A nerve that acts as a ‘superhighway’ between brain and body is increasingly seen as key to controlling inflammation, the root cause of a swathe of killer diseases. In a new book, US neurosurgeon Kevin J Tracey explores the promise – and the myths – of vagus nerve stimulation.
Today, thanks to antibiotics, vaccines and modern sanitation, we reasonably expect to live to old age. We mostly die from non-infectious causes: heart disease and stroke, diabetes and obesity, cancer and neurodegenerative diseases such as Alzheimer’s and Parkinson’s account for two-thirds of the roughly 60 million human deaths each year.
These, says Dr Kevin J Tracey, are all diseases of inflammation. And the annual death toll does not account for the millions more suffering from autoimmune diseases and other inflammatory conditions.
Tracey, a US neurosurgeon, inventor and CEO of a large New York medical research organisation, turned to the investigation of immunology and inflammation after being shocked and puzzled by an 11-month-old burns victim who died of sepsis while in his care. The discoveries of Tracey’s lab include how the nervous system communicates inflammation to the brain, how the body’s chemical messengers can cause shock and damage to tissues, and how vagus nerve stimulation can relieve symptoms of pain, inflammation and disability from autoimmune diseases.
The vagus nerve is the longest and most important in our body. Actually a paired bundle of nerve fibres, it reaches from the base of our brain, exiting our skull at about the level of our ears, and runs down either side of the neck before branching out to the organs throughout the chest and abdomen. Known for centuries simply as the great nerve, the vagus (Latin for “wandering”) nerve forms a system of two-way communication between the body and the brain that’s responsible for the function and balance of our vital organs and structures, including our immune system.
In his new book, The Great Nerve, Tracey says vagus nerve stimulation is poised to revolutionise the way millions of people are cared for by treating inflammation, which has “replaced infection as the greatest threat to healthful human longevity”.
“Like the strings, reeds, skins and soundboards of an orchestra, the 200,000 or so nerve fibres of your vagus vibrate in tune with health. The vibrations are the music, and the song is life,” he writes.
Using the latest research, patient stories and personal insights, Tracey explains how the vagus nerve works, how vagus stimulation therapy has treated hundreds of thousands for epilepsy and depression, and the trials exploring if it can treat diabetes and obesity, anxiety, Alzheimer’s, strokes, multiple sclerosis and other conditions.
“In my 40-year fascination with the brain and inflammation, I have learned that the vagus nerve holds the potential to alleviate pain and suffering,” he writes in his introduction. “This is why I go to work in the lab every day …”
Despite his ringing endorsement, he is wary of the hype and the many purported techniques for vagus nerve stimulation circulating online. “If you are fairly healthy but overwhelmed by the billions of web impressions, #vagusnerve, and claims on the internet and social media telling you to do this, that, or the other thing to stimulate your vagus nerve, I understand,” he notes. “I also find the advice swirling ‘out there’ to be a lot. Worse, it is often inaccurate and sometimes completely wrong. Many popular recommendations and proposed therapies, if they do stimulate your vagus nerve at all, may or may not have proven health benefits. But some of these ideas are grounded in verifiable scientific mechanisms and physiological understanding, warranting additional thought and discussion.”
In this edited extract from The Great Nerve, Kevin J Tracey explores popular therapies including meditation, breathing techniques, exposure to cold, and exercise, and what’s known about their potential to stimulate the protective and healing reflexes of the vagus nerve.
MEDITATION
From paying attention to every breath or repeating a word or mantra to sitting cross-legged while channelling blue light down both sides of your neck or walking a sandy shoreline, meditation encompasses a range of practices and techniques designed to nurture inner peace, compassion, and the ability to recognise the fleeting experiences of your sensations, thoughts, and emotions. Meditation is widely practised to promote mental clarity, emotional stability and adaptability to change.
I am not a meditation expert, but I do meditate. I assume a relaxed physical posture and hold attention on my breath or on a specific intention, such as wishing for the wellbeing of others. Then I simply note the emotions, thoughts, and sensations that arise in the present moment, practising a state of nonreactive awareness of their appearance and disappearance.
Hundreds of clinical studies using brain imaging with functional MRI [fMRI] and PET scans have attempted to determine what these meditative practices are doing to the brain, nervous system and vagus nerve. The results so far, while interesting, leave plenty of unanswered questions.
For example, one systematic review of 78 of these functional neuroimaging studies revealed consistent patterns of brain activation and deactivation in 527 participants doing various meditation practices. Each exhibited a different pattern of brain activity on fMRI and PET scans. Specific brain regions, such as the insula, prefrontal and supplementary motor cortices, anterior cingulate cortex and frontopolar cortex, were consistently activated across multiple meditation techniques. However, the brain activity patterns observed across different meditative practices were largely distinct.
After reviewing all this data, the authors concluded the jury is still out, and … much more research is needed for us to understand how meditation works in the brain to influence psychological and physical wellbeing.
