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“No prescriptions, no medicines, no injections. That’s the future. That’s what gets me out of bed in the morning.” Kevin Tracey, MD.

Dysautonomia International really scored when they got Kevin Tracey MD to be the keynote speaker at their 2020 Virtual Conference. He’s not involved in dysautonomia and knows nothing about postural orthostatic tachycardia syndrome (POTS), but his work has real implications for people with dysautonomia, ME/CFS and/or fibromyalgia.

Tracey has been at the forefront of the “bioelectronics revolution” in medicine.

Tracey has got credentials up the wazoo. He’s a neurosurgeon, a groundbreaking researcher and an inventor and author. He’s the president and CEO of the Feinstein Institute for Medical Research, where he helped create the Center for Bioelectronic Medicine, and which New York State recently gifted with a $30 million grant. He’s also a professor of neurosurgery and molecular medicine at Hofstra/Northwell, and president of the Elmezzi Graduate School of Molecular Medicine.

He’s been recognized as one of the most cited researchers in the world. He’s also the author of “The Fatal Sequence: the Killer Within“, a book about his experience with a badly burned girl with sepsis which changed him profoundly.

A clear and engaging speaker, Tracey’s focus was on a topic which interests us all – inflammation. Inflammation, Tracey said, was the leading the cause of death and disease in the world today, and pointed to the major killers of our age – heart disease, diabetes, autoimmune diseases, etc.

The Surprise of His Life

Back in 1996, Tracey said he got the surprise of his life. He knew that a biological drug called CNI-1493 (Semapimod) was able to reduce the levels of the pro-inflammatory cytokine TNF-a in the body. Tracey hoped that if he inserted Semapimod into the brain, it would reduce TNF-a levels there as well – and it did – but to his utter shock, putting Semapimod in the brain also reduced TNF-a levels in the body (lung, liver, kidney, spleen) as well.

That didn’t make sense. Given the small amount of Semapimod he’d injected, it was clearly not working its way down to the body. Since everyone knew that the brain and body had their own separate and independent immune systems, how reducing inflammation in the brain could simultaneously reduce inflammation in the body was a mystery.

The vagus nerve interacts with every organ in the body.

There was this thing called the vagus nerve, though. They knew that signals travelled up the vagus nerve to the body. Could they also be traveling down it?

They cut the vagus nerve – and low and behold, the inflammation crept up again. With the vagus nerve connection cut, Semapimod wasn’t having any effect on the body. With that, a new understanding of the immune system was borne, and the budding field of neuroimmunology took a big step forward.

The next big question was: how was the vagus nerve doing it?

The Vagus Nerve

The vagus nerve has an incredible reach. The largest neural network in the body, the vagus nerves densely innervate every ‘sensing area’ of the body. Tracey cautioned against viewing the vagus nerve as a single nerve. It’s actually a complex bundle of nerves that contain over 100,000 fibers. Eighty percent of those fibers carry signals to the brain, and 20% send signals back down to the body.

vagus nerve

The vagus nerve is a collection of more than 100,000 separate nerves…

It affects virtually every part of the body. In the cardiovascular system, the vagus nerve regulates our heart and breathing rates, blood pressure and blood flows. In the gut, it’s responsible for gut motility (the passage of food through the gut), gut secretions, inflammatory responses, the integrity of the gut lining and even appetite.

Information on touch, heat/cold, pain and chemical, metabolic, and hormonal operations of the organs are all transmitted via the vagus nerve to the brain.

No one had suspected, though, that it might regulate the immune system. It took over 20 years of work for Kidder and others to understand what was happening. Signals flowing down the vagus nerve to the spleen are converted into norepinephrine, which then interacts with T-cells to produce acetycholine – which then turns off immune cells called monocytes/macrophages. The vagus nerve, it turns out, plays a key role in enhancing the anti-inflammatory response. Poor vagus nerve functioning results in an overactive immune response and inflammation.

It’s now believed that vagus nerve regulation of the immune system may play a role in asthma, allergies, arthritis, ischemia, hypertension, gut disorders, sepsis, inflammatory and autoimmune diseases and pain states.

Research indicated that the immune regulation goes both ways: signals traveling down the vagus nerve regulate the immune system in the body, while signals traveling up the vagus nerve send inflammatory signals to the brainstem and then up to the brain. This up and down signaling came to be called the “the inflammatory reflex”.

Bioelectronic Medicine – A New Frontier?

Biologic drugs which target cytokines and tone down the immune response have proved very helpful for some, but are incredibly expensive and don’t help everyone. Tracey had uncovered, however, a very different pathway to ramping down overt immune expression – manipulating, or rather stimulating, the vagus nerve.

From SetPoint – how to electronically regulate the immune system.

It was not until 2007 that Tracey dared to produce a device which could electronically regulate the immune system. Founding a company called SetPoint, he got to work.  Finding a lead researcher to take on the clinical trial was difficult given the novelty of the effort.

