by Jo Marchant
She had a couple of crises. On Tuesday, May 7, her blood pressure suddenly plummeted and she fell into a coma: a phenomenon known as septic shock. Without sufficient blood pressure, the heart can no longer effectively pump blood around the body. Deprived of oxygen and nutrients, cells and organs die. In up to half of cases, septic shock is fatal.3
At the time, doctors thought septic shock was caused by toxins from bacterial infection. But often, as in Janice’s case, no infecting bug is ever found. Tracey and his colleagues pumped gallons of intravenous fluid into Janice to try to raise her blood pressure, and infused adrenaline to boost her heartbeat and constrict her arteries. By Wednesday, however, Janice’s hands and feet were turning gray, and her lungs and kidneys were starting to fail.
On Thursday morning, the crisis was suddenly over; Janice recovered as quickly and mysteriously as she had succumbed. But on Sunday, May 12, she developed another complication.
Tracey describes Janice’s new problem, severe sepsis, as the “pestilence of the 21st century.”4 It is one of the most common causes of death worldwide, killing nearly a quarter of a million people a year in the U.S. alone. It often affects patients who are already ill—with burn injuries like Janice’s, for example, or heart disease, cancer, infections or trauma.
In the 1980s, doctors assumed that severe sepsis too was caused by toxins produced by invading bacteria. It develops more slowly than septic shock. Patients show signs of infection and inflammation throughout the body, and gradually their organs stop working. This time, tests did show microbes in Janice’s bloodstream. She developed a 104-degree fever. Then her kidneys, gut, lungs and liver all began to fail.
Antibiotics cleared the bacteria from Janice’s blood, but her condition didn’t improve. She was on life support for days, with her family (who were only allowed to see her during brief visiting hours) keeping a desperate vigil by the elevators.
Once more, amazingly, this tiny child bounced back. By May 28, her first birthday, it seemed for the first time that she was going to make it. Janice looked healthier than at any time since the tragic accident. She had drunk her first milk, and her burns were starting to heal. They had a party; Tracey recalls chocolate cake, streamers, and Janice laughing, with rosy cheeks. Everyone—her family and the entire medical team—was celebrating not just Janice’s birthday but her miraculous recovery, her precious life. Just one more round of relatively minor surgery, and she could go home.
The next day, a nurse was feeding Janice a bottle of milk when her eyes rolled back in her head and her heart stopped. Tracey and a colleague carried out CPR, injected adrenaline, and repeatedly shocked Janice with defibrillators. They kept it up for 85 minutes. They even inserted an electrical pacemaker. But her heart did not restart.
When he was five, Tracey’s mother had died of a brain tumor, and after the funeral the young boy asked his grandfather, a pediatrician, why surgeons couldn’t just cut the tumor out. The tumor sends projections into the surrounding tissue, the man replied. It wasn’t possible to remove it without destroying the healthy brain too.
The five-year-old said that when he grew up, he was going to do medical research—he would find better techniques so that next time doctors would not have to stand by and watch a person die. Yet now, 22 years later, he was forced into exactly the same position with Janice. There had been nothing he could do.
Unable to speak even to pronounce the time of death, Tracey walked out of the room. He did not see Janice’s body, or her family, again. But the case haunted him. He suffered recurring nightmares, reliving her story yet each time with the awful knowledge of how it was going to end.
Tracey tells Janice’s story in his 2005 book, Fatal Sequence. In the book, he says that when Janice died, he was due to start two years of research and hadn’t been sure what his project should be, but now he knew. “Janice’s story compelled me to study sepsis,” he writes.5 He wanted to understand what went wrong in Janice, and how it could be fixed.
His research would ultimately lead him to the same structure in the body as that targeted by HRV biofeedback: a meandering bundle of fibers called the vagus nerve.
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PAUL LEHRER, a psychiatry professor at Rutgers University in New Jersey, has dedicated his career to studying biofeedback. He wasn’t convinced by its benefits at first, but then he saw a group of Russian children playing an intriguing computer game.
There are lots of different types of biofeedback, and the general idea is that by monitoring different aspects of our physiology in real time, we can learn how to shift our bodies into particular desired states—for example a state of relaxation. Lehrer studied electromyograph (EMG) biofeedback, which monitors muscle tension, for example, and finger temperature biofeedback, which is based on the fact that when we’re relaxed, our extremities, including our fingertips, get warmer. They worked, but didn’t seem to be more effective than more direct methods to relax the body, such as progressive muscle relaxation (a technique that involves tensing and then relaxing different muscle groups in turn).
Then in 1992, Lehrer visited St. Petersburg, Russia, where his son was studying. While there he asked around to see if anyone was studying biofeedback, and was directed to a private clinic treating children with asthma. Staff at the clinic were using computer games to help the children increase their HRV. “The best one involved a paint brush painting a fence that was filled with apparently rather funny Russian graffiti,” recalls Lehrer. “If the amplitude of heart rate fluctuations was high enough, the fence was completely painted. If not, part of the fence was missed.”6
It was intriguing, but Lehrer had no idea if or how boosting HRV might work, for asthma patients or anyone else. A couple of years later, Lehrer visited St. Petersburg again, and was introduced to a physiologist and engineer named Evgeny Vaschillo, who had studied HRV biofeedback in Russian cosmonauts. Vaschillo showed the cosmonauts a sine-wave pattern on an oscilloscope, and asked them to match it with their heart rate. With practice, the cosmonauts achieved huge fluctuations of up to 60 bpm.
Lehrer helped Vaschillo to get his work published in the U.S.,7 but not before the paper was rejected by various physiology journals. One reviewer objected that such a huge variation in heart rate simply isn’t possible. Either the data were inaccurate or faked, or Vaschillo was studying “some kind of yogis.”8 In fact, what was happening to the cosmonauts’ hearts was a simple physical phenomenon: something that Vaschillo, with his engineering background, recognized, but that the physiologists had missed.
There are several processes in the body that cause our heart rate to fluctuate. One is the “baroreflex.” Reflexes controlled by the nervous system monitor conditions in the body and act to keep us safe, without requiring any conscious thought. Some affect our behavior; if you touch something hot, for example, a reflex causes you to pull back your hand. Others constantly adjust various aspects of our physiology to keep them within safe limits.
The baroreflex does this for blood pressure. It’s controlled by stretch receptors in artery walls. If blood pressure goes up, this activates the stretch receptors, sending a signal to the brain stem, which then sends a signal back to slow the heart so that blood pressure falls. If blood pressure falls too low, the stretch receptors send the opposite signal, and our heart rate goes up again.
A second process that varies our heart rate is called “respiratory sinus arrhythmia” (RSA). When we breathe out, our heart rate falls slightly, bouncing back up again when we breathe in. This maximizes oxygen transfer around the body when we have a lungful of fresh air, while slowing the heart and allowing it to rest as we exhale.
Both forms of variability are essential for a healthy, resilient heart; people with low HRV are much more likely to die of heart disease.9 This is partly because having a more sensitive baroreflex (defined as a greater change in heart rate for each shift in blood pressure) makes us better able to recover from changes in blood pressure, like those we experience during stress or exercise. And if the hea
rt fails to slow when we breathe out, our overall heart rate is higher. This strains the heart, increasing the risk of hypertension, stroke and other cardiovascular problems.
Usually these two patterns of heart rate variation happen on different timescales. RSA causes the heart rate to go up and down as we breathe, while the baroreflex is slower, taking about five seconds each way. When the two are superimposed, we get an irregular, jumpy pattern.
But if we slow our breathing down to match the baroreflex—five seconds in, five seconds out—the two patterns occur on the same timescale, and their peaks and troughs become superimposed, making a single smooth wave. And if we get it just right (the exact speed depends on how big you are and how much blood you have), this leads to a phenomenon known to engineers as “resonance.” Each time the baroreflex goes up or down, the extra variation from the RSA gives it a little kick at precisely the right moment—like pushing a playground swing—causing the fluctuation in heart rate to become bigger and bigger.
