Sex/gender differences in children with autism spectrum disorder: A brief overview on epidemiology, symptom profile, and neuroanatomy.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose shared core features are impairments in social interaction and communication as well as restricted patterns of behavior, interests, and activities. The significant and consistent male preponderance in ASD prevalence has historically affected the scientific knowledge of autism in females as regards, inter alia, the clinical presentation, the genetic architecture, and the structural brain underpinnings. Indeed, females with ASD are under-investigated as samples recruited for clinical research typically reflect the strong male bias of the disorder. In the last years, the study of the various aspects of sex/gender (s/g) differences in ASD is gaining increased clinical and research interest resulting in a growing number of investigations on this topic. Here, I review and discuss evidence emerged from epidemiological, clinical, and neuroimaging studies in the last decade focusing on s/g differences in children with ASD. These studies are the prerequisites for the development of assessment and treatment practices which take into consideration s/g differences in ASD. Ultimately, a better understanding of s/g differences aims at improving healthcare for both ASD males and females.

Subtly altered topological asymmetry of brain structural covariance networks in autism spectrum disorder across 43 datasets from the ENIGMA consortium.

Small average differences in the left-right asymmetry of cerebral cortical thickness have been reported in individuals with autism spectrum disorder (ASD) compared to typically developing controls, affecting widespread cortical regions. The possible impacts of these regional alterations in terms of structural network effects have not previously been characterized. Inter-regional morphological covariance analysis can capture network connectivity between different cortical areas at the macroscale level. Here, we used cortical thickness data from 1455 individuals with ASD and 1560 controls, across 43 independent datasets of the ENIGMA consortium's ASD Working Group, to assess hemispheric asymmetries of intra-individual structural covariance networks, using graph theory-based topological metrics. Compared with typical features of small-world architecture in controls, the ASD sample showed significantly altered average asymmetry of networks involving the fusiform, rostral middle frontal, and medial orbitofrontal cortex, involving higher randomization of the corresponding right-hemispheric networks in ASD. A network involving the superior frontal cortex showed decreased right-hemisphere randomization. Based on comparisons with meta-analyzed functional neuroimaging data, the altered connectivity asymmetry particularly affected networks that subserve executive functions, language-related and sensorimotor processes. These findings provide a network-level characterization of altered left-right brain asymmetry in ASD, based on a large combined sample. Altered asymmetrical brain development in ASD may be partly propagated among spatially distant regions through structural connectivity.

DNA Methylation Biomarkers for Young Children with Idiopathic Autism Spectrum Disorder: A Systematic Review.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition, the underlying pathological mechanisms of which are not yet completely understood. Although several genetic and genomic alterations have been linked to ASD, for the majority of ASD patients, the cause remains unknown, and the condition likely arises due to complex interactions between low-risk genes and environmental factors. There is increasing evidence that epigenetic mechanisms that are highly sensitive to environmental factors and influence gene function without altering the DNA sequence, particularly aberrant DNA methylation, are involved in ASD pathogenesis. This systematic review aimed to update the clinical application of DNA methylation investigations in children with idiopathic ASD, investigating its potential application in clinical settings. To this end, a literature search was performed on different scientific databases using a combination of terms related to the association between peripheral DNA methylation and young children with idiopathic ASD; this search led to the identification of 18 articles. In the selected studies, DNA methylation is investigated in peripheral blood or saliva samples, at both gene-specific and genome-wide levels. The results obtained suggest that peripheral DNA methylation could represent a promising methodology in ASD biomarker research, although further studies are needed to develop DNA-methylation-based clinical applications.

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure.

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA-ADHD and ENIGMA-ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA-ADHD and -ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case-control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case-control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow-up analyses continue that include more imaging modalities (diffusion MRI and resting-state functional MRI), collaborations with other large databases, and samples with dual diagnoses.

Feeding disorders in preschoolers: a short-term outcome study in an Italian Family Care Program.

