Unravelling the secrets of the vagus nerve will revolutionize medicine
August 22, 2023
By Grace Wade a health reporter for New Scientist

AS I peered at its sinewy, tentacle-like tendrils, I thought the pale structure splayed on the table before me resembled a huge tapeworm, or perhaps a scrawny squid.
Its lacklustre appearance didn’t match with the wonder of what I knew it to be: a human vagus nerve, the sensory superhighway that connects our brain to most of our vital organs and helps regulate everything from the movement of food through our intestines to the steady beating of our heart.

I was at the Feinstein Institutes for Medical Research in New York, viewing one of 30 vagus nerve samples being diced, sliced and imaged by Stavros Zanos and his colleagues. The goal? To create a detailed map of the roughly 160,000 nerve fibres along its structure.

This ambitious effort comes after recent research has revealed the vagus nerve’s role in a wider array of processes than we ever realised – not only monitoring organ function, but helping discern facial expressions and even regulating mood. Most enticingly, we are starting to understand how it governs inflammation, the immune response that runs rampant in conditions ranging from heart disease to Parkinson’s.

Already, electrical devices called vagus nerve stimulators are used to treat epilepsy, depression, migraines and obesity. But they are limited by our rudimentary understanding of the nerve’s complex structure. Now, efforts to untangle its mysteries are allowing us to map each of its branches and even discover specialised cell types we never knew existed. Not only might these insights enable us to control inflammation, they could open a whole new frontier for precision medicine.

What is the vagus nerve?
The vagus nerve is a bundle of neural fibres that starts at the brain stem. It splits into two channels that run along either side of the neck, then rejoin at the heart before descending to the gut and other organs.

The earliest evidence of its crucial function dates back almost 2000 years to when the ancient Roman physician Galen accidentally severed a sheaf of nerves in a pig, stopping its squeals but not its squirms. It turned out he had sliced a branch of the vagus nerve responsible for transmitting signals from the brain to the vocal cords.

Subsequent experiments revealed that the vagus nerve regulates functions of the heart, stomach, lungs, liver and more. But it wasn’t until about three decades ago that we began to tap into it for medical treatments.

The earliest success was with epilepsy. In the late 1980s, J. Kiffin Penry and Joan Christine Dean, then at Wake Forest University in North Carolina, showed that implanting a vagus nerve stimulator reduces or even eliminates seizures for some people with the condition. Most of these stimulators use a pulse generator slightly larger than a poker chip, which is implanted under the skin on the chest. This sends electrical impulses via a wire to a cuff wrapped around the vagus nerve in the neck. The first such stimulator was approved by the US Food and Drug Administration (FDA) in 1997 for treating drug-resistant epilepsy.

Since then, the FDA has approved an implantable device for treatment-resistant depression, after trials showed that it lessened symptoms for about 40 per cent of people who had already tried four or more other treatments without success. A device called VBLOC has also been approved for treating obesity: people using it lost about 8 per cent more excess weight than those in a control group. Most recently, the FDA approved a stimulator for regaining upper body movement after a stroke.

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Research also indicates that stimulators can be used to regulate blood pressure and lower blood sugar.
Most tantalising is the role the vagus nerve plays in controlling inflammation. Hints of this first emerged in the 1990s, when Kevin Tracey, now at the Feinstein Institutes for Medical Research, and his colleagues developed an anti-inflammatory drug to block production of proteins called cytokines, which spur the body’s immune response to infection or illness. In modest amounts, cytokines and the ensuing inflammation fend off foreign pathogens and heal injuries, but an overabundance of them has the opposite effect, damaging tissues and potentially causing chronic illness or even organ failure.

Tracey and his team injected their new drug into the brains of rats experiencing stroke from bacterial infections. As they hoped, it dampened inflammation in the brain. But to their surprise, the effect also extended throughout the rodents’ whole bodies.
With drugs given orally or intravenously, you would expect widespread effects, but the researchers weren’t anticipating this after injecting the medication directly into the brain. “For months, we agonised over what the mechanism could be,” says Tracey. Eventually, they tried severing the animals’ vagus nerves. “When we did that, the drug in the brain no longer turned off inflammation,” he says. “Scientists don’t say ‘eureka’ any more, they say ‘holy shit’, and that’s what happened.”

The inflammatory reflex
Tracey dubbed the vagus nerve’s ability to mediate inflammation the inflammatory reflex. It kicks in when specialised neurons detect cytokines and send signals to the brain, which in turn relays messages to the spleen to start churning out white blood cells. The discovery suggested that we might be able to interrupt inflammation with an electrode, not just drugs, he says.
In 2012, a device using an electrode that Tracey designed while at SetPoint Medical, a biotechnology company in California, was tested in a small group of people with the chronic inflammatory condition rheumatoid arthritis. Of those, 70 per cent had at least a 20 per cent reduction in symptoms, and almost half saw a 50 per cent improvement.

The effect is similar to that of some drugs, but there is a major advantage: anti-inflammatory medications often severely suppress immune function, leaving people vulnerable to infection. Not so with this approach. Vagus nerve stimulation causes white blood cells to shut down cytokine production enough to avoid runaway inflammation, but not so much that our immune system is disarmed completely, says Tracey.
 
SetPoint Medical is now conducting a trial of the device in about 250 people. Tracey is hopeful that the FDA could approve the treatment for rheumatoid arthritis within a few years. Meanwhile, similar devices have also shown promise in treating conditions characterised by chronic inflammation, including inflammatory bowel disease, multiple sclerosis and Parkinson’s disease.
“What diseases are affected by inflammation? Pretty much every chronic illness,” says Zanos. “I’m not saying vagus nerve stimulation will work for every single one of them, but it makes sense to test it out in some way or another.”

