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)。其影响 随着神经调节技术的临床相关性和程度的提高 机制尚不清楚。千赫频率下的脊髓刺激(KHzSCS)经历了一个飞跃的过程 在没有公认的机械论假说的情况下，临床和市场上涨。Khz最奇特的特征 SCS的机制是，快速双相刺激破坏了传统的电刺激机制 刺激。但是，我们注意到快速脉冲的这一相同特征导致高刺激功率，从而导致我们的 假设KHzSCS会增加组织温度。我们建议临床上建立的植入物 电刺激装置会出乎意料地发挥作用，通过焦耳加热是颠覆性和创新性的，因此 作为第一步，需要确定千赫兹SCS期间的温度升高程度。为此，我们的 研究计划开发最先进的工具，用于多物理生物热建模(目标1)，多隔室3D- 格子模型验证(目标2)，以及在猪模型中的验证(目标3)，以系统地测试假设 KHzSCS会产生0.5-2摄氏度的温升。多物理模型(目标1)将在#年达到最新水平 解剖分辨率，内部引线架构，以及第一个将焦耳热、热传导和 对流(脑脊液流动)、新陈代谢和血流灌流。热幻影(目标2)将是脊椎的第一个 基于新型3D点阵打印隔间的脐带刺激。猪模型(目标3)被选择用于 解剖学上与人类脊髓和椎管相似，并将包括定制的 用于活体温度标测的导线/传感器组合阵列。KHzSCS最特殊的临床特征是 缺乏感觉异常，与传统的SCS相关。我们将开发一个供暖的背角网络模型- 通过整合实验验证的温度升高、疼痛处理网络实现基于止痛的止痛(目标4 动力学和膜对温度的敏感性(Q10)。我们假设气温上升0.5-20摄氏度 通过与传统SCS(门控)相同的最终MOA产生疼痛缓解，但不需要起搏 关联性感觉异常症。RFA做出了回应，这个“计算模型结合了细胞的异质性”， 兴奋性与抑制性背角浅层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显然是在外面 RFA范围，建立新的MOA和在每个目标中开发的最先进的工具，隐含地推动和 为这些发展奠定了基础。RFA的直接反应，我们“提高了对神经生物学的理解 通过开发现有方法的基础，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)，以指导设计更好的神经调节工具“。 事实上，由于供暖MOA从根本上是创新的，因此需要新的工具。