Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by social atypicalities and repetitive behaviors. Growing evidence suggests that alterations in brain networks may contribute to ASD symptoms. The cerebellum, with its widespread connections to the cortex, has emerged as a potential key player in ASD. Non-invasive neuromodulation techniques, such as transcranial direct current stimulation (tDCS) or repetitive transcranial magnetic stimulation (rTMS) offer a promising avenue for modulating brain activity and potentially alleviating ASD symptoms. In addition, preclinical studies in rodents further emphasize the therapeutic effect of cerebellar stimulation to target autism-related symptoms. This article reviews both clinical and preclinical studies aiming to modulate cerebellar circuits to improve symptoms of ASD. We found ten relevant studies assessing the effect of cerebellar neuromodulation in human and preclinical models. Posterior cerebellar tDCS represented the most frequent neuromodulation method and suggested that cerebellar tDCS can lead to improvements in symptoms of ASD and restore cerebellar connectivity in individuals with ASD. In neurotypical participants, there is evidence that cerebellar tDCS can enhance social cognitive abilities. These results are in line with preclinical studies, suggesting that chemogenetic stimulation can modulate cerebellar circuits involved in ASD and improve related behaviors. Further research is needed to establish standardized protocols, assess long-term effects, and investigate the underlying mechanisms of cerebellar stimulation. We examine research questions that need to be addressed before launching large scale randomized clinical trials.

Transcranial Direct Current Stimulation (tDCS) has shown potential in modulating cortical activity and treating depression. Despite its promise, variability in electrode montage configurations and electric field strength across studies has resulted in inconsistent outcomes. Traditional meta-analytic methods assessing the effect of tDCS in depression typically do not compare tDCS montage and the anatomical distribution of electric field, which is a major source of inter-experimental variability. We hypothesize that considering these parameters and anatomical variability in a meta-analysis might unravel brain regions associated with tDCS response in patients with depression. We correlate the clinical outcome (Effect size) with electric field intensities across 8 diverse head models, analyzing data from 29 studies involving 1766 patients between 2000 and 2023. Our analysis found a significant effect of tDCS on depression, with a Hedge's g = 0.66 (95 % CI: 0.565 to 0.767). Although studies aimed to target the L-DLPFC, particularly Brodmann area (BA) 46, based on the Frontal Brain Asymmetry theory, our findings show that all the montages do not selectively target the L-DLPFC as intended. Instead, our findings indicated that the electric field impact was dispersing broadly across the frontal lobes and exhibiting significant heterogeneity. We found a correlation between electric field strength and clinical outcomes in BA 10, BA 11, and the anterior part of BA 46 despite tDCS montages heterogeneity and individual variability, suggesting that targeting frontopolar prefrontal and orbitofrontal cortices could be ideal for tDCS in treating depression. Our work underscores brain regions associated with tDCS response and highlights the need for simulation-guided, personalized trials that consider individual anatomical differences.

The cerebellum has been involved in social abilities and autism. Given that the cerebellum is connected to the cortex via the cerebello-thalamo-cortical loop, the connectivity between the cerebellum and cortical regions involved in social interactions, that is, the right temporo-parietal junction (rTPJ) has been studied in individuals with autism, who suffer from prototypical deficits in social abilities. However, existing studies with small samples of categorical, case-control comparisons have yielded inconsistent results due to the inherent heterogeneity of autism, suggesting that investigating how clinical dimensions are related to cerebellar-rTPJ functional connectivity might be more relevant. Therefore, our objective was to study the functional connectivity between the cerebellum and rTPJ, focusing on its association with social abilities from a dimensional perspective in a transdiagnostic sample. We analyzed structural magnetic resonance imaging (MRI) and functional MRI (fMRI) scans obtained during naturalistic films watching from a large transdiagnostic dataset, the Healthy Brain Network (HBN), and examined the association between cerebellum-rTPJ functional connectivity and social abilities measured with the social responsiveness scale (SRS). We conducted univariate seed-to-voxel analysis, multivariate canonical correlation analysis (CCA), and predictive support vector regression (SVR). We included 1404 subjects in the structural analysis (age: 10.516 ± 3.034, range: 5.822-21.820, 506 females) and 414 subjects in the functional analysis (age: 11.260 ± 3.318 years, range: 6.020-21.820, 161 females). Our CCA model revealed a significant association between cerebellum-rTPJ functional connectivity, full-scale IQ (FSIQ) and SRS scores. However, this effect was primarily driven by FSIQ as suggested by SVR and univariate seed-to-voxel analysis. We also demonstrated the specificity of the rTPJ and the influence of structural anatomy in this association. Our results suggest that there is a complex relationship between cerebellum-rTPJ connectivity, social performance and IQ. This relationship is specific to the cerebellum-rTPJ connectivity, and is largely related to structural anatomy in these two regions. PRACTITIONER POINTS: We analyzed cerebellum-right temporoparietal junction (rTPJ) connectivity in a pediatric transdiagnostic sample. We found a complex relationship between cerebellum and rTPJ connectivity, social performance and IQ. Cerebellum and rTPJ functional connectivity is related to structural anatomy in these two regions.

