Chronic pain is a debilitating condition for which there is a pressing need for safe, effective treatments as is highlighted by the ongoing opioid crisis. One potential solution to this problem are neuromodulatory devices such as spinal cord stimulators and dorsal root ganglion stimulators that are currently approved by the FDA for the treatment of pain. While these devices have consistently generated promising results, they are only used in a fraction of chronic pain patients as an intervention of last resort. One of the reasons that these devices are not used more broadly is because their mechanism of action is largely unknown. Here we propose a series of parallel and complementary experiments to investigate the mechanisms of pain relief for spinal cord (SCS) and dorsal root ganglion (DRGS) stimulation, where conventional stimulation parameters will be used for DRGS, and conventional, burst and kilohertz (kHz) stimulation will be used for SCS. We will focus on the two prevailing models used to explain the therapeutic efficacy of these devices: 1) Gate-control, wherein stimulation of large diameter afferent fibers activates inhibitory interneurons that block nociceptive signals from reaching the brain; and 2) T-junction filtering, wherein stimulation of sensory neurons leads to conduction failure at the T-junction in nociceptive fibers in the DRG, blocking nociceptive inputs from reaching the spinal cord. Experiments designed to test these models are described under four Specific Aim in mice and rats with and without chronic pain induced with chronic compression of the DRG, and in a human DRG nerve preparation. In Aim 1 we will determine which neurons (primary afferent and/or dorsal horn) are activated by SCS and DRGS with 2P-calcium imaging in mice, and single unit recording in rats and human tissue. We will use the data generated at an unprecedented level of detail to refine computational models of the cells and circuits engaged by these devices. In Aim 2 we will confirm the efficacy of DRGS and SCS neuromodulation on simple reflexive responses and complex nociceptive behaviors in rats and mice. The timing and relative efficacy of the site and parameters of neuromodulation will inform computational models and mechanistic studies. In Aim 3 we will directly test the gate-control model using a novel strategy of 2P Ca2+ imaging in mice enabling identification of subpopulations of inhibitory, excitatory, and projection neurons in the same preparation. This will be combined with single unit and MEA recordings from rats and mice, all done in an iterative fashion with computational modeling. In Aim 4 we will test the T-junction filtering model with direct measurements of transmission efficiency in rat and human tissue. Pharmacological studies and computational modeling will investigate specific mechanisms responsible for this filtering. The results from these conceptually and technically innovative studies will provide a major advance in our understanding of the mechanisms underlying the effectiveness of these neuromodulatory devices and potentially offer new treatment strategies for improved pain relief.

Project Narrative Although neurostimulation therapies, such as dorsal root ganglion stimulation and spinal cord stimulation, have shown promising results in the treatment of chronic pain, the mechanisms underlying their efficacy are largely unknown. We are proposing parallel and complementary experiments using innovative behavioral, electrophysiological, imaging, and computational modeling techniques to address this lack of knowledge. The results of these studies will provide novel insights on the mechanisms fundamental to the effectiveness of these neurostimulation therapies and potentially offer new treatment strategies for improved pain relief.