Closed-Loop rTMS Induces Frequency-Specific Cortical Network Reorganization Distinct from Open-Loop Stimulation in Healthy Humans

Objective: To determine whether mu-phase-locked closed-loop repetitive transcranial magnetic stimulation (rTMS) induces distinct changes in corticospinal excitability and large-scale cortical functional connectivity (FC) compared with conventional open-loop stimulation. Methods: Ten healthy volunteers underwent randomized, single-blind closed-loop, open-loop, and sham sessions in a crossover design. Closed-loop rTMS targeted the left primary motor cortex and was synchronized with the predicted negative peak of the individual mu rhythm; open-loop stimulation was delivered at 10 Hz. Each active session comprised 1,500 pulses. Motor-evoked potentials (MEPs) and resting-state high-density EEG were acquired before and after stimulation. Source-space weighted phase-lag index connectivity was analyzed across canonical frequency bands using the Network-Based Statistic. Results: Both active protocols increased corticospinal excitability relative to baseline, whereas sham stimulation did not. The MEP increase was greater after closed-loop than open-loop stimulation (143.3+-13.6% vs 132.5+-16.0%; p=0.031). Open-loop rTMS reduced alpha-band FC. Closed-loop rTMS similarly reduced alpha-band FC but additionally increased beta- and high-gamma-band connectivity. Direct comparisons of individual FC changes confirmed significantly greater beta- and high-gamma increases after closed-loop than after open-loop stimulation, whereas alpha-band changes did not differ between the protocols. No significant changes in FC occurred after sham stimulation. Conclusions: mu-phase-locked closed-loop rTMS enhanced corticospinal facilitation and induced broader, frequency-specific network reorganization than 10 Hz open-loop stimulation. Significance: These preliminary findings indicate that stimulation timing relative to the ongoing cortical state may critically shape both local excitability and distributed network plasticity, supporting the further development of brain-state-dependent neuromodulation in future, larger, phase-controlled clinical studies.