Tracey’s first surgically implanted vagus nerve stimulator (VNS) had immediate effects in a rheumatoid arthritis (RA) patient who’d been living on his couch in pain for 8 years. The stimulator was so effective that the patient started playing tennis while the trial was still in progress. Another woman who, after 16 years of severe RA, was so sick that that she was unable to lift a pencil, was able to ride a bicycle again within months. (Read her story in the New York Times.) Another young woman who’d spent 15 years in and out of her wheelchair had fruitlessly tried every drug in the book. A VNS worked – and she now works in his office.

Successful pilot trials in Crohn’s disease and rheumatoid arthritis followed and recruitment is expected to begin soon in a larger, “pivotal” trial in 250 moderate to severe RA patients who have not responded to other therapies. If the trial is successful, electrical modulation of the immune system could be available for RA patients in just a few years.

Tracey also helped to create The Center for Bioelectronic Medicine to map the vagus nerve in detail so that devices could be built to specifically calm specific nerves. Tracey, who at 63 was full of enthusiasm, believes the bioelectrical revolution may ultimately be able to help just about any kind of inflammation-associated disease. Stimulate the right nerve in the vagus nerve and you may be able to tone down inflammation in virtually any part of the body.

The most recent device, which is about the size of a penny, has a battery, computer chip, antenna and electrode and is controlled via an iPad.

Non-Invasive Vagus Nerve Stimulation

Non-invasive vagus nerve stimulation is cheaper and easier. Instead of being implanted in the neck, the non-invasive vagus nerve stimulator simply clips onto the ear. Lauren Stiles of Dysautonomia International reported that DI is funding no less that 3 trials on non-invasive vagus nerve stimulation in POTS.

While noting studies show that non-invasive vagus nerve stimulation can work, Tracey noted that the vagus nerve branch in the ear relays sensory signals, not autonomic ones. Given that, he doesn’t understand how non-invasive vagus nerve stimulation is working when it does.

non-invasive VNS

Given that only sensory vagus nerves permeate the ear, it’s not clear how non-invasive VNS works – but sometimes it does work.

With implanted devices, on the other hand, he knows what the device is doing to the nerve and how much charge to give it. The holy grail for Tracey over the next 10 or 20 years is to be able to develop devices which stimulate specific fibers in the vagus nerve.

In the Q&A section of his talk, Tracey suggested an interesting hypothesis – a broken vagus nerve is behind POTS. A balky vagus nerve that’s not doing its part to tone down inflammation could lead to the autoimmunity which appears to be present in POTS.

When asked what treatments people with dysautonomia could do now to support vagal tone, Tracey provided the usual suspects: meditation, prayer, fish oil, cold showers, ice water splashed on the face, aerobic exercise – all increase vagus nerve activity and decrease inflammation.

The Vagus Nerve, Chronic Fatigue Syndrome (ME/CFS) and Fibromyalgia

It bears noting that the B2 adrenergic receptors being explored with regard to autoimmunity in ME/CFS are the same receptors that produce anti-inflammatory effects via the vagus nerve. The alpha adrenergic sympathetic nervous system receptors, on the other hand, that help to produce the fight/flight response that is amped up in ME/CFS, also stimulate the production of pro-inflammatory cytokines such as TNF-a.

The low heart rate variability (HRV) findings in ME/CFS and FM indicate that parasympathetic nervous system/vagal nerve activity is inhibited – suggesting that the stage has been set  for increased inflammation.

In a 2011 article, “The Pulse of Inflammation: Heart Rate Variability, the Cholinergic Anti-Inflammatory Pathway, and Implications for Therapy“, that linked low HRV with inflammation, Tracey proposed that low HRVs could be used to target people who would benefit from vagus nerve therapies. Note as well that one of the drugs Dr. Klimas’s modeling efforts predicted would work in ME/CFS was a TNF-a blocker. It was TNF-a that Tracey blocked in the rheumatoid arthritis patients with his implants.

With regard to fibromyalgia and pain, the first hints that VNS might be helpful in reducing pain came when epilepsy patients reported experiencing reduced pain. VNS may be effective with chronic pain because it appears to be able to affect many of the factors known to contribute to it including: inflammation, oxidative stress, autonomic nervous system activity, the opioid response, central sensitization, and pain perception.

Check out a remarkable story of woman who recovered from severe fibromyalgia after having a vagus nerve stimulator implanted in her neck.

“Reborn” – Reversing Fibromyalgia with Vagus Nerve Stimulation

The Future

It’s not clear if non-invasive or invasive VNS will work in ME/CFS or FM. The low HRV readings, the increased fight/flight response, and the immune issues suggest that it could.

Implanted vagus nerve stimulators, though, are extremely expensive, are not covered by insurance and are hard to come by. No studies appear to be assessing them in either disease.

Non-invasive VNS provide a much more affordable option and have been shown in at least one small study to be potentially effective, but are tricky. It’s not clear what the proper signal strength should be, how long they should be used, which devices work the best, etc.

