December 8, 2022 | Researchers have their sights set on creating a first-of-its-kind anatomical map of the vagus nerve. Stavros Zanos of the Feinstein Institutes for Medical Research is leading a three-year-long research study called Reconstructing Vagal Anatomy (REVA), along with collaborators at the Feinstein Institutes, the Zucker School of Medicine at Hofstra/Northwell Health, and Temple University. The NIH-supported project plans to share the map with the greater scientific community in hopes of leading to new breakthroughs in the field of bioelectronic medicine.
Deeper Understanding Could Lead to New Ways of Treating Disease
The vagus is one of the longest and most complex nerves, running from the brainstem to the abdomen and many of the body’s major organs. It consists of thousands of motor and sensory fibers grouped in bundles that form branches reaching out to organs like the heart, lungs, liver, and intestines.
The reason the vagus nerve is so crucial is that it continuously sends vast amounts of information between the brain and peripheral organs, acting as the main “highway of communication” between the brain and the body, Zanos, an associate professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes for Medical Research, told Diagnostics World.
For organs like the heart, lungs, or stomach to work properly, they must work together. That coordination happens, to a large extent, through brain function. The brain collects information about each organ, processes the information, and controls their function, he said. All this back and forth occurs through nerves, and the vagus plays a significant role in homeostasis.
It also appears to play a crucial role in diseases that impact these organs. As disease mechanisms are studied more and more, we have come to realize that the way the brain communicates with organs is impacted when those organs are diseased, Zanos said, and in some instances the communication itself is responsible for illness.
He and colleagues are interested in learning how the vagus is implicated in diseases by visualizing how the motor and sensory fibers are arranged. The hope is that by mapping the nerve right down to its singular fibers, it will become possible to learn how the vagus controls healthy organ function and how it is involved in conditions affecting organs, which could ultimately lead to new ways of treating patients.
Step by Step Project Overview
This research will dissect, image, and map out the locations and trajectories of the nerve fibers and bundles throughout the vagus nerve and its branches. (Although commonly referred to as a singular nerve, the vagus is actually comprised of two nerves—a left and a right vagus—and this project intends to map both.)
Because this involves incredibly detailed work on the nerves themselves, the researchers will rely upon nerves collected from 30 human cadavers that have been donated for scientific research. An anatomist who understands the branching and how the vagus moves between different organs and cavities will excise the nerves “one by one, branch by branch” and label the various parts along the way.
A series of high-resolution imaging methods will then be deployed. A micro-CT scanner will enable the team to see the 3D structure of these branches and the vagus nerve itself at a very fine resolution, Zanos said.
Next, they will perform additional stains and procedures that make it possible to look at individual fibers. There are hundreds of thousands of them within the vagus nerve, he explained, but powerful microscopes and chemicals that color different parts of those fibers make it possible to image singular fibers and understand their function.
The micro-CT scanning and the histological microscopy methods produce a massive amount of data that would be impossible for a single human—or many humans—to analyze manually, which is where the artificial intelligence tools come into play. The team has an entire suite of algorithms and tools that they either have developed or will develop over the next few years.
An entire team of investigators is working on this aspect of creating algorithms that can analyze the data and extract information in ways that enable scientists, engineers, and physicians to understand what they are seeing.
The final step is compiling helpful information out of this extensive dataset that the scientific community and the general public can interact with, whether using the graphical user interface accessible on the web or logging into a site and posing queries, such as how many branches from this nerve are distributed to the heart? Or how long are those branches?
How the Greater Scientific Community Stands to Benefit
We currently have a limited understanding of which parts of the vagus nerve are responsible for which functions. The hope is that the dataset, the visualization tools, and the presentation tools will be used to understand the functions of the vagus nerve in health and in disease. “But I think the main reason why we’re excited about this is the potential to use this knowledge, this dataset, in the design of better bioelectronic devices,” he said.
“There are devices right now in the market that stimulate the vagus with electrical energy,” he explained, and they have FDA approval to treat diseases such as epilepsy and depression. “However, those devices have been designed with no detailed knowledge of the structure of the vagus nerve.” The new knowledge generated throughout this project is expected to help contribute to the development of improved tools capable of altering how the vagus communicates back and forth in pathological conditions—and helping patients with those conditions recover.
