State-dependent associative plasticity highlights function-specific premotor-motor pathways crucial for arbitrary visuomotor mapping.

Arbitrary visuomotor mapping (AVMM) showcases the brain's ability to link sensory inputs with actions. The ventral premotor cortex (PMv) is proposed as central to sensorimotor transformations, relaying descending motor commands through the primary motor cortex (M1). However, direct evidence of this pathway's involvement in AVMM remains elusive. In four experiments, we used cortico-cortical paired associative stimulation (ccPAS) to enhance (ccPAS) or inhibit (ccPAS) PMv-to-M1 connectivity via Hebbian plasticity. Leveraging state-dependent properties of transcranial magnetic stimulation, we targeted function-specific visuomotor neurons within the pathway, testing their physiological/behavioral relevance to AVMM. State-dependent ccPAS, applied during motor responses to target visual cues, enhanced neurophysiological and behavioral indices of AVMM, while ccPAS had an opposite influence, with the effects being more pronounced for target relative to control visual cues. These results highlight the plasticity and causal role of spatially overlapping but functionally specific neural populations within the PMv-M1 pathway in AVMM and suggest state-dependent ccPAS as a tool for targeted modulation of visuomotor pathways.