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Objective Research suggests abnormalities in reward-based processes in anorexia nervosa (AN). However, few studies have explored if such alterations might be associated with different temporal activation patterns. This study aims to characterize alterations in time-dependent processes in the ventral striatum (VS) during social feedback in AN using functional magnetic resonance imaging (fMRI). Method Twenty women with restrictive-subtype AN and 20 age-matched healthy controls (HC) underwent a social judgment experimental fMRI task. Temporal VS hemodynamic responses were extracted in SPM for each participant and each social condition (acceptance/rejection). Results Compared with age-matched HC, patients with AN showed a significant time by group interaction of peak VS response throughout the task, with a progressive blunting of peak activation responses, accompanied by a progressive increase in baseline activity levels over time. Discussion The results suggest an attenuated response pattern to repetitive social rejection in the VS in patients with AN, together with a difficulty in returning to baseline. The information obtained from this study will guide future, design-specific studies to further explore alterations temporal dynamics.

Weeland et al.1 discuss the relationship between subregional thalamic volumes and obsessive-compulsive symptoms (OCS) in children from the general population. The thalamus is the last relay node of the so-called corticostriatal-thalamocortical (CSTC) circuits before information reenters the cortex. There are different CSTC circuits involved in motor, cognitive, and affective/motivational processes whose information is conveyed in parallel through different thalamic nuclei.2 Studies have shown that patients with obsessive-compulsive disorder (OCD) show pervasive alterations in these circuits.3 Indeed, such alterations are central to prevailing neurobiological models of OCD, which are largely based on the results from neuroimaging research conducted with clinical OCD samples over the last 3 decades.3 This research includes magnetic resonance imaging studies identifying a range of structural changes in relay nodes within CSTC circuits. In one of the earliest reports, Gilbert et al.4 identified enlarged thalamic volumes in a small sample of treatment-naive children with OCD, which normalized after treatment with paroxetine. Although treatment effects have not been replicated, recent research with larger datasets from the ENIGMA international consortium confirmed these initial findings in unmedicated children with OCD.5 Likewise, in a previous study conducted with children from the population-based birth cohort Generation R, the same sample used in the study by Weeland et al.,1 total thalamic volume was also associated with OCS.6.

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 1,024 OCD patients and 1,028 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.

Background Cognitive-behavior therapy (CBT) is a well-established first-line intervention for anxiety-related disorders, including specific phobia, social anxiety disorder, panic disorder/agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder. Several neural predictors of CBT outcome for anxiety-related disorders have been proposed, but previous results are inconsistent. Methods We conducted a systematic review and meta-analysis of task-based functional magnetic resonance imaging (fMRI) studies investigating whole-brain predictors of CBT outcome in anxiety-related disorders (17 studies, n = 442). Results Across different tasks, we observed that brain response in a network of regions involved in salience and interoception processing, encompassing fronto-insular (the right inferior frontal gyrus-anterior insular cortex) and fronto-limbic (the dorsomedial prefrontal cortex-dorsal anterior cingulate cortex) cortices was strongly associated with a positive CBT outcome. Conclusions Our results suggest that there are robust neural predictors of CBT outcome in anxiety-related disorders that may eventually lead (probably in combination with other data) to develop personalized approaches for the treatment of these mental disorders.

Objective Commonly observed subclinical obsessive-compulsive symptoms in healthy children may predispose to obsessive-compulsive disorder (OCD). Therefore, investigating the underlying neurobiology may be relevant to identify alterations in specific brain circuits potentially accounting for clinical heterogeneity in OCD without the confounding effects of clinical samples. We analyzed the brain correlates of different obsessive-compulsive symptoms in a large group of healthy children using functional connectivity measures. Method We evaluated 227 healthy children (52% girls; mean [SD] age 9.71 [0.86] years; range, 8–12.1 years). Participants underwent clinical assessment with the Obsessive-Compulsive Inventory–Child Version and a resting-state functional magnetic resonance imaging examination. Total and symptom-specific severity were correlated with voxelwise global functional connectivity degree values. Significant clusters were then used as seeds of interest in seed-to-voxel analyses. Modulating effects of age and sex were also assessed. Results Global functional connectivity of the left ventral putamen and medial dorsal thalamus correlated negatively with total obsessive-compulsive symptom severity. Seed-to-voxel analyses revealed specific negative correlations from these clusters with limbic, sensorimotor, and insular regions in association with obsessing, ordering, and doubt-checking symptoms, respectively. Hoarding symptoms were associated with negative correlations between the left medial dorsal thalamus and a widespread pattern of regions, with such associations modulated by sex and age. Conclusion Our findings concur with prevailing neurobiological models of OCD on the importance of cortico-striato-thalamo-cortical dysfunction to account for symptom severity. Notably, we showed that changes in cortico-striato-thalamo-cortical connectivity are present at subclinical stages, which may result in an increased vulnerability for OCD. Moreover, we mapped different symptom dimensions onto specific cortico-striato-thalamo-cortical circuit attributes.

Background Major depressive disorder (MDD) and borderline personality disorder (BPD) are highly prevalent and often comorbid psychiatric conditions, with abnormal processing of negative affect resulting from psychological stress. Characteristics of central processing of autonomic response to stress in each disorder are not clearly settled. Methods We obtained whole brain 3T fMRI with concurrent skin conductance, respiration rate, and heart rate variability measures in a cohort of MDD (N=19), BPD (N=19) patients, and healthy (N=20) individuals. Experiments were conducted in resting conditions, during a control mental arithmetic task, during highly stressful mental arithmetic, and in the period immediately following psychological stress. Results Widespread activation of central autonomic network (CAN) structures was observed during stress compared to a control task in the group of healthy participants, whereas CAN activation during stress was less intense in both BPD and MDD. Both patient groups displayed increased sympathetic and decreased parasympathetic activation compared to healthy subjects, as previously reported. The relationship between peripheral sympathetic or parasympathetic activity and simultaneous regional brain BOLD activity was similar in BPD patients and healthy subjects, and markedly different from that seen in MDD patients. Limitations The sample size, the fact it belonged to a single study site, and low grade affective symptomatology in both patient groups limit the generalizability of the present findings. Conclusions The diverging neurobiological signature in the homeostatic response to stress in MDD and BPD possibly represents a heuristically valuable candidate biomarker to help discern MDD and BPD patients.

