Critical role of rhythms in prefrontal transcranial magnetic stimulation for depression: A randomized sham‐controlled study

Repetitive transcranial magnetic stimulation (rTMS) is an alternative treatment for depression, but the neural correlates of the treatment are currently inconclusive, which might be a limit of conventional analytical methods. The present study aimed to investigate the neurophysiological evidence and potential biomarkers for rTMS and intermittent theta burst stimulation (iTBS) treatment. A total of 61 treatment‐resistant depression patients were randomly assigned to receive prolonged iTBS (piTBS; N = 19), 10 Hz rTMS (N = 20), or sham stimulation (N = 22). Each participant went through a treatment phase with resting state electroencephalography (EEG) recordings before and after the treatment phase. The aftereffects of stimulation showed that theta‐alpha amplitude modulation frequency (fam) was associated with piTBS_Responder, which involves repetitive bursts delivered in the theta frequency range, whereas alpha carrier frequency (fc) was related to 10 Hz rTMS, which uses alpha rhythmic stimulation. In addition, theta‐alpha amplitude modulation frequency was positively correlated with piTBS antidepressant efficacy, whereas the alpha frequency was not associated with the 10 Hz rTMS clinical outcome. The present study showed that TMS stimulation effects might be lasting, with changes of brain oscillations associated with the delivered frequency. Additionally, theta‐alpha amplitude modulation frequency may be as a function of the degree of recovery in TRD with piTBS treatment and also a potential EEG‐based predictor of antidepressant efficacy of piTBS in the early treatment stage, that is, first 2 weeks. The present study, utilizing HHSA to study the nonlinear cross‐frequency modulation, provided evidence of the distinct antidepressant neural correlates of 10 Hz rTMS and piTBS for TRD. The findings suggested that the TMS treatment, whatever protocol was applied, may provide lasting benefits, with the possible entrainment aftereffects seemingly revealed in resulting brain oscillation changes. Furthermore, our findings imply that theta‐alpha amplitude modulation frequency changes may indicate a function of response to piTBS treatment, not for rTMS, which may also indicate a possible predictive biomarker for treatment efficacy of piTBS in the early treatment stage, that is, first 2 weeks.