain region among the non-responders, compared with the responders. In addition, no significant correlations between the regional GM or WM volumes at baseline and the reduction in the Y-BOCS score were observed among either the non-responders or the responders.
Table 4 shows both the GM and the WM volume differences between non-responders with OCD and healthy participants. At the time of the baseline assessments, the non-responders exhibited significantly smaller GM volumes in several brain areas including the right thalamus, the right caudate, the left posterior cingulate cortex and ACC (Brodmann 30, 24, 32), the left occipital cortex (Brodmann 19), the left cingulate cortex (Brodmann 24, 33), and the right ACC (Brodmann 32), compared with the healthy participants. No significantly larger GM volumes in any brain region were observed among the non-responders, compared with the healthy participants. Also at the time of the baseline assessments, the non-responders exhibited significantly smaller WM volumes in the right inferior frontal WM and the left cingulate bundle, compared with the healthy participants. No significantly larger WM volumes in any brain region were seen among the non-responders, compared with the healthy participants.
Table 5 shows both the GM and WM volume differences between responders with OCD and healthy participants. At the time of the baseline assessments, the responders exhibited significantly smaller GM volumes in several brain areas including the bilateral dorsolateral prefrontal cortex (DLPFC) (Brodmann 8, 9), the left superior temporal cortex (Brodmann 22), and the left postcentral gyrus (Brodmann 2), compared with the healthy participants. No significantly larger GM volumes in any brain region were seen among the responders, compared with the healthy participants. Also at the time of the baseline assessments, the responders with OCD exhibited significantly smaller WM volumes in left superior frontal WM, the left external capsule, the left cingulate bundle, and the left temporal WM, compared with the healthy participants. No significantly larger WM volumes were observed in any brain region among the responders, compared with the healthy participants.

