#22 Vagus Nerve & inflammation: the body’s healing reflex with Dr. Kevin Tracey

(upbeat music) Welcome to Make Visible, the podcast Shining a Light on Complex Chronic Elness. I am your host, Emily Kate Stevens. (upbeat music) Welcome back. This week I had the pleasure of talking to Dr. Kevin Tracy, a neurosurgeon scientist and entrepreneur CEO of the Fine Steen Institute in New York. He is a leader in Neural Circuitry and Bioelectronic medicine. And I had the pleasure of discussing his incredible work into understanding the vagus nerve and inflammation and the techniques that he and his team have developed to modulate them with impact across a host of diseases. (upbeat music) You are author of a relatively new book of a few months ago, it came out in the UK. Is there a couple of months in the US as well? Exactly, yeah, but it came out early in May. And I want to thank you first for having me on the show to talk about that and anything else we feel like talking about. So the book, the great nerve, the new science of the vagus nerve and how to harness its healing reflexes. I'd just like to say congratulations on creating a book as a medical professional that is so accessible and informative to those of us who are not medical and also say that I found it incredibly beautiful. Some of your analogies, the brain is a universe, the vagus nerve as an orchestra. I mean, it took me on such journey, it was amazing. Well first, thank you for your kind words about my book. That means a lot coming from you. The point of the book really was to make it a complex story very accessible at a time right now when we're at a tipping point in this story arguably because the recent FDA approval, which I'm sure we'll get into of a vagus nerve therapy. I mean, as we sit here today, there's one and a half million eligible rheumatoid arthritis patients now who are gonna have questions about this. What is the therapy? What is the vagus nerve? How does it work? Why now? And the doctors treating those patients are gonna have the same questions. So I wanted to have a book that would lay a ground basis of sort of first principles based on first on the science that we know and the history. And second on what's new in inflammation and the vagus nerve and third, whether the sort of the practical things we can now ask new questions to talk about. If it resonates with you at the right level, the people will be excited about them, then I'm thrilled. So thank you for that. The premise for your book and for your work that you spent the last four decades is actually it comes from quite a personal point for you. So can you talk me through how you went from being a child who wanted to understand what was happening to people, to being someone now who is running an institute with over a hundred principal investigators labs and eight and a half thousand staff. As far as my personal journey, I mean, I like to say that when you're 67 years old and you connect the dots from your life, you leave out a lot of stuff, you know? Like, sometimes you don't know what the plan is until you look back on what happened. For me, the key has been from a very young age to spend time asking the question of, how do I want to spend my time? There is, I think, a sense today and I see it among young people and when I work with young people, I try to bring this point home. It's critically important at any age of youth that you stop and think about your personal values. What it is you want to do and why? And if today was the last day you had on Earth, would you have, feel fulfilled? Would you have filled that whatever gifts you have been given that you used them to give something back? And I think having a strong personal philosophy and investing the time and energy into it allows you to make conscious choices and not just be dragged down checklists and task lists 'cause then to do's. So I tell my lab every week, what is your plan for next week? And how many hours have you spent on thinking about what you're gonna do today, tomorrow, and the next day? Because that time of thinking about what you want to do turns out to be, I think, the most important investment you can make in sort of a career, in a life. Where does it pretty profound from the, oh, isn't it? And I think that's something that is so relevant to the people that you try to treat, who are these people, who essentially so many of the conditions that you look at and that you are trying to understand with your research into the Vegas nerve, are people who have these chronic conditions, incredibly complex. And one of the things that kept echoing throughout your book was this idea with so many of the diseases that you look at with crombs, with epilepsy, rheumatoid arthritis, depression, is we do not understand the mechanisms for so many of these things. And I think that ties so much into what we do with this podcast, the conditions that we are looking into. And I hope that as we delve into this conversation, you'll be able to tell me the relevance of, or how relevant the Vegas nerve is in all of these. But, ME, Long COVID, fibromyalgia, EDS, so many of these things that have this dysregulation, we don't understand the mechanisms of them. - Well, because of that, I think I'm gonna tell you right now, it's not a simple answer. When you look at the billions of web impressions and the millions, if not billions, of social media posts that talk about, do this that or the other thing for your Vegas nerve, I wish it was that simple. And for your patients, especially, I recoil at some of the recommendations and some of the sales pitches, just do this and you'll be fine. Because, come on, if it was as easy as doing a couple more setups, then we would have already cured rheumatoid arthritis worldwide. I mean, you don't think these patients who are suffering, they can't pick up a pencil, they can't go to work, they can't take care of the kids. You don't think they've tried doing a couple sit ups? It's like not that easy. And it comes down to, again, the reason for the book now was to explain this is what we understand. And this is what we can go to the bank with as facts. And this is what we can do with those facts. And these are the facts that if