New FDA-approved bioelectric Vagus nerve stimulator treats Rheumatoid Arthritis

0:01 Have you heard about the vagus nerve? And I don't mean Las Vegas? Thanks for watching episode #118 of the Doctor Podcast, Sicard File Show where you will learn about the vagus nerve today from one of the leading neurosurgeons in the country. And you'll find out how this nerve will increasingly affect your well-being and health. I'm Doctor Robert Sichert, creator and host of the Doctor podcast video podcast program. And by the way, please subscribe, follow, like, repost and share Doctor podcasts and this episode so we can have more great guests like we have today.

0:39 Our guest today is renowned neurosurgeon Doctor Kevin J Tracy. Doctor Tracy's a physician neurosurgeon. He's also a scientist and the president and CEO of the Feinstein Institutes for Medical Research at Northwell Health in Manhasset, Long Island in New York. He's a pioneering leader in inflammation neuroscience and the emerging field of bioelectronic medicine, which we'll talk about in great detail and which he founded. He's the author of the new book The Great Nerve, The New Science of the Vagus Nerve and How to Harness Its Healing Reflexes, and that book was released just a couple of months ago.

1:23 He discovered the inflammatory reflex, which links the nervous and immune systems via vagus nerve stimulation and is revolutionizing disease treatment. Thanks to him, he holds over 120 US patents and has authored more than 450 scientific publications and is ranked among the world's most cited scientists. He also Co founded the Global Sepsis Alliance and previously authored another book called Fatal Sequence. He's inspired by a personal experience, an unfortunate experience with a toddler's death from sepsis, driving decades of research into inflammation and innovative therapies.

2:06 So, Doctor Tracy, thanks very much for taking time from your busy schedule to join us today to talk about the vagus nerve and related topics. We appreciate it. Well, thank you for having me on. It's really great to be here. I'm looking forward to a conversation. Great. So tell us about your medical training 1st and how you got interested in neurosurgery. I was a medical student at Boston University and an undergraduate at Boston College, where I studied chemistry, and by the time I finished medical school, I knew I wanted to pursue a career that combined science and medicine.

2:47 I went into general surgery at the New York Hospital, now the Cornell Medical Center, Weil Cornell in Manhattan, with the intent of being a general surgeon running a research laboratory that was a fairly well supported by the surgeon at the time there, Doctor Tom Shires, who was one of the renowned academic general surgeons of that era. But during the course of that, a little girl named Janice died in my arms, basically after a a tragic kitchen accident. She was scalded by accident. And so the, the, the, the, the, the personal effect that had on me was to focus my, my scientific interests on understanding what, what, what had, what caused her to die, which turned out to be overwhelming inflammation and septic shock.

3:46 And so as I'm in the laboratory studying inflammation, I, I, I, I, I changed my career path from general surgery to neurosurgery, believe it or not, because it gave a broader opportunity to, to build a laboratory in, in that time at, at New York Hospital, neurosurgery was mostly elective. It was minimal trauma surgery at New York Hospital back then. And it gave me a path where I could schedule elective surgery, say on Mondays and spend the rest of the week in the laboratory. And so that's the path I I pursued at then North Shore Hospital, now in Northwell Health in New York.

4:28 My laboratory started in a small building on the campus of North Shore University Hospital, which has now grown to become the Feinstein Institute, which is now home to 100 laboratories, 100 principal investigators, and thousands of full time and part time employees working in those research programs. So it's a, it's a in retrospect, it's a simple story. I always wanted to combine science and and medicine and in in the long run. It's a neurosurgery inflammation story as well. Right, very fascinating.

5:05 And it's it's grown to huge proportions. That's great. Now tell us what bioelectronic medicine is and how did you become interested in that? Bioelectronic medicine came out of the story I was just telling, which is if inflammation is a is a problem that can affect all of us. Yet most of the time inflammation is fairly well controlled. It doesn't cause autoimmune disease in the majority of people, but it doesn't some. Then what is it about the control of inflammation that that could go wrong? What is it about evolution that built into the system the protection against inflammation?

5:49 And thinking about this in the lab one day we did an experiment putting molecules that were anti-inflammatory was a experimental molecule, we called it 1493 into the brains of animals, mice and rats with a stroke. And we expected that blocking inflammation in the brains of those animals would reduce the size of the stroke. And that's and that happened and that's what we expected. What we didn't expect to see was that blocking inflammation with this 1493 molecule in the brain also stopped inflammation in the body.

6:27 And this was a surprise, unexpected surprise and caused us to stop and think for first for weeks and ultimately for months. How could the signals from the brain be turning off inflammation in the body? And ultimately that led to the discovery of what today we call the inflammatory reflex, which is that signals in the vagus nerve turn off inflammation. And we could talk about how that works. But once once we realize that signals traveling in a nerve from the brain to the body could could be like the brakes on your car to stop inflammation.

