Neuromodulatory mechanisms and therapeutic effects of repetitive transcranial magnetic stimulation (rTMS) in multiple sclerosis: A systematic review and exploratory meta-analysis.

Noninvasive neuromodulatory interventions, particularly repetitive Transcranial Magnetic Stimulation (rTMS) and intermittent Theta Burst Stimulation (iTBS), are increasingly emerging as alternative and complementary approaches for symptomatic management of Multiple Sclerosis (MS). This systematic review and exploratory meta-analysis synthesized evidence from 11 Randomized Controlled Trials (RCTs) evaluating the clinical efficacy and underlying mechanisms of rTMS. Across individual trials, directionally consistent short-term improvements were observed in spasticity, fatigue, balance, gait, dexterity, and cerebellar functions. Exploratory Meta-analytic results indicated a reduction in spasticity, as well as modest improvements in fatigue and depressive symptoms. Neuroimaging findings further suggested microstructural changes consistent with altered white matter properties. Potential mechanisms include modulation of cortical excitability, synaptic plasticity, interhemispheric balance, and neuroimmune processes. Despite these promising directional trends, small sample sizes, variability in stimulation protocols, and limited geographic representation limit the broader generalizability and robustness of these findings. Overall, rTMS appears generally well tolerated in small trials, with short-term symptomatic improvements reported in some domains. These preliminary findings highlight the need for longitudinal trials employing standardized stimulation protocols and multimodal outcome assessments to elucidate sustained efficacy and underlying mechanisms.