Kelly, a case manager for an insurance company, spent years battling both migraines and Crohn's, a disease in which the immune system attacks the intestines.
For many people, like Kelly, a stronger electric boost to the vagus nerve could be life-changing.
After she had her large intestine removed, her body couldn't absorb migraine medication. Last year, about twice a month, she endured migraines so bad she couldn't function. "It would go up to a ten, and I would rock, wait it out," she said. The pain might last for three days.
Then her neurologist showed her a new device, gammaCore, that tames migraines by stimulating a nerve—not medication. "I don't have to put a chemical in my body," she said. "I was thrilled."
At first, Kelly used the device at the onset of a migraine, applying electricity to her pulse at the front of her neck for six minutes. The pain peaked at about half the usual intensity--low enough, she said, that she could go to work. Four months ago, she began using the device for two minutes each night as prevention, and she hasn't had a serious migraine since.
The Department of Defense and Veterans Administration now offer gammaCore to patients, but it hasn't yet been approved by Medicare, Medicaid, or most insurers. A month of therapy costs $600 before insurance or a generous financial assistance program kicks in.
A patient uses gammaCore, a non invasive vagal nerve stimulator device that was FDA approved in November 2018, to treat her migraine.
(Photo captured from a patient video at gammacore.com)
If the poet Walt Whitman wrote "I Sing The Body Electric" today, he might get specific and point to the vagus nerve, a bundle of fibers that run from the brainstem down the neck to the heart and gut. Singing stimulates it—and for many people, like Kelly, a stronger electric boost to the nerve could be life-changing.
The mind-body connection isn't just an idea — the vagus nerve literally carries signals from the mind to the body and back. It may explain the link between childhood trauma and illnesses such as chronic pain and headaches in adults. "How is it possible that a psychological event causes pain years later?" asked Peter Staats, co-founder of electroCore, which has won approval for its new device from the Food and Drug Administration (FDA) for both migraine and cluster headaches. "There has to be a mind-body interface, and that is the vagus nerve," he said.
Scientists knew that this nerve controlled your heart rate and blood pressure, but in the past decade it has been linked to both pain and the immune system.
"Everything is gated through the vagus -- problems with the gut, the heart, and the lungs," said Chris Wilson, a researcher at Loma Linda University, in California. Wilson is studying how vagus nerve stimulation (VNS) could help pre-term babies who develop lung infections. "Nearly every one of our chronic diseases, including cancer, Alzheimer's, Parkinson's, chronic arthritis and rheumatoid arthritis, and depression and chronic pain…could benefit from an appropriate stimulator," he said.
It's unfortunate that Kelly got her device only after her large intestine was gone. SetPoint Medical, a privately held California company founded to develop electronic treatments for chronic autoimmune diseases, has announced early positive results with VNS for both Crohn's and rheumatoid arthritis.
As SetPoint's chief medical officer, David Chernoff, put it, "We're hacking into the nervous system to activate a system that is already there," an approach that, he said, could work "on many diseases that are pain- and inflammation-based." Inflammation plays a role in much modern illness, including depression and obesity. The FDA already has approved VNS for both, using surgically implanted devices similar to pacemakers. (GammaCore is external.)
The history of VNS implants goes back to 1997, when the FDA approved one for treating epilepsy and researchers noticed that it rapidly lifted depression in epileptic patients. By 2005, the agency had approved an implant for treatment-resistant depression. (Insurance companies declined to reimburse the approach and it didn't take off, but that might change: in February, the Center for Medicare and Medicaid Services asked for more data to evaluate coverage.) In 2015, the FDA approved an implant in the abdomen to regulate appetite signals and help obese people lose weight.
The link to inflammation had emerged a decade earlier, when researchers at the Feinstein Institute for Medical Research, in Manhasset, New York, demonstrated that stimulating the nerve with electricity in rats suppressed the production of cytokines, a signaling protein important in the immune system. The researchers developed a concept of a hard-wired pathway, through the vagus nerve, between the immune and nervous system. That pathway, they argued, regulates inflammation. While other researchers argue that VNS is helpful by other routes, there is clear evidence that, one way or another, it does affect immunity.
At the same time, investors are seeking alternatives to drugs.
