Cumulative timing-dependent changes in corticospinal excitability during suprathreshold paired-pulse transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) is widely used to assess inhibitory and facilitatory circuits within the primary motor cortex. However, accumulating evidence suggests that even brief TMS paradigms may induce unintended changes in corticospinal excitability. Here, we examined whether suprathreshold paired-pulse TMS delivered at inter-stimulus intervals (ISIs) associated with intracortical facilitation or long-interval cortical inhibition (LICI) elicits cumulative changes in motor-evoked potential (MEP) amplitude. In experiment 1, we reanalysed data from 17 participants who received 20 suprathreshold paired-pulses at eight ISIs (10-200 ms) and 40 unconditioned single pulses. Stimulation was pseudo-randomised and distributed evenly across four blocks. A linear mixed-effects model assessed trial-wise changes in MEP amplitude across ISIs. We replicated the design in an independent sample (n=10, experiment 2). A significant trial-by-ISI interaction was observed in both cohorts. Specifically, MEP amplitudes increased across trials for ISIs of 20 and 30 ms (p<0.05), but remained stable at LICI-related ISIs (100-150 ms). A similar increase was also seen with single-pulse TMS. These findings demonstrate that suprathreshold paired-pulse TMS at short ISIs can cumulatively enhance corticospinal excitability during stimulation. Furthermore, the results suggest potential for using these protocols not just for probing cortical circuits, but also as interventions to modulate motor system excitability.