Driving Hebbian plasticity over ventral premotor-motor projections transiently enhances motor resonance

Background: Making sense of others' actions relies on the activation of an action observation network (AON), which maps visual information about observed actions onto the observer's motor system. This motor resonance process manifests in the primary motor cortex (M1) as increased corticospinal excitability finely tuned to the muscles engaged in the observed action. Motor resonance in M1 is facilitated by projections from higher-order AON regions. However, whether manipulating the strength of AON-to-M1 connectivity affects motor resonance remains unclear. Methods: We used transcranial magnetic stimulation (TMS) in 48 healthy humans. Cortico-cortical paired associative stimulation (ccPAS) was administered over M1 and the ventral premotor cortex (PMv), a key AON node, to induce spike-timing-dependent plasticity (STDP) in the pathway connecting them. Single-pulse TMS assessed motor resonance during action observation. Results: Before ccPAS, action observation increased corticospinal excitability in the muscles corresponding to the observed movements, reflecting motor resonance in M1. Notably, ccPAS aimed at strengthening projections from PMv to M1 (PMv -> M1) induced short-term enhancement of motor resonance. The enhancement specifically occurred with the ccPAS configuration consistent with forward PMv -> M1 projections and dissipated 20 min poststimulation; ccPAS administered in the reverse order (M1 -> PMv) and sham stimulation did not affect motor resonance. Conclusions: These findings provide the first evidence that inducing STDP to strengthen PMv input to M1 neurons causally enhances muscle-specific motor resonance in M1. Our study sheds light on the plastic mechanisms that shape AON functionality and demonstrates that exogenous manipulation of AON connectivity can influence basic mirror mechanisms that underlie social perception.