Alexander Rafael Kent - US grants

DESCRIPTION (provided by applicant): Deep brain stimulation (DBS) has demonstrated remarkable clinical effectiveness in improving the motor symptoms of Parkinson's disease (PD) and essential tremor (ET). However, there remains disagreement regarding the physiological mechanisms of action of DBS. Further, there are few data describing the relationship between stimulation parameters and clinical outcomes, making selection of stimulation parameters a significant clinical burden that often leaves the patient with sub-optimal treatment. The overall aim of this project is to measure and characterize the electrically evoked compound action potentials (ECAPs) generated by activated neurons near the DBS electrode. The outcome will shed light on the underlying mechanisms of DBS and provide a means for rational selection of stimulation parameters. The first aim is to measure ECAPs and changes in motor symptoms during DBS as a function of the stimulation parameters in human subjects with PD or ET. The purposes of these experiments are to a) determine how the magnitude and character of the recorded ECAP varies with the intensity and frequency of DBS, and b) correlate the ECAP signal characteristics with changes in motor symptoms to identify ECAP signatures of clinical effectiveness. These experiments will be performed in an intraoperative setting that allows direct connection of our external stimulation and recording system to the DBS brain lead during battery replacement surgery. The second aim is to implement and analyze biophysically-based computational models of DBS to determine which neural elements generate the clinically-observed ECAPs. The goal of this aim is to understand better the type and spatial extent of neural element activation required for clinical effectiveness, which will provide insight into the mechanisms of action of DBS. We will characterize the effects of DBS stimulation parameters on the activation of neural elements and resulting modeled ECAP response, and use this to interpret the outcomes observed in human subjects. This work may also enable the design of novel electrodes and stimulation waveforms for targeted stimulation of the neural elements that produce maximal effectiveness in symptom reduction. In the future, the measured ECAPs can serve as feedback signals for closed-loop DBS systems that optimize treatment by modulating stimulation parameters in real time. PUBLIC HEALTH RELEVANCE: Deep brain stimulation (DBS) is an established treatment for movement disorders, such as Parkinson's disease (PD) and essential tremor (ET), and is under investigation for treatment of symptoms in persons with depression and epilepsy. Nevertheless, the mechanisms of action of DBS for PD or ET treatment remain unclear, making selection of stimulation parameters a significant clinical burden that often yields sub-optimal outcomes for symptom relief. Measuring and characterizing the neural electrical activity evoked by DBS will improve the understanding of the mechanisms of action of DBS, facilitate the rational selection of stimulation parameters, and provide a feedback signal for closed-loop DBS systems that optimize treatment by modulating stimulation parameters in real-time.