State-Dependent Modulation of Corticospinal and Cortical Responses by Closed-Loop Paired-pulse TMS

Brain oscillations shape cortical excitability in a phase-dependent manner. Cortical excitability reflects the net output of intracortical circuits, including inhibitory and facilitatory pathways. However, whether the phase of ongoing brain rhythms differentially modulates inhibitory and facilitatory responses remains unknown. Paired-pulse transcranial magnetic stimulation (ppTMS) can selectively engage these circuits, providing a unique tool to dissociate their contributions. We combined real-time EEG-guided closed-loop TMS with single- and paired-pulse TMS in 24 healthy adults (13 female) to probe how sensorimotor mu (8–13 Hz) and beta (14–30 Hz) oscillatory phase shapes responses associated with intracortical inhibitory and facilitatory processes. Single-pulse TMS (spTMS), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were delivered at four phases (peak, falling, trough, rising). Motor evoked potentials (MEPs) and TMS-evoked potentials (TEPs) were recorded to assess corticospinal and cortical responses, respectively. We found that MEP amplitude was phase-dependent across all three stimulation types, with spTMS-evoked and ICF-conditioned MEPs showing the largest amplitudes at the rising phase, whereas SICI-conditioned MEPs were largest at the peak phase of the mu oscillation. TEP P60-N100 amplitude was modulated by oscillatory phase across all stimulation types, with maximal responses at the trough phase. SICI showed opposing phase patterns between the two measures, revealing a dissociation between cortical and corticospinal responses. MEP and TEP preferred phases were correlated across participants only in the ICF condition. These findings extend phase-dependent spTMS effects to paired-pulse stimulation and show that ongoing mu phase differentially shapes responses to SICI and ICF across cortical and corticospinal levels. Significance Statement Ongoing brain oscillations are known to shape cortical excitability across their phase cycle. However, whether this effect differentially influences inhibitory and facilitatory responses has remained unresolved. Here, using closed-loop EEG-guided transcranial magnetic stimulation in healthy adults, we probed how SICI- and ICF-conditioned responses vary across different phases of the sensorimotor mu and beta rhythms. We show that corticospinal and cortical responses to inhibitory and facilitatory paired-pulse protocols exhibit distinct phase-dependent patterns in the sensorimotor mu rhythm. These findings extend phase-dependent stimulation effects beyond single-pulse TMS and reveal that the relationship between cortical state and stimulation response differs across paired-pulse protocols.