Vagus Nerve Stimulation & Inflammation | Kevin Tracey | Episode 288

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how the vagus nerve works and how it affects inflammation. I haven't gotten through all of it yet, but it's a very interesting book and it talks a lot about the research you've been involved in over the years. Do you want to just give everyone a very, very brief overview of the book and what its basic message is?

And this all comes, uh, frankly, in in in this present era on the heels of of work that led to the FDA approving a vagus nerve stimulation device from a from a company I co founded called Set Point Medical. And this device is now FDA approved to treat inflammation. So there's a lot of a lot of people have a lot of questions. What is the vagus nerve? How does it work? If I have rheumatoid arthritis, how do I get a vagus nerve stimulator? How does that work?

And I I wrote the book for for patients who were curious about this, for their family members, for people who were curious about their own vagus nerve in their in their in their normal healthy habits a and and and home health hacks and and I wrote it for doctors and scientists who are also hearing a lot about the vagus nerve, but if they're not working on working on it, um, they'll be able to use this as a resource to answer questions. And you're right, I

I told it in the context of of of my own stories from the laboratory, from clinical trials, from starting companies. And uh and and I and I hope it I hope it serves the purpose of of giving sort of a a baseline for people to start talking about the vagus nerve. Because frankly, when when I go online and start looking at all the information, I get confused and I've been thinking about this for a long time. So

So you share some, you know, interesting and disturbing facts at the beginning of the book. You say things like inflammation has replaced infection as the greatest threat to healthful human longevity. And you, you know, you share some some stats and some figures related to that. Something like two-thirds of deaths annually each year, right now, are due to.

Heart disease and stroke, diabetes and obesity, neurodegeneration like Alzheimer's and Parkinson's, or cancer, right? So those are those are all the big things that are, you know, upsetting people's health and and contributing to to mortality each year. And you say that all of those diseases are diseases of inflammation. So what exactly does that mean? And can you give us just sort of a a lay of the land here in terms of the problem of inflammation in general?

Neurodegeneration, Alzheimer's, Parkinson's disease, and a couple of others, all all of those conditions are either caused in part or directly by inflammation, or made worse by inflammation. And so It that's a that's a big difference from a hundred years ago. Uh uh at at the at the turn of the last century, uh in the early nineteen hundreds, late eighteen hundreds. In the city of Boston, Massachusetts, 80% of the deaths were caused by infectious diseases.

And and that's just not th the case today worldwide according to the WHO. The the the so so the argument the argument would be if if the leading cause of death Uh if those are the leading causes of death and they could be treated,'cause arguably none of those can be effectively cured. None of those conditions that you said and I repeated uh can be effectively cured today.

And neither can inflammation. Inflammation and we'll get into what it is, but there there's no cures for inflammation today. So the question is, if we could cure inflammation, whatever that means And if inflammation is contributing to those conditions and they the mortality of those conditions uh was either attenuated or

or went away, then what would happen to to to health span? What would happen to lifespan of the human race? It I don't know. It's it's a f but it's a fair question and a f and a fair hypothesis to say it it we would we would enjoy gains in health span if we could eradicate inflammation today, like we have enjoyed gains in health span.

from uh nineteen hundred to today. In fact we've we've enjoyed some thirty or forty years of additional health span by eradicating infectious diseases through vaccines. through antibiotics, through um better uh public health and and hygiene, clean food, clean water. So it it's food for thought. It's I I I was trying to provoke in that uh opening th uh thought that you referred to and I hope I hope it does exactly that. What what if we could cure inflammation?

When we look under the hood and think about things at the tissue and the cellular level, what exactly is inflammation and what would you say its biological purpose is when it's functioning properly in a healthy individual?

uh is little changed. And and in fact when most of the time when people refer to inflammation, that's what they're referring to. Now inflammation has been conserved throughout the mammalian kingdom, throughout the animal kingdom.

uh as a as a helpful response to help eradicate the infection and eradicate or help us accelerate the healing from from an injury. So that that's all good. What's the problem? The problem is Uh uh the problem comes if inflammation either spreads throughout the body Uh or does not resolve.

So if if if it if if inflammation persists, for instance, in your kidneys, you you you can end up with kidney failure. In your liver, liver failure. In your brain, you may end up with Alzheimer's disease. So so these conditions of persisting chronic inflammation

are are are contributing to d to the diseases that we listed, the ones I just said, and e and even even cancer. So about thirty, forty years ago, We shifted our understanding uh about inflammation from a descriptive you know, heat swelling Pain and redness from a descriptive view.

uh phenomenon to to understanding at the level of individual cells and molecules that that cause inflammation. And so today we understand that white blood cells, leukocytes, monocytes, lymphocytes, Neutrophils, that th they make molecules that either cause other cells to become inflamed or contribute directly to those cardinal signs of inflammation. And these molecules have names like

cytokines and icosinoids and and and leucotrienes and prostaglandins and the list goes on and on and on. We've become we uh scientists studying inflammation have become very sophisticated. at at at putting labels on these molecules and identifying individual conditions where blocking such molecules can actually help reduce the s signs and symptoms of inflammation. And so a great example of that, which my colleagues and I in New York

had a hand on in the in the early days was a molecule called T N F or tumor necrosis factor. And um we showed that if you administer anti T N F monoclonal antibodies to baboons that are subjected to widespread uh systemic inflammation caused by injecting bacteria directly into the the bloodstream, we showed that removing the TNF without removing the bacteria actually prevented the uh the the shock and the tissue injury that occurred.

because we had removed the cause of the shock and tissue injury, which was not the bacteria. It was actually directly the cytokine TNF. And so that that really opened the door to those kinds of experiments and clinical trials. That led later in later years now, we're back to the to the nineteen nineties. That led to the FDA uh in the US and in Europe and then worldwide approving the use of monoclonal anti-TNF antibodies to treat inflammation in conditions such as rheumatoid arthritis.

Crohn's disease, psoriatic arthritis, and today it's it's it's hard to believe actually, but today uh drugs like anti TNF, anti-IL1, anti-IL6, That are in the class of biologics, they represent a significant percentage of the global pharmaceutical industries. um annual sales. So these have become very important drugs going after specific molecules that have specific roles in inflammation. It's it's been a game changer. Um

But we still I like to I like to point out we still don't really completely understand inflammation. These molecules these monoclonal antibodies, for instance They they they have serious side effects. They they are immunosuppressive because they don't just reduce the inflammation a little bit so the patient feels better. They they turn inflammation off a hundred percent. Right.

And immunosuppression is not something you want. You don't want to be susceptible to other infections. You don't want your wounds not to heal. You don't want to have an increased risk of getting a a case of cancer. So So these drugs are are are not perfect despite but they're the best we have for treating some of these conditions. So there's a there's a balance here. Yeah. Um you have you have these injectable drugs.

that have immeasurably improved the lives of millions of people, but they only work about half the time. And that's also r remarkable. And these same these same therapies, you see them advertise on the nightly news, every night on the network news, and and er pretty much every football game in football season on Sunday afternoon, these are these are the drugs where Th the the the the the subject, the patient, the woman is and the or the man is skipping through the tulips.

uh talking about how much better they feel and the voiceover goes on for ninety seconds afterwards with the lawyer listing all the complications. So The the problem is they're not based on an evolutionary mechanism. They're sort of a they're a man-made construct. They are monoclonal antibodies that were designed specifically to

uh immunosuppress the the cytokine response. And the the real advance that that came along from studying the vagus nerve, which we'll come back to in a few minutes, was that the vagus nerve represents an evolutionarily conserved uh a a natural reflex, if you will, that normally regulates inflammation. But but let's come back to that.'Cause I said we would go we would go from the clinical s the cardinal signs of inflammation

to the fact that we've gotten very sophisticated at understanding the molecules and cells that produce inflammation in particular diseases like rheumatoid arthritis. But we still have a big, I think, a big problem that's not being discussed very much. Because we now move to call in conditions where cytokines are over are being overproduced.

in the tissues and we're calling that inflammation. So so let's let's do Alzheimer's because it's such an important uh condition today. If you look in the brain of an Alzheimer's patient, i um obviously uh d a at at postmortem at autopsy. And you look in the tissues of that brain, you you will find that there's higher higher amounts of cytokines being produced in the tissues.

