CAREER: Understanding Peripheral Neuromodulation to Enhance Non-drug Management of Chronic Pain

慢性疼痛困扰着美国三分之一的成年人，并造成了巨大的经济负担（每年5600 - 6350亿美元）。此外，用于治疗疼痛的处方阿片类药物导致目前处方阿片类药物滥用的流行，每年在医疗，经济，社会和刑事后果方面花费5000亿美元。阿片类药物最严重的副作用，包括身体依赖和成瘾，是由于对中枢神经系统（CNS）的非预期作用。疼痛通常是从外周诱发的，因此靶向外周神经系统（PNS）可以缓解疼痛，而不会产生非预期的CNS效应。然而，选择性靶向PNS的基于药物的治疗在很大程度上仍然不成功。外周神经调节通过将物理能量（通常是电流）集中递送到PNS组织来治疗慢性疼痛。然而，目前的外周神经调节方法是不可预测的，并且仅使一部分慢性疼痛患者受益。该项目旨在开发新的实验和计算工具，以促进我们对周围神经调节的机械理解，从而提供新的实验和理论数据，以改善神经调节，使更广泛的慢性疼痛患者群体受益。该项目还将教育公众神经调节作为阿片类药物的替代品，并让K-12，本科生和研究生参与与疼痛相关的STEM教育和研究。 活动包括：教育K-8学生在受伤后获得适当的医疗护理和物理治疗的重要性，以减少在以后的生活中发展慢性疼痛的机会;教育合作学校的体育教练，以提高对儿童明显疼痛的认识，这不仅是慢性疼痛的风险因素，也是以后生活中滥用阿片类药物的风险因素;创建一个网站，向全国K-8学生的教练和家长宣传这一信息，并为高中教师举办为期一周的关于疼痛科学和疼痛非药物治疗的年度研讨会。长期职业研究目标是在多模态神经调节和电极-神经界面等工程干预的背景下，显着推进对生理和病理生理条件下外周神经/神经元生物物理学的理解。为了实现这一目标，该项目是实验确定选择性激活/抑制周围神经调制通过生物电记录从单个神经轴突（单单位记录）在收获的小鼠周围神经和开发计算模拟预测选择性激活/抑制。中心假设是外周神经调节对外周神经元/轴突亚组的选择性由其不同的神经功能和每个神经元/轴突周围的解剖环境决定。研究计划是根据两个目标组织的。第一个目的是定量离体外周神经调节的选择性激活/抑制。 新的方法将建立同时从传入（感觉）和传出（运动）轴突在背侧和腹侧神经根的单单位记录，并在感觉神经元的细胞体的单单位光学记录。 神经轴突将在功能上分为低阈值传入神经、伤害感受器（损伤感知传入神经）和传出神经，并确定其传导速度。 将测试神经调节对所识别类别的轴突的影响，以映射神经调节与改变的外周神经功能之间的先前未知的机制关系。 第二个目的是预测选择性激活/抑制周围神经调节在体内和验证与测量的行为结果。将通过耦合有限元（FE）分析和神经模拟来建立多尺度计算模型，以预测神经调节对沿着外周神经元/轴突的动作电位（AP）传播的影响。该模型将结合宏观（例如，骨）和微观（例如，结缔组织）的环境，如通过X射线断层摄影术和组织学所确定的。该模型将用于预测各种神经调节方案选择性激活/抑制传入亚组的有效性。模型预测将在经历有害的结肠直肠扩张和外周神经调节的小鼠中用行为测定进行验证。这项研究的结果将建立对周围神经调节的新的理论理解，这可能会加速新的神经调节方案，技术和模式的开发，这些方案，技术和模式针对PNS来管理慢性疼痛等疾病，同时限制脱靶副作用。通过改进的选择性，神经调节装置可以最大化其相对于药物的优势（例如，该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Chronic pain afflicts one in three adults in the US and poses an enormous economic burden ($560-$635 billion annually). In addition, prescribed opioids for treating pain have led to the current epidemic of prescription opioid abuse, costing $500 billion annually in medical, economic, social and criminal ramifications. The most serious side effects of opioids, including physical dependence and addiction, arise from un-intended effects on the central nervous system (CNS). Pain is generally evoked from the periphery and thus targeting the peripheral nervous system (PNS) could alleviate pain without un-intended CNS effects. However, drug-based treatments to selectively target the PNS remain largely unsuccessful. Peripheral neuromodulation treats chronic pain by focused delivery of physical energy (usually electrical current) to PNS tissues. However, current peripheral neuromodulation methods are unpredictable and only benefit a fraction of chronic pain patients. This project aims to develop novel experimental and computational tools to advance our mechanistic understanding of peripheral neuromodulation, and thus will provide new experimental and theoretical data to improve neuromodulation for benefiting a broader patient population with chronic pain. This project will also educate the public on neuromodulation as an alternative to opioids and engage K-12, undergraduate and graduate students with pain-related STEM education and research. Activities include: educating K-8 students about the importance of getting proper medical care and physical therapy after injury to reduce chances of developing chronic pain later in life; educating athletic coaches in partner schools to increase awareness of overt pain in children as a risk factor not only for chronic pain, but also for opioid abuse later in life; creating a website to amplify this message to coaches and parents of K-8 students nationwide and hosting an annual one week workshop for high school teachers on the science of pain and non-drug treatment of pain.The principal investigator's long-term career research goal is to significantly advance understanding of the biophysics of peripheral nerves/neurons in physiological and pathophysiological conditions in the context of engineering interventions like multi-modal neuromodulation and electrode-nerve interfaces. Toward this goal, this project is to experimentally determine selective activation/inhibition of peripheral neuromodulation via bioelectrical recording from individual nerve axons (single-unit recordings) in harvested mouse peripheral nerves and develop computational simulations to predict selective activation/inhibition. The central hypothesis is that the selectivity of peripheral neuromodulation on subgroups of peripheral neurons/axons is determined by their different neural functions and anatomical environments surrounding each neuron/axon. The Research Plan is organized under two objectives. The FIRST OBJECTIVE is to quantify selective activation/inhibition of peripheral neuromodulation ex vivo. Novel methods will be established for simultaneous single-unit recordings from both afferent (sensory) and efferent (motor) axons at the dorsal and the ventral nerve root, and for single unit optical recordings at cell bodies of sensory neurons. Nerve axons will be functionally classified into low-threshold afferents, nociceptors (injury sensing afferents) and efferents, and their conduction velocities will be established. The effect of neuromodulation on identified classes of axons will be tested to map previously unknown mechanistic relationships between neuromodulation and altered peripheral neural functions. The SECOND OBJECTIVE is to predict selective activation/inhibition of peripheral neuromodulation in vivo and validate with measured behavioral outcomes. A multi-scale computational model will be established by coupling finite element (FE) analysis with neural simulation to predict the effect of neuromodulation on action potential (AP) propagation along peripheral neurons/axons. The model will incorporate macroscopic (e.g., bones) and microscopic (e.g., connective tissues) environments of individual axons as determined by X-ray tomography and histology. The model will be used to predict the effectiveness of various neuromodulation schemes to selectively activate/inhibit afferent subgroups. Model predictions will be validated with behavioral assays in mice undergoing noxious colorectal distension and peripheral neuromodulation. Outcomes of this research will establish a novel theoretical understanding of peripheral neuromodulation, which will likely accelerate development of new neuromodulation schemes, techniques and modalities that target the PNS to manage diseases like chronic pain while limiting off-target side effects. Through improved selectivity, neuromodulation devices can maximize their advantage over drugs (e.g., minimal off-target side effects) and become a widespread treatment option for patients.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.