we do those things, then these outcome we can expect or hope for these outcomes. These are the things that we know are patently false and maybe even dangerous. And then you have this enormous area in between where it doesn't mean people are hiding things or trying to keep this information from other people or bury the lead. It's just that it's complicated. And, but you can ask now, when you know what you know and you know what you don't know, you can now frame new questions and you can do new experiments and you can do new clinical trials. But if you're going to do that, they should be carefully and thoughtfully done. They should be appropriately randomized. They should be appropriately sized clinical trials. And they should be highly replicable. And when you dive in to the current, many of these recommendations that are being foisted on your listeners, many of them just don't have the, they don't pass that rigor. Yeah. And that is one thing that keeps recurring through the book. It's your idea that yes, we have anecdotal evidence of this or this. But we need to test it. We need to see that replicate across the board. I have contributed to some small people in this business clinical research we call them pilot clinical trials. That would be 15, 20, 30 patients and sometimes they're randomized and sometimes they're not. That would be an uncontrolled trial. And that's where you start. That's where you start. The problem comes when someone goes online or they use AI and they find the result of these pilot studies and they start marketing it as the cure all for whatever, long COVID. And that if people have money, they want to excel experiment and they check with their doctor and it's safe. That's all fine if you want a self experiment and try to improve your own life. But it's not fine if people are profiteering off it. That's the first problem. Because not everybody can afford to buy everything that's being offered. And the second problem, which to me, is really serious and is not talked about enough, is that crappy science, shitty science, undermines good science. And good science is expensive and difficult and takes decades. And it can be undermined by crappy science. And so I recoil against that. - Yeah, and it's that idea that we can just expedite some of these things without going through all of the stages that we need to go through to actually have it proven. - Look, you can expedite it for yourself, right? If you're doing something safe and you can afford it and your doctor says it's okay and you wanna expedite and try it yourself, that's fine. It does not necessarily have any validity for everybody else. If it makes you feel better, great. Good. I mean, patient self-avocacy among patients is wonderful, is what drives change, which is the other reason I wrote the book. When you look at the history of medicine, when something's truly new and pioneering, it requires patience and activists like you to drive change, the medical industry and perhaps with some appropriateness doesn't race into new space quickly. You don't necessarily want your doctor. I don't want my doctor chasing every shiny new object. I want there to be some caution and some thoughtfulness and care. And that's a systemic thing. It doesn't mean doctors are resisting change. It doesn't mean they're bad people. I'm a doctor, I'm not a bad person. You have to be careful. But patients accelerate the attention that can be put on a problem or a new solution. and that makes things go faster. Mary Tyler Moore advocating for diabetes, the NFL football players wearing the pink ribbons for breast cancer, the HIV activist marching on Tony Fauci's office and the early days of AIDS. I mean, these are important contributions to the history of medicine. - Yeah, and especially in terms of raising the awareness and bringing the funding and starting to get moving. But yes, we need to take our time and maintain that scientific rigor, 100%. In terms of what we do know, let us start with your multiple decades of research. I would love for people to subsequently go and delve into your book. But please, for our audience, tell us what is the vagus nerve that everyone talks about, everyone's pushing on social media. And as you say, there's so much misinformation out there. - So is your understanding. And to begin simply, you have two vagus nerves, like two thumbs and two kidneys. And it is a cranial nerve. It starts in your brain at about the level of your ears. It's the 10th of 12 cranial nerve pairs. And it travels down your neck on both sides, cross your chest and into your abdomen. And along the way, it sends off branches to all the organs, the lungs, the heart, all the organs in your abdomen. You don't think about all day long. And what's fascinating is that it's a critical information to it like a transatlantic cable. And it takes information from your organs, what's going on in your kidneys, what's going on in your pancreas, what's going on in your heart. And it sends that information up into the brain. So 80% of the information is actually sensory going up to the brain. And then 20% of the information coming down is motor. Now what's commonly overlooked, oversimplified, and it's really important is that you don't really have two vagus nerves because inside of each of them is 100,000 fibers. And that means you really have 200,000 vagus nerves. Now, the key to that is that you can walk and chew gum at the same time. So what do I mean by that? Well, I mean that each of those 200,000 fibers has a unique origin, a place where it starts in the brain or the body and a unique destination, a place where it goes in the brain or the body. And that carries information from that specific place to that other specific place. And it carries information that's encoded in electrical spikes, which controls specific functions. So you can walk into gum because the nerves that control your chewing are different than the nerves that control your walking. You can play the piano and talk to your dog. You can sing and play the piano because different nerves control different functions. So when people talk about the vagus nerve, I want to stimulate my vagus nerve. I say, oh really, you have 