DARPA’s Electrical Prescriptions (ElectRx) program is 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). PTSD is a condition in which individuals feel anxiety and panic when reminded of a traumatic event.
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.”
“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.
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.
“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.”
DARPA’s Electrical Prescriptions (ElectRx) program
DARPA has selected seven teams of researchers to begin work on the Agency’s Electrical Prescriptions (ElectRx) program,
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. 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 (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.”
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.
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. 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.
“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
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.
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.
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
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
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.
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.
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.
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
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.”
National Institute of Health’s SPARC Initiative
“Peripheral nerves, the nerves outside of the brain and spinal cord, make connections with and influence the function of every organ in the body. Modulation of peripheral nerve signals to control the functions of the organs they supply has been recognized as a potentially powerful way to treat many diseases and conditions, such as hypertension, heart failure, gastrointestinal disorders, type II diabetes, inflammatory disorders, and more,” says NIH.
However, the underlying physiology and mechanisms of action for neuromodulation therapies are poorly understood. The design of more effective and minimally invasive neuromodulation therapies requires knowing exactly what nerves one must stimulate and how they must be stimulated to achieve the desired effect on organ function. It also requires knowing exactly what nerves one must avoid to prevent unwanted side-effects.
The Common Fund’s Stimulating Peripheral Activity to Relieve Conditions (SPARC) is uniquely positioned to serve as a community resource that provides the broader public and private research communities with the scientific foundation necessary to advance neuromodulation therapies towards precise neural control of end-organ system function to treat diseases and conditions.
This high-risk, goal-driven program is structured as a consortium of four distinct research areas that will function in an integrated and iterative way, fostering discovery and broad dissemination of the fundamental physiology and biological mechanisms underlying peripheral autonomic and sensory control of internal organ function and changes attributable to disease states and conditions.
In turn, these discoveries will enable development of next generation closed-loop neuromodulation therapies, investigation of approved devices for new indications and adoption of improved computational tools and modeling methods. The SPARC program tentatively plans to support interdisciplinary teams of investigators to deliver neural circuit maps of several organ systems, novel electrode designs, minimally invasive surgical procedures, and stimulation protocols, driven by an end goal to develop new neuromodulation therapies.
Current plans include initiatives to:
- Capitalize on recent technology advances and anticipated new technology developments facilitated by the program to deliver detailed, predictive, functional and anatomical neural circuit maps of the autonomic and sensory innervation of multiple internal organs or organ systems.
- Leverage recent biological discoveries to develop technologies including novel electrode designs and sensors, stimulation protocols, and minimally invasive surgical procedures with an end goal to improve existing and pilot new, next generation closed-loop neuromodulation therapies.
- Establish effective public-private partnerships to use existing approved neuromodulation technologies and therapies to explore new indications.
- Assemble data from other SPARC initiatives into a publicly available and centralized resource for the wider research community to access as well as provide new computer modeling methods and user-friendly computational tools.