7:06 We conceived of building computer chips, nerve stimulating devices to activate the signals in the nerve like the brakes on your car to stop inflammation. And the idea, and this goes back to the late 1990s, the idea was if we could build these chips and implant them, they would be bioelectronic. They would be chips interacting with nerves, and they would be medicine because they would be delivering signals that effectively acted by mechanisms that are similar to how today very powerful biologics work by blocking inflammation.

7:41 And that turned out to be true. The clinical trials were successfully announced just a few months ago in November at the American College of Rheumatology. And as we speak and by the time this podcast comes out, it may well be that the FDA has issued approval for this idea for the use of these bioelectronic devices stimulating the vagus nerve to treat patients with rheumatoid arthritis in the United States, patients that are currently not responding to the these powerful therapies that are available today.

8:12 It'll be amazing. Wow, that would be awesome because a lot of them are taking steroids and other immunosuppressive agents and biologics that have lots of potential harmful side effects. So if you could treat their condition and other autoimmune conditions with vagus nerve stimulation, that would be fantastic. Tell us for people who don't have medical background, which is most of our audience, tell us what the vagus nerve is. Now there are 12 cranial nerves. These are nerves that come from the brain and and most of them just supply facial areas and head and neck.

8:53 But the vagus nerve is is very different. Tell us about the cranial nerves and then the vagus nerve specifically. The cranial nerves originate in the base of your brain at about the level of your ears and lower actually down to the top of your spinal cord. And the vagus nerve is special, as you say, because it's the longest nerve in in your body and it travels as you say throughout your body. It doesn't just stop in the head and neck area. So to begin, we call it the vagus nerve. But you actually have two of them, like 2 thumbs and two kidneys, one on each side.

9:27 And it travels down the neck on both sides, across your chest, down into your abdomen. And along the way it sends branches or projections touching all the organs, the lungs, the, the heart, the, the, the kidneys that the liver, the pancreas, all the organs that you don't think about all day long. Now, it's not an organ, it's a nerve. That means it's transmitting signals back and forth. We say 2 vagus nerves. Now I'm going to add one more layer of interest. There's 100,000 fibers on each side. So you actually have 200,000 vagus nerves.

10:04 Now, 80% of them carry the information from the body to the brain. In other words, most of the vagus nerve information going from the body to the brain, sensory or A for afferent. And that means that all day long when you're not thinking about how your organs are working, your brain is getting the information about how they are working through the vagus nerve. What happens with this incoming information with the input to the brain is it activates reflex response circuits that send signals back to the organs either through the vagus nerve directly or through other nerves or through the pituitary gland or other regulating responses.

10:48 But these reflexes work just like when the doctor taps your patellar tendon and you're sitting at the end of the exam table and your leg pops up and you said, who did that? This, this is how reflexes work. And so all day long, there's a change in your glucose levels in your liver, and the brain reacts to that. And there's a change in your insulin release from your pancreas, and the brain reacts to that. And there's a change in your heart rate and the brain reacts to that. These signals all are happening up and down through the vagus nerve, and it's the culmination or the summation and the synchronization of all of these reflexes working in harmony that produces what we call homeostasis or the balanced function of your organs and homeostasis.

11:35 Homeostasis is synonymous with health. And so when things go wrong, just like the Internet cable coming into your house, when, when, when things go wrong with the signals going in and out, if we get interrupted on this call because of the interruption in the signals, we have to wait and do a reset. And that's exactly what happens if you have a problem with your vagus nerve. So this, this is the classic physiological textbook understanding of of the vagus nerve and how it functions in Physiology.

12:05 The surprise was that we could apply those basic principles to inflammation as well. Wow, that's amazing. So this this nerve is in touch with pretty much every organ and every organ system in your body and is monitoring it and gives feedback to the brain and then the brain can make adjustments via that nerve and via release of various hormones from various glands in the body. Absolutely. And it's that harmony that matters. So and and and we know that when dysfunction occurs, it can cause serious problems.

12:42 So very not long ago, few towards the end of the COVID pandemic, what we saw was some some very elegant studies out of Spain and then replicated elsewhere of patients who had either died from, from SARS or had suffered serious complications from COVID. They call it long COVID or. And when they looked at the vagus nerves at autopsy and some of these patients who died, they found virus in the vagus nerve and they found severe inflammation and damage in the vagus nerve. And when you look at imaging studies, very sophisticated high resolution ultrasound or F Mr. is in some of these patients.

13:29 There was evidence in in long, long COVID patients of damage or inflammation and scarring in their vagus nerves. Now, what's interesting is many of the long COVID sufferers have autonomic dysfunction. They have irregular heartbeats and, and, and irregular blood pressure swings. And these may, you know, observations like this do not approve cause and effect. But it's a very interesting possibility that damage to the vagus nerve may unleash some of the inflammation that complicates some syndromes like long COVID, like autoimmune disease.

14:07 And it might be part of the problem, much like a brake failure in a car going down a mountain. There's a lot of people, a lot of people are pursuing these questions as we speak. Right. So when you injected that chemical substance in the rat brain and it affected other parts of the rat, that was the rat's vagus nerve basically interacting with with its body, right? That's right. Years later, we we we figured out that the drug we were injecting in the brain was actually interacting with a a receptor called a muscarinic receptor in the brain.

