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

项目摘要 基于疼痛的门控理论，传统脊髓刺激治疗慢性腰腿痛 利用40-60赫兹的刺激，激活脊髓背柱，引起患者疼痛的感觉异常 区域。这种基于感觉异常的SCS只对40%-50%的慢性背部/腿部疼痛患者有效，而 随着时间的推移，疗效会逐渐降低。SCS的最新进展采用了高频(10 KHz)双相 刺激波形(HF10-SCS)在无感觉异常感的亚阈值强度。HF10-SCS有效 对于80%-90%的患者来说，与传统的SCS相比，长期(24个月)疗效更好和更持久。 HF10-SCS相对于传统SCS的优势和无感觉异常的特点表明，一种机制 与门控理论不同，痛觉可能参与了HF10-SCS。因为众所周知， 先前的研究表明，高频双相刺激(HFBS)可以阻断轴突传导 提示HF10-SCS可阻断后根轴突或脊髓轴突/神经元。然而， 最近的计算机模拟和动物研究表明，无感觉异常感、低强度的HF10-SCS并非如此 强大到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， 我们需要首先了解单个轴突的HFBS阻断的机制。不幸的是，如何 HFBS阻断了单个轴突，目前尚不清楚。因此，在这次拨款申请中，我们将重点揭示 HFBS阻断单轴突起的机制。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传导阻滞；2.在刺激期间和之后发生的刺激后传导阻滞 HFBS。尽管急性神经阻滞需要进行阈值以上的高频BS，但刺激后的神经阻滞可以 在不产生感觉异常的情况下，以亚阈值强度进行HFBS诱导。了解HFBS如何 阻断单个轴突对于进一步了解抑制HF10-SCS的机制至关重要。 疼痛。我们建议将建模分析和动物实验相结合来揭示离子的变化 HFBS轴突阻滞下的梯度、离子通道和离子泵与传导恢复 顺着街区走。我们将在轴突细胞膜离子通道水平上揭示HFBS背后的生物物理机制 通过对HFBS诱导的轴突反应/阻断进行系统的表征、建模和验证。这个 从我们的研究中获得的知识对于理解单个轴突对HFBS的神经反应很重要 在中枢神经系统(脊髓或大脑)或外周神经系统中的水平。我们的项目 对公共卫生具有重要意义，因为它不仅提供了基本知识，还有助于了解临床- HF10-SCS疗法已获证实的疗效，但也用于开发在中央或 周围神经系统。

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.