Developing Novel Direct Current Stimulation Technology for Safe Precision Pain Treatment

开发新型直流电刺激技术以实现安全精准疼痛治疗

• 批准号: 9227078
• 负责人: Yun Guan
• 金额: $ 20.39万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227078
• 关键词: Action Potentials; Advanced Development; Adverse effects; Affect; Afferent Neurons; Amyloid beta-Protein; Animal Behavior; Animal Model; Animals; Attenuated; Biological; C Fiber; Caliber; Charge; Corrosion; Development; Devices; Electrodes; Electrophysiology (science); Equilibrium; Evolution; Fiber; Goals; Histologic; Hydrolysis; Hypersensitivity; Individual; Injection of therapeutic agent; Life; Mediating; Metals; Modeling; Nerve; Nerve Fibers; Neural Inhibition; Neurons; Nociception; Pain; Pain management; Pathway interactions; Performance; Peripheral; Peripheral Nerves; Peripheral Nervous System; Pharmacotherapy; Posterior Horn Cells; Process; Proprioception; Prostheses and Implants; Prosthesis; Rattus; Reaction; Refractory; Safety; Saline; Sensory; Signal Transduction; Spinal; Stimulus; Techniques; Technology; Testing; Tissues; Touch sensation; Tube; animal pain; awake; base; behavior test; biological systems; chronic pain; design; dorsal horn; extracellular; in vivo; injured; innovation; insight; nerve injury; neuroregulation; neurotransmission; new technology; novel; pain behavior; pain inhibition; painful neuropathy; relating to nervous system; response; sensory input; transmission process

Electrical neuromodulation is an important strategy for treating chronic pain conditions that are refractory to pharmacotherapies. However, currently available neurostimulation pain therapies are associated with limited efficacy and side effects. We created novel Safe Direct Current Stimulation (SDCS) that enables implantable neuroelectronic prostheses to safely modulate neuronal activity by using ionic direct current (iDC). Our preliminary studies provide promising evidence that iDC applied at peripheral nerves induces effective and reversible inhibition of neural activity in pain pathways. Intriguingly, iDC may be optimized to preferentially inhibit “pain” signals, while allowing the other nerve signals to pass. The central goal of our study is to uncover neurophysiologic mechanisms, optimize stimulation parameters, and establish the experimental framework for advancing the development of novel SDCS-based neuroelectronic prostheses for precision pain treatment. In Aim 1, we will examine how iDC modulates the conduction and excitability of different subtypes of afferent sensory neurons in a rat model of neuropathic pain. By recording compound action potentials and activity in teased nerve fibers, we will determine how to optimize the polarity, intensity, and duration of iDC in a way that preferentially suppresses propagation of “pain” signals in the peripheral nervous system. In Aim 2, we will uncover spinal neurophysiologic mechanisms for pain inhibition by iDC. Specifically, we will record local field potential in dorsal horn to examine if iDC differentially affects spinal transmission of sensory inputs from nociceptive C-fibers and non-nociceptive Aβ-fibers. Single-unit recording will be used to further determine how iDC affects responses of individual pain-processing dorsal horn neurons to peripheral stimuli. If iDC induces neuronal excitation, we will determine if the excitation can be reduced by using multipolar and phasic-array iDC paradigms. In Aim 3, we will conduct animal behavior tests to optimize the suppression of pain manifestations by iDC and examine potential side effects. Histologic and immunocytochemical studies will be used to evaluate the biosafety of iDC with short- and long-term use. Novel non-pharmacologic strategies are greatly needed for chronic pain treatment, and the performance of SDCS in biological systems is just now being explored. Our findings will help to conceptualize the biological basis of SDCS techniques for precision pain inhibition. Based on iDC mechanisms, our findings will provide rationales and critical insights for the development of testable SDCS-based “electroceuticals” that may revolutionize current approaches to chronic pain treatment.

电神经调节是治疗难治性的慢性疼痛状况的重要策略 进行药物治疗。但是，目前可用的神经刺激疼痛疗法与有限 效果和副作用。我们创建了可实现可植入的新型安全直流刺激（SDC） 使用离子直流（IDC），神经电原义假体可安全地调节神经元活动。我们的 初步研究提供了有希望的证据，表明在外围神经上应用IDC会影响有效和 疼痛途径中神经活动的可逆抑制。有趣的是，IDC可以优先优化 抑制“疼痛”信号，同时允许其他神经信号通过。我们研究的核心目标是揭露 神经生理机制，优化模拟参数并建立实验框架 推进基于SDCS的新型神经电子假体的发展，以进行精确疼痛治疗。在 AIM 1，我们将研究IDC如何调节不同亚型的传入的传导和令人兴奋性 神经性疼痛大鼠模型中的感觉神经元。通过记录复合动作电位和活动 嘲笑神经纤维，我们将确定如何以IDC的极性，强度和持续时间优化 优先抑制周围神经系统中“疼痛”信号的传播。在AIM 2中，我们将 发现IDC抑制疼痛的脊柱神经生理机制。具体来说，我们将记录本地字段 背角的潜力检查IDC是否对感官输入的脊柱传播是否不同 伤害性C纤维和非伤害性Aβ纤维。单单元记录将用于进一步确定 IDC会影响单个疼痛处理背角神经元对外围刺激的反应。如果IDC影响 神经元兴奋，我们将通过使用多极和阵列IDC来确定是否可以减少兴奋 范式。在AIM 3中，我们将进行动物行为测试以优化抑制疼痛表现 通过IDC并检查潜在的副作用。组织学和免疫细胞化学研究将用于评估 IDC的生物安全具有短期和长期使用。非常需要新颖的非药物策略 慢性疼痛治疗以及SDC在生物系统中的性能刚刚探索。我们的 发现将有助于概念化SDCS技术的生物学基础，以抑制精确的疼痛。基于 关于IDC机制，我们的发现将为开发可测试提供理由和关键见解 基于SDCS的“电气会”可能会彻底改变当前的慢性疼痛治疗方法。