200,000, which one do you want to stimulate? And right from that simple sort of story comes a thousand new questions because we do have the tools in the laboratory, at least in the laboratory, in animals. We have the tools to look at the activity and function of each and every individual fiber. We can't do that in humans. And this is actually, I think it's reference in your book, "The Stavros Anos" is doing vagus nerve mapping currently, but until now we have not really had a clear overview in the human body of what is where and what is connected to where. Remarkably important points, as I speak, "Stavros is upstairs in the lab, I hope it's 830 here in the United States, I hope everybody is upstairs in all the labs." He is, as you said, leading a large team effort here and collaborating with several large teams at other universities across the United States. And they are taking human vagus nerves from cadavers that they've carefully dissected out from the brainstem and traveling all the way to the ending of each branch to all the organs. And they're sectioning it at like five microns at a time. So a quarter the size of a red blood cell in slices. And they're looking across and they can see 100,000 fibers and they're staining them with different chemicals that reveal different features of each fiber. And they're using antibodies to look at the expression of specific proteins in each fiber, which is like a fingerprint. And they're also looking at single cell RNA-seq to look at the genes that are being expressed in each fiber. That's why there's so many centers involved. You can imagine the amount of work. And then using like a CAT scan approach, they can take all these slices and put it back together again. It'll be the first proper model of the human vagus nerve since its anatomy was first being sort of studied carefully by Galen 2,000 years ago. Think about that. I mean, much of the stuff on the internet today, on social media, points to pictures that were drawn in the 16th century, 17th century. It's amazing. It's just insane. But the complexity of what you have just described, also later on in our discussion shows how we really cannot treat the vagus nerve with this one size fits all approach in terms of let's just clip something on our ear and that's going to sort out everything. It's so much more complex than that. We talked about the vagus nerve in its role of keeping the human body in what we call homeostasis. So let's start with you're sitting in the doctor's office and she thumps your knee with a rubber hammer and your leg pops up and you watch this whole thing and say, who did that? That's a reflex. And what happens when the rubber hammer hits your patellar tendon, it activates stretch receptors, which send a sensory nerve signal into your spinal cord. That activates a return signal, motor nerves to your quadriceps femoris, your thigh muscles, which pop your leg up. OK, so far so good. That's simple. Everybody understands a reflex. Well, the key that most people don't think about is that reflexes are also controlling all your organs. So your glucose level goes up a little bit in your liver. That activates sensory nerves, which go up into your brain stem, a lot of it through the vagus nerve. And that activates response networks in the brain that send signals back to your body. If the glucose levels are high in your liver, the signals may drive back down to your liver to accelerate glycinogenesis, making more glycogen out of the excess glucose. They may send signals down to your pancreas to increase the release of insulin to bring the glucose levels down. And maybe 100 of the things are 1,000. They're all reflex responses. When you look at blood pressure, you stand up quickly and your blood pressure drops a little bit. That falling pressure is sensed by nerves. Those signals travel up your vagus nerve into your brain, which activates a corrective response that sends signals down your sympathetic nervous system, your sympathetic chain, to increase cardiac contractility, tighten up your blood vessels, and raise your blood pressure back up again so you don't faint. So on and on and on, every little thing you can think of. And why is it every little thing? Because as it turns out, if I had a solution, a tub full of liquid that I could submerge you in. And it would dissolve all your body cells, but it would leave all your nerves intact. When I pulled you out, you would look the same. Almost every cell in your body is encased or touching or around next to a nerve. You're a walking neural network in your body. And your brain is, of course, a neural network. And what connects them is your spinal cord and your vagus nerve. But I think that's a really interesting point there is that the neural network is not just the brain. It is the entire body. So our way in the medical system of separating out the brain from the rest of the body is actually a complete misanomal. And much of that is connected through the vagus nerve, isn't it? It's everything is being controlled by this system. - Yeah, so I have an enormous new program in my lab that we're very excited about that's trying to study exactly that. If the brain networks and the body networks are connected and they are, and if they influence each other and there's tremendous new data now that they do, how does that work? And so they're in lies the rub, right? So Plato said it a long time ago, right? Heal the body, heal the soul. And you can't do one without the other, right? I think by soul he meant mind and by mind I mean brain. If that's true, which it appears to be, there's an entire psychological vocabulary around how to do that. And there's an entire medical and scientific vocabulary that focuses on the body with how to control little specific cogs and gears in the engine of the body. But there's not a good dialogue for how they mesh. - Yeah. - There's not a good way for a scientist in a lab or a doctor in a clinic to reduce the conversation to a specific nerve fiber or a specific mechanism that explains both ends of the spectrum, how the brain's networks are working and how the body networks are working. There's just no way to do that with the tools we have today in humans. So