Accelerated intermittent theta burst stimulation targeting personalized fronto-parietal control network improves core symptoms of autism spectrum disorder: a double-blind, randomized controlled trial

Autism Spectrum Disorder (ASD) presents a substantial global challenge, yet no pharmacological treatments effectively target its core symptoms, especially in individuals with severe cognitive or adaptive impairments. This double-blind, sham-controlled, randomized clinical trial assessed accelerated intermittent theta burst stimulation (iTBS) targeting the personalized fronto-parietal network (FPN) in ASD. Participants (6-30 years) were randomized in a 2:1 ratio to active or sham iTBS (three daily sessions, 1800 pulses/session) over 12 weeks (324k pulses) alongside behavioral training. The primary outcome was defined as the response rate, charaterized by a ≥ 1-point reduction in ADOS-2 SA at week 12. Of 132 individuals screened, 67 were randomized (mean age 10.04 ± 4.22 years; 88.1% male; all with cognitive/adaptive delays), with 59 completing the study. Active iTBS resulted in a significantly higher response rate (55% vs. 29%) and higher symptom improvement than sham (cohen's d = -0.53), with mild local pain in only 5% of iTBS group. In the profound autism subgroup, the active group exhibited language improvement alongside amelioration of core symptoms. These findings suggest that prolonged, accelerated FPN-targeted iTBS is a safe and efficacious intervention for severe ASD, offering a promising therapeutic approach.Registration ClinicalTrials.gov Identifier: NCT05890846.