Stimulation Parameters Recruit Distinct Cortico-Cortical Pathways: Insights from Microstate Analysis on TMS-Evoked Potentials

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) represent an innovative measure for examining brain connectivity and developing biomarkers of psychiatric conditions. Minimizing TEP variability across studies and participants, which may stem from methodological choices, is therefore vital. By combining classic peak analysis and microstate investigation, we tested how TMS pulse waveform and current direction may affect cortico-cortical circuit engagement when targeting the primary motor cortex (M1). We aim to disentangle whether changing these parameters affects the degree of activation of the same neural circuitry or may lead to changes in the pathways through which the induced activation spreads. Thirty-two healthy participants underwent a TMS-EEG experiment in which the pulse waveform (monophasic, biphasic) and current direction (posterior-anterior, anterior-posterior, latero-medial) were manipulated. We assessed the latency and amplitude of M1-TEP components and employed microstate analyses to test differences in topographies. Results revealed that TMS parameters strongly influenced M1-TEP components' amplitude but had a weaker role over their latencies. Microstate analysis showed that the current direction in monophasic stimulations changed the pattern of evoked microstates at the early TEP latencies, as well as their duration and global field power. This study shows that the current direction of monophasic pulses may modulate cortical sources contributing to TEP signals, activating neural populations and cortico-cortical paths more selectively. Biphasic stimulation reduces the variability associated with current direction and may be better suited when TMS targeting is blind to anatomical information.