Project Summary / Abstract (unchanged from original proposal, except supplement in red) There is a need to understand the mechanisms of neural stimulation technologies (RFA-NS-18-018). The impact of such research increases with both the clinical relevance of a neuromodulation technology and the extent mechanisms are unknown. Spinal Cord Stimulation at kHz frequencies (kHz SCS) has undergone a meteoric clinical and market rise, in the absence of an accepted mechanistic hypothesis. The most peculiar feature of kHz SCS mechanistically is that rapid biphasic stimulation undermines traditional mechanisms of electrical stimulation. But, we note this same feature of rapid pulsing results in high stimulation power leading to our hypothesis that kHz SCS increases tissue temperature. Our proposal that a clinically-established implanted electrical stimulation device would unexpectantly function by joule heating is disruptive and innovative and so requires, as the first step, to establish the degree of temperature increase during kHz SCS. To this end, our research plan develops state-of-the-art tools for multi-physics bioheat modeling (Aim 1), multi-compartment 3D- lattice phantom verification (Aim 2), and validation in a swine model (Aim 3) to methodically test the hypothesis that kHz SCS produces a 0.5-2 oC temperature rise. The multi-physics model (Aim 1) will be state-of-the-at in anatomical resolution, internal lead architecture, and the first to couple joule heat, heat conduction and convection (CSF flow), metabolism, and blood flow perfusion. The heat phantom (Aim 2) will be the first for spinal cord stimulation based on novel 3D-lattice printed compartments. The swine model (Aim 3) is selected for anatomical similarities to the human spinal cord and vertebral canal, and will include a custom fabricated combination lead/sensor array for in vivo temperature mapping. The most peculiar clinical feature of kHz SCS is lack of paresthesia, associated with conventional SCS. We will develop a dorsal horn network model of heating- based analgesia (Aim 4) by integrating experimentally validated temperature increases, pain processing network dynamics, and membrane sensitivity to temperature (Q10). We hypothesize a 0.5-2 0C temperature rise generates pain relief through the same final MoA as conventional SCS (gate-control) but without pacing associated paresthesia. While device design, disease models, and clinical trials are explicitly outside RFA scope, establishing a novel MoA and state-of-the-art tools developed in each Aim implicitly drive and underpin such developments. Directly RFA responsive, we “improve understanding of the neurobiological underpinnings of existing methods and lay the foundation for the next generation technologies by developing models (Aim 1, 4), systems (Aim 2), and procedures (Aim 3) to guide the design of better neuromodulation tools”. Indeed, because the heating MoA is fundamentally innovative, new tools are needed. Responsive to NOT...