I think the advance we made in understanding how the brain networks traveling through the Vegas nerve can shut down inflammation in the body, that has opened a new way of thinking for a lot of people. That's opened a new way of thinking about how to approach this problem. - Now let's talk about this about the role of, so the Vegas nerve is, as you've said, attached to or influences and is influenced by the gastro, the endocrine system, the cardiac system, the rena hepatic system, the immune system. And within that information has a huge role to play in both directions in the efferent and the afferent signals. Effort that signals from the brain to the body and afference. from the body to the brain. - Talk to me about what you discovered or the taper that you first put out, was it in 1992 that you really, really leapt forwards in terms of this understanding of the role of the vagal nerve in inflammation? Is that right? When you were looking at two-minute crisis factor. - We were, yes, it's correct. That it was all a bit later than that, but in the 1990s, we were looking at how we could control TNF, which is a cytokine that became very well-known during COVID because cytokine storms became a household name. And so we've known since the late 1980s, mid 1990s, that too much TNF, too much of that cytokine causes inflammation and that if you block it with powerful immunosuppressing drugs like antibodies, that you can reduce the TNF activity, and that is one way of treating things like rheumatotic arthritis and Crohn's disease. - And a way that is used still to this day, is it not? - It absolutely is. It's a very important therapy for millions of patients and it is a very important source of revenue for the pharmaceutical industry. It's a huge segment of the market. So those are important targets. The question I had is if too much TNF is bad for you and all of our immune systems can make TNF, what were the evolutionary mechanisms that evolved over millions of years to control this? 'Cause most people walking around don't have too much TNF. Most of us have the right amount. And what we discovered quite unexpectedly, because we were studying the effects of putting a drug in the brain of mice and rats with a stroke, what we noticed in those experiments completely unexpectedly is when we put these molecules in the brain, very small amounts of these molecules, that the animals stopped having inflammation in their body. And this made no sense, but the effects won away when we cut the vagus nerve. And so now we know from that simple experiment that signals arising in the brain, traveling down the vagus nerve, stopped inflammation in the body. And from that, from that day, we sketched on the back of a napkin literally. If it's true that the signals were in the vagus nerve and if it's true that the brakes on your car are slowing down inflammation, then we should be able to make a device, a vagus nerve stimulating device to activate those signals that we called the inflammatory reflex. And then that device would turn off the inflammation. And that's what we proposed in the late 1990s. And that turns out to be 100% true now with FDA approval of a device to treat rheumatoid arthritis. It's not just TNF, these signals control inflammation. So they lower TNF, IL-1, IL-6, and other cytokines, which again, all came into prominence during the COVID thing because those are all of the inflammatory, are those all cytokines? Are they quite-- - They're all cytokines, they're all inflammatory. And the key is that they have synergistic toxicity, which means that if you have high levels of one plus high levels of another, the side effects of those cytokines are actually more potent than if you just added them together. So they amplify each other's toxicity. So when you lower several cytokines with the vagus nerve stimulation to activate the inflammatory reflex, you significantly reduce the toxicity of those cytokines. And that's how it works. - So again, has that feedback loop within the nose? You're kind of creating a snowboard, is that what you're saying? - Well, we call it a reflex because-- and we've learned a lot about this now from 20 years of studying this very carefully with very sophisticated molecular, genetic, and neuroscience techniques. And essentially, all the results from my lab have been replicated by colleagues in laboratories all around the world. And what we understand is when inflammation occurs, say you have an infection in your liver or you have an injury in your intestines, that starts the inflammation and the tissues. And the presence of cytokines in that inflammation activates vagus nerve signals and that's the sensory input to the reflex loop to the brain. So now the brain says, oh, there's inflammation in the liver, there's inflammation in the necolin. Let's send some slow down signals to see if we can keep it from spinning out of control. And that's what the vagus nerve inflammatory reflex does. It keeps things balanced. You said homeostasis before. Homeostasis reflects balance between the function of organs. Homeostasis means health. - And in terms of that homeostasis, and one of the big roles of the vagus nerve is the maintenance of a balance between the parasympathetic and the sympathetic nervous system. And I think this is another thing that is massively oversimplified in that whole sort of social media space. It's that you want to completely shut off your sympathetic drive and you want to really, really maintain your parasympathetic. And something that your book does brilliantly is describes the way in which you are actually looking to optimize the way that this swings together. So can you talk to me about the role of the vagus nerve in that, in our parasympathetic and sympathetic drives? - Your point cannot be overstated about how massively oversimplified this is. You could actually say much of it's grossly incorrect based on what we know already. And I'm glad you said it first. So I don't have to be the bad guy. It's really, really, really important. So let's take a simple example. And it's one of my favorite stories in the book. It's the sheep exercising on a treadmill in New Zealand. I mean, all I could think of is a