Interventional rTMS for Improving Social Perception in Autism (IRIS-gaze)

Autism spectrum disorder (ASD) is a neurodevelopmental condition mainly characterized by persistent difficulties in social communication and interaction, together with restricted and repetitive patterns of behavior. Despite substantial progress in understanding the neurobiological mechanisms underlying ASD, therapeutic options specifically targeting core social difficulties remain limited. Non-invasive brain stimulation techniques, including transcranial magnetic stimulation (TMS), therefore represent a promising approach for investigating and potentially modulating neural networks involved in social functioning.

Neuroimaging studies have consistently identified structural and functional abnormalities localized in the superior temporal sulcus (STS) in individuals with ASD. The STS is a key component of the social brain network and is involved in the processing and integration of socially relevant information, including faces, gaze, voices, biological motion, and other dynamic social cues. Functional and structural abnormalities of this region, as well as altered connectivity between the STS and other components of the social brain network, have been reported in ASD. These findings provide the neurobiological rationale for targeting the STS in the present study.

Previous work by our research team has investigated whether modulation of the right posterior STS (pSTS) using TMS can influence social perception. A first study in typically developing adults established a causal relationship between modulation of pSTS activity and changes in visual exploration of socially relevant information. Subsequent studies in young adults with ASD demonstrated the feasibility and good tolerability of excitatory intermittent theta-burst stimulation (iTBS) targeting the right pSTS. More recently, a pilot randomized, double-blind, sham-controlled clinical trial in young adults with ASD evaluated repeated iTBS sessions targeting this region. The intervention was feasible and well tolerated, and preliminary findings suggested differential changes in social behavior following active compared with sham stimulation. These findings support further investigation of this approach using a more intensive stimulation protocol.

The IRIS-gaze study investigates an accelerated iTBS protocol targeting the right pSTS in pre-adolescents and adolescents with ASD. Adolescence represents a developmental period characterized by substantial brain plasticity and may therefore constitute a particularly relevant period for neuromodulatory interventions. Accelerated TMS protocols, in which several stimulation sessions are administered each day over a limited number of days, are designed to induce cumulative neuroplastic effects while substantially reducing the overall duration of treatment compared with conventional repeated TMS schedules.

IRIS-gaze is an interventional, randomized, double-blind, sham-controlled crossover clinical trial. Sixteen participants will receive both active and sham stimulation in a randomized order. Each treatment period consists of five iTBS sessions per day for four consecutive days, for a total of 20 sessions per treatment period. The two treatment periods are separated by a washout period of approximately three months (3 months ± 2 weeks), selected to minimize potential carry-over effects between active and sham stimulation. The crossover design allows each participant to serve as his or her own control, thereby reducing the influence of inter-individual variability, and insures that all participants receive the active condition.

Stimulation will be performed using a MAGSTIM RAPID2® stimulator and a cooled figure-of-eight coil. The right pSTS target will be individually identified from each participant's structural MRI and localized during stimulation using MRI-guided neuronavigation. Before stimulation, the individual motor threshold will be determined using single-pulse TMS. Each iTBS session will deliver 1,800 pulses, consisting of bursts of three pulses at 50 Hz repeated at 5 Hz, delivered in 2-second trains separated by 8-second intervals. Five sessions will be administered each day, separated by 50-minute intervals.

The sham condition will follow the same schedule and procedures as active stimulation. A dedicated sham coil will reproduce the appearance, acoustic characteristics, and sensory experience of active stimulation without inducing cortical stimulation. Investigators conducting MRI, eye-tracking, and clinical assessments will remain blinded to stimulation condition.

A multimodal evaluation strategy will be used to characterize potential effects of the intervention. Social visual behavior will be objectively assessed using infrared eye-tracking during the presentation of dynamic social stimuli. Brain MRI will complement the behavioral assessment by investigating potential changes in cerebral perfusion, resting-state functional connectivity, and white-matter microstructure. Clinical assessments completed with parents will provide complementary information regarding social behavior and overall functioning. Assessments will be performed at predefined time points throughout the crossover protocol, allowing comparison of changes associated with active and sham stimulation.

The study combines targeted non-invasive neuromodulation with objective behavioral measurements and multimodal neuroimaging to investigate the effects of accelerated iTBS on neural systems involved in social functioning in young people with ASD. Beyond evaluating the potential clinical relevance of this approach, IRIS-gaze aims to improve understanding of the relationship between modulation of the right pSTS, brain network plasticity, and social behavior in ASD. Ultimately, this study could pave the way for a novel non-invasive therapeutic approach aimed at improving social functioning in children and adolescents with ASD.