Richard Delorme

Background: Autism clinical trials are hampered by the lack of treatment response biomarkers. We investigated N170 latency (N170L), an electrophysiological (EEG) index of face processing speed, as a candidate biomarker of treatment response to arbaclofen, a selective GABA-B agonist. We previously reported that N170L is, on average, slower in autism, and linked to genetic, neurobiological, and socialisation variability. Here, we explored whether: 1) arbaclofen modulates N170L over 16 weeks; 2) baseline N170L or change in N170L (ΔN170L) predicts change in social functioning over 16 weeks; 3) N170L improves estimation of treatment effects. Methods: In this phase II, randomised, double-blind, placebo-controlled trial, 122 autistic children and adolescents (aged 5–17) were administered arbaclofen ( N = 59) or placebo ( N = 63) for 16 weeks. N170L was extracted from EEG recorded during passive viewing of upright faces at week 0 (baseline; N = 96) and week 16 (endpoint; N = 87). Treatment efficacy on social functioning was assessed using the Socialization domain of the Vineland Adaptive Behavior Scales, 3rd edition, alongside parent/clinician-rated outcomes. Pre-registered hypotheses were tested using linear mixed-effects models. Results: N170L remained stable over 16 weeks, with no significant change overall ( p = 0.371), and arbaclofen did not modulate N170L relative to placebo ( p = 0.737). Baseline N170L did not predict change in any clinical outcome (all p > 0.472). However, individual differences in ΔN170L were associated with selected clinical outcomes. In the placebo group, slowing of N170L was associated with greater peer interaction difficulties ( p = 0.032) and improved global clinical status ( p = 0.002). For social cognition, the associations differed by treatment group ( p = 0.022), with N170L slowing linked to greater social-cognitive difficulties under placebo, but fewer social-cognitive difficulties under arbaclofen. Baseline N170L and ΔN170L minimally impacted treatment effects estimation as covariates. Limitations: Interpretation of N170L–clinical associations is limited by short trial duration and reliance on broad, informant-based social measures that, while clinically meaningful, indirectly index face-processing abilities. Conclusions: N170L showed limited utility as treatment response biomarker in this trial, although its relevance in other therapeutic contexts remains to be determined. We also demonstrated feasibility of integrating EEG into multi-site autism clinical trials, supporting future biomarker-enabled pharmacological research. Trial registration: ClinicalTrials.gov, NCT03682978. Registered September 25, 2018.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with complex genetic and environmental underpinnings. A clinically significant subset of children with ASD experience developmental regression ( _reg ASD), characterized by the acute loss of previously acquired skills. The mechanisms, predictors, and molecular basis of _reg ASD remain poorly understood. We retrospectively and prospectively analyzed a cohort of 505 children diagnosed with ASD at the Center of Excellence for Autism and Neurodevelopmental Disorders (Paris, France) between 2017 and 2023. Clinical, neurodevelopmental, and genetic data were collected, including detailed developmental histories, standardized diagnostic assessments (ADI‐R, ADOS‐2, VABS), and chromosomal microarray analysis (CMA). Statistical analyses included classification tree algorithms and principal component analysis to identify clinical predictors of regression, and gene ontology enrichment to explore molecular pathways. Developmental regression was detected in 74 children (15%). Prior to regression, _reg ASD children exhibited more favorable neurodevelopmental profiles, including lower rates of prematurity, higher birth weight and height, and earlier acquisition of first words, compared with nonregressive ASD (non‐ _reg ASD) peers. However, after regression, _reg ASD children had significantly more severe neurodevelopmental impairments across cognitive, adaptive, and social domains ( p < 0.001). Routine clinical variables did not reliably predict the onset of regression. CMA revealed that _reg ASD is associated with distinct genetic deletions enriched in immune, inflammatory (particularly Type I interferon), oxidative stress, angiogenesis, and synaptic pathways, with minimal overlap with non‐ _reg ASD genetic profiles. Our findings are consistent with the hypothesis that _reg ASD may represent a distinct clinical and molecular subgroup within ASD. The molecular signatures identified in _reg ASD suggest involvement of immune and synaptic pathways, highlighting the need for further targeted research to clarify their potential therapeutic implications for this subgroup.