far side cartoon. Every time I think of those sheep. It turns out this is a really important scientific advance. And all the references are in the end notes. It's a carefully done study by brilliant colleagues in New Zealand. The reason they were exercising sheep in the lab on a treadmill is because they monitored these sheep, these sheep, they monitored the sheep. So they could look at the activity of the vagus nerve, the activity of the sympathetic nerves, the activity of the heart, the cardiac output, blood flow, blood flow in the coronary arteries, things you can't do it in people. I mean, you can do it, but it would require essentially open heart surgery. And you wouldn't do it during the course of running on a treadmill. So what they found, now the dogma, as you say, and this dogma is repeated over and over and over that fight or flight on rest and digest off false. They prove this is completely wrong. What they showed is that when the sheep were exercising, of course they have fight or flight responses. Their heart rate goes up and their blood, norapeneffin levels go up. And you can see this in the, you can see the byproducts of norapeneffin in the urine. All this is known from people. Of course there's fight or flight. But there's also they measured increased activity in the vagus nerve, which would be called rest and digest by the oversimplified model. This increased activity in the vagus nerve turned out to be incredibly important to the cardiac performance because when they blocked it pharmacologically or surgically, they blocked the vagus nerve signals to the heart. Cardiac function got worse. And so there was less blood flow in the coronary arteries. Now this was actually something very similar to this had been done years ago by a Japanese research team that published in the proceedings of the National Academy of Sciences. I'm sorry, I forget where the New Zealand paper was published. But like I said, Google the sheep and New Zealand it'll come up very quickly. It was only a couple of years ago. And I'll add that reference in the show nights. What the Japanese studies showed was that if you stimulate the fight or flight chain, the sympathetic chain to the heart, nerve to the heart, of course, heart rate goes up, cardiac output goes up. And if you stimulate the vagus nerve to the heart, of course, heart rate slows, cardiac output goes down a little bit. But what happens when you stimulate them together? This has been known for 20 plus years. If you stimulate them together, cardiac output goes up more than sympathetic stimulation alone. And the reason is the input from the vagus nerve slows the heart enough, heart rate enough so that cardiac filling is optimized. And when the filling is optimized, you get a more efficient cardiac output. The point of both of those, and both in the context of exercise, where everybody knows everything about fight or fight versus rest and digest and exercise is wrong. Actually, our both exercise activates your vagus nerve and your sympathetic chain. And that's really important. Because at the end, as you said correctly, it's not about turning one off and the other on. It's about having, you can think of it as flow between them or balance or harmony, that they act in harmony. Yeah, I think you describe it in the book as a two-system model of operation. And you're looking for optimal, efficient oscillation. Is that right? Yes. So it's about, it's very much a flow between them. And in so many of these conditions, it is so oversimplified. And people are told that they are stuck in fight or flight. And they need to move into rest and digest. But actually, our bodies, that understanding that our bodies need both, and they need to be able to, what you're searching for is to be able to switch between the two as efficiently as possible. Right. And understanding what we talked about before, that you have a massive neural network in your body, which is influenced if you have, what if you have inflammation somewhere hidden in your colon or your liver? And you're not really aware of it, but it's constantly sending these signals up your vagus nerve into your brain. Your brain knows the inflammation is there, even if you don't. And your brain is going to be having activation of brain networks in response to that. I've asked this question many times, and there's a plea in the book to my colleagues to do more research on it, because it may be that inflammatory signals in the body, driving up the vagus nerve into the brain, are a source of depression and anxiety. So this goes right back. to wherever I started this research, which was I read a book by Professor at Cambridge called Edward Bulmore, who talks about the way in which depression is actually inflammation. This is when I first got long-haired, this is the thing that sort of caused me to start looking into everything. And it's actually. Edward's a wonderful scholar, he's a great guy, he and I have shared the podium once or twice. Have you? My God, I would love to speak to him as well. I think there's an online. I think there's a video of us giving a talk in London once. I'll let you know. Yeah, no, I agree, his work's very important. But it was just mind-blowing, that idea of the way in which inflammation in the brain drives the physical symptoms. And that was actually just something that's been going over my brain when you were talking about the inflammation is, can we really understand whether it is inflammation in the body or inflammation in the brain? If we have this constant passage between the two, how do we establish where, like whether it is. Is there. Can you get inflammation in the brain? Or is it actually just a signal from the body? Or both. So here. Well, we could talk about this for an hour. But let's start again with first principles. What is inflammation? So inflammation was defined by Galen and others, you know, 2000 years ago. It's heat, pain, swelling, and redness that occurs at the site of an injury or an infection. So if you sprain your ankle, you have heat, pain, swelling, redness. If you get an infected mosquito bite, you have heat, pain, swelling, redness. Okay, when you look in the brain of a depressed person or an