14:45 And activating the muscarinic receptors in the brain was a signal to the neurons in the brain to turn on the vagus nerve. So the the the molecule 1493 was like a pharmacological vagus nerve stimulator. Interesting now in the early days of bioelectronic medicine, what were the toughest scientific and or institutional hurdles that you faced and how did you navigate them to keep this research alive and going to the point where it is now? It's an interesting question because the scientific obstacles are broken down with data and then later the regulatory and clinical obstacles are broken down with data and then the the final obstacle, the adoption into clinical practice.

15:37 That's, that's the turns out maybe to be the hardest one of all. So we'll see. But in order the the scientific data came fairly fast and furious. For 10 years, my colleagues and I at the Feinstein Institute had a series of publications that revealed in how individual neurons in the brain sent signals down the vagus nerve into the abdomen, how those signals interacted in one group of nerves with a second group of nerves outside of the spleen. And the electrical signals there were converted to chemical signals.

16:12 We, we, we deduced the nature of the chemicals, first acetylcholine and then norepinephrine and then inside the spleen we kept going further down the funnel and discovered that there was a white blood cell, a type of white blood cell called a lymphocyte that actually was responding to the norepinephrine from the nerve ending. The white blood cell responded in its own way by making acetylcholine. That that meant we had discovered a, a new kind of, of T lymphocyte that we named Tchat for T choline acetyl transferase that interacts with a receptor on macrophages and monocytes that are making the cytokines.

16:52 And that receptor is called A7. So by the time all this work was done, it was millions of dollars of, of research done by hundreds of people and replicated by dozens of laboratories around the world at every step of the way. There was very little scientific controversy about the existence of this neural pathway, the inflammatory reflex that was capable of suppressing cytokine storms, cytokine molecules like TNF, aisle 1 and and aisle 6. So that that hurdle was, was just science being science. My colleagues and I doing experiments one after the other.

17:31 The the clinical hurdles were interesting because now you bring in other groups of people. You bring in investors who want a return on their investment. You bring in company employees who have to work very, very hard in a completely new and unknown space to develop new devices at brilliant engineers, people like Mike Faultes and Yakov Levine at the company I started called Set Point Medical. Then you have to bring in the clinical development experts to launch clinical trials and, and this is another huge effort.

18:10 Regulators, FDA regulators, ethical regulators at individual universities and hospitals. By the end of the day, hundreds and then thousands of people touch this project over a 2025 year period. And finally, there's a clinical trial which culminated last November, as I said, 242 patients who get a tremendous amount of credit too. They're, they're these are brave, well meaning people who enter clinical trials in the hope they don't know if it's going to work and no one does. And, and they do this because they believe it's the right thing to do and they hope it might help them, of course, but they also hope it will help other people.

18:52 242 patients. The trial hits its primary endpoint and of statistical significance, which was designated a breakthrough device, a breakthrough trial by the FDA even before the trial started. So now as we speak, we're waiting on the the FDA decision, which will then lead to the the final phase of this 25 year story plus, which means now everybody has to think different. It's not you know your patient, the primary care or the internist sees the patient with arthritis and says I want you to see a rheumatologist.

19:25 The rheumatologist starts going down a checklist of prescription drugs. OK, If the first two don't work or the 1st 3 and the patient says I want a Vegas nurse stimulator, how does that work? That's all new now. Somebody has to call a neurosurgeon. Insurance companies have to think differently. Payers have to think differently. Hospitals have to think differently. It's a whole new idea and I think it works. The data are that it works, but it's a whole new idea. So that's the next phase. And that's why I, that's why I wrote the book, frankly, was to lay all the information out so that not only patients but also caregivers could have a reference point to begin to form their opinions on what they think about all this.

20:13 Totally new paradigm. It's a new paradigm completely. And you know, people say new paradigms like it's a new, a new drug target or something. And this is a new paradigm. This requires everybody to behave differently. And that's what's going to be so interesting. I mean, the the follow up care of the rheumatology patients with their doctor will still be every six weeks. That's like the old days. But the doctor won't necessarily be typing in a prescription into Epic. They'll be actually manipulating the the the controls on the implanted device the size of a of a vitamin tablet on their tablet, which is communicating directly with their device to turn it up, turn it down, change the time of day, or whatever.

20:57 Now where is this device implanted? What part of the rain? It's implanted in the neck, in the left neck at about the level of the Adam's apple. The incisions about an inch and a half long with a skilled experience surging doing it. The multivitamin or Tylenol capsule size device will be implanted at about the level of the Adam's apple in about an hour or less. It'll be a same day surgery, come in in the morning and go home in the afternoon kind of thing. The device is fully contained with a a nerve stimulating component called the lead.

21:33 It has a computer chip, an ASIC, it has a battery, and it has an antenna that talks to the doctor's tablet or or iPad and. Is it all under the skin so it's wireless transmission or are there wires coming out? No wires, it's under the skin, it's under the external cloud on mastoid, the strap muscles in your so you won't see anything and if it's a a nice cosmetic wound closure in the skin lines, you won't won't hardly be a scar. Now is there a battery in this device so that it it lasts? The battery is part of the device.

