Augmenting LTP-Like Plasticity in Human Motor Cortex by Spaced Paired Associative Stimulation

Paired associative stimulation (PAS(LTP)) of the human primary motor cortex (M1) can induce LTP-like plasticity by increasing corticospinal excitability beyond the stimulation period. Previous studies showed that two consecutive PAS(LTP) protocols interact by homeostatic metaplasticity, but animal experiments provided evidence that LTP can be augmented by repeated stimulation protocols spaced by ~30min. Here we tested in twelve healthy selected PAS(LTP) responders the possibility that LTP-like plasticity can be augmented in the human M1 by systematically varying the interval between two consecutive PAS(LTP) protocols. The first PAS(LTP) protocol (PAS1) induced strong LTP-like plasticity lasting for 30-60min. The effect of a second identical PAS(LTP) protocol (PAS(2)) critically depended on the time between PAS(1) and PAS(2). At 10min, PAS(2) prolonged the PAS(1)-induced LTP-like plasticity. At 30min, PAS(2) augmented the LTP-like plasticity induced by PAS(1), by increasing both magnitude and duration. At 60min and 180min, PAS(2) had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS(1) and PAS(2) at 30min exceeded significantly the effect of PAS(1) alone, and the cumulative PAS(1) and PAS(2) effects at 60min and 180min. In summary, consecutive PAS(LTP) protocols interact in human M1 in a time-dependent manner. If spaced by 30min, two consecutive PAS(LTP) sessions can augment LTP-like plasticity in human M1. Findings may inspire further research on optimized therapeutic applications of non-invasive brain stimulation in neurological and psychiatric diseases.