Project Summary Spinal cord stimulation (SCS) is a nonpharmacological intervention for the treatment of chronic pain. Importantly, SCS may be more effective than opioids for pain relief and has been demonstrated to reduce opioid misuse in pain patients. Current SCS therapy uses time-invariant pulses (TIP), which is based on stimulation with fixed parameter pulse trains. However, SCS based on TIP stimulation has two critical challenges: 1) limited ability to contour the location and quality of the paresthesia coverage and 2) loss of treatment effect due to tolerance. To overcome these challenges, we propose the use of novel stimulation time variant pulse (TVPs) patterns, in which a stimulation parameter changes according to a modulatory time-varying function. TVPs may provide better therapy than TIPs in two ways. First, TVPs can change the recruitment of dorsal column fibers on a pulse by pulse basis in a way impossible via TIPs. Support for this comes from our pilot pre-clinical study in which we demonstrated that TVPs can generate dorsal column evoked compound action potentials (ECAPs) whose morphologies vary with the applied TVPs. Second, the time-varying nature of TVPs may produce better sensory encoding compared to TIPs. Support for this comes from preliminary results from our own and an independent pilot, acute clinical study suggesting that TVPs can produce dynamic, enhanced coverage of the painful region and improved perceived sensations in chronic pain patients. Our central hypotheses is that TVPs can improve outcomes for SCS by enhancing paresthesia coverage and reducing tolerance by varying spatial neuronal recruitment. In this proposal, we will develop devices capable of delivering TVPs and perform long-term clinical testing in chronic pain patients to define the role of TVP SCS in the management of intractable chronic pain. In this study, we will develop the firmware and software to deliver TVPs, and obtain IRB and IDE approval for a clinical study using an implantable pulse generator capable of delivering TVPs (Aim 1/UG3). Then, we will conduct a First in Human feasibility study with a double-blind, randomized-controlled design (Aim 2/UH3), to determine the extent to which SCS TVP can reduce pain and disability.