Hundreds of other clinical studies have explored how meditation influences cardiovascular health. In some studies, meditation practices enhance vagal tone, with measurable effects including slower resting heart rate and reduced blood pressure. But other studies have failed to reach the same conclusion.
Given the public health implications, the American Heart Association sponsored a study to define recommendations for the potential advantages of meditation to protect against cardiovascular disease as a safe, cheap, and widely accessible adjunct to traditional medical therapies.
Their review of 69 clinical studies expressed concern that the quality of many studies was limited because the subjects were not appropriately randomised, lacked sufficient study population sizes, or had insufficient follow- up. The authors cautiously concluded that the evidence hints at a possible cardiovascular benefit, while acknowledging that the overall quality and, in some cases, quantity of data are modest. However, given the low costs and low risks of meditation, the study suggested that anyone interested may want to consider it “with the understanding that the benefits of such intervention remain to be better established”. In other words, it won’t hurt, it may help, but we don’t know for certain if it is worth your time, cardiovascularly speaking.
The evidence is more promising regarding meditation’s potential to reduce inflammation, whether through traditional practices or mindfulness-based interventions (MBIs). A study that reviewed 48 randomised controlled trials encompassing 4683 subjects found that compared to control groups, individuals practising MBIs had decreased levels of C-reactive protein and interleukin 6, serum proteins that correspond to the amount of inflammation in the body. The study also found evidence for positive changes in telomere length, the molecules … that prevent your chromosomes from deteriorating and are related to the risk of inflammation, cardiovascular disease and other conditions. While these findings are encouraging, they are not definitive proof of a causal relationship between meditation and vagus nerve activation … The final scientific word requires more study.
Breathing techniques
While Wim Hof breathing [a technique developed by the Dutch cold-water enthusiast] activates stress responses to suppress acute inflammation, other research has shown that slow deep breathing, which stimulates the vagus nerve, can also reduce inflammation. So, breathwork triggers fight-or-flight, which reduces inflammation, and breathwork triggers rest-and-digest, which reduces inflammation? Yes and yes, both are true.
As studies have shown, deep, diaphragmatic inhalations followed by prolonged, slow exhalations decrease your heart rate and increase your vagal tone, a kind of internal vagus nerve stimulator, no device required. And at Stanford University, researchers studied three different five-minute daily breathwork exercises compared to an equivalent duration of mindfulness meditation over one month. They compared cyclic sighing, emphasising extended exhalations; box breathing, involving equal durations of inhalation, breath retention, and exhalation; and cyclic hyperventilation with retention, featuring longer inhalations and shorter exhalations, somewhat akin to Wim Hof’s breathing. Each of these breathwork exercises reduced the subjects’ respiratory rate and improved their overall mood and sense of wellbeing significantly more than subjects who practised meditation without breathwork.
The group practising cyclic sighing had the most significant improvement in positive affect scores. The precise mechanisms remain uncertain, but the authors speculate that vagus nerve pathways to the brain, by carrying signals into the brain centres controlling emotion, may be the reason daily five-minute sessions of cyclic sighing help alleviate stress. Although the argument for cause and effect remains open, cyclical sighing with extended exhalations can transiently decrease heart rate and increase heart rate variability and decrease the production of inflammatory cytokines, a possible cause or contributor to anxiety and depression.
What else is there to know about the effects of breathing on the activity of the sympathetic [fight or flight] and parasympathetic [rest and digest] nervous systems, and these links to inflammation and emotional wellbeing? A lot. And we are only beginning to unravel the mysteries of the great nerve and its reflexes, because it’s complicated. Out of the 100,000 vagus nerve fibres on each side of your neck, perhaps a few hundred are required to control breathing, and a few thousand or fewer are required to control inflammation. Yet we don’t know if these are the same or different fibres, and we don’t know how they contribute to other protective, homeostatic [regulatory] and healing reflexes and brain centres. The daunting complexity of neural signals travelling in these other more than 195,000 vagus nerve fibres represents a major challenge to unravel.
Extreme cold
Studies of various types of cold exposure, ranging from complete immersion in freezing cold water to standing in a refrigerated room, report a wide range of immune system cytokine responses. Here’s the summary of what we can be confident we know so far: first, whole-body cold is a major stressor, which can be dangerous to some people with underlying cardiovascular conditions. So, you should ask your doctor before exposing yourself to extreme cold.
Second, the initial response to extreme cold activates your sympathetic nervous system’s fight-or-flight response and coactivates your vagus nerve. Shivering and vigorous effort from hyperventilation generate muscle work, which can stimulate inflammation. The surge of stress hormones can also both stimulate and inhibit inflammatory cytokine production.
Third, if cold exposure persists, your vagus nerve will be stimulated, gradually slowing down your heart. This vagus nerve stimulation may also significantly inhibit inflammatory cytokine production. But this final point remains conjecture. It’s an interesting hypothesis requiring further study from randomised controlled trials, which I certainly hope someone somewhere pursues carefully.
