Cortico-cortical paired associative stimulation highlights the functional role of the cortical pathway from the right inferior frontal gyrus to the primary motor cortex in motor inhibition

Motor inhibition is the ability to suppress inappropriate motor responses. Dual-site transcranial magnetic stimulation studies suggest that the right inferior frontal gyrus (rIFG) can inhibit the primary motor cortex (M1), but it remains unclear whether inducing plasticity along this pathway affects motor inhibition. To address this issue, we used cortico-cortical paired associative stimulation (ccPAS) in healthy participants and assessed behavioral and electrophysiological markers of inhibition. In two sessions, we administered a ccPAS protocol to boost rIFG-M1 connections via Hebbian-like plasticity (ccPAS-rIFG-M1) and a reverse-order protocol (ccPAS-M1-rIFG) as a control. Consistent with well-documented inter-individual variability in response to brain stimulation, we divided participants into higher- and lower-sensitivity groups based on the progressive increase in motor excitability during ccPAS-rIFG-M1. Behavioral performance in the Go-NoGo task did not change as a function of ccPAS. However, independently of the ccPAS protocol, higher-sensitivity participants maintained an efficient proactive inhibitory strategy over time, whereas lower-sensitivity participants displayed increased response readiness at the expense of inhibitory control, suggesting stable individual differences rather than direct effects of stimulation. Furthermore, electrophysiological findings revealed that, following ccPAS-rIFG-M1, higher-sensitivity individuals showed a state-dependent increase of rIFG inhibitory influence over M1 only when viewing NoGo-cues. No comparable modulation was found for Go-cues, in lower-sensitivity individuals, or after ccPAS-M1-rIFG. These findings indicate that ccPAS-rIFG-M1 selectively modulates rIFG-M1 inhibitory interactions in a state- and sensitivity-specific manner, supporting a specific involvement of the targeted circuit in motor inhibition and linking individual plasticity capacity to stable differences in proactive inhibitory control.