22:08 It will be fully recharged. The patient will put on a a collar once a week and charge the device through the skin. What's amazing about this device there's there's a couple of things that are amazing about it. First is that it's so small, 2nd that it only delivers electric current into the nerve for one minute a day at about 400 micro amps. So it's a a vanishingly small amount of of of current, which is one of the reasons the battery will last so long. But secondly, it means that symptoms, any symptoms associated with the electric current flowing, which would might be if you're speaking like I am now, there might be a buzzing in my voice.

22:51 If the device is firing, some patients say they feel a little tingling in their neck when it's firing. Other patients sleep right through it because some of these devices are programmed to fire at 4:30 in the morning and some patients wake up and some patients don't. Now, does the patient decide when to fire this? Or or the doctor programs it? Or how does that work? So there'll be a conversation between the doctor and the patient about when to when to fire it, when to have the device operate. And the clinical trial was done, as I said, the vast majority of the patients in the clinical trial were rheumatoid arthritis patients who had been on multiple medications and still had severe symptoms.

23:35 And the device was programmed to fire, I think and in, in the default time was 430. So what the label is going to say on the on the on the guidance documents when it comes out, we'll have to wait and and see whether we'll be able to change the time of day and change the current amount. I suspect it'll become a flexible time of day depending on patient preference, but that that I don't know that. Right now, does this device directly adjacent to the vagus nerve or how does it talk to the vagus nerve?

24:08 So it sits directly on the vagus nerve, and to keep it in place, because it's the size of a, as I said, of a multivitamin tablet, to keep it in place, it's encased in a little silastic Peapod. And so the Peapod sits around the nerve and the device as a whole through the bottom of the Peapod for the nerve to run in one side and out to the other. And there's a stitch. The surgeon, the neurosurgeon, puts a stitch through the top of the silastic Peapod and keep everything in place. Now in in the very unusual or unlikely event that the device would be removed, that it's possible to just go and cut the stitch, open up the silastic pot, and pop everything out.

24:52 Wow. So it could be removed potentially if if there's some issues or or problems with it. Yes, in the clinical trial that was not a that was a very rare, I think it I think in the clinical trial with the first couple 100 patients, there was only one or two device X plants. I see. And what's the name of this device? Is there a name for it yet? And which company manufacturers it? So the the company that will be doing a product launch and the manufacturing is called Set Point Medical. This company Full disclosure that I that I Co founded in 2007 and that device will be called, it's been called up until now the micro regulator because it is what it's actually doing is as we've been talking about is it's stimulating A reflex which is inherent to the vagus nerve itself.

25:45 It's a normal reflex circuit that can be activated through this micro regulator device. And so this impulse, electrical impulse goes through the vagus nerve. The vagus nerve then transmits it to all the receptor organs and the the lymphocytes and that somehow reduces inflammation in the body. That is the working model. In animal models and mice, and in and in rats and another species, it's possible to work through all the specific activity connecting the nerve signals in the vagus nerve to the individual white blood cells making the cytokines.

26:25 As I talked about earlier, in humans, it's much harder to to prove all those endpoints. But what we do know is a couple things. First, what we do know is that we don't really know how biologics stop inflammation in RA, despite the fact they've been around for decades and have been used by millions of people and in in the 40% or so of patients that they have significant beneficial effect. They're wonderful drugs, but 60% of the patients either don't have a good clinical response or have severe side effects or can't afford them at $100,000 a year in the United States and don't like injecting themselves with invasive medication.

27:09 So we don't really, despite all the, the, the widespread use of the biologic agents, we don't really understand how they work. And they don't actually stop the progression of the disease. They reduce the symptoms and signs, but they don't stop the progression. So these, these are, these are, you know, these are the reasons why people are seeking alternatives with the, with the, when we, when we look at the cytokine responses, which are the molecules that are the targets of the biologics and we measure those responses in patients with vagus nerve stimulation, they are decreased.

27:49 What's important is they're not decreased to 0. So if if if if you give a patient an anti TNF for instance, that TNF response will be blocked by the monoclonal antibodies to nearly 100%, which is why the side effect of the biologics is immunosuppression. You need some amount of cytokines to have a normal healthy immune response. With vagus nerve stimulation, we see a reduction of the amount of TNF and Illinois one and Illinois 6, but only by 50% or 60%, not 100%. So there's still cytokine activity that can participate in normal immune responses without having the dangerous amount of cytokines that cause inflammatory damage.

28:39 So we know that that's true. But when you get down to the specific question of how does vagus nerve stimulation work in a specific patient with a specific rheumat condition like rheumatoid arthritis, the answer is it seems to be reducing the toxicity or the damage caused by cytokine storm, but doing it without immunosuppression. So might that be a treatment for other conditions, for example like sepsis, which we talked about earlier where there's cytokine storms that that cause problems? And is this treatment possibly relevant for other conditions that are not autoimmune like I think obesity was mentioned and and some other diseases?

