Developing Novel Direct Current Stimulation Technology for Safe Precision Pain Treatment

电神经调节是治疗难治性慢性疼痛的重要策略 到药物治疗然而，目前可用的神经刺激疼痛疗法与有限的 疗效和副作用。我们创造了一种新型的安全直流电刺激（SDCS）， 神经电子假体通过使用离子直流电（iDC）安全地调节神经元活动。我们 初步研究提供了有希望的证据，即应用于外周神经的iDC诱导了有效的， 疼痛通路中神经活动的可逆抑制。有趣的是，iDC可以被优化以优先 抑制“疼痛”信号，同时允许其他神经信号通过。我们研究的中心目标是揭示 神经生理机制，优化刺激参数，并建立实验框架， 推进新型SDCS神经电子假体的开发，用于精确疼痛治疗。在 目的1，我们将研究iDC如何调节不同亚型的传入神经元的传导和兴奋性， 神经病理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， 我们将确定如何优化iDC的极性、强度和持续时间， 优先抑制“疼痛”信号在周围神经系统中的传播。在目标2中，我们将 揭示iDC抑制疼痛的脊髓神经生理学机制。具体来说，我们将记录本地字段 在背角的潜力，以检查iDC是否差异影响脊髓传输的感觉输入，从 伤害性C纤维和非伤害性Aβ纤维。将使用单个单元记录来进一步确定 iDC影响单个疼痛处理背角神经元对外周刺激的反应。如果iDC诱导 神经元兴奋，我们将确定是否可以通过使用多极和相控阵iDC减少兴奋 范例在目标3中，我们将进行动物行为测试，以优化疼痛表现的抑制 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短期和长期使用的生物安全性。非常需要新的非药物策略， 慢性疼痛治疗，以及SDCS在生物系统中的性能目前正在探索中。我们 这些发现将有助于概念化SDCS技术精确疼痛抑制的生物学基础。基于 在iDC机制上，我们的研究结果将为可测试的发展提供理论基础和关键见解。 SDCS为基础的“electroceuticals”，可能会彻底改变目前的方法来治疗慢性疼痛。

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.