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Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA‐Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population‐level mapping of average asymmetry was achieved, including an intriguing fronto‐occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi‐dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive–compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders. Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Over the last four years, the ENIGMA‐Laterality Working Group has published six studies of grey matter morphological asymmetry in health and disease, based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. Here we review the findings from these six studies.

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.

Abstract Compulsions are repetitive, stereotyped thoughts and behaviors designed to reduce harm. Growing evidence suggests that the neurocognitive mechanisms mediating behavioral inhibition (motor inhibition, cognitive inflexibility) reversal learning and habit formation (shift from goal-directed to habitual responding) contribute toward compulsive activity in a broad range of disorders. In obsessive compulsive disorder, distributed network perturbation appears focused around the prefrontal cortex, caudate, putamen, and associated neuro-circuitry. Obsessive compulsive disorder-related attentional set-shifting deficits correlated with reduced resting state functional connectivity between the dorsal caudate and the ventrolateral prefrontal cortex on neuroimaging. In contrast, experimental provocation of obsessive compulsive disorder symptoms reduced neural activation in brain regions implicated in goal-directed behavioral control (ventromedial prefrontal cortex, caudate) with concordant increased activation in regions implicated in habit learning (presupplementary motor area, putamen). The ventromedial prefrontal cortex plays a multifaceted role, integrating affective evaluative processes, flexible behavior, and fear learning. Findings from a neuroimaging study of Pavlovian fear reversal, in which obsessive compulsive disorder patients failed to flexibly update fear responses despite normal initial fear conditioning, suggest there is an absence of ventromedial prefrontal cortex safety signaling in obsessive compulsive disorder, which potentially undermines explicit contingency knowledge and may help to explain the link between cognitive inflexibility, fear, and anxiety processing in compulsive disorders such as obsessive compulsive disorder.

Subcortical neuronal activity is highly relevant for mediating communication in large-scale brain networks. While electroencephalographic (EEG) recordings provide appropriate temporal resolution and coverage to study whole brain dynamics, the feasibility to detect subcortical signals is a matter of debate. Here, we investigate if scalp EEG can detect and correctly localize signals recorded with intracranial electrodes placed in the centromedial thalamus, and in the nucleus accumbens. Externalization of deep brain stimulation (DBS) electrodes, placed in these regions, provides the unique opportunity to record subcortical activity simultaneously with high-density (256 channel) scalp EEG. In three patients during rest with eyes closed, we found significant correlation between alpha envelopes derived from intracranial and EEG source reconstructed signals. Highest correlation was found for source signals in close proximity to the actual recording sites, given by the DBS electrode locations. Therefore, we present direct evidence that scalp EEG indeed can sense subcortical signals. Electroencephalography (EEG) allows the measurement of electrical signals associated with brain activity, but it is unclear if EEG can accurately measure subcortical activity. Here, the authors show that source dynamics, reconstructed from scalp EEG, correlate with activity recorded from human thalamus and nucleus accumbens.

Nearly one billion people worldwide suffer from obsessive–compulsive behaviors 1 , 2 , yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive–compulsive behaviors as maladaptive habit learning 3 , 4 , which may be associated with abnormal beta–gamma neurophysiology of the orbitofrontal–striatal circuitry during reward processing 5 , 6 . We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta–gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive–compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive–compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive–compulsive behavior, suggest a unifying functional role of rhythms in the beta–gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders. Selective and personalized neuromodulation of orbitofrontal beta–gamma rhythms in humans, achieved with an alternating current, robustly attenuates obsessive–compulsive behavior for 3 months.

