Paired-pulse TMS of premotor cortex produces non-linear suppressive effects on neural activity in the targeted...

Transcranial magnetic stimulation (TMS) activates neural circuits in targeted and connected areas, yet it remains unclear how "TMS-dose" relates to local or network responses, particularly outside the primary motor hand area.

Eighteen healthy volunteers received TMS pulse-pairs (ppTMS) of the left dorsal premotor cortex (PMd) during functional magnetic resonance imaging (fMRI) at 3 Tesla, using an inter-pulse interval of 33 ms. We mapped stimulus-response profiles across the premotor-motor network, applying ppTMS as slow-frequency trains of pulse-pairs (i.e., blocked design) or single pulse-pairs (i.e., event-related design). Pulse-pairs were delivered at intensities of 65, 80, 95, or 110 % of resting motor threshold (RMT).

Pooling the effects of ppTMS across intensities revealed that both, single pulse-pairs and ppTMS trains produced a bilateral reduction in regional activity within the targeted dorsal premotor-motor network. Dose-dependent analysis revealed a non-linear dose-response pattern, with maximal suppression of left and right PMd activity at 80 % of RMT. The event-related and blocked fMRI design yielded similar results with net suppressive effects being more consistent during trains and dose-response dependencies being more consistent in response to single pulse-pairs. Auditory co-stimulation triggered bilateral increases in the auditory cortices.

Focal ppTMS may exert a net suppressive effect on neural activity within the targeted network. Network effects may follow a non-linear response pattern and may peak at relatively low stimulation intensities. These findings highlight the value of interleaved TMS-fMRI in elucidating the impact of stimulation parameters on regional and network-level brain dynamics.