State-Dependent Neuromodulation Reveals Link Between Online and Offline Corticospinal Excitability

The post-intervention effects of non-invasive neuromodulation techniques are critical for their translational potential in neurorehabilitation and depend on the dynamic state of neural networks at the time of stimulation. In the motor system, state-dependent interventions can modulate corticospinal excitability (CSE), but the relationship between during-intervention (online) and post-intervention (offline) effects remains unclear. We tested whether online CSE changes during state-dependent neuromodulation are associated with offline plasticity of corticospinal pathways. Healthy participants underwent five combinations of single-pulse transcranial magnetic stimulation (TMS) and robotic peripheral stimulation (PS) controlled by event-related beta-band desynchronization (ERD) during motor imagery (MI). We quantified the run-wise evolution of motor-evoked potential (MEP) amplitudes during the intervention and related it to post-intervention changes in plateau corticospinal recruitment (MEPmax). MI-based interventions produced progressive online CSE increases, with the strongest facilitation when TMS and PS were delivered synchronously during ERD. Only this combined intervention showed a significant association between online MEP and offline MEPmax, whereas rest conditions showed no progressive online effects and reduced offline CSE. These results support online CSE as a biomarker for refining closed-loop neuromodulation and for developing individualized dosing strategies in translational neurorehabilitation.