29:29 Yes, yes and yes. So I think what you're going to see first are clinical trials targeting conditions that are treated with biologics because we can connect the dots pretty well on the mechanism on the mechanistic understanding side. So we've already seen clinical, successful clinical trials using vagus nerve stimulation to treat inflammatory bowel disease, which is an autoimmune condition treated with biologics. And there's very good reason to believe or hope that the same will apply to psoriatic arthritis, which is another condition treated with biologics.

30:06 So those are quite likely to, to, to, to, to, to see the light of day in the coming years. Another condition where we have very good experimental evidence now and we've published some of this work with our colleagues at Feinstein and at Set Point in, in the Proceedings of the National Academy of Sciences a year or two ago. And that is in the animal, the the animal model of multiple sclerosis. And what's, what's so important about those early results is that not only did the vagus nerve stimulation reduce the amount of inflammatory damage, as you would not be surprised to hear, but it also enhanced the rate of remyelination, which is what happens in multiple sclerosis is the inflammation damages the, the, the myelin around the nerves.

30:57 And unless you put that myelin back in place, it's very hard to get a, a recovery of that function. And that seems to be happening in, in these, these early experiments. So I fully expect they'll be soon, maybe later this year, a clinical trial of vagus nerve stimulation in in multiple sclerosis. But as you point out correctly, there's a lot of other data in laboratory and clinical research. Much of it has been published. Some of it's not. We've seen results targeting vagus nerve in the liver using focus ultrasound in, in one instance where you can actually send signals through the skin into the porta hepatitis in the center of the liver where there are vagus nerve fibers that sense glucose.

31:44 And so when you activate those fibers with ultrasound in, in diabetic patients, you're tricking the brain into thinking that the glucose levels are rising. That causes the brain to send signals to the pancreas to release more insulin and to the liver to suppress Glucagon. So there's very, there's a lot of interest in, in diabetes. There's a great deal of interest in metabolic syndrome and obesity because the GLP ones, it turns out they actually work by targeting the vagus nerve. So in, in this has been done both in mice and humans.

32:20 If you, if you administer GLP ones and, and you see the blood glucose go down and anorexia develop, if you cut the vagus nerve, that effect is lost. And this was done in a clinical, recent clinical trial in gastric cancer patients before and after their surgery. They when they had their vagus nerves under the diaphragm of course cut as part of the surgery, they lost the response to GLP once. So there's real interest in how, how does that work and what can you know, what can we do about that with bioelectronic strategies?

32:56 Sounds like possibly many diseases are due to vagus nerve dysfunction or disease as possibly the primary cause for various conditions. Is that a possibility? It's a possibility. It's a reasonable, testable hypothesis, which is how we do science, right? Someone asks the right question, and now you can start to design the experiments. There's a lot of interest in in these conditions because they're all made worse by or in Some of them are caused by inflammation. Inflammation that's not resolving. Inflammation that resolves.

33:33 When you have a sprained ankle or a sprained wrist or an infected Abscess on your arm, resolving inflammation is a good thing. It fights off the infection and it and then it heals. It heals the injured wound. But if inflammation doesn't resolve, it can cause cancer, it can cause diabetes, it can cause obesity. It can cause lots of it can cause Alzheimer's and Parkinson's. These are the major unsolved problems of for for health span and and longevity facing the human race. So the the question is how big a role does the vagus nerve have in controlling this?

34:11 Now, neither you or I would ever say that this is a cure all or a snake oil and it's going to solve every absolutely not. I'm not saying that. I am saying it absolutely is a plausible hypothesis that should be studied exhaustively because it's from these. It's from these completely new and unknown questions that come that come the answers. You know, the idea that the the idea that we know the answer before we dozen before we do an experiment is, I mean, it's laughable, right? I mean, Albert Einstein, Albert Einstein said it.

34:46 He said if we knew what it was we were doing, it wouldn't be called research, would it? But but you do it, and sometimes you actually make discoveries that that change how people think about disease. And that's what keeps us all going. Right now, are you collaborating with with the pharmaceutical companies as well? Maybe. Perhaps if it doesn't completely get rid of the rheumatoid arthritis, it might allow for reduced dosages of medications and reduced side effects. So we have been working in the public space, reporting our results in peer reviewed journals and explaining everything we're doing all along the way to the whole world.

35:30 And I fully believe and expect the Pharmaceutical industry has been watching extremely closely the whole time. There are several major pharmaceutical company investors invested in Setpoint Medical. So they're fully aware of of the clinical trial progress and the results. And some of the pharmaceutical companies also are important developers of bioelectronic strategies for various conditions. So, but the pharmaceutical companies also have a vested interest in maintaining their profit margins from these enormous blockbuster drugs.

36:10 I mean, the biologics in the account for a major percentage of global Pharmaceutical industry sales. You're looking at billions and billions of dollars of annual revenue for the biologics alone just to treat some of the conditions we talked about. So it's a complicated story. The Pharmaceutical industry in my view is in the business of making and selling cures and they will be involved in in this as as it is adopted into practice. They can make that. I don't see how they can not be. Involved in it at.