Recent evidence suggests that presupplementary motor area (pre‐SMA) and inferior frontal gyrus (IFG) play an important role in response inhibition. However, no study has investigated the relationship between these brain networks at resting‐state and response inhibition in obsessive–compulsive disorder (OCD). We performed resting‐state functional magnetic resonance imaging scans and then measured the response inhibition of 41 medication‐free OCD patients and 49 healthy control (HC) participants by using the stop‐signal task outside the scanner. We explored the differences between OCD and HC groups in the functional connectivity of pre‐SMA and IFG associated with the ability of motor response inhibition. OCD patients showed a longer stop‐signal reaction time (SSRT). Compared to HC, OCD patients exhibit different associations between the ability of motor response inhibition and the functional connectivity between pre‐SMA and IFG, inferior parietal lobule, dorsal anterior cingulate cortex, insula, and anterior prefrontal cortex. Additional analysis to investigate the functional connectivity difference from the seed ROIs to the whole brain voxels revealed that, compared to HC, OCD exhibited greater functional connectivity between pre‐SMA and IFG. Also, this functional connectivity was positively correlated with the SSRT score. These results provide additional insight into the characteristics of the resting‐state functional connectivity of the regions belonging to the cortico‐striato‐thalamo‐cortical circuit and the cingulo‐opercular salience network, underlying the impaired motor response inhibition of OCD. In particular, we emphasize the importance of altered functional connectivity between pre‐SMA and IFG for the pathophysiology of motor response inhibition in OCD. Obsessive–compulsive disorder patients had significantly different associations between the abilities of motor response inhibition and the resting‐state functional connectivity from pre‐SMA to IPL, IFG, dACC and anterior‐insula. Additionally, compared to healthy control, OCD exhibited greater functional connectivity between pre‐SMA and IFG, and this functional connectivity was correlated with the the abilities of motor response inhibition.

Obsessive compulsive disorder (OCD) and major depressive disorder (MDD) are common, often refractory, neuropsychiatric conditions for which new treatment approaches are urgently needed. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel surgical technique permitting incisionless ablative neurosurgery. We examined the safety profile, clinical response, and imaging correlates of MRgFUS bilateral anterior capsulotomy in patients with refractory obsessive compulsive disorder (OCD, N = 6) and major depressive disorder (MDD, n = 6). There were no serious adverse events. Nonserious adverse events included headaches and pin-site swelling in 7/12 patients. The response rate was 4/6 and 2/6 in the OCD and MDD cohorts respectively. To delineate the white-matter tracts impacted by capsulotomy, a normative diffusion MRI-based structural connectome was used, revealing tracts terminating primarily in the frontal pole, medial thalamus, striatum, and medial-temporal lobe. Positron emission tomography (PET) analysis (nine subjects) revealed widespread decreases in metabolism bilaterally in the cerebral hemispheres at 6 months post treatment, as well as in the right hippocampus, amygdala, and putamen. A pretreatment seed-to-voxel resting-state functional magnetic resonance imaging (rs-fMRI) analysis (12 subjects) revealed three voxel clusters significantly associated with eventual clinical response. MRgFUS capsulotomy appears to be safe, well tolerated, and according to these initial results, may be an important treatment option for patients with refractory OCD and MDD. MRgFUS capsulotomy results in both targeted and widespread changes in neural activity, and neuroimaging may hold potential for the prediction of outcome.

Despite an increasing focus on transdiagnostic approaches to mental health, it remains unclear whether different diagnostic categories share a common neuronatomical basis. The current investigation sought to investigate whether a transdiagnostic set of structural alterations characterized schizophrenia, depression, post-traumatic stress disorder, and obsessive-compulsive disorder, and determine whether any such alterations reflected markers of psychiatric illness or pre-existing familial vulnerability. A total of 404 patients with a psychiatric diagnosis were recruited (psychosis, n = 129; unipolar depression, n = 92; post-traumatic stress disorder, n = 91; obsessive-compulsive disorder, n = 92) alongside n = 201 healthy controls and n = 20 unaffected first-degree relatives. We collected structural magnetic resonance imaging scans from each participant, and tested for transdiagnostic alterations using Voxel-based morphometry. Inferences were made at p < 0.05 after family-wise error correction for multiple comparisons. The four psychiatric groups relative to healthy controls were all characterized by significantly greater gray matter volume in the putamen (right: z-score: 5.97, p-value < 0.001; left: z-score: 4.97, p-value = 0.001); the volume of this region was positively correlated with severity of symptoms across groups (r = 0.313; p < 0.001). Putamen enlargement was also evident in unaffected relatives compared to healthy controls (right: z-score: 8.13, p-value < 0.001; left: z-score: 9.38, p-value < 0.001). Taken collectively, these findings indicate that increased putamen volume may reflect a transdiagnostic marker of familial vulnerability to psychopathology. This is consistent with emerging conceptualizations of psychiatric illness, in which each disorder is understood as a combination of diagnosis-specific features and a transdiagnostic factor reflecting general psychopathology.

