Characterizing the pathophysiological role of the pallido-thalamocortical motor pathway in Parkinson's disease - ABSTRACT Although studied for decades, the physiological changes in the basal ganglia thalamocortical (BGTC) circuit that underlie the development of motor signs of Parkinson’s disease (PD) remain under debate. Excessive synchronization and coherence in neural activity has been demonstrated within the internal segment of the globus pallidus (GPi) and between GPi - motor cortex (M1). However, the relationship of coherence within and across subcortical-cortical regions to severity of motor signs of PD, specifically bradykinesia, is not well understood. Deep brain stimulation (DBS) targeting the posterolateral sensorimotor region of GPi has been shown to be an effective location for reducing clinical motor signs, however, there is debate around the optimal subregion (e.g. ventral vs. dorsal) within GPi for stimulation. There is evidence that stimulating the pallidothalamic pathway, specifically the lenticular fasciculus, is associated with improved motor severity. There is also evidence that GPi-M1 coherence reduces with DBS and is associated with improved bradykinesia. However, the relationship between pathways and neurophysiological activity, is unknown. This project will explore the spatial distribution of pathophysiological activity within the GPi and across the pallidothalamocortical network, how it modulates with movement and changes stimulation directed toward regions of GPi exhibited relatively high level of coherence with M1. This information will provide the rationale for the development of precise, patient-specific stimulation paradigms and lay the groundwork for novel closed-loop stimulation algorithms. The goals of this study are: 1) to describe the characteristics of low/high beta and high frequency oscillations that underlie bradykinesia. 2) describe the characteristics and dynamics of coherence in the beta band between GPi-M1 and their relationship to quantified measures of bradykinesia, and 3) describe the relationship between pallidothalamic pathway activation and measures of bradykinesia using real-time measure of GPi-M1 coherence to direction stimulation in GPi. This project will leverage access to recordings in the operating room during DBS lead implant surgery to record simultaneous local field potentials (LFP) from microelectrodes, segmented DBS leads and electrocorticography (ECoG) strips while the patient performs a self-initiated reach-to-target task in order to examine the modulation of GPi-M1 coherence during movement (SA1,2). We will use high field 7T imaging and biophysical computational models to correlate activated pallidothalamic pathways to changes in quantified measures of bradykinesia using real- time measures of GPi-M1 coherence to direct stimulation toward regions of GPi showing relatively high or low GPi-M1 coherence while the patients performs a self-initiated reach task (SA3). This study will provide the rationale for precise biomarkers and pathway-based stimulation targeting within the sensorimotor region of GPi, developing patient-specific closed-loop algorithms and incorporating spatially localized pathophysiological activity into model-based programming.
