NCS-FO: Closed-loop neuromodulation for chronic pain

提案标题：NSF-FO：慢性疼痛的闭环神经调节Pain是一种复杂和多维的体验，但在人们的日常生活中却很常见。慢性疼痛影响着全球15亿人，并导致了主要的医疗成本。慢性疼痛的治疗仍然不足，当前的阿片类药物流行凸显了这一点。在过去的几十年里，神经科学研究提供了关于中枢神经系统疼痛处理的积累知识。然而，副作用有限的有效止痛选择仍然难以捉摸，这在很大程度上是因为人们对慢性疼痛在大脑中的感知和调节机制知之甚少。这项提议试图用慢性疼痛治疗的啮齿动物模型来挑战现状。啮齿动物模型的使用将使研究人员能够在细胞分辨率下检查特定局部神经回路的大脑活动，并进一步为基于神经调节的疼痛治疗提供指导。该项目具有巨大的翻译潜力，可以促进个性化止痛药的发展，并为与广泛的神经精神障碍相关的慢性疼痛提供治疗。该项目还将促进教育和培养本科生/研究生或博士后研究员的多样性，并将致力于数据共享和外联活动，以最大限度地造福社会。该研究项目将整合行为学和电生理学研究，以探讨慢性疼痛条件下神经调节对新皮质回路的因果影响。这项建议的最终目标是开发一种非侵入性脑机接口系统，用于检测和缓解啮齿动物模型中的慢性疼痛。一方面，这个项目将调查和研究关于复杂感觉和情感过程背后的神经变异性的基本神经科学问题。另一方面，该项目将研究一种治疗慢性疼痛的微创神经调节策略。在目标1中，将记录自由行为慢性疼痛治疗大鼠初级躯体感觉皮层和前扣带回皮质的在体细胞外神经活动(包括整体棘波活动和局部场电位)。这将使研究人员能够表征不同慢性疼痛条件下的伤害性反应变异性。在目标2中，将开发一个用于慢性疼痛控制的闭环式啮齿动物神经调节接口，该接口结合了疼痛信号的检测(检测臂？)神经调节(？治疗臂？)。这一目标将利用多区域局部场电位来优化神经信号处理，并进一步利用神经调制技术的进步，在目标大脑区域(如初级运动皮质)上使用头盖骨电流刺激。在目标3中，将使用在线神经反馈来优化当前的刺激参数(例如，强度和持续时间)，以根据强化学习来提高神经调节的效率。综上所述，脑机接口系统将梳理出皮层疼痛回路的机制，并表征不同(炎症性和神经病理性)慢性疼痛条件下伤害性反应的变异性。总而言之，这些结果将揭示对慢性疼痛回路机制的新见解。这一奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Proposal Title: NSF-FO: Closed-loop neuromodulation for chronic painPain is a complex and multi-dimensional experience that nevertheless occurs commonly in people's daily lives. Chronic pain affects 1.5 billion people worldwide and has contributed to major healthcare costs. The treatment of chronic pain remains insufficient, highlighted by the current opioid epidemic. In the past few decades, neuroscience research has provided accumulating knowledge of pain processing in the central nervous system. However, effective analgesic options with limited side effects remain elusive, in large part because the neural mechanism for how chronic pain is perceived and modulated in the brain is poorly understood. This proposal tries to challenge the status quo using chronic pain-treated rodent models. The use of rodent models would allow researchers to examine the brain activity at specific localized neural circuits at a cellular resolution, and to further provide a guideline for neuromodulation-based pain treatment. The project has great translational potential to advance personalized pain medicine and provide therapy for the chronic pain associated with a wide range of neuropsychiatric disorders. This project will also promote education and diversity in training undergraduate/graduate students or postdoctoral fellows, and will be committed to data sharing and outreach activity in order to maximize the benefit to society. This research project will integrate behavior and electrophysiology studies to investigate the causal impact of neuromodulation on neocortical circuits in chronic pain conditions. The ultimate objective of this proposal is to develop a noninvasive brain machine interface system for detecting and relieving chronic pain in a rodent model. On the one hand, this project will investigate examine basic neuroscience questions regarding the neural variability underlying complex sensory and affective processes. On the other hand, this project will investigate a minimally invasive neuromodulation strategy for treating chronic pain. In Aim 1, in vivo extracellular neural activity (including the ensemble spike activity and local field potentials) will be recorded from the primary somatosensory cortex and anterior cingulate cortex of freely behaving chronic pain-treated rats. This will allow researchers to characterize nociceptive response variability under different chronic pain conditions. In Aim 2, a closed-loop rodent neuromodulation interface will be developed for chronic pain control, which combines the detection of pain signals (?detection arm?) and neuromodualtion (?treatment arm?). This aim will optimize neural signal processing using multi-region local field potentials and further leverage advances in neuromodulation techniques to employ epicranial current stimulation on the targeted brain region (such as the primary motor cortex). In Aim 3, the current stimulation parameters (e.g., intensity and duration) will be optimized using online neurofeedback to improve the efficacy of neuromodulation in light of reinforcement learning. In summary, the brain-machine interface system will tease apart the mechanism of cortical pain circuits, and characterize the nociceptive response variability under different (inflammatory vs. neuropathic) chronic pain conditions. Together, these results will reveal novel insights into circuit mechanisms of chronic pain.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.