Service members are subject to extreme physical injury and mental stress. Wounded soldiers often experience substantial pain, which must be addressed before returning to active duty or civilian life. Pain represents a serious and widespread problem both over the short term for wounded soldiers on the battlefield and during rehabilitation, and over the long term for many veterans. The prevalence of certain conditions associated with the development of chronic pain, including traumatic brain injury and post-traumatic stress disorder (PTSD), is higher among military veterans than among the general civilian population. PTSD is a condition in which individuals feel anxiety and panic when reminded of a traumatic event.
US Military therefore implements measures to research pain in wounded soldiers and veterans, and to improve the management of acute pain resulting from combat-related injuries and surgery, and the management of chronic pain in veterans. By providing adequate analgesia, military health care services aim to provide immediate control of pain and restore function, as well as to reduce the risk of developing complications associated with under-managed pain, which may be serious and require extended care. Improvement of acute pain management for combat-related injuries in the military has largely focused on determining which pain control methods can be readily administered and provide adequate pain relief during immediate field hospital care, transport and subsequent care at military treatment facilities.
DARPA’s BTO is developing capabilities to better prepare warfighters for their missions by improving readiness and resilience, and creating technologies to restore function to injured warfighters when necessary. DARPA launched Electrical Prescriptions (ElectRx) program in 2015, a blanket program for a diverse range of research being conducted in using electrical stimulation of the peripheral nerves to treat conditions such as chronic pain, inflammation, and post-traumatic stress disorder (PTSD).
ElectRx seeks to deliver non-pharmacological treatments for pain, general inflammation, post-traumatic stress, severe anxiety, and trauma that employ precise, closed-loop, non-invasive modulation of the patient’s peripheral nervous system. “Much like a thermostat monitors, an ElectRx device would monitor and recognize when the system is moving away from homeostasis and into a diseased state. Eventually, a regulator would provide therapeutic stimulus, then a modulator would signal nerves,” Wu said
“The peripheral nervous system is the body’s information superhighway, communicating a vast array of sensory and motor signals that monitor our health status and effect changes in brain and organ functions to keep us healthy, “said Doug Weber, the ElectRx program manager and a biomedical engineer who previously worked as a researcher for the Department of Veterans Affairs. “We envision technology that can detect the onset of disease and react automatically to restore health by stimulating peripheral nerves to modulate functions in the brain, spinal cord and internal organs.”
“Through the combination of a growing understanding of how the nervous system regulates many aspects of our health and advancing technology to measure and stimulate nerve signals, I believe we’re poised to make fundamental changes to the way we diagnose and treat disease,” Weber said. “To that end, DARPA has assembled a performer team and outlined a research way-ahead that we anticipate can move us toward a capability to safely and reliably modulate the peripheral nervous system to fight disease.”
The Electrical Prescriptions (ElectRx) program aims to support military operational readiness by reducing the time to treatment, logistical challenges, and potential off-target effects associated with traditional medical interventions for a wide range of physical and mental health conditions commonly faced by our warfighters. However, DARPA’s goals go beyond treatment and into prevention. “We envision technology that can detect the onset of disease and react automatically to restore health by stimulating peripheral nerves to modulate functions in the brain, spinal cord and internal organs.”
“Using the peripheral nervous system as a medium for delivering therapy is largely new territory and it’s rich with potential to manage many of the conditions that impact the readiness of our military and, more generally, the health of the nation,” Weber said. “It will be an exciting path forward.”
In 2018, DARPA announced that following successes in early proof-of-concept studies, the ElectRx devices and therapeutic systems under development are entering into clinical studies. If successful, such precise neuromodulation capability technology would reduce dependence on traditional drugs and create new treatments that could be automatically and continuously tuned to the needs of warfighters without side effects. The technology could also help doctors evaluate and predict various physiological states, and characterize host response in patients with severe infections, providing a quantitative framework to guide operations and therapy.
Electrical Prescriptions (ElectRx) program
The human nervous system already plays a vital role in maintaining all aspects of physical and mental health. Our bodies maintain a state of equilibrium, or homeostasis, through our peripheral nervous system, through neural reflexes that modulate the function of organ systems such as the heart, stomach, intestines, or bladder. The vagus nerve travels from the base of the brain to the chest and abdomen, carrying a wide assortment of signals to and from the brain. It supplies the heart, lungs, digestive tract, pancreas and other organs. It has only recently been discovered that it controls inflammation.
For instance, the vagus nerve linking the brain to the heart can stimulate the heart when an anxiety stimulus is experienced or can stimulate the stomach when hunger is recorded. If researchers could map the neural circuits governing these systems, they might then be able to develop minimally invasive neural and bio-interface technologies with unprecedented levels of precision, targeting, and scale.
