John G. Semmler

Repetitive paired‐pulse transcranial magnetic stimulation (TMS) at indirect (I)‐wave periodicity (iTMS) can increase plasticity in primary motor cortex (M1). Both TMS coil orientation and muscle activation can influence I‐wave activity, but it remains unclear how these factors influence M1 plasticity with iTMS. We therefore investigated the influence of TMS coil orientation and muscle activation on the response to iTMS. Thirty‐two young adults (24.2 ± 4.8 years) participated in three experiments. Each experiment included two sessions using a modified iTMS intervention with either a posterior–anterior orientation (PA) or anterior–posterior (AP) coil orientation over M1. Stimulation was applied in resting (Experiments 1 and 3) or active muscle (Experiments 2 and 3). Effects of iTMS on M1 excitability were assessed by recording motor evoked potentials (MEPs) and short‐interval intracortical facilitation (SICF) with PA and AP orientations in both resting (all experiments) and active (Experiment 2) muscle. For the resting intervention, MEPs were greater after AP iTMS (Experiment 1, P = .046), whereas SICF was comparable between interventions (all P > .10). For the active intervention, responses did not vary between PA and AP iTMS (Experiment 2, all P > .14), and muscle activation reduced the effect of AP iTMS during the intervention (Experiment 3, P = .002). Coil orientation influenced the MEP response after iTMS, and muscle activation reduced the response during iTMS. While this suggests that AP iTMS may be beneficial in producing a neuroplastic modulation of I‐wave circuits in resting muscle, further exploration of factors such as dosing is required.