The Feinstein rat research concluded that it took only a minute a day of stimulation and tiny amounts of energy to activate an anti-inflammatory reflex. This means you can use devices "the size of a coffee bean," said Chernoff, much less clunky than current pacemakers—and advances in electronic technology are making them possible.
At the same time, investors are seeking alternatives to drugs. "There's been a push back on drug pricing," noted Lisa Rhoads, a managing director at Easton Capital Investment Group, in New York, which supported electroCore, "and so many unintended consequences."
In 2016, the U.S. National Institutes of Health began pumping money into relevant research, in a program called "Stimulating Peripheral Activity to Relieve Conditions," which focuses on "understanding peripheral nerves — nerves that connect the brain and spinal cord to the rest of the body — and how their electrical signals control internal organ function."
GlaxoSmithKline formed Galvani Bioelectronics with Google to study miniature implants. It had already invested in Action Potential Venture Capital, in Cambridge, Massachusetts, which holds SetPoint and seven other companies "that are all targeting a nerve to treat a chronic disease," noted partner Imran Eba. "I see a future in which bioelectronics medicine is competing directly with drugs," he said.
Treating the body with electricity could bring more ease and lower costs. Many people with serious auto-immune disease, for example, have to inject themselves with drugs that cost $60,000 a year. SetPoint's implant would cost less and only need charging once a week, using a charger worn around the neck, Chernoff said. The company receives notices remotely and can monitor compliance.
Implants also allow the treatment to target a nerve precisely, which could be important with Parkinson's, chronic pain, and depression, observed James Cavuoto, editor and publisher of Neurotech Reports. They may also allow for more fine-turning. "In general, the industry is looking for signals, biomarkers that indicate when is the right time to turn on and turn off the stimulation. It could dramatically increase the effectiveness of the therapy and conserve battery life," he said.
Eventually, external devices could receive data from biomarkers as well. "It could be something you wear on your wrist," Cavuoto noted. Bluetooth-enabled devices could communicate with phones or laptops for data capture. External devices don't require surgery and put the patient in charge. "In the future you'll see more customer specification: Give the patient a tablet or phone app that lets them track and modify their parameters, within a range. With digital devices we have an enormous capability to customize therapies and collect data and get feedback that can be fed back to the clinician," Cavuoto said.
Slow deep breathing, the traditional mind-body intervention, is "like watching Little League. What we're doing is Major League."
It's even possible to stimulate the vagus through the ear, where one branch of the bundle of fibers begins. In a fetus, the tissue that becomes the ear is also part of the vagus nerve, and that one bit remains. "It's the same point as the acupuncture point," explained Mark George, a psychiatrist and pioneer researcher in depression at Medical University of South Carolina in Charleston. "Acupuncture figured out years ago by trial and error what we're just learning about now."
Slow deep breathing, the traditional mind-body intervention, also affects the vagus nerve in positive ways, but gently. "That's like watching Little League," Staats, the co-founder of electroCore, said. "What we're doing is Major League."
In ten years, researcher Wilson suggested, you could be wearing "a little ear cuff" that monitors your basic autonomic tone, a heart-attack risk measure governed in part by the vagus nerve. If your tone looked iffy, the stimulator would intervene, he said, "and improve your mood, cognition, and health."
In the meantime, we can take some long slow breaths, read Whitman, and sing.
Mindy D. had suffered from constipation for years when her gastroenterologist advised her, at 38, to take a popular over-the-counter probiotic. Over the next two years, she experimented with different dosages, sometimes taking it three times a day. But she kept getting sicker—sometimes so ill she couldn't work.
"We shouldn't just presume probiotics are safe."
Her symptoms improved only after she traveled from Long Island to Georgia to see Satish S. C. Rao, a gastroenterologist at Augusta University. "The key thing was taking her off probiotics and treating her with antibiotics," he says.
That solution sounds bizarre, if, like many, you believe that antibiotics are bad and probiotics good. Millions of Americans take probiotics—live bacteria deemed useful—assuming there can be only positive effects. The truth is that you really don't know how any probiotic will affect you. To quote the American Gastroenterological Association Center for Gut Microbiome Research and Education, "It remains unclear what strains of bacteria at what dose by what route of administration are safe and effective for which patients."