And if you look really carefully in in some of these brains, not all of them, you might see evidence of increased numbers of white blood cells. Or you might see evidence of of glial cells, the the substrate of the brain that's not the neurons or the microglial cells that that now the pathologist will say, well they're activated. Well what does that mean? It means they're inflamed.

And so all of a sudden we're talking about inflammation in the brain that's not redness, heat, pain, uh uh and swelling. And and that's that's that's a semantic shortcoming, frankly. Is is what we're seeing in the brain of an Alzheimer's patient is it inflammation, or do we need new words like meta inflammation or something, or inflammaging, or some other descriptor and and and I you know the the school is out on this but I think we have to be very careful when when we measure an increase

level of cytokines being produced in a tissue and we we label it inflammation'cause it may be very, very different than what we've been talking about as inflammation for the last two thousand years.

is to correct something and return you to a state, a tissue state you used to be in. Basically to remove stuff that isn't supposed to be. It could be a pathogen infecting your cells. It could be damaged or decaying tissue. And then, you know, there's just stuff in there that has to be cleared out. So you got to move stuff in, you got to take stuff out. And the ultimate goal is to return a tissue to some prior state that it's, you know, supposed to be in, so to speak.

So, what is this, what is the concept of homeostasis? And why is that important maybe as an anchor point when we think about normal healthy inflammation and then thinking ahead to like when the inflammatory mechanisms themselves sort of go out of bad.

which maintains a uh uh the the the the temperature around a set point through through homeostatic mechanisms, meaning when the temperature deviates from the set point, the thermos the thermostat sends out the the signals calling either or from for more heat or for more cool air. Now it's it's

Th it's interesting. Um that's uh that's only part of the analogy I like to use when talking about homeostasis in a living system because What what ac w w a better analogy is is how in in a hermetically sealed building like a skyscraper somewhere, th the um i if you only turned the heat off

when it got too cold or only turn the air conditioner on when it got too hot, you would have f you'd you'd have fluctuations that would be very uncomfortable a as the temperature either fell too far or rose too high. And so the solution for that is you have a a few thermostats and you run the air conditioner and you run the heater all year long.

And so you're you're constantly pushing and pulling. And that's a very good analogy to how homeostasis is maintained in in the body. So for instance, uh everyone knows that that insulin lowers glucose levels. When you have too much sugar in your blood, you activate a glucose response. Um and that I'm sorry, when you have too much sugar in your blood, you activate an insulin response. Insulin's release from the pancreas.

And this helps bring the glucose levels back down by depositing in the tissues. But what's often overlooked is the You're often in those situations co stimulating. uh with an another molecule, glycogen, which acts in opposition to insulin. And so you've got the pushing and pulling and think of blood clotting. When you when you activate a a clotting cascade in order to stop a hemorrhage.

Uh you also activate a fibroanalytic cascade to start dissolving the clot. So there's a fine balancing act that's going on uh in in an individual uh at levels of individual mechanisms of pushing and pulling. Now, over time, in order in order to keep the the output of all the different organs uh functioning in harmony, or homeostasis, which means i functioning in a healthy way, saying that you are healthy.

Um you have a short term uh regulation and you have a long term regulation. And the short term regulation, frankly, and simply are are reflexes in the nervous system. So when your heart accelerates Uh the the above a set point, the set point's established in the brainstem. Traveling in nerves, notify the brainstem, the heart's going faster than the set point, and the set point responds by sending signals down your vagus nerve to slow the heart.

Uh and similarly if the heart's going too slow, uh signals travel down your uh sympathetic nerves to the heart to accelerate the heart. And so you can go organ by organ and look at these minute to minute or sometimes second to second inputs that that help produce a balanced function. Now over many weeks, months, or years, you also have hormonal responses. which travel through the bloodstream of course, not the information travels as hormones traveling through the

through the circulation, not not not through nerve endings. And so things things happen more slowly. It takes a while for the hormones to travel from from the adrenal glands to the other organs in your body.

takes takes longer for the levels of the hormones to reach a steady state level. And this this is a way that long term um um set points are maintained w and whether that's your your your baseline blood pressure or or your baseline sensitivity to insulin and we could go down uh or your baseline sensitivity to thyroid hormones, you could go down the whole down the whole list.

But together, this this rapid reflex control of responses and the long-term humoral or endocrine control of responses is what gives homeostasis uh uh h health. to to to people. Now what's really interesting is when you study what happens to people who are are really sick, cause If you y if you walk in the ICU of any major medical center And and with very little work, you you you'll notice that that on a given patient who who may be very, very ill,

the their their their heartbeat is very, very regular. It's very, very regular. They've lost the variability uh in the in the individual uh time between individual heartbeats that characterizes Um And so that that's an example where you're losing the the effect of pushing and pulling because the system, whether it's the brain, the brainstem, the nerves, or s or the heart itself, is is now not showing that that that flexibility, that evidence of homeostasis, which is pushing and pulling.

regulatory motif or information pattern at all almost all levels of biology where you've got these push-pull dynamics where you might have excitation and inhibition that are both instigated by the same thing. You know, in gene regulation, you might have an activator that gets turned on together with repressors, and it helps something from

becoming too activated. In the nervous system, you often have, you know, a stimulus that um gives you excitation, but then simultaneously or nearly simultaneously, inhibition, uh like feed forward inhibition as well. And and basically what this does is it patterns and constrains Information flow and activity within a biological system so that you don't have, so that you have just the right amount of it, right? It's it's a properly balanced response, not too much.

not too little. You don't want too much excitation in the brain because then you get epilepsy. You don't want too much inflammation, right? Because it's going to cause collateral damage. Kind of like you were alluding to before with some of those early experiments. Um, it's not necessarily the endotoxin or the inflammatory instigating uh agent that causes the damage, it's the inflammatory response itself. So an important concept I want to talk to you a little bit more about is

the spatial and the temporal regulation of the inflammatory response, right? We want inflammation to come when we when we need it, but not last too long and not uh bleed out in space to places where we don't actually need it. So

When when you sit at the in the doctor's office and she taps your knee with a rubber hammer and your leg goes up and you say, Who did that? That's a reflex. That's a simple reflex everybody can understand. And Everyone thought they understood it pretty simply until Charles Sherrington came along and explained what you just said. And that what he what he explained is, yes, when when the when the rubber hammer taps the the patellar tendon, that sends a signal to the spinal cord.

that activates um signals that return back to the quadriceps femoris, which contracts and your leg goes up. Right. That's what you see, that's what you feel. That okay, we get that. What he goes, but that's That's not sufficient to explain what's really happening. And what's really happening is the the stretch the stretch receptors that activated that incoming thing to the spinal cord.

