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.