36:42 Some point, I think you're absolutely right. I think you're going to see clinical responses in some patients who using the vagus nerve stimulator will use that as their sole therapy. I think you're going to see like in every, like in everything, you're going to see another group that has a minimal response to the vagus nerve stimulator, but still feels better. And maybe, as you said, they take lower doses of medications or they change their medications to a safer, less immunosuppressive strategy.

37:11 And then you'll have patients who don't gain benefit from it for reasons that we we probably won't completely understand. Right now, this device that you're implanting, since you can charge it externally, sounds like it doesn't need to be removed. I, I interviewed the pacemaker chief from Medtronic months ago and they have these tiny pacemakers that they implant now in the heart. So they're, they're wireless, but they last 10-15 years. Eventually the batteries run out. In this case, it sounds like you never need to replace this, right?

37:46 That's right. So I can't say that that's a question for the company. I, but I don't, I don't have, I don't have the, the, the, the regulatory data on that. However, I, I think you're exactly right. I think that the device will have some label of 10 years or something. But because it's fully rechargeable, if the battery keeps working, it may never have to be replaced. It's fully MRI compatible. So there's no restrictions to going through, you know, airport screens or MRI machines. So yeah, you're absolutely right.

38:17 This may be a once for life thing as opposed to, you know, people say, well, it's a surgery. Well, patients taking these biologics are have have they're invasive and they have black box warnings for their immunosuppression. We already know from the experience of vagus nerve stimulation from treating epilepsy and depression, which has been around for 40 years, that I estimate a million patients, it could be more have had this therapy for those conditions. It's not immunosuppressive. It doesn't cause black box warnings.

38:49 It'll be a one time expense. Maybe it'll cost the same as one year of therapy from a biologic, but that will be for life. So I think when you, when you, when you hear some are quick to say, well, you know, nobody wants a surgery. Well, ask the patients. Right. It ask the patients if they want to keep injecting themselves every week or every month with drugs that are bankrupting them. And that's a common problem with these drugs, with drugs that have these dangerous warnings versus in and out of the in and out of the hospital.

39:25 1 and done for a one hour procedure for the rest of your life to potentially not guaranteed but potentially be free to those drugs. Of course, the patients are going to pick that. Yeah, it sounds I would do that if if the surgery worked and there were low risks to it, then that's better than taking biologics and steroids and other immunosuppressives for years or or decades. Years or decades and recall and they're not helping. Right, right. Yeah, I'm, I'm an ophthalmologist, but I have many patients who have eye problems from rheumatoid arthritis and various other autoimmune diseases.

40:07 And they're these patients are not happy taking the biologics, but they, they have to. Yeah, and they don't want their kids to have to take them. So we'll see. You know, the next step is waiting, waiting for the FDA announcement and and after that there will be obviously the clinical experience will grow exponentially as as patients go from having AI estimate a few 100 patients have been treated worldwide up till now. And I suspect in the coming years it'll be several thousand and we'll have a lot more data.

40:36 Right now this requires A neurosurgeon, but it sounds like maybe ENT head and neck surgeon could also implant this as well, no? That time will tell. Time will tell on that. You know, if you're the, if you're, if you, if you invent, if you're a company, if you invent and launch a new product, it's critically important that the early users of that new product, you know, if you invented, you yourself invented a, a new eye implant and you knew how to implant it, you know, and you knew how to implant it, would you, you wouldn't want any, any old person implanting it.

41:10 So there will be, there will be some restrictions I think, or training or identification of centers of excellence perhaps. At Northwell, we opened a couple months ago a center of excellence in bioelectronic medicine. And we've been convening the neurosurgeons and the rheumatologist and the gastroenterologist and the neurologist and getting everybody together to begin developing best practices and, and, and share information and, and frankly generate resources not only for the patients, but for the caregivers and for the regulators and for the payers and for everybody.

41:47 It's a It's a new way of thinking about everything. Right. Seems to me, you know, I have a lot of patients also with irritable bowel syndrome, which is this mysterious condition. Nobody knows what causes the treatments may or may not work. Sounds like that may also be controlled by the vagus nerve and maybe there's some applications there. I'm just kind of making an educated guess, but based on what you've told me so far, I don't know if you've studied that. There have been a few small studies out there.

42:20 I have not studied it, but this there, there's a lot of interest in your idea and it it, it warrants further, it definitely warrants further studies. Some of the early studies have been very suggestive or promising, but it's too early to say we don't. I mean, at the end of the day, bioelectronic medicine is really defined in a way that's very similar to how you define any pharmacological mechanism. So you begin with the disease, OK? In this case, it's, let's say, rheumatoid arthritis first, what is the drug targeting rheumatoid arthritis?