"We shouldn't just presume probiotics are safe," says Purna Kashyap, a gastroenterologist from the Mayo Clinic, in Rochester, Minnesota, and a member of the Center's scientific advisory board. Neither the U.S. Food and Drug Administration or the European Food Safety Authority have approved probiotics as a medical treatment. Things can go very wrong in the ill: Among patients with severe acute pancreatitis, one study found that a dose of probiotics increased the chance of death. Even randomized controlled trials of probiotics rarely report harms adequately and the effect over the long-term has not been studied.
Many people pick up a product at a drug store or health store without ever telling a doctor. Doctors are fans, too: in a 2017 survey of healthcare providers at Stanford, more than 60 percent of the respondents said they prescribed probiotics. Many did so inconsistently, leaving the choice of which probiotic up to the patient. Healthy people take them for a range of unproven benefits, including protection from infections or heart disease or to sharpen their brains.
It's fine—unless it isn't. "Probiotics are capable of altering the microbiome in unpredictable ways," explains Leo Galland, an internist in New York who specializes in difficult digestions. "I've had patients who got gas and bloating, constipation or diarrhea from probiotics."
Your Microbiome Is Unique
The booming probiotic market has fed on excitement about the new science of the microbiome, the genetic material of all the microbes that live in our bodies and on our skin. Microbes make up 1 to 3 percent of every human being's body mass—you carry trillions of them, including more than a hundred species and thousands of strains. To identify a microbe, you need to know the genus, species and strain. For example, in Lactobacillus rhamnosus GG, the ingredient in the OTC probiotic Culturelle, Lactobacillus is the genus, rhamnosus is the species and GG is the strain designation.
Variations in your microbiome could help explain why you put on weight or suffer from Crohn's or depression. Each of us has our own unique mix.
A decade ago, the U.S. National Institute of Health (NIH) launched the Microbiome Project to establish a baseline description of health. Scientists sequenced the DNA in more than 2,200 strains, still a small fraction of the whole.
Within a couple of years, we had evidence that our microbiomes are distinctive. Another team used the NIH data set to look into the idea of microbial "fingerprints." A classic computer science algorithm allowed it to assign individuals "codes" defined by DNA sequences of their microbes—no human DNA required. Using information solely from the guts, "Eighty percent of individuals could still be uniquely identified up to a year later," they wrote.
That distinctiveness makes a difference when we try to change our mix by swallowing bacteria considered "pro." Even in healthy people, the reactions to probiotics vary widely, according to a study in Cell in September. The team examined the intestines of healthy volunteers who had taken a cocktail of eleven strains of probiotics for the experiment. Which took up residence in the intestinal lining? The answer depended on the person. Led by Eran Segal and colleagues at the Weizmann Institute of Science, in Rehovot, Israel, the authors concluded that effective supplements would have to be personalized.
Patients with "brain fog" improved dramatically when they were taken off their probiotics and given antibiotics as well.
To truly customize a probiotic, however, we'd have to know the state of an individual's gut microbiome, identify danger signs and link them to symptoms, isolate relevant strains of probiotics that might be needed, and get them into the gut lining effectively. Commercial tests are still at step one. Several companies claim to assess your microbiome based on a stool sample—but the Weizmann team has also shown that the differences between our gut linings aren't apparent from our stool. Galland has explored testing his patients looking for ways to help. "I've concluded that uBiome, American Gut Project, and others don't yield useful information," he observes.
Can A Probiotic Make Your Brain Foggy?
Besides taking her probiotic, Mindy D. had cut out gluten and upped her vegetables and fruits. But soon after she ate her seemingly healthy meals, she would begin to feel dizzy and sometimes even slurred her words, as if she were drunk. "It was such an intense feeling," she said.
A slender 5 ft. 2 inches, she dropped 20 pounds, becoming unhealthily thin. She traveled to see specialists in Minnesota and Connecticut and took two month-long medical leaves before she found Rao in Georgia.
In June, Rao created a stir when he and his coauthors reported that a cluster of his patients with "brain fog"—the "intense feeling" Mindy D. described—improved dramatically when they were taken off their probiotics and given antibiotics as well.
His idea was that lactobacilli and other bacteria colonized their small intestines, rather than making it to the colon as intended—a condition known as "small intestinal bacteria overgrowth" (SIB0) that some gastroenterologists treat with antibiotics. In this group, he argues, the small intestine produced the brain fog symptoms as a consequence of D-lactic acidosis, a phenomenon usually associated with damaged intestines. "If you have brain fogginess along with gas and bloating, please don't take probiotics," Rao says.
The paper prompted a rebuttal at the end of September from Eamonn Quigley, a gastroenterologist at Houston Methodist, who criticized the methodology in detail. Kashyap, of the Mayo Clinic, is skeptical as well. "People were picked for their brain fogginess and they were taking probiotics. Probiotics could be an innocent bystander," he says.
"It's hard for me to imagine the mechanism of say, Culturelle, causing SIB0," says Shira Doron, a specialist in infectious diseases and associate professor at Tufts University School of Medicine who studies probiotics. "The vast majority of people will never suffer a side effect from a probiotic. But probiotics are a live organism so they have a unique set of potential risks that other supplements don't have. They can give you a severe infection in very rare circumstances."
The larger point is that probiotics should be used under a doctor's care. In April, a panel of 14 experts on behalf of the European Society for Primary Care Gastroenterology concluded that "specific probiotics are beneficial in certain lower GI problems." That does not mean any over-the-counter probiotic is likely to help you because it helped your cousin.
"Even your doctor may be going by anecdotal experience, rather than hard science."
Both Galland and Rao use probiotics in their practice, but carefully. "We advise caution against excessive and indiscriminate use of probiotics especially without a well-defined medical indication, and particularly in patients with gastrointestinal dysmotility," when the muscles of the digestive system don't work normally, Rao's team wrote.
"Because there are so many studies out there that are poorly done, that aren't looking at side effects, the science is murky. Even your doctor may be going by anecdotal experience, rather than hard science," Doron adds. Your doctor may tell you that many of his patients report a great experience with probiotics. As Doron points out, however, with disorders like irritable bowel syndrome, the most common gastrointestinal diagnosis, the placebo effect is very strong. Many patients could "respond to anything if they believe it works," she says.
For Tony Y., 37, healing from heartbreak is slow and incomplete. Each of several exes is associated with a cluster of sore memories. Although he loves the Blue Ridge Mountains, he can't visit because they remind him of a romantic holiday years ago.
If a new drug made rejections less painful, one expert argues, it could relieve or even prevent major depression.
Like some 30 to 40 percent of depressed patients, Tony hasn't had success with current anti-depressants. One day, psychiatrists may be able to offer him a new kind of opioid, an anti-depressant for people suffering from the cruel pain of rejection.
A Surprising Discovery
As we move through life, rejections -- bullying in school, romantic breakups, and divorces -- are powerful triggers to depressive episodes, observes David Hsu, a neuroscientist at Stony Brook University School of Medicine in Long Island, New York. If a new drug made them less painful, he argues, it could relieve or even prevent major depression.
Our bodies naturally produce opioids to soothe physical pain, and opioid drugs like morphine and oxycodone work by plugging into the same receptors in our brains. The same natural opioids may also respond to emotional hurts, and painkillers can dramatically affect mood. Today's epidemic of opioid abuse raises the question: How many lives might have been saved if we had a safe, non-addictive option for medicating emotional pain?
Already one anti-depressant, tianeptine, locks into the mu opioid receptor, the target of morphine and oxycodone. Scientists knew that tianeptine, prescribed in some countries in Europe, Asia, and Latin America, acted differently than the most common anti-depressants in use today, which affect the levels of other brain chemicals, serotonin and norepinephrine. But the discovery in 2014 that tianeptine tapped the mu receptor was a "huge surprise," says co-author Jonathan Javitch, chief of the Division of Molecular Therapeutics at Columbia University.
The news arrived when scientists' basic understanding of depression is in flux; viewed biologically, it may cover several disorders. One of them could hinge on opioids. It's possible that some people release fewer opioids naturally or that the receptors for it are less effective.
Javitch has launched a startup, Kures, to make tianeptine more effective and convenient and to find other opioid-modulators. That may seem quixotic in the midst of an opioid epidemic, but tianeptine doesn't create dependency in low, prescription doses and has been used safely around the world for decades. To identify likely patients, cofounder Andrew Kruegel is looking for ways to "segment the depressed population by measures that have to do with opioid release," he says.
Is Emotional Pain Actually "Pain"?
No one imagines that the pain from rejection or loss is the same as pain from a broken leg. Physical pain is two perceptions—a sensory perception and an "affective" one, which makes pain unpleasant.
Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s.
The sensory perception, processed by regions of the brain called the primary and secondary somatosensory cortices and the posterior insula, tells us whether the pain is in your arm or your leg, how strong it is and whether it is a sting, ache, or has some other quality. The affective perception, in another part of the brain called the dorsal anterior cingulate cortex and the anterior insula, tells us that we want the pain to stop, fast! When people with lesions in the latter areas experience a stimulus that ordinarily would be painful, they don't mind it.
Science now suggests that emotional pain arises in the affective brain circuits. Exploration of an overlap between physical and what research psychologists call "social pain" has heated up since the mid-2000s. Animal evidence goes back to the 1970s: babies separated from their mothers showed less distress when given morphine, and more if dosed with naloxone, the opioid antagonist.
Parents, of course, face the question of whether Baby feels alone or wet whenever she howls. And the answer is: both hurt. Being abandoned is the ultimate threat in our early life, and it makes sense that a brain system to monitor social threats would piggyback upon an existing system for pain. Piggybacking is a feature of evolution. An ancestor who felt "hurt" when threatened by rejection might learn adaptive behavior: to cooperate or run.
In 2010, a large multi-university team led by Nathan DeWall at the University of Kentucky, reported that acetaminophen (Tylenol) reduced social pain. Undergraduates took 500 mg of acetaminophen upon awakening and at bedtime every day for three weeks and reported nightly about their day using a previously-tested "Hurt Feelings Scale," rating how strongly they agreed with questions like, "Today, being teased hurt my feelings."
Over the weeks, their reports of hurt feelings steadily declined, while remaining flat in a control group that took placebos. In a second experiment, the research group showed that, compared to controls, people who had taken acetaminophen for three weeks showed less brain activity in the affective brain circuits while they experienced rejection during a virtual ball-tossing game. Later, Hsu's brain scan research supported the idea that rejection triggers the mu opioid receptor system, which normally provides pain-dampening opioids.
More evidence comes from nonhuman primates with lesions in the affective circuits: They cry less when separated from caregivers or social groups.
Heartbreak seems to lie in those regions: women with major depression are more hurt by romantic rejection than normal controls are and show more activity in those areas in brain scans, Hsu found. Also, factors that make us more vulnerable to rejection -- like low self-esteem -- are linked to more activity in the key areas, studies show.
The trait "high rejection sensitivity" increases your risk of depression more than "global neuroticism" does, Hsu observes, and predicts a poor recovery from depression. Pain sensitivity is another clue: People with a gene linked to it seem to be more hurt by social exclusion. Once you're depressed, you become more rejection-sensitive and prone to pain—a classic bad feedback loop.
"Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug."
Helen Mayberg, a neurologist renowned for her study of brain circuits in depression, sees, as Hsu does, the possibility of preventing depressions. "Nobody would suggest we treat routine bad social pain with drugs. But it is true that in susceptible people, losing a partner, for example, can lead to a full-blown depression," says Mayberg, who is the founding director of The Center for Advanced Circuit Therapeutics at Mount Sinai's Icahn School of Medicine in New York City. "Ideally, we'd have biomarkers to distinguish when loss becomes complicated grief and then depression, and we might prevent the transition with a drug. It would be like taking medication when you feel the warning symptoms of a headache to prevent a full-blown migraine."
A Way Out of the Opioid Crisis?
The exploration of social pain should lead us to a deeper understanding of pain, beyond the sharp distinctions between "physical" and "psychological." Finding our way out of the current crisis may require that deeper understanding. About half of the people with opioid prescriptions have mental health disorders. "I expect there are a lot of people using street opioids—heroin or prescriptions purchased from others--to self-medicate psychological pain," Kreugel says.
What we may need, he suggests, is "a new paradigm for using opioids in psychiatry: low, sub-analgesic, sub-euphoric dosing." But so far it hasn't been easy. Investors don't flock to fund psychiatric drugs and in 2018, the word opioid is poison.
As for Tony Y., he's struggled for three years to recover from his most serious relationship. "Driving around highways looking at exit signs toward places we visited together sometimes fills me with unbearable anguish," he admits. "And because we used to do so much bird watching together, sometimes a mere glimpse of a random bird sets me off." He perks up at the idea of a heartbreak drug. "If the side effects didn't seem bad, I would consider it, absolutely."