Abstract Background Autism spectrum disorder (ASD) is characterized by social communication difficulties, restricted and repetitive behaviors, and sensory atypicalities. Its pathophysiology remains poorly understood, and no diagnostic biomarker is currently available. However, studies support the hypothesis of an imbalance in the neuronal excitation/inhibition (E/I) balance. Beta and gamma oscillatory powers are described in the literature as indirect electrophysiological features reflecting network dynamics related to this balance. This study takes a dimensional approach to investigate whether alterations in these rhythms are linked to the severity of autistic symptoms. Methods A total of 127 individuals with ASD, including a sensory-assessed subgroup of 57 participants, all aged 5 to 17 years, underwent resting-state high-density electroencephalography (HD-EEG) recordings with eyes closed. Absolute power was extracted from the beta and gamma frequency bands for six regions of interest. Multiple linear regression models were used to investigate the relationships between beta and gamma powers and the clinical dimensions of ASD, while controlling for the effects of age and sex. Results Beta power was positively correlated with sensory hyposensitivity across all regions (all corrected p<.02, n = 57) and with sensory hypersensitivity in the central, parietal, and left temporal regions (all corrected p<.05, n = 57). In addition, an exploratory result suggested that an increase in gamma power may be associated with the severity of restricted and repetitive behaviors (RRBs) in the right temporal region (uncorrected p=.01, n = 127). Conclusions These innovative results call for further analysis, including an investigation of other electrophysiological markers providing indirect profiles of E/I balance. Nevertheless, they open new avenues for a better understanding of the neurobiological processes and early diagnosis of ASD.

Maternal immune activation (MIA) during pregnancy induces autism spectrum disorder (ASD)-like phenotypes in offspring. While maternal IL-17 signaling has been implicated in prenatal brain alterations, the postnatal mechanisms sustaining this phenotype remain unknown. Here, we show that MIA in mice imprints a persistent postnatal insufficiency of regulatory T cells (Tregs) in offspring, characterized by altered DNA methylation, transcriptional dysregulation, and impaired in vivo suppressive function. This Treg insufficiency drives sustained meningeal inflammation marked by infiltration of neutrophils and IL-17-producing immune cells, resulting in region-specific alterations in brain structure and functional connectivity. Functional MRI revealed hypoconnectivity in sensory networks together with hyperconnectivity in regions involved in emotional regulation, reward processing, and interhemispheric cognitive and motor integration. Postnatal stimulation of endogenous Tregs with low-dose interleukin-2 (IL-2) in MIA offspring expanded meningeal Tregs, eliminated IL-17-producing cells, resolved meningeal inflammation, normalized brain connectivity, and reversed MIA-induced ASD-like behaviors in adulthood. Extending these findings to humans, two children with ASD associated with documented maternal immune activation received treatment with low-dose IL-2 for six months. Treatment expanded circulating Tregs and was associated with marked and progressive clinical improvement across all assessed domains - social communication, socialization, interpersonal relationships, adaptive coping, and play. To our knowledge, this represents an unprecedented pharmacological improvement of core ASD symptoms. Together, our results redefine MIA-ASD as a chronic neuroimmune disorder amenable to therapeutic intervention, and establish Treg stimulation as a clinically actionable strategy with implications extending beyond autism to other MIA-associated neuropsychiatric disorders.

Purpose AUTS2-related syndrome is characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters, AUTS2 encodes 2 distinct long and short isoforms encoding a putative transcriptional activator. Methods Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2-related syndrome cohort of 58 patients harboring genomic rearrangements or single-nucleotide variants (SNVs). Results Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent of the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties, and speech delay are common features of AUTS2-related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both longer and shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, microretrognathia, broad nasal base, and anteverted nares. Behavioral disorders were more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only observed in patients with SNVs. Conclusion This study provides a comprehensive clinical characterization of AUTS2-related syndrome, reveals few genotype-phenotype correlations, and suggests that the disruption of the 2 distinct AUTS2 transcripts has a different impact on the clinical phenotype.