PURPOSE: To provide a description about a cohort of preschoolers with feeding disorders (FD) recruited from the therapeutic nursery "Cerco Asilo" of a tertiary care University Hospital, and to evaluate the short-term clinical outcome after 6 months of multidisciplinary treatment. METHODS: The present inception cohort study was based on an observational longitudinal research design comparing families who underwent the multidisciplinary treatment and those who did not. 42 children (47.6% female; 52.4% males-mean age 36.7 months, SD 17.2, range 2.3-65 months) underwent FD assessment according to the DC-0-3R diagnostic criteria (T0). At the end of the assessment, 62% of families with FD children agreed to be included in the family-based treatment. Both treated and untreated children with FD underwent a follow-up clinical evaluation after 6 months (T1) from baseline. Comparison of clinical features at T0 between groups of subjects resolving or not the FD was performed. To evaluate baseline factors associated with FD resolution, principal components analysis (PCA) was used to identify new synthetic variables that were then used in a logistics analysis. Moreover, clinical differences between T1 and T0 were compared with a t test. RESULTS: Two third of the cases (66.7%) resolved the FD, while one third (33.3%) did not. Children who had the FD resolved displayed at T0 significant differences in clinical features with respect to those who did not. Specifically, the FD subtype Feeding Disorder of Caregiver-Infant Reciprocity was strongly associated with resolution, while the subtype Infantile Anorexia was not. In addition, the component depicting "Anxious-Depressed", "Mood" and "Isolation" problems was independently associated with a significantly higher probability of resolution, similar to children having FD other than anorexia. CONCLUSIONS: FD in preschoolers are associated with problems in emotional development and in the relationship with parents. These difficulties tend to accentuate if the disorder persists. The study suggests the need to investigate the maintaining factors of FD in preschool age. LEVEL OF EVIDENCE: Level IV: Evidence obtained from multiple time series with and without the intervention.

George Frankl: an undervalued voice in the history of autism.

This paper aims to propose that the psychiatrist George Frankl had more than a marginal role in the early history of autism. Frankl's conception of autism as characterized by a lack of affective language has influenced both Asperger and Kanner. First, this proposal is historically supported; second it is corroborated by Frankl's unpublished manuscript on Autism. We found that Frankl's perspective about autism was, and still can be, considered innovative for multiple reasons. Specifically, Frankl proposed that autism could cover a spectrum of conditions; that it is a state of mind that is not necessarily abnormal; and that it is a neurobiological condition, which primarily needs to be understood by others. Finally, Frankl's concepts of affective contact and affective language are reconsidered with reference to contemporary neuropsychology from which autism emerges not as a higher-order cognitive deficit, but as a result of an impairment of primordial ability to process low level sensory, motor and perceptual information gained through experiencing other persons.

The broad autism phenotype in real-life: clinical and functional correlates of autism spectrum symptoms and rumination among parents of patients with autism spectrum disorder.

OBJECTIVE: Increasing literature reported higher rates of psychiatric disorders in parents of children with autism spectrum disorder (ASD), as well as of autistic-like features in social and cognitive functioning. However, little attention has been paid to the association between autistic traits (AT) and global functioning in this population. The aim of the present work was to investigate clinical and functional correlates of AT among parents of ASD children, with a specific focus on ruminative thinking. METHODS: One hundred and twenty parents of ASD children were assessed by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM-5), the Adult Autism Subthreshold Spectrum (AdAS Spectrum), the Ruminative Response Scale (RRS), the Social and Occupational Functioning Assessment Scale (SOFAS). RESULTS: Subjects with at least 1 psychiatric disorder (39.2%) showed significantly higher AdAS Spectrum and RRS scores. Subjects with a history of school difficulties and with language development alterations scored significantly higher on specific AdAS Spectrum domains. A significant negative correlation was found between SOFAS and AdAS Spectrum scores, as well as between SOFAS and RRS scores. AdAS Spectrum nonverbal communication domain score was identified has a statistically predictive variable for the presence of psychiatric disorders and lower SOFAS scores. Finally, we found a significant indirect effect of AdAS total score on SOFAS score, which was fully mediated by RRS total score. CONCLUSIONS: AT in parents of ASD children seem to be associated with a higher vulnerability toward psychopathology and with a lower global functioning. Ruminative thinking may play a role in the relationship between AT and functional outcome.

Brainstem enlargement in preschool children with autism: Results from an intermethod agreement study of segmentation algorithms.

