Intermittent Theta Burst Stimulation Modulates Overlapping Network Architecture Through Neurochemical and Gene-Regulatory Pathways in Autism Spectrum Disorder With Insomnia

BackgroundOverlapping system-level architecture in the brain, supporting both functional integration and multifunctional regional engagement, may serve as a candidate biomarker for autism spectrum disorder (ASD) interventions. However, the biological mechanisms underlying the modulation of intermittent theta-burst stimulation (iTBS) for the overlapping system patterns are poorly characterized. MethodsSeventy ASD patients with chronic insomnia were randomly allocated to real or sham iTBS group targeting the left orbitofrontal cortex, with one session per day for 8 weeks. Insomnia Severity Index (ISI) and functional magnetic resonance imaging (fMRI) were collected at baseline and post-intervention. To explore the brain overlapping system, the Shannon-entropy diversity coefficient was calculated. Then we used JuSpace toolbox to quantify spatial correlation linking iTBS-induced reorganization to atlas-based nuclear-imaging derived neurotransmitter maps. Transcriptomic-neuroimaging association analysis were subsequently interrogated with Allen Human Brain Atlas gene expression data. ResultsSleep improvement following real iTBS was associated with restored functional integration across 13 multifunctional regions. Furthermore, these changes aligned with mGluR5 and GABAA receptor densities. The overlapping regions were strongly linked to glutamatergic synaptic transmission and calcium-dependent pathways, enriched in cortical excitatory neurons with peak expression during adolescence, and converged into a highly interconnected protein-protein interaction (PPI) network centered on the Ca{superscript 2}-PKA signaling axis. ConclusionsThis study provides multi-scale evidence for the biological mechanisms underlying iTBS modulation of the overlapping system patterns among ASD with chronic insomnia.