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Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome

  • W. Li
  • W. Sun
  • J. Su
  • F. Yang
  • X. Qiu
  • Y. Zhuo
  • Z. Yang
  • Z. Wang1
  • Z. Chen
  • T. Huang
  • H. Wang1
  • H. Xing
4 more authors
  • W. Ji
  • T.-F. Yuan
  • Y. Chen
  • J. Wang1
  1. 1Kunming University of Science and Technology
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Abstract

Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene, currently lacks effective treatments. The motor cortex is a pivotal hub in RTT and autism spectrum disorders, and its impairments contribute to motor, social, and cognitive deficits. Here we examined the effects of repetitive transcranial magnetic stimulation (rTMS) targeting motor area in non-human primate of RTT (MECP2-mutant monkey) and investigated neuromolecular basis underlying therapeutic effects. We identified a new treatment target, ventral premotor cortex (PMv), for RTT and found that following a 20-day rTMS course, several behavioral and functional connectivity measures showed directional changes. Neuroimaging analyses confirmed that rTMS induced reorganization of large-scale functional connectivity with enhanced functional integration between the somatomotor and the salience networks and normalized coupling between the motor cortex and both the thalamus and the anterior cingulate cortex. Notably, single-nucleus RNA sequencing revealed that rTMS triggered cell-type-specific transcriptional reprogramming: it rescued pathological hyperactivity of excitatory neurons by restoring the expression and regulatory networks of immediate early genes (e.g., FOS, EGR1) and corrected dysregulated intercellular signaling (e.g., NRG, WNT). These findings indicate that targeting motor cortical areas with brain stimulation may treat RTT, which warrants further clinical validation.

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Cite

BibTeXRIS
BibTeX
@misc{li2026repetitive,
  title = {{Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome}},
  author = {W. Li and W. Sun and J. Su and F. Yang and X. Qiu and Y. Zhuo and Z. Yang and Z. Wang and Z. Chen and T. Huang and H. Wang and H. Xing and W. Ji and T.-F. Yuan and Y. Chen and J. Wang},
  howpublished = {bioRxiv},
  year = {2026},
  month = oct,
  doi = {10.64898/2026.10.20.760437},
  url = {https://www.biorxiv.org/content/10.64898/2026.10.20.760437v1},
  note = {CC BY},
}
RIS
TY  - UNPB
TI  - Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome
AU  - W. Li
AU  - W. Sun
AU  - J. Su
AU  - F. Yang
AU  - X. Qiu
AU  - Y. Zhuo
AU  - Z. Yang
AU  - Z. Wang
AU  - Z. Chen
AU  - T. Huang
AU  - H. Wang
AU  - H. Xing
AU  - W. Ji
AU  - T.-F. Yuan
AU  - Y. Chen
AU  - J. Wang
PY  - 2026
DA  - 2026/10/20
PB  - bioRxiv
DO  - 10.64898/2026.10.20.760437
UR  - https://www.biorxiv.org/content/10.64898/2026.10.20.760437v1
AB  - Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene, currently lacks effective treatments. The motor cortex is a pivotal hub in RTT and autism spectrum disorders, and its impairments contribute to motor, social, and cognitive deficits. Here we examined the effects of repetitive transcranial magnetic stimulation (rTMS) targeting motor area in non-human primate of RTT (MECP2-mutant monkey) and investigated neuromolecular basis underlying therapeutic effects. We identified a new treatment target, ventral premotor cortex (PMv), for RTT and found that following a 20-day rTMS course, several behavioral and functional connectivity measures showed directional changes. Neuroimaging analyses confirmed that rTMS induced reorganization of large-scale functional connectivity with enhanced functional integration between the somatomotor and the salience networks and normalized coupling between the motor cortex and both the thalamus and the anterior cingulate cortex. Notably, single-nucleus RNA sequencing revealed that rTMS triggered cell-type-specific transcriptional reprogramming: it rescued pathological hyperactivity of excitatory neurons by restoring the expression and regulatory networks of immediate early genes (e.g., FOS, EGR1) and corrected dysregulated intercellular signaling (e.g., NRG, WNT). These findings indicate that targeting motor cortical areas with brain stimulation may treat RTT, which warrants further clinical validation.
ER  -