A sophisticated network of sensory nerves continuously monitors health status and triggers reflexive responses in the brain and spinal cord when an infection or injury is detected. These reflexes normally adjust organ function to initiate and control the healing process. However, some diseases can disrupt healthy functioning of these processes and produce nerve signaling that causes pain, metabolic disorders such as diabetes, and autoimmune disorders such as rheumatoid arthritis. ElectRx technology would exploit and supplement the body’s natural ability to quickly and effectively heal itself, intervening when required to correct or bolster nervous system activity.
The oldest and simplest example of this concept is the cardiac pacemaker, which uses brief pulses of electricity to stimulate the heart to beat at a healthy rate. Extending this concept to other organs like the spleen may offer new opportunities for treating inflammatory diseases such as rheumatoid arthritis. Fighting inflammation may also provide new treatments for depression, which growing evidence suggests might be caused in part by excess levels of inflammatory biomolecules. Peripheral nerve stimulation may also be used to regulate production of neurochemicals that regulate learning and memory in the brain, offering new treatments for post-traumatic stress and other mental health disorders.
ElectRx is establishing the underlying science and developing the technologies that could enable artificial modulation of peripheral nerves to restore healthy patterns of signaling in these neural circuits. The program seeks to advance understanding of the anatomy and physiology of specific neural circuits and their role in health and disease. In parallel, the program also seeks to develop novel biological-interface technologies for monitoring biomarkers and peripheral nerve activity, and delivering therapeutic signals to peripheral nerve targets. Potential new approaches include in vivo, real-time biosensors and novel neural interfaces using optical, acoustic, electromagnetic, or engineered biology strategies to achieve precise targeting with potentially single-axon resolution.
Following successes in early proof-of-concept studies, the ElectRx devices and therapeutic systems under development are entering into clinical studies. If successful, such precise neuromodulation capability technology would reduce dependence on traditional drugs and create new treatments that could be automatically and continuously tuned to the needs of warfighters without side effects. The technology could also help doctors evaluate and predict various physiological states, and characterize host response in patients with severe infections, providing a quantitative framework to guide operations and therapy.
Electrical Prescriptions (ElectRx) program awards
The main thrusts for Phase I of ElectRx are fundamental studies to map the neural circuits governing the physiology of diseases of interest to DARPA and preliminary development of novel, minimally invasive neural and bio-interface technologies with unprecedented levels of precision, targeting and scale.
DARPA has selected seven teams of researchers to begin work on the Agency’s Electrical Prescriptions (ElectRx) program.
The teams will initially pursue a diverse array of research and technological breakthroughs in support of the program’s technical goals. Ultimately, the program envisions a complete system that can be tested in human clinical trials aimed at conditions such as chronic pain, inflammatory disease, post-traumatic stress and other illnesses that may not be responsive to traditional treatments. The teams include a mix of first-time and prior DARPA performers. Many have partnered with established medical device manufacturers to support trials in the near term and ultimately facilitate transition of ElectRx interface devices as they mature.
Circuit Therapeutics to optimize gene therapy and light delivery to nerves
Circuit Therapeutics (Menlo Park, Calif.), a start-up co-founded by Karl Deisseroth and Scott Delp, is a new DARPA performer. Circuit’s patented optogenetics technology allows targeted and immediate modulation of specific nerves and neurons in the central and peripheral nervous systems, which has led to a number of successful preclinical programs to directly treat nervous system disorders. The ElectRx award allows Circuit to expand into yet another therapeutic area, by facilitating preclinical studies that optimize gene therapy and light delivery to nerves that control neuropathic pain. The team plans to further develop its experimental optogenetic methods for treating neuropathic pain, building toward testing in animal models before seeking to move to clinical trials in humans.
“We couldn’t be more thrilled about the opportunity to work with DARPA, an agency that has funded a number of revolutionary technologies through the years,” said Fred Moll, Chairman and CEO of Circuit Therapeutics. “Chronic pain and other conditions of the peripheral nervous system cause terrible problems for our troops, our veterans, and society at large. With DARPA’s help, we hope to create therapies that have never existed before—therapies that reduce chronic pain and give people more quality time with their friends and families.”
Columbia University will use non-invasive, targeted ultrasound
A team at Columbia University (New York), led by Elisa Konofagou, will pursue fundamental science to support the use of non-invasive, targeted ultrasound for neuromodulation. The team aims to elucidate the underlying mechanisms that may make ultrasound an option for chronic intervention, including activation and inhibition of nerves.
“What we’re working on is a very exciting application for ultrasound,” says Konofagou, who has a joint appointment in radiology (physics). “We could, for the first time, provide a noninvasive approach to nerve and organ stimulation while at the same time advance our understanding of the coupling between the mechanical and electrical activity at the cellular, multi-cellular, and organ levels. We think targeted ultrasound could be a good option for managing conditions such as chronic pain and neuropathy.”