The cognitive reappraisal of emotion is hypothesized to involve frontal regions modulating the activity of subcortical regions such as the amygdala. However, the pathways by which structurally disparate frontal regions interact with the amygdala remains unclear. In this study, 104 healthy young people completed a cognitive reappraisal task. Dynamic causal modeling (DCM) was used to map functional interactions within a frontoamygdalar network engaged during emotion regulation. Five regions were identified to form the network: the amygdala, the presupplementary motor area (preSMA), the ventrolateral prefrontal cortex (vlPFC), dorsolateral prefrontal cortex (dlPFC), and ventromedial prefrontal cortex (vmPFC). Bayesian Model Selection was used to compare 256 candidate models, with our winning model featuring modulations of vmPFC-to-amygdala and amygdala-to-preSMA pathways during reappraisal. Moreover, the strength of amygdala-to-preSMA modulation was associated with the habitual use of cognitive reappraisal. Our findings support the vmPFC serving as the primary conduit through which prefrontal regions directly modulate amygdala activity, with amygdala-to-preSMA connectivity potentially acting to shape ongoing affective motor responses. We propose that these two frontoamygdalar pathways constitute a recursive feedback loop, which computes the effectiveness of emotion-regulatory actions and drives model-based behavior.

The relationship between structural brain alterations and prediction of clinical improvement in first-episode psychosis (FEP) has been scarcely studied. We investigated whether structural covariance, a well-established approach to identify abnormal patterns of volumetric correlation across distant brain regions, which allows incorporating network-level information to structural assessments, is associated with longitudinal clinical course. We assessed a sample of 74 individuals from a multicenter study. Magnetic resonance imaging scans were acquired at baseline, and clinical assessments at baseline and at a 2-year follow-up. Participants were split in two groups as a function of their clinical improvement after 2 years (i.e., ≥ 40% reduction in psychotic symptom severity, (n = 29, n = 45)). We performed a seed-based approach and focused our analyses on 3 cortical and 4 subcortical regions of interest to identify alterations in cortical and cortico-subcortical networks. Improvers presented an increased correlation between the volumes of the right posterior cingulate cortex (PCC) and the left precentral gyrus, and between the left PCC and the left middle occipital gyrus. They also showed an increased correlation between right posterior hippocampus and left angular gyrus volumes. Our study provides a novel mean to identify structural correlates of clinical improvement in FEP, describing clinically-relevant anatomical differences in terms of large-scale brain networks, which is better aligned with prevailing neurobiological models of psychosis. The results involve brain regions considered to participate in the multisensory processing of bodily signals and the construction of bodily self-consciousness, which resonates with recent theoretical accounts in psychosis research.

Altres ajuts: The study was funded by the grant COPERNICO from the Spanish Ministry of Health/National Drugs Plan, and by the Norte Portugal Regional Operational Programme (NORTE 2020) under the Portugal 2020 Partnership Agreement (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023). VC was supported by the grant PID2019-105077RJ-I00/AEI/10.13039/501100011033. AVG was supported by a Medical Research Future Fund fellowship (MRF1141214). ABL has received research support from the Universitat Jaume I (UJI-B2020-23). MPP was supported by the Spanish Ministry of Universities, with funds from the European Union - NextGenerationEU (MAZ/2021/11). Cocaine use disorder (CUD) and gambling disorder (GD) share clinical features and neural alterations, including emotion regulation deficits and dysfunctional activation in related networks. However, they also exhibit differential aspects, such as the neuroadaptive effects of long-term drug consumption in CUD as compared to GD. Neuroimaging research aimed at disentangling their shared and specific alterations can contribute to improve understanding of both disorders. We compared CUD (N = 15), GD (N = 16) and healthy comparison (HC; N = 17) groups using a network-based approach for studying temporally coherent functional networks during functional magnetic resonance imaging (fMRI) of an emotion regulation task. We focused our analysis in limbic, ventral frontostriatal, dorsal attentional (DAN) and executive networks (FPN), given their involvement in emotion regulation and their alteration in CUD and GD. Correlations with measures of emotional experience and impulsivity (UPPS-P) were also performed. The limbic network was significantly decreased during emotional processing both for CUD and GD individuals compared to the HC group. Furthermore, GD participants compared to HC showed an increased activation in the ventral frontostriatal network during emotion regulation. Finally, networks' activation patterns were modulated by impulsivity traits. Functional network analyses revealed both overlapping and unique effects of stimulant and gambling addictions on neural networks underpinning emotion regulation.

Psychotic major depression (PMD) is hypothesized to be a distinct clinical entity from nonpsychotic major depression (NPMD). However, neurobiological evidence supporting this notion is scarce. The aim of this study is to identify gray matter volume (GMV) differences between PMD and NPMD and their longitudinal change following electroconvulsive therapy (ECT). Structural magnetic resonance imaging (MRI) data from 8 independent sites in the Global ECT-MRI Research Collaboration (GEMRIC) database (n = 108; 56 PMD and 52 NPMD; mean age 71.7 in PMD and 70.2 in NPMD) were analyzed. All participants underwent MRI before and after ECT. First, cross-sectional whole-brain voxel-wise GMV comparisons between PMD and NPMD were conducted at both time points. Second, in a flexible factorial model, a main effect of time and a group-by-time interaction were examined to identify longitudinal effects of ECT on GMV and longitudinal differential effects of ECT between PMD and NPMD, respectively. Compared with NPMD, PMD showed lower GMV in the prefrontal, temporal and parietal cortex before ECT; PMD showed lower GMV in the medial prefrontal cortex (MPFC) after ECT. Although there was a significant main effect of time on GMV in several brain regions in both PMD and NPMD, there was no significant group-by-time interaction. Lower GMV in the MPFC was consistently identified in PMD, suggesting this may be a trait-like neural substrate of PMD. Longitudinal effect of ECT on GMV may not explain superior ECT response in PMD, and further investigation is needed. Funding Agencies|Keio University Medical Science Fund [99-095-0007]; AMED [JP20dm0307102h0003]; Research Foundation Flanders (FWO) grantFWO [G0C0319N]; KU Leuven Fund [C24/18/095]; Sequoia Fund for Research on Ageing and Mental Health; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [MH125126, MH111826]; Carlos III Health InstituteInstituto de Salud Carlos III [CD20/00189]; Lundbeck FoundationLundbeckfonden; Western Norway Regional Health Authority [911986, 912238]

Background/Objective: Neuroimaging studies have reported abnormalities in the examination of functional connectivity in late-life depression (LLD) in the default mode network (DMN). The present study aims to study resting-state functional connectivity within the DMN in people diagnosed with late-life major depressive disorder (MDD) compared to healthy controls (HCs). Moreover, we would like to differentiate these same connectivity patterns between participants with high vs. low anxiety levels. Method: The sample comprised 56 participants between the ages of 60 and 75; 27 of them were patients with a diagnosis of MDD. Patients were further divided into two samples according to anxiety level: the four people with the highest anxiety level and the five with the lowest anxiety level. Clinical aspects were measured using psychological questionnaires. Each participant underwent functional magnetic resonance imaging (fMRI) acquisition in different regions of interest (ROIs) of the DMN. Results: There was a greater correlation between pairs of ROIs in the control group than in patients with LLD, being this effect preferentially observed in patients with higher anxiety levels. Conclusions: There are differences in functional connectivity within the DMN depending on the level of psychopathology. This can be reflected in these correlations and in the number of clusters and how the brain lateralizes (clustering).

