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 (PAS₂) critically depended on the time between PAS₁ and PAS₂. At 10min, PAS₂ prolonged the PAS₁-induced LTP-like plasticity. At 30min, PAS₂ augmented the LTP-like plasticity induced by PAS₁, by increasing both magnitude and duration. At 60min and 180min, PAS₂ had no effect on corticospinal excitability. The cumulative LTP-like plasticity after PAS₁ and PAS₂ at 30min exceeded significantly the effect of PAS₁ alone, and the cumulative PAS₁ and PAS₂ 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.