Double-blind, sham-controlled, pilot study of trigeminal nerve stimulation for autism spectrum disorder.

Trigeminal nerve stimulation (TNS) is a minimal-risk, noninvasive neuromodulation method with growing evidence of efficacy across psychiatric conditions. However, its safety and potential effects in autism spectrum disorder (ASD) remain underexplored. This exploratory pilot study aimed primarily to evaluate the safety and tolerability, and secondarily to explore changes in ASD-related symptoms - including impairments in social communication and reciprocity, attention, executive functioning, emotional regulation, sleep, and sensory processing - in children with ASD, and to examine associated changes using quantitative electroencephalography (qEEG). This double-blind, sham-controlled, randomized exploratory pilot trial enrolled 29 children aged 7-12 years with ASD. The participants were randomized to receive 28 nightly sessions of active or sham TNS over 4 weeks. At baseline and week 4, we assessed safety, clinical outcomes and Clinical Global Impression scales, in addition to analyzing qEEG band power. No serious adverse events were observed, and TNS was well tolerated. Exploratory analyses showed nominal between-group differences (unadjusted) favoring the TNS group in maladaptive behavior (Vineland-II: 1.38 vs 0.08; p = .017) and social reciprocity (Social Responsiveness Scale-2: 12.07 vs -1.43; p = .025). Exploratory qEEG analyses revealed decreased gamma/high-frequency and increased alpha power in the left frontal and parietal regions, changes that significantly correlated with improvements in social (r = -0.917; p = .001) and overall (r = -0.680; p = .030) functioning. TNS was safe and showed preliminary evidence of potential benefits in improving behavioral and social functioning in children with ASD. Larger trials are required to confirm these findings. Clinical trial registration information: http://clinicaltrials.gov/; NCT06233279.