Uh also activate another set of signals that leave the spinal cord and go to your hamstring muscles and inhibit them. Right, right. So if your hamstring muscles were not relaxed, your leg would not pop up. And so so it's exactly what we talked about with with blood clotting or with insulin and glucagon or with the hermetically sealed office building where you're turning on the heat and air conditioner at the same time sometimes. This there are the this reflexes

r uh require activation of one response, they often require for a smooth for a smooth biologic response, it requires the inhibition of another response. So in the context of inflammation, we we made a a a a very surprising discovery in the in the late nineteen nineties that that there are nerve fibers in the vagus nerve. which uh a have a have a have the have the job or the capacity of of of of specifically slowing down

the amount of cytokines that are being produced and therefore specifically slowing down inflammation. And as as you might expect from this conversation, and I don't I don't go into it much in the book. Uh but we've since discovered fibers in the vagus nerve that ac can can turn inflammation on as well. And so so the the vagus nerve, you know, we call it the vagus nerve, but you have one on each side, so like two thumbs or two kidneys, you have two vagus nerves.

But it's more complicated than that because within each of these two vagus nerves is a hundred in a human is a hundred thousand fibers. And each of those fibers has a specific origin and insertion and a specific function. And so we estimate that uh within one of the two vagus nerves, probably a few thousand fibers at most, it may be just a few hundred, are sufficient to turn down the inflammatory response in patients with rheumatoid arthritis. Just a few hundred so there's still

You know, a hundred and and ninety-eight thousand more fibers to go. If we're just talking about a few hundred, a couple thousand that turn off inflammation. There's probably a few hundred that turn inflammation back on, and those have different characteristics. Uh we've designed a device as the setpoint medical engineers

uh led by people like Mike Faultes and and Yaakov Levine. They designed devices that would deliver such a small amount of current into the vagus nerve of humans on the in in the left neck.

that it would was it would be a sufficient amount of electric current to turn on the brakes to slow the inflammatory response without slowing the heart or doing other side effects. And so That kind of understanding of of how homeostasis is controlled, whether it's inflammation or heart rate or blood pressure or or or blood sugar, it's the same basic principle uh as that you were making of uh uh antagonizing some uh systems and and stimulating or a or agonizing others.

make make you behave in the way that you need to and to make sure that responses are appropriate, that they're not too big or too small or they don't last too long and so on and so forth. Um another way that this manifests

Right. There's many mechanisms of inflammation. There's many ways it's regulated. There's not just one pathway. There's lots of different types of inflammation that rely on somewhat different mechanisms. Um, but one of them is the balance of of

pro-inflammatory and anti-inflammatory signals. And there's probably many different examples you could you could talk about, Doctor, but you know, one of them are are the inflammator pro-inflammatory and anti-inflammatory lipids, things like the omega-6s and the omega-3s. And we start to study these pathways, you see that, oh, these things are sort of supposed to be in balance because they actually get co-deployed to regulate the spatial and the temporal extent of inflammation.

Um, uh are there any examples or anything else you want to say there about sort of this idea of balancing of pro and anti-inflammatory signals?

in uh in studies of of sepsis or other serious infections. And what we know in a in a laboratory situation is that When we know in a laboratory exactly when the infection starts because we have the laboratory the the mouse models when we can give the infection and we can measure the responses and and and we can we can see exactly that. the pro inflammatory response has begun or the anti inflammatory response has be has begun. When you move these kind of

of questions into clinical trials, it gets extremely confusing very quickly. If in in the laboratory we we w people tend to say that the the early response is is pro inflammatory. Uh and then this is followed by uh anti inflammatory accumulation of anti inflammatory responses which uh would hopefully tend to Stop the inflammatory damage and s and start the healing. But it but it's not black and white p p for the reasons we've already talked about. If you look hard enough you will see that

anti inflammatory responses are turned on almost immediately at the time the the pro inflammatory responses are turned on. So so so I try to stay I try to stay away from that for that reason. But for the other reason is when you move in into the clinical clinical situation. Uh again, back into the ICU where where you'll have some percentage of the patients in the ICU are there because they have severe sepsis.

And you go carefully through the history and you ask the family members, well when did when did your mother get sick and what time was it? And you almost always find out that that patients Uh the onset of sepsis as denoted when they got to the emergency room of the ICU versus the onset of the condition that caused the sepsis, there could be a days or a week separating that onset. So you never really know exactly where you are. in the time course of the condition. But when you look at how

How these things are regulated by the nervous system, you can start to make sense of it. You can definitely start to make sense of it because Look, the vagus nerve I said is complicated'cause there's two hundred thousand fibers. But you can go to simpler animals. You can go all the way back to a round worm under a rock, a C elegant. And and a C elegans it doesn't have many nerves at all. A hundred or a hundred and twenty a hundred and twelve or a hundred and twenty nerves in a C elegans.

But if a couple of them use acetylcholine, which is the major neurotransmitter of the vagus nerve, a couple of these nerve fibers in the worm use acetylcholine. And guess what that does? It turns off the inflammatory response. in the gut of the worm. And so how does that have anything to do with us walking around? Well as as nervous systems evolved and became more complex,

Evolution would would would retain regulatory mechanisms that were still useful. And so you can find what we call today, we call these things inflammatory reflexes. which are the signals in the vagus nerve that are turned on by inflammation and then in turn turn off TNF and other cytokines. That's an inflammatory reflex. We find inflammatory reflexes in in in mice. in in dogs, in pigs, and in in and in humans.

So evolution conserves these rapidly acting reflexes to to to to put the brakes on inflammation that can be damaged. And what turns on this inflammatory reflex is you guessed it, uh, inflammation. Yeah. So it's a closed loop system.

You know, sometimes people will say, well, this study saw an increase in CRP or that study didn't. But if you're not very careful to measure particular signals at particular times relative to a known stimulus and to look at the serum or look at specific tissues, These these things often kind of get garbled in the literature because they're they're very exquisitely regulated both spatially and temporally. Um I want to talk a

uh in the case of hemoglobin A1C. So uh glucose can undergo a non-enzymatic uh chemical reaction with proteins with amino acids on long life proteins and it forms an irreversible adduct. Which is called an ad advanced glycation end product. One example of that is hemoglobin A one C. So hemoglobin is a long live protein, and as this chemistry progresses at a slow and steady non enzymatic rate over a long period of time,

The amount of hemoglobin A one C that accumulates in your body is uh related to the amount of glucose that you've been carrying around in your body. So now we have a very good, very well understood Uh we understand the chemistry, we understand the kinetics. uh marker of of your long term glucose exposure over the preceding couple of of weeks.

We don't have that for inflammation. There there is no there is no agreed upon or or or well established evidence that any marker that we have today in the blood is is a uh uh has that ability to

um bring uh to integrate or bring together all of the previous amount of inflammation that you've been carrying. So we just don't have that. Um this is you're talking to someone who in the n late nineteen eighties was involved on the team that did some of the first measurements of of TNF uh in various conditions, uh clinical samples and and and and an animal laboratory uh disease models, animal models.

And to this day now, so what is that? Uh uh forty years later, give or take, there is still no clinical condition where measuring cytokines

which everybody knows has to do with inflammation. We've been talking about it already, but there's no there's no diagnostic value in measuring cytotines in any condition to it to my knowledge. Now We know in in in cases of fulminant Um meningocoxemia, fulminant meningitis, that extraordinarily high levels of TNF have been measured in humans and and and the highest levels occur in the in the patients that had the worst outcomes and or died and or died.

But but we can't measure T and F in you or me. And say, well, this means that, you know, y y you have th had this much inflammation or are having this much inflammation. Even in the case where we have drugs that block TNF, the monoclonal antibodies, that are used to treat rheumatoid arthritis and Crohn's disease. There's no way to predict.

uh by measuring TNF in patients, whether the the the antibodies will be will be therapeutically effective in in one patient versus another. And in fact it w we know even less about it than that because You can have you can have a patient, you you treat them with one monoclonal antibody, and they they don't have any response to it, but then you treat them with another monoclonal antibody against the same cytokine, and now they do have a response.

