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！ 有必要了解神经刺激技术的机制（RFA-NS-18-018）。影响 此类研究的数量随着神经调节技术的临床相关性和程度的增加而增加 机制尚不清楚。 kHz 频率 (kHz SCS) 的脊髓刺激经历了飞速发展 在缺乏公认的机制假设的情况下，临床和市场的增长。 kHz 最独特的特征 从机制上讲，SCS 是快速双相刺激破坏了传统的电机制 刺激。但是，我们注意到快速脉冲的相同特征会导致高刺激功率，从而导致我们 假设 kHz SCS 会增加组织温度。我们的建议是临床上建立的植入物 电刺激装置会通过焦耳加热出乎意料地发挥作用，这是颠覆性和创新性的，所以 第一步需要确定 kHz SCS 期间温度升高的程度。为此，我们的 研究计划开发最先进的多物理生物热建模工具（目标 1）、多室 3D- 晶格体模验证（目标 2），并在猪模型中进行验证（目标 3），以系统地检验假设 kHz SCS 会产生 0.5-2 oC 的温升。多物理场模型（目标 1）将在 解剖分辨率、内部引线结构，以及第一个耦合焦耳热、热传导和 对流（脑脊液流动）、新陈代谢和血流灌注。热体模（目标 2）将是第一个用于脊柱的 基于新型 3D 点阵打印隔室的脊髓刺激。选择猪模型（目标 3） 与人类脊髓和椎管在解剖学上相似，并将包括定制的 用于体内温度测绘的组合引线/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。我们将开发一个加热的背角网络模型 基于实验验证的温度升高、疼痛处理网络的镇痛（目标 4） 动力学和膜对温度的敏感性 (Q10)。我们假设温度上升 0.5-2 0C 通过与传统 SCS（门控）相同的最终 MoA 产生疼痛缓解，但无需起搏 相关的感觉异常。 RFA 响应，这种“计算模型融合了细胞异质性”， 特别是兴奋性与抑制性浅表背角中间神经元的电生理学数据，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不在范围之内 RFA 范围，建立新颖的 MoA 和在每个目标中开发的最先进的工具，隐含地驱动和 支撑此类发展。直接 RFA 响应，我们“提高对神经生物学的理解” 通过开发现有方法的基础，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）来指导更好的神经调节工具的设计”。 事实上，由于加热 MoA 从根本上来说是创新的，因此需要新的工具。