Contralesional cTBS promotes motor function by enhancing synaptic plasticity and axonal remodeling via TGF-β/Smad3/Foxp3 signaling axis in ischemic stroke rats.

BACKGROUND: Intracortical microstimulation (ICMS), an emerging therapeutic neuromodulation strategy, has shown promise in improving stroke recovery. However, the mechanisms of ICMS in promoting neurological restoration remain elusive. METHODS: We assessed motor dysfunction in middle cerebral artery occlusion/reperfusion (MCAO/R) rats following 3-week contralesional intermittent versus continuous theta-burst stimulation (iTBS vs. cTBS) in the subacute phase. Subsequently, we evaluated cTBS efficacy with or without TGF-β1 inhibitor (SB431542). We investigated structural and molecular alterations via RNA sequencing, magnetic resonance imaging, in-vivo electrophysiology, anterograde viral tract tracing, and histological methods. RESULTS: Contralesional cTBS significantly ameliorated MCAO/R-induced motor and structural deficits, which may depend on the TGF-β signaling and myelination pathways as confirmed by RNA sequencing. cTBS significantly increased the expressions of proteins such as MBP, PSD-95, SYN, pro-BDNF in the peri-infarct region and enhanced axonal fiber density as assessed by confocal images. Further results revealed that cTBS effectively shifted the neuro-inflammatory balance by elevating IL-10 and restraining pro-inflammatory IL-17 in the peri-infarct cortex via activating the TGF-β/Smad3/Foxp3 axis. TGF-β1 inhibition (SB431542) significantly reversed the behavioral and synaptic plasticity improvements following cTBS treatment. CONCLUSION: Contralesional cTBS could promote motor recovery by enhancing neuroplasticity and axonal remodeling via the TGF-β/Smad3/Foxp3 pathway.