Over the past three decades, non-invasive brain stimulation (NIBS) techniques have gained worldwide attention and demonstrated therapeutic potential in various medical fields, particularly psychiatry. The emergence of these novel techniques has led to an increased need for robust training programs to provide practitioners, whether clinicians or scientists, with the necessary skills and knowledge. In response, a comprehensive training curriculum for NIBS in psychiatry has been developed in France. This curriculum was developed by a group of researchers and psychiatrists interested in the clinical application of NIBS in psychiatry, called STEP - Stimulation Transcranienne en Psychiatrie, under the auspices of the French Association of Biological Psychiatry. This perspective outlines the development and implementation of this course, tracing its inception, the evolution of the program, and the challenges encountered along the way. The position of the course in the national and international environment and its future prospects are also discussed. Through this perspective, we aim to summarize the collaborative efforts to promote NIBS teaching and research in French psychiatry.

Abstract Background With 11,558 deaths and 200,000 suicide attempts in 2019, France is among the European countries most affected. The aim of this study was to determine the costs and burden of suicides and suicide attempts in France (population 67 million). Methods We estimated direct costs, comprising healthcare, as well as post-mortem costs including autopsy, body removal, funeral expenses, police intervention and support groups; indirect costs comprised lost productivity, daily allowances; the burden of disease calculations used a monetary value for death and disability based on incidence data. Data was obtained from the national statistics, health and social care database, registries, global burden of disease, supplemented by expert opinion. We combined top down and bottom up approaches. Results The total costs and burden of suicides and suicide attempts was estimated at €18.5 billion and €5.4 billion, respectively. Direct costs were €566 million and €75 million; indirect costs were €3.8 billion and €3.5 billion; monetary value for death and disability was €14.6 billion and €1.3. The monetary value for death and disability represented 79.1% and 24.8% of total costs for suicide and suicide attempt respectively. Some costs were based upon expert opinion, caregivers’ burden was not counted and pre COVID data only is reported. Conclusions In France, the total cost and burden of suicides and suicide attempts was several billion €, suggesting major potential savings from public health interventions.

Abstract Background The cerebellum contains more than 50% of all neurons in the brain and is involved in a broad range of cognitive functions, including social communication and social cognition. Inconsistent atypicalities in the cerebellum have been reported in individuals with autism compared to controls suggesting the limits of categorical case control comparisons. Alternatively, investigating how clinical dimensions are related to neuroanatomical features, in line with the Research Domain Criteria approach, might be more relevant. We hypothesized that the volume of the “cognitive” lobules of the cerebellum would be associated with social difficulties. Methods We analyzed structural MRI data from a large pediatric and transdiagnostic sample (Healthy Brain Network). We performed cerebellar parcellation with a well-validated automated segmentation pipeline (CERES). We studied how social communication abilities—assessed with the social component of the Social Responsiveness Scale (SRS)—were associated with the cerebellar structure, using linear mixed models and canonical correlation analysis. Results In 850 children and teenagers (mean age 10.8 ± 3 years; range 5–18 years), we found a significant association between the cerebellum, IQ and social communication performance in our canonical correlation model. Limitations Cerebellar parcellation relies on anatomical boundaries, which does not overlap with functional anatomy. The SRS was originally designed to identify social impairments associated with autism spectrum disorders. Conclusion Our results unravel a complex relationship between cerebellar structure, social performance and IQ and provide support for the involvement of the cerebellum in social and cognitive processes.

