Parkinson?s disease patients experience excessive motor inhibition when they are off dopaminergic medications. Common symptoms include slowness in movements, rigidity, and freezing of gait. Dopaminergic medication can lead to insufficient inhibition, producing involuntary movements. The circuit mechanisms of motor inhibition in Parkinson?s disease, and how they are modulated by medication, are not fully understood. A hyderdirect pathway between the inferior frontal cortex (IFC) and subthalamic nucleus (STN) has been hypothesized to modulate rapid stopping. However, there is still no evidence of an IFC-STN hyperdirect pathway in humans. Furthermore, spatiotemporally precise characterization of stopping-related activity in both sites has never been studied in patients due to methodological constraints. The goal of this study is to use multisite, high-resolution electrophysiology, in both acute and chronic settings, to assess the role of the IFC and STN during movement inhibition in Parkinson?s patients. First, we will characterize the topography of fronto-STN connectivity using acute, intraoperative, high-resolution electrocorticography in the prefrontal cortex and penetrating deep brain electrodes in the STN. We will use short-latency evoked potentials to confirm a monosynaptic hyperdirect pathway between the IFC and STN. Then, using the same intraoperative recording paradigm, we will characterize the circuit?s role in rapid movement inhibition. Patients will perform a stop signal task, and we will assess task-related IFC-STN coherence as a measure of connectivity during stopping. We will perturb stopping-related activity by stimulating in task-relevant areas of the prefrontal cortex. Finally, we will use a chronically implanted bidirectional neural interface, which has simultaneous recording and stimulation capabilities, to assess how dopaminergic medications affect the IFC-STN circuit as patients fluctuate in symptomatology. These experiments will be the first to characterize: 1) IFC-STN hyperdirect circuit anatomy, 2) IFC-STN circuit activity during stopping, and 3) IFG-STN network modulation by medication. This work will inform pathophysiology for symptoms of abnormal movement inhibition, such as freezing of gait. It may lead to the development of feedback-driven, therapeutic stimulation to perturb network activity and improve symptoms.
Parkinson?s disease is a movement disorder characterized by excessive motor inhibition in the off- dopaminergic medication state and insufficient motor inhibition in the on-medication state. We aim to understand the network mechanisms of motor inhibition by characterizing prefrontal cortico-basal ganglia activity at rest, during stopping, and in on/off medication states. This work will expand our understanding of Parkinsonian pathophysiology, informing the development of symptom-specific stimulation therapies to perturb the network.
