2023 NINDS Landis Mentoring Award

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Our long-term goal is to understand the brain rhythms underlying specific signs and symptoms of movement disorders at fast time scales, determine the effects of deep brain stimulation (DBS) on these brain rhythms, and utilize this knowledge to develop closed loop or “adaptive” stimulation. DBS of the globus pallidus (GP) is increasingly performed for Parkinson's disease (PD), based on its greater safety with respect to cognition and mood compared with subthalamic nucleus (STN) DBS, but its mechanism is not well understood. Invasive field potential recordings in the basal ganglia in humans has led to the influential hypothesis that specific patterns of abnormal oscillatory synchronization underlie the motor signs of PD. Abnormal rhythms in the beta band (13-30 Hz) are thought to be “antikinetic” while higher frequency (60-90 Hz) rhythms are “prokinetic.” Other frequencies may be “tremorogenic”. Our general approach is to extend this conceptual foundation to motor cortex and utilize network analyses from simultaneous cortical and subcortical recordings. In the initial grant period 2014-18, we focused on STN and its cortical interactions. Here, we will study pallidal and pallidocortical responses to levodopa and pallidal DBS, utilizing the technical approach developed in the previous grant period: chronic multisite field potential recording from basal ganglia and cortical electrodes, utilizing a totally implantable bidirectional neural interface. We employ a newly available second generation interface, RC+S (Medtronic) which holds substantial advantages with respect to recording quality and programmability over the first generation device (PC+S). We will use this device to understand electrophysiologic effects of antiparkinsonian medications (Aim 1) and of therapeutic pallidal DBS (Aim 2) on the basal-ganglia thalamocortical circuit; and build on these results to prototype algorithms for adaptive stimulation in which brain signals are utilized to adjust stimulation parameters according to changing brain needs (Aim 3). In addition to in-clinic recordings in defined medication states (on or off), we will use home recordings, with continuous “data streaming” from the implanted device and from wearable monitors, to increase the odds of biomarker identification. The impact of these studies will be to: 1) Provide a mechanistic understanding of the effects of therapeutic pallidal DBS on the basal ganglia-thalamocortical circuit. This may translate into improved physiological criteria for electrode placement and to rational and streamlined programing strategies. 2) Create a foundation for the development of “adaptive” DBS, perhaps the first major technical advance in DBS therapy since its introduction 25 years ago. 3) Develop a novel paradigm in human neuroscience, that of chronic ambulatory brain network recording in totally naturalistic environments, providing a platform for answering fundamental questions on basal ganglia-cortical interactions. Mechanisms elucidated in this study may be applicable to other disorders of brain circuits for which DBS has shown therapeutic promise.