Whether the heterogeneity of psychiatric conditions converges on shared neurophysiological alterations or translates into distinct signatures remains unclear. We assembled high-density electroencephalogram (hd-EEG) resting-state recordings from 4,812 individuals aged 5 months to 66 years across 11 psychiatric conditions, a broad spectrum of rare genetic variants, and typically developing (TD) individuals. We established normative developmental trajectories of source-space EEG across spectral organization, connectivity, and signal complexity. Psychiatric conditions showed small deviations, revealing a shared transdiagnostic profile. In contrast, single rare variants showed substantially larger, distinct and sometimes mirror-opposite signatures that collapsed toward the psychiatric profile when pooled. Autism Spectrum Disorder showed some of the smallest group-level effects yet the largest individual deviations, indicating substantial but directionally inconsistent alterations. EEG deviations followed a cortical gradient, with larger effects in sensorimotor regions. We demonstrate that sample sizes in the hundreds are required for robust associations with psychiatric diagnoses. This interactive open resource provides normative scores to benchmark future results.

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.

Background: Motor as well as attentional skills are deficient in children with attention deficit hyperactivity disorder (ADHD). The aim of the present study was to explore whether a short immersive rehabilitation therapy could improve motor and visuo-attentional capabilities in children with ADHD. Methods: Forty children with ADHD participated in this study; IQ-, sex- and age-matched children were splitted in two groups (G1 and G2) of twenty. An unpredictable random sequence was used to allocate a child to group G1 (trained group) or G2 (control group). Oculomotor and postural performance for both groups of children were objectively assessed twice (before and after 16 min) by using an eye tracker and platform. Group G1 only underwent 16 min of immersive rehabilitation therapy, while the control group (G2) had 16 min of resting. The immersive therapy consisted of performing physical movement while training visual discrimination, attention and spatial orientation skills. Results: After 16 min, significant improvements in the fixation area (p = 0.008) and in the number of catch-up saccades during pursuit eye movements (p < 0.001), as well as a smaller postural instability index (PII) (p < 0.001), were observed for the trained group (G1) only. Conclusions: These findings suggest that children with ADHD could benefit from a short immersive therapy to improve both visual–attention and motor performances. This new immersive therapy is a useful tool allowing a better integration of both visual and motor sensory inputs via the cortico/cerebellar network. Follow-up studies on a larger number of children with ADHD will be necessary to explore the eventual possible persistence of such a training effect and imaging works will help to understand where such adaptive mechanisms take place.

Background/Objectives: Children with dyslexia report poor motor control; several studies have shown poor eye movements control during reading and important body instability in these children. The present study aimed to test in children whether reading and postural abilities in children with dyslexia could benefit from a short combined reading and postural training program. Methods: Thirty-two children with dyslexia were randomly assigned to training group (G1) or control group (G2). All participants completed eye movements recording during reading and postural recording under an unstable support before and after the intervention. G1 underwent a 10 min combined reading and postural training while G2 had a 10 min rest. During reading, the reading time, the duration of fixations, as well as the occurrence, amplitude, and number of forward saccades (saccades from the left to the right) and backward saccades (saccades from the right to the left) were measured. The PII (postural instability index) was measured under unstable support. G1 exhibited a significant decrease after training in reading time, fixation duration, and the number of forward saccades. Furthermore, we observed a significant reduction in postural instability. In contrast, G2 failed to show any significant changes in eye movements and postural recordings. Conclusions: We suggest such a combined reading and postural training approach could help dyslexic children to improve motor abilities. Adaptive mechanisms through improved cerebellar activity could be responsible for such motor enhancement.

Aim: The aim of this preliminary study was to explore the visual attention in children with ADHD using eye-tracking, and to identify a relevant quantitative proxy of their attentional control. Methods: Twenty-two children diagnosed with ADHD (aged 7 to 12 years) and their 24 sex-, age-matched control participants with typical development performed a visual sustained-fixation task using an eye-tracker. Fixation stability was estimated by calculating the bivariate contour ellipse area (BCEA) as a continuous index of gaze dispersion during the task. Results: Children with ADHD showed a significantly higher BCEA than control participants (p < 0.001), reflecting their increased gaze instability. The impairment in gaze fixation persisted even in the absence of visual distractors, suggesting intrinsic attentional dysregulation in ADHD. Conclusions: Our results provide preliminary evidence that eye-tracking coupled with BCEA analysis, provides a sensitive and non-invasive tool for quantifying visual attentional resources of children with ADHD. If replicated and extended, the increased use of gaze instability as an indicator of visual attention in children could have a major impact in clinical settings to assist clinicians. This analysis focuses on overall gaze dispersion rather than fine eye micro-movements such as microsaccades.