tDCS Improves Sleep in Adolescent Schizophrenia by Reorganizing Overlapping Brain Networks with Neurochemical and Transcriptomic Signatures: a Randomized Controlled Trial

BackgroundChronic insomnia is a highly prevalent and disabling comorbidity in adolescent schizophrenia. Although schizophrenia has been increasingly conceptualized as a disorder of large-scale brain network disconnection, the mechanisms by which neuromodulation acts on overlapping system-level network architecture to improve sleep remain poorly understood. Here, we investigated the network, neurochemical, and transcriptomic mechanisms underlying transcranial direct current stimulation-based sleep improvement in adolescents with schizophrenia. MethodsIn a randomized, double-blind, sham-controlled trial, 78 adolescent schizophrenia with chronic insomnia received either active or sham transcranial direct current stimulation (tDCS). The anode was positioned over the left dorsolateral prefrontal cortex (DLPFC) and the cathode over the right DLPFC (20 sessions over 4 weeks). Insomnia Severity Index (ISI) and resting-state functional magnetic resonance imaging (fMRI) were assessed at baseline and post-treatment. We employed a multiscale analytical framework: Shannon-entropy diversity coefficients quantified overlapping system architecture; JuSpace toolbox assessed spatial correspondence with neurotransmitter maps; and the Allen Human Brain Atlas interrogated transcriptomic correlates. ResultsActive tDCS significantly improved insomnia symptoms compared to sham stimulation. This clinical improvement was accompanied by reorganization of overlapping network architecture involving 15 cortical regions with cross-network participation across attention, somatomotor, visual, and default-mode systems. Greater reduction in Shannon-entropy diversity coefficients was correlated with greater insomnia improvement. Spatially, such Shannon-entropy diversity coefficients changes aligned with the distribution of the dopaminergic transporter (DAT), metabotropic glutamate receptor 5 (mGluR5), and vesicular acetylcholine transporter (VAChT). At the molecular level, expression of 104 genes correlated with tDCS-sensitive regions, enriched for ionotropic glutamatergic signaling and AMPA/NMDA receptor complexes, and showed peak expression in cortical excitatory neurons during adolescence. ConclusionstDCS alleviates insomnia in adolescents with schizophrenia by restoring dysfunctional overlapping system architecture, a process spatially constrained by dopaminergic, glutamatergic, and cholinergic systems and supported by an adolescent-relevant glutamate gene network. Our findings reveal a multiscale pathway for neuromodulation and provide a biologically-grounded blueprint for developing sleep-focused personalized interventions in serious mental illness. Trial registrationThis study was registered in the Chinese Clinical Trial Registry (No. ChiCTR2600116100). Registered 5 January 2026 - Retrospectively registered, https://www.chictr.org.cn/showproj.html?proj=288899