An overview of the first 5 years of the ENIGMA obsessive–compulsive disorder working group: The power of worldwide collaboration

Abstract Neuroimaging has played an important part in advancing our understanding of the neurobiology of obsessive?compulsive disorder (OCD). At the same time, neuroimaging studies of OCD have had notable limitations, including reliance on relatively small samples. International collaborative efforts to increase statistical power by combining samples from across sites have been bolstered by the ENIGMA consortium; this provides specific technical expertise for conducting multi-site analyses, as well as access to a collaborative community of neuroimaging scientists. In this article, we outline the background to, development of, and initial findings from ENIGMA's OCD working group, which currently consists of 47 samples from 34 institutes in 15 countries on 5 continents, with a total sample of 2,323 OCD patients and 2,325 healthy controls. Initial work has focused on studies of cortical thickness and subcortical volumes, structural connectivity, and brain lateralization in children, adolescents and adults with OCD, also including the study on the commonalities and distinctions across different neurodevelopment disorders. Additional work is ongoing, employing machine learning techniques. Findings to date have contributed to the development of neurobiological models of OCD, have provided an important model of global scientific collaboration, and have had a number of clinical implications. Importantly, our work has shed new light on questions about whether structural and functional alterations found in OCD reflect neurodevelopmental changes, effects of the disease process, or medication impacts. We conclude with a summary of ongoing work by ENIGMA-OCD, and a consideration of future directions for neuroimaging research on OCD within and beyond ENIGMA

Changes in functioning of mesolimbic incentive processing circuits during the premenstrual phase

The premenstrual phase of the menstrual cycle is associated with marked changes in normal and abnormal motivated behaviors. Animal studies suggest that such effects may result from actions of gonadal hormones on the mesolimbic dopamine (DA) system. We therefore investigated premenstrual changes in reward-related neural activity in terminal regions of the DA system in humans. Twenty-eight healthy young women underwent functional magnetic resonance imaging on 2 days during the menstrual cycle, once during the late follicular phase and once during the premenstrual phase, in counterbalanced order. Using a modified version of the monetary incentive delay task, we assessed responsiveness of the ventral striatum to reward anticipation. Our results show enhanced ventral striatal responses during the premenstrual as compared to the follicular phase. Moreover, this effect was most pronounced in women reporting more premenstrual symptoms. These findings provide support for the notion that changes in functioning of mesolimbic incentive processing circuits may underlie premenstrual changes in motivated behaviors. Notably, increases in reward-cue responsiveness have previously been associated with DA withdrawal states. Our findings therefore suggest that the sharp decline of gonadal hormone levels in the premenstrual phase may trigger a similar withdrawal-like state

Multimodal multi-center analysis of electroconvulsive therapy effects in depression: Brainwide gray matter increase without functional changes

Background: Electroconvulsive therapy (ECT) is an effective treatment for severe depression and induces gray matter (GM) increases in the brain. Small-scale studies suggest that ECT also leads to changes in brain functioning, but findings are inconsistent. In this study, we investigated the influence of ECT on changes in both brain structure and function and their relation to clinical improvement using multicenter neuroimaging data from the Global ECT-MRI Research Collaboration (GEMRIC). Methods: We analyzed T1-weighted structural magnetic resonance imaging (MRI) and functional resting-state MRI data of 88 individuals (49 male) with depressive episodes before and within one week after ECT. We performed voxel-based morphometry on the structural data and calculated fractional amplitudes of low-frequency fluctuations, regional homogeneity, degree centrality, functional connectomics, and hippocampus connectivity for the functional data in both unimodal and multimodal analyses. Longitudinal effects in the ECT group were compared to repeated measures of healthy controls (n = 27). Results: Wide-spread increases in GM volume were found in patients following ECT. In contrast, no changes in any of the functional measures were observed, and there were no significant differences in structural or functional changes between ECT responders and non-responders. Multimodal analysis revealed that volume increases in the striatum, supplementary motor area and fusiform gyrus were associated with local changes in brain function. Conclusion: These results confirm wide-spread increases in GM volume, but suggest that this is not accompanied by functional changes or associated with clinical response. Instead, focal changes in brain function appear related to individual differences in brain volume increases.publishedVersio

New insights into atmospherically relevant reaction systems using direct analysis in real-time mass spectrometry (DART-MS)