Introduction The cerebellum, most known for its role in motor control, exerts a key role in cognition. Multiple lines of evidence across human functional, lesion and animal data point to a role of the cerebellum, in particular of Crus I, Crus II and Lobule VIIB, in cognitive function. However, whether cerebellar substrates pertaining to distinct facets of cognitive function exist is not known. Methods We analyzed structural neuroimaging data from the Healthy Brain Network (HBN). Cerebellar parcellation was performed via a standard validated automated segmentation pipeline (CERES) with stringent visual quality check (n = 662 subjects retained from initial n = 1452). We used data-driven canonical correlation analyses (CCA) to examine regional gray matter volumetric (GMV) differences in association to cognitive function assessed with the NIH Toolbox Cognition Domain (NIH-TB). Our multivariate analyses accounted for psychopathology severity, age, sex, scan location and intracranial volume. Results Multivariate CCA uncovered a significant correlation between two components entailing a latent cognitive canonical variate composed of NIH-TB subscales and the brain canonical variate (cerebellar regions’ GMV and intracranial volume, ICV). A bootstrapping and a permutation procedure ensured the results are statistically significant and the CCA model, stable. The identified components correspond to only partly shared cerebellar -cognitive function relationship with a first map encompassing cognitive flexibility (r=0.89) and speed of processing (r=0.65) associated with regional gray matter volume in Crus II (r=0.57) and Lobule X (r=0.59) and a second map including the Crus I (r=0.49) and Lobule VI (r=0.49) associated with cognitive control (r=-0.51). Working memory associations were similarly present in both these maps (Crus II, Lobule X, Crus I and Lobule VI) for the first (r=0.52) and second (r=0.51) component. Discussion Our results show evidence in favor of structural sub-specialization in the cerebellum, independently of psychopathology contributions to cognitive function and brain structure. Overall, these findings highlight a prominent role for the human cerebellum in cognitive function for flexible and stable adaptive behavior.

Multiple lines of evidence across human functional, lesion, and animal data point to a cerebellar role, in particular of crus I, crus II, and lobule VIIB, in cognitive function. However, a mapping of distinct facets of cognitive function to cerebellar structure is missing. We analyzed structural neuroimaging data from the Healthy Brain Network (HBN). Cerebellar parcellation was performed with a validated automated segmentation pipeline (CERES) and stringent visual quality check (n = 662 subjects retained from initial n = 1452). Canonical correlation analyses (CCA) examined regional gray matter volumetric (GMV) differences in association to cognitive function (quantified with NIH Toolbox Cognition domain, NIH-TB), accounting for psychopathology severity, age, sex, scan location, and intracranial volume. Multivariate CCA uncovered a significant correlation between two components entailing a latent cognitive canonical (NIH-TB subscales) and a brain canonical variate (cerebellar GMV and intracranial volume, ICV), surviving bootstrapping and permutation procedures. The components correspond to partly shared cerebellar-cognitive function relationship with a first map encompassing cognitive flexibility (r = 0.89), speed of processing (r = 0.65), and working memory (r = 0.52) associated with regional GMV in crus II (r = 0.57) and lobule X (r = 0.59) and a second map including the crus I (r = 0.49) and lobule VI (r = 0.49) associated with working memory (r = 0.51). We show evidence for a structural subspecialization of the cerebellum topography for cognitive function in a transdiagnostic sample.

Converging results from cognitive neuroscience and lesion studies suggest that the cerebellar vermis, frequently described as the “limbic cerebellum” plays a key role in emotional cognitive processes. Bipolar disorder symptoms, such as manic or depressive episodes have been reported in patients with vermal lesions. Vermis structural or functional alterations in bipolar disorder have been reported inconsistently and studied separately. We thus aimed to conduct the first multimodal study of the posterior vermis in bipolar disorder.

Mental disorders often begin early in life and constitute five of the top ten causes of disability. Their total cost across Europe is estimated at more than 4% of GDP (more than € 600 billion). The last study investigating the cost of mental disorders in France by our group was based on data from 2007 and yielded an estimated indirect and direct cost of € 109 billions. The objective of this study was thus to provide an overall updated cost of mental health in France ten years later and before the COVID-19 pandemic. We estimated the costs related to the direct healthcare and medico-social system, loss of productivity and loss of quality of life. We conducted a literature search to identify direct healthcare, medico-social, indirect (loss of productivity and income compensation) and loss of quality of life during 2018. We included costs related to major psychiatric disorders, including autism and intellectual disability, but excluded the costs related to dementia. Our estimate of the total cost of mental disorders in France, including medical (14%), social (8%), indirect (27%) and loss of quality of life (51%), was € 163 billions in 2018. This total cost includes money spend, forgone earnings and DALYs lost. We found a 50% increase in costs relative to our previous 2007 study. Large-scale cost-effective interventions such as specialized consultations or the development of ambulatory care could help decrease direct healthcare costs related to hospitalization and productivity loss while greatly improving the quality of life of patients.