The Electroceutical Revolution

electric brain

Could harnessing the electrical currents in the body be the future in medicine? (Image by Gerd Altmann from Pixabay )

The future is where the real opportunity for diseases like ME/CFS, FM, and POTS lies. An enormous amount of money has quietly gone into sparking an electroceutical/bioelectronic revolution medicine. The possibilities are enormous. Instead of flooding the body with drugs, bioelectronics could conceivably precisely target the nerves involved – reducing side effects and increasing efficacy.

Tracey estimated that $800 million has been invested in bioelectronic medicine and listed a slew of major companies and institutions that have jumped into the field. In 2018, the state of New York invested $30 million in Tracey’s Center for Bioelectronic Medicine as part of its innovative, economic investments program. From the Center:

“Our two primary discoveries are first, that inflammation is the central phenomenon in virtually all disease, from cancer to diabetes, and second, inflammation can be controlled through the vagus nerve, the body’s main “highway” of neural information that prompts and curbs inflammation. The institute’s work in molecular biology to fully understand the vagus system and other nerve networks has led to a means to both monitor the neural signals produced by the body and decode them, not only to control inflammation, but to anticipate incipient disease before it takes hold.”

In “A Spark in the Periphery”, Emily Walz reported that GlaxoSmithKline and Verily Life Sciences (formerly Google Life Sciences) are pumping more than $700 million into a new company called Galvani Bioelectronics, which will develop miniaturized electronic devices to stimulate nerves in the body. (Aloisio Galvani was an 18th century Italian scientist who discovered he could make frogs’ legs twitch with electricity.)

 

Recently, Astellas Pharma snapped up Iota Biosciences to capitalize on its ability to develop tiny millimetre-sized implantable devices to treat disease. After participating in an R&D agreement with Iota, Astella decided not to tread water any longer and plunked down $304 million to buy the entire company. Astella pledged to spend $125 million over the next five years to “aggressively” expand Iota’s work. (Iota was formed in 2017!)

DARPA, the Defense Advanced Research Projects Agency, is throwing $90 million into the hunt for better electroceuticals.

SPARC

In 2014 Tracey reported that the NIH played a leading role in supporting work on bioelectronic medicine when no one else would. Three years after that  the NIH announced that its “Stimulating Peripheral Activity to Relieve Conditions (SPARC)” Initiative would spend $250 million in an attempt to learn how to manipulate nerves to reduce pain, relieve inflammation, heal heart problems, fix gut disorders and more.

SPARC-ing an Electroceutical Revolution – A Fibromyalgia and ME/CFS Perspective

Understanding the neural anatomy in exquisite detail is key. Many of the funded grants are attempting to map exactly which nerves control what. Working off a DARPA grant, a University of Wisconsin team recently had a breakthrough in that.

They found that the 100,000 nerves in the vagus nerve were organized in very specific ways that allowed the researchers to predict where they would end up. That should allow researchers to move forward more quickly on the mapping problem. Other studies include:

  • A SPARC research team at Duke University is determining that different nerve fibers can be activated by different patterns of electrical pulses.
  • Purdue University is mapping the autonomic circuitry of the gut – a task of interest to ME/CFS/FM and POTS  patients, given the problems with gut motility – which can impact gut flora and leaky gut – present.
  • A Mass General study aims to make non-invasive vagus nerve stimulation more effective by mapping how the nerves in the ear impact the cardiovascular functioning. They’ll be tracing signal production all the way to the brainstem.
  • The Icahn School of Medicine at Mt. Sinai is using non-invasive radiowave and magnetic field signals, nanoparticles and bioengineered ion channels, which can be used to remotely activate and inhibit central nervous system activity.

Conclusion

While nothing is going to happen tomorrow, the large amounts of money being poured into the “bioelectronics revolution” are encouraging. Just 25 years after we learned that the brain, through the vagus nerve, is impacting inflammation, researchers are tracking down in exquisite detail which of the 100,000 nerves in the vagus nerve impact which organs and body tissues.

In 2014, Tracey wrote in a piece called The Body Electric:

“The promise of bioelectronic medicine is that by targeting a specific organ, at a specific time, in a specific amount, many side effects can be eliminated. Prescription refills can be accomplished through a wireless interface. There will be no more daily injections, and no interruption to daily life. The potential exists for developing treatments for ailments ranging from rheumatoid arthritis to Parkinson’s to diabetes to cancer; the immune system contributes to all of these.”

Tracey has predicted that bioelectronics will eventually replace the drug industry. As was noted – this is not going to happen tomorrow. Whether the major breakthroughs in bioelectronic medicine that seem likely to occur will happen in time for people like me it is unclear, that but what is clear is that an era of bioelectronic medicine is coming, and younger people, at least, should reap its rewards.

With the autonomic nervous system issues present in diseases like ME/CFS, FM and POTS, we should ultimately be able to benefit from these advances. Tracey suggests that diseases characterized by the low heart rate variability found in ME/CFS, FM and POTS are good potential candidates for vagus nerve manipulation.

Plus, emerging evidence of neuroinflammation in ME/CFS and FM provides an intriguing possibility – tamp down the inflammation in the brain – and reductions in inflammation in the body may follow.

 

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