There is just one hiccup in all of this: how exactly these treatments work is largely a mystery. It is unclear which fibres the stimulators even target. Is it those closest to the electrode? The ones furthest away? The small ones? The large ones? We simply don’t know. We just turn on the device and hope for the best.

With obesity, for instance, the stimulator is meant to work by mimicking signals that travel along the vagus nerve to tell the brain to stop eating when the stomach is full. In people with epilepsy, though, vagus nerve devices may provide benefits by stimulating nerve cells that increase blood flow to a brain region called the thalamus, which processes information from most senses. It may also work in part by triggering the release of the neurotransmitter noradrenaline, which can reduce seizure symptoms. Boosting noradrenaline may be the way stimulation eases depression symptoms, too. But which particular nerve fibres play a role in this is unknown.

Vagus nerve stimulators
It is even trickier to pin down exact targets of devices that zap the vagus through the skin. Today, these transcutaneous stimulators can be purchased in many countries without a prescription from about $200. They are often marketed as a way to boost “vagal tone”, a supposed measure of vagal activity. But researchers say the concept isn’t terribly scientific (see “What is vagal tone?”, below).

Some transcutaneous stimulators have been rigorously tested, though. In 2018, the FDA approved one for treating chronic migraines and cluster headaches after research showed that it significantly lowered the number of days that people experience them. Tracey says it is important to talk with your doctor before using this kind of technology. These devices may not be suitable for some people with heart conditions, as they can affect heart rhythms.

Therein lies the problem. The extraordinary complexity of the vagus nerve is what makes it an avenue for improving so many aspects of health, but the lack of specificity in treatments also means they can have unintended side effects. It may also be why some applications simply fail.

“The way neuromodulation has been done for many years is creating an electrode and then placing it on a nerve or in the brain and hoping for the best,” says Zanos. For more consistent results, and to expand the potential applications, we need a much more detailed understanding of what we are aiming for.
All of which explains how I find myself staring at the stringy tissue in Zanos’s lab. He and his colleagues are embarking on a three-year, $6.7-million project funded by the US National Institutes of Health to map the vagus in its entirety. That involves identifying every single nerve fibre and tracking its location along the structure’s meandering pathway.

It is painstaking work, beginning with the process of extracting the vagus nerve from a cadaver. At points, it is thinner than a cotton thread, and researchers must carefully label what organs its many branches connect to.
The researchers then chop it into pieces that, at their thickest, resemble cannellini beans, which are moulded into blocks of wax. These are placed into what is essentially a deli meat slicer, where the encased nerve sections are shaved into slivers as thin as a human hair.

Finally, the team bathes the segments in staining solutions to reveal their inner complexity. Zanos shows me an image on his computer. What was once a rather dull, brown blob is now a motley of red, green and blue fluorescence. Each colour correlates to a different type of nerve fibre, yielding clues to its function, he says.

We can tell what types of signals neurons ferry based on their distinct anatomical features. Afferent neurons transmit sensory information towards the brain, while efferent neurons relay signals for controlling movement from the brain to our muscles. Fibres that are insulated in a fatty coating called myelin generally fire faster than those without it. “So, if it is myelinated and efferent, we know that most likely mediates muscle contractions,” says Zanos.

Mapping the vagus nerve’s anatomy won’t only allow us to better predict the effects of placing an electrode anywhere along the nerve’s structure, but could also lead to the creation of ultra-selective stimulators that act only on certain fibres, he says.

Creating a detailed map
Zanos and his colleagues have already shown proof of this concept. After they mapped the vagus nerve of pigs, they developed an ultra-selective vagus nerve stimulator with 10 separate contact points. In research published earlier this year, they showed that, when implanted into live pigs, the device altered the animals’ breathing while minimising effects on other organs.

Mapping the vagus nerve is just the first step, says Cristin Welle at the University of Colorado. “The next step is going to be, how do each of those fibre types then interact with the rest of the nervous system?” she says. She and her team are charting the vagus nerve in the opposite direction, identifying which brain regions it activates. Last year, they showed that vagus nerve stimulation targets neurons in the primary motor cortex of mice, enhancing the animal’s ability to learn motor skills.

Stephen Liberles at Harvard University believes we can achieve even greater precision by elucidating the mechanisms of specific neurons with genetic sequencing. Of particular interest are sensory neurons, which constitute about 80 per cent of all nerve fibres in the vagus and use specialised receptors to detect changes in an environment. “Some of our landmark discoveries in the external senses were discovering odourant receptors or vision receptors,” says Liberles. “We don’t know the receptors for almost any internal organ sense.”

Already, he and his colleagues have identified previously unknown types of vagal neurons that mediate breathing, control blood pressure and detect nutrients in the gut. He believes we will eventually be able to develop drugs that act only on specific vagal cells. If the vagus nerve is our body’s superhighway, such drugs would control the movement of individual cars, while vagus nerve stimulators would dictate general traffic flow across multiple lanes.

“When you understand how all these vital body-to-brain communication pathways operate, that will open the door to therapies by which you can toggle [these] different pathways with greater selectivity,” says Liberles. Being able to modulate inflammation or other physical functions with this level of precision would be nothing short of game-changing for modern medicine.

As I leave Zanos’s lab, I steal a final look at the ribbon of white tissue, marvelling at its extraordinary potential – and the power of science to map it and manipulate it.
Grace Wade is a health reporter for New Scientist