Obsessive-compulsive symptoms (OCSs) during childhood predispose to obsessive-compulsive disorder and have been associated with changes in brain circuits altered in obsessive-compulsive disorder samples. OCSs may arise from disturbed glutamatergic neurotransmission, impairing cognitive oscillations and promoting overstable functional states. A total of 227 healthy children completed the Obsessive Compulsive Inventory-Child Version and underwent a resting-state functional magnetic resonance imaging examination. Genome-wide data were obtained from 149 of them. We used a graph theory-based approach and characterized associations between OCSs and dynamic functional connectivity (dFC). dFC evaluates fluctuations over time in FC between brain regions, which allows characterizing regions with stable connectivity patterns (attractors). We then compared the spatial similarity between OCS-dFC correlation maps and mappings of genetic expression across brain regions to identify genes potentially associated with connectivity changes. In post hoc analyses, we investigated which specific single nucleotide polymorphisms of these genes moderated the association between OCSs and patterns of dFC. OCSs correlated with decreased attractor properties in the left ventral putamen and increased attractor properties in (pre)motor areas and the left hippocampus. At the specific symptom level, increased attractor properties in the right superior parietal cortex correlated with ordering symptoms. In the hippocampus, we identified two single nucleotide polymorphisms in glutamatergic neurotransmission genes (GRM7, GNAQ) that moderated the association between OCSs and attractor features. We provide evidence that in healthy children, the association between dFC changes and OCSs may be mapped onto brain circuits predicted by prevailing neurobiological models of obsessive-compulsive disorder. Moreover, our findings support the involvement of glutamatergic neurotransmission in such brain network changes.

Impulsivity and compulsivity are multidimensional constructs that are increasingly considered determinants of obesity. Studies using functional magnetic resonance imaging (fMRI) have provided insight on how differences in brain response during tasks exploring facets of impulsivity and compulsivity relate to the ingestive behaviors that support the etiology and maintenance of obesity. In this narrative review, we provide an overview of neuroimaging studies exploring impulsivity and compulsivity factors as they relate to weight status. Special focus will be placed on studies examining the impulsivity-related dimensions of attentional bias, delayed gratification and emotion regulation. Discussions of compulsivity within the context of obesity will be restricted to fMRI studies investigating habit formation and response flexibility under shifting contingencies. Further, we will highlight neuroimaging research demonstrating how alterations in neuroendocrine functioning are linked to excessive food intake and may serve as a driver of the impulsive and compulsive behaviors observed in obesity. Research on the associations between brain response with neuroendocrine factors, such as insulin, peptide YY (PYY), leptin, ghrelin and glucagon-like peptide 1 (GLP-1), will be reviewed.

Cognitive behavioral therapy (CBT) including exposure and response prevention is a well-established treatment for obsessive-compulsive disorder (OCD) and is based on the principles of fear extinction. Fear extinction is linked to structural and functional variability in the ventromedial prefrontal cortex (vmPFC) and has been consistently associated with glutamate neurotransmission. The relationship between vmPFC glutamate and fear extinction and its effects on CBT outcome have not yet been explored in adults with OCD. We assessed glutamate levels in the vmPFC using 3T magnetic resonance spectroscopy, and fear extinction (learning and recall) using skin conductance responses during a 2-day experimental paradigm in OCD patients (n = 17) and in healthy controls (HC; n = 13). Obsessive-compulsive patients (n = 12) then received manualized CBT. Glutamate in the vmPFC was negatively associated with fear extinction recall and positively associated with CBT outcome (with higher glutamate levels predicting a better outcome) in OCD patients. Glutamate levels in the vmPFC in OCD patients were not significantly different from those in HC, and were not associated with OCD severity. Our results suggest that glutamate in the vmPFC is associated with fear extinction recall and CBT outcome in adult OCD patients.

Obsessive-compulsive disorder (OCD) has been consistently associated with structural and functional alteration of the orbitofrontal cortex (OFC) and its subcortical connections. In exploring these alterations, a neurodevelopmental basis to OCD has been suggested. While some studies have examined outcomes of early cortical maturation processes, such as global cortical thickness and gyrification, no work has specifically examined the OFC. Within the OFC, three types of sulcogyral patterns have been identified as a result of variance in cortical folding. The distribution of these patterns has been found to differ in patients of various neuropsychiatric disorders relative to the general population, however no study has yet investigated this distribution in individuals with OCD. Eighty OCD patients and 78 healthy controls were evaluated using magnetic resonance imaging, with identification of the sulcogyral pattern based on the method of Chiavaras and Petrides (2000). While gross changes in OFC sulcogyral patterning did not distinguish OCD patients from healthy controls, expression of both the Type II and Type III patterns was significantly associated with increased OCD illness severity. This finding indicates that early neurodevelopmental factors may influence illness severity.

Background: Cognitive regulation can affect the process of decision making. Generalized anxiety disorder (GAD) patients seem to have an impairment in cognitive regulation of reward processing concerning food stimuli. This study aims to explore the impact of GAD in cognitive regulation of food-related rewards. Methods: GAD patients (n=11) and healthy controls (n=15) performed a cognitive regulation craving task with food images while undergoing a functional magnetic resonance imaging (fMRI) acquisition. Between-group differences in functional connectivity were measured using dorsolateral prefrontal cortex (dlPFC) and ventromedial prefrontal cortex (vmPFC) seeds during cognitive regulation. Results: During cognitive regulation, there was a significant interaction for functional connectivity between the right dlPFC and bilateral vmPFC with the thalamus. GAD patients had lower functional connectivity for cognitive regulation conditions (distance and indulge) than for the non-regulated condition in these clusters, while control participants presented the opposite pattern. GAD group presented fixed food valuation scores after cognitive regulation. Conclusions: GAD participants showed inflexibility while valuating food images, that could be produced by cognitive regulation deficits underpinned by functional connectivity alterations between prefrontal regions and the thalamus. These results show cognitive inflexibility and difficulty in the modulation of cognitive responses during decision making in GAD patients.

Imaging studies on neuronal network formation provide relevant information as to how the brain matures during adolescence. We used a novel imaging approach combining well-established MRI measures of local functional connectivity that jointly provide qualitatively different information relating to the functional structure of the cerebral cortex. To investigate the adolescent transition into adulthood, we comparatively assessed 169 preadolescents aged 8-12 years and 121 healthy adults. Whole-brain functional connectivity maps were generated using multi-distance measures of intracortical neural activity coupling defined within iso-distant local areas. Such Iso-Distant Average Correlation (IDAC) measures therefore represent the average temporal correlation of a given brain unit, or voxel, with other units situated at increasingly separated iso-distant intervals. The results indicated that between-group differences in the functional structure of the cerebral cortex are extensive and implicate part of the lateral prefrontal cortex, a medial frontal/anterior cingulate region, the superior parietal lobe extending to the somatosensory strip and posterior cingulate cortex, and local connections within the visual cortex, hippocampus, amygdala and insula. We thus provided detail of the cerebral cortex functional structure maturation during the transition to adulthood, which may serve to establish more accurate links between adolescent performance gains and cerebral cortex maturation. Remarkably, our study provides new information as to the cortical maturation processes in prefrontal areas relevant to executive functioning and rational learning, medial frontal areas playing an active role in the cognitive appraisal of emotion and anxiety, and superior parietal cortices strongly associated with bodily self-consciousness in the context of body image formation. This work was supported in part by the European Research Council under the ERC [grant number 268479] – the BREATHE project and the Carlos III Health Institute grants PI13/01958 and PI16/00889.

