Sources of the N15 TMS-Evoked Potential Following Motor Cortex Stimulation Localize Rostral to TMS-Induced Electric Fields and Depend on Dose

Abstract

Transcranial magnetic stimulation (TMS) elicits characteristic cortical responses known as TMS-evoked potentials (TEPs) measured via electroencephalography (EEG). An early negative peak can be consistently evoked over the motor cortex at around 15 ms (N15). It remains elusive whether N15 overlaps with the cortical regions receiving the highest TMS-induced electric field (E-field). We characterized the source activity of the N15 component relative to the TMS-induced E-field in 16 healthy adults who underwent TMS-EEG over the left primary motor hand area at six stimulus intensities (-8% to +12% maximum stimulator output relative to resting motor threshold) during rest and tonic contraction. Individualized head models, based on T1 and T2 MRI scans, were used for E-field simulations and source localization with LCMV, dSPM, and eLORETA as inverse solvers. Linear mixed-effects models and spatial clustering were used to assess dose- and state-dependent effects. The N15 source field was consistently located rostral to the TMS-induced electric field, with the spatial disparity decreasing as the stimulation dose increased. N15 source activity primarily clustered in the left premotor and primary motor cortex, while the TMS E-field peaked in the crowns of the pre- and postcentral gyri. All three inverse solvers yielded similar results, demonstrating consistent dose- and state-dependent effects on the N15 and suggesting that solver choice had minimal impact. These findings demonstrate a spatial mismatch between early TMS-evoked potentials following motor cortex stimulation and the cortical regions exposed to peak electric fields. Combined with prior literature, our findings provide evidence that the rostral N15 source activity reflects transsynaptic propagation via direct cortico-cortical or indirect cortico-subcortico-cortical pathways.