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

13/08/2026

AI Summary

Real iTBS over left orbitofrontal cortex improved insomnia in ASD and reorganised overlapping network architecture across 13 cortical regions.
iTBS-related network changes corresponded spatially with mGluR5 and GABA_A receptor density maps, implicating glutamatergic and GABAergic systems.
Affected regions enriched for excitatory neuronal signatures, glutamatergic synaptic and calcium-dependent signalling, organised into a Ca2+-PKA centred protein interaction network.

AI Summary

However, the biological context underlying intermittent theta-burst stimulation (iTBS)-related changes in overlapping network architecture remains poorly understood.

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.

Basic summary

CNS Neurosci Ther. 2026 Aug;32(8):e71041. doi: 10.1002/cns.71041.

ABSTRACT

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.

PMID:42590803 | DOI:10.1002/cns.71041

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