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

kHz 频率脊髓刺激：基于温度的新型作用机制

• 批准号: 10709773
• 负责人: MAROM BIKSON
• 金额: $ 35.07万
• 依托单位: CITY COLLEGE OF NEW YORK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709773
• 关键词: kHz; frequency; Spinal; Cord; Stimulation

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.

项目（摘要（/摘要！ 需要了解神经刺激技术的机制（RFA-NS-18-018）。影响 这种研究的增加随着神经调节技术的临床相关性和程度而增加 机制是未知的。 KHz频率（KHz SCS）的脊髓刺激发生了气象 在没有公认的机械假设的情况下，临床和市场上升。 KHz最奇特的功能 SCS机械上是，快速双相刺激破坏了电气的传统机制 刺激。但是，我们注意到快速脉动的同样特征导致高刺激能力导致我们 假设KHz SC会增加组织温度。我们提出的临床建立的植入 电刺激装置将通过焦耳加热意外运行是破坏性和创新性的，因此 作为第一步，要求建立KHz SCS期间温度升高的程度。为此，我们的 研究计划开发多物理生物学建模的最新工具（AIM 1），多校区3D- 晶格幻影验证（AIM 2）和猪模型中的验证（AIM 3）有条不紊地检验假设 KHz SCS产生0.5-2的OC温度升高。多物理模型（AIM 1）将是最新的 解剖分辨率，内部铅架构以及第一个逐对焦热，热传导和 对流（CSF流），代谢和血流灌注。热幻影（AIM 2）将是脊柱的第一个 基于新颖的3D晶格印刷室的绳索刺激。选择猪模型（AIM 3） 与人脊髓和椎管的解剖相似性，并将包括定制的制造 用于体内温度映射的组合铅/传感器阵列。 KHz SCS最特殊的临床特征是 缺乏异常，与常规SC相关。我们将开发一个加热的背喇叭网络模型 通过整合实验验证的温度升高，疼痛处理网络，基于镇痛（AIM 4） 动力学和膜对温度的敏感性（Q10）。我们假设0.5-2 0c温度升高 通过与常规SCS（登机口）相同的最终MOA产生疼痛缓解，但没有起搏 相关的异常。 RFA响应迅速，这种“计算模型结合细胞异质性”， 特定于兴奋性与抑制性表面背角中间神经元的电生理数据，包括 对加热的差异反应。虽然设备设计，疾病模型和临床试验明确在外面 RFA范围，建立一个新颖的MOA和最先进的工具，在每个目标中都隐含地驱动和 基于此类发展。直接响应式RFA，我们“提高了对神经生物学的理解 现有方法的基础，并通过开发为下一代技术奠定了基础 模型（AIM 1，4），系统（AIM 2）和程序（AIM 3）指导设计更好的神经调节工具的设计。 确实，由于加热MOA从根本上是创新的，因此需要新的工具。