Discussion

To our knowledge this is the first MRI study to examine baseline structural differences between BT responder OCD patients and non-responders using VBM. Compared with responders, non-responders exhibited smaller GM volumes in several clinically important areas such as the right ventromedial prefrontal cortex (Brodmann 25), the right OFC (Brodmann 11), and the left ACC (Brodmann 24), which are implicated in the pathogenesis of OCD. In addition, non-responders exhibited smaller WM volumes in the left cingulate bundle, the left external capsule, and bilateral anterior cingulate bundles, which are also key regions implicated in WM abnormalities of OCD.
The most important finding of this study is that compared with the responders, the non-responders had smaller GM volumes in the right ventromedial prefrontal cortex and right OFC. Previous VBM studies have shown volume alterations in either the OFC or the medial frontal cortex; although some studies have reported smaller GM volumes in the OFC , 31,32,33,34other studies35,36 have reported larger OFC volumes. Interestingly, a recent volumetric MRI study (using an ROI approach) in patients with OCD demonstrated that smaller OFC volumes are associated with treatment resistance to selective serotonin reuptake inhibitors. 37The OFC is thought to play important roles in decision-making ability, reversal learning, and fear extinction. 38,39 The core features of OCD with ineffective behavior adaptation to day-to-day activities are characterized by such cognitive dysfunctions. Although BT involves various cognitive aspects, which aspects of cognitive dysfunction can be improved by BT in patients with OCD symptoms remain unclear. However, a recent functional magnetic resonance imaging (fMRI) study using a reversal learning task demonstrated an influence on brain activity after CBT for OCD. 13 In addition, several neuroimaging studies (PET, SPECT) have suggested that OFC function in patients with OCD may be associated with a better response to BT. 14,15 More importantly, both the OFC and the adjacent ventromedial prefrontal cortex may be involved in fear extinction, which is thought to be the core of BT. 18,38,39 Thus, the smaller GM volumes in the right ventromedial prefrontal cortex and right OFC in non-responders may underlie the biological mechanisms responsible for the lack of a response to BT.
Consistent with most of the previous VBM studies, our study showed a smaller GM volume in the left ACC of non-responders, compared with that of responders. We also observed a smaller GM volume in the bilateral ACC of non-responders, compared with that of healthy participants. In addition, similar to several previous studies, 31,40 we observed a smaller GM volume in the right precentral gyrus (Brodmann 25). The ACC is known to be involved in attention control. Some evidence suggests that the ACC in OCD patients is associated with action monitoring in processing competing information, 11error detection, 11the expression of fear responses. 38The precentral areas are assumed to be related to the coordination of complex motor activities. 40 Thus, structural abnormalities in both the left ACC and right precentral areas may result in dysfunctions in the cognitive abilities required for a response to BT in OCD.
With regard to WM abnormalities, the non-responders had smaller WM volumes in both the left cingulate bundle and the left external capsule, compared with the responders. Most previous studies5,6,7,41,42examining WM pathology in patients with OCD used diffusion tensor imaging (DTI) and revealed microstructural WM abnormalities in cingulate bundles. An anterior cingulotomy is known to be an effective neurosurgical treatment for treatment-refractory OCD, disrupting the connections between the frontal lobes and subcortical structures. 43 Thus, our study supports the hypothesis that the cingulate bundle is one of the main WM tracts involved in the pathogenesis of OCD. Although we could not detect WM abnormalities in the anterior limb of the internal capsule, disorganizations in connectivity in the external capsule (which is connected to both the inferior fronto-occipital fasciculus and the superior longitudinal fasciculus) were observed in patients with OCD in a DTI study. 7 In addition, the external capsule exists near the basal ganglia (the putamen), which has been implicated in the mediation of OCD symptoms. 1 In contrast, relative to the healthy participants, a smaller WM volume in the external capsule was only observed among the responders. Furthermore, our study showed a smaller WM volume in the left cingulate bundle in both the responders and the non-responders, compared with the healthy participants. The reason for this discrepancy is unclear. Additional studies using DTI are needed to clarify differences in WM abnormalities among OCD patients, including both responders and non-responders, and normal controls.
Although significant structural differences in either the thalamus or the caudate were not
observed between the responders and the non-responders, compared with the healthy participants, the non-responders exhibited significantly smaller GM volumes on the right side of
both areas. Both the thalamus and the caudate are key structures in cortico-basal ganglia-thalamic'cortical loops, which are known neuroanatomical modes of OCD. More importantly, previous neuroimaging studies have suggested the modulation of neural function in these two regions in response to BT. 8,9,10 Thus, the GM volume reductions in these two areas in non-responders may reflect the dysfunction of abilities required for a response to BT in patients with OCD. A smaller GM volume in the bilateral DLPFC was identified only among the responders, compared with the healthy participants. Recently, the DLPFC has been considered to have an especially important role in executive functions associated with not only planning, but also working memory in patients with OCD. 44 The DLPFC is thought to be involved in the dorsolateral prefrontal-striatal loop, one of two independent frontal-striatal networks. However, only a few studies using VBM have detected volume abnormalities in the DLPFC. 33,45 In addition, with the exception of one study, 11 previous neuroimaging studies examining the effects of behavior therapy (BT) in patients with OCD patients have failed to detect regional changes in the DLPFC. These findings suggest that the DLPFC may contribute to the biological mechanisms responsible for the lack of a response to BT.
Previous studies14,15 have suggested that an higher pretreatment rCBF/metabolic activity in the OFC at baseline in patients with OCD was associated with a clinical improvement in OCD severity. However, in the current study a significant correlation was not observed between the change in the Y-BOCS score and the regional GM or WM volumes at baseline in either responders or non-responders. One plausible explanation is that the current study did not examine the structural brain changes in patients with OCD after treatment. Unlike previous functional neuroimaging studies (PET, SPECT, f MRI), the detectability of structural changes in OCD patients after successful BT may be uncertain. Another possibility, as suggested by Togao et al., 33is that our study did not include patients with mild level of severity in OCD.
Finally, we must address several limitations. Firstly, all the patients with OCD were taking SRIs. As suggested by several studies46,47 serotonergic drugs may affect the regional brain volume. In our study, however, the average daily dose of SRIs was not significantly different between responders and non-responders with OCD. Secondly, we could not perform a second MRI study after the last BT treatment. Thus, whether structural brain changes may occur after BT in patients with OCD remains unclear. Future longitudinal studies are needed to clarify the effects of successful BT on both GM and WM volumes in patients with OCD. Thirdly, we did not include a placebo control group. We therefore had to rely on within-group changes to examine the effects of BT. Fourthly, recent structural MRI studies using VBM have demonstrated that several major symptom dimensions are associated with specific brain abnormalities. 34 In addition, specific symptom dimensions are associated with a poor outcome of BT. 48However, we could not observe any significant difference in symptom dimensions between responders and non-responders with OCD. Additional large MRI studies using VBM in OCD patients are needed to clarify the effect of BT on different types of symptom dimensions.
Despite these limitations, the results of the current study provide clinically important findings: among patients with OCD, non-responders to BT have smaller baseline volumes of not only the GM in the right ventromedial prefrontal cortex, right OFC, and left ACC, but also the WM in the left cingulate bundle and left external capsule. Our study implicates these areas in the pathogenesis of OCD as it relates to the role of BT. For clinical intervention, the use of a VBM approach may enable a better understanding of the neural basis underlying differences in brain abnormalities between responders and non-responders to BT.

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