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

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

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

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

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

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.</p

Image_2_Increased Default Mode Network Connectivity in Obsessive–Compulsive Disorder During Reward Processing.JPEG

<p>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.</p><p>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.</p><p>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).</p><p>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.</p

Image_1_Increased Default Mode Network Connectivity in Obsessive–Compulsive Disorder During Reward Processing.JPEG

<p>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.</p><p>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.</p><p>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).</p><p>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.</p

Transgenic modeling of Ndr2 gene amplification reveals disturbance of hippocampus circuitry and function

Duplications and deletions of short chromosomal fragments are increasingly recognized as the cause for rare neurodevelopmental conditions and disorders. The NDR2 gene encodes a protein kinase important for neuronal development and is part of a microduplication region on chromosome 12 that is associated with intellectual disabilities, autism, and epilepsy. We developed a conditional transgenic mouse with increased Ndr2 expression in postmigratory forebrain neurons to study the consequences of an increased gene dosage of this Hippo pathway kinase on brain circuitry and cognitive functions. Our analysis reveals reduced terminal fields and synaptic transmission of hippocampal mossy fibers, altered hippocampal network activity, and deficits in mossy fiber-dependent behaviors. Reduced doublecortin expression and protein interactome analysis indicate that transgenic Ndr2 disturbs the maturation of granule cells in the dentate gyrus. Together, our data suggest that increased expression of Ndr2 may critically contribute to the development of intellectual disabilities upon gene amplification