Cortical signatures across facilitatory neuromodulation protocols over the primary motor cortex: A TMS-EEG study

Repetitive transcranial magnetic stimulation (TMS) protocols, including high-frequency repetitive stimulation (rTMS), intermittent theta-burst stimulation (iTBS) and paired associative stimulation (PAS) are widely used for diagnostic and therapeutical purposes. Their mechanisms and sources of response variability remain unclear. TMS combined with electroencephalography (TMS-EEG) enables to track cortical dynamics induced by TMS interventions.

In this within-subject TMS-EEG study, we compared cortical and corticospinal aftereffects of three commonly used protocols applied over the primary motor cortex (M1). Twenty healthy volunteers completed three randomized sessions (iTBS, 10 Hz rTMS and PAS). Corticospinal excitability was assessed by motor evoked potentials (MEPs), whereas cortical reactivity by TMS-evoked potentials (TEPs) and TMS-related spectral perturbations (TRSP). Predictors of corticospinal facilitation were tested using hierarchical stepwise regression models.

All protocols increased MEP amplitude at the group level. Responder rates were 70% for iTBS, 75% for 10 Hz rTMS, and 85% for PAS, with partial overlap across individuals. iTBS and 10 Hz rTMS showed nominal increases in the N15 TEP component, whereas PAS showed nominal P60 modulation, but none of these effects survived correction for multiple comparisons. PAS induced a statistically significant theta-band TRSP modulation. Regression analyses identified protocol-specific TMS-EEG associations with corticospinal responses, involving baseline P60 and high-beta power for iTBS, high-beta modulation for 10 Hz rTMS, and P60 and theta modulation for PAS.

iTBS, 10 Hz rTMS, and PAS induce comparable corticospinal facilitation but distinct cortical signatures and protocol-specific cortical-corticospinal coupling profiles, supporting partially different mechanisms and the need for biomarker-guided personalization of neuromodulation.