The vagus (from the Latin meaning “wandering”) nerve is the longest nerve that travels from the brainstem down to the colon and controls crucial functions, such as heartrate, blood pressure, digestion, breathing, and immune response.

Vagus nerve stimulation (VNS) modulates neuronal excitability and plasticity in the brain and has been used therapeutically in several neurological disorders. The FDA has approved VNS as a non-pharmacological treatment for brain diseases such as epilepsy and depression.

“Vagus nerve stimulation holds tremendous potential to treat some of the most serious conditions, like Crohn’s disease or pulmonary hypertension, but the question of which fibers of the vagus to stimulate and more importantly, when—like when the body is resting or active—remains unknown,” said Stavros Zanos, MD, PhD, assistant professor at the Feinstein Institutes. “By observing and understanding the effects of VNS on brain function, we can create personalized, fine-tuned treatments for those diseases, whether they affect the brain or peripheral organs.”

When the vagus nerve is activated, vagal-evoked potentials (VEPs) can be observed in the cerebral cortex—the thin layer of soft, creased neural tissue that sits atop the reptilian brain. VEPs are thought to be transmitted through ascending neural systems that connect using the neurotransmitter molecules acetylcholine and noradrenaline. Whether VEPs are modulated by the wakeful or sleeping state of the brain, at the time of stimulation, was unknown until now.

A team of scientists led by Zanos, in collaboration with scientists at the University of Washington, stimulated the vagus nerve in freely moving macaque monkeys at different times of day and activity levels to determine the criteria for most effective VNS.

The findings reported in the Cerebral Cortex article, “Cortical Responses to Vagus Nerve Stimulation Are Modulated by Brain State in Nonhuman Primates,” adds to a growing body of research on the role of the vagus nerve in brain function that will help health care providers select optimal clinical practices for using VNS to treat diseases such as Crohn’s disease or rheumatoid arthritis.

“This research allows us to keep track of biomarkers during stimulation—a way to measure stimulation. This measurement tool will help doctors calibrate treatment and doses of VNS in the future,” said Zanos.

Stavros Zanos, MD, PhD, assistant professor at the Feinstein Institutes is senior author on this study.

The scientists reported that the effects of VNS depend on the subject’s brain state and determine when it is best to stimulate the vagus. Also, the output energy recorded is a powerful tool in understanding and observing the stimulation.

To accomplish this the researchers used a longterm vagus nerve implant and a wearable automatic stimulation-and-recording device (Neurochip), to deliver VNS and simultaneously record electrical brain activity in response to VNS through electrodes implanted into the brain.

The state of the brain when VNS is delivered significantly affects the neural responses to stimulation, across the entire brain. [Source: Stavros Zanos/ Feinstein Institutes]
The team found that electrical stimuli to the vagus activates many brain regions within milliseconds and ultimately results in the stimulation of large populations of neurons in the cerebral cortex measurable as VEPs. The magnitude of the intermediate (70–250 milliseconds after VNS) and late (over 250 milliseconds) components of VEPs was largest during the phase of sleep when the eyeballs do not move under the closed lids (called NREM or non-rapid eye movement sleep) and smallest when the subject was awake, whereas that of the early component (less than 70 milliseconds) was not modulated by the brain’s state.

The findings suggest that the effects of VNS on brain function are largely modulated by the state of the brain when the electrical stimuli to the vagus are delivered. This suggests sensory stimuli from peripheral organs that travel through the vagus may be received differently by the brain at different times of day. It also suggests that VEPs can be used as markers of engagement of vagal fibers to observe and tailor VNS treatment in individual patients.

“The brain monitors and controls healthy organ function because it receives and processes information in the vagus nerve,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes. “Dr. Zanos’ important research sheds light on how the brain processes these signals and offers new clues into how to advance bioelectronic medicine.”

Zanos added, “Bioelectronic medicine is a promising emerging field of medical research and clinical practice that is using electricity as an alternative to traditional pharmaceuticals to treat often chronic and severe conditions like Crohn’s disease or rheumatoid arthritis.”