So there are so many questions in this seemingly simple idea about cytokines and inflammation. And part of, you know, I I uh in the book I I one of the one thing I do do is I I I have various please to my colleagues in various domains of of what I think are important unanswered questions. And this is one of them.

You know, people will say things like, you know, they did such and such uh study and they measured whatever, tumor necrosis factor, CRP, pick your favorite inflammatory marker, and they'll say, you know, we did X, but we didn't see marker Y go up in the serum. And that will be taken or interpreted to mean that the intervention didn't have an inflammatory effect or something like that. Why is that a tricky or dangerous way to think about this stuff?

Um you you'll find our levels are in the range of uh 10, 20, 10 or 15 picograms per milliliter. The the the sensitivity of the Elizas that that are used to measure this are in that same range. So I've seen many papers where where people um measure serum cytokines in condition in condition A, B, C, or D, and they and they say that the the TNF levels increased from eight to twelve or nine to fourteen. I mean, frankly that's

questionable statistically based on the sensitivity of the assays. I'm not I'm not gonna make those criticisms, but it's definitely makes no sense biologically because the the range of TNF's biologic effects goes from from that normal level of ten or twelve picograms per mil up to nanograms per mil. Ten twenty na so ten twenty thousand times more.

Static levels of serum inflammatory markers haven't proved to be diagnostically effective. Let's look at function. And the way we look at function is we Uh take our baseline sample and we take the and we take the the blood, which now has white blood cells that are still alive in the tube and we culture them, we keep them warm uh at thirty seven degrees for several hours, and we measure

How much cytokines they will produce if we provoke them with endotoxin or LPS or something. So that you would say, um, that that if I gave you endotoxin right now, the what in your veins. the the white blood cells in your body would react that way and make lots of cytokines. We have a marker of what your white blood cells would do by taking but we took them out of your body to study them rather than put the poison, the endotoxin into your body.

You can do that too in other experiments, but it's a lot easier to take the blood out. Then you intervene with a vagus nerve stimulation method and repeat the experiment. And now what we see after vagus nerve stimulation is we see Uh the white blood cells, again, from your arm, uh, after vagus nerve stimulation, are making less cytokines in the test tube than they did uh uh before we stimulated your vagus nerve.

So that looks exactly like the animal experiments. In the animal experiments you can do the intervention all directly in the animal. But in the human, that's a pretty good surrogate. When I went through the literature uh as best I could the world literature to write the book looking for specific um um vagus nerve interventions that people uh recommend uh online uh to do this, that or the other thing to reduce your inflammation. I found very, very few uh uh studies that that I could validate

w with with a functional response as I just described. Um the best ones were actually with cold exposure. Uh there's some pretty good studies where where cold exposure um will will decrease that inflammatory response. And with with breath holding, frankly. Breath holding which uh uh actually induces a fight or flight response and an acute fight or flight response voluntarily a controlled fight or flight response is is a powerful anti inflammatory stimulus. So my point is

We have to be very careful. We have to be careful uh in the words that we use and we have to keep doing the research because we don't have a hemoglobin A one C for inflammation.

Um, but also there's lots of internal things that get exposed or that uh change in some way that our body recognizes. Um, you know, if tissue is physically damaged and something from inside of the cell gets to the outside of the cell that isn't supposed to be there, um the body can recognize that. Um, I just did a podcast with a sleep researcher who talked about how, you know, in the brain, um, basically macrophages come in.

And the purpose of them coming in is to clear out rancid fats. So the brain has oxidized fats and they're supposed to be there. They're supposed to get oxidized. But then, you know, the trash needs to get taken out after things go bad, so to speak.

Um, so what are some of the common threads for what gets recognized as um uh something that's not supposed to be there, the the sort of common denominators between things like pathogens that come from the outside and then things on the inside that are supposed to be there, but then we need to dispose of them as well.

gets into your bloodstream and causes sepsis. What's happening in that case is that the the gram-negative bacteria are covered in molecules called lipopolysaccharides, which What happens in an E. coli infection is that the the bacteria, these gram they're called gram-negative bacteria, get into your uh either your bloodstream or your tissues. and they interact with macrophages or or neutrophils or uh other white blood cells that are carrying a receptor

f uh called called the tol like receptor, uh particularly tol like four in this case. And tolic four ha has an exquisite ability to bind to lipopolysaccharide, which is a molecule on the surface of the E. coli bacteria.

And if that happens, if there's a binding between TOLFOR and and LPS in uh in in this context, it it it it converts the macrophage from sort of a a quiet um Pac-Man sort of roaming around looking for things kind of creature into an you know, an angry bulldog and that that starts firing off all of its weapons and calling in all of its friends.

And this is the inciting event that leads to the release of TNF and IL1 and and the cytokine cascade, which, if not carefully controlled, can rapidly s s spin into a condition of tissue injury, of necrosis and and and of shock. And so that's a that's a fun the fundamental step is when the LPS on the bacteria interacts with the toll four receptor on the on the macrophage. That's what starts the cytokine storm.

I I I I I I didn't buy that. I I I thought it I I thought what if the body has a molecule That is released when when cells are injured, uh, either from ischemia, lack of of blood flow, or from trauma, getting punctured or or smashed. Um what if what if the release of of some molecules from from the body's own cells could also activate TOLFOR? And if that's the case

Um you would end up with cytokines being released and you would look like you had an infection. And it it turns out that turns out to be the case. So my colleagues and I discovered a molecule That uh is called HMGB One, High Mobility Group Box Protein One. And then that protein has a day job. It's normally uh involved in keeping the structure of DNA um stabilized. So it's a nuclear protein. There's lots of it in the cell nucleus.

But when cells when macrophages get activated or when cells get injured or are subjected to ischemia. Something happens and the cells literally export the HMG from the nucleus into the cytoplasm and then from the cytoplasm they crank it out of the cell and so now this stuff is floating around and and uh

And and can interact with with TOL4 receptors. What it does is it picks up other molecules along the way. HMG is a very, very sticky molecule. And so it will pick up lipoproteins that are oxidized. And it will pick up bacterial toxins other than LPS. And it brings them to this TOL4 receptor system. which can uh a or t or another receptor system called called uh toll nine which lives inside the cell. And now what you have is a way

Where HMGB1 is is like radar. It's out there gathering up signals and bringing them back to the mothership. And the mothership, the the macrophage in this case can process the signals and decide how robustly to respond. But what you end up with with a cytokine response. is you end up with two very different conditions, one caused by a sterile injury. And we can do this experimentally. We can cause sterile injuries in the laboratory using uh chemical

agents that cause cell death or rupture cells and those animals look as if we gave them an infection because because the mechanisms do do converge. So that that's one broad area. And the and the second one we don't have to spend a lot of time on, but it's obviously the fact that you can make antibodies against your own proteins or your own molecules. And now you have the the bodies

If inflammation is caused by the innate immune system, the antibody responses are controlled by the body's adaptive immune system. And now if you have antibodies targeting your body's own cells, you have another type of immune-mediated attack that can cause damage to your normal organs by your immune system making antibodies against you rather than against the invader.

Those things aren't just foreign entities from the external world, like pathogens that have come from the outside in. They could be things that have come from the inside out, something that's exported or leaking out of our cells because a cell has died or become punctured or whatever. And Both both things are recognized by the immune system. There's lots of stuff that's in us that's supposed to be there, but then it sort of leaks to somewhere it's not supposed to be or gets.

chemically modified or damaged or something. And so the immune system will dispose of the trash whether or not it's originating from inside the body or outside.

