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

在美国，三分之一的成年人患有慢性疼痛，并造成巨大的经济负担(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了目前处方阿片类药物滥用的流行，每年造成5000亿美元的医疗、经济、社会和刑事后果。阿片类药物最严重的副作用，包括身体依赖和成瘾，源于对中枢神经系统(CNS)的意外影响。疼痛通常是从外周诱发的，因此靶向外周神经系统(PNS)可以减轻疼痛，而不会产生意外的中枢神经系统影响。然而，选择性地针对三叉神经痛的药物治疗在很大程度上仍然不成功。外周神经调节通过向三叉神经节组织集中传递物理能量(通常是电流)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，只对一小部分慢性疼痛患者有利。本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机制的理解，从而为改善神经调节提供新的实验和理论数据，使更广泛的慢性疼痛患者受益。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年级的学生在受伤后获得适当的医疗和物理治疗的重要性，以减少日后发展为慢性疼痛的机会；教育伙伴学校的运动教练，提高儿童对公开疼痛的认识，不仅是慢性疼痛的危险因素，而且是以后生活中阿片类药物滥用的危险因素；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，并每年为高中教师举办一次为期一周的关于疼痛科学和非药物疼痛治疗的研讨会。主要研究人员的长期职业研究目标是在多模式神经调节和电极-神经接口等工程干预的背景下，显著促进对周围神经/神经元在生理和病理生理条件下的生物物理学的理解。为了达到这一目标，本项目从实验上确定了通过从采集的小鼠周围神经中的单个神经轴突(单位记录)进行生物电记录来选择性激活/抑制周围神经调制，并开发计算机模拟来预测选择性激活/抑制。中心假设是，周围神经调节对周围神经元/轴突亚群的选择性是由它们不同的神经功能和周围每个神经元/轴突周围的解剖环境决定的。研究计划按两个目标组织。第一个目标是量化体外外周神经调节的选择性激活/抑制。将建立一种新的方法，用于同时记录背侧和腹侧神经根的传入(感觉)和传出(运动)轴突的单个单位，以及在感觉神经元的细胞体上进行单个单位的光学记录。神经轴突将从功能上分为低阈值传入、伤害性传入和传出，并确定它们的传导速度。神经调节对确定的轴突类别的影响将被测试，以映射神经调节和周围神经功能改变之间先前未知的机制关系。第二个目标是预测体内外周神经调节的选择性激活/抑制，并用测量的行为结果进行验证。将有限元(FE)分析与神经模拟相结合，建立多尺度计算模型，以预测神经调制对动作电位(AP)沿周围神经元/轴突传播的影响。该模型将结合X射线断层扫描和组织学确定的单个轴突的宏观(例如骨骼)和微观(例如结缔组织)环境。该模型将被用来预测各种神经调节方案选择性激活/抑制传入亚群的有效性。模型预测将通过接受有害的结直肠扩张和外周神经调节的小鼠的行为分析来验证。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、技术和模式的发展，这些方案、技术和模式针对三叉神经核，在控制慢性疼痛等疾病的同时限制非靶标副作用。通过提高选择性，神经调节设备可以最大限度地发挥其相对于药物的优势(例如，最小的非靶向副作用)，并成为患者广泛的治疗选择。该奖项反映了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。

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.