Cerebellar abnormalities have been reported in autism spectrum disorder (ASD). Beyond its role in hallmark features of ASD, the cerebellum and its connectivity with forebrain structures also play a role in navigation. However, the current understanding of navigation abilities in ASD is equivocal, as is the impact of the disorder on the functional anatomy of the cerebellum. In the present study, we investigated the navigation behavior of a population of ASD and typically developing (TD) adults related to their brain anatomy as assessed by structural and functional MRI at rest. We used the Starmaze task, which permits assessing and distinguishing two complex navigation behaviors, one based on allocentric learning and the other on egocentric learning of a route with multiple decision points. Compared to TD controls, individuals with ASD showed similar exploration, learning, and strategy performance and preference. In addition, there was no difference in the structural or functional anatomy of the cerebellar circuits involved in navigation between the two groups. The findings of our work suggest that navigation abilities, spatio-temporal memory, and their underlying circuits are preserved in individuals with ASD.

BACKGROUND:Bipolar disorder (BD) is a severe chronic psychiatric disorder affecting 0.5 to 1% of the population worldwide. To date, most studies have estimated the cost of BD via information sourced from insurance claims with limited information on clinical characteristics and course of BD. The aims of this study are (i) to estimate the direct healthcare cost associated with BD and to identify contributing factors and (ii) to study the evolution of cost during a two-year follow-up period.METHOD:We analyzed a sample of 1116 individuals with BD included in the Advanced Centers of Expertise in Bipolar Disorder cohort. We estimated the direct healthcare cost per year and per patient, and we identified the clinical features of patients with BD associated with higher direct healthcare costs. In a subsample of patients followed up for two years centers of expertise for BD, we studied the evolution of direct healthcare cost.RESULTS:The average cost of bipolar disorder was € 6910 per year and per patient. Clinical features of BD, sociodemographic characteristics, and associated addiction were associated with higher direct healthcare costs. In the subsample of patients followed-up for two years, direct healthcare cost dropped by more than 50%, strongly suggesting the beneficial effect of specialized care organization.LIMITATION:We did not estimate indirect healthcare and intangible costs.CONCLUSION:Our study investigates the cost of BD and its evolution in a deeply phenotyped longitudinal sample. Cost-utility and cost-effectiveness analyses are required to inform resource allocation decisions and to promote innovative healthcare organizations.

Background: In 2008, the U.S. FDA approved rTMS as a treatment against medication-resistant depression. However, real-world rTMS outcomes remain understudied. This study investigates how rTMS for depression is delivered in routine clinical practice in France, and measures its effectiveness as well as its moderators. Methods: Five centers provided retrospective data on patients who were treated with rTMS for treatment-resistant depression from January 2015 to December 2020. Patients were assessed twice using a hetero-questionnaire, with baseline and immediate post-treatment assessments. We conducted univariate analyses to study which factors were significantly associated with rTMS effectiveness. We then included age, gender, and significant factors in a multivariate model. Results: We collected data from 435 patients with a mean age of 51.27 (14.91): 66 % were female, and 26 % suffered from bipolar depression. Stimulation was delivered using four different stimulation parameters: 1 Hz (7 % of the individuals), 10 Hz (43 %), 20 Hz (12 %), and 50 Hz (intermittent Theta Burst Stimulation, iTBS) (38 %). The mean improvement of depressive symptoms was 33 % (p < 0.001, effect-size: 0.79). Response and remission rates were of 31 % and 22.8 %, respectively. In the multivariate analysis, improvement in depressive symptoms was associated with higher baseline symptoms. Conclusion: This is one of the largest studies that investigates, with careful clinician-rated scales by trained psychiatrists, the effect of rTMS in naturalistic settings. Repetitive TMS appears to be effective in routine clinical practice, although its efficacy could be improved by analyzing predictors of response, as well as personalized targeting of specific brain areas.

BACKGROUND: The cerebellum contains more than 50% of the brain's neurons and is involved in social cognition. Cerebellar anatomical atypicalities have repeatedly been reported in individuals with autism. However, studies have yielded inconsistent findings, likely because of a lack of statistical power, and did not capture the clinical and neuroanatomical diversity of autism. Our aim was to better understand cerebellar anatomy and its diversity in autism. METHODS: We studied cerebellar gray matter morphology in 274 individuals with autism and 219 control subjects of a multicenter European cohort, EU-AIMS LEAP (European Autism Interventions-A Multicentre Study for Developing New Medications; Longitudinal European Autism Project). To ensure the robustness of our results, we conducted lobular parcellation of the cerebellum with 2 different pipelines in addition to voxel-based morphometry. We performed statistical analyses with linear, multivariate (including normative modeling), and meta-analytic approaches to capture the diversity of cerebellar anatomy in individuals with autism and control subjects. Finally, we performed a dimensional analysis of cerebellar anatomy in an independent cohort of 352 individuals with autism-related symptoms. RESULTS: We did not find any significant difference in the cerebellum when comparing individuals with autism and control subjects using linear models. In addition, there were no significant deviations in our normative models in the cerebellum in individuals with autism. Finally, we found no evidence of cerebellar atypicalities related to age, IQ, sex, or social functioning in individuals with autism. CONCLUSIONS: Despite positive results published in the last decade from relatively small samples, our results suggest that there is no striking difference in cerebellar anatomy of individuals with autism.