Florey Institute of Neuroscience and Mental Health to map the nerve pathways
A team at the Florey Institute of Neuroscience and Mental Health (Parkville, Australia), led by John Furness, is a first-time DARPA performer. Team members will seek to map the nerve pathways that underlie intestinal inflammation, with a focus on determining the correlations between animal models and human neural circuitry. They will also explore the use of neurostimulation technologies based on the cochlear implant —developed by Cochlear, Inc. to treat hearing loss, but adapted to modulate activity of the vagus nerve in response to biofeedback signals—as a possible treatment for inflammatory bowel disease.
Inflammatory bowel diseases (Crohn’s disease and ulcerative colitis) are common, chronic debilitating conditions. The increased incidence of inflammatory bowel disease (IBD) in war veterans may be stress-related. Post-traumatic stress causes immune deficiencies which, in turn, can trigger lung, gut and other inflammatory illnesses. The Florey Institute of Neuroscience and Mental Health is leading the four-year, $6.07 million project to study neuromodulation of inflammatory diseases with the University of Melbourne, the Bionics Institute and Austin Health.
Professor Rob Shepherd, Director of the Bionics Institute and a principal investigator on the project, notes the strength of multi-disciplinary research in Melbourne citing the development of the cochlear implant and a bionic eye as examples. “Therapeutic nerve stimulation for the treatment of inflammatory conditions is a novel approach that requires the specialist team of scientists, engineers, computer scientists and clinicians that we are able to bring together in Melbourne for its successful translation to the clinic,” he says.
Johns Hopkins University to explore the root mechanisms of inflammatory bowel disease
A team at the Johns Hopkins University (Baltimore), led by Jiande Chen, aims to explore the root mechanisms of inflammatory bowel disease and the impact of sacral nerve stimulation on its progression. The team will apply a first-of-its-kind approach to visualize intestinal responses to neuromodulation in animal models.
Massachusetts Institute of Technology to employ magnetic nanoparticles
Researchers at MIT have developed a method to stimulate brain tissue using external magnetic fields and injected magnetic nanoparticles — a technique allowing direct stimulation of neurons, which could be an effective treatment for a variety of neurological diseases, without the need for implants or external connections.In their study, the team injected magnetic iron oxide particles just 22 nanometers in diameter into the brain. When exposed to an external alternating magnetic field — which can penetrate deep inside biological tissues — these particles rapidly heat up.
A team at the Massachusetts Institute of Technology (Cambridge, Mass.), led by Polina Anikeeva, will aim to advance its established work in magnetic nanoparticles for localized, precision in vivo neuromodulation through thermal activation of neurons in animal models. The team’s work will target the adrenal gland and the splanchnic nerve circuits that govern its function. To increase specificity and minimize potential side effects of this method of stimulation, the team seeks to develop nanoparticles with the ability to bind to neuronal membranes. Dr. Anikeeva was previously a DARPA Young Faculty Awardee.
The resulting local temperature increase can then lead to neural activation by triggering heat-sensitive capsaicin receptors — the same proteins that the body uses to detect both actual heat and the “heat” of spicy foods. (Capsaicin is the chemical that gives hot peppers their searing taste.) Anikeeva’s team used viral gene delivery to induce the sensitivity to heat in selected neurons in the brain.
Purdue University to advance design of clinical neuromodulation devices
A team at Purdue University (West Lafayette, Ind.), led by Pedro Irazoqui, will leverage an existing collaboration with Cyberonics to study inflammation of the gastrointestinal tract and its responsiveness to vagal nerve stimulation through the neck. Validation of the mechanistic insights that emerge from the effort will take place in pre-clinical models in which novel neuromodulation devices will be applied to reduce inflammation in a feedback-controlled manner. Later stages of the effort could advance the design of clinical neuromodulation devices.
University of Texas will use vagal nerve stimulation (VNS)
A team at the University of Texas, Dallas, led by Robert Rennaker and Michael Kilgard, will examine the use of vagal nerve stimulation (VNS) to induce neural plasticity for the treatment of post-traumatic stress. VNS is an FDA-approved method for treating various illnesses, such as depression and epilepsy. It involves sending a mild electric pulse through the vagus nerve, which is in the neck, and relays information about the state of the body to the brain.
As envisioned, stimulation could enhance learned behavioral responses that reduce fear and anxiety when presented with traumatic cues. Dr. Rennaker is a U.S. Marine Corps veteran who served in Liberia, Kuwait and Yugoslavia. “Using the peripheral nervous system as a medium for delivering therapy is largely new territory and it’s rich with potential to manage many of the conditions that impact the readiness of our military and, more generally, the health of the nation,” Weber said. “It will be an exciting path forward.”
A primary focus of the project is to improve PTSD modeling, which will help boost the effectiveness of targeted plasticity therapy. “The current preclinical models of fear are poor models for PTSD,” said Dr. Robert Rennaker, Texas Instruments Distinguished Chair in Bioengineering, director of the Texas Biomedical Device Center and chairman of the Department of Bioengineering. “This grant includes a new preclinical model so we can better understand the mechanisms behind PTSD before moving it to clinical trials.”
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