Combined intermittent and continuous theta-burst stimulation of the primary motor cortices for upper-extremity motor recovery and cortical excitability in ischemic stroke:a randomized controlled trial

Ischemic stroke remains a leading global cause of persistent motor disability, with upper-extremity paresis severely impairing functional independence in most survivors. Intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS) exert bidirectional neuromodulatory effects on cortical excitability, yet the therapeutic efficacy and neurophysiological mechanisms of combined bilateral TBS targeting primary motor cortices (M1) remain poorly elucidated for subacute stroke rehabilitation. This randomized, double-blind, sham-controlled pilot trial evaluated the safety, clinical efficacy, and neurophysiological correlates of ipsilesional iTBS combined with contralesional cTBS (i-cTBS) for upper-extremity motor recovery in subacute ischemic stroke, with a hierarchical statistical framework to distinguish confirmatory secondary endpoints from exploratory neurophysiological outcomes. Sixty-four patients with first-ever unilateral ischemic stroke (within 3 weeks post-onset) and upper-extremity motor impairment were randomized 1:1 to real i-cTBS ( n = 32) or sham stimulation ( n = 32). All participants received 10 daily sessions (5 sessions per week over 2 consecutive weeks) immediately followed by standardized task-oriented upper-extremity physiotherapy. The primary outcome was total Fugl-Meyer Assessment of Upper Extremity (FMA-UE) score. Tremor, dysmetria, and movement speed subscores served as confirmatory secondary endpoints with Bonferroni correction; motor-evoked potential (MEP) amplitude and resting motor threshold were exploratory neurophysiological measures. Group × time interactions were analyzed using a mixed-design analysis of variance. After the 2-week intervention, a significant group × time interaction was detected for total FMA-UE scores, with greater improvements in the real i-cTBS group ( p < 0.001, = 0.365). Tremor and dysmetria subscores showed pronounced benefits, while movement speed showed no between-group difference. MEP amplitude of the ipsilesional M1 was selectively potentiated only in the real group ( p < 0.001), and its gains were moderately correlated with motor functional improvement. No serious adverse events related to the intervention were documented. i-cTBS is a safe, well-tolerated intervention that delivers meaningful upper-extremity motor recovery in subacute ischemic stroke, with particular amelioration of tremor and dysmetria. The therapeutic effects are likely mediated by bidirectional normalization of interhemispheric excitability gradients and enhanced ipsilesional corticospinal plasticity, supporting its translational potential as an adjuvant therapy for early post-stroke neurorehabilitation.