Distinct Motor Cortex Interneuron Plasticity and Its Association with Prefrontal Brain Volume in Parkinson’s Disease

Abstract Parkinson’s disease (PD) is characterized by motor and cognitive deficits, including abnormal primary motor cortex (M1) excitability and diminished sensorimotor neuroplasticity. While paired associative stimulation (PAS) can induce M1 plasticity, people with PD (PwPD) demonstrate variability that cannot be accounted for by disease progression or medication status. Distinct M1 interneuron populations and attention-related brain structures may influence the reduced PAS- induced neuroplasticity. We aimed to characterize M1 interneuron plasticity in PwPD using attention-modulated PAS and identify neurostructural correlates. PwPD underwent MRI, then a PAS protocol with task-relevant attention. Transcranial magnetic stimulation (TMS) assessments of corticospinal excitability using posterior-to-anterior (PA) and anterior-to-posterior (AP) current directions were employed before and three post-PAS time-points. PAS induced distinct time- dependent M1 interneuron excitability changes. PA TMS showed increased corticospinal excitability at all post-PAS time-points; AP TMS increased only at 30 minutes. Rostral middle frontal gyrus volume uniquely explained variance in PA-sensitive M1 interneuron plasticity. In contrast, AP-sensitive plasticity was associated with baseline AP TMS excitability and age. These findings highlight that M1 interneuron circuits show unique neuroplasticity patterns in PwPD and relate to prefrontal brain volume. Our results suggest a complex interplay between motor and cognition-related deficits as interrelated pathophysiological features in PD.