Examining Differences in Fear Learning in Patients With Obsessive-Compulsive Disorder With Pupillometry, Startle Electromyography and Skin Conductance Responses.

Obsessive-compulsive disorder (OCD) is characterized by recurrent, persistent thoughts and repetitive behaviors causing stress and anxiety. In the associative learning model of OCD, mechanisms of fear extinction are supposed to partly underlie symptom development, maintenance and treatment of OCD, proposing that OCD patients suffer from rigid memory associations and inhibitory learning deficits. To test these assumptions, previous studies have used skin conductance and subjective ratings as readouts in fear conditioning paradigms, finding impaired fear extinction learning, impaired fear extinction recall or no differences between individuals with OCD and healthy controls. Against this heterogeneous background, we tested fear acquisition and extinction in 37 OCD patients and 56 healthy controls, employing skin conductance as well as pupillometry and startle electromyography. Extinction recall was also included in a subsample. We did not observe differences between groups in any of the task phases, except a trend toward higher startle amplitudes during extinction for OCD. Overall, sensitive readouts such as pupillometry and startle responses did not provide evidence for moderate-to-large inhibitory learning deficits using classical fear conditioning, challenging the assumption of generically impaired extinction learning and memory in OCD.

Homogeneous grey matter patterns in patients with obsessive-compulsive disorder.

BACKGROUND: Changes in grey matter volume have frequently been reported in patients with obsessive-compulsive disorder (OCD). Most studies performed whole brain or region-of-interest based analyses whereas grey matter volume based on structural covariance networks has barely been investigated up to now. Therefore, the present study investigated grey matter volume within structural covariance networks in a sample of 228 participants (n = 117 OCD patients, n = 111 healthy controls). METHODS: First, an independent component analysis (ICA) was performed on all subjects' preprocessed T1 images to derive covariance-dependent morphometric networks. Then, grey matter volume from each of the ICA-derived morphometric networks was extracted and compared between the groups. In addition, we performed logistic regressions and receiver operating characteristic (ROC) analyses to investigate whether network-related grey matter volume could serve as a characteristic that allows to differentiate patients from healthy volunteers. Moreover, we assessed grey matter pattern organization by correlating grey matter volume in all networks across all participants. Finally, we explored a potential association between grey matter volume or whole-brain grey matter pattern organization and clinical characteristics in terms of symptom severity and duration of illness. RESULTS: There were only subtle group differences in network-related grey matter volume. Network-related grey matter volume had moreover a very poor discrimination performance. We found, however, significant group differences with regard to grey matter pattern organization. When correlating grey matter volume in all networks across all participants, patients showed a significantly higher homogeneity across all networks and a significantly lower heterogeneity, as assessed by the coefficient of variation across all networks as well as in several single networks. There was no association with clinical characteristics. CONCLUSION: The findings of the present study suggest that the pathological mechanisms of OCD reduce interindividual grey matter variability. We assume that common characteristics associated with the disorder may lead to a more uniform, disorder-specific morphometry.

White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group.

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.

Structural neuroimaging biomarkers for obsessive-compulsive disorder in the ENIGMA-OCD consortium: medication matters.

No diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Here, we aimed to identify magnetic resonance imaging (MRI) biomarkers for OCD, using 46 data sets with 2304 OCD patients and 2068 healthy controls from the ENIGMA consortium. We performed machine learning analysis of regional measures of cortical thickness, surface area and subcortical volume and tested classification performance using cross-validation. Classification performance for OCD vs. controls using the complete sample with different classifiers and cross-validation strategies was poor. When models were validated on data from other sites, model performance did not exceed chance-level. In contrast, fair classification performance was achieved when patients were grouped according to their medication status. These results indicate that medication use is associated with substantial differences in brain anatomy that are widely distributed, and indicate that clinical heterogeneity contributes to the poor performance of structural MRI as a disease marker.

Frontoparietal and salience network alterations in obsessive­compulsive disorder: insights from independent component and sliding time window analyses

Background: Resting-state functional MRI (fMRI) studies commonly report alterations in 3 core networks in obsessive­compulsive disorder (OCD) ­ the frontoparietal network, the default mode network and the salience network ­ defined by functionally connected infraslow oscillations in ongoing brain activity. However, most of these studies observed static functional connectivity in the brains of patients with OCD. Methods: To investigate dynamic functional connectivity alterations and widen the evidence base toward the triple network model in OCD, we performed group-based independent component and sliding time window analyses in 49 patients with OCD and 41 healthy controls. Results: The traditional independent component analysis showed alterations in the left frontoparietal network as well as between the left and right frontoparietal networks in patients with OCD compared with healthy controls. For dynamic functional connectivity, the sliding time window approach revealed peak dysconnectivity between the left and right frontoparietal networks and between the left frontoparietal network and the salience network. Limitations: The number of independent components, noise in the resting-state fMRI images, the heterogeneity of the OCD sample, and comorbidities and medication status in the patients could have biased the results. Conclusion: Disrupted modulation of these intrinsic brain networks may contribute to the pathophysiology of OCD.

Mapping Cortical and Subcortical Asymmetry in Obsessive-Compulsive Disorder: Findings From the ENIGMA Consortium.