The intermethod agreement between automated algorithms for brainstem segmentation is investigated, focusing on the potential involvement of this structure in Autism Spectrum Disorders (ASD). Inconsistencies highlighted in previous studies on brainstem in the population with ASD may in part be a result of poor agreement in the extraction of structural features between different methods. A sample of 76 children with ASD and 76 age-, gender-, and intelligence-matched controls was considered. Volumetric analyses were performed using common tools for brain structures segmentation, namely FSL-FIRST, FreeSurfer (FS), and Advanced Normalization Tools (ANTs). For shape analysis SPHARM-MAT was employed. Intermethod agreement was quantified in terms of Pearson correlations between pairs of volumes obtained by the different methods. The degree of overlap between segmented masks was quantified in terms of the Dice index. Both Pearson correlations and Dice indices, showed poor agreement between FSL-FIRST and the other methods (ANTs and FS), which by contrast, yielded Pearson correlations greater than 0.93 and average Dice indices greater than 0.76 when compared with each other. As with volume, shape analyses exhibited discrepancies between segmentation methods, with particular differences noted between FSL-FIRST and the others (ANT and FS), with under- and over-segmentation in specific brainstem regions. These data suggest that research on brain structure alterations should cross-validate findings across multiple methods. We consistently detected an enlargement of brainstem volume in the whole sample and in the male cohort across multiple segmentation methods, a feature particularly driven by the subgroup of children with idiopathic intellectual disability associated with ASD.

Contextual priors do not modulate action prediction in children with autism.

Bayesian accounts of autism suggest that this disorder may be rooted in an impaired ability to estimate the probability of future events, possibly owing to reduced priors. Here, we tested this hypothesis within the action domain in children with and without autism using a behavioural paradigm comprising a familiarization and a testing phase. During familiarization, children observed videos depicting a child model performing actions in diverse contexts. Crucially, within this phase, we implicitly biased action-context associations in terms of their probability of co-occurrence. During testing, children observed the same videos but drastically shortened (i.e. reduced amount of kinematics information) and were asked to infer action unfolding. Since during the testing phase movement kinematics became ambiguous, we expected children's responses to be biased to contextual priors, thus compensating for perceptual uncertainty. While this probabilistic effect was present in controls, no such modulation was observed in autistic children, overall suggesting an impairment in using contextual priors when predicting other peoples' actions in uncertain environments.

Vocal and motor behaviors as a possible expression of gastrointestinal problems in preschoolers with Autism Spectrum Disorder.

BACKGROUND: Gastrointestinal (GI) problems are one of the most frequent comorbidities in Autism Spectrum Disorder (ASD) but can be under-recognized due to the concomitant communication difficulties of this population. Accordingly, some associated behaviors (AB) such as verbal and motor behaviors (VB and MB, respectively) have been identified as a possible expression of an underlying GI problem and evaluated through an ad hoc questionnaire (the Associated Behaviors Questionnaire -ABQ-). The aims of this study were to investigate the presence and the type of AB in an Italian sample of ASD preschoolers, and to determine their correlations with GI problems. METHODS: We included 85 ASD preschoolers (mean age 4.14 years; SD 1.08) splitted into two groups (GI and No-GI) through the GI Severity Index instrument. AB were evaluated through the ABQ that includes VB, MB and Changes in overall state (C) clusters. Specific tools were administered to evaluate the ASD core ad associated symptoms, as well as the intellective and adaptive functioning. RESULTS: The GI group (N = 30) showed significantly higher scores in all the three ABQ areas (VB, MB and C) than the No-GI group (N = 55), with a positive correlation between GI symptoms and some specific AB as well as ABQ Total score. By dividing the whole sample in verbal and non-verbal individuals, both specific and shared AB emerged in the two groups. CONCLUSIONS: Our results alert clinicians to consider behavioral manifestations as a possible expression of GI problems in ASD subjects. Therefore, the evaluation of AB may be useful to identify the presence of GI problems in the ASD populations, and especially in non-verbal ASD children.

Autonomic Nervous System Response during Light Physical Activity in Adolescents with Anorexia Nervosa Measured by Wearable Devices.