Lehrer believes that this provides a beneficial workout for the heart and the baroreflex, making them more resilient.10 Supporting this idea, there’s some evidence that biofeedback improves HRV over time, even after the treatment is over, and that it helps to lower blood pressure.11 Trials have also found benefits for pain, anxiety and depression, however, suggesting that the effects of HRV biofeedback aren’t limited to the heart.12 So why would changing our pattern of heartbeats affect our emotional state?
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IN THE 1960S, a Harvard cardiologist named Herbert Benson was studying blood pressure in monkeys when a group of practitioners of transcendental meditation (TM) turned up at the medical school. They believed that they could lower their blood pressure just by meditating and they wanted the professor to study them. Benson didn’t initially want to get involved in such a “far out” practice,13 but they persisted, and Benson was intrigued by their apparent abilities. So he turned his attention from monkeys to meditation.
In fact their blood pressure didn’t change—the meditators had low blood pressure all the time (although Benson found in future experiments that TM did lower blood pressure in patients with hypertension).14 But he was surprised to find that by meditating, the TM devotees could induce an ultra–chilled out state in which their breathing and metabolism slowed and their heart rate dropped.15 Benson called it the relaxation response.
This response, it turns out, is the opposite of fight or flight. Whereas the arousal of fight or flight is triggered by the sympathetic nervous system, the relaxation response is orchestrated by an opposing nerve network called the parasympathetic nervous system. It’s the parasympathetic system that calms us down after an emergency, pushing the balance back towards the non-urgent activities—digestion, sex, growth and repair—that we engage in when we’re safe and at rest.
The main component of the parasympathetic nervous system is the vagus nerve. From the brain stem it wanders down through the neck and torso, with branches that lead to various major organs, including the lungs, gut, kidney and spleen. One of its jobs is to act as a brake on the heart. The stronger the activity of the vagus nerve (described as “vagal tone”), the more our heart rate slows during the baroreflex and as we exhale—and after stress—and the greater our heart rate variability. In fact, HRV is often used as a measure of vagal tone, and an indicator of how active our parasympathetic nervous system is in general.
As well as turning down stress throughout the body when we perceive that a threat has passed, the vagus nerve relays messages from the body back to the brain (in fact around 80% of its fibers run in this direction). Brain imaging studies show that people with high HRV also have more flexible and adaptive emotional responses to stress, whereas those with low HRV are hypervigilant, seeing even small problems as significantly stressful.16 People with high HRV tend to have better working memory and can focus their attention better, and they are better able to regulate their own emotions and facial expressions.
Some studies even suggest that people with high HRV form stronger social relationships, and get more pleasure from social interactions. By contrast, people with low resting HRV aren’t just at risk of heart disease. They are also more likely to have a range of psychiatric disorders including anxiety, schizophrenia and depression.
“HRV is important not so much for what it tells us about the state of the heart,” writes Julian Thayer, a psychologist and expert on HRV at Ohio State University, Columbus, but “for what it tells us about the state of the brain.”17
When we slow our breathing to push up HRV, this stimulates the vagus nerve, which in turn tells the brain to switch off fight or flight. Biofeedback and meditation (and possibly other activities such as yoga and tai chi, which encourage slow, controlled breathing) probably have a similar effect. When biofeedback researcher Lehrer studied a group of Zen monks, he found that they were indeed creating a strong state of resonance.18
He argues though that because the speed of breathing needed to achieve resonance is slightly different for each person, maximizing the effect with meditation alone can take years of practice, whereas with biofeedback, we can learn it in a few minutes. “Most people are able to pick it up right away,” he tells me. “That’s very different from living in a Zen monastery for ten years!”