The application of direct analysis in real-time mass spectrometry (DART-MS), which is finding increasing use in atmospheric chemistry, to two different laboratory model systems for airborne particles is investigated: (1) submicron C3–C7 dicarboxylic acid (diacid) particles reacted with gas-phase trimethylamine (TMA) or butylamine (BA) and (2) secondary organic aerosol (SOA) particles from the ozonolysis of α-cedrene. The diacid particles exhibit a clear odd–even pattern in their chemical reactivity toward TMA and BA, with the odd-carbon diacid particles being substantially more reactive than even ones. The ratio of base to diacid in reacted particles, determined using known diacid–base mixtures, was compared to that measured by high-resolution time-of-flight aerosol mass spectrometry (HR-ToF-AMS), which vaporizes the whole particle. Results show that DART-MS probes  ∼  30 nm of the surface layer, consistent with other studies on different systems. For α-cedrene SOA particles, it is shown that varying the temperature of the particle stream as it enters the DART-MS ionization region can distinguish between specific components with the same molecular mass but different vapor pressures. These results demonstrate the utility of DART-MS for (1) examining reactivity of heterogeneous model systems for atmospheric particles and (2) probing components of SOA particles based on volatility

Effectiveness of Emotional Memory Reactivation vs Control Memory Reactivation Before Electroconvulsive Therapy in Adult Patients With Depressive Disorder A Randomized Clinical Trial:A Randomized Clinical Trial

Importance: Although electroconvulsive therapy (ECT) is often effective, approximately half of patients with depression undergoing ECT do not benefit sufficiently, and relapse rates are high. ECT sessions have been shown to weaken reactivated memories. The effect of emotional memory retrieval on cognitive schemas remains unknown. Objective: To assess whether emotional memory retrieval just before patients receive ECT sessions weakens underlying cognitive schemas, improves ECT effectiveness, increases ECT response, and reduces relapse rates. Design, Setting, and Participants: In this multicenter randomized clinical trial conducted from 2014 to 2018 in the departments of psychiatry in 3 hospitals in the Netherlands, 72 participants were randomized 1:1 to 2 parallel groups to receive either emotional memory reactivation (EMR-ECT) or control memory reactivation (CMR-ECT) interventions before ECT sessions. The Hamilton Depression Rating Scale (HDRS [total score range: 0-52, with 0-7 indicating no depression and ≥24 indicating severe depression]) was used to measure symptoms of depression during and after ECT, with a 6-month follow-up period. Participants were between ages 18 and 70 years with a primary diagnosis of unipolar major depressive disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision) and in whom ECT was indicated. Data analysis was performed from July to November 2019. Interventions: EMR-ECT or CMR-ECT interventions prior to ECT sessions. Main Outcomes and Measures: Depression scores and relapse rates within 6 months were assessed with the HDRS and analyzed using logistic and linear multiple regression analyses. Results: A total of 66 patients (mean [SD] age, 49.3 [12.3] years; 39 [59.1%] women) were randomized to the EMR-ECT group (n = 32) or the CMR-ECT group (n = 34). Regardless of the memory intervention, 42.4% (28 of 66) of patients responded (≥50% decrease of symptom severity on the HDRS). Of patients who responded, 39.3% (11 of 28) relapsed within 6 months. Remission rates (CMR-ECT group, 29.4% [10 of 34] vs EMR-ECT group, 25.0% [8 of 32]; P = .58), mean (SD) HDRS scores after the ECT course (CMR-ECT group, 14.6 [8.6] vs EMR-ECT group, 14.9 [8.8]; P = .88), total mean (SD) number of required ECT sessions for response (CMR-ECT group, 14.9 [7.9] vs EMR-ECT group, 15.6 [7.3]; P = .39), and relapse rates (CMR-ECT group, 46.7% [7 of 15] vs EMR-ECT group, 30.8% [4 of 13]; P = .33) were not significantly altered by the intervention. Conclusions and Relevance: Study findings suggest that the EMR-ECT intervention just before patient receipt of ECT for depression did not improve effectiveness, increase speed of response, or reduce relapse rates after the ECT course compared with patients receiving CMR-ECT. Trial Registration: Trialregister.nl Identifier: NL4289

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

Perceived threat predicts the neural sequelae of combat stress

Exposure to severe stressors increases the risk for psychiatric disorders in vulnerable individuals, but can lead to positive outcomes for others. However, it remains unknown how severe stress affects neural functioning in humans and what factors mediate individual differences in the neural sequelae of stress. The amygdala is a key brain region involved in threat detection and fear regulation, and previous animal studies have suggested that stress sensitizes amygdala responsivity and reduces its regulation by the prefrontal cortex. In this study, we used a prospective design to investigate the consequences of severe stress in soldiers before and after deployment to a combat zone. We found that combat stress increased amygdala and insula reactivity to biologically salient stimuli across the group of combat-exposed individuals. In contrast, its influence on amygdala coupling with the insula and dorsal anterior cingulate cortex was dependent on perceived threat, rather than actual exposure, suggesting that threat appraisal affects interoceptive awareness and amygdala regulation. Our results demonstrate that combat stress has sustained consequences on neural responsivity, and suggest a key role for the appraisal of threat on an amygdala-centered neural network in the aftermath of severe stress

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors