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Óscar F Gonçalves,1–3 Marcelo C Batistuzzo,4 João R Sato5 1Neuropsychophysiology Lab, CIPsi, School of Psychology, University of Minho, Braga, Portugal; 2Spaulding Neuromodulation Center, Department of Physical Medicine & Rehabilitation, Spaulding Rehabilitation Hospital and Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; 3Social and Cognitive Neuroscience Laboratory, Center for Health and Biological Sciences, Mackenzie Presbyterian University, 4Department and Institute of Psychiatry, University of São Paulo Medical School (FMUSP), 5Mathematics, Computing, and Cognition Center, Universidade Federal do ABC – UFABC, São Paulo, Brazil Abstract: The current literature provides substantial evidence of brain alterations associated with obsessive-compulsive disorder (OCD) symptoms (eg, checking, cleaning/decontamination, counting compulsions; harm or sexual, symmetry/exactness obsessions), and emotional problems (eg, defensive/appetitive emotional imbalance, disgust, guilt, shame, and fear learning/extinction) and cognitive impairments associated with this disorder (eg, inhibitory control, working memory, cognitive flexibility). Building on this evidence, new clinical trials can now target specific brain regions/networks. Real-time functional magnetic resonance imaging (rtfMRI) was introduced as a new therapeutic tool for the self-regulation of brain–mind. In this review, we describe initial trials testing the use of rtfMRI to target brain regions associated with specific OCD symptoms (eg, contamination), and other mind–brain processes (eg, cognitive – working memory, inhibitory control, emotional – defensive, appetitive systems, fear reduction through counter-conditioning) found impaired in OCD patients. While this is a novel topic of research, initial evidence shows the promise of using rtfMRI in training the self-regulation of brain regions and mental processes associated with OCD. Additionally, studies with healthy populations have shown that individuals can regulate brain regions associated with cognitive and emotional processes found impaired in OCD. After the initial “proof-of-concept” stage, there is a need to follow up with controlled clinical trials that could test rtfMRI innovative treatments targeting brain regions and networks associated with different OCD symptoms and cognitive-emotional impairments. Keywords: real-time fMRI, obsessive-compulsive disorder, self-regulation, neurofeedback, neuromodulation

Only a small number of studies have assessed structural differences between the two hemispheres during childhood and adolescence. However, the existing findings lack consistency or are restricted to a particular brain region, a specific brain feature, or a relatively narrow age range. Here, we investigated associations between brain asymmetry and age as well as sex in one of the largest pediatric samples to date (n = 4265), aged 1-18 years, scanned at 69 sites participating in the ENIGMA (Enhancing NeuroImaging Genetics through Meta-Analysis) consortium. Our study revealed that significant brain asymmetries already exist in childhood, but their magnitude and direction depend on the brain region examined and the morphometric measurement used (cortical volume or thickness, regional surface area, or subcortical volume). With respect to effects of age, some asymmetries became weaker over time while others became stronger; sometimes they even reversed direction. With respect to sex differences, the total number of regions exhibiting significant asymmetries was larger in females than in males, while the total number of measurements indicating significant asymmetries was larger in males (as we obtained more than one measurement per cortical region). The magnitude of the significant asymmetries was also greater in males. However, effect sizes for both age effects and sex differences were small. Taken together, these findings suggest that cerebral asymmetries are an inherent organizational pattern of the brain that manifests early in life. Overall, brain asymmetry appears to be relatively stable throughout childhood and adolescence, with some differential effects in males and females., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Non-invasive neuromodulation is a promising intervention for obsessive-compulsive disorder (OCD), although its neurobiological mechanisms of action are still poorly understood. Recent evidence suggests that abnormalities in the connectivity of the default mode network (DMN) and the supplementary motor area (SMA) with other brain regions and networks are involved in OCD pathophysiology. We examined if transcranial direct current stimulation (tDCS) alters these connectivity patterns and if they correlate with symptom improvement in treatment-resistant OCD., Methods: In 23 patients from a larger clinical trial (comparing active tDCS to sham) who underwent pre- and post-treatment MRI scans, we assessed resting-state functional MRI (rs-fMRI) data. The treatment involved 30-minute daily tDCS sessions for four weeks (weekdays only), with the cathode over the SMA and the anode over the left deltoid. We conducted whole-brain connectivity analysis comparing active tDCS-treated to sham-treated patients., Results: We found that active tDCS, but not sham, led to connectivity increasing between the DMN and the bilateral pre/postcentral gyri (p = 0.004, FDR corrected) and temporal-auditory areas plus the SMA (p = 0.028, FDR corrected). Also, symptom improvement was directly associated with connectivity increasing between the left lateral sensorimotor network and the left precuneus (r = 0.589, p = 0.034)., Limitations: Limited sample size (23 participants with resting-state neuroimaging), inability to analyze specific OCD symptom dimensions (e.g., harm, sexual/religious, symmetry/checking, cleaning/contamination)., Conclusions: These data offer novel information concerning functional connectivity changes associated with non-invasive neuromodulation interventions in OCD and can guide new brain stimulation interventions in the framework of personalized interventions., Competing Interests: Declaration of competing interest All authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Previous diffusion MRI studies have reported mixed findings on white matter microstructure alterations in obsessive-compulsive disorder (OCD), likely due to variation in demographic and clinical characteristics, scanning methods, and underpowered samples. The OCD global study was created across five international sites to overcome these challenges by harmonizing data collection to identify consistent brain signatures of OCD that are reproducible and generalizable. Single-shell diffusion measures (e.g., fractional anisotropy), multi-shell Neurite Orientation Dispersion and Density Imaging (NODDI) and fixel-based measures, were extracted from skeletonized white matter tracts in 260 medication-free adults with OCD and 252 healthy controls. We additionally performed structural connectome analysis. We compared cases with controls and cases with early (<18) versus late (18+) OCD onset using mixed-model and Bayesian multilevel analysis. Compared with healthy controls, adult OCD individuals showed higher fiber density in the sagittal stratum (B[SE] = 0.10[0.05], P = 0.04) and credible evidence for higher fiber density in several other tracts. When comparing early (n = 145) and late-onset (n = 114) cases, converging evidence showed lower integrity of the posterior thalamic radiation -particularly radial diffusivity (B[SE] = 0.28[0.12], P = 0.03)-and lower global efficiency of the structural connectome (B[SE] = 15.3[6.6], P = 0.03) in late-onset cases. Post-hoc analyses indicated divergent direction of effects of the two OCD groups compared to healthy controls. Age of OCD onset differentially affects the integrity of thalamo-parietal/occipital tracts and the efficiency of the structural brain network. These results lend further support for the role of the thalamus and its afferent fibers and visual attentional processes in the pathophysiology of OCD., (© 2024. The Author(s).)

White matter pathways, typically studied with diffusion tensor imaging (DTI), have been implicated in the neurobiology of obsessive-compulsive disorder (OCD). However, due to limited sample sizes and the predominance of single-site studies, the generalizability of OCD classification based on diffusion white matter estimates remains unclear. Here, we tested classification accuracy using the largest OCD DTI dataset to date, involving 1336 adult participants (690 OCD patients and 646 healthy controls) and 317 pediatric participants (175 OCD patients and 142 healthy controls) from 18 international sites within the ENIGMA OCD Working Group. We used an automatic machine learning pipeline (with feature engineering and selection, and model optimization) and examined the cross-site generalizability of the OCD classification models using leave-one-site-out cross-validation. Our models showed low-to-moderate accuracy in classifying (1) "OCD vs. healthy controls" (Adults, receiver operator characteristic-area under the curve = 57.19 ± 3.47 in the replication set; Children, 59.8 ± 7.39), (2) "unmedicated OCD vs. healthy controls" (Adults, 62.67 ± 3.84; Children, 48.51 ± 10.14), and (3) "medicated OCD vs. unmedicated OCD" (Adults, 76.72 ± 3.97; Children, 72.45 ± 8.87). There was significant site variability in model performance (cross-validated ROC AUC ranges 51.6-79.1 in adults; 35.9-63.2 in children). Machine learning interpretation showed that diffusivity measures of the corpus callosum, internal capsule, and posterior thalamic radiation contributed to the classification of OCD from HC. The classification performance appeared greater than the model trained on grey matter morphometry in the prior ENIGMA OCD study (our study includes subsamples from the morphometry study). Taken together, this study points to the meaningful multivariate patterns of white matter features relevant to the neurobiology of OCD, but with low-to-moderate classification accuracy. The OCD classification performance may be constrained by site variability and medication effects on the white matter integrity, indicating room for improvement for future research., (© 2024. The Author(s).)

Studies examining the neurocognitive and circuit-based etiology of psychiatric illness are moving toward inclusive, global designs. A potential confounding effect of these associations is general intelligence; however, an internationally validated, harmonized intelligence quotient (IQ) measure is not available. We describe the procedures used to measure IQ across a five-site, multinational study and demonstrate the harmonized measure's cross-site validity. Culturally appropriate intelligence measures were selected: four short-form Wechsler intelligence tests (Brazil, Netherlands, South Africa, United States) and the Binet Kamat (India). Analyses included IQ scores from 255 healthy participants (age 18-50; 42% male). Regression analyses tested between-site differences in IQ scores, as well as expected associations with sociodemographic factors (sex, socioeconomic status, education) to assess validity. Harmonization (e.g., a priori selection of tests) yielded the compatibility of IQ measures. Higher IQ was associated with higher socioeconomic status, suggesting good convergent validity. No association was found between sex and IQ at any site, suggesting good discriminant validity. Associations between higher IQ and higher years of education were found at all sites except the United States. Harmonized IQ scores provide a measure of IQ with evidence of good validity that can be used in neurocognitive and circuit-based studies to control for intelligence across global sites., Competing Interests: In the last 12 months, H.B.S. has received royalties from UpToDate Inc. and a stipend from the American Medical Association for serving as Associate Editor of JAMA Psychiatry. D.J.S. has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. The remaining authors have no competing interests to declare., (© The Author(s) 2024.)

Objectives: To study the impact of coronavirus disease 2019 on the routine of patients with obsessive-compulsive disorder (OCD) and changes in symptoms and suicidal-related behavior, mainly in those with cleaning symptoms., Methods: In this cross-sectional study, 58 patients completed an online self-report questionnaire that included the Obsessive-Compulsive Inventory-Revised, Coronavirus Stress and Traumatic Events Scale, Coronavirus Health Impact Survey, Beck Anxiety and Beck Depression inventories, and Suicide-Related Behaviors Questionnaire. Comparisons were made with another pre-pandemic sample (n=524) regarding the last three measures., Results: During the pandemic, the patients spent more days inside their homes (χ² = 33.39, p = 0.007), changed their alcohol consumption patterns (χ² = 87.6, p < 0.001), and increased social media usage (χ² = 68.83, p < 0.001). Participants with cleaning symptoms did not significantly differ from the others in relation to stress, anxiety/depressive symptoms, or suicidal-related behaviors. Finally, our sample did not differ from an equivalent OCD sample assessed before the pandemic in terms of anxiety and depressive symptom severity or suicidal-related behaviors., Conclusion: Overall, patients with OCD showed no lifestyle changes associated with higher stress levels during the pandemic. Patients with and without cleaning symptoms and patients before and during the pandemic presented similar results., Competing Interests: RGS has received speaker honoraria from Lundbeck. The other authors report no conflicts of interest.

Objective: We investigated whether social skills are impaired in patients with obsessive-compulsive disorder (OCD), whether they changed over the course of treatment, and whether OCD severity, age of onset, and illness duration were associated with social skills deficit., Methods: A total of 41 treatment-naïve patients with OCD and 34 healthy controls were assessed using the Social Skills Inventory. Patients were reevaluated 12 weeks after standardized treatment. Group differences and the effects of treatment on OCD symptomatology over time were analyzed with independent and paired tests, respectively. OCD severity, age at illness onset, and illness duration were tested as predictors of social skills., Results: The patient group had lower overall social skill scores than controls (p < 0.001). After treatment, although OCD symptomatology (p < 0.001) improved, there was no significant difference in social skills (p = 0.673). Earlier age of symptom onset predicted lower social skill scores (p = 0.016)., Conclusion: Our results suggest that, despite improved OCD symptoms, social skills did not change after treatment. Subsequent investigations with larger sample sizes and longer follow-up periods could determine whether social skills are likely to increase over time., Competing Interests: The authors report no conflicts of interest.

Specific brain activation patterns during fear conditioning and the recall of previously extinguished fear responses have been associated with obsessive-compulsive disorder (OCD). However, further replication studies are necessary. We measured skin-conductance response and blood oxygenation level-dependent responses in unmedicated adult patients with OCD (n = 27) and healthy participants (n = 22) submitted to a two-day fear-conditioning experiment comprising fear conditioning, extinction (day 1) and extinction recall (day 2). During conditioning, groups differed regarding the skin conductance reactivity to the aversive stimulus (shock) and regarding the activation of the right opercular cortex, insular cortex, putamen, and lingual gyrus in response to conditioned stimuli. During extinction recall, patients with OCD had higher responses to stimuli and smaller differences between responses to conditioned and neutral stimuli. For the entire sample, the higher the response delta between conditioned and neutral stimuli, the greater the dACC activation for the same contrast during early extinction recall. While activation of the dACC predicted the average difference between responses to stimuli for the entire sample, groups did not differ regarding the activation of the dACC during extinction recall. Larger unmedicated samples might be necessary to replicate the previous findings reported in patients with OCD., Competing Interests: Declaration of Competing Interest Dr Diniz has received speaker's fees from Lundbeck and Janssen Cilag for lectures that were unrelated to the contents of this work. Dr. RGS has received a consultancy fee from Lundbeck Remaining authors have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Current knowledge about functional connectivity in obsessive-compulsive disorder (OCD) is based on small-scale studies, limiting the generalizability of results. Moreover, the majority of studies have focused only on predefined regions or functional networks rather than connectivity throughout the entire brain. Here, we investigated differences in resting-state functional connectivity between OCD patients and healthy controls (HC) using mega-analysis of data from 1024 OCD patients and 1028 HC from 28 independent samples of the ENIGMA-OCD consortium. We assessed group differences in whole-brain functional connectivity at both the regional and network level, and investigated whether functional connectivity could serve as biomarker to identify patient status at the individual level using machine learning analysis. The mega-analyses revealed widespread abnormalities in functional connectivity in OCD, with global hypo-connectivity (Cohen's d: -0.27 to -0.13) and few hyper-connections, mainly with the thalamus (Cohen's d: 0.19 to 0.22). Most hypo-connections were located within the sensorimotor network and no fronto-striatal abnormalities were found. Overall, classification performances were poor, with area-under-the-receiver-operating-characteristic curve (AUC) scores ranging between 0.567 and 0.673, with better classification for medicated (AUC = 0.702) than unmedicated (AUC = 0.608) patients versus healthy controls. These findings provide partial support for existing pathophysiological models of OCD and highlight the important role of the sensorimotor network in OCD. However, resting-state connectivity does not so far provide an accurate biomarker for identifying patients at the individual level., (© 2023. The Author(s).)

Obsessive-compulsive disorder (OCD) affects 2-3% of the population. One-third of patients are poorly responsive to conventional therapies, and for a subgroup, gamma knife capsulotomy (GKC) is an option. We examined lesion characteristics in patients previously treated with GKC through well-established programs in Providence, RI (Butler Hospital/Rhode Island Hospital/Alpert Medical School of Brown University) and São Paulo, Brazil (University of São Paolo). Lesions were traced on T1 images from 26 patients who had received GKC targeting the ventral half of the anterior limb of the internal capsule (ALIC), and the masks were transformed into MNI space. Voxel-wise lesion-symptom mapping was performed to assess the influence of lesion location on Y-BOCS ratings. General linear models were built to compare the relationship between lesion size/location along different axes of the ALIC and above or below-average change in Y-BOCS ratings. Sixty-nine percent of this sample were full responders (≥35% improvement in OCD). Lesion occurrence anywhere within the targeted region was associated with clinical improvement, but modeling results demonstrated that lesions occurring posteriorly (closer to the anterior commissure) and dorsally (closer to the mid-ALIC) were associated with the greatest Y-BOCS reduction. No association was found between Y-BOCS reduction and overall lesion volume. GKC remains an effective treatment for refractory OCD. Our data suggest that continuing to target the bottom half of the ALIC in the coronal plane is likely to provide the dorsal-ventral height required to achieve optimal outcomes, as it will cover the white matter pathways relevant to change. Further analysis of individual variability will be essential for improving targeting and clinical outcomes, and potentially further reducing the lesion size necessary for beneficial outcomes., (© 2023. The Author(s).)

Objective: Cognitive-behavioral therapy (CBT) is considered a first-line treatment for obsessive-compulsive disorder (OCD) in pediatric and adult populations. Nevertheless, some patients show partial or null response. The identification of predictors of CBT response may improve clinical management of patients with OCD. Here, we aimed to identify structural magnetic resonance imaging (MRI) predictors of CBT response in 2 large series of children and adults with OCD from the worldwide ENIGMA-OCD consortium., Method: Data from 16 datasets from 13 international sites were included in the study. We assessed which variations in baseline cortical thickness, cortical surface area, and subcortical volume predicted response to CBT (percentage of baseline to post-treatment symptom reduction) in 2 samples totaling 168 children and adolescents (age range 5-17.5 years) and 318 adult patients (age range 18-63 years) with OCD. Mixed linear models with random intercept were used to account for potential cross-site differences in imaging values., Results: Significant results were observed exclusively in the pediatric sample. Right prefrontal cortex thickness was positively associated with the percentage of CBT response. In a post hoc analysis, we observed that the specific changes accounting for this relationship were a higher thickness of the frontal pole and the rostral middle frontal gyrus. We observed no significant effects of age, sex, or medication on our findings., Conclusion: Higher cortical thickness in specific right prefrontal cortex regions may be important for CBT response in children with OCD. Our findings suggest that the right prefrontal cortex plays a relevant role in the mechanisms of action of CBT in children., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. All rights reserved.)

Objectives: We describe the harmonized MRI acquisition and quality assessment of an ongoing global OCD study, with the aim to translate representative, well-powered neuroimaging findings in neuropsychiatric research to worldwide populations., Methods: We report on T1-weighted structural MRI, resting-state functional MRI, and multi-shell diffusion-weighted imaging of 140 healthy participants (28 per site), two traveling controls, and regular phantom scans., Results: Human image quality measures (IQMs) and outcome measures showed smaller within-site variation than between-site variation. Outcome measures were less variable than IQMs, especially for the traveling controls. Phantom IQMs were stable regarding geometry, SNR, and mean diffusivity, while fMRI fluctuation was more variable between sites., Conclusions: Variation in IQMs persists, even for an a priori harmonized data acquisition protocol, but after pre-processing they have less of an impact on the outcome measures. Continuous monitoring IQMs per site is valuable to detect potential artifacts and outliers. The inclusion of both cases and healthy participants at each site remains mandatory., (© 2022 The Authors. International Journal of Methods in Psychiatric Research published by John Wiley & Sons Ltd.)

In neurosurgery, spatial normalization emerged as a tool to minimize inter-subject variability and study target point locations based on standard coordinates. The Montreal Neurological Institute's 152 brain template (MNI152) has become the most widely utilized in neuroimaging studies, but has been noted to introduce partial volume effects, distortions, and increase structure size in all directions (x/y/z axes). These discrepancies question the accuracy of the MNI template, as well as its utility for studies that examine and form conclusions from group-level data. Given that surgical precision in obsessive-compulsive disorder is essential to patient outcomes, we retrospectively investigated lesion size and location in patients (n = 21) who underwent capsulotomy for intractable OCD, comparing deviations in the native scans to those in standard space. MNI measurements were significantly larger than native measurements across several structures in both coronal and axial slices, and we found that MNI transformation increases the size of many subcortical structures in a significant and proportional way for both females and males. These findings urge caution when using MNI as a reference space, as well as a stronger consideration of population-specific brain templates when examining connectivity-based networks., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Published by Elsevier B.V.)

Objective: Cross-national work on neurocognitive testing has been characterized by inconsistent findings, suggesting the need for improved harmonization. Here, we describe a prospective harmonization approach in an ongoing global collaborative study., Method: Visuospatial N -Back, Tower of London (ToL), Stop Signal task (SST), Risk Aversion (RA), and Intertemporal Choice (ITC) tasks were administered to 221 individuals from Brazil, India, the Netherlands, South Africa, and the USA. Prospective harmonization methods were employed to ensure procedural similarity of task implementation and processing of derived task measures across sites. Generalized linear models tested for between-site differences controlling for sex, age, education, and socioeconomic status (SES). Associations with these covariates were also examined and tested for differences by site with site-by-covariate interactions., Results: The Netherlands site performed more accurately on N -Back and ToL than the other sites, except for the USA site on the N -Back. The Netherlands and the USA sites performed faster than the other three sites during the go events in the SST. Finally, the Netherlands site also exhibited a higher tolerance for delay discounting than other sites on the ITC, and the India site showed more risk aversion than other sites on the RA task. However, effect size differences across sites on the five tasks were generally small (i.e., partial eta-squared < 0.05) after dropping the Netherlands (on ToL, N -Back, ITC, and SST tasks) and India (on the RA task). Across tasks, regardless of site, the N -Back (sex, age, education, and SES), ToL (sex, age, and SES), SST (age), and ITC (SES) showed associations with covariates., Conclusions: Four out of the five sites showed only small between-site differences for each task. Nevertheless, despite our extensive prospective harmonization steps, task score performance deviated from the other sites in the Netherlands site (on four tasks) and the India site (on one task). Because the procedural methods were standardized across sites, and our analyses were adjusted for covariates, the differences found in cognitive performance may indicate selection sampling bias due to unmeasured confounders. Future studies should follow similar cross-site prospective harmonization procedures when assessing neurocognition and consider measuring other possible confounding variables for additional statistical control. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Widely used psychotropic medications for obsessive-compulsive disorder (OCD) may change the volumes of subcortical brain structures, and differently in children vs. adults. We measured subcortical volumes cross-sectionally in patients finely stratified for age taking various common classes of OCD drugs., Methods: The ENIGMA-OCD consortium sample (1081 medicated/1159 unmedicated OCD patients and 2057 healthy controls aged 6-65) was divided into six successive 6-10-year age-groups. Individual structural MRIs were parcellated automatically using FreeSurfer into 8 regions-of-interest (ROIs). ROI volumes were compared between unmedicated and medicated patients and controls, and between patients taking serotonin reuptake inhibitors (SRIs), tricyclics (TCs), antipsychotics (APs), or benzodiazepines (BZs) and unmedicated patients., Results: Compared to unmedicated patients, volumes of accumbens, caudate, and/or putamen were lower in children aged 6-13 and adults aged 50-65 with OCD taking SRIs (Cohen's d = -0.24 to -0.74). Volumes of putamen, pallidum (d = 0.18-0.40), and ventricles (d = 0.31-0.66) were greater in patients aged 20-29 receiving APs. Hippocampal volumes were smaller in patients aged 20 and older taking TCs and/or BZs (d = -0.27 to -1.31)., Conclusions: Results suggest that TCs and BZs could potentially aggravate hippocampal atrophy of normal aging in older adults with OCD, whereas SRIs may reduce striatal volumes in young children and older adults. Similar to patients with psychotic disorders, OCD patients aged 20-29 may experience subcortical nuclear and ventricular hypertrophy in relation to APs. Although cross-sectional, present results suggest that commonly prescribed agents exert macroscopic effects on subcortical nuclei of unknown relation to therapeutic response., Competing Interests: Conflict of Interest Dr. Arnold reported holding the Alberta Innovates Translational Health Chair in Child and Youth Mental Health outside the submitted work. Prof. Mataix-Cols receives royalties for contributing articles to UpToDate, Wolters Kluwer Health and fees from Elsevier for editorial tasks (all unrelated to the submitted work). Dr. Narayanaswamy reported Government of India grants DST INSPIRE faculty grant IFA12-LSBM-26 and BT/06/IYBA/2012 outside the submitted work. Dr. Reddy reported Government of India grants SR/S0/HS/0016/2011 and BT/PR13334/Med/30/259/2009 outside the submitted work. Dr. Venkatasubramanian reported Wellcome-DBT India Alliance grant 500236/Z/11/Z outside the submitted work. Dr. Simpson reported Biohaven Research support for a clinical trial and royalties from UpToDate, Inc. and Cambridge University Press outside the submitted work. Dr. Soreni reported support from Lundbeck-IIT outside the submitted work. Dr. Walitza has received in the last 3 years royalties from Thieme Hogrefe, Kohlhammer, Springer, Beltz; Her work was supported in the last 3 years by the Swiss National Science Foundation (SNF), diff. EU FP7s, HSM Hochspezialisierte Medizin of the Kanton Zurich, Switzerland, Bfarm Germany, ZInEP, Hartmann Müller Stiftung, Olga Mayenfisch, Gertrud Thalmann Fonds (all unrelated to the submitted work). Dr. Thompson has received a research grant from Biogen, Inc., unrelated to the topic of this paper., (Copyright © 2022. Published by Elsevier B.V.)

Objective: Neuroimaging studies of obsessive-compulsive disorder (OCD) patients have highlighted the important role of deep gray matter structures. Less work has however focused on subcortical shape in OCD patients., Methods: Here we pooled brain MRI scans from 412 OCD patients and 368 controls to perform a meta-analysis utilizing the ENIGMA-Shape protocol. In addition, we investigated modulating effects of medication status, comorbid anxiety or depression, and disease duration on subcortical shape., Results: There was no significant difference in shape thickness or surface area between OCD patients and healthy controls. For the subgroup analyses, OCD patients with comorbid depression or anxiety had lower thickness of the hippocampus and caudate nucleus and higher thickness of the putamen and pallidum compared to controls. OCD patients with comorbid depression had lower shape surface area in the thalamus, caudate nucleus, putamen, hippocampus, and nucleus accumbens and higher shape surface area in the pallidum. OCD patients with comorbid anxiety had lower shape surface area in the putamen and the left caudate nucleus and higher shape surface area in the pallidum and the right caudate nucleus. Further, OCD patients on medication had lower shape thickness of the putamen, thalamus, and hippocampus and higher thickness of the pallidum and caudate nucleus, as well as lower shape surface area in the hippocampus and amygdala and higher surface area in the putamen, pallidum, and caudate nucleus compared to controls. There were no significant differences between OCD patients without co-morbid anxiety and/or depression and healthy controls on shape measures. In addition, there were also no significant differences between OCD patients not using medication and healthy controls., Conclusions: The findings here are partly consistent with prior work on brain volumes in OCD, insofar as they emphasize that alterations in subcortical brain morphology are associated with comorbidity and medication status. Further work is needed to understand the biological processes contributing to subcortical shape., (© 2022 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Individuals with obsessive-compulsive disorder (OCD) more often think about, attempt, and die by suicide than individuals from the general population. Sexual and religious obsessions (i.e., taboo obsessions) have been linked to increased risk of suicidality, but it is unclear if they explain additional risk over and above other risk factors. We refined the recently proposed multidimensional hierarchical model of OCD and explored how each symptom dimension in the model was associated with suicidality in a random half (n = 500) of a well-characterized cohort of patients with OCD. Symptom dimensions and other risk factors significantly associated with suicidality were included in a confirmatory multivariable model conducted with the other half of the sample (n = 501). The predictive confirmatory model accounted for 19% of the variance in suicidality. Taboo obsessions, the general OCD factor (i.e., having many different OCD symptoms at the same time), lifetime major depression, and lifetime substance use disorders significantly predicted suicidality in this model. Lifetime major depression explained most unique variance in suicidality (5.6%) followed by taboo obsessions and the general OCD factor (1.9% each). Taboo obsessions explain a small but significant proportion of variance in suicidality and should be considered an independent risk factor for suicidality in patients with OCD., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

Larger thalamic volume has been found in children with obsessive-compulsive disorder (OCD) and children with clinical-level symptoms within the general population. Particular thalamic subregions may drive these differences. The ENIGMA-OCD working group conducted mega- and meta-analyses to study thalamic subregional volume in OCD across the lifespan. Structural T 1 -weighted brain magnetic resonance imaging (MRI) scans from 2649 OCD patients and 2774 healthy controls across 29 sites (50 datasets) were processed using the FreeSurfer built-in ThalamicNuclei pipeline to extract five thalamic subregions. Volume measures were harmonized for site effects using ComBat before running separate multiple linear regression models for children, adolescents, and adults to estimate volumetric group differences. All analyses were pre-registered ( https://osf.io/73dvy ) and adjusted for age, sex and intracranial volume. Unmedicated pediatric OCD patients (<12 years) had larger lateral (d = 0.46), pulvinar (d = 0.33), ventral (d = 0.35) and whole thalamus (d = 0.40) volumes at unadjusted p-values <0.05. Adolescent patients showed no volumetric differences. Adult OCD patients compared with controls had smaller volumes across all subregions (anterior, lateral, pulvinar, medial, and ventral) and smaller whole thalamic volume (d = -0.15 to -0.07) after multiple comparisons correction, mostly driven by medicated patients and associated with symptom severity. The anterior thalamus was also significantly smaller in patients after adjusting for thalamus size. Our results suggest that OCD-related thalamic volume differences are global and not driven by particular subregions and that the direction of effects are driven by both age and medication status., (© 2022. The Author(s).)

Objectives: Although the Dimensional Yale-Brown Obsessive-Compulsive Scale (DY-BOCS) is a widely used instrument for assessing different obsessive-compulsive symptom dimensions, its factor structure has never been studied in a Brazilian population. Thus, we aimed to assess the goodness-of-fit indexes and factor loadings of two higher-order models of the DY-BOCS using confirmatory factor analysis (CFA) in a large obsessive-compulsive disorder (OCD) sample., Methods: We tested two CFA models in a sample of 955 adults with OCD who had been assessed with the DY-BOCS in a cross-sectional multi-site study. The first model encompassed the symptom checklist (present or absent), whereas the second focused on items related to severity scores., Results: Both models presented adequate goodness-of-fit indexes. The comparative fit index, Tucker-Lewis index, and omega were > 0.9, while the root mean square error of approximation was ≤ 0.06 for both models. Factor loadings for each item of each dimension are presented and discussed., Conclusion: Higher-order factor models showed adequate goodness-of-fit indexes, indicating that they appropriately measured OCD dimensions in this Brazilian population.

Background: While previous studies have implicated white matter (WM) as a core pathology of obsessive-compulsive disorder (OCD), the underlying neurobiological processes remain elusive. This study used free-water (FW) imaging derived from diffusion magnetic resonance imaging to identify cellular and extracellular WM abnormalities in patients with OCD compared with control subjects. Next, we investigated the association between diffusion measures and clinical variables in patients., Methods: We collected diffusion-weighted magnetic resonance imaging and clinical data from 83 patients with OCD (56 women/27 men, age 37.7 ± 10.6 years) and 52 control subjects (27 women/25 men, age 32.8 ± 11.5 years). Fractional anisotropy (FA), FA of cellular tissue, and extracellular FW maps were extracted and compared between patients and control subjects using tract-based spatial statistics and voxelwise comparison in FSL Randomise. Next, we correlated these WM measures with clinical variables (age of onset and symptom severity) and compared them between patients with and without comorbidities and patients with and without psychiatric medication., Results: Patients with OCD demonstrated lower FA (43.4% of the WM skeleton), lower FA of cellular tissue (31% of the WM skeleton), and higher FW (22.5% of the WM skeleton) compared with control subjects. We did not observe significant correlations between diffusion measures and clinical variables. Comorbidities and medication status did not influence diffusion measures., Conclusions: Our findings of widespread FA, FA of cellular tissue, and FW abnormalities suggest that OCD is associated with microstructural cellular and extracellular abnormalities beyond the corticostriatothalamocortical circuits. Future multimodal longitudinal studies are needed to understand better the influence of essential clinical variables across the illness trajectory., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

An important challenge in mental health research is to translate findings from cognitive neuroscience and neuroimaging research into effective treatments that target the neurobiological alterations involved in psychiatric symptoms. To address this challenge, in this review we propose a heuristic neurocircuit-based taxonomy to guide the treatment of obsessive-compulsive disorder (OCD). We do this by integrating information from several sources. First, we provide case vignettes in which patients with OCD describe their symptoms and discuss different clinical profiles in the phenotypic expression of the condition. Second, we link variations in these clinical profiles to underlying neurocircuit dysfunctions, drawing on findings from neuropsychological and neuroimaging studies in OCD. Third, we consider behavioral, pharmacological, and neuromodulatory treatments that could target those specific neurocircuit dysfunctions. Finally, we suggest methods of testing this neurocircuit-based taxonomy as well as important limitations to this approach that should be considered in future research., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited part of Springer Nature.)

Background: The non-clinical presentation of obsessive-compulsive symptoms (OCS) in women may impact not only their daily lives and well-being but also increase the risk for emotional and behavioral problems in their children. This study aims to investigate the OCS dimension distribution in a large sample of mothers from a cohort of school age children and the association between these OCS dimensions with their own psychopathology, and with the presence of OCS and other psychopathology in their children. Method: Our final sample consisted of 2,511 mother-children dyads recruited from the elementary schools of two large cities. Throughout multiple regression analysis, we examined the correlations between demographic and clinical variables of mothers assessed by the Mini International Psychiatric Interview (MINI) and the Dimensional Yale-Brown Obsessive-Compulsive Scale-Short Version (DY-BOCS-SV) with children's psychopathology status reported by the Child Behavior Checklist (CBCL). Results: The overall prevalence of mothers who reported experiencing at least one OCS was 40% ( N = 1,004). "Aggression/violence" was the most frequent symptom dimension (32.2%), followed by the "symmetry/ordering" (16.4%) and the "sexual/religious" dimensions (13.8%). There was a significant correlation between the presence of OCS and maternal psychopathology in general ( p < 0.001, r = 0.397). Not only the presence but also the severity of the mother's OCS were strongly correlated to the total ( p < 0.001), internalizing ( p < 0.001), externalizing ( p < 0.001), and OCS subscale scores ( p < 0.001) on the CBCL. Conclusion: OCS dimensions are highly prevalent in women. Presence and severity of maternal OCS are related to children's psychopathology and behavioral problems., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Blanco-Vieira, Hoexter, Batistuzzo, Alvarenga, Szejko, Fumo, Miguel and do Rosário.)

Background: Recent studies using magnetic resonance spectroscopy ( 1 H-MRS) indicate that patients with obsessive-compulsive disorder (OCD) present abnormal levels of glutamate (Glu) and gamma aminobutyric acid (GABA) in the frontal and striatal regions of the brain. These abnormalities could be related to the hyperactivation observed in cortico-striatal circuits of patients with OCD. However, most of the previous 1 H-MRS studies were not capable of differentiating the signal from metabolites that overlap in the spectrum, such as Glu and glutamine (Gln), and referred to the detected signal as the composite measure-Glx (sum of Glu and Gln). In this study, we used a two-dimensional JPRESS 1 H-MRS sequence that allows the discrimination of overlapping metabolites by observing the differences in J-coupling, leading to higher accuracy in the quantification of all metabolites. Our objective was to identify possible alterations in the neurometabolism of OCD, focusing on Glu and GABA, which are key neurotransmitters in the brain that could provide insights into the underlying neurochemistry of a putative excitatory/inhibitory imbalance. Secondary analysis was performed including metabolites such as Gln, creatine (Cr), N-acetylaspartate, glutathione, choline, lactate, and myo-inositol. Methods: Fifty-nine patients with OCD and 42 healthy controls (HCs) underwent 3T 1 H-MRS in the ventromedial prefrontal cortex (vmPFC, 30 × 25 × 25 mm 3 ). Metabolites were quantified using ProFit (version 2.0) and Cr as a reference. Furthermore, Glu/GABA and Glu/Gln ratios were calculated. Generalized linear models (GLMs) were conducted using each metabolite as a dependent variable and age, sex, and gray matter fraction (fGM) as confounding factors. GLM analysis was also used to test for associations between clinical symptoms and neurometabolites. Results: The GLM analysis indicated lower levels of Glu/Cr in patients with OCD ( z = 2.540; p = 0.011). No other comparisons reached significant differences between groups for all the metabolites studied. No associations between metabolites and clinical symptoms were detected. Conclusions: The decreased Glu/Cr concentrations in the vmPFC of patients with OCD indicate a neurochemical imbalance in the excitatory neurotransmission that could be associated with the neurobiology of the disease and may be relevant for the pathophysiology of OCD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JO'N declared a shared consortium with several of the authors, MB, MH, JD, and EM, at time of review., (Copyright © 2021 Batistuzzo, Sottili, Shavitt, Lopes, Cappi, de Mathis, Pastorello, Diniz, Silva, Miguel, Hoexter and Otaduy.)

Background: Thalamic volume measures have been linked to obsessive-compulsive disorder (OCD) in children and adolescents. However, it is unclear if alterations in thalamic volumes occur before or after symptom onset and if there is a relation to the presence of sub-clinical obsessive-compulsive symptoms (OCS). Here, we explore the relationship between OCS and the rate of thalamic volume change in a cohort of children and youth at high risk to develop a mental disorder. A secondary aim was to determine if there is a relationship between OCS and the individual's OCD polygenic risk score (OCD-PRS) and between the rate of thalamic volume change and the OCD-PRS. Methods: The sample included 378 children enrolled in the longitudinal Brazilian High-Risk Cohort for Mental Conditions. Participants were assessed for OCS and the symmetrized percent change (SPC) of thalamic volume across two time-points separated by 3 years, along with the OCD-PRS. Zero-altered negative binomial models were used to analyze the relationship between OCS and thalamic SPC. Multiple linear regressions were used to examine the relationship between thalamic SPC and OCD-PRS. Results: A significant relationship between OCS and the right thalamus SPC ( p = 0.042) was found. There was no significant relationship between changes in thalamic volume SPC and OCD-PRS. Conclusions: The findings suggest that changes in the right thalamic volume over the course of 3 years in children may be associated to OCS. Future studies are needed to confirm these results and further characterize the specific nature of OCS symptoms associated with thalamic volumes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ravagnani Salto, Santoro, Hoexter, Jackowski, Pan, Rosário, Belangero, Alvarenga, Doretto, Fumo, Batistuzzo, Macul Ferreira de Barros, Timpano, Ota, Rohde, Miguel, Leckman and Zugman.)

Obsessive-compulsive disorder (OCD) is a frequent, disabling disorder with high rates of treatment resistance. Transcranial direct current stimulation (tDCS) is a safe, tolerable noninvasive neuromodulation therapy with scarce evidence for OCD. This double-blind, randomized, and sham-controlled study investigates the efficacy of tDCS as add-on treatment for treatment-resistant OCD (failure to respond to at least one previous pharmacological treatment). On 20 consecutive weekdays (4 weeks), 43 patients with treatment-resistant OCD underwent 30 min active or sham tDCS sessions, followed by a 8 week follow-up. The cathode was positioned over the supplementary motor area (SMA) and the anode over the left deltoid. The primary outcome was the change in baseline Y-BOCS score at week 12. Secondary outcomes were changes in mood and anxiety and the occurrence of adverse events. Response was evaluated considering percent decrease of baseline Y-BOCS scores and the Improvement subscale of the Clinical Global Impression (CGI-I) between baseline and week 12. Patients that received active tDCS achieved a significant reduction of OCD symptoms than sham, with mean (SD) Y-BOCS score changes of 6.68 (5.83) and 2.84 (6.3) points, respectively (Cohen's d: 0.62 (0.06-1.18), p = 0.03). We found no between-group differences in responders (four patients in the active tDCS and one in the sham group). Active tDCS of the SMA was not superior to sham in reducing symptoms of depression or anxiety. Patients in both groups reported mild adverse events. Our results suggest that cathodal tDCS over the SMA is an effective add-on strategy in treatment-resistant OCD.

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.

Objectives: While theoretical models link obsessive-compulsive disorder (OCD) with executive function deficits, empirical findings from the neuropsychological literature remain mixed. These inconsistencies are likely exacerbated by the challenge of high-dimensional data (i.e., many variables per subject), which is common across neuropsychological paradigms and necessitates analytical advances. More unique to OCD is the heterogeneity of symptom presentations, each of which may relate to distinct neuropsychological features. While researchers have traditionally attempted to account for this heterogeneity using a symptom-based approach, an alternative involves focusing on underlying symptom motivations. Although the most studied symptom motivation involves fear of harmful events, 60-70% of patients also experience sensory phenomena, consisting of uncomfortable sensations or perceptions that drive compulsions. Sensory phenomena have received limited attention in the neuropsychological literature, despite evidence that symptoms motivated by these experiences may relate to distinct cognitive processes., Methods: Here, we used a supervised machine learning approach to characterize neuropsychological processes in OCD, accounting for sensory phenomena., Results: Compared to logistic regression and other algorithms, random forest best differentiated healthy controls (n = 59; balanced accuracy = .70), patients with sensory phenomena (n = 29; balanced accuracy = .59), and patients without sensory phenomena (n = 46; balanced accuracy = .62). Decision-making best distinguished between groups based on sensory phenomena, and among the patient subsample, those without sensory phenomena uniquely displayed greater risk sensitivity compared to healthy controls (d = .07, p = .008)., Conclusions: Results suggest that different cognitive profiles may characterize patients motivated by distinct drives. The superior performance and generalizability of the newer algorithms highlights the utility of considering multiple analytic approaches when faced with complex data., Practitioner Points: Practitioners should be aware that sensory phenomena are common experiences among patients with OCD. OCD patients with sensory phenomena may be distinguished from those without based on neuropsychological processes., (© 2020 The British Psychological Society.)

Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation intervention investigated for the treatment of depression. Clinical results have been heterogeneous, partly due to the variability of electric field (EF) strength in the brain owing to interindividual differences in head anatomy. Therefore, we investigated whether EF strength was correlated with behavioral changes in 16 depressed patients using simulated electric fields in real patient data from a controlled clinical trial. We hypothesized that EF strength in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC), brain regions implicated in depression pathophysiology, would be associated with changes in depression, mood and anxiety scores. SimNIBS were used to simulate individual electric fields based on the MRI structural T1-weighted brain scans of depressed subjects. Linear regression models showed, at the end of the acute treatment phase, that simulated EF strength was inversely associated with negative affect in the bilateral ACC (left: β = - 160.463, CI [- 291.541, - 29.385], p = 0.021; right: β = - 189.194, CI [- 289.479, - 88.910], p = 0.001) and DLPFC (left: β = - 93.210, CI [- 154.960, - 31.461], p = 0.006; right: β = - 82.564, CI [- 142.867, - 22.262], p = 0.011) and with depression scores in the left ACC (β = - 156.91, CI [- 298.51, - 15.30], p = 0.033). No association between positive affect or anxiety scores, and simulated EF strength in the investigated brain regions was found. To conclude, our findings show preliminary evidence that EF strength simulations might be associated with further behavioral changes in depressed patients, unveiling a potential mechanism of action for tDCS. Further studies should investigate whether individualization of EF strength in key brain regions impact clinical response.

Differences in hippocampus volume have been identified in adult patients with obsessive-compulsive disorder (OCD). However, the role of this limbic structure in pediatric patients is unclear. This study aimed to investigate the hippocampus and its subregions in a sample of 29 children and adolescents with OCD compared to 28 healthy controls, matched for age, sex, education, and IQ. Volumetric segmentation was performed using the Freesurfer software to calculate the volumes of the subregions that reflect the hippocampal cytoarchitecture. The volumes of three anatomic subregions (tail, body, and head) were also calculated. ANCOVA was performed to investigate differences of these volumes between patients and controls, controlling for total gray matter volume. After Bonferroni correction for multiple comparisons (p-value < 0.00556 for the body and < 0.00625 for the head structures), patients presented statistically significant larger volumes of the following structures: left subiculum body; left CA4 body; left GC-DG body; left molecular layer body; right parasubiculum; left CA4 head; left molecular layer head; right subiculum head and right molecular layer head. These enlarged volumes resulted in larger left and right whole hippocampi in patients, as well as bilateral hippocampal heads and left hippocampal body (all p-values < 0.00625). There were no associations between OCD severity and hippocampal volumes. These findings diverge from previous reports on adults and may indicate that larger hippocampal volumes could reflect an early marker of OCD, not present in adults., (Copyright © 2020. Published by Elsevier B.V.)

Environmental factors are at least as important as genetic factors for the development of obsessive-compulsive symptoms (OCS), but the identification of such factors remain a research priority. Our study aimed to investigate the association between a broad scope of potential risk factors and OCS in a large community cohort of children and adolescents. We evaluated 1877 participants and their caregivers at baseline and after 3 years to assess various demographic, prenatal, perinatal, childhood adversity, and psychopathological factors. Mean age at baseline was 10.2 years (SD 1.9) and mean age at follow-up was 13.4 years (SD 1.9). Reports of OCS at baseline and follow-up were analyzed using latent variable models. At preliminary regression analysis, 15 parameters were significantly associated with higher OCS scores at follow-up. At subsequent regression analysis, we found that eight of these parameters remained significantly associated with higher follow-up OCS scores while being controlled by each other and by baseline OCS scores. The significant predictors of follow-up OCS were: lower socioeconomic status (p = 0.033); lower intelligence quotient (p = 0.013); lower age (p < 0.001); higher maternal stress level during pregnancy (p = 0.028); absence of breastfeeding (p = 0.017); parental baseline OCS (p = 0.038); youth baseline anxiety disorder (p = 0.023); and youth baseline OCS scores (p < 0.001). These findings may better inform clinicians and policymakers engaged in the mental health assessment and prevention in children and adolescents.

Objective: Attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. The authors sought to directly compare these disorders using structural brain imaging data from ENIGMA consortium data., Methods: Structural T 1 -weighted whole-brain MRI data from healthy control subjects (N=5,827) and from 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. The authors examined subcortical volume, cortical thickness, and cortical 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 intracranial volume for subcortical and surface area measures)., Results: No shared differences were found among all three disorders, and shared differences between any two disorders did not survive correction for multiple comparisons. Children with ADHD compared with those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller intracranial volume than control subjects and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared with adult control subjects and other clinical groups. No OCD-specific differences were observed across different age groups and surface area differences among all disorders in childhood and adulthood., Conclusions: The study findings suggest robust but subtle differences across different age groups among ADHD, ASD, and OCD. ADHD-specific intracranial volume and hippocampal differences in children and adolescents, and ASD-specific cortical thickness differences in the frontal cortex in adults, support previous work emphasizing structural brain differences in these disorders.

Background: Cognitive performance has been studied in adults with obsessive-compulsive symptoms (OCS) and in adult relatives of patients with obsessive-compulsive disorder (OCD) Meanwhile, few studies have been conducted with children under the same conditions. This study compared the neurocognitive domains previously associated with dysfunction in OCD, especially visuoconstructive ability, visuospatial memory, executive functions, and intelligence, in children and adolescents at high risk (HR) for OCD (n = 18) and non-OCD controls (NOC) (n = 31)., Methods: For the HR group, we considered the first-degree relatives of patients with OCD that present OCS, but do not meet diagnostic criteria for OCD. Psychiatric diagnosis was assessed by experienced clinicians using the Structured Clinical Interview for DSM-IV and OCS severity was measured by the Yale-Brown Obsessive-Compulsive Scale. Neurocognitive assessment was performed with a comprehensive neuropsychological battery. Performance on the cognitive domains was compared between groups using Multivariate Analysis of Variance, whereas performance on the neuropsychological variables was compared between groups using independent t-tests in a cognitive subdomain analysis., Results: The cognitive domain analysis revealed a trend towards significance for impairments in the motor and processing speed domain (p = 0.019; F = 3.12) in the HR group. Moreover, the cognitive subdomain analysis identified a statistically significant underperformance in spatial working memory in the HR group when compared to the NOC group (p = 0.005; t = - 2.94), and a trend towards significance for impairments in non-verbal memory and visuoconstructive tasks in the HR group., Conclusions: Our results suggest impairments in spatial working memory and motor and processing speed in a non-clinical sample of HR participants. Considering the preliminary nature of our findings, further studies investigating these neurocognitive domains as potential predictors of pediatric OCD are warranted.

Objectives: The Yale-Brown Obsessive-Compulsive Scale has been considered the gold standard scale to assess obsessive-compulsive disorder severity. Previous studies using exploratory factor analysis and confirmatory factor analysis with this scale showed mixed findings in terms of factor structure and fit of models. Therefore, we used confirmatory factor analysis to compare different Yale-Brown Obsessive-Compulsive Scale models in a large sample aiming to identify the best model fit., Methods: We assessed adult obsessive-compulsive disorder patients ( n  = 955) using three measures: Yale-Brown Obsessive-Compulsive Scale severity ratings, the Dimensional Yale-Brown Obsessive-Compulsive Scale and the clinical global impression scale. We tested all factor structures reported by previous studies to investigate which model best fitted the data: one-factor, two-factor, three-factor and their equivalent high-order solutions. We also investigated Yale-Brown Obsessive-Compulsive Scale items correlations with scores from the other measures of obsessive-compulsive disorder severity., Results: Confirmatory factor analysis models presented mediocre to fair goodness-of-fit indexes. Severity items related to resistance to obsessions and compulsions presented low factor loadings. The model with the best fit indexes was a high-order model without obsessive-compulsive disorder resistance items. These items also presented small correlations with other obsessive-compulsive disorder severity measures., Conclusion: The obsessive-compulsive disorder field needs to discuss further improvements in the Yale-Brown Obsessive-Compulsive Scale and/or continue to search for better measures of obsessive-compulsive disorder severity.

Evidence points to an independent relationship among childhood maltreatment, impairments in executive functions (EF) and disruptive behavior disorders (DBD). However, it is still not fully understood how these three factors are interrelated. This study evaluated the association between childhood maltreatment and DBD testing the role of EF performance as a mediator or moderator. We studied a probabilistic school-based sample of 2016 children from 6 to 12 years. Mental disorders were assessed using the Development and Well-Being Assessment with parents and children. Children answered questions about exposure to child maltreatment and were evaluated with a set of cognitive tasks addressing inhibitory control, working memory, cognitive flexibility and planning. Childhood maltreatment was strongly associated with DBD (OR = 7.7, CI 95% 4.5-12.9). No association was found between childhood maltreatment and EF performance. Children with DBD showed worse performance in cognitive flexibility, which was not identified as a mediator or moderator of the association between childhood maltreatment and DBD. Results indicate that the association between maltreatment and disruptive behavior occurs regardless of performance in executive function in a community sample. Future studies are essential to confirm these findings and elucidate the cognitive mechanisms involved in this association.

Behavioral evidence of impaired response inhibition (RI) and hyperactive error monitoring (EM) in obsessive-compulsive disorder (OCD) is inconsistent. Recent neuroimaging work suggests that EM plays a role in RI impairments in OCD, but this has rarely been investigated using behavioral measures. The aims of this study were to (1) compare RI and EM performance between adults with OCD and non-psychiatric controls (NPC) while investigating possible moderators, and (2) assess whether excessive EM influences RI in OCD. We compared RI and EM performance on the Stop-Signal Task (SST) between 92 adults with OCD and 65 NPC from two Brazilian sites. We used linear regression to investigate which variables (group, age, medication use, clinical symptomatology) influenced performance, as well as to examine possible associations between RI and EM. OCD and NPC did not differ in RI and EM. However, age moderated RI performance in OCD with a medium effect size, reflecting differential effects of age on RI between groups: age was positively associated with RI in OCD but not NPC. Further, OCD severity predicted EM with a medium to large effect size, suggesting that more symptomatic patients showed greater monitoring of their mistakes. Finally, group moderated the relationship between RI and EM with a small effect size. Our findings suggest that demographic factors may influence RI, whereas clinical factors may influence EM. Further, we found preliminary behavioral evidence to indicate that impaired RI and excessive EM are related in OCD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Attentional bias (AB) refers to increased allocation of attention on threat stimuli when compared to neutral stimuli. It is not clear if AB occurs in subjects with obsessive-compulsive disorder (OCD). We tested AB for symmetry and cleaning symptoms of OCD. Sixty-two patients with OCD and 40 healthy controls matched by gender, age and IQ, completed a computerized dot-probe task where two pictures (with symmetry or cleaning related content) were shown. The probe appeared in the location previously occupied by one of the pictures. Within-subjects linear mixed-effect models were used to investigate the effects of the factors: group (patients vs controls), OCD dimension (cleaning vs symmetry), task condition (neutral, congruent and incongruent), and the interaction among them. We also correlated AB scores with the clinical and demographic variables. No positive interaction resulted among the factors, but positive results were observed in group and condition, separately. Patients were significantly slower than controls (p-value = 0.014) (an effect that was accounted for by depression and anxiety symptoms and comorbidity) and the neutral condition was significantly faster when compared the other two conditions (congruent and incongruent, p-value = 0.013). No association was found between AB scores and clinical symptoms. There was no AB toward specific, content-related, stimuli in this sample of OCD patients., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Episodic memory is the ability to learn, store and recall new information. The prefrontal cortex (PFC) is a crucial area engaged in this ability. Cognitive training has been demonstrated to improve episodic memory in adults and older subjects. However, there are no studies examining the effects of cognitive training on episodic memory encoding in typically developing children and adolescents. This study investigated the behavioral effects and neural correlates of semantic categorization strategy training in children and adolescents during verbal episodic memory encoding using functional magnetic resonance imaging (fMRI). Participants with age range: 7-18 years were scanned before and after semantic categorization training during encoding of word lists. Results showed improved memory performance in adolescents, but not in children. Deactivation of the anterior medial PFC/anterior cingulate and higher activation of the right anterior and lateral orbital gyri, right frontal pole and right middle frontal gyrus activation were found after training in adolescents when compared to children. These findings suggest different maturational paths of brain regions, especially in the PFC, and deactivation of default mode network areas, which are involved in successful memory and executive processes in the developing brain., Competing Interests: The authors have declared that no competing interests exist.

Background: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results., Methods: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations., Discussion: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

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., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Gamma ventral capsulotomy (GVC) is a radiosurgical procedure which aims to create lesions in the ventral part of the anterior limb of the internal capsule (ALIC). It has been used as a treatment option for patients with intractable obsessive-compulsive disorder (OCD) who do not respond to several first-line treatments attempts. However, changes in personality disorder symptoms after GVC have not been investigated. The aims of this study are to investigate changes in personality disorder symptoms after GVC and to search for baseline personality disorder symptoms that may predict clinical response to GVC. Fourteen treatment-intractable OCD patients who underwent GVC completed the Structured Clinical Interview for DSM-IV Personality Disorders (SCID-II) at baseline and one year after the procedure. Wilcoxon signed-rank test was performed to investigate personality disorder symptom changes before and after surgery. Linear regression models were utilized to predict treatment response, using baseline personality disorder symptoms as independent variables. We did not observe any quantitative changes in personality disorder symptoms after GVC, compared with baseline. Higher severity of obsessive-compulsive personality disorder symptoms at baseline was correlated with worse treatment response after GVC for OCD (β = -0.085, t-value = -2.52, p-value = 0.027). These findings advocate for the safety of the GVC procedure in this specific population of intractable OCD patients, in terms of personality disorder symptom changes. They also highlight the importance of taking into account the severity of obsessive-compulsive personality disorder symptoms when GVC is indicated for intractable OCD patients., (Copyright © 2020 Copetti, Lopes, Requena, Johnson, Greenberg, Noren, McLaughlin, Shavitt, Miguel, Batistuzzo and Hoexter.)

Visuospatial memory (VSM) is the ability to represent and manipulate visual and spatial information. This cognitive function depends on the functioning of the hippocampal formation (HF), located in the medial portion of the temporal cortex. The present study aimed to investigate whether there is an association between the volume of the HF and performance in VSM tests. High-resolution structural images (T1) and neuropsychological tests evaluating VSM were performed on 31 healthy individuals. A VSM index was created by grouping 5 variables from 5 tasks (4 from the CANTAB battery and 1 from the Rey-Osterrieth Complex Figure test). Multiple linear regression models using the volumes of HF subregions as independent variables and the VSM index as the dependent variable were conducted to test the hypothesis that memory performance could be predicted by HF volumes. We also conducted analyses to explore the role of covariates that may mediate this relationship, specifically age and intelligence quotient (IQ). We found significant associations between the hippocampal subregions of the left hemisphere and the VSM index (F(7,22)=2.758, P=0.032, R2a=0.298). When IQ was accounted for as a covariate, we also found significant results for the right hemisphere (F(8,21)=2.804, P=0.028, R2a=0.517). We concluded that the bilateral hippocampal formations contributed to performance on VSM tasks. Also, VSM processing is essential for a diverse set of daily activities and may be influenced by demographic variables in healthy subjects.