Promoting spike-timing-dependent plasticity via paired associative stimulation: From healthy subjects to clinical applications

Paired Associative Stimulation (PAS) protocols have been widely employed to study functional neural connections along the cortico-spinal pathways and between interconnected brain regions. PAS protocols induce spike-timing-dependent plasticity, underscoring their potential as therapeutic neurostimulation tools. Cortico-peripheral PAS is based on the temporal pairing of peripheral nerve stimulation (PNS) and cortical transcranial magnetic stimulation (TMS) pulses, applied repeatedly at specific inter-stimulus intervals, to modulate the activity of the corticospinal tract. In contrast, cortico-cortical PAS involves the application of TMS pulses at two different brain areas to induce long-term changes in functional connectivity. In this review, we provide a comprehensive overview of existing PAS protocols and the factors influencing their effects, with particular emphasis on the critical role of the inter-stimulus interval. We trace the development of PAS from initial experiments in healthy subjects to its emerging therapeutic applications in various pathological conditions. We summarize current preliminary findings, discuss limitations, outline future directions, and review ongoing clinical trials. Although still in its early stages, PAS, particularly cortico-peripheral PAS, shows promising efficacy in motor recovery for stroke and spinal cord injury patients. Furthermore, initial evidence points to potential benefits in Alzheimer's disease and generalized anxiety disorders, supporting the expanding therapeutic scope of PAS protocols.