Closed-Loop rTMS Induces Frequency-Specific Cortical Network Reorganization Distinct from Open-Loop Stimulation in Healthy Humans
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Objective
To determine whether μ-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 μ 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 α-band FC. Closed-loop rTMS similarly reduced α-band FC but additionally increased β- and high-γ-band connectivity. Direct comparisons of individual FC changes confirmed significantly greater β- and high-γ increases after closed-loop than after open-loop stimulation, whereas α-band changes did not differ between the protocols. No significant changes in FC occurred after sham stimulation.
Conclusions
μ-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.
