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

高频 (kHz) 双相刺激神经传导阻滞的机制

• 批准号: 9795292
• 负责人: Changfeng Tai
• 金额: $ 23.48万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9795292
• 关键词: Acute; Animal Experiments; Animals; Applications Grants; Attention; Axon; Back; Biology; Biophysics; Brain; Caliber; Chronic; Clinical; Computer Simulation; Conflict (Psychology); Electrodes; Frequencies; Hodgkin-Huxley model; Hour; Ion Channel; Ion Pumps; Ions; Kinetics; Knowledge; Lead; Membrane; Modeling; Na(+)-K(+)-Exchanging ATPase; Nerve; Nerve Block; Nerve-Muscle Preparations; Neural Conduction; Neuraxis; Neurons; Neurostimulation procedures of spinal cord tissue; Oryctolagus cuniculus; Pain; Pain in lower limb; Paresthesia; Patients; Peripheral Nervous System; Pharmacology; Potassium; Potassium Channel; Public Health; Rana; Ranvier' s Nodes; Recovery; Role; Sodium; Sodium Channel; Spinal; Spinal Cord; Temperature; Time; Voltage-Gated Potassium Channel; base; control theory; dorsal column; experimental study; extracellular; next generation; novel therapeutics; pain relief; relating to nervous system; response; sciatic nerve; spinal nerve posterior root

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.

项目摘要 基于疼痛的栅极控制理论，传统的脊髓刺激（SC）治疗慢性背部/腿部疼痛 利用40-60 Hz刺激，激活脊柱背柱以引起患者痛苦的parasthesia 地区。基于异常的SCS仅对40-50％的慢性背部/腿痛患者有效，而 SCS员工最近的进步高频（10 kHz）双相 刺激波形（HF10-SCS）在不含异常的亚阈值强度下。 HF10-SC是有效的 对于80-90％的患者，比传统SC的患者长期更好，更持久（24个月）。 HF10-SC的优越性超过传统SC和无异常的功能，表明一种机制 HF10-SC与疼痛的栅极控制理论不同。因为众所周知 高频（KHz）双相刺激（HFBS）可以阻止轴突传导，以前的研究具有 建议HF10-SCS阻断脊髓背根或轴突/神经元中的轴突。然而， 最近的计算机建模和动物研究表明，不含异常的低强度HF10-SC不是 足够强大以激活或阻止脊髓中的轴突。为了解决这些矛盾的假设， 我们需要首先了解单个轴突的HFBS块的基础机制。不幸的是，怎么了 HFBS阻止了一个轴突目前未知。因此，在此赠款申请中，我们将专注于揭示 单轴突的HFBS块的机制。我们假设有两种类型的HFBS神经Bock： 1。仅在HFBS期间发生的急性神经阻滞； 2。在刺激后块发生在期间和之后 HFBS。尽管急性神经阻滞需要上阈值HFB，但刺激后神经阻滞可以 在不产生异常的情况下以亚阈值强度诱导的HFB诱导。了解HFB 阻断单轴突对于进一步了解HF10-SCS抑制的机制至关重要 疼痛。我们建议将建模分析和动物实验结合起来，以揭示离子的变化 梯度，离子通道和离子泵，其基于HFBS轴突阻滞和传导的回收率 跟随块。我们将在轴突膜离子通道水平上揭示HFB的生物物理学 通过系统地表征，建模和验证HFBS诱导的轴突响应/块。这 从我们的研究中获取的知识对于理解单个轴突的中性响应很重要 中枢神经系统（脊髓或大脑）或周围神经系统中的水平。我们的项目 对于公共卫生而言是重要的，因为它不仅提供了基本知识来理解临床上的知识 HF10-SCS疗法的可靠有效性，也用于开发在中央或 周围神经系统。