Driving associative plasticity in premotor-motor connections through a novel paired associative stimulation based on long-latency cortico-cortical interactions

Repeated pre- and post-synaptic neuronal activation is fundamental for strengthening synaptic connections, a key mechanism referred to as spike-time-dependent plasticity (STDP). In humans, associative plasticity with STDP properties can be induced through a TMS protocol, named cortico-cortical paired associative stimulation (ccPAS). There is no evidence that ccPAS protocols based on long-latency interactions (i.e., ll-ccPAS) can induce associative plasticity in humans. Here we empirically address this question by testing the effect of 3 ll-ccPAS protocols on PMv-M1 interactions in healthy volunteers. We show that a novel ccPAS tuned to informed long-latency interactions is effective in modulating premotor-motor long-latency connectivity. Our study suggests that ll-ccPAS can strengthen wider networks through indirect pathways modulations, a feature that might be desirable for efficient modulation of network-to-network connectivity engaging complex brain functions.