Whether all this translates into significant health effects long-term, however, is still up for debate. Lehrer points to clinical trials showing that HRV biofeedback helps with stress-related conditions from high blood pressure to asthma.19 But the studies are generally small and haven’t been well-assessed in meta-analyses.
“Unfortunately we don’t have big drug companies out there supporting research on 20,000 people for each condition, so I can’t say it works the same way penicillin works for infection,” admits Lehrer. “The problem is that no one can make money doing this. Biofeedback equipment is easy to copy and cheap to make.” Even so, he characterizes the evidence as “pretty good.” Plus, he says, “It’s a nondrug treatment with very powerful effects. It’s easy to learn. Why isn’t everybody doing it?”
Lehrer appears to have hit the impasse suffered by many mind–body therapies—with nothing to sell, there’s limited funding for research. But thanks to Kevin Tracey’s work, interest in the vagus nerve is now exploding.
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IN 1985, when Tracey started working on sepsis and septic shock, doctors believed that these conditions were caused by invading bacteria. But, mysteriously, there were often no detectable pathogens. It hadn’t occurred to anyone that devastating symptoms like those suffered by Janice could be created instead by our own bodies.
Scientists used to assume that any damage done when we have an infection was caused by the infecting organism. Slowly they realized, however, that many of the symptoms we suffer when we’re ill—fever, weight loss, tissue damage, even fatigue and depression—are triggered not by pathogens but by our own immune systems, mediated by messenger proteins called cytokines.
Sometimes these symptoms are a necessary by-product of the body’s attempt to tackle infection. The raised temperature we experience during a fever helps to kill off invaders. Fatigue and depression encourage us to rest while we’re ill, and to stay away from others so we don’t spread the infection. Inflammation is crucial for fighting bacteria and clearing damaged cells.
But our bodies can get the balance wrong. Children, especially, can suffer dangerous seizures if their fever spikes too high. Sometimes the fatigue triggered by an infection never lifts. And Tracey showed that the acute septic shock suffered by Janice is caused when the body produces excessive amounts of a cytokine called TNF.
In a crucial experiment, he injected TNF into a rat; despite there being no infecting bacteria, the animal went into profound shock, its blood pressure fell catastrophically, and it died.20 Instead of triggering an appropriate and proportionate inflammatory response, Tracey found, too-high levels of TNF essentially activate every white blood cell in the body. These clog up blood vessels, blocking blood flow
and starving cells downstream of oxygen and nutrients. In other experiments, he discovered that severe sepsis—Janice’s second crisis—is caused when a different cytokine, called HMGB1, rages out of control.21
Tracey realized that these cytokines can cause other problems too. If TNF storms through the whole body, we suffer from acute shock. But if confined to particular locations it causes other inflammatory conditions—too much TNF in the joints contributes to rheumatoid arthritis; in the gut it can cause Crohn’s disease. This insight led to a new class of drugs designed to inhibit or neutralize cytokines, including anti-TNF, which has since been used successfully to treat millions of patients.
It still wasn’t clear why the body would unleash damaging amounts of these cytokines. Then in the early 1990s, while working at North Shore University Hospital in Manhasset, Long Island, Tracey made another revolutionary discovery. His team was working on an experimental drug called CNI-1493, which blocked production of TNF and other cytokines by white blood cells.
Tracey wanted to see if the drug could help treat stroke in rats. Ischemic stroke causes brain damage when blood flow is blocked to a region of the brain. That damage is made worse when the dying cells release TNF. One series of experiments involved trying to prevent this by injecting a tiny amount of CNI-1493 directly into the brain.
But one day, CNI-1493 was accidentally injected into brains of rats with a different condition. These rats had endotoxemia, in which bacterial toxins cause very high levels of TNF to be released into the bloodstream, triggering septic shock. To Tracey’s surprise, the tiny dose of drug in the rats’ brains shut off TNF production throughout their bodies.22 It was 300,000 times more effective than injecting the drug into a vein.