Until then, despite what you see on social media, the effects of cold exposure on the immune system and the vagus nerve’s role remain unclear. We also lack sufficient data on the long-term benefits or harm from repeated cold exposure. So be careful what you believe from online hullabaloo and ask your doctors what they think.
Meanwhile, as with meditation and breathwork, while I await the evidence from additional studies, I take cold showers. Why? Because I find some confidence in the consistent conclusions of the clinical studies that voluntary activation of a fight-or-flight response by cold exposure inhibits inflammation. And inhibiting inflammation is a good way to reduce the risks of cardiovascular diseases, neurodegeneration (including Alzheimer’s), obesity, diabetes and cancer.
So, three or four days a week, I end my regular shower by turning the water to full cold for two or three minutes. Once again, I cannot make recommendations about what you or anyone else should do based on my experience. But I have noticed a few interesting things about this practice.
First, it is very uncomfortable. Every single time. After hundreds of episodes over several years, I continue to feel stinging pain from the cold water (about 11°C). But strangely, as the cold water beats down, after 30 seconds or so, I notice fewer negative emotional reactions to it. It seems as if I can witness the pain signals arising from my skin’s nociceptors and arriving inside my brain, but at the same time, not react out of indignation, rage or panic. It’s like I’m observing someone else endure the cold. This mindset, when emotions do not have their usual sway over my consciousness and pain, is not “unpleasant”, it is freeing.
Second, when it’s over, I smile, every time. And, as I have said, I like to be happy. I am not sure why this occurs. Perhaps the vagus nerve stimulation is sending signals up into my brain that contribute to a positive outlook. Or maybe daily vagus nerve stimulation helps lower the total bodily burden of inflammatory cytokines, reducing their negative consequences on my affective brain. Or maybe the afterglow of fight-or- flight combined with cold-mediated vagus nerve stimulation feels good. Or perhaps it’s the relief of surviving the cold. Science hasn’t decided, but I’ll keep doing this thing that makes me smile.
Exercise
Regular, moderate-intensity, aerobic exercise – like brisk walking, elliptical training, cycling, rowing, or gardening, which increase your heart rate and breathing while allowing for sustained activity and conversation – has been linked to slower resting heart rates and higher heart rate variability (HRV) compared to committed couch potatoes.
Numerous studies, including an influential one at the University of Washington in Seattle, have established this link. The Seattle one studied 24 men ranging in age from 24 to 82. After six months of supervised bicycling, walking, and running, the subjects’ heart rates were significantly decreased, and their HRV significantly increased. The investigators concluded that “exercise training increases parasympathetic tone at rest in both the healthy older and young men, which may contribute to the reduction in mortality associated with regular exercise”. That conclusion, published in 1998, the same year my colleagues and I discovered that the vagus nerve’s inflammatory reflex inhibits inflammation, is enough to motivate me to exercise more.
Numerous large studies confirm the benefit of exercise, like one study of 122,000 people over eight years showing reduced all-cause mortality in proportion to increasing cardiorespiratory fitness. The investigators in this study also found that the increased mortality risk from being out of shape was comparable to the well-known risks of smoking, or having other conditions including diabetes and coronary artery disease.
However, proving that exercise is beneficial because it reduces inflammation is not so simple. There are many reasons for this, beginning with how we measure cytokines and other inflammatory molecules. The problem is there are no gold standard blood tests of whole-body inflammation.
An overwhelming amount of clinical evidence indicates that consistent, vigorous exercise enhances heart rate variability and vagus nerve activity and is beneficial for the body. But regular exercise is also associated with improvements in brain and emotional health, as evidenced by studies linking exercise to improved cognitive function, reduced risk of anxiety, depression and age- related cognitive decline, and enhanced longevity.
Why this happens is unclear. There are many possible explanations, some including a role for the vagus nerve. It could be that exercise increases the sensory vagus nerve signals that activate brain regions associated with enhanced positive emotions and a sense of enhanced wellbeing and happiness. Another possibility is that vagus nerve signals travelling away from the brain and back into the body decrease inflammation and inhibit the production of cytokines that cause depression, anxiety, fatigue and negative emotions.
More work is necessary to help us understand why exercise is beneficial and whether and how the vagus nerve plays into these benefits. Meanwhile, I try to exercise five days a week for 30 to 45 minutes, combining aerobic exercise, stretches, and yoga with resistance and weight training.
Some of the people who seem to be most trustworthy on this subject, like the Stanford University Medical School-educated and Johns Hopkins University-trained physician and bestselling longevity author Peter Attia, also advise us to listen to our body, adjusting exercise intensity as we need to and finding activities that are enjoyable and sustainable over the long term. Whoever first said the best exercise routine is the one you actually do may have also said it best.
The Great Nerve, by Dr Kevin J Tracey (Penguin Life, $40) is out now.