Alzheimer's patient, which is an Alzheimer's is class everyone agrees now, it's not 100%. But most. Most in the Alzheimer's field would agree that inflammation is playing some important role in the pathogenesis of Alzheimer's disease. But when you look in the brain of an Alzheimer patient, deceased Alzheimer patient, at all times, you don't see heat, pain, redness, and swelling. You might see a few white blood cells here and there that are out of place. You might see that the glial network of the brain, which are sort of like the macrophages, the pacment of the brain, you might see that they've been, quote, unquote, activated. But that's not the same thing that you see when you sprain your ankle or have an infected mosquito bite. But what happened was in the 80s and 90s, in the period you were referred to before, when we were discovering cytokines and discovering their role in causing inflammation. And before that, a prize-winning work led to the discoveries of icosenoids and other molecules that cause inflammation. All of our language in the lab, much of it, has shifted to studying inflammation by studying the presence or absence of those molecules. And so if you look in the Alzheimer's brain, you will see overexpression of various inflammatory molecules, various inflammatory cytokines. I've been arguing recently and I haven't made a sort of a king's case out of it yet, but it's probably important to think carefully about semantics. We probably need different words. You know, people have tried in the world of senescence and aging. They've tried talking about inflammation, which makes some people laugh. But I know exactly what they mean. You see in elderly animals and people, you see more signs of these inflammatory molecules. What does that mean? They don't, they're not walking around necessarily with swollen ankles and infected mosquito bites. But they have more of these inflammatory markers. So maybe the simple answer to your point is you're asking the right questions. But in human beings, we don't have agreed upon standardized tools and methods to answer the questions. Well, I'm glad that you're trying, that you're making some roads into it. Well, I mean, it's such a strange, abstract concept, this idea of inflammation. And you're talking about it being very specific activation of cells. But yes, the average human would say it's that puffy redness. Right, that's the disconnect. So let's go back to depression, right, where you asked about. So if you look at clinical studies of vagus nerve stimulation, which by the way does not cause immunosuppression, does not have black box warnings, and has been FDA approved in Europe and the United States, which is contrary to the SSR rise and things that you're saying there. Exactly. This is the vagus nerve stimulation. FDA approved in Europe and the United States to treat depression in patients who are not benefiting from all the other therapies, SSR rise and everything else. So what's the data show from that? This is decades of data. Well, at first it's safe. There's no black box warnings. There's no immunosuppression. So vagus nerve stimulation is, it wasn't invented yesterday. It was invented in the 1980s and 90s. And we know how to do it and it's safe. Second, about half the patients with severe depression get significantly better with vagus nerve stimulation. That's amazing, right? These are people, some of them, they can't take care of their kids, some of them are suicidal, they can't work, and they're out of options medically. And half of them are getting better. Why don't you know about this? Why isn't everybody talking about this? I mean, the fascinating thing with it as well, though, is that the depression is so often put down to being a psychological thing. But what you're actually saying with the vagal nerve stimulation is it is a completely physiological fix, a completely physiological influence for something that has for so long been determined as being so psychological. Well, maybe, maybe. I really. That's the rub. So because it's half the patients, there's a whole series of new questions. And because the signal's on a vagus nerve stimulation go up into the brain and down into the body. The question becomes, why did half of them get better? Is it because they have some specific brain network that is activated by the vagus nerve signals going up? Or is it possible? And this is new. And these are questions. I don't have the answers to this. And this requires a new ways of doing clinical studies. Is it possible that the people that got better had too much inflammation maybe in their body that was the source of their depression and that the vagus nerve signals into their body actually reduced the inflammation and now they feel better? But I mean, I think there should be a call to action because of the importance of this. Let's see if we can figure out if it's 50% of the patients. And I understand you don't want to do surgery on 100% of patients, if only half are going to get better. But let's figure out how this works so that we can only put the device in people who are going to respond to it. These are obvious questions that are right before us that we don't have the answers for. Let's talk about that very specifically in terms of what you talk about when you're talking about vagal-sternov stimulation in depressed patients. What you're talking about with your FDA-approved vagal stimulation for rheumatoid arthritis patients, you are not talking about a device that someone buys on Amazon and pops somewhere on their body. That's 100% correct, incredibly important point. So there are FDA-approved devices to specifically stimulate the vagus nerve. I call them Gen 1 and Gen 2. The Gen 1 devices go back to the 90s. They're like a pacemaker that's implanted in the chest under the clavicle with a wire or a lead that goes up into the left vagus nerve in the neck. That's the device for which there's decades of experience. More than a quarter of a million people have been studied for follow-up over 30 years. I estimate more than a million people are walking around with such devices and planted for either epilepsy or depression. The rub there is there's no consensus on why it works. And