Project Summary The goal of this study is to elucidate the mechanisms of action of dorsal root ganglion stimulation (DRGS) for chronic pain. Chronic pain affects approximately 100 million Americans, and accounts for more than 600 billion dollars in healthcare costs each year. DRGS is an FDA-approved neurostimulation therapy for chronic pain that is refractory to conventional medical management. Although some patients receive sufficient pain relief in response to DRGS, clinical outcomes are often inconsistent. This variation in pain relief across patients may be due to poor understanding of the physiological mechanisms governing stimulation-induced pain relief. Therefore, we seek to uncover these mechanisms to ultimately optimize DRGS and improve clinical outcomes. This study is driven by previous computer modeling results from our lab showing that within stimulation parameter ranges used clinically, DRGS is likely driving the activity of large myelinated sensory neurons. In this proposed study, we will further investigate these mechanisms using computational models to determine sources of interpatient variability in DRGS outcomes. Furthermore, we will validate these models using clinical electrophysiological data, and inform the cellular anatomy of our models using histological data. We hypothesize that electrode location will be the largest source of variability in DRGS outcomes, and that positive DRGS outcomes will predict predominant activation of large myelinated sensory neurons. This project aims to characterize the mechanisms of action of DRGS to improve the implementation and outcomes of the therapy, and the models resulting from this project could be used to systematically design and test novel stimulation technologies (e.g. electrode and waveform design).