Differential neural responses to rhythmic and patterned TMS protocols: Insights from EEG spectral analysis

Repetitive Transcranial Magnetic Stimulation (rTMS) engages brain networks for the treatment of Major Depressive Disorder (MDD), using either rhythmic (e.g., 10 Hz) or patterned (e.g., intermittent Theta Burst, or iTBS) stimulation protocols. The distinct effects of these protocols on brain function are not well understood. Sixteen subjects with MDD underwent a TMS-electroencephalography (TMS-EEG) "interrogation" paradigm, in which a broad range of rhythmic and patterned stimulation frequencies were administered in a randomized order to the left dorsolateral prefrontal cortex (L-DLPFC). rTMS-induced changes in oscillatory activity and effective connectivity to the DLPFC were examined at each frequency. Linear mixed-effects models revealed widespread changes in power and connectivity, with magnitude and regional distribution of change dependent upon both protocol and frequency of stimulation. Increases in beta band power were most prominent with patterned stimulation, while rhythmic stimulation increased both alpha and beta power at stimulation frequencies greater than 7 Hz (p < 0.05). Source localization showed that patterned and rhythmic stimulation elicited activation in distinct subregions of the cingulate. Rhythmic and patterned stimulation also had distinct effects on connectivity: notably, only rhythmic stimulation increased connectivity with regions near the stimulation site, while only patterned stimulation decreased connectivity to the left precuneus. Both protocols increased the effective connectivity to the orbitofrontal cortex in the theta and beta response bands (p < 0.05). These results indicate that rhythmic and patterned rTMS engage distinct brain regions in a protocol- and frequency-dependent manner. Future studies should examine how these mechanistic differences may relate to clinical outcomes.