Mechanisms of cognitive-behavioral therapy for obsessive-compulsive disorder involve robust and extensive increases in brain network connectivity.

Cognitive-behavioral therapy (CBT) is effective for obsessive compulsive disorder (OCD); however, little is understood about its mechanisms related to brain network connectivity. We examined connectivity changes from resting-state functional magnetic resonance imaging data pre-to-post-CBT in 43 OCD participants, randomized to receive either 4 weeks of intensive CBT or 4 weeks waitlist followed by 4 weeks of CBT, and 24 healthy controls before and after 4 weeks of no treatment. Network-based-statistic analysis revealed large-magnitude increases in OCD connectivity in eight networks. Strongest increases involved connectivity between the cerebellum and caudate/putamen, and between the cerebellum and dorsolateral/ventrolateral prefrontal cortices. Connectivity increases were associated with increased resistance to compulsions. Mechanisms of CBT may involve enhanced cross-network integration, both within and outside of classical cortico-striatal-thalamo-cortical regions; those involving cerebellar to striatal and prefrontal regions may reflect acquisition of new non-compulsive goal-directed behaviors and thought patterns. Our findings have implications for identifying targets for enhancing treatment efficacy and monitoring treatment progress

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium.

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions

Functional connectivity alterations between default mode network and occipital cortex in patients with obsessive-compulsive disorder (OCD)

Altered brain network connectivity is a potential biomarker for obsessive-compulsive disorder (OCD). A meta-analysis of resting-state MRI studies by Gürsel et al. (2018) described altered functional connectivity in OCD patients within and between the default mode network (DMN), the salience network (SN), and the frontoparietal network (FPN), as well as evidence for aberrant fronto-striatal circuitry. Here, we tested the replicability of these meta-analytic rsfMRI findings by measuring functional connectivity during resting-state fMRI in a new sample of OCD patients (n = 24) and matched controls (n = 33). We performed seed-to-voxel analyses using 30 seed regions from the prior meta-analysis. OCD patients showed reduced functional connectivity between the SN and the DMN compared to controls, replicating previous findings. We did not observe significant group differences of functional connectivity within the DMN, SN, nor FPN. Additionally, we observed reduced connectivity between the visual network to both the DMN and SN in OCD patients, in particular reduced functional connectivity between lateral parietal seeds and the left inferior lateral occipital pole. Furthermore, the right lateral parietal seed (associated with the DMN) was more strongly correlated with a cluster in the right lateral occipital cortex and precuneus (a region partly overlapping with the Dorsal Attentional Network (DAN)) in patients. Importantly, this latter finding was positively correlated to OCD symptom severity. Overall, our study partly replicated prior meta-analytic findings, highlighting hypoconnectivity between SN and DMN as a potential biomarker for OCD. Furthermore, we identified changes between the SN and the DMN with the visual network. This suggests that abnormal connectivity between cortex regions associated with abstract functions (transmodal regions such as the DMN), and cortex regions associated with constrained neural processing (unimodal regions such as the visual cortex), may be important in OCD

Patterns of default mode network deactivation in obsessive compulsive disorder

The objective of the present study was to research the patterns of Default Mode Network (DMN) deactivation in Obsessive Compulsive Disorder (OCD) in the transition between a resting and a non-rest emotional condition. Twenty-seven participants, 15 diagnosed with OCD and 12 healthy controls (HC), underwent a functional neuroimaging paradigm in which DMN brain activation in a resting condition was contrasted with activity during a non-rest condition consisting in the presentation of emotionally pleasant and unpleasant images. Results showed that HC, when compared with OCD, had a significant deactivation in two anterior nodes of the DMN (medial frontal and superior frontal) in the non-rest pleasant stimuli condition. Additional analysis for the whole brain, contrasting the resting condition with all the non-rest conditions grouped together, showed that, compared with OCD, HC had a significantly deactivation of a widespread brain network (superior frontal, insula, middle and superior temporal, putamen, lingual, cuneus, and cerebellum). Concluding, the present study found that OCD patients had difficulties with the deactivation of DMN even when the non-rest condition includes the presentation of emotional provoking stimuli, particularly evident for images with pleasant content.The first author was funded by the Brazilian National Counsel for Scientific and Technological Development (CNPq) as a Special Visiting Researcher of the Science Without Borders program (grant number: 401143/20147). This study was partially conducted at the Neuropsychophysiology Lab from the Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145FEDER-007653).info:eu-repo/semantics/publishedVersio

Basolateral amygdala-ventromedial prefrontal cortex connectivity predicts cognitive behavioural therapy outcome in adults with obsessive-compulsive disorder