Most current autism research focuses on categorical comparisons (e.g., autistic vs. neurotypical people) and usually examines only one biological domain (e.g., cognition, genetics, or brain imaging). Here, we present a comprehensive resource integrating quantitative phenotypic data, whole genome sequencing, brain magnetic resonance imaging, and electroencephalography. A total of 5,549 people were recruited in Europe through LEAP and InovAND, including 2,061 autistic people, 62 people with intellectual developmental disability who do not meet diagnostic criteria for autism, 2,551 undiagnosed relatives and 875 neurotypical people. Among these people, 2,531 have both clinical and genetic data, and 875 people additionally have neuroimaging data (EEG and/or MRI). We stratified people based on autistic traits and cognitive skills, revealing clusters with distinct genetic and brain signatures. Differences were observed in both rare and common variants, particularly in synaptic and chromatin remodeling genes pathways, and suggesting distinct trajectories of cortical maturation at early stages of development. This resource is available to support research into the complex links between genes, brain structures/functions, and autism. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by Institut Pasteur, Universite Paris Cite, the Simons Foundation Autism Research Initiative (SFARI award #240059), the Bettencourt-Schueller Foundation, the GenMed Labex, and AIMS-2-TRIALS, which received support from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 777394 for the project AIMS-2-TRIALS. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA and AUTISM SPEAKS, Autistica, SFARI, and the Inception program (Investissement d'Avenir grant ANR-16-CONV-0005). This project has received funding from the European Union's Horizon 2020 Research and Innovation Program under grant 847818 (CANDY), and from Horizon Europe under grant 101057385 (R2D2-MH). Views and opinions expressed are, however, those of the authors only and do not necessarily reflect those of the European Union. Neither the European Union nor the granting authority can be held responsible for them. This work benefited from the DNA & cell bank core facility, at the ICM-Paris Brain Institute. This work received support from the French government, managed by the National Research Agency (Agence Nationale de la Recherche), under the France 2030 program, reference ANR-23-IAHU-0010. Part of this work was funded by a grant from the Conseil Regional d'Ile de France (grant number EX024087). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study is multi-site; Ethical approval was obtained through ethics committees at each site: The London Queen Square Health Research Authority Research Ethics Committee of King's College London & University of Cambridge (KCL & UCAM) gave ethical approval for this work (13/LO/1156). The Radboud Universitair Medisch Centrum Instituut Waarborging Kwaliteit en Veiligheid Commissie Mensgebonden Onderzoek Regio Arnhem-Nijmegen (Radboud University Medical Centre Institute Ensuring Quality and Safety Committee on Research Involving Human Subjects Arnhem-Nijmegen) from Radboud University Nijmegen Medical Centre (RUNMC) & University Medical Centre Utrecht (UMCU) gave ethical approval for this work (2013/455). The UMM Universitatsmedizin Mannheim, Medizinishe Ethik Commission II (UMM University Medical Mannheim, Medical Ethics Commission II) from Central Institute of Mental Health (CIMH) gave ethical approval for this work (2014-540N-MA). The Universita Campus Bio Medica De Roma Comitato Etico (University Campus Bio-Medical Ethics Committee De Roma) from the University Campus Bio-Medico (UCBM) gave ethical approval for this work (18/14 PAR ComET CBM). The Centrala Etikprovningsnamnden (Central Ethical Review Board) from Karolinska Institutet (KI) gave ethical approval for this work (32 2010). The Ethics Committee overseeing the INOVAND cohort (Inserm C07 33) cohorts gave ethical approval for this work (CEER 2008 A00019 46). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The datasets generated and analyzed in this study, including all modalities from the LEAP (EUAIMS / AIMS2 TRIALS) and InovAND cohorts are securely stored on ELIXIR LU servers, part of the European infrastructure for life science information, based at the Luxembourg Centre for Systems Biomedicine (LCSB) and supported by the Luxembourg National Data Service (LNDS). The LEAP dataset (clinical, cognitive, eye-tracking, neuroimaging, and genetic data) is available via the ELIXIR Luxembourg data catalog. The InovAND dataset will be made available through the same repository upon publication. Access to both datasets is granted upon reasonable request following review and approval by the Data Access Committee, including scientific leads, ethics experts, and Autism community representatives. Requests should be submitted via the data catalog website with a detailed project proposal describing the intended use of the data and must be aligned with General Data Protection Regulation (GDPR) requirements as well as the AIMS2 TRIALS consortium or InovAND data sharing policies, respectively.