Anorexia nervosa (AN) is associated with a wide range of disturbances of the autonomic nervous system. The aim of the present study was to monitor the heart rate (HR) and the heart rate variability (HRV) during light physical activity in a group of adolescent girls with AN and in age-matched controls using a wearable, minimally obtrusive device. For the study, we enrolled a sample of 23 adolescents with AN and 17 controls. After performing a 12-lead electrocardiogram and echocardiography, we used a wearable device to record a one-lead electrocardiogram for 5 min at baseline for 5 min during light physical exercise (Task) and for 5 min during recovery. From the recording, we extracted HR and HRV indices. Among subjects with AN, the HR increased at task and decreased at recovery, whereas among controls it did not change between the test phases. HRV features showed a different trend between the two groups, with an increased low-to-high frequency ratio (LF/HF) in the AN group due to increased LF and decreased HF, differently from controls that, otherwise, slightly increased their standard deviation of NN intervals (SDNN) and the root mean square of successive differences (RMSSD). The response in the AN group during the task as compared to that of healthy adolescents suggests a possible sympathetic activation or parasympathetic withdrawal, differently from controls. This result could be related to the low energy availability associated to the excessive loss of fat and lean mass in subjects with AN, that could drive to autonomic imbalance even during light physical activity.

The effect of age, sex and clinical features on the volume of Corpus Callosum in pre-schoolers with Autism Spectrum Disorder: a case-control study.

A growing body of literature has identified volume alterations of the corpus callosum (CC) in subjects with autism spectrum disorders (ASD). However, to date very few investigations have been conducted on pre-school-age ASD children. This study aims to compare the volume of CC and its sub-regions between pre-schoolers with ASD and controls (CON) and to examine their relationship to demographic and clinical variables (sex, age, non-verbal IQ -NVIQ-, expressive non-echolalic language, emotional and behavioural problems, and autism severity). The volume of CC of 40 pre-schoolers with ASD (20 males and 20 females; mean age: 49 ± 12 months; mean NVIQ: 73 ± 22) and 40 sex-, age-, and NVIQ-matched CON subjects (20 M and 20 F; mean age: 49 ± 14 months; mean NVIQ: 73 ± 23) were quantified applying the FreeSurfer automated parcellation software on Magnetic Resonance images. No significant volumetric differences in CC total volume and in its sub-regions between ASD and CON were found using total brain volume as a covariate. Analogously, absence of CC volumetric differences was evident when boys and girls with ASD were compared with their matched controls. The CC total volume of younger ASD male subjects was found significantly larger with respect to matched CON, which is consistent with the atypical growth trajectory widely reported in these young children. The CC total volume was negatively correlated with autism severity, whereas no association between CC volume and other clinical variables was detected. If replicated, the indirect relationship between CC volume and autism severity suggests the involvement of CC in core ASD symptoms.

Excessive physical activity in young girls with restrictive-type anorexia nervosa: its role on cardiac structure and performance.

PURPOSE: The aim of this study was to investigate the influence of hyperactivity on left ventricular mass (LVM) in Anorexia Nervosa restricting-type (AN-R) and the correlation between LVM and auxologic parameters/circulating hormones. METHODS: Echocardiography was performed in 44 AN-R girls, subgrouped in 24 hyperactive (ANH+) and 20 non-hyperactive (ANH-), and in 20 controls (HC). LVM indexed to Body Surface Area (LVMi) and LVM indexed to height (LVMh) were calculated. RESULTS: LVMi and LVMh were significantly lower in the AN-R subjects compared to HC. Moreover, both LVMi and LVMh were higher in the ANH+ than in the ANH-. In the HC, LVMi was higher when compared to the ANH- subjects than to the ANH+. Stepwise analysis revealed that in the ANH+ group, fT4 was the only independent predictor of LVMh, while in the ANH- group, height was the only independent predictors of LVMi. CONCLUSIONS: Despite its negative influence on disease severity and outcome, hyperactivity from the standpoint of cardiac function makes the LVM of AN-R young girls more similar to HC. LEVEL OF EVIDENCE: Level III, case-control study.

Gut to brain interaction in Autism Spectrum Disorders: a randomized controlled trial on the role of probiotics on clinical, biochemical and neurophysiological parameters.