And what what what they proposed many years ago i is called the immunologist's dirty little secret. And that is if you make a a a a protein that you want to have your body have an antibody response to. So obviously you ha you have a bacteria or a virus, it has a protein. You identify the protein and you i i i i i you you now want to use that as a vaccine so that you want to induce antibodies against that protein. It won't work if you just use the protein as the vaccine.

You have to actually add add what we today call adjuvants. And what the adjuvants based basically do is they cause they cause cell death. So the the when when the reason you're the reason your vaccination shot hurt is from the adjuvant. Yeah. The adjuvant causes um some some tissue injury. And that and it's it's the tissue injury com that that activates the immune response you need so that during the immune response

the lymphocytes that come in and the and the antigen presenting cells that come in will actually focus on the protein that's there to make the antibodies. But if you don't If you don't have the the the the the the inju the injured tissues, you will not have a good antibody response.

And you gotta clean it up. And so stuff that's supposed to be encased inside the cells, when it becomes uh liberated from the cell due to tissue damage, that can simulate immune response that's almost identical to the one simulated by a pathogen, sort of like the example you gave before where people look like they have sepsis, but then there's no infection.

and and the and the mechanisms going on inside of those cells. But w in the last few years Uh probably the hottest field in all of science today, I think, other than AI, is neuroimmunology. And it's the idea that yes, we have to understand these basic cellular and molecular mechanisms of the immune cells themselves.

But but they're they're all operating in the context of a neural network. If you if you look at at at any tissue in in your body and you and you look carefully for the nerves, you'll find there's a nerve close by to almost every cell in your body. And what's happening we now understand with increasing precision. is that the nervous system is monitoring all of these interactions.

And they're and so sensory nerves are being stimulated by the presence of these inflammatory molecules or by the presence of the white blood cells themselves. And these sensory nerves are not only sending signals up into the nervous system,

to get the brain into the game, uh, but they're also sending signals back down into the tissue that are actually changing how the white blood cells are responding. So so for instance, there's a there's a famous condition uh called necrotizing fasciitis, which is a very dangerous, rapidly s pr spreading infection that that can occur uh after even a very minor wound or a or a or a unremarkable surgical incision.

If this infection um sets in place, it it can s it can spread very quickly between the layers of tissues in your body along the fascial planes. And and it can be highly lethal or cause serious amputations if it's not uh diagnosed very, very quickly and recognized. Well, there's a laboratory uh uh uh in i in Harvard that uh led by um Isaac Chu and his colleagues and and they made a very fundamental discovery. They discovered that the uh signals traveling in sensory neurons

than the role of the of the other white blood cells that are actually directly interacting with the bacteria. So it's as if the bacteria learned

that if if the bacteria could trick the nerves by sending signals not only to the white blood cells but also into the sensory nerves themselves, that the bacteria could gain an edge and have an advan an advantage. But I think that's a very healthy way That combined with the reflex control of inflammatory responses from from from the from from the central level through the vagus nerve and other nerves.

Those two things combined give give us a window into neuroimmunology that I think will will open the path to a lot of new therapies in the future. It already has with vagus nerve stimulation for rheumatoid arthritis.

in your in in in your neck tissues with the carotid pulse. It enters into the thorax to the to the chest. Along the way it sends off branches to your larynx, your voice box. to your heart uh and to your lungs. And it keeps going. It wraps around th I I said before, there's one on each side, but it it has branches or fibers that wrap around the esophagus.

down crosses the diaphragm, innervates the stomach, uh s uh th the the pancreas, the liver, and and and continues on down to to innervate the the intestines and and and the bladder. So what you end up with is a is a network. When you look at there's a very famous, you can if you Google it, you can see it in two seconds. There's a famous ink drawing by Vesalius.

uh f from hundreds of years ago and and it's a and and he's drawn a a human brain and the vagus nerve dangling beneath it and and it really looks like a man of war jellyfish. because the the the tentacles, these two hundred thousand fibers of the vagus nerve

as they travel below the neck, they just they just spread out and and and and mesh many of the organs that that that you don't think about all day long. And that's the that's the key, right? So eighty percent of these two hundred thousand fibers are actually carrying information from the organs up into the brainstem. So they're sensory, they're A for afferin. And that's really, really important because everything begins with input.

you know, I think we tend to to anthropomorphosize all of us. We tend to think about the power of the human brain and how important we are in the evolutionary cascade of the animal kingdom. But in reality, We are um reacting constantly to changes in the environment, and that's that's what creates the reflex outputs that give homeostasis.

So we don't we don't begin with outputs. We don't have a we don't have a thought that then induces a change in our heart rate. There's a signal that our heart rate has changed. And that activates a reflex to to correspond it. And if we happen to be thinking at our about our heart rate, we might notice that it's changing. Right.

And it's also sending signals out from the brain and to the body. So so the information is flowing in both directions here. When we think about information going from the body. through the vagus and into the nervous system up to the brain. What are some of the key areas of the brain that the vagus nerve is hooked up to that that we can talk about?

for the sensory input travelling in the vagus nerve. From there it it it the fibers of the of the NTS are then connected with with other brain regions and it gets very complicated very quickly. There are there are lots of oversimplifications uh online. I I just wanna I just wanna point out that you have two hundred thousand vagus nerve fibers and each and every one of them has a highly specific

path it follows and a highly specific function. And almost all of us can walk and chew gum at the same time because the entire nervous system is organized in a way that individual fibers have individual functions. And lastly, what Charles Sherrington taught us again it in the early nineteen hundreds of

is that it's critically important to understand the function of each and every individual fiber as it may or may not contribute to a specific reflex response. But at the end of the day, all the reflexes in your body are connected because all the nerves are connected. Mm-hmm. So that level of complexity is is hard to get your head around and there's there's th but there's too much oversimplification online. So let me give let me give you a great example. Just on this one

On this one uh idea of the sensory input. Um There are there there there are some that say, well, when when you take a deep breath, you've stimulated your vagus nerve. Well, what does that mean? What it means is if you take a big breath, you expand your uh your chest, you expand your thorax, you've changed the you've changed the pressure in your chest.

And you've changed the content of gases in your lungs. And you've changed the pressure in the uh pulmonary vessels in your lungs. All of those things are being sensed. by vagus nerve fibers, the the the the mixture of gases, the amount of pressures, and those are all funneled into the nucleus tractus solitaris.

Which then distributes the in the information in ways that frankly nobody understands. Um it processes these reflexes so that the outputs correspond to things like slowing your heart rate. So for instance, um it's it's always a fun experiment to to do a few um big deep breaths while you carefully monitor your pulse. It's easier now, everybody has some wearable they can watch their heart rate. But if you watch it closely.

You will notice your your heart speed up and slow down when as you take a big breath in and a long, slow breath out. And and that's because signals have traveled up your vagus nerve to transmit information about the changing pressures and gases. And then they've traveled back down your vagus nerve to to slow to slow your heart down. Is that really is that vagus nerve stimulation or is that a really complicated process that um

That involves the signals going into the the NTS and then some of the signals being relayed over to the origin of the motor fibers of the vagus nerve called the DMV and the NA. Those those Nuclear centers in the brainstem are are the home of the neurons that send signals lots of places, but some of them go to the heart to slow down the heart when you're exhaling.