OBJECTIVES:France has significantly expanded its provision of care and services for autistic children over the past decade. Yet, there is little research on families' experiences accessing these services, particularly for the most socially vulnerable. This study investigates autism care pathways in France, focusing on how a Centre of excellence for autism located in a socially disadvantaged area, impact families. STUDY DESIGN:Qualitative research with semi-structured interviews. METHODS:Following fieldwork to describe the practices of healthcare professionals involved in the care of autistic children in the environment of the Centre d'excellence, located in the Robert Debré University Hospital in Paris, we conducted semi-structured interviews with 31 families followed at the Centre d'excellence. We analyzed the data using reflexive thematic analysis. RESULTS:The findings reveal persistent gaps between national policies and the realities experienced by the most vulnerable families. While excellence centres improve diagnostic accuracy and promote innovative interventions, they often seem distant from local practices. Many families experience delays in receiving diagnoses and struggle to navigate the care system due to administrative and financial barriers. The study identifies four family coping profiles, ranging from well-informed to disconnected families, illustrating how social backgrounds shape engagement with autism services. CONCLUSIONS:The research underscores the importance of parental guidance and trust-building to reduce disparities in access and improve outcomes for children with autism.

ObjectifLe syndrome d’Ondine (SO) est caractérisé par une hypoventilation alvéolaire et un dysfonctionnement du SNA nécessitant une ventilation pendant le sommeil. Des patients atteints de trouble du spectre autistique (TSA) ont rarement été rapportés dans cette population. L’objectif de l’étude est de déterminer la prévalence du TSA chez les patients atteints du SO, d’identifier les facteurs de risque et d’explorer la relation entre le SNA et le fonctionnement adaptatif (FA) à l’aide du Vineland 2.MéthodesCette étude rétrospective est basée sur l’analyse des dossiers d’enfants atteints du SO suivis dans le centre de référence. Le TSA a été diagnostiqué par un psychiatre, selon les critères du DSM. Le FA a été évalué à l’aide de l’échelle de Vineland 2 et les index de variabilité cardiaque (RMSSD diurne comme indice de modulation parasympathique) ont été obtenus à partir du holter ECG fait le même jour.RésultatsLa prévalence du TSA chez les patients atteint du SO suivis dans le centre de référence est de 8,7 %. Dans une étude cas témoin avec appariement sur le sexe, la durée d’hospitalisation initiale ainsi que les troubles de la régulation de la glycémie étaient associés au TSA. Des corrélations ont été observées entre le RMSSD et 3 sous domaines de l’échelle de Vineland 2 (communication : R=0,50, p=0,028 ; aptitudes à la vie quotidienne : R=0,60, p=0,006 ; socialisation : R=0,52, p=0,021).ConclusionNotre étude met en évidence une prévalence élevée de TSA chez les patients atteints du SO. Un défaut de modulation parasympathique était associé à un FA altéré.

Introduction: Fetal Alcohol Spectrum Disorders (FASD) are characterized by a variety of multiple cognitive and behavioral impairments, with intellectual, attentional, and executive impairments being the most commonly reported. In populations with multiple neurodevelopmental disorders, the Full Scale Intelligence Quotient (FSIQ) may not be a proper measure of intellectual abilities, rarely interpreted in FASD clinical practice because the heterogeneity of the cognitive profile is deemed too strong. We propose a quantitative characterization of this heterogeneity, of the strengths and weaknesses profile, and a differential analysis between global cognitive (FSIQ) and elementary reasoning abilities in a large retrospective monocentric FASD sample. Methods: Using clinical and cognitive data (Wechsler Intelligence Scale for Children) from 107 children with FASD, we characterized subject heterogeneity (variance and scatter of scaled/composite scores), searched for strengths and weaknesses, and specified intellectual functioning in terms of FSIQ and elementary reasoning (General Abilities Index, Highest Reasoning Scaled Score), in comparison with standardization norms and a Monte-Carlo-simulated sample from normalization data. Results: Performance of children with FASD was lower on all subtests, with a significant weakness in working memory and processing speed. We found no increase in the variance and scatter of the scores, but a discordance between the assessment of global cognitive functioning (28% borderline, 23% deficient) and that of global and elementary reasoning abilities (23-9% borderline, 15-14% deficient). Conclusion: Our results question the notion of WISC profile heterogeneity in FASD and point to working memory and processing speed over-impairment, with global repercussions but most often preserved elementary reasoning abilities.