The ability to assign safety to stimuli in the environment is integral to everyday functioning. A key brain region for this evaluation is the ventromedial prefrontal cortex (vmPFC). To investigate the importance of vmPFC safety signaling, we used neuroimaging of Pavlovian fear reversal, a paradigm that involves flexible updating when the contingencies for a threatening (CS+) and safe (CS−) stimulus reverse, in a prototypical disorder of inflexible behavior influenced by anxiety, Obsessive Compulsive Disorder (OCD). Skin conductance responses in OCD patients (n = 43) failed to differentiate during reversal compared with healthy controls (n = 35), although significant differentiation did occur during early conditioning and amygdala BOLD signaling was unaffected in these patients. Increased vmPFC activation (for CS+ > CS−) during early conditioning predicted the degree of generalization in OCD patients during reversal, whereas vmPFC safety signals were absent throughout learning in these patients. Regions of the salience network (dorsal anterior cingulate, insula, and thalamus) showed early learning task-related hyperconnectivity with the vmPFC in OCD, consistent with biased processing of the CS+. Our findings reveal an absence of vmPFC safety signaling in OCD, undermining flexible threat updating and explicit contingency knowledge. Although differential threat learning can occur to some extent in the absence of vmPFC safety signals, effective CS− signaling becomes crucial during conflicting threat and safety cues. These results promote further investigation of vmPFC safety signaling in other anxiety disorders, with potential implications for the development of exposure-based therapies, in which safety signaling is likely to play a key role.

Obsessive–compulsive disorder (OCD) displays alterations in regional brain activity represented by the amplitude of low‐frequency fluctuation (ALFF), but the time‐varying characteristics of this local neural activity remain to be clarified. We aimed to investigate the dynamic changes of intrinsic brain activity in a relatively large sample of drug‐naïve OCD patients using univariate and multivariate analyses. We applied a sliding‐window approach to calculate the dynamic ALFF (dALFF) and compared the difference between 73 OCD patients and age‐ and sex‐matched healthy controls (HCs). We also utilized multivariate pattern analysis to determine whether dALFF could differentiate OCD patients from HCs at the individual level. Compared with HCs, OCD patients exhibited increased dALFF mainly within regions of the cortical–striatal–thalamic–cortical (CSTC) circuit, including the bilateral dorsal anterior cingulate cortex, medial prefrontal cortex and striatum, and right dorsolateral prefrontal cortex (dlPFC). Decreased dALFF was identified in the bilateral inferior parietal lobule (IPL), posterior cingulate cortex, insula, fusiform gyrus, and cerebellum. Moreover, we found negative correlations between illness duration and dALFF values in the right IPL and between dALFF values in the left cerebellum and Hamilton Depression Scale scores. Furthermore, dALFF can distinguish OCD patients from HCs with the most discriminative regions located in the IPL, dlPFC, middle occipital gyrus, and cuneus. Taken together, in the current study, we demonstrated a characteristic pattern of higher variability of regional brain activity within the CSTC circuits and lower variability in regions outside the CSTC circuits in drug‐naïve OCD patients. We used the dynamic amplitude of low‐frequency fluctuation to determine the temporal variability properties of regional brain activity. We demonstrated a characteristic pattern of higher time‐varying intrinsic activity within the cortical–striatal–thalamic–cortical circuits and lower variability in regions outside the circuits in drug‐naïve obsessive–compulsive disorder (OCD) patients. We emphasize that the dysfunction of regions outside the cortical–striatal–thalamic–cortical circuits, particularly the parietal cortex and cerebellum, plays an important role in the pathophysiology of OCD. ​