On the other hand, when you're inhaling, the NTS has sent vagus nerve it's gotten this input from the vagus nerve and it's sent signals over to the locus ceruleus. That's the origin of your fight or flight neurons. So when your heart is speeding up, it's because you stimulated your vagus nerve. And when your heart is slowing down, it's because you've stimulated your vagus nerve.

So when someone tells me I wanna do this, that or the other thing to stimulate my vagus nerve, I say you have two hundred thousand fibers, which one are you gonna stimulate and how you gonna do that?

And as an option for you, you know, one place we can start here is a classic paper you have from 2000 where you did vagus nerve stimulation to attenuate the systemic inflammatory response in animals to bacterial endotoxin. But whether you want to use that example or another one that you might think is better, how do how does what do we know about how the inflammatory response is affected by vagus nerve stimulation generally?

We we had we had been working for years on a molecule to stop inflammation in tissues because we were we were hoping to develop a new therapy, a new anti inflammatory therapy. And one one day we were studying the effects of this drug blocking inflammation in animals with a stroke, with cerebral ischemia. And we put this drug which we called fourteen ninety three, we put it directly into the brains of the animal.

Because we wanted the drug to be at the place where the stroke was and stop the inflammation near the stroke in the hopes if there was less inflammation the stroke would be smaller. And guess what? It worked beautifully. The we were so excited the animals had a had a much better neurologic outcome. There was less inflammation and therefore the stroke was less severe.

As we continued to analyze and study those animals, we kept doing more controls to control for the effects of the inflammation in the brain, and we made this stunning observation that when the drug fourteen ninety three was in the brains of the animals That inflammation also stopped not only in the brain, but it stopped in the liver, it stopped in the spleen, it stopped in the heart. And this was a a uh a WTF moment. It's like there was no way to explain how

a vi a very teeny amount of this drug in the brain, fourteen ninety three, would would be shutting off inflammation in the body. And so we went to the library

The animal will get what's called sickness behavior. It'll have changes in body temperature, either fever or hypothermia, it'll get anorexia, it'll get behavioral withdrawal, it'll feel like it has the flu, just like happens to us. That sickness behavior disappeared when she cut the vagus nerves of these animals. So that that meant.

to her and to me when I read her paper that the presence of inflammation was activating the brain by sending signals up the vagus nerve and the brain was producing the sickness behavior. I said, well, so I'm a neurosurgeon at this point and then I'm tapping people's knees in my office during the day and I'm in the lab uh uh uh uh uh uh uh uh other days and and nights and weekends.

And I'm thinking, if Linda's observation is correct, and I had no reason to doubt it wasn't, then she had discovered a sensory input that might represent a reflex input. And if that was the case, then perhaps we had discovered a reflex output traveling from the brain to turn off inflammation. And if that was the case, maybe that the the reflex was embedded in the vagus nerve.

And so we repeated the experiments, and when we cut the vagus nerve, now the the drug in the brain no longer stopped the inflammation. So to prove the the existence of this reflex. We did the experiment you alluded to and published it in Nature. We electrically stimulated the vagus nerve, like activating the brakes on your car.

to slow the car down. When we electrically stimulated the vagus nerve, we we showed that this slowed down the production of of TNF and other cytokines. It slowed down the inflammatory response. So I wrote a

I wrote a another paper for Nature, uh in which I proposed basically, based on all the data that we had collected up till then, I proposed that this would be a way to understand neuroimmunology. This would be the way to understand How reflexes evolved to control specific aspects of the immune response.

And in this case, a reflex evolved to control inflammation to protect inf the body from inflammation spinning out of control. And it turned out it turned out to be turned out to be a very robust uh idea because the uh well we've replicated it and and and and s and

and and dove now down deep into the molecular mechanisms over the last twenty years or more. And pretty much all of the findings we proposed have been have been confirmed and extended and replicated by laboratories around the world. It's a very robust mechanism to control inflammation, w which is by sending signals down the vagus nerve to to suppress the cytokine response.

that if we can stimulate them selectively, and we've published a couple of papers on this now. But there are other fibers in the vagus nerve that will turn inflammation up. So there are there are there are there have been things said and written that that the the vagus nerve is an anti inflammatory um mechanism. Yes, it is. When we target it with a very specific selective method using

A s a small amount of electric current giving giving pulses for a few minutes a day. But there are other other ways you can stimulate the vagus nerve to increase inflammation. Now we don't understand those as well. Um what we understand in exquisite detail. Is that uh and these these are from experiments using optogenetic using pharmacogenetics, using uh very sophisticated um neural recording devices and nerve stimulating devices and and and micro neurosurgery to to create lesions.

What we know from the combined efforts of all of this work over many, many years in many, many laboratories, is that there are neurons in the dorsal motor nucleus of the brainstem, Which use acetylcholine as the primary neurotransmitter. And these neurons send fibers down the vagus nerve, down the neck. uh into the abdomen, where they terminate on a collection of nerve cell bodies, which we call a ganglia. Uh it's it's it's actually uh

It goes by different anatomic names this ganglia, but it's outside the spleen and and we we refer to it as the the the the celiac superior mesenteric ganglion complex because it's several ganglia all close together. If you follow the vagus remote. nerve endings into that ganglia, you can see nerve endings that release acetylcholine that that make contact with or synaps on. Cell bodies that send their projections into the spleen. Now that that's fascinating because

The spleen the splenic neurons are actually not cholinergic. They use norepinephrine as their primary neurotransmitter. So the the neuro the neurology textbooks, the neuroscience textbooks, they call that a sympathetic neuron. The the splinic nerve is is sympathetic in all the books. But the vagus nerve in this in this work clearly controls the activity of the sympathetic

splenic nerve. And so that overturns dogma, but it's we've proved it and others have replicated this. Inside the spleen, the norepinephrine interact with uh a a lymphocyte uh population that we discovered called TCHAT. They're T cells that express choline acetyl transferase, the the rate limiting enzyme in the biosynthesis of acetylcholine.

And and this is the biochemistry you alluded to earlier. The norepinephrine causes the T cells to make acetylcholine. The acetylcholine interacts with the macrophages in the spleen, in the red pulp. And marginal zones of the spleen. And these macrophages express a receptor for acetylcholine called nicotinic alpha-7 receptors. These are homopentameric receptors. The acetylcholine interacts with the nicotinic receptor, and this causes an ion flux.

And and and that leads to a series of intracellular signal transduction events that essentially turn off the uh uh production of cytokines. And so you have this complicated cascade and and we can we can activate it. U uh in the brainstem with a pulse of laser light that's very, very short. And even a a very short stimulation of those DMV neurons in the origin of the vagus nerve will lead to measurable amounts of norepinephrine and acetylcholine coming out of the splenic vein for hours.

So so what does that mean? It means it's a massive amplification system.

But they're actually in a capacity of healing uh the tissues. And so that's what we see. We're actually seeing in patients with vagus nerve stimulation. We're seeing evidence. that their joints are healing even though the vagus nerve doesn't go to your wrist or your

And they are, could you say they're basically providing some kind of instructions for T cells, for immune cells that are going to tell them how to respond, how strongly to respond, how aggressive to act. Even when they migrate elsewhere in the body, which is why you can have effects throughout the body, even though the vagus nerve might not literally touch every point in the body.

We've seen significant benefits in animal models of multiple sclerosis and those clinical trials are happening in the United States for MS a as we speak. And in all of these cases We the we we th th th the those trials are happening as as we speak.

way um autoimmunity can arise, at least in certain cases, is perhaps your immune cells have been misinformed or instructed inappropriately by the central nervous system via the vagus nerve. Is that kind of where some of this goes?

ranging uh in conditions that range from multiple sclerosis to lupus to rheumatoid arthritis to inflammatory ball disease. It's a it's a it's a global problem. It affects millions and millions of people worldwide. Uh uh in fact Uh no one knows, uh, with with now a few exceptions, no one knows what causes most autoimmune diseases.