Congenital central hypoventilation syndrome (CCHS) is a rare condition characterized by alveolar hypoventilation and autonomic nervous system (ANS) dysfunction requiring long-term ventilation. CCHS could constitute a risk factor of autism spectrum disorder (ASD) due to birth injury related to respiratory failure, which remains to be determined. ANS dysfunction has also been described in ASD and there are indications for altered contribution of ANS-central nervous system interaction in processing of social information; thus, CCHS could be a risk factor for ASD based on pathophysiological background also. Our study aimed to determine the prevalence of ASD among CCHS patients, identify risk factors, and explore the relationship between the ANS, evaluated by heart rate variability indices, and adaptative functioning. Our retrospective study, based on the analysis of records of a French national center of patients with CCHS under 20 years of age, determined that the prevalence of ASD (diagnosed by a psychiatrist, following the criteria of DSM-4 or DSM-5) was 6/69 patients, 8.7

Autism represents a large spectrum of diverse individuals with varying underlying genetic architectures and needs. For some individuals, a single de novo or ultrarare genetic variant has a large effect on the intensity of specific dimensions of the phenotype, while, for others, a combination of thousands of variants commonly found in the general population are involved. The variants with large impact are found in up to 30% of autistic individuals presenting with intellectual disability, significant speech delay, motor delay, and/or seizures. The common variants are shared with those found in individuals with attention-deficit/hyperactivity disorder, major depressive disorders, greater educational attainment, and higher cognitive performance, suggesting overlapping genetic architectures. The genetic variants modulate the function of chromatin remodeling and synaptic proteins that influence the connectivity of neuronal circuits and, in interaction with the environment of each individual, the subsequent cognitive and personal trajectory of the child. Overall, this genetic heterogeneity mirrors the phenotypic diversity of autistic individuals and provides a helpful bridge between biomedical and neurodiversity perspectives. We propose that participative and multidisciplinary research should use this information to understand better the assessment, treatments, and accommodations that individuals with autism and families need.

Sensory features, executive and attentional impairments are frequently reported in individuals with autism spectrum disorders (ASD). However, little is known about their complex relationships. In this study, we aim to examine the executive and attentional difficulties related to distinct sensory profiles. We identified sensory profiles with a Latent Profile Analysis (LPA) based on scores on the Short Sensory Profile (SSP) questionnaire in 95 children with ASD aged 6 to 17 years. Executive and attention functions were assessed using the Behavior Rating Inventory of Executive Functions (BRIEF) questionnaire and Attention-Deficit Hyperactivity Disorder Rating Scale (ADHD-RS). A three-cluster solution based on raw SSP scores identified a “high’’, a “medium” and a “low’’ SSP profile. We found a significant relationship between executive functions, attentional skills and the global severity of sensory features, reinforcing findings of previous studies in the literature. A two-cluster solution based on normalized SSP (i.e. equalized for the global severity) identified distinct sensory profiles, mainly discriminated by the score of underresponsive/seeks sensation. We found no significant difference between these two clusters for the BRIEF and ADHD-RS related scores. Our study suggests that the heterogeneity of sensory features in ASD may not be explained by differences in executive and attention functions. Future studies are needed to refine the link between sensory features and executive functions in autism.

While over 100 genes have been associated with autism, little is known about the prevalence of variants affecting them in individuals without a diagnosis of autism. Nor do we fully appreciate the phenotypic diversity beyond the formal autism diagnosis. Based on data from more than 13,000 individuals with autism and 210,000 undiagnosed individuals, we estimated the odds ratios for autism associated to rare loss-of-function (LoF) variants in 185 genes associated with autism, alongside 2,492 genes displaying intolerance to LoF variants. In contrast to autism-centric approaches, we investigated the correlates of these variants in individuals without a diagnosis of autism. We show that these variants are associated with a small but significant decrease in fluid intelligence, qualification level and income and an increase in metrics related to material deprivation. These effects were larger for autism-associated genes than in other LoF-intolerant genes. Using brain imaging data from 21,040 individuals from the UK Biobank, we could not detect significant differences in the overall brain anatomy between LoF carriers and non-carriers. Our results highlight the importance of studying the effect of the genetic variants beyond categorical diagnosis and the need for more research to understand the association between these variants and sociodemographic factors, to best support individuals carrying these variants.

