Pathophysiology-based approaches to deep brain stimulation for Parkinson's disease

ABSTRACT The overall goal of project 1 of the University of Minnesota (UMN) Udall Center is to characterize the pathophysiological basis underlying the development of parkinsonian motor signs and use this information to refine current and develop alternative deep brain stimulation (DBS) strategies for the treatment of Parkinson?s disease (PD). Parkinson?s disease is a devastating neurodegenerative disease, yet we understand little about the pathophysiological changes that underlie the abnormal movements associated with this disorder. Although deep brain stimulation (DBS) has been demonstrated to reduce motor signs and improve the quality of life for patients with PD, outcomes vary significantly among patients and for individual motor signs within patients. This project will examine the relationship between changes in synchronized neural activity and motor behavior directly in patients by leveraging opportunities afforded by intra-operative, microelectrode mapping of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during DBS surgical procedures as well as post-operatively in patients with temporarily externalized DBS leads and using the fully- implanted Medtronic Activa© RC+S ?Brain Radio? system. The specific aims of this project are to: (1) identify the changes in oscillatory brain activity that are associated with abnormal movements through intraoperative recordings of neuronal (single and paired) and LFP activity during the performance of reaching and repetitive movement tasks; (2) further characterize the changes in that oscillatory activity in response to pharmacological and DBS treatment that reduces motor signs; (3) evaluate the potential role of these oscillatory changes as pathophysiological biomarkers for use in adaptive, closed-loop DBS systems; and (4) evaluate the acute and carry-over effects of coordinated reset (CR) DBS of the STN on both motor signs and oscillatory activity using the Activa© RC+S implant. The RC+S implant allows for subcortical local field potential (LFP) recordings and novel stimulation paradigms to be administered post-operatively, in the fully implanted patient, thus providing a unique opportunity to postoperatively evaluate the potential role of synchronized oscillatory activity in specific frequency spectrums as therapeutic biomarkers in next-generation DBS systems. The simultaneous collection of neuronal and LFP data during motor behavior intra-operatively is unique and will clarify the role of changes in neural activity, including synchronized oscillatory activity within and across specific frequency spectrums within the GPi, GPe and STN with abnormalities in motor performance. Overall this project will enhance our understanding of the pathophysiological basis of PD motor signs, clarify the changes in oscillatory activity that occur within the pallidum and STN during movement and how they change in response to interventions that improve motor signs. This study will also provide the rationale for the development of closed-loop and novel DBS paradigms designed to induce long term improvements even after discontinuation of stimulation.