In the last few years, uh brilliant work led by Larry Steiman and his colleagues out of Stanford, uh, in California, and and and and another group in Harvard at at Harvard has showed that um mul that multiple sclerosis, this this relapsing condition of of demyelination in the in the central nervous system. That this i is associated with a previous Epstein-Barr virus infection, the virus that causes mononucleosis. And the the the theory is. that not everybody who gets

mononucleosis is going to get multiple sclerosis. In fact, most people, by the time they're adults, h have antibodies against Epstein-Barr virus, evidence of previous infection. But in in some um patients and some people due to uh e either either the the modifications in the chemical background or of their own genetics or of their environmental exposure.

The th the chemist the chemical modifications that occur during the antibody reaction to the virus lead to antibodies that also interact with the central nervous system. And this is um quite likely a major cause of multiple sclerosis, if not in all the multiple sclerosis patients, in many of them. And so th those kinds of insights are still occurring and we don't have those insights for many of the other autoimmune conditions.

But hopefully that understanding will lead to new therapies for MS and maybe someday to to prevent some sort of preventative therapy to prevent future generations from even knowing what MS is. So that's one approach to uh one therapeutic approach to understanding autoimmune disease. uh and and and its cause. Another is to look at how we presently treat uh autoimmune disease complications in people and it's by blocking inflammation.

And so um anti anti TNF antibodies we talked about before were first FDA approved to treat rheumatoid arthritis and inflammatory bowel disease back in the nineteen nineties. And as good as those drugs have been, they reduce inflammation and and and about half of the time patients have significant benefit. We don't really understand why they only work half the time. Nobody knows.

What is different about vagus nerve stimulation? It doesn't just block TNF. So all of the antibodies block whatever target they were designed to block. Anti-TNF blocks TNF. Anti-IL-1 blocks IL1. Anti-IL6 blocks IL6. And they're not. They're almost never used in in combination. So what you end up with is immunosuppression when you use those drugs because you're eradicating one hundred percent of the drug target in the patient getting treated with that with that drug.

That's not how that's not how evolution selected vagus nerve control of inflammation. What we see experimentally and in the clinic now is uh uh vagus nerve stimulation does not block one hundred percent of TNF responses. It blocks 80%. It doesn't block 100% of IL1 responses. It blocks 50%. Right.

that evolution has retained or selected, whatever however um um descriptor you like, uh evolution has retained these vagus nerve mechanisms for millions, if not hundreds of millions of years. Because it doesn't immunosuppress, but it does immunomodulate and it and it prevents the damage of too much inflammation without subjecting us, all of us. To the danger of immunosuppression. Right.

The uh publication describing the clinical trial was just published a few months ago in Nature Medicine. The first author is John Tesser. And what that study showed is that in uh 242, I believe it was, patients with Severe rheumatoid arthritis. These are people who've tried biologic drugs. They either had no response to them or the drugs made them worse or they couldn't afford the drugs.

They the the patients who were intolerant of these drugs or did not benefit from them were eligible for the clinical trial to have a vagus nerve implant placed in their neck. The implant was about this is about the size of a of a Tylenol capsule or a fish oil pill. And it sits deep in the neck. Once it's implanted through a one and a half inch incision, you can't you can't see it or feel it.

It delivers a stimulating current to the vagus nerve for about one minute a day. 400 microamps. Many of the patients slept through the treatment. And this was sufficient to turn on the inflammatory reflex and give people significant clinical benefit despite the fact they were having not having clinical benefit from these powerful, powerful drugs. In fact, at the end of one year of follow up, eighty percent of the patients had had had evidence of significant clinical benefit. So

Is this a is this snake oil? Is this gonna cure everybody from everything? No, of course not. Nobody's saying that. But when you ask those patients who felt they were out of options, how does it feel eighty percent of the time to feel better, you have a lot of very, very happy um people who are interested in this technology today.

Um and this could be a place where we sort of compare and contrast the classic pharmaceutical approach to treating inflammatory conditions versus vagus nerve stimulation and some of the things that you've worked on. Um maybe one hook into this is. You know, as you said, a lot of these drugs will target like one particular factor or, you know, one cytokine or whatever it is, and they'll turn it completely off. Um, but that's a very non-natural way of modulating uh the immune response.

And uh just to give you an anecdote, I was just um I was just visiting relatives. I was somewhere where I was exposed to a lot of commercials, many of which were pharmaceutical commercials. And I would say probably half or more of the ones that I witnessed. were anti-inflammatory drugs of some kind, drugs for rheumatoid arthritis or mild to moderate plaxoriasis. And as you so often see, the side effect list on these were were almost comically long for many of them.

What are give us a sense? You mentioned this at the very beginning, but give us a sense for how widely used anti-inflammatory pharmaceuticals are today, how that connects with. just how pervasive the problem of inflammation is generally, and what sort of the major benefits and then problems and pitfalls of the pharmaceutical anti-inflammatories are.

when you look at the those the uh you know, when you look at a aspirin, aspirin and and Tylenol and and and over the counter products, the people who use those are all technically a anti inflammatory um drugs. And they're used and they're used for pain and they're used for um

uh responses to infection and then and and the flu or the common cold. So When you look at all of those molecules, plus the molecules we're talking about, the biologics which go after the conditions you just listed and that you see advertised on uh uh uh regularly on on on T V uh everywhere. It's an enormous part of the global pharmaceutical market. It may be as much as half of the trillion dollar pharmaceutical industry in one way or another touches or targets um the inflammatory conditions.

Can help the people for whom these drugs are not helping? And this is really the the important question because. w we can we can look at devices that deliver a therapy for one minute a day. Maybe one minute twice a day someday, in a way that has essentially no serious adverse events, no serious side effects. after one year of use. And we know that we can do this safely because we've been doing surgery on the vagus nerve for epilepsy and depression for four decades.

So there when you look at the black box warnings on some of the drugs used to treat inflammation, it gives you pause. The side effects include the possibility of cancer, the possibility of immunosuppression, the possibility of tuberculosis or sepsis. And and I and I have met patients

And I've met the parents of patients who uh are like, I don't want to keep taking these drugs. I want to get pregnant. My doctor says I shouldn't be on these drugs when I get pregnant. I don't want my child who's going off to college to be immunosuppressed and have to take these drugs. I don't want to have to keep injecting myself. with some of these biologic trusts. I have met patients

were bankrupted by the copies for some of these biologics. Uh and then you look at the fact that they only work half the time. My my point of writing the book The Great Nerve was to explain this. Not to throw the pharmaceutical industry and all the people who work on making all these drugs under the bus.

I I've contributed in in helping make some drugs and I contributed directly to some of the first papers on the description of monoclonal anti TNF antibodies. So I th they have helped immeasurable numbers of people. uh for many, many decades. But we need more. And I think that vagus nerve stimulation, immunoregulation by activating uh one of the body's natural reflexes that that's embedded in the vagus nerve.

W is a path forward. We call this field, we call it bioelectronic medicine because it's the tip of the iceberg. The fact that we understand the these vagus nerve mechanisms has allowed us to develop the devices that the FDA has now approved t to to treat rheumatoid arthritis patients. But this is the tip of the iceberg. There's gonna be other devices developed targeting other nerves to other organs for other conditions. And that that's what that's what has my colleagues and I so excited.

It's not about disrupting everybody else. It's about giving hope uh and and and therapeutic options to people for whom the current therapies are not working.

