Plasma Proteomics Provides Insights Into the Molecular Mechanisms of Repetitive Transcranial Magnetic Stimulation in Stroke Recovery

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive, safe intervention that has demonstrated efficacy in modulating motor, cognitive, and language functions in patients with stroke. However, the underlying molecular mechanisms remain inadequately characterized. This study aimed to investigate plasma proteomic changes associated with rTMS and to explore potential mechanisms contributing to its neuroprotective effects in stroke recovery. Six patients diagnosed with cerebral ischemia were enrolled in the study to monitor changes following a 4-week rTMS regimen. Plasma samples were collected before treatment initiation and at 4 weeks posttreatment. Mass spectrometry-based proteomic analysis was conducted to identify differentially expressed proteins. Comparative proteomic analysis revealed 142 differentially expressed plasma proteins following rTMS, with 84 upregulated and 58 downregulated. Gene ontology enrichment analysis indicated significant involvement in angiogenesis and neural plasticity. Pathway analysis revealed that rTMS might predominantly modulate the PI3K/Akt signaling pathway. Additionally, CAMK4, phosphoglycerate kinase 1, receptor-type tyrosine protein phosphatase delta, SERPINE1, programmed cell death protein 6, and beta-adducin exhibited strong positive associations with Fugl-Meyer Assessment-Upper Extremity scores and activities of daily living. The findings delineate a plasma proteomic signature associated with rTMS in patients with ischemic stroke, suggesting the PI3K/Akt pathway may serve as a potential regulatory mechanism. The identified proteins present candidate biomarkers worthy of further investigation, providing preliminary insights into the molecular changes associated with rTMS in neurorehabilitation.