BACKGROUND: Lateralized dysfunction has been suggested in obsessive-compulsive disorder (OCD). However, it is currently unclear whether OCD is characterized by abnormal patterns of brain structural asymmetry. Here we carried out what is by far the largest study of brain structural asymmetry in OCD. METHODS: We studied a collection of 16 pediatric datasets (501 patients with OCD and 439 healthy control subjects), as well as 30 adult datasets (1777 patients and 1654 control subjects) from the OCD Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) Consortium. Asymmetries of the volumes of subcortical structures, and of measures of regional cortical thickness and surface areas, were assessed based on T1-weighted magnetic resonance imaging scans, using harmonized image analysis and quality control protocols. We investigated possible alterations of brain asymmetry in patients with OCD. We also explored potential associations of asymmetry with specific aspects of the disorder and medication status. RESULTS: In the pediatric datasets, the largest case-control differences were observed for volume asymmetry of the thalamus (more leftward; Cohen's d = 0.19) and the pallidum (less leftward; d = -0.21). Additional analyses suggested putative links between these asymmetry patterns and medication status, OCD severity, or anxiety and depression comorbidities. No significant case-control differences were found in the adult datasets. CONCLUSIONS: The results suggest subtle changes of the average asymmetry of subcortical structures in pediatric OCD, which are not detectable in adults with the disorder. These findings may reflect altered neurodevelopmental processes in OCD.

Altered Cortico-Striatal Functional Connectivity During Resting State in Obsessive-Compulsive Disorder.

Background: Neuroimaging studies show that obsessive-compulsive disorder (OCD) is characterized by an alteration of the cortico-striato-thalamo-cortical (CSTC) system in terms of an imbalance of activity between the direct and the indirect loop of the CSTC. As resting-state functional connectivity (FC) studies investigated only specific parts of the CSTC in patients with OCD up to now, the present study aimed at exploring FC in the CSTC as a whole. Methods: We investigated potential alterations in resting-state FC within the CSTC system in 44 OCD patients and 40 healthy controls by taking into consideration all relevant nodes of the direct and indirect CSTC loop. Results: Compared to healthy controls, OCD patients showed an increased FC between the left subthalamic nucleus (STN) and the left external globus pallidus (GPe), as well as an increased FC between the left GPe and the left internal globus pallidus (GPi). Conclusion: These findings may contribute to a better understanding of the OCD pathophysiology by providing further information on the connectivity alterations within specific regions of the CSTC system. In particular, increased FC between the STN and the left GPe may play a major role in OCD pathology. This assumption is consistent with the fact that these regions are also the main target sites of therapeutic deep brain stimulation in OCD.

Specific Substantial Dysconnectivity in Schizophrenia: A Transdiagnostic Multimodal Meta-analysis of Resting-State Functional and Structural Magnetic Resonance Imaging Studies.

BACKGROUND: This study investigated characteristic large-scale brain changes in schizophrenia. Numerous imaging studies have demonstrated brain changes in schizophrenia, particularly aberrant intrinsic functional connectivity (iFC) of ongoing brain activity, measured by resting-state functional magnetic resonance imaging, and aberrant gray matter volume (GMV) of distributed brain regions, measured by structural magnetic resonance imaging. It is unclear, however, which iFC changes are specific to schizophrenia compared with those of other disorders and whether such specific iFC changes converge with GMV changes. To address this question of specific substantial dysconnectivity in schizophrenia, we performed a transdiagnostic multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies in schizophrenia and other psychiatric disorders. METHODS: Multiple databases were searched up to June 2017 for whole-brain seed-based iFC studies and voxel-based morphometry studies in schizophrenia, major depressive disorder, bipolar disorder, addiction, and anxiety. Coordinate-based meta-analyses were performed to detect 1) schizophrenia-specific hyperconnectivity or hypoconnectivity of intrinsic brain networks (compared with hyperconnectivity or hypoconnectivity of each other disorder both separately and combined across comparisons) and 2) the overlap between dysconnectivity and GMV changes (via multimodal conjunction analysis). RESULTS: For iFC meta-analysis, 173 publications comprising 4962 patients and 4575 control subjects were included, and for GMV meta-analysis, 127 publications comprising 6311 patients and 6745 control subjects were included. Disorder-specific iFC dysconnectivity in schizophrenia (consistent across comparisons with other disorders) was found for limbic, frontoparietal executive, default mode, and salience networks. Disorder-specific dysconnectivity and GMV reductions converged in insula, lateral postcentral cortex, striatum, and thalamus. CONCLUSIONS: Results demonstrated specific substantial dysconnectivity in schizophrenia in insula, lateral postcentral cortex, striatum, and thalamus. Data suggest that these regions are characteristic targets of schizophrenia.

Increased Default Mode Network Connectivity in Obsessive-Compulsive Disorder During Reward Processing.