42:54 Well, it's TNF or aisle one or aisle 6. OK, fine. So rather than make a molecule to hit those molecules directly, we'll find a nerve that turns off those molecules, we'll build a device, and now that's bioelectronic medicine. OK? Now fibromyalgia, let's start. That's the disease. What's the molecular mechanism? Nobody knows. And so it's very hard to. You don't want to be in the situation where you're putting devices in everybody and then looking to see if they work. You really, you really want to target the molecular mechanism like we're doing for rheumatoid arthritis, like we're doing for multiple sclerosis and inflammatory bowel disease.

43:32 And it takes more time, but it's scientifically the better way to do it because you know what you're doing. You should team up with Elon Musk because he's doing bioelectronic medicine also with his neural link. Absolutely. Well, we, we are also doing similar projects at the Feinstein Institute. My colleague Chad Bouton has been implanting chips into the brains of patients with spinal cord injury. And these chips interact with the neurons in the brain, in the motor cortex and the sensory cortex. And they pick up the signals as the patient thinks about moving his arm or arm, arm so far, but eventually arms or legs.

44:14 And what what Chad's been able to do is restore movement in the arms of patients with complete spinal cord injury because the chip picks up the signals and bypasses the spinal cord and sends it straight into the the muscles and nerves of the arm. So that we have now a couple of patients in Chad's study who are able to regain some reasonable use of their hands and arms because there's a, a chip in their brain. So the chip that's Chad isn't planning. It's called a Utah array. And it, it has, I don't know if it's 96 or a couple 100 leads.

44:52 You can check that. I don't know the exact number. But now what, what neurolink is developing are brain implants that have thousands of of leads. And so, you know, there are some that are quick to criticize Elon Musk's approach to neurolink and say that he needs to be doing more science. And I I respond by saying we're doing the science with, with worse chips, with simpler chips, cruder chips and, and making tremendous progress in understanding the bioelectronic medicine mechanisms to reanimate humans with quadriplegia.

45:32 And Chad now recently actually restored the sensation of touch into one of his patients. So not only can this patient pick up a coffee cup, but he can feel the coffee cup in his own brain because of the these computer interfaces. So if, if Neuralink, if Elon makes leads and chips with thousands of times more capacity, imagine what what we could do? I think it, I think it has to be, I think it has to be an approach that combines powerful engineering and, and careful science and careful clinical investigation.

46:06 And, you know, I think that's what's going to happen. I don't think it'll be any one person or company that figures this out. I think you're going to see around the world, you're going to see this happening in leaps and bounds. There's tremendous work coming out of Switzerland and other US centers out of Duke and, and Princeton and, and some West Coast centers where patients previously wheelchair bombed paraplegics are now able to walk because of, of, of various spinal cord implants and brain implants.

46:34 So this is happening really fast. And what we're bumping up against is something you and I talked about already. You're, you're bumping up against very quickly against the fact that adoption of truly new paradigm shifting things requires everybody to think and behave differently. And that's that's the next obstacle. It's tough breaking old habits. Old habits and, and old workflows and, and old bureaucratic systems. You know, there's no, there's no bad guys and gals in this. Everybody's doing their job.

47:04 And everybody wants to help other people. And, you know, some people want to make money. There's nothing wrong with that either. But when the incentives are aligned and the system's working, it works. But when something completely disruptive comes along, everybody says, oh, I want to be a disruptor. Yeah, you want to be a disruptor, but you don't want to be disrupted.

47:24 Exactly. It's an exciting, fantastic, growing field. If it's not the most exciting field, new field in science today, it's one of them. Bioelectronic medicine gives you the opportunity to harness the power of Silicon Valley, of computing, of AI and apply it directly to the biology that patients need so that they feel better. So as a, as a young person starting off on this career, you're looking at a, at a noble calling, you're looking at the opportunity to use all your powers of, of excellence and ingenuity and, and passion to helping people.

48:04 And that's a wonderful, wonderful combination. If you, if you broaden the, the, the scope a little bit from bioelectronic medicine to the closely related field of neuroimmunology, we've been talking for the last few minutes about 1 aspect, the vagus nerve stimulation as it relates to inflammation. But if you think that all of the things the immune system does and all of the things that the nervous system do are, are interacting at every step of the way. Imagine if we understood how, how, how to control vaccine responses through, through through neurological devices or, or how to stop the growth of cancer cells or to reverse the damage of Alzheimer's disease.

48:49 All of these things are are are the future. All of these things to be studied are the are the future ideas in these fields. So what could be more exciting than that? I can't think of anything. Yeah, it sounds awesome. Now you wrote this, this book, The Great Nerve about the vagus nerve and just came out a couple of months ago. What was your main reason for writing this book? To get the word out for patients and caregivers who might be hear about this, hear about the vagus nerve stimulation to treat inflammation and wonder, is this right for me?

49:26 And in order to provide a, a, a, a starting point, a basis, a, a, a, a reference work for where these ideas came from. What is it that we know is true? What is it that we know is false and what is it that warrants a lot more study and and should be pursued more? I tried to cover that ground to give a framework for these conversations because I I think I think they're going to affect millions of people. Right now, you've done decades of groundbreaking work here as we discussed what what continues to fuel your passion and motivation to do research instead of just sitting on the beach?

