Daily prefrontal closed-loop repetitive transcranial magnetic stimulation (rTMS) produces a progressive entrainment-dependent clinical response in depressed adults

In recent decades, increasing evidence suggests the alpha phase is an index of excitation and inhibition across or within networks. Therefore, whether the phase of the endogenous EEG alpha rhythms mediates top-down influences in the human brain, particularly in response to stimulation (e.g., TMS), is an active area of investigation. Under the hypothesis that phase-locked TMS pulse delivering may affect brain dynamics and neurostimulation efficacy, our group developed a novel closed-loop EEG-rTMS system where we could trigger the TMS pulse train at a specific phase of each patient's prefrontal EEG quasi-alpha rhythm (6-13 Hz).

In this double-blind study, 24 patients with major depressive disorder received daily treatments of rTMS over six weeks. They were randomly assigned to either a synchronized or unsynchronized treatment group. When rTMS is applied over the dorsal lateral prefrontal cortex and synchronized to the patient's EEG rhythm, patients develop increasing alpha phase entrainment over the stimulation site. In addition, at the end of the treatment course, patients who showed more robust phase entrainment across entire treatments would have a better clinic improvement. We did not observe similar effects in the group given rTMS without initial EEG synchronization. The entrainment effects build over days/weeks, suggesting that these effects engage neuroplastic changes. Moreover, this observed entrainment across treatments in the synchronized group has clinical consequences for depression.