Relationships among childhood maltreatment (CM), hypothalamic-pituitary-adrenal (HPA) axis disturbances, major depressive disorder (MDD), poor functionality, and lower quality of life (QoL) in adulthood have been described. We aimed to study the roles of the remission status of depression and HPA axis function in the relationships between CM and functionality and QoL. Ninety-seven patients with MDD and 97 healthy controls were included. The cortisol awakening response, cortisol suppression ratio in the dexamethasone suppression test, and diurnal cortisol slope were assessed. Participants completed measures of psychopathology, CM, functionality, and QoL. Multiple linear regression analyses were performed to study the relationships between CM and functionality and QoL. Only non-remitted MDD patients showed lower functionality and QoL than controls, indicating that depressive symptoms may partly predict functionality and QoL. Cortisol measures did not differ between remitted and non-remitted patients. Although neither HPA axis measures nor depression remission status were consistently associated with functionality or QoL, these factors moderated the effects of CM on functionality and QoL. In conclusion, subtle neurobiological dysfunctions in stress-related systems could help to explain diminished functionality and QoL in individuals with CM and MDD and contribute to the persistence of these impairments even after the remission of depressive symptoms.

Background: Childhood maltreatment (CM) is associated with impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback and cognitive dysfunction, resembling those abnormalities linked to major depressive disorder (MDD). Objectives: We aimed to assess the potential modulating effects of MDD diagnosis or HPA axis function in the association between different types of CM and cognitive performance in adulthood. Methods: Sixty-eight MDD patients and 87 healthy controls were recruited. CM was assessed with the Childhood Trauma Questionnaire. We obtained three latent variables for neuropsychological performance (verbal memory, visual memory and executive function/processing speed) after running a confirmatory factor analysis with cognitive tests applied. Dexamethasone suppression test ratio (DSTR) was performed using dexamethasone 0.25 mg. Results: Different types of CM had different effects on cognition, modulated by MDD diagnosis and HPA axis function. Individuals with physical maltreatment and MDD presented with enhanced cognition in certain domains. The DSTR differentially modulated the association between visual memory and physical neglect or sexual abuse. Conclusions: HPA axis-related neurobiological mechanisms leading to cognitive impairment might differ depending upon the type of CM. Our results suggest a need for early assessment and intervention on cognition and resilience mechanisms in individuals exposed to CM to minimize its deleterious and lasting effects., Summary HIGHLIGHTS • We studied the effects of childhood maltreatment (CM), HPA axis feedback (DST), and depression on cognition. • Different types of CM had a distinct impact on cognitive performance. • MDD diagnosis and DST modulated the association between CM and cognition.

In the last 20 years, functional magnetic resonance imaging (fMRI) has been extensively used to investigate system-level abnormalities in the brain of patients with obsessive-compulsive disorder (OCD). In this chapter, we start by reviewing the studies assessing regional brain differences between patients with OCD and healthy controls in task-based fMRI. Specifically, we review studies on executive functioning and emotional processing, protocols in which these patients have been described to show alterations at the behavioral level, as well as research using symptom provocation protocols. Next, we review studies on brain connectivity alterations, focusing on resting-state studies evaluating disruptions in fronto-subcortical functional connectivity and in cortical networks. Likewise, we also review research on effective connectivity, which, different from functional connectivity, allows for ascertaining the directionality of inter-regional connectivity alterations. We conclude by reviewing the most significant findings on a topic of translational impact, such as the use of different fMRI measurements to predict response across a variety of treatment approaches. Overall, results suggest that there exists a pattern of regions, involving, but not limited to, different nodes of the cortico-striatal-thalamo-cortical circuits, showing robust evidence of functional alteration across studies, although the nature of the alterations critically depends on the specific tasks and their particular demands. Moreover, such findings have been, to date, poorly translated into clinical practice. It is suggested that this may be partially accounted for by the difficulty to integrate into a common framework results obtained under a wide variety of analysis approaches.

Special Issue: The ENIGMA Consortium: the first 10 years.-- Karolinska Schizophrenia Project (KaSP)., Age has a major effect on brain volume. However, the normative studies available are constrained by small sample sizes, restricted age coverage and significant methodological variability. These limitations introduce inconsistencies and may obscure or distort the lifespan trajectories of brain morphometry. In response, we capitalized on the resources of the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to examine age-related trajectories inferred from cross-sectional measures of the ventricles, the basal ganglia (caudate, putamen, pallidum, and nucleus accumbens), the thalamus, hippocampus and amygdala using magnetic resonance imaging data obtained from 18,605 individuals aged 3–90 years. All subcortical structure volumes were at their maximum value early in life. The volume of the basal ganglia showed a monotonic negative association with age thereafter; there was no significant association between age and the volumes of the thalamus, amygdala and the hippocampus (with some degree of decline in thalamus) until the sixth decade of life after which they also showed a steep negative association with age. The lateral ventricles showed continuous enlargement throughout the lifespan. Age was positively associated with inter-individual variability in the hippocampus and amygdala and the lateral ventricles. These results were robust to potential confounders and could be used to examine the functional significance of deviations from typical age-related morphometric patterns., National Institute of Mental Health, Grant/Award Numbers: MH104284, MH116147, R01MH113619, R01 MH090553, R01MH117014, R01MH042191; Karolinska Institutet; Stockholm County Council; Southern and Eastern Norway Regional Health Authority; German Centre for Cardiovascular Research; DZHK; Siemens Healthineers; University of Queensland; US National Institute of Child Health and Human Development, Grant/Award Number: RO1HD050735; Australian National Health and Medical Research Council; Eunice Kennedy Shriver National Institute of Child Health & Human Development; National Institute on Drug Abuse, Grant/Award Numbers: UL1 TR000153, 1 U24 RR025736-01, 1 U24 RR021992; Brain Injury Fund Research Grant Program; Indiana State Department of Health Spinal Cord; Parents Against Childhood Epilepsy; Epilepsy Therapy Project, Fight Against Childhood Epilepsy and Seizures; Epilepsy Foundation; American Epilepsy Society; Knut and Alice Wallenberg Foundation; European Community's Horizon 2020 Programme; Vici Innovation Program; NWO Brain & Cognition Excellence Program; Netherlands Organization for Scientific Research; Hersenstichting Nederland; Netherlands Organization for Health Research and Development; Geestkracht Programme of the Dutch Health Research Council, Grant/Award Number: 10-000-1001; Universiteit Utrecht; FP7 Ideas: European Research Council; Nederlandse Organisatie voor Wetenschappelijk Onderzoek; National Center for Advancing Translational Sciences; National Institutes of Health; National Center for Research Resources; Consortium grant, Grant/Award Number: U54 EB020403; U.S. National Institutes of Health, Grant/Award Numbers: R01 CA101318, P30 AG10133, R01 AG19771; Medical Research Council, Grant/Award Number: G0500092; Fundación Instituto de Investigación Marqués de Valdecilla, Grant/Award Numbers: API07/011, NCT02534363, NCT0235832; Instituto de Salud Carlos III, Grant/Award Numbers: PI14/00918, PI14/00639, PI060507, PI050427, PI020499; the Research Council, Grant/Award Number: 223273; South Eastern Norway Regional Health Authority, Grant/Award Numbers: 2017-112, 2019107; Swedish Research Council; European Community's Seventh Framework Programme, Grant/Award Number: 602450; King's College London; South London and Maudsley NHS Foundation Trust; Biomedical Research Centre; National Institute for Health Research.

