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

职业：了解周围神经调节以加强慢性疼痛的非药物治疗

• 批准号: 1844762
• 负责人: Bin Feng
• 金额: $ 54.97万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1844762&HistoricalAwards=false
• 关键词: CAREER; Understanding; Peripheral; Neuromodulation; Enhance

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.

在美国，慢性疼痛折磨着三分之一的成年人，造成了巨大的经济负担（每年5600亿至6350亿美元）。此外，用于治疗疼痛的处方类阿片导致了目前处方类阿片滥用的流行，每年在医疗、经济、社会和刑事方面造成5000亿美元的损失。阿片类药物最严重的副作用，包括身体依赖和成瘾，是由对中枢神经系统（CNS）的意外影响引起的。疼痛通常是从外周引起的，因此针对外周神经系统（PNS）可以减轻疼痛，而不会对中枢神经系统产生意想不到的影响。然而，选择性靶向PNS的药物治疗在很大程度上仍然是不成功的。外周神经调节通过向PNS组织集中传递物理能量（通常是电流）来治疗慢性疼痛。然而，目前的周围神经调节方法是不可预测的，只受益于一小部分慢性疼痛患者。该项目旨在开发新的实验和计算工具，以推进我们对周围神经调节的机制理解，从而为改善神经调节提供新的实验和理论数据，从而使更广泛的慢性疼痛患者受益。该项目还将教育公众将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年级学生在受伤后获得适当医疗护理和物理治疗的重要性，以减少以后生活中发生慢性疼痛的机会；教育合作学校的体育教练，提高对儿童明显疼痛的认识，这不仅是慢性疼痛的危险因素，也是以后生活中滥用阿片类药物的危险因素；创建了一个网站，向全国K-8学生的教练和家长宣传这一信息，并为高中教师举办了为期一周的关于疼痛科学和非药物治疗疼痛的研讨会。首席研究员的长期职业研究目标是在多模态神经调节和电极-神经接口等工程干预的背景下，显著推进对生理和病理生理条件下周围神经/神经元生物物理学的理解。为了实现这一目标，本项目是通过实验确定周围神经调节的选择性激活/抑制，通过采集小鼠周围神经的单个神经轴突（单单位记录）的生物电记录，并开发计算模拟来预测选择性激活/抑制。核心假设是，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每个神经元/轴突周围的解剖环境决定的。研究计划有两个目标。第一个目的是量化外周神经调节的选择性激活/抑制。将建立新的方法，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元记录，并在感觉神经元的细胞体的单单元光学记录。将神经轴突在功能上分为低阈传入、伤害感受器（损伤感知传入）和传出，并建立它们的传导速度。神经调节对已识别的轴突的影响将被测试，以绘制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周围神经调节的选择性激活/抑制，并通过测量的行为结果进行验证。将有限元分析与神经模拟相结合，建立多尺度计算模型，预测神经调节对动作电位（AP）沿外周神经元/轴突传播的影响。该模型将结合由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。该模型将用于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。模型预测将通过行为分析在小鼠进行有害的结肠膨胀和周围神经调节验证。这项研究的结果将为周围神经调节建立一个新的理论认识，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、技术和模式将针对PNS来管理慢性疼痛等疾病，同时限制脱靶副作用。通过提高选择性，神经调节装置可以最大限度地发挥其优于药物的优势（例如，最小的脱靶副作用），并成为患者的广泛治疗选择。该奖项反映了美国国家科学基金会的法定使命，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。

项目成果

Optimal Multichannel Artifact Prediction and Removal for Neural Stimulation and Brain Machine Interfaces

• DOI: 10.3389/fnins.2020.00709
• 发表时间: 2020-07-17
• 期刊: FRONTIERS IN NEUROSCIENCE
• 影响因子: 4.3
• 作者: Najafabadi, Mina Sadeghi;Chen, Longtu;Escabi, Monty A.
• 通讯作者: Escabi, Monty A.

Extracellular single-unit recordings from peripheral nerve axons in vitro by a novel multichannel microelectrode array

• DOI: 10.1016/j.snb.2020.128111
• 发表时间: 2020-07-15
• 期刊: SENSORS AND ACTUATORS B-CHEMICAL
• 影响因子: 8.4
• 作者: Guo, Tiantian;Chen, Longtu;Feng, Bin
• 通讯作者: Feng, Bin

Using electrodermal activity to validate multilevel pain stimulation in healthy volunteers evoked by thermal grills

• DOI: 10.1152/ajpregu.00102.2020
• 发表时间: 2020-09-01
• 期刊: AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY
• 影响因子: 2.8
• 作者: Posada-Quintero, Hugo F.;Kong, Youngsun;Chon, Ki H.
• 通讯作者: Chon, Ki H.