Functional and effective connectivity between dorsolateral prefrontal and subgenual anterior cingulate cortex depends on the timing of transcranial magnetic stimulation relative to the phase of prefrontal alpha EEG

BACKGROUND The communication through coherence model posits that brain rhythms are synchronized across different frequency bands and that effective connectivity strength between interacting regions depends on their phase relation. Evidence to support the model comes mostly from electrophysiological recordings in animals while evidence from human data is limited. METHODS Here, an fMRI-EEG-TMS (fET) instrument capable of acquiring simultaneous fMRI and EEG during noninvasive single pulse TMS applied to dorsolateral prefrontal cortex (DLPFC) was used to test whether prefrontal EEG alpha phase moderates TMS-evoked top-down influences on subgenual, rostral and dorsal anterior cingulate cortex (ACC). Results in healthy volunteers (n=11) were compared to those from patients with major depressive disorder (MDD) (n=17) collected as part of a ongoing clinical trial investigation. RESULTS In both groups, TMS-evoked functional connectivity between DLPFC and subgenual ACC (sgACC) depended on the EEG alpha phase. TMS-evoked DLPFC to sgACC effective connectivity (EC) was moderated by EEG alpha phase in healthy volunteers, but not in the MDD patients. Top-down EC was inhibitory for TMS onsets during the upward slope of the alpha wave relative to TMS timed to the downward slope of the alpha wave. Prefrontal EEG alpha phase dependent effects on TMS-evoked fMRI BOLD activation of the rostral anterior cingulate cortex were detected in the MDD patient group, but not in the healthy volunteer group. DISCUSSION Results demonstrate that TMS-evoked top-down influences vary as a function of the prefrontal alpha rhythm, and suggest clinical applications whereby TMS is synchronized to the brain’s internal rhythms in order to more efficiently engage deep therapeutic targets. ### Competing Interest Statement Authors SPP, JRM, GTS, XS, JD, JF, YL, JBT, AB, RIG, SH, TRB have no relevant conflicts of interest to report. Dr. George reports being a paid consultant to Sooma Medical (tDCS) and Neuralief (VNS, trigeminal), and being an unpaid consultant to Mecta (ECT), Brainsway (TMS), Magnus Medical (TMS), Magstim (TMS), Brainsonix (ultrasound). He was a paid DSMB member for Microtransponder (VNS). He has loaned research equipment from MECTA, and Magstim. He has held research grants from Brainsway, Neuralief, Livanova. Dr. Sajda reports being a paid consultant for Optios Inc. and OpenBCI LLC.