Neural Signatures in the Motor Cortex and their Relation to Parkinson’s Disease, Dyskinetic Movements, and Sub-Anesthetic Ketamine

Abstract

The motor network plays a critical role in the control and selection of movements. Loss of dopaminergic neurons, as in neurodegenerative disorders like Parkinson’s disease (PD), significantly alters the electrophysiological features throughout the motor network specifically in the cortico-striato-thalamic loop. The results of these dysfunctional changes are the cardinal motor symptoms of PD which slows and impairs voluntary motor control. Levodopa-induced dyskinesia (LID), which is a common side effect of dopamine replacement therapy with levodopa (L-DOPA) for PD, causes debilitating uncontrolled, involuntary, and excessive movements because of further and opposing alterations to the cortico-striato-thalamic loop. Unfortunately, the treatment options for PD and LID are limited and not effective in almost half of the patients. Sub-anesthetic ketamine has emerged as a potential treatment for LID and induces significant electrophysiological changes that disrupt motor symptoms and neural signatures of PD and LID. However, the functional nature of these neurophysiological features during these states, like beta and finely-tuned gamma oscillations, ketamine-induced gamma activity, aberrant changes in motor cortex neurons firing patterns and ensemble state changes, are not well understood. This thesis provides insight into the role of motor cortex and dorsomedial striatum neural activity at the intersection of PD, LID and sub-anesthetic ketamine from neural recordings of >3500 individual neurons and local-field potential activity in preclinical rodent models. Investigation into the relationship between motor cortex activity and dyskinetic movements revealed a significant decoupling of motor cortex neurons and local-field activity from movement speed. Overall, this data highlighted the role of motor cortex in mediating inhibition of competing movements as functional decoupling of motor cortex activity may allow for aberrant movements to emerge in downstream motor circuits leading to involuntary movements seen in LID. This decoupling of motor cortex activity was partially rescued with sub-anesthetic ketamine. Additionally, the pathological oscillatory feature of LID, finely-tuned gamma, was disrupted by sub-anesthetic ketamine accompanied by reduction in dyskinetic behaviors. Analysis of the motor cortex neural populations during sub-anesthetic ketamine during LID showed that ketamine decreased state similarity specifically in the dopamine depleted condition. This is the first study to show changes in state and cell-pair interactions under ketamine in dopamine depleted and LID states, where ketamine introduced a larger magnitude and deviant cell-pair alterations selective to these states. Moreover, ketamine-induced gamma activity in the dopamine depleted condition showed higher power and more focal gamma frequency range in the lesioned and intact hemispheres of the dopamine lesioned animals. Together, these findings provide insight into ketamine’s mechanisms of action which is influenced to a certain extent by the underlying neural state.