Background The locus coeruleus (LC) is the major noradrenergic source in the central nervous system. Structural alterations in the LC contribute to the pathophysiology of different neuropsychiatric disorders, which may increase to a variable extent the likelihood of developing neurodegenerative conditions. The characterization of such alterations may therefore help to predict progression to neurodegenerative disorders. Despite the LC cannot be visualized with conventional magnetic resonance imaging (MRI), specific MRI sequences have been developed to infer its structural integrity. Methods We quantified LC signal Contrast Ratios (LCCRs) in late-life major depressive disorder (MDD) (n = 37, 9 with comorbid aMCI), amnestic Mild Cognitive Impairment (aMCI) (n = 21, without comorbid MDD), and healthy controls (HCs) (n = 31), and also assessed the putative modulatory effects of comorbidities and other clinical variables. Results LCCRs were lower in MDD compared to aMCI and HCs. While no effects of aMCI comorbidity were observed, lower LCCRs were specifically observed in patients taking serotonin/norepinephrine reuptake inhibitors (SNRIs). Conclusion Our results do not support the hypothesis that lower LCCRs characterize the different clinical groups that may eventually develop a neurodegenerative disorder. Conversely, our results were specifically observed in patients with late-life MDD taking SNRIs. Further research with larger samples is warranted to ascertain whether medication or particular clinical features of patients taking SNRIs are associated with changes in LC neurons.

Background Sleep disturbances have been reported in obsessive-compulsive disorder (OCD) patients, with heterogeneous results. The aim of our study was to assess sleep function in OCD and to investigate the relationship between sleep and the severity of obsessive-compulsive (OC) symptoms, depressive symptoms and trait anxiety. Methods Sleep quality was measured in 61 OCD patients and 100 healthy controls (HCs) using the Pittsburgh Sleep Quality Index (PSQI). Multiple linear regression was conducted to explore the association between sleep and psychopathological measures; a mediation analysis was also performed. Results OCD patients showed poor sleep quality and more sleep disturbances compared to HCs. The severity of depression, trait anxiety and OC symptomatology were correlated with poor sleep quality. Multiple linear regression analyses controlling for potential confounders revealed that the severity of depression and trait anxiety were independently related to poor sleep quality in OCD. A mediation analysis showed that both the severity of trait anxiety and depression mediate the relationship between the severity of OC symptoms and poor sleep quality among patients with OCD. Conclusions Our findings support the existence of sleep disturbances in OCD. Trait anxiety and depression play a key role in sleep quality among OCD patients.

Dopamine‐replacing therapies are an effective treatment for the motor aspects of Parkinson's disease. However, its precise effect over the cognitive resting‐state networks is not clear; whether dopaminergic treatment normalizes their functional connectivity‐as in other networks‐ and the links with cognitive decline are presently unknown. We recruited 35 nondemented PD patients and 16 age‐matched controls. Clinical and neuropsychological assessments were performed at baseline, and conversion to dementia was assessed in a 10 year follow‐up. Structural and functional brain imaging were acquired in both the ON and practical OFF conditions. We assessed functional connectivity in both medication states compared to healthy controls, connectivity differences within participants related to the ON/OFF condition, and baseline connectivity of PD participants that converted to dementia compared to those who did not convert. PD participants showed and increased frontoparietal connectivity compared to controls: a pattern of higher connectivity between salience (SN) and default‐mode (DMN) networks both in the ON and OFF states. Within PD patients, this higher SN‐DMN connectivity characterized the participants in the ON state, while within‐DMN connectivity prevailed in the OFF state. Interestingly, participants who converted to dementia also showed higher SN‐DMN connectivity in their baseline ON scans compared to nonconverters. To conclude, PD patients showed higher frontoparietal connectivity in cognitive networks compared to healthy controls, irrespective of medication status, but dopaminergic treatment specifically promoted SN‐DM hyperconnectivity., In this work, Aracil‐Bolaños et al. investigate the effects of dopaminergic treatment over the large‐scale cognitive networks of nondemented Parkinson's disease patients and healthy controls. Baseline frontoparietal connectivity was higher in Parkinson's disease than in controls irrespective of medication, but dopaminergic treatment within patients specifically promoted salience network connectivity.

Autobiographical memory (AM) has been largely investigated as the ability to recollect specific events that belong to an individual's past. However, how we retrieve real-life routine episodes and how the retrieval of these episodes changes with the passage of time remain unclear. Here, we asked participants to use a wearable camera that automatically captured pictures to record instances during a week of their routine life and implemented a deep neural network-based algorithm to identify picture sequences that represented episodic events. We then asked each participant to return to the lab to retrieve AMs for single episodes cued by the selected pictures 1 week, 2 weeks and 6–14 months after encoding while scalp electroencephalographic (EEG) activity was recorded. We found that participants were more accurate in recognizing pictured scenes depicting their own past than pictured scenes encoded in the lab, and that memory recollection of personally experienced events rapidly decreased with the passing of time. We also found that the retrieval of real-life picture cues elicited a strong and positive ‘ERP old/new effect’ over frontal regions and that the magnitude of this ERP effect was similar throughout memory tests over time. However, we observed that recognition memory induced a frontal theta power decrease and that this effect was mostly seen when memories were tested after 1 and 2 weeks but not after 6–14 months from encoding. Altogether, we discuss the implications for neuroscientific accounts of episodic retrieval and the potential benefits of developing individual-based AM exploration strategies at the clinical level., This work was supported by Ministerio de Ciencia e Innovación, which is part of Agencia Estatal de Investigación, through the project PSI2016-80489-P and PID2019-111199GB-I00 (Co-funded by European Regional Development Fund. ERDF, a way to build Europe) and by ICREA Academia, to L.F. P.R. is supported by TIN2018-095232-B-C21, SGR-2017 1742, Greenhabit EIT Digital program. We thank CERCA Programme/Generalitat de Catalunya for institutional support. We thank the Editor and two anonymous reviewers for their constructive criticisms, remarks and advices.

Integrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks. The study was supported by Fundació Lluita Contra la SIDA (FLS-ANT 2015-01). IMZ was supported by a P-FIS grant (FI17/00294) and CSM by a Miguel Servet contract (CPII16/00048) from the Instituto de Salud Carlos III. NPA was partially supported by grants MTM2015-64465-C2-1-R (MINECO/FEDER) and 2017 SGR 622 (GRBIO)

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in the central nervous system and is involved intensively in modulating pain and stress-related disorders (e.g., major depressive disorder and anxiety) and in their comorbidity. However, the mechanisms involving the LC that underlie these effects have not been fully elucidated, in part owing to the technical difficulties inherent in exploring such a tiny nucleus. However, novel research tools are now available that have helped redefine the LC system, moving away from the traditional view of LC as a homogeneous structure that exerts a uniform influence on neural activity. Indeed, innovative techniques such as DREADDs (designer receptors exclusively activated by designer drugs) and optogenetics have demonstrated the functional heterogeneity of LC, and novel magnetic resonance imaging applications combined with pupillometry have opened the way to evaluate LC activity in vivo. This review aims to bring together the data available on the efferent activity of the LC-noradrenergic system in relation to pain and its comorbidity with anxiodepressive disorders. Acute pain triggers a robust LC stress response, producing spinal cord-mediated endogenous analgesia while promoting aversion, vigilance, and threat detection through its ascending efferents. However, this protective biological system fails in chronic pain, and LC activity produces pain facilitation, anxiety, increased aversive memory, and behavioral despair, acting at the medulla, prefrontal cortex, and amygdala levels. Thus, the activation/deactivation of specific LC projections contributes to different behavioral outcomes in the shift from acute to chronic pain.

In the last 20 years, functional magnetic resonance imaging (fMRI) has been extensively used to investigate system-level abnormalities in the brain of patients with obsessive-compulsive disorder (OCD). In this chapter, we start by reviewing the studies assessing regional brain differences between patients with OCD and healthy controls in task-based fMRI. Specifically, we review studies on executive functioning and emotional processing, protocols in which these patients have been described to show alterations at the behavioral level, as well as research using symptom provocation protocols. Next, we review studies on brain connectivity alterations, focusing on resting-state studies evaluating disruptions in fronto-subcortical functional connectivity and in cortical networks. Likewise, we also review research on effective connectivity, which, different from functional connectivity, allows for ascertaining the directionality of inter-regional connectivity alterations. We conclude by reviewing the most significant findings on a topic of translational impact, such as the use of different fMRI measurements to predict response across a variety of treatment approaches. Overall, results suggest that there exists a pattern of regions, involving, but not limited to, different nodes of the cortico-striatal-thalamo-cortical circuits, showing robust evidence of functional alteration across studies, although the nature of the alterations critically depends on the specific tasks and their particular demands. Moreover, such findings have been, to date, poorly translated into clinical practice. It is suggested that this may be partially accounted for by the difficulty to integrate into a common framework results obtained under a wide variety of analysis approaches.

The high comorbidity of Major Depressive Disorder (MDD), Anxiety Disorders (ANX), and Posttraumatic Stress Disorder (PTSD) has hindered the study of their structural neural correlates. The authors analyzed specific and common grey matter volume (GMV) characteristics by comparing them with healthy controls (HC). The meta-analysis of voxel-based morphometry (VBM) studies showed unique GMV diminutions for each disorder (p < 0.05, corrected) and less robust smaller GMV across diagnostics (p < 0.01, uncorrected). Pairwise comparison between the disorders showed GMV differences in MDD versus ANX and in ANX versus PTSD. These results endorse the hypothesis that unique clinical features characterizing MDD, ANX, and PTSD are also reflected by disorder specific GMV correlates.

[Background]: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms., [Methods]: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms., [Results]: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms., [Conclusions]: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation., This study has been funded by the Project Grant IRONMET (PI15/01934) from the ISCIII, and the Project ThinkGut (EFA345/19) 65% co-financed by the European Regional Development Fund (ERDF) through the Interreg V-A Spain-France-Andorra program (POCTEFA 2014–2020) (JM Fernández-Real). Partial support was also obtained by the Ministerio de Economia y Competitividad, Spain, reference MTM2015-64465-C2-1-R (ML Calle). O Contreras-Rodriguez is funded by a “PERIS” postdoctoral fellowship (SLT006/17/00236) from the Health Department of the Catalan Government and by a “Miguel Servet” contract (CP20/00165) from the ISCIII. M Arnoriaga-Rodríguez is funded by a predoctoral Rio Hortega contract (CM19/00190) co-funded by European Social Fund “Investigating in your future” from the ISCIII.

