kHz frequency Spinal Cord Stimulation: Novel Temperature-Based Mechanisms of Action

项目（摘要（/（摘要！ 需要了解神经刺激技术的机制（RFA-NS-18-018）。的影响 这种研究的增加与神经调节技术的临床相关性和程度 机制不明。kHz频率下的脊髓刺激（kHz SCS）经历了一个短暂的 临床和市场的崛起，在没有一个公认的机制假说。kHz的最大特点 SCS的机制是快速双相刺激破坏了电刺激的传统机制， 刺激.但是，我们注意到快速脉冲的这种相同特征导致高刺激功率， 假设kHz SCS会增加组织温度。我们的建议是，一个临床上建立的植入 电刺激装置将通过焦耳加热意外地起作用是破坏性的和创新的， 作为第一步，需要确定kHz SCS期间的温度升高程度。为此，我们 研究计划开发最先进的工具，用于多物理场生物热建模（目标1），多室3D- 点阵体模验证（目标2）和猪模型中的验证（目标3），以系统地检验假设 kHz SCS产生0.5-2 oC的温升。多物理场模型（Aim 1）将在 解剖分辨率，内部导线结构，以及第一个耦合焦耳热，热传导和 对流（CSF流动）、代谢和血流灌注。加热体模（Aim 2）将是脊柱的第一个 基于新型3D点阵打印隔室的脊髓刺激。选择猪模型（目标3）用于 解剖学上与人类脊髓和椎管相似，并将包括定制的 用于体内温度标测的组合导线/传感器阵列。kHz SCS最独特的临床特征是 缺乏与传统SCS相关的感觉异常。我们将建立一个背角加热网络模型- 通过整合实验验证的温度升高、疼痛处理网络 动力学和膜对温度的敏感性（Q10）。我们假设温度上升0.5-2摄氏度 通过与传统SCS（门控）相同的最终MoA缓解疼痛，但无起搏 相关感觉异常RFA反应灵敏，这种“计算模型包含细胞异质性”， 特别是兴奋性与抑制性浅表背角中间神经元的电生理数据，包括 对加热的不同反应。虽然设备设计、疾病模型和临床试验明确地在 RFA范围，建立一个新的MoA和最先进的工具，在每个目标开发隐含驱动器， 支持这种发展。直接RFA反应，我们“提高了对神经生物学的理解， 现有方法的基础，并为下一代技术奠定基础， 模型（目标1，4），系统（目标2）和程序（目标3），以指导更好的神经调节工具的设计。 事实上，由于加热MoA从根本上是创新的，因此需要新的工具。

Project(Summary(/(Abstract! 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. RFA responsive, this “computational model incorporates cellular heterogeneity”, specifically electrophysiological data on of excitatory vs inhibitory superficial dorsal horn interneurons, including differential responses to heating. 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.