50:08 There's more to do. There's more to learn. I mean, we're looking now at trying to understand the the, the very nature of the information being carried in the nerves. What is it about those electrical spikes as they travel along that the brain is processing? You know, there's a model. There's a model that the answer lies in electrical signals being converted to chemical signals. But what is the language? What is the language being carried in those electrical signals? And can we decode it? That's what we're working on now because it just fascinates me.

50:46 Right now, are there mental health applications also possibly for this, Like for treating depression, anxiety, things like that? There definitely are. The early work on vagus nerve stimulation was actually done back dating back to the 80s and 90s to treat patients with epilepsy. And that was work that dated back to post World War Two out of out of Italy, believe it or not. So so decades of work led to the first vagus nerve stimulators being used to treat epilepsy patients. And it works pretty well for patients who have no other options.

51:23 Their drugs are not helping them and some of these patients do do quite well. What happened it it they didn't help everybody. And so the surgeons offered to remove the device from the patients. It wasn't helping. And the patient said, no, you're not taking the device out. It makes me happy. It makes me feel better. That led to clinical trials over many, many years to treat patients with depression. And once again, it works about half the time. And this has led to some, you know, resistance to the use of these devices to treat depression.

51:57 And at the end of the day, the real issue comes back to what we talked about before. We don't really know the mechanism that causes depression. And if you don't know the mechanism that's causing the condition, then it's very difficult to iterate, improve or tune the device or the drug to treat the disease cause it's hard to know exactly what you're doing. So I expect there's going to be a lot more work on these kinds of devices and depression and anxiety and frankly, the the idea of of targeting inflammation opens a new way of thinking about depression because when you get inflamed, you get a form of depression.

52:41 So if I inject you with cytokines right now, and this is done sometimes to treat some diseases, if I inject you with cytokines, you will develop a depression like syndrome. And so the real question comes in those fifty to me, the real question as a scientist comes in those 50% of patients who actually get better from vagus nerve stimulation with depression, is it because their depression is being caused by some kind of inflammation in their body that's being treated by the vagus nerve stimulator?

53:10 It's possible. So I think you're going to see new new questions asked, new mechanisms being studied and new clinical trials, but it will take some time before I think it's broadly accepted. Right. I think after patients are treated for rheumatoid arthritis and or autoimmune conditions, we may find some benefit with other conditions and then we can study that down the road. Now I understand you have a a $7,000,000 NIH grant that the Feinstein Institutes to research the vagus nerve. Is that right?

53:45 There is a very important grant I believe the what you're we have yes, we have many, many grants from the National Institutes of Health and from other federal and non federal funding agencies to support our research and we're very grateful for that support and it's very important to our ability to fulfill our mission. My colleague Stavros Zanos, who is mapping the human vagus nerve as part of a large NIH consortium. This will be the first ever, if you can believe it, the first ever high resolution detailed map of the human vagus nerve.

54:20 You would think after all these thousands of years of research that this would all have been done already, but this is a really important contribution. Looking at, I said in the beginning, there are about 200,000 fibers. So Stavros and his colleagues are tracing each and every fiber from the origin in the brain stem to the insertion and all the different organs and reassembling it Micron by Micron as part of a high resolution 3D map that will reveal these structures for the first time. So yeah, it's a very important, it's a very important grant.

54:54 Right. Once we know where all these nerve endings go, we might figure out what they do as well. Well, we'll be able to ask new questions about their function and ask new questions and maybe provide new answers about building better devices to target specific aspects of each and each, as you said, each and every individual fiber. Right now I think I know the answer to this next question, but tell me, what are you most proud of as as your biggest accomplishment in your career so far? In my professional life, the, the, the happiest days have been the days I've met patients who tell me that their, that their life has been improved or enhanced because a vagus nerve stimulator stopped the inflammation.

55:47 And I, that's now happened to me 3 * 3 three. And each, each time that happens, it brings tears to my eyes, tears of joy, of course. And when you set off on a, on a path to use a scientific approach to inventing something to help people and it actually works, there's, there's no better feeling. I mean, there's no better feeling than that. Every, everyone wants to talk about how difficult it is now to be a, a scientist or a doctor, how hard it is to do research. And, and you know, there's just not enough, there's not enough to talk about the rewards of, of, of seeing, of, of seeing something for the first time.

56:33 When, when you, when you get to discover something or invent something, seeing it work and then meeting a direct beneficiary of that. I mean, how do you, how do you put words into that? Well, that's the other reason I wrote the book. I guess I wanted to tell some of those stories. And I think they're important. They're important stories because others can do this and others should do this. And the world needs more of this. Absolutely right. But I want to thank you very much for taking the time to talk about this fascinating subject.

57:03 I really learned a lot from our discussion today. I'm sure the audience will as well. And I'm sure they're going to buy your book and read it to find out more about this. So thanks again for joining us today. Well, thank you for having me on. I really enjoyed it and maybe we'll talk again sometime. I'd like that too. Sounds great.