Fil: Wainsztein, Agustina E. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Wainsztein, Agustina E. Fundación FLENI. Servicio de Psiquiatría; Argentina Fil: Castro, Mariana N. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Psiquiatría y Salud Mental; Argentina Fil: Castro, Mariana N. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Castro, Mariana N. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Fisiología; Argentina Fil: Goldberg, Ximena. Universitat Autònoma de Barcelona. Institut d'Investigació i Innovació Parc Taulí I3PT. Hospital Universitario Parc Taulí. Área de Investigación en Neurociencias y Salud Mental. Departamento de Salud Mental; España Fil: Camacho-Téllez, Vicente. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Camacho-Téllez, Vicente. Fundación FLENI. Servicio de Psiquiatría; Argentina Fil: Camacho-Téllez, Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Vulcano, Mercedes. Fundación FLENI. Servicio de Psiquiatría; Argentina Fil: Vulcano, Mercedes. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Psiquiatría y Salud Mental; Argentina Fil: Abulafia, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Abulafia, Carolina Andrea. Pontificia Universidad Católica Argentina. Instituto de Investigaciones Biomédicas; Argentina Fil: Abulafia, Carolina Andrea. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Ladrón de Guevara, M. Soledad. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Ladrón de Guevara, M. Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Cardoner, Narcís. Universitat Autònoma de Barcelona. Institut d'Investigació i Innovació Parc Taulí I3PT. Hospital Universitario Parc Taulí. Área de Investigación en Neurociencias y Salud Mental. Departamento de Salud Mental; España Fil: Nemeroff, Charles B.Universidad de Texas en Austin. Institute for Early Life Adversity Research, Dell Medical School; Estados Unidos Fil: Menchón, José M. Hospital Universitario de Bellvitge. Departamento de Psiquiatría. Instituto de Investigación Biomédica de Bellvitge-IDIBELL; España Fil: Soriano-Mas, Carles. Universidad de Texas en Austin. Institute for Early Life Adversity Research, Dell Medical School; Estados Unidos Fil: Villarreal, Mirta F. Instituto de Neurociencias FLENI-CONICET. Grupo de Investigación en Neurociencias Aplicadas a las Alteraciones de la Conducta; Argentina Fil: Villarreal, Mirta F. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Villarreal, Mirta F. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Física; Argentina Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Salud Mental; Argentina Fil: Guinjoan, Salvador M. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Guinjoan, Salvador M. Laureate Institute for Brain Research; Estados Unidos Fil: Guinjoan, Salvador M. Universidad de Buenos Aires. Facultad de Psicología; Argentina Abstract: Adverse childhood experiences (ACEs) have lifelong effects on emotional behavior and are frequent in Borderline Personality Disorder (BPD) and Major Depressive Disorder (MDD). The Central Autonomic Network (CAN), which modulates heart rate variability (HRV), comprises brain regions that mediate emotion regulation processes. However, it remains unclear the effect of ACEs on CAN dynamics and its relationship with HRV in these disorders. We studied the effects of ACEs on the brain and HRV simultaneously, during regulation of psychological stress in 19 BPD, 20 MDD and 20 healthy controls (HC). Participants underwent a cognitive reappraisal task during fMRI with simultaneous ECG acquisition. ACEs exposure was associated with increased activity of CAN and salience network components in patients with MDD compared to BPD during cognitive reappraisal. A brain-autonomic coupling was found in BPD relative to HC during emotion regulation, whereby greater activity of left anterior cingulate and medial superior frontal gyrus areas was coupled with increased HRV. Results suggest that ACEs exposure is associated with a distinct activation of the CAN and salience network regions governing responses to psychological stress in MDD compared to BPD. These alterations may constitute a distinctive neurobiological mechanism for abnormal emotion processing and regulation related to ACEs in MDD.

Recent neurobiological models of obsessive-compulsive disorder (OCD) have highlighted the potential role of abnormalities in fear learning processes. We compared brain activation -as assessed with whole-brain functional magnetic resonance imaging- during fear conditioning, fear extinction learning, and fear extinction recall in patients with OCD (n = 18) and healthy controls (n = 18). We also investigated whether brain activation during any of these processes was associated with exposure-based cognitive-behavioral therapy (CBT) outcome in patients. Patients with OCD showed significantly lower brain activation in the right insulo-opercular region and the dorsal anterior cingulate cortex during fear conditioning in comparison to healthy controls. Moreover, brain activation in the right insula predicted CBT outcome, with lower activation predicting a better outcome. Brain activation during extinction learning or recall did not differ between patients and controls or predicted CBT outcome in patients. Our results suggest that neural activations during fear conditioning in patients with OCD are abnormal and predict CBT outcome.

Non-Invasive Brain Stimulation (NIBS) techniques and in particular, repetitive Transcranial Magnetic Stimulation (rTMS), are developing beyond mere clinical application. Although originally purposed for the treatment of resistant neuropsychiatric disorders, NIBS is also contributing to a deeper understanding of psychiatric disorders. rTMS is also changing the model of the disorder itself, from "mental" to one of neural connectivity. TMS allows the assessment of brain circuit excitability and eventually, of plastic changes affecting these circuits. While a clinical translational approach is, at the present time, the most adequate to meet the dimensional-circuit base model of the disorder, it refines the standard categorical classification of psychiatric disorders. The discovery of the fundamental importance of the balance between neuroplasticity and inflammation is also now explored through neuro-modulation findings consistently with the evidence of anti-inflammatory actions of the magnetic pulses. rTMS may activate, inhibit, or otherwise interfere with the activity of neuronal cortical networks, depending on stimulus frequency and intensity of brain-induced electric field. Of particular interest, yet still unclear, is how the relatively unspecific nature of TMS stimulation may lead to specific neuronal reorganization, as well as a definition of the TMS-triggered reorganization of functional brain modules, raising attention on the importance of the active participation of the patient to the treatment.. Configuration and state of consciousness of the subject have made subjective experience under treatment regain importance in the neuro-scientific Psychiatry based on the requirement of United States National Institute of Health (NIH) and the substantial importance of the consciousness state in the efficacy of the TMS treatment. By focusing on the subjective experience, a renaissance of the phenomenology offers Psychiatry an opportunity to become proficient and to distinguish itself from other disciplines. For all these reasons, TMS should be included in the cluster of the sub-specialties as a new "Super-Specialty" and an appropriate training course has to be inaugurated. Psychiatrists are nowadays multi-specialists, moving from a specialty to another, vs super-specialist. The cultivation of a properly trained cohort of TMS psychiatrists will better meet the challenges of treatment-resistant psychiatric conditions (disorders of connectivity), through appropriate and ethical practice, meanwhile facilitating an informed development and integration of additional emerging neuro-modulation techniques. The aim of this consensus paper is to underline the interdisciplinary nature of NIBS, that also encompasses the subjective experience and to point out the necessity of a neuroscience-applied approach to NIBS in the context of the European College of Neuro-psychopharmacology (ECNP).

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of “big data” (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA’s activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material.

ObjectiveNo diagnostic biomarkers are available for obsessive-compulsive disorder (OCD). Magnetic resonance imaging (MRI) studies have provided evidence for structural abnormalities in distinct brain regions, but effect sizes are small and have limited clinical relevance. To investigate whether individual patients can be distinguished from healthy controls, we performed multivariate analysis of structural neuroimaging data from the ENIGMA-OCD consortium.MethodWe included 46 data sets with neuroimaging and clinical data from adult (≥18 years) and pediatric (1images from 2,304 OCD patients and 2,068 healthy controls were analyzed using standardized processing to extract regional measures of cortical thickness, surface area and subcortical volume. Machine learning classification performance was tested using cross-validation, and possible effects of clinical variables were investigated by stratification.ResultsClassification performance for OCD versus controls using the complete sample with different classifiers and cross-validation strategies was poor (AUC—0.57 (standard deviation (SD)=0.02;Pcorr=0.19) to 0.62 (SD=0.03;Pcorrcorr>.99) to 0.54 (SD=0.08;Pcorr>.99)). In contrast, good classification performance (>0.8 AUC) was achieved within subgroups of patients split according to their medication status.ConclusionsParcellated structural MRI data do not enable good distinction between patients with OCD and controls. However, classifying subgroups of patients based on medication status enables good identification at the individual subject level. This underlines the need for longitudinal studies on the short- and long-term effects of medication on brain structure.