BACKGROUND: A high prevalence of a variety of gastrointestinal (GI) symptoms is frequently reported in patients with Autism Spectrum Disorders (ASD). The GI disturbances in ASD might be linked to gut dysbiosis representing the observable phenotype of a "gut-brain axis" disruption. The exploitation of strategies which can restore normal gut microbiota and reduce the gut production and absorption of toxins, such as probiotics addition/supplementation in a diet, may represent a non-pharmacological option in the treatment of GI disturbances in ASD. The aim of this randomized controlled trial is to determine the effects of supplementation with a probiotic mixture (Vivomixx®) in ASD children not only on specific GI symptoms, but also on the core deficits of the disorder, on cognitive and language development, and on brain function and connectivity. An ancillary aim is to evaluate possible effects of probiotic supplementation on urinary concentrations of phthalates (chemical pollutants) which have been previously linked to ASD. METHODS: A group of 100 preschoolers with ASD will be classified as belonging to a GI group or to a Non-GI (NGI) group on the basis of a symptom severity index specific to GI disorders. In order to obtain four arms, subjects belonging to the two groups (GI and NGI) will be blind randomized 1:1 to regular diet with probiotics or with placebo for 6 months. All participants will be assessed at baseline, after three months and after six months from baseline in order to evaluate the possible changes in: (1) GI symptoms; (2) autism symptoms severity; (3) affective and behavioral comorbid symptoms; (4) plasmatic, urinary and fecal biomarkers related to abnormal intestinal function; (5) neurophysiological patterns. DISCUSSION: The effects of treatments with probiotics on children with ASD need to be evaluated through rigorous controlled trials. Examining the impact of probiotics not only on clinical but also on neurophysiological patterns, the current trial sets out to provide new insights into the gut-brain connection in ASD patients. Moreover, results could add information to the relationship between phthalates levels, clinical features and neurophysiological patterns in ASD. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02708901 . Retrospectively registered: March 4, 2016.

Temporal lobe connects regression and macrocephaly to autism spectrum disorders.

Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70%) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder.

Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain.

The involvement of melatonin in mammalian brain pathophysiology has received growing interest, but information about the anatomical distribution of its two G-protein-coupled receptors, MT1 and MT2 , remains elusive. In this study, using specific antibodies, we examined the precise distribution of both melatonin receptors immunoreactivity across the adult rat brain using light, confocal, and electron microscopy. Our results demonstrate a selective MT1 and MT2 localization on neuronal cell bodies and dendrites in numerous regions of the rat telencephalon, diencephalon, and mesencephalon. Confocal and ultrastructural examination confirmed the somatodendritic nature of MT1 and MT2 receptors, both being localized on neuronal membranes. Overall, striking differences were observed in the anatomical distribution pattern of MT1 and MT2 proteins, and the labeling often appeared complementary in regions displaying both receptors. Somadendrites labeled for MT1 were observed for instance in the retrosplenial cortex, the dentate gyrus of the hippocampus, the islands of Calleja, the medial habenula, the suprachiasmatic nucleus, the superior colliculus, the substantia nigra pars compacta, the dorsal raphe nucleus, and the pars tuberalis of the pituitary gland. Somadendrites endowed with MT2 receptors were mostly observed in the CA3 field of the hippocampus, the reticular thalamic nucleus, the supraoptic nucleus, the inferior colliculus, the substantia nigra pars reticulata, and the ventrolateral periaqueductal gray. Together, these data provide the first detailed neurocytological mapping of melatonin receptors in the adult rat brain, an essential prerequisite for a better understanding of melatonin distinct receptor function and neurophysiology.

Children with Autism Spectrum Disorder and Abnormalities of Clinical EEG: A Qualitative Review.

Over the last decade, the comorbidity between Autism Spectrum Disorder (ASD) and epilepsy has been widely demonstrated, and many hypotheses regarding the common neurobiological bases of these disorders have been put forward. A variable, but significant, prevalence of abnormalities on electroencephalogram (EEG) has been documented in non-epileptic children with ASD; therefore, several scientific studies have recently tried to demonstrate the role of these abnormalities as a possible biomarker of altered neural connectivity in ASD individuals. This narrative review intends to summarize the main findings of the recent scientific literature regarding abnormalities detected with standard EEG in children/adolescents with idiopathic ASD. Research using three different databases (PubMed, Scopus and Google Scholar) was conducted, resulting in the selection of 10 original articles. Despite an important lack of studies on preschoolers and a deep heterogeneity in results, some authors speculated on a possible association between EEG abnormalities and ASD characteristics, in particular, the severity of symptoms. Although this correlation needs to be more strongly elucidated, these findings may encourage future studies aimed at demonstrating the role of electrical brain abnormalities as an early biomarker of neural circuit alterations in ASD, highlighting the potential diagnostic, prognostic and therapeutic value of EEG in this field.