KCNQ2 mutations are a common cause of early-onset epileptic syndromes. They are associated with heterogeneous developmental profiles, from mild to severe cognitive and social impairments that need better characterization. We report a case of an inherited KCNQ2 mutation due to a deletion c.402delC in a heterozygous state, in the exon 3 of the KCNQ2 gene. A 5-year-old boy presented a cluster of sudden-onset generalized tonic-clonic seizures at three months of age, after an unremarkable postnatal period. Multiplex ligation-dependent probe amplification identified a familial mutation after an investigation in the family revealed that this mutation was present on the father’s side. The patient was diagnosed with autism and intellectual deficiency in a context of KCNQ2 -encephalopathy. We describe his clinical features in light of current literature. This report highlights the importance of appropriate genetic counseling and psychiatric assessment in planning the medical and social follow-up of a disorder with complex socio-behavioral features.

Background Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into ‘motor-driven’ and ‘cognitively driven’. RRBI symptomatology depends on the individual’s clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context [autistic individuals, their relatives and typical developing (TD) individuals]. We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI and that these dimensions are associated with neuroanatomical signatures—involving cortical and subcortical areas. Method A sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects ( n = 152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models. Results We identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the ‘motor-driven’ RRBI symptoms; Factor 2 and 3 (respectively, 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the ‘cognitively driven’ RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 and FA3 (all uncorrected p < 0.05). FA1 was negatively associated with the left amygdala (uncorrected p < 0.05), and FA2 was positively associated with the left parietal structure (uncorrected p = 0.001). Conclusion Our results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen’s integrative role in RSBI needs to be strengthened in further studies.

Maternal immune activation (MIA), related to autoimmune/inflammatory diseases or acute infections, during the two first trimesters of pregnancy is a risk factor for autism spectrum disorders (ASD) in offspring. In mice, MIA has a long-term impact on offspring’s immune equilibrium resulting in a pro-inflammatory phenotype. We therefore hypothesized that children with ASD and a history of MIA could display a similar phenotype specifically assessed by a higher neutrophil to lymphocyte ratio (NLR). In this study, we used a retrospective sample of 231 dyads involving children with ASD and their mothers. Among ASD patients, 12% had a history of MIA. The multivariate analysis revealed a significant association between NLR in children with ASD and maternal history of MIA (F = 2.27, p = 0.03). Using a categorical approach, we observed an abnormal NLR (over 3) in 7.4% of children with ASD MIA+ compared to 1.9% for MIA−. Our study supports the hypothesis suggesting an impact of MIA on the risk of ASD. Further studies could contribute to the development of biomarkers in MIA+ ASD and enable the development of targeted immunomodulatory therapies.

Autism spectrum disorder (ASD) are neurodevelopmental conditions characterised by deficits in social communication and interaction and repetitive behaviours. Maternal immune activation (MIA) during the mid-pregnancy is a known risk factor for ASD. Although reported in 15% of affected individuals, little is known about the specificity of their clinical profiles. Adaptive skills represent a holistic approach to a person's competencies and reflect specifically in ASD, their strengths and difficulties. In this study, we hypothesised that ASD individual with a history of MIA (MIA+) could be more severely socio-adaptively impaired than those without MIA during pregnancy (MIA-). To answer this question, we considered two independent cohorts of individuals with ASD (PARIS study and FACE ASD) screened for pregnancy history, and used supervised and unsupervised machine learning algorithms. We included 295 mother-child dyads with 14% of them with MIA+. We found that ASD-MIA+ individuals displayed more severe maladaptive behaviors, specifically in their socialization abilities. MIA+ directly influenced individual's socio-adaptive skills, independent of other covariates, including ASD severity. Interestingly, MIA+ affect persistently the socio-adaptive behavioral trajectories of individuals with ASD. The current study has a retrospective design with possible recall bias regarding the MIA event and, even if pooled from two cohorts, has a relatively small population. In addition, we were limited by the number of covariables available potentially impacted socio-adaptive behaviors. Larger prospective study with additional dimensions related to ASD is needed to confirm our results. Specific pathophysiological pathways may explain these clinical peculiarities of ASD- MIA+ individuals, and may open the way to new perspectives in deciphering the phenotypic complexity of ASD and for the development of specific immunomodulatory strategies.

