Stimulus predictability rather than inter-trial interval itself affects motor evoked potential amplitudes

The inter-trial interval (ITI) of transcranial magnetic stimulation (TMS) can modulate motor-evoked potential (MEP) amplitude and may thus confound assessments of corticospinal excitability. We tested whether this effect depends on the ITI duration per se or the associated temporal predictability and whether intracortical inhibitory processes mediate these effects on. In 26 healthy participants, we recorded single-pulse MEPs and paired-pulse measures of short-interval intracortical inhibition (SICI; 2-ms interstimulus interval) and long-interval intracortical inhibition (LICI; 100-ms interstimulus interval) at ITIs of 2, 5, and 10 s. ITIs were presented in different Patterns, i.e., separate fixed blocks (FXD), randomly intermingled within blocks (RND), or randomly intermingled but auditorily cued at 950 ms pre-TMS (RNDC). MEPs showed significant effects of ITI, Pattern, and their interaction, being smaller at 2 s than at longer ITIs in FXD but not in RND and RNDC. However, RNDC produced marked MEP suppression across all ITI. SICI showed a Pattern x ITI interaction but no main effect of Pattern or between-pattern differences per ITI, whereas LICI showed complex Pattern x ITI interaction and both main effects. Notably, ITI affected SICI and LICI oppositely. While GABA-A-receptor mediated inhibition (SICI) showed an ITI dependency compatible with the ITI effects on single-pulse MEPs, it was unlikely mediating the predictability effects but may rather relate to an independent ITI driven suppression. In contrast, GABA-B-receptor mediated inhibition (LICI), was clearly modulated by predictability, but incompatible with the observed ITI effects on MEP amplitude. In summary, the effect of ITI duration on MEP amplitude seems to be largely explained by anticipatory suppression of corticospinal excitability based on the predictability of TMS pulses as derived from their temporal context, being easier for shorter and more regular ITIs and maximal for explicit cues immediately preceding the TMS pulse. SICI and LICI are modulated by ITI as well, with the latter affected by predictability, but neither can explain the observed predictability effects on single-pulse MEP amplitudes.