Background: cognitive behavioural therapy (CBT), including exposure and ritual prevention, is a first-line treatment for obsessive-compulsive disorder (OCD), but few reliable predictors of CBT outcome have been identified. Based on research in animal models, we hypothesized that individual differences in basolateral amygdala-ventromedial prefrontal cortex (BLA-vmPFC) communication would predict CBT outcome in patients with OCD. Methods: we investigated whether BLA-vmPFC resting-state functional connectivity (rs-fc) predicts CBT outcome in patients with OCD. We assessed BLA-vmPFC rs-fc in patients with OCD on a stable dose of a selective serotonin reuptake inhibitor who then received CBT and in healthy control participants. Results: we included 73 patients with OCD and 84 healthy controls in our study. Decreased BLA-vmPFC rs-fc predicted a better CBT outcome in patients with OCD and was also detected in those with OCD compared with healthy participants. Additional analyses revealed that decreased BLA-vmPFC rs-fc uniquely characterized the patients with OCD who responded to CBT. Limitations: we used a sample of convenience, and all patients were receiving pharmacological treatment for OCD. Conclusion: in this large sample of patients with OCD, BLA-vmPFC functional connectivity predicted CBT outcome. These results suggest that future research should investigate the potential of BLA-vmPFC pathways to inform treatment selection for CBT across patients with OCD and anxiety disorders

The Emotional Brain in Obsessive-Compulsive Disorder

Background Obsessive-compulsive disorder (OCD) is characterized by distressing obsessions and time-consuming compulsions. The disorder affects 1-3% and can be highly impairing to daily functioning and detrimental to the quality of life. Cognitive behavioral therapy is an effective treatment for 50-75% of people with OCD, leaving a considerable minority who do not benefit from the best available treatments we have today. Neuroimaging has related the disorder to the function and structure of cortico-striato-thalamo-cortical and fronto-limbic circuits. A better understanding of these circuits might contribute to a better understanding of the disorder, how current treatments change the brain, and how we can help non-responders with better treatments in the future. This is likely particularly true for fronto-limbic and affective circuits, given their role in the formation, maintenance, and extinction of fear as well as motivating behavior. The aim of this dissertation was, first, to investigate how OCD is related to brain activation during emotional processing of aversive stimuli. Secondly, we wanted to examine if unaffected siblings of OCD patients showed similar anxiety, brain activation, and connectivity during emotion provocation and regulation as their OCD-affected siblings compared to unrelated healthy controls. Lastly, we wanted to investigate if the resting-state network structure changes in OCD patients directly after the Bergen 4-Day Treatment (B4DT), a concentrated and exposure-based psychological therapy. Methods Paper I was a meta-analysis of 25 functional neuroimaging studies comparing OCD patients and healthy controls during emotion processing, when participants were exposed to aversive or neutral stimuli. In Paper II we used functional magnetic resonance imaging (fMRI) to investigate distress, brain activation, and fronto-limbic connectivity during emotion provocation and regulation of neutral, fear-related, and OCD-related stimuli in 43 unmedicated OCD patients, 19 unaffected siblings, and 38 healthy controls. In Paper III we used resting-state fMRI to study the network structure of 28 OCD patients (21 unmedicated) and 19 healthy controls the day before and three days after B4DT. We examined static and dynamic graph metrics at the global, subnetwork, and regional levels, as well as between-subnetwork connectivity. Results In Paper I, we found that OCD patients showed more activation than healthy controls in the orbitofrontal cortex (OFC), extending into the subgenual anterior cingulate cortex (sgACC) and ventromedial prefrontal cortex (vmPFC), bilateral amygdala (extending into the right putamen), left inferior occipital cortex, and right middle temporal gyrus during aversive versus neutral stimuli. Meta-regressions showed that medication status and comorbidity moderated amygdala, occipital and ventromedial prefrontal cortex hyperactivation, while symptom severity moderated hyperactivation in medial frontal prefrontal and superior parietal regions. In Paper II we showed that unaffected siblings resembled healthy controls in task-related distress, less amygdala activation/altered timing than OCD patients during emotion provocation. During OCD-related emotion regulation siblings showed no significant difference in dmPFC activation versus either OCD patients or healthy controls, but showed more temporo-occipital activation and dmPFC-amygdala connectivity compared to healthy controls. In Paper III we found that unmedicated OCD patients showed more frontoparietal-limbic connectivity before treatment than healthy controls. This, along with sgACC flexibility, was reduced in OCD patients directly after B4DT. Conclusions OCD patients show hyperactivation of the amygdala and related structures, but this characteristic is not directly shared with unaffected siblings during provocation or regulation of emotional information. However, siblings seem to show compensatory activation and connectivity in other areas. The rapid changes in frontoparietal-limbic connectivity and subgenual ACC flexibility suggests that concentrated treatment leads to a more independent and stable network state. OCD is related to subtle alterations in limbic activation and fronto-limbic connectivity during both emotional tasks and resting-state, which seems to vary with comorbidity and is sensitive to treatment

