This human study demonstrates distinct, time-dependent motor cortex interneuron plasticity in Parkinson's disease measured with direction-specific TMS/PAS and links PA-sensitive plasticity to rostral middle frontal gyrus volume while AP-sensitive plasticity relates to baseline excitability and age.

The work provides potential biomarkers and mechanistic guidance for stratifying patients and optimizing non‑invasive neuromodulation (TMS/PAS) therapies in PD, though it does not identify molecular drug targets for pharmacological discovery.

OBJECTIVE: 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. METHODS: PwPD underwent an MRI, followed by 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 PAS and at three post-PAS time points. RESULTS: PAS induced distinct time-dependent M1 interneuron excitability changes. At 110% RMT, PA TMS showed increased corticospinal excitability at all post-PAS time points; AP TMS increased only at 30-min post. In contrast, 130% RMT revealed a substantial increase in corticospinal excitability for both current directions post-PAS, indicating a general enhancement in M1 plasticity. 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. CONCLUSION: These findings highlight that M1 interneuron circuits exhibit unique neuroplasticity patterns in PwPD and are associated with prefrontal brain volume. SIGNIFICANCE: Our results suggest a complex interplay between motor and cognition-related deficits as interrelated pathophysiological features in PD.