Background: Intermittent Theta Burst Stimulation (iTBS) is a design of repetitive Transcranial Magnetic Stimulation (rTMS) and could be a candidate to replace rTMS in the treatment of depression, thanks to its efficacy, shorter duration, and ease of use. The antidepressant mechanism of iTBS, and whether this mechanism is mediated by a modulation of cortical excitability, remains unknown. Methods: Using a randomized double-blind, sham-controlled trial, 30 healthy volunteers received either iTBS or a sham treatment targeting the left DorsoLateral PreFrontal Cortex (L-DLPFC), twice a day over 5 consecutive days. Cortical excitability was measured before and after the 5 days of stimulation. Results: No difference in cortical excitability was observed between active or sham iTBS. Conclusion: Our study does not support any effect on cortical excitability of repetitive iTBS targeting the L-DLPFC.

Background: Brain development is of utmost importance for the emergence of psychiatric disorders, as the most severe of them arise before 25 years old. However, little is known regarding how early transdiagnostic symptoms, in a dimensional framework, are associated with cortical development. Anxiety and irritability are central vulnerability traits for subsequent mood and anxiety disorders. In this study, we investigate how these dimensions are related to structural changes in the brain to understand how they may increase the transition risk to full-blown disorders. Methods: We used the opportunity of an open access developmental cohort, the Healthy Brain Network, to investigate associations between cortical surface markers and irritability and anxiety scores as measured by parents and self-reports. Results: We found that in 658 young people (with a mean age of 11.6) the parental report of irritability is associated with decreased surface area in the bilateral rostral prefrontal cortex and the precuneus. Furthermore, parental reports of anxiety were associated with decreased local gyrification index in the anterior cingulate cortex and dorsomedial prefrontal cortex. Conclusions: These results are consistent with current models of emotion regulation network maturation, showing decreased surface area or gyrification index in regions associated with impaired affective control in mood and anxiety disorders. Our results highlight how dimensional traits may increase vulnerability for these disorders.

Background Lithium (Li) is the gold standard treatment for bipolar disorder (BD). However, its mechanisms of action remain unknown but include neurotrophic effects. We here investigated the influence of Li on cortical and local grey matter (GM) volumes in a large international sample of patients with BD and healthy controls (HC). Methods We analyzed high-resolution T1-weighted structural magnetic resonance imaging scans of 271 patients with BD type I (120 undergoing Li) and 316 HC. Cortical and local GM volumes were compared using voxel-wise approaches with voxel-based morphometry and SIENAX using FSL. We used multiple linear regression models to test the influence of Li on cortical and local GM volumes, taking into account potential confounding factors such as a history of alcohol misuse. Results Patients taking Li had greater cortical GM volume than patients without. Patients undergoing Li had greater regional GM volumes in the right middle frontal gyrus, the right anterior cingulate gyrus, and the left fusiform gyrus in comparison with patients not taking Li. Conclusions Our results in a large multicentric sample support the hypothesis that Li could exert neurotrophic and neuroprotective effects limiting pathological GM atrophy in key brain regions associated with BD.

Background: Intermittent theta burst stimulation (iTBS) is a form of repetitive transcranial magnetic stimulation that has shown to be effective in treatment-resistant depression. Through studying the effect of iTBS on healthy subjects, we wished to attain a greater understanding of its impact on the brain. Our objective was to assess whether 10 iTBS sessions altered the neural processing of emotional stimuli, mood and brain anatomy in healthy subjects. Methods: In this double-blind randomized sham-controlled study, 30 subjects received either active iTBS treatment (10 sessions, two sessions a day) or sham treatment over the left dorsolateral prefrontal cortex. Assessments of mood, structural magnetic resonance imaging (MRI) and functional MRI (fMRI) were performed before and after iTBS sessions. During the fMRI, three different categories of stimuli were presented: positive, negative and neutral photographs. Results: This study showed that, during the presentation of negative stimuli (compared with neutral stimuli), 10 sessions of iTBS increased activity in the left anterior insula. However, iTBS did not induce any change in mood, regional gray matter volume or cortical thickness. Conclusions: iTBS modifies healthy subjects’ brain activity in a key region that processes emotional stimuli. (AFSSAPS: ID-RCB 2010A01032-37).