Differential Effect of Conditioning Sequences in Coupling Inhibitory/Facilitatory Repetitive Transcranial Magnetic Stimulation for PostStroke Motor Recovery

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While neuromodulation through unihemispheric repetitive transcranial magnetic stimulation (rTMS) has shown promise for the motor recovery of stroke patients, the effectiveness of the coupling of different rTMS protocols remains unclear. We aimed to test the long-term efficacy of this strategy with different applying sequences and to identify the electrophysiological correlates of motor improvements to the paretic hand. In our sham-controlled, double-blinded parallel study, 48 stroke patients (2-6 months poststroke) were randomly allocated to three groups. Group A underwent 20-session rTMS conditioning initiated with 10-session 1 Hz rTMS over the contralesional primary motor cortex (M1), followed by 10-session intermittent theta burst stimulation (iTBS) consequently over the ipsilesional M1; Group B underwent the same two paradigms but in reverse; and Group C received sham stimulation that was identical to Group A. We tested cortical excitability and motor assessments at the baseline, postpriming rTMS, postconsequent rTMS, and at 3-months follow-up. Group A manifested greater improvement than Group B in Fugl-Meyer Assessment (FMA), Wolf Motor Function testing (WMFT) score, and muscle strength (P = 0.001-0.02) post the priming rTMS. After the consequent rTMS, Group A continued to present a superior outcome than Group B in FMA (P = 0.015) and WMFT score (P = 0.008) with significant behavior-electrophysiological correlation. Conditioning the contralesional M1 prior to ipsilesional iTBS was found to be optimal for enhancing hand function, and this effect persisted for at least 3 months. Early modulation within 6 months poststroke rebalances interhemispheric competition and appears to be a feasible time window for rTMS intervention.