Altered corticostriatal functional connectivity in obsessive-compulsive disorder

Context: neurobiological models of obsessive-compulsive disorder (OCD) emphasize disturbances in the function and connectivity of brain corticostriatal networks, or 'loops.' Although neuroimaging studies of patients have supported this network model of OCD, very few have applied measurements that are sensitive to brain connectivity features. Objective: using resting-state functional magnetic resonance imaging, we tested the hypothesis that OCD is associated with disturbances in the functional connectivity of primarily ventral corticostriatal regions, measured from coherent spontaneous fluctuations in the blood oxygenation level-dependent (BOLD) signal. Design: case-control cross-sectional study. Setting: hospital referral OCD unit and magnetic resonance imaging facility. Participants: a total of 21 patients with OCD (10 men, 11 women) and 21 healthy control subjects matched for age, sex, and estimated intelligence. Main outcome measures: voxelwise statistical parametric maps testing the strength of functional connectivity of 4 striatal seed regions of interest (dorsal caudate nucleus, ventral caudate/nucleus accumbens, dorsal putamen, and ventral putamen) with remaining brain areas. Results: for both groups, there was a clear distinction in the pattern of cortical connectivity of dorsal and ventral striatal regions, consistent with the notion of segregated motor, associative, and limbic corticostriatal networks. Between groups, patients with OCD had significantly increased functional connectivity along a ventral corticostriatal axis, implicating the orbitofrontal cortex and surrounding areas. The specific strength of connectivity between the ventral caudate/nucleus accumbens and the anterior orbitofrontal cortex predicted patients' overall symptom severity (r(2) = 0.57; P < .001). Additionally, patients with OCD showed evidence of reduced functional connectivity of the dorsal striatum and lateral prefrontal cortex, and of the ventral striatum with the region of the midbrain ventral tegmental area. Conclusions: this study directly supports the hypothesis that OCD is associated with functional alterations of brain corticostriatal networks. Specifically, our findings emphasize abnormal and heightened functional connectivity of ventrolimbic corticostriatal regions in patients with OCD

Brain structural covariance networks in obsessive-compulsive disorder: a graph analysis from the ENIGMA Consortium

Brain structural covariance networks reflect covariation in morphology of different brain areas and are thought to reflect common trajectories in brain development and maturation. Large-scale investigation of structural covariance networks in obsessive-compulsive disorder (OCD) may provide clues to the pathophysiology of this neurodevelopmental disorder. Using T1-weighted MRI scans acquired from 1616 individuals with OCD and 1463 healthy controls across 37 datasets participating in the ENIGMA-OCD Working Group, we calculated intra-individual brain structural covariance networks (using the bilaterally-averaged values of 33 cortical surface areas, 33 cortical thickness values, and six subcortical volumes), in which edge weights were proportional to the similarity between two brain morphological features in terms of deviation from healthy controls (i.e. z-score transformed). Global networks were characterized using measures of network segregation (clustering and modularity), network integration (global efficiency), and their balance (small-worldness), and their community membership was assessed. Hub profiling of regional networks was undertaken using measures of betweenness, closeness, and eigenvector centrality. Individually calculated network measures were integrated across the 37 datasets using a meta-analytical approach. These network measures were summated across the network density range of K = 0.10-0.25 per participant, and were integrated across the 37 datasets using a meta-analytical approach. Compared with healthy controls, at a global level, the structural covariance networks of OCD showed lower clustering (P < 0.0001), lower modularity (P < 0.0001), and lower small-worldness (P = 0.017). Detection of community membership emphasized lower network segregation in OCD compared to healthy controls. At the regional level, there were lower (rank-transformed) centrality values in OCD for volume of caudate nucleus and thalamus, and surface area of paracentral cortex, indicative of altered distribution of brain hubs. Centrality of cingulate and orbito-frontal as well as other brain areas was associated with OCD illness duration, suggesting greater involvement of these brain areas with illness chronicity. In summary, the findings of this study, the largest brain structural covariance study of OCD to date, point to a less segregated organization of structural covariance networks in OCD, and reorganization of brain hubs. The segregation findings suggest a possible signature of altered brain morphometry in OCD, while the hub findings point to OCD-related alterations in trajectories of brain development and maturation, particularly in cingulate and orbitofrontal regions