And because the vagus is involved in many different organs and diseases, he believes “we should not limit ourselves to just brain diseases or to just epilepsy and depression.” The same technology can potentially be used to treat other issues, including various autoimmune, cardiovascular, and metabolic diseases. Once the organization of the nerve is better understood, next-generation devices will hopefully be able to target function more precisely so that patients with one illness might be treated with a different device than patients with another.
Kevin Tracey, president and CEO of the Feinstein Institutes and the Karches Family Distinguished Chair in Medical Research, called the vagus nerve a “super highway” that transmits information between the brain and the body in both directions. He also noted that the nerve is capable of turning the immune system on and off. This research “generates fundamental new knowledge that will transform our understanding of the human vagus nerve and open new ways to hack the vagus nerve and cure disease with bioelectronic devices,” he said in a news release.
The vagus nerve is one of the “most essential yet underappreciated nerves” in the body, according to Peter Staats, Chief Medical Officer of New Jersey-based electroCore, a bioelectronic medicine company with an FDA-cleared device that delivers electrical stimulation to the vagus nerve. He also serves as President of the World Institute of Pain and Chief Medical Officer for National Spine and Pain Centers.
Staats, who is not involved with the mapping research project, told Diagnostics World that the vagus nerve “controls various physiologic functions, and is implicated in numerous pathologic states.” Staats also noted that there are “signals of efficacy or demonstrated efficacy” in an array of conditions, including headache, epilepsy, anxiety, asthma, rheumatoid arthritis, Parkinson’s disease, gastrointestinal disorders, COVID-19, and PTSD.
“It is crucial to map out the anatomic distribution to understand the profound impact that vagus nerve stimulation can have on these diseases and health,” Staats added. “Developing a deeper understanding of the vagus nerve’s role in disease processing will likely lead to new treatments and strategies for a range of diseases. In addition, it will likely validate the importance of stimulating this nerve as a treatment across numerous diseases.”
The Bigger Picture: Other Synergistic Efforts Underway
This project is part of the NIH's Stimulating Peripheral Activity to Relieve Conditions (SPARC) program, which has been active for several years now, Zanos said. It is just entering its second phase, geared toward translating knowledge generated in recent years—mostly in animal models and technologies—to understand the function of the vagus in humans.
A late October announcement highlighting the launch of SPARC’s Phase 2 noted the work intends to “transform our understanding of nerve-organ interactions” in hopes of moving bioelectronic medicine toward treatments capable of changing people’s lives. The financial awards doled out to various institutions are meant to “spur the next generation of neuromodulation therapeutics informed by the systematic development of high-resolution anatomical and functional neural circuit maps of the vagus and other nerves.”
There are several prongs in this next phase. In addition to REVA, which encompasses The Feinstein Institutes for Medical Research project and another led by Case Western Reserve University, two other synergistic initiatives are involved. One seeks to understand the effects of stimulating the vagus in humans with existing devices, he added, and another is geared toward developing technologies for stimulating the vagus and other peripheral nerves with clinical-grade devices.
VNS Endpoints from Standardized Parameters (VESPA) looks to “identify the physiological effects of altering vagus nerve activity to discover how best to stimulate nerve fibers for specific therapeutic effects,” according to the Phase 2 announcement, and includes researchers from the University of Minnesota, Baker Heart and Diabetes Institute, and Mayo Clinic.
Meanwhile, Human Open Research for Neural Engineering, or HORNET, is developing “an open source, clinical grade neuromodulation platform by seeking technologies and components to safely modulate nerve function” and could help “advance the clinical translation of peripheral neuromodulation therapies in humans.” Awardees include researchers from the University of Southern California, Med Ally LLC, Medipace Incorporated, Case Western Reserve University, University of California, Los Angeles, and the Louis Stokes Cleveland VA Medical Center.
Together, the three prongs create an ecosystem of scientific, clinical, and engineering knowledge that will be shared with the greater scientific community over the next several years. “The main end goal is to help companies, to help physicians, to help scientists and engineers to build the next generation of devices that can deliver very targeted, effective, and safe therapies to people with a multitude of diseases,” Zanos explained, ranging from diabetes, hypertension, and heart failure to various diseases of the brain.
“It’s a very tall order, but it has been done with very careful central design and with very well-coordinated effort between teams,” he said. Those teams will be interacting with one another and aligning their methods and deliverables over the next several years to maximize the impact of their research, Zanos added.
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.