is it in the same location? Yes, for both of them. Yeah, the left cervical vagus nerve. And there's reasons for that that have to do with that's the safest place to put it. But it's really important. There is no consensus on the molecular mechanism or why this therapy works in half of the patients with epilepsy and half of the patients with depression. And one, you can't explain how something works. That seeds of doubt, it makes it harder for payers to pay for it. It makes it harder for doctors to explain to their patients whether or not they should have it. And so that's Gen 1. The new device, which is made by a company now that I co-founded in 2007 to do these clinical trials, that company is called SEPP point medical. And their device is the size of a of a fish oil pill. It's about the size of a multivitamin. And that's the whole system. It's called an immunoregulator and it sits in the left neck at about the level of the atom's apple. The clinical trial results that led to FDA approving this therapy for rheumatoid arthritis. Those results are now, and they were posted coming up on a year ago at the American College of Rheumatology. The paper will be coming out soon, I hope. But the data around the SEPP point medical website for anyone who wants to look at it with rheumatoid arthritis. And what it showed was in 242 patients. Now again, these are people who are essentially running out of medical options. They have serious arthritis symptoms, rheumatoid arthritis. And they're not getting better from the therapies with biologics, the anti-TNFs, the anti-IL ones. And they're not getting better with the jack inhibitors. Those drugs, by the way, have black box warnings and at least the biologics are invasive. They have to be injected. So these subjects enrolled in the trial. They were randomized into two arms. They all had the device implanted. But it was only turned on in half. Now, it's only activated for one minute a day, which is actually quite remarkable. And the reason for that is because we learned that the mechanisms, the systems that carry the information into the immune system, amplify for hours and hours and hours after a single one-minute stimulation. And what we saw was absolutely incredible. So the clinical trial, the chief medical officer, Dr. David Churnoff and the CEO, Murthy, and the trial that they sponsored, talk about the fact that within the end of one year, 80% of the patients had significant clinical benefit. And now, it's not just 80% of all people with rheumatoid arthritis. These are people who've been treated many of them for years with no significant clinical benefit. And now they're having significant clinical benefits. This is a new era. This is a new era in rheumatoid arthritis therapy. It's very-- And when I was reading about some of these people in your book, I was crying because some of these people had had their lives completely destroyed. And the turnaround in terms of the speed at which this was able to help them was remarkable, wasn't it? Yes, it's this idea of using a surgically implanted device, the size of a multivitamin, instead of biologic drugs that are injected and cost in the United States $50 to $100,000 a year and compankment people. This is a totally new idea. And this requires patience and doctors and payers and everybody to think differently about it. So again, back to your first question of this podcast is why I wrote the book. That's why I wrote the book. I wanted to have a groundwork where people could turn to, to, this is what we know, this is what we don't know. This is how it works. And as a whole chapter, as you know, called FAQs and the questions are for patients to ask their healthcare providers. And the answers to the FAQs are for the patients and for the healthcare providers, 'cause this is new for everybody. You know, nobody, you know as much now about the Vegas nerve as many healthcare providers who haven't thought about it in 20 years, frankly. So it's an exciting new era. I'm really happy. You talk about the patient stories. I've had the opportunity to meet several patients and you say they brought tears to your eyes. It brings tears to mind too when I hug them. And they thank me and I thank them. You know, they take all the risk, right? I get to do what I love to do. I get to do science. I get to try to discover and invent things with brilliant colleagues. I mean, I have the best career path in the world, but the patients, they didn't choose to have these conditions. And they volunteered nonetheless to participate in these trials to help move the world forward. And so, you know, plus them, right? The difference in position for the array versus the depression and the epilepsy. Does that heralds that there might be multiple different locations for future in the future for different conditions? The primary difference between the pacemaker-like devices is that they were invented long time ago. OK. And now we've got sophisticated electronics. I mean, the device, the immunoregulator, has a rechargeable battery that charged with the patient puts a collar on once a week. It has essentially a circuit board. It has an antenna so that it can communicate with the doctor's tablet and she can adjust it in her office. And it has the leads that sit on the vagus nerve. So when you put all that together, it's a remarkable thing. What's so exciting to me and Sir Mark Feldman, who of course won the last surprise for his work on antitannia for rheumatoid arthritis, he and I had lunch recently. And what we're so excited about is the idea that the biologic therapy for rheumatoid arthritis does not stop the progression of the disease. It doesn't cure the disease. And the question on the table now is, does the vagus nerve stimulating approach, the immunoregulator approach, does that actually slow the disease progression and accelerate healing in the joints? And the MRI results from the set point study, which you can see on their website, they speak to the fact that it accelerates joint healing, which is a remarkable finding. So are you saying that that means that sometimes this is potentially reversible? We don't know. I mean, it hasn't been up to date. So that's what people are