Intermittent Theta Burst Stimulation Improves Sleep in Autism Spectrum Disorder by Reorganizing Overlapping Brain Networks With Neurochemical and Transcriptomic Signatures: A Randomized Controlled Trial.

BACKGROUND

Overlapping network architecture supports functional integration and multifunctional regional engagement in the brain, and may serve as a candidate biomarker for interventions in autism spectrum disorder (ASD). However, the biological context underlying intermittent theta-burst stimulation (iTBS)-related changes in overlapping network architecture remains poorly understood.

METHODS

Seventy patients with ASD and chronic insomnia were randomly assigned to receive either real or sham iTBS targeting the left orbitofrontal cortex, administered once daily for 8 weeks. The Insomnia Severity Index (ISI) and resting-state functional magnetic resonance imaging (fMRI) data were collected at baseline and after the intervention. The Shannon-entropy diversity coefficient was calculated to characterize overlapping network architecture. The JuSpace toolbox was used to assess spatial correspondence between iTBS-related network changes and neurotransmitter systems. Transcriptomic-neuroimaging association analyses were then performed using gene-expression data from the Allen Human Brain Atlas.

RESULTS

Sleep improvement following real iTBS was accompanied by changes in overlapping network architecture across 13 cortical regions. These changes showed spatial correspondence with mGluR5 and GABA_A receptor density maps. Regions showing iTBS-related network changes were associated with glutamatergic synaptic transmission and calcium-dependent signaling, enriched for cortical excitatory neuronal signatures with peak expression during adolescence, and organized into a highly interconnected protein-protein interaction network centered on the Ca²⁺-PKA signaling axis.

CONCLUSIONS

This study provides multiscale evidence for the biological context underlying iTBS-related changes in overlapping network architecture in ASD with chronic insomnia.

© 2026 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.