Objective: Obsessive-compulsive disorder (OCD) is characterized by anxiety-provoking, obsessive thoughts (i.e., obsessions) which patients react to with compulsive behaviors (i.e., compulsions). Due to the transient feeling of relief following the reduction of obsession-induced anxiety, compulsions are often described as relieving or even rewarding. Several studies investigated functional activation during reward processing in OCD, but findings are heterogeneous up to now and little is known about potential alterations in functional connectivity. Method: Against this background we studied OCD patients (n = 44) and healthy controls (n = 37) during the receipt of monetary reward by assessing both activation and functional connectivity. Results: Patients showed a decreased activation in several frontal regions and the posterior cingulate (PCC, BA31) together with a stronger connectivity between the PCC and the vmPFC (BA10). Conclusion: Present findings demonstrate an increased connectivity in patients within major nodes of the default mode network (DMN)-a network known to be involved in the evaluation of internal mental states. These results may indicate an increased activity of internal, self-related processing at the expense of a normal responsiveness toward external rewards and incentives. This, in turn, may explain the constant urge for additional reinforcement and patients' inability to inhibit their compulsive behaviors.

Network-based decoupling of local gyrification in obsessive-compulsive disorder.

Gyrification is associated with cortical maturation and closely linked to neurodevelopmental processes. Obsessive-compulsive disorder has previously been associated with neurodevelopmental risk factors. Using graph theoretical modeling we examined structural covariance patterns to assess potential disruptions in processes associated with neurodevelopment in OCD. In total 97 patients and 92 healthy controls underwent magnetic resonance imaging. Structural covariance networks based on local gyrification indices were constructed using an atlas-based parcellation scheme. Network properties were assessed using the network-based statistic as well as global and local graph theoretical measures. Correlations between gyrification and symptom severity as well as age of disease onset were examined. Network-based statistic analysis revealed one cluster with significantly decreased structural covariance in patients comprising mainly ventral brain regions (p = .041). Normalized characteristic path length was found to be impaired in patients (p = .051). On a nodal level, left middle frontal sulcus displayed a significantly decreased local clustering coefficient (p < .001). Finally, gyrification in several inferior frontal nodes significantly correlated with age of onset but not symptom severity. The decrease in a gyrification-based covariance network in OCD appears to be mostly confined to ventral areas in which gyrification starts the latest during development. This pattern may indicate that alterations taking place during development are potentially time locked to specific periods. Correlations between gyrification in inferio-frontal nodes and age of onset potentially indicate a structural trait rather than state marker for OCD. Finally, a trend in impaired global integration capabilities may point towards potentially widespread global alterations during neurodevelopment in patients.

Frontoparietal areas link impairments of large-scale intrinsic brain networks with aberrant fronto-striatal interactions in OCD: a meta-analysis of resting-state functional connectivity.

Neuroimaging studies report evidence for two distinct pathophysiological models of obsessive-compulsive disorder (OCD): disrupted fronto-striatal circuits and impaired large-scale fronto-parietal-limbic intrinsic brain networks, defined by functionally connected (FC) infra-slow oscillations in ongoing brain activity. To synthesize this literature and overcome inconsistencies, we conducted a coordinate-based meta-analysis of 18 whole-brain resting-state functional magnetic resonance imaging (fMRI) studies (541 patients, 572 healthy controls) comparing seed-based FC between OCD patients and healthy controls. In patients, the meta-analysis revealed (1) consistent hypoconnectivity within frontoparietal and salience network, and between salience, frontoparietal and default-mode network, and (2) consistent general dysconnectivity (no specific direction of connectivity change) within default-mode and frontoparietal network, as well as between frontoparietal, default-mode, and salience networks. Between-network hypoconnectivity provides evidence for the triple-network model in OCD, while aberrant within-network connectivity of frontoparietal and striatal regions supports reports of aberrant fronto-striatal circuitry. Therefore, results corroborate both models of OCD pathophysiology and link them by underlining the importance of intrinsic connectivity of frontoparietal regions which are common to both models.

Association between hippocampus volume and symptom profiles in obsessive-compulsive disorder.

BACKGROUND: The hippocampus has recently been identified to play a key role in the pathophysiology of adult obsessive-compulsive disorder (OCD). Surprisingly, there is only limited evidence regarding the potential relationships with symptom dimensions. Due to the heterogeneity of symptoms in OCD, we aimed at further examining, whether hippocampal volume differences might be related to symptom profiles instead of single symptom dimensions. METHODS: In order to find out more about the potential association between clinical symptom profiles and alterations in hippocampal volume we categorized a large sample of OCD patients (N = 66) into distinct symptom profile groups using K-means clustering. In addition, hippocampal volumes of the different symptom profile groups were compared with hippocampal volumes in a sample of 66 healthy controls. RESULTS: We found significant differences in hippocampal volume between the different symptom profile groups which remained significant after correcting for age, sex, total intracranial volume, OCI-total score, depression, medication, disease duration and scanner. The patient group characterized by overall lower symptom scores and without high symptom severity in any specific domain showed the highest hippocampal volume. Finally, the comparison with healthy controls demonstrated significantly lower hippocampal volumes in those patients whose symptom profile was characterized by a high severity of ordering and checking symptoms. CONCLUSIONS: Present results provide further confirmation for alterations in hippocampus structure in OCD and suggest that symptom profiles which take into account the multi-symptomatic character of the disorder should be given greater attention in this context.