Stable Enhancement of Corticospinal Excitability by the Combination of Paired Associative Stimulation and Interlimb Cortical Network

Inter-individual variability is a common issue of noninvasive brain stimulation. This study aimed to augment neuroplasticity induced by paired associative stimulation (PAS) through leveraging interlimb neural interactions. Specifically, we assessed lower-limb corticospinal excitability when voluntary ipsilateral upper-limb muscle contraction (UMC) was integrated into lower-limb PAS in 19 able-bodied young adults. PAS targeted the right soleus muscle (i.e., a lower-limb muscle), pairing peripheral nerve stimulation (PNS) with transcranial magnetic stimulation (TMS) to modulate cortical excitability. Experiment 1 evaluated motor-evoked potentials (MEPs) and Hoffmann reflex (H-reflex) after PAS + UMC, PAS, and UMC interventions. Experiment 2 investigated the modulation of MEP and short-interval intracortical inhibition (SICI) following PAS + UMC and PAS interventions, with focused attention on PNS. During PAS + UMC intervention, participants performed right wrist flexion at 30% maximum voluntary contraction coinciding with stimulation. Results showed a significant increase in MEPs 30 min after PAS + UMC intervention, with enhanced increase under controlled attention. The H-reflex slightly increased 15 and 30 min after PAS + UMC intervention. SICI increased 30 min after PAS + UMC intervention, though the correlation between MEP and SICI observed in PAS intervention was absent in PAS + UMC intervention. Our findings suggest that combining lower-limb PAS with UMC can facilitate lower-limb corticospinal excitability more effectively than conventional PAS, despite the complex neural mechanism underlying PAS.