Mechanism underlying Nerve Conduction Block by High Frequency (kHz) Biphasic Stimulation

项目摘要 基于疼痛的门控理论，传统的脊髓刺激（SCS）治疗慢性背痛/腿痛 利用40-60 Hz的刺激，激活脊髓背柱， 地区这种基于感觉异常的SCS仅对40-50%的慢性背痛/腿痛患者有效， 效力随时间逐渐降低。SCS的最新进展采用高频（10 kHz）双相 刺激波形（HF 10-SCS）在无感觉异常的阈下强度下。HF 10-SCS有效 对于80-90%的患者，其长期（24个月）疗效优于传统SCS。 HF 10-SCS相对于传统SCS的优越性和无感觉异常的特征表明， 与疼痛的门控理论不同，HF 10-SCS可能涉及疼痛的门控理论。因为众所周知， 高频（kHz）双相刺激（HFBS）可以阻断轴突传导，以前的研究已经 表明HF 10-SCS阻断背根中的轴突或脊髓中的轴突/神经元。然而，在这方面， 最近的计算机建模和动物研究表明，无感觉异常的低强度HF 10-SCS不是 足以激活或阻断脊髓中的轴突为了解决这些相互矛盾的假设， 我们首先需要了解HFBS阻断单个轴突的机制。不幸的是，如何 HFBS阻断单个轴突目前尚不清楚。因此，在这次拨款申请中，我们将重点揭示 HFBS阻断单个轴突的机制。我们假设有两种类型的HFBS神经块： 1.仅在HFBS期间发生的急性神经阻滞; 2.刺激后阻滞，发生在 HFBS。虽然急性神经阻滞需要阈上HFBS，但刺激后神经阻滞可以 在阈下强度下由HFBS诱导而不产生感觉异常。了解HFBS如何 阻断单个轴突对于进一步理解HF 10-SCS抑制的机制至关重要。 痛苦我们建议将联合收割机建模分析与动物实验相结合， 梯度、离子通道和离子泵是HFBS轴突阻滞和传导恢复的基础 跟着块。我们将在轴突膜离子通道水平揭示HFBS的生物物理学基础 通过系统地表征、建模和验证HFBS诱导的轴突反应/阻滞。的 从我们的研究中获得的知识对于理解HFBS在单个轴突上的神经反应是重要的 在中枢神经系统（脊髓或脑）或外周神经系统中的水平。我们的项目 对公共卫生意义重大，因为它不仅提供了了解临床的基本知识， HF 10-SCS治疗的有效性已得到证实，但也可用于开发在中枢或中枢神经系统中使用HFBS的新疗法， 外周神经系统

Project Summary Based on the gate-control theory of pain, traditional spinal cord stimulation (SCS) to treat chronic back/leg pain utilizes 40-60 Hz stimulation that activates spinal dorsal columns to elicit paresthesia over a patient’s painful region. This paresthesia-based SCS is only effective for 40-50% of patients with chronic back/leg pain, and the efficacy gradually reduces over time. A recent advance in SCS employs a high-frequency (10 kHz) biphasic stimulation waveform (HF10-SCS) at a subthreshold intensity that is paresthesia-free. HF10-SCS is effective for 80-90% of patients with a better and more sustained long-term (24 months) efficacy than traditional SCS. The superiority of HF10-SCS over traditional SCS and the paresthesia-free feature indicate that a mechanism different from the gate-control theory of pain is probably involved in HF10-SCS. Since it is well known that high-frequency (kHz) biphasic stimulation (HFBS) can block axonal conduction, previous studies have suggested that HF10-SCS blocks axons in the dorsal roots or axons/neurons in the spinal cord. However, recent computer modeling and animal studies suggest that paresthesia-free, low intensity HF10-SCS is not strong enough to either activate or block the axons in the spinal cord. To resolve these conflicting hypotheses, we need to first understand the mechanisms underlying HFBS block of a single axon. Unfortunately, how HFBS blocks a single axon is currently unknown. Therefore, in this grant application we will focus on revealing the mechanisms of HFBS block of single axons. We hypothesize that there are two types of HFBS nerve bock: 1. acute nerve block that occurs only during HFBS; 2. post-stimulation block that occurs during and after HFBS. Although the acute nerve block requires a supra-threshold HFBS, the post-stimulation nerve block can be induced by HFBS at a sub-threshold intensity without producing paresthesia. Understanding how HFBS blocks a single axon is critical for further understanding the mechanisms underlying HF10-SCS suppression of pain. We propose to combine modeling analysis and animal experiments to reveal the changes in ion gradients, ion channels, and ion pumps that underlie HFBS axonal block and the recovery of conduction following the block. We will reveal the biophysics underlying HFBS at the axonal membrane ion channel level by systematically characterizing, modeling, and validating the axonal response/block induced by HFBS. The knowledge acquired from our studies is important for understanding neural response to HFBS at a single axon level either in the central nervous system (spinal cord or brain) or in the peripheral nervous system. Our project is significant for public health because it provides the basic knowledge not only for understanding the clinically- proven efficacy of HF10-SCS therapy but also for developing new therapies employing HFBS in the central or peripheral nervous system.