Deep learning based joint fusion approach to exploit anatomical and functional brain information in autism spectrum disorders.

BACKGROUND: The integration of the information encoded in multiparametric MRI images can enhance the performance of machine-learning classifiers. In this study, we investigate whether the combination of structural and functional MRI might improve the performances of a deep learning (DL) model trained to discriminate subjects with Autism Spectrum Disorders (ASD) with respect to typically developing controls (TD). MATERIAL AND METHODS: We analyzed both structural and functional MRI brain scans publicly available within the ABIDE I and II data collections. We considered 1383 male subjects with age between 5 and 40 years, including 680 subjects with ASD and 703 TD from 35 different acquisition sites. We extracted morphometric and functional brain features from MRI scans with the Freesurfer and the CPAC analysis packages, respectively. Then, due to the multisite nature of the dataset, we implemented a data harmonization protocol. The ASD vs. TD classification was carried out with a multiple-input DL model, consisting in a neural network which generates a fixed-length feature representation of the data of each modality (FR-NN), and a Dense Neural Network for classification (C-NN). Specifically, we implemented a joint fusion approach to multiple source data integration. The main advantage of the latter is that the loss is propagated back to the FR-NN during the training, thus creating informative feature representations for each data modality. Then, a C-NN, with a number of layers and neurons per layer to be optimized during the model training, performs the ASD-TD discrimination. The performance was evaluated by computing the Area under the Receiver Operating Characteristic curve within a nested 10-fold cross-validation. The brain features that drive the DL classification were identified by the SHAP explainability framework. RESULTS: The AUC values of 0.66±0.05 and of 0.76±0.04 were obtained in the ASD vs. TD discrimination when only structural or functional features are considered, respectively. The joint fusion approach led to an AUC of 0.78±0.04. The set of structural and functional connectivity features identified as the most important for the two-class discrimination supports the idea that brain changes tend to occur in individuals with ASD in regions belonging to the Default Mode Network and to the Social Brain. CONCLUSIONS: Our results demonstrate that the multimodal joint fusion approach outperforms the classification results obtained with data acquired by a single MRI modality as it efficiently exploits the complementarity of structural and functional brain information.

European Autism GEnomics Registry (EAGER): protocol for a multicentre cohort study and registry.

INTRODUCTION: Autism is a common neurodevelopmental condition with a complex genetic aetiology that includes contributions from monogenic and polygenic factors. Many autistic people have unmet healthcare needs that could be served by genomics-informed research and clinical trials. The primary aim of the European Autism GEnomics Registry (EAGER) is to establish a registry of participants with a diagnosis of autism or an associated rare genetic condition who have undergone whole-genome sequencing. The registry can facilitate recruitment for future clinical trials and research studies, based on genetic, clinical and phenotypic profiles, as well as participant preferences. The secondary aim of EAGER is to investigate the association between mental and physical health characteristics and participants' genetic profiles. METHODS AND ANALYSIS: EAGER is a European multisite cohort study and registry and is part of the AIMS-2-TRIALS consortium. EAGER was developed with input from the AIMS-2-TRIALS Autism Representatives and representatives from the rare genetic conditions community. 1500 participants with a diagnosis of autism or an associated rare genetic condition will be recruited at 13 sites across 8 countries. Participants will be given a blood or saliva sample for whole-genome sequencing and answer a series of online questionnaires. Participants may also consent to the study to access pre-existing clinical data. Participants will be added to the EAGER registry and data will be shared externally through established AIMS-2-TRIALS mechanisms. ETHICS AND DISSEMINATION: To date, EAGER has received full ethical approval for 11 out of the 13 sites in the UK (REC 23/SC/0022), Germany (S-375/2023), Portugal (CE-085/2023), Spain (HCB/2023/0038, PIC-164-22), Sweden (Dnr 2023-06737-01), Ireland (230907) and Italy (CET_62/2023, CEL-IRCCS OASI/24-01-2024/EM01, EM 2024-13/1032 EAGER). Findings will be disseminated via scientific publications and conferences but also beyond to participants and the wider community (eg, the AIMS-2-TRIALS website, stakeholder meetings, newsletters).