What type of medical intervention is approved by the U.S. Food and Drug Administration across different devices and indications to help treat conditions as disparate as epilepsy, stroke rehabilitation, depression, migraine, cluster headaches and, most recently, rheumatoid arthritis?
It’s vagus nerve modulation —an umbrella term for therapies that use controlled signals (often gentle electrical pulses) to influence brain circuits, inflammation and organ function. In a new review published in Comprehensive Physiology, UC San Diego-led researchers synthesize what’s known about how these therapies work and weigh in on what it will take to create next-generation treatments.
“There are now hundreds of papers talking about different mechanisms — how stimulating or blocking the vagus nerve modulates brain circuits, the immune system and organ systems like the heart, lungs and kidneys,” said the paper’s first author Troy (Yifeng) Bu, a recent PhD graduate from the UC San Diego Department of Electrical and Computer Engineering, UC San Diego Qualcomm Institute affiliate and director of design engineering for InflammaSense . “However, the field has lacked a comprehensive summary of these mechanisms and their effects. With more than 660 references, our paper offers a unified synthesis.”
Vagus nerve modulation targets the nerve of the same name, a “superhighway” of the autonomic nervous system that runs down both sides of our necks from the brainstem to the chest and abdomen. For some patients, that can mean a non-drug option or add-on that aims to change the underlying nerve signals driving disease-mediated symptoms.
“The paper identifies the most important discoveries and groups from the literature,” said senior author Imanuel Lerman, MD, professor of anesthesiology at UC San Diego School of Medicine, affiliate of UC San Diego Qualcomm Institute and VA San Diego Healthcare System, and co-founder and CEO of InflammaSense. “It also tells the story of how the government, including DARPA, funded this work early on with the ElectRx program that, with follow-on agency funding via the NIH SPARC initiative, spurred this huge panoply of different treatments and therapeutics.
“However, we don't want to get ahead of ourselves, because we need to develop treatments specific for the person, organ and disease,” he continued. “We need to make sure the new therapeutics are appropriate for their specific uses.”
Mapping a Complex Landscape
In the paper, the authors reveal the complex network of mechanisms and therapeutic approaches associated with the vagus nerve to date.
Bu, for one, admitted even he was surprised to find so many mechanisms — from synaptic plasticity to endocrine integration — many of which interact with each other. One of the review’s contributions is a table that links conditions to proposed mechanisms and the strength of evidence across organ systems.
“While a lot of researchers understand their own area of specialty,” Lerman said, “we provide a larger platform so that others can start to make broader connections to see patterns and gaps across fields that usually don’t talk to each other.”
The paper also highlights the lack of uniformity in parameters such as frequency, strength and location of stimulation. These variations create challenges comparing one study to another. This lack of standardization extends to devices approved by the FDA, which are individually approved for specific use cases.
“It isn’t always possible to say that one device can do something because it's similar to another,” Lerman noted. “There are many things that may not be equivalent, such as waveforms, electrical current, voltage or directed energy-based platforms.”
The Problem of Individual Variability
Differences among people add another critical factor to navigate in developing therapies targeting the vagus nerve.
“Patients are going to be very different,” Lerman said. “People’s anatomy is different, and their network systems at the level of brain processing and peripheral nerve activity are different. There's heterogeneity in their autonomic set points and in thresholds required for stimulating certain fibers within the vagus. Comorbid diseases, such as COPD, heart disease and mental health disorders, change how a patient’s autonomic nervous system responds to stress and how it regulates inflammation. All of these factors matter in vagus nerve stimulation.”
According to the authors, one potential solution to the problem of individual variability is self-regulating “closed loop” systems that can adjust according to biometric feedback from the patient. Devices with sensors could provide individualized medicine by continuously adjusting doses based on a patient’s biomarkers.
Other opportunities the authors identify to advance the field include the use of artificial intelligence, for example to optimize parameters and predict responders, and the targeting of selective fibers within the vagus nerve to produce specific effects.
“Writing the paper has been an incredible journey,” Lerman concluded. “Our goal throughout has been to provide a framework to build system models where we can identify affected organs, understand how they may interact with different vagal nerve stimulation devices and anticipate on-target and off-target effects — all to provide the right therapy to the right site.”
In addition to Bu and Lerman, authors of the paper, “ A Review of Vagus Nerve Stimulation For Disease: Comprehensive Theory And Evidence For Mechanisms of Action ,” are: Alex Liang, Benjamin Hoffman, Andres Gottfried-Blackmore and Ravinder Mittal of the UC San Diego School of Medicine, Dawn Schiehser, Alan Simmons and Ruth Klaming of UC San Diego and VA San Diego Healthcare System, Oliver Case of University College London, Christopher Puleo of Rensselaer Polytechnic Institute and Hubert Lim of University of Minnesota and SecondWave System Incorporated.
Comprehensive Physiology
Systematic review
People
A Review of Vagus Nerve Stimulation For Disease: Comprehensive Theory And Evidence For Mechanisms of Action
4-Mar-2026
Yifeng Bu and Imanuel Lerman are affiliated with InflammaSense. Hubert Lim serves as Chief Science Officer of the SecondWave System. The remaining authors declare no conflicts of interest.