SHANK3-related Phelan-McDermid syndrome (PMS) is caused by a loss of the distal part of chromosome 22, including SHANK3, or by a pathological SHANK3 variant. There is an important genetic and phenotypic diversity among patients who can present with developmental delay, language impairments, autism, epilepsy, and other symptoms. SHANK3, encoding a synaptic scaffolding protein, is deleted in the majority of patients with PMS and is considered a major gene involved in the neurological impairments of the patients. However, differences in deletion size can influence clinical features, and in some rare cases, deletions at the 22q13 locus in individuals with SHANK3-unrelated PMS do not encompass SHANK3. These individuals with SHANK3-unrelated PMS still display a PMS-like phenotype. This suggests the participation of other 22q13 genes in the pathogenesis of PMS. Here, we review the biological function and potential implication in PMS symptoms of 110 genes located in the 22q13 region, focusing on 35 genes with evidence for association with neurodevelopmental disorders, including 13 genes for epilepsy and 11 genes for microcephaly and/or macrocephaly. Our review is restricted to the 22q13 region, but future large-scale studies using whole genome sequencing and deep-phenotyping are warranted to develop predictive models of clinical trajectories and to target specific medical and educational care for each individual with PMS.

Abstract Background. Repetitive and restricted behaviors and interests (RRBI) are core symptoms of autism with a complex entity and are commonly categorized into ‘motor-driven’ and ‘cognitively-driven’. RRBI symptomatology depends on the individual’s clinical environment limiting the understanding of RRBI physiology, particularly their associated neuroanatomical structures. The complex RRBI heterogeneity needs to explore the whole RRBI spectrum by integrating the clinical context (autistic individuals, their relatives and typical developing (TD) individuals). We hypothesized that different RRBI dimensions would emerge by exploring the whole spectrum of RRBI, and that these dimensions are associated with neuroanatomical signatures - involving cortical & subcortical areas. Method. A sample of 792 individuals composed of 267 autistic subjects, their 370 first-degree relatives and 155 TD individuals was enrolled in the study. We assessed the whole patterns of RRBI in each individual by using the Repetitive Behavior Scale-Revised and the Yale-Brown Obsessive Compulsive Scale. We estimated brain volumes using MRI scanner for a subsample of the subjects (n=152, 42 ASD, 89 relatives and 13 TD). We first investigated the dimensionality of RRBI by performing a principal component analysis on all items of these scales and included all the sampling population. We then explored the relationship between RRBI-derived factors with brain volumes using linear regression models. Results. We identified 3 main factors (with 30.3% of the RRBI cumulative variance): Factor 1 (FA1, 12.7%) reflected mainly the ‘motor-driven’ RRBI symptoms; Factor 2 and 3 (respectively 8.8% and 7.9%) gathered mainly Y-BOCS related items and represented the ‘cognitively-driven’ RRBI symptoms. These three factors were significantly associated with the right/left putamen volumes but with opposite effects: FA1 was negatively associated with an increased volume of the right/left putamen conversely to FA2 & FA3 (all uncorrected p<0.05). FA1 was negatively associated with the left amygdala (uncorrected p<0.05), and FA2 was positively associated with the left parietal structure (uncorrected p=0.001). Conclusion. Our results suggested 3 coherent RRBI dimensions involving the putamen commonly and other structures according to the RRBI dimension. The exploration of the putamen’s integrative role in RSBI needs to be strengthened in further studies.

ABSTRACTBackgroundExploring neural network dynamics during social interaction could help to identify biomarkers of Autism Spectrum Disorders (ASD). Recently, the cerebellum, a brain structure that plays a key role in social cognition, has attracted growing interest. Here, we investigated the electrophysiological activity of the cortico-cerebrum network during real-time social interaction in ASD. We focused our analysis on theta oscillations (3-8 Hz), which have been associated with large-scale coordination of distant brain areas and might contribute to interoception, motor control, and social event anticipation, all skills known to be altered in ASD.MethodsWe combined the Human Dynamic Clamp, a paradigm for studying realistic social interactions using a virtual avatar, with high-density electroencephalography (HD-EEG). Using source reconstruction, we investigated power in the cortex and the cerebellum, along with coherence between the cerebellum and three cortical areas, and compared our findings in a sample of participants with ASD and with typical development (TD) (n = 140). We developed an open-source pipeline to analyse neural dynamics at the source level from HD-EEG data.ResultsIndividuals with ASD showed a significant increase in theta band power during social interaction compared to resting state, unlike individuals with TD. In particular, we observed a higher theta power over the cerebellum and the frontal and temporal cortices in the ASD group compared to the TD group, alongside bilateral connectivity alterations between the cerebellum and the sensorimotor and parietal cortices.ConclusionsThis study uncovered ASD-specific alterations in the theta dynamics, especially in a network between the cerebellum and social-associated cortical networks.