wondering. Well, I'm wondering it. I mean, it's a question, right? It's not a promise. And it's, look, let's be really clear about this. Like every other new therapy, this isn't going to work in everybody. There were patients in the clinical trial who had significantly less responses and patients in the trial who had significantly better responses. But we can start to ask the question in long-term follow-up studies, you know, will this implanted device therapy eventually replace the need for some medications? Right now, the answer is definitely maybe, because I've met some patients who are taking no medications and have no signs and symptoms of their arthritis. It's amazing. Let us discuss, though, if people are listening to you and think, "Okay, I'll go and buy the Vegas Nav, what's described as a Vegas Nav stimulator online and pop it on my ear, pop it on my neck." Is that going to have the same results as these implanted devices? It's not a Vegas Nav stimulator. The only way to stimulate the Vegas Nav is to implant a surgical device on it. Or if you're on a laboratory and you have access to a focused ultrasound machine which we have here, you can use focused ultrasound to stimulate the Vegas Nav. That's it. That's a whole section that we haven't discussed, isn't that? Yeah, it is. Sadly, we're running out of time, but we are absolutely running out of time. I can talk to you all day whether we can't do it today. So we'll maybe have to come back and pick up on some of the other things because there is a huge amount still to talk about. That'd be great. There's a lot of devices being marketed online called Vegas Nav stimulators. The FDA is in Europe and the US. They don't carefully, particularly mandate what you call your device. And there is a branch of the Vegas nerve to the ear. Whether the device that you put in your ear is stimulating your Vegas nerve, the answer is a definite maybe. Yeah, because it might be a different now. So the Vegas nerve branch is called the Euricular Branch of the Vegas nerve. And it goes to the cartilage of your external ear, but there's many other nerves to your ear. So when you put something in your ear, your finger or a Q-tip or a nurse stimulator, you may or may not be stimulating a sensory branch of the Vegas nerve. And oh, by the way, it's a sensory branch. That means you're sending signals into the brain. And from there, the brain can do whatever it wants with it. It's absolutely not the same thing as putting a device on your Vegas nerve in your neck. Now, that being said, there's a lot of interesting clinical studies. We talked about this in the beginning. I would call them pilot studies. The only large clinical studies of stimulating the Euricular Branch of the Vegas nerve in the ear is an epilepsy. And it was done by a company called ServoMed. And that is FDA approved to treat epilepsy and it works about half the patients. All the other studies of the ear devices that a people cite, oh, there's one other one for improving quality of sleep, which is interesting. But all the ones for inflammatory conditions are either small studies or not randomized or not well controlled or not well replicated. And in terms of that control, one of the major things that you cite in the book is that the massive issue with these things is the compliance in terms of where are people putting it on, when are they putting it on? So when it's not an implantative device, there are so many variables that really, really influence the results. Oh, 100%. It's like, you talked to somebody who-- this thing didn't work. I said, really? How long did you-- oh, I tried it for two weeks. I said, really? Did you do it twice a day for five minutes in the same place every time? Well, no. I missed a week. And then I did it for two more days. It's like, come on. It happens to all of it. It happens to the best of us, you know? Dr. Tracy, I would love to talk to you for hours, but you have to actually go and do your work. So I would love to pick back up a conversation in the future and talk about more of your work, go into more depth about some of it, and then talk to you about some of the things that patients can possibly do for themselves and whether we have any evidence and the scientific rigor behind some of the self-help things that are being pushed out there. But for now, I would like to just offer you a huge thanks for your time today. It has been such a pleasure. It's been my pleasure. Thank you for all your hard work. You're obviously incredibly well prepared and insightful on this, and it's been a pleasure chatting with you. [MUSIC PLAYING] This was a great conversation from someone who is so deeply involved in the science of the Vegas Nub. And yet I find his words and teachings so accessible. I hope that you did too. And do check out his book. I've included some of the references that we talked about in the show notes. So all the details are there. Go and check it out. I'm going to follow up this episode in the future with practical advice on how we can influence the Vegas Nub and our auto-inoic nervous system. We have other hugely exciting conversations coming up, aiming to bring you strands of science, the practical, and the personal. And I would love to hear all your opinions on what and who most resonates with you. It's amazing to receive your comments and reviews to understand how we can best shape this show to suit your needs. So please continue to write the comments on your podcast app, email me, or contact us via our social media platforms. This show is about creating a community. And I would love to know what best serves you. [MUSIC PLAYING] Thank you for listening to Make Visible. Please do like, follow, or subscribe to listen to our next episode, where we'll be uncovering more insights into complex chronic illness. This was brought to you by the team at Visible, a group of scientists and engineers whose lives have been affected by energy limiting health conditions. We're building wearable technology that's helping 100,000 people measure and manage their complex chronic illness. To find out more about what we're working on and how visible could help you, visit our website at makevisible.com. [MUSIC PLAYING]