Mechanisms and effects of pallidal deep brain stimulation on levodopa resistant motor signs in Parkinson's disease

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Project Summary/Abstract A large percentage of people with Parkinson’s disease (PD) will develop debilitating levodopa-resistant impairment in postural stability and gait disturbances, including freezing of gait, over the course of disease. Many of these individuals will be become candidates for treatment with deep brain stimulation (DBS) due to disease progression and adverse effects associated with prolonged use of dopamine replacement therapy. While subthalamic nucleus (STN) and globus pallidus (GP) DBS using standard clinical targets and stimulation parameters can be highly effective for the treatment of the cardinal motor symptoms of PD, both treatments often fail to control levodopa-resistant motor features of PD. Previous studies, and our ongoing research, have provided evidence that the most effective site for alleviating akinesia and bradykinesia was the posterolaterodorsal region of the GPi, near the border between the internal and external (GPe) segments, dorsal to the region typically targeted for GPi DBS. Moreover, DBS in this region can be effective for levodopa-resistant motor signs. Currently, the mechanisms mediating the prokinetic effects of stimulation near the GPi-GPe border (GPi/e-DBS) are poorly understood. The primary goal of this project is to gain a better understanding of the pathways mediating the benefits of GPi/e-DBS on levodopa-resistant motor signs. The project will leverage technical advances in DBS lead design that allow current steering and adjustment of electric field orientation, in conjunction with patient-specific computational models, to tune stimulation to preferentially activate prokinetic axonal pathways (Aims 1 and 3). In addition, we will wirelessly record local field potentials from leads chronically implanted in people with GP DBS (Aim 2), and use wearable technology to monitor gait and mobility during chronic stimulation in the home environment (Aim 2). Aim 1 will examine the effects of altering the orientation of the electric field induced by GPi/e-DBS to be either parallel or orthogonal (lowest or highest net axonal activation thresholds, repectively) to putative striato-GPi and GPe to GPi afferent pathways (prokinetic connections of the basal ganglia). Aim 2 will use the Medtronic Percept™ PC DBS system with active sensing to study: (i) pallidal oscillations associated with the re-emergence (wash-out) and suppression (wash-in) of gait impairment with GPi/e-DBS, (2) the up- and down-stream effects of GP DBS on motor network activity using 3T fMRI, and (iii) the relationship between fluctuations in gait and GP LFPs during activities of daily living (recorded over 4 weeks). Aim 3 will examine the effects of stimulation in the associative/limbic region of the GPe on gait and postural control with and without an increased cognitive load (dual-task). Together, these experiments will provide critical insight into the mechanisms and effects of GPi/e-DBS on basal ganglia and cortical-subcortical circuitry and measures of gait and postural control. This could lead to a new approach to using GP DBS to treat levodopa- resistant motor signs of PD.