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

Seasonal changes in mood and diurnal preference are two well-characterized chronobiological phenotypes in major depressive disorder (MDD) and bipolar disorder (BD). The biological mechanisms regulating physiological changes related to seasonality and chronotype involve several genes known as "clock" or circadian genes. Our goal was to study the relationship between the polygenic risk score (PRS) obtained from a set of clock genes and chronobiological traits in patients with mood disorders. The sample included 445 patients with mood disorders (256 MDD; 189 BD). Seasonality was assessed using the Seasonal Pattern Assessment Questionnaire (SPAQ), and chronotype was assessed using the Horne and Östberg Morningness-Eveningness Questionnaire. We selected 248 single nucleotide polymorphisms located within 19 genes. PRS for both MDD and BD was calculated using the Psychiatric Genetics Consortium latest datasets as discovery samples. Another PRS was calculated using results from a genome-wide association study focusing on chronotype. SPAQ results were significantly associated with MDD-PRS (p = 0.037) and chronotype-PRS (p = 0.019), which also showed a significant interaction with age (p = 0.039). No significant association was observed between the measured PRS and chronotype. Our results reflect that small effect variants associated with MDD and chronotype within clock genes are associated with seasonality traits in patients with mood disorders, further explaining the mechanism through which the circadian system might influence mood disorder clinical presentation. Future studies measuring PRS from specific gene sets and focusing on biological endophenotypes will help to elucidate the pathways from genetic variations to clinical outcome.

Accepted Manuscript, 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 = -20.21). 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., This research was funded by the Max Planck Society (Germany). Additional funding was from the Japan Society for the Promotion of Science (KAKENHI Grant No. 18K15523 [to YA], KAKENHI Grant No. 16K04344 [to YH], KAKENHI Grant Nos. 16K19778 and 18K07608 [to TNakam], and KAKENHI Grant No. 26461762 [to AN]); the Carlos III Health Institute (Grant No. PI14/00419 [to PA], Grant No. PI040829 cofunded by European Regional Development Fund [to LL], Grant No. FI17/00294 [to IM-Z], Grant No. PI16/00950 [to JMM], and Grant Nos. CPII16/00048, PI13/01958, and PI16/00889 cofunded by European Regional Development Funds [to CS-M]); the Ontario Mental Health Foundation (Research Training Fellowship [to SHA]); Alberta Innovates Translational Health Chair in Child and Youth Mental Health (to PDA), the Ontario Brain Institute (to PDA); the National Institute of Mental Health (Grant No. K23MH104515 [to JTB], Grant No. K23-MH092397 [to BPB], Grant No. K23MH082176 [to KDF), Grant No. R21MH101441 [to RM], Grant No. R01MH081864 [to JO and JP], and Grant No. R01MH085900 [to JO and JF], Grant No. R21MH093889 [to HBS]); Fundação de Amparo à Pesquisa do Estado de São Paulo (Grant No. 2011/21357–9 [to MCB], Grant No. 2011/21357–9 [to GFB], Grant No. 2011/21357–9 [to MQH], and Grant No. 2011/21357–9 [to ECM]); the Swiss National Science Foundation (Grant No. 320030_130237 [to SB; principal investigator, Susanne Walitza]); the Hartmann Müller Foundation (Grant No. 1460 [to SB]); the David Judah Fund at the Massachusetts General Hospital (to BPB); EU FP7 Project TACTICS (Grant No. 278948 [to JB]); the National Natural Science Foundation of China (Grant No. 81560233 [to YC] and Grant No. 81371340 [to ZW]); the International OCD Foundation (Grant No. K23 MH115206 [to PG]); the Wellcome Sir Henry Dale Fellowship (Grant No. 211155/Z/18/Z [to TUH]); the Jacobs Foundation (to TUH); the Brain and Behavior Research Foundation (2018 NARSAD Young Investigator Grant No. 27023 [to TUH]); the Agency for Medical Research and Development (Grant No. JP18dm0307002 [to YH]); the Michael Smith Foundation for Health Research (to FJ-F); the Federal Ministry of Education and Research of Germany (Grant No. BMBF-01GW0724 [to NK]); the Deutsche Forschungsgemeinschaft (Grant No. KO 3744/7–1 [to KK]); the Helse Vest Health Authority (Grant Nos. 911754 and 911880 [to GK]); the Norwegian Research Council (Grant No. HELSEFORSK 243675 [to GK]); the Marató TV3 Foundation (Grant Nos. 01/2010 and 091710 [to LL]); the Agency for Management of University and Research Grants (Grant No. 2017 SGR 881 [to LL] and 2017 SGR 1247 from the Generalitat de Catalunya [to JMM]); Fundação para a Ciência e a Tecnologia (Grant No. PDE/BDE/113604/2015 from the PhD-iHES Program [to RM], Grant No. PDE/BDE/113601/2015 from the PhD-iHES Program [to PSM]); the Japanese Ministry of Education, Culture, Sports, Science and Technology (Grant-in-Aid for Scientific Research (Grant Nos. 22591262, 25461732, and 16K10253 [to TNakao]); the Government of India Department of Science and Technology (DST INSPIRE Faculty Grant No. -IFA12-LSBM-26 [to JCN] and Grant No. SR/S0/HS/0016/2011 [to YCJR]); the Government of India Department of Biotechnology (Grant No. BT/06/IYBA/2012 [to JCN] and Grant No. BT/PR13334/Med/30/259/2009 [to YCJR]); the New York State Office of Mental Health (to HBS); the Italian Ministry of Health (Grant No. RC13-14-15-16A [to GS]); the National Center for Advancing Translational Sciences (Grant No. UL1TR000067/KL2TR00069 [to ERS]); the Canadian Institutes of Health Research (to SES); the Michael Smith Foundation for Health Research (to SES); the British Columbia Provincial Health Services Authority (to SES); the Netherlands Organization for Scientific Research (Grant No. NWO/ZonMW Vidi 917.15.318 [to GAvW]); the Wellcome-DBT India Alliance (Grant No. 500236/Z/11/Z [to GV]); the Shanghai Key Laboratory of Psychotic Disorders (Grant No. 13dz2260500 [to ZW]).

Obsessive-compulsive disorder (OCD) has been associated with a wide range of biological and neurocognitive findings, which could assist in the search for biomarkers. We conducted an umbrella review of systematic reviews and meta-analyses to assess and grade the strength of the evidence of the association between OCD and several potential diagnostic biomarkers while controlling for several potential biases. Twenty-four systematic reviews and meta-analyses were included, comprising 352 individual studies, more than 10,000 individuals with OCD, and covering 73 potential biomarkers. OCD was significantly associated with several neurocognitive biomarkers, with varying degrees of evidence, ranging from weak to convincing. A number of biochemical, neurophysiological, and neuroimaging biomarkers also showed statistically significant, albeit weak, associations with OCD. Analyses in unmedicated samples (123 studies) weakened the strength of the evidence for most biomarkers or rendered them non-significant. None of the biomarkers seem to have sufficient sensitivity and specificity to become a diagnostic biomarker. A more promising avenue for future biomarker research in OCD might be the prediction of clinical outcomes rather than diagnosis.