But when it works, these are these can be dramatic effects. You can have people having um sixty seizures an hour, uh, can't leave their home, can't work, uh, going to l having normal lives and getting a driver's license. Um you you y uh the same can be said of uh of depression. That's another condition for which vagus nerve stimulation was approved many decades ago.

And most people don't know about this, uh, which which I find uh quite frustrating actually. Um it again, it only works about half the time. And we don't know why it it works in some people and not others. And But but it but when it works it's it's very important because these many of these patients have have are are completely out of therapeutic options. They've tried talk therapy, they've they've tried all the available medications, they've tried electroconvulsive therapy.

And um some of them are suicidal. Many of them can't take care of of uh of their families or their jobs. And So I'm sorry if you're one of those people have a vacus nerve stimulator and and now you're back at work or you're back with your family and I mean that's a pretty significant i that's a pretty s significant impact on on lifestyle and lifespan.

So that's historically where we have the most experience. The FDA, as I said, approved this approach for rheumatoid arthritis in treatment refractory patients just last August. Um, we at Northwell Health in New York at at my center have implanted, I believe we've implanted eight patients so far. I think we are the United States leaders in uh in implanting patients so far. The responses have been quite favorable. I've I've had the distinct pleasure of meeting a couple of the patients who um

Well, it's a very emotional thing when when you meet someone who tells you they're able to button their blouse and and take care of their children and go back to work after having been unable to do that for years. Um so Nationwide, there are a million and a half patients who are eligible for this according to the current FDA guidelines, meaning treatment refractory rheumatoid arthritis.

And I my understanding is Set Point Medical is doing a phased rollout of the device for um selected centers across the United States. I believe it's about six to begin implanting these. The good news was the Center for Medicaid, Medicare Services in the White House approved this for payment. So that's going to help accelerate adoption.

What are what is this actually what what does like the technology here actually look like that's used for stimulation? Is this some kind of implant and and what is it how does it actually work?

uh an an and and a syllastic cuff. It looks like a peapod. So the so the device sits on the nerve and the and and the cuff holds it in place and then there's one stitch through the cuff itself. And patients come in in the morning for the surgery, go home in the afternoon. Two weeks later they go to the rheumatology office where the rheumatologist

programs the device to turn it on. Like I said before, for about one minute a day, usually four or four or four thirty in the morning. Most patients, as I said, sleep through this. those that wake up sometimes feel a little buzzing in their neck for a minute or so if they um Uh what was really interesting is that the clinical study uh had a placebo arm. So every every subject, every volunteer had the surgery, but only half of them had the electric uh charge turned on. Um

And then they were asked afterwards if they thought they were in the control group or the treated group. And the number of of patients in the placebo group who were not having any electric current in the first part of the study uh being turned on. They they had the same they had the same response rate thinking they felt the current as the treated group did. So it's evidence of a blind, which which is pretty good evidence. And

The device the battery for the device is fully rechargeable. So once a week or so the patient puts a collar uh on which it recharges the battery through the skin. So like when you charge your your f your your your cell phone by putting it on a on an induction coil. In this case the patient puts the induction coil around their neck to charge the the battery on the device. The the battery is M Ri the the device is MRI compatible. and uh doesn't trigger airport um um alarms.

And will be um the label says that it the battery should last ten years or more. The engineers I've spoken to tell me they think this device will last l a lot longer than than than ten years. Got it.

Uh uh when the trial was opened the investigators needed about two hundred and fifty people to participate and the final trial number I believe was two hundred and forty two. But guess how many people tried to enroll in the study online. Take a guess.

uh to to know the questions they should ask their doctor. If you have rheumatoid arthritis and y you're not having a response to your therapy, why don't you ask your doctor some of these questions? The answers are for the patients. And the questions and answers are also for the doctors. Now frankly, most doctors

uh uh uh no matter what their specialty, most doctors haven't thought about the vagus nerve since medical school. It's just not it's just not uh a mainstream kind of problem or topic or or But the but the evidence now uh suggests that a lot more people should know a lot more about it because a uh a lot more opportunities are are are there and a lot more decisions are gonna have to be made and you wanna be informed.

And so I I in my in the book I really I really wanted to give a a baseline vocabulary and and knowledge set. of where where this all came from and where it could go in order in order to provide a a an opening for important dialogues that are gonna happen. I think

I think a lot of people are gonna want this vagus nerve stimulator implanted in the next two years. I think it's gonna take off um for rheumatoid arthritis and I think that's gonna drive the interest in other conditions like multiple sclerosis, inflammatory bowel disease. Um and others.

But there's a lot of stuff out there that's maybe oversimplified or misleading and so on and so forth. When it comes to how people can modulate their own vagus nerve with anti-inflammatory effects in mind. Are there any reliable ways that can be done cheaply or even for free at home by doing things like behavior modification that are available to anyone?

Uh focusing on things in life that you can control, avoiding excessive anxiety. Uh what am I forgetting? The the the the the the healthy lifestyle habits. uh uh are all associated in population studies with lowering resting heart rate. A uh a lower rest or heart resting A lower resting heart rate means that you have increased activity of the vagus nerve fibers, at least the few hundred or so, that are responsible for slowing your heart rate. So you can connect the dots.

Uh and but whether it's semantic or absolute mechanism or not, we we don't know. Because why? Because we don't know. in all those cases, if you're also stimulating the fibers of your vagus nerve that are slowing your inflammation, or is it just a a a sign of overall good health and and and and less inflammatory stimulation because you're doing things through other mechanisms that we don't understand. So do I do those things? Absolutely. I do my best to

to to to eat a balanced diet, get regular exercise, get a get a get get a good night's sleep, try to avoid excessive stress, try to maintain strong social connections. That's the one that I forgot in the last listing of this. And and and those things are all associated with with a lower resting heart rate. Yeah. Huge, huge population studies, whether it's the Framingham study or a or uh even much larger study in France.

of resting heart rate indicate that that's the only predictor of longevity in a population. The population with the slower heartbeats tends to live longer than the population with the faster heartbeats.

And it's and it's the science for which we have exquisite evidence and proof of mechanism that we walked through from the D M V to the spleen to the white blood cells to the acetylcholine to the

Cytokine cascade to the inflamed joint. When you have that kind of mechanistic understanding, you can guide therapy under FDA approved guidelines that it has the potential to help millions of people. And and but when you throw out generalizations and and nonspecific proclamations about this, that, or the other thing for the vagus nerve, you dilute that.

And and my fear is that too much dilution of uh of that nature will actually prevent people from from getting therapies that are that are effective. And uh and may and may have tremendous uh benefits on individual lives. And that's what it's all about. Mm-hmm.

So we keep talking about the hundred thousand fibers on each side. Each of those fibers has different characteristics and and one of the one of the features that is determined by these variable characteristics is how easy or difficult it is to stimulate the fiber with an electric pulse. So here we we got a little lucky. We all got a little lucky because the fibers that are stimulated The fibers that turn off inflammation can be stimulated with a very small amount of electric current.

So 400 microamps is sufficient to stimulate these fibers that stop inflammation to give you a To give you an idea of the range, when when you stimulate the vagus nerve to treat depression or epilepsy, the d those devices deliver up to five milliamps of current. So, um

There's the the th we're look we're there y in order to slow the heart rate you have to put in milliamps of current. But by putting only microamps of current a thousandfold less, now you're you're able to fortunately stimulate the fibers that stop inflammation, but we're not seeing effects on on heart rate or uh or other uh muscle contractions and and other side effects.

So so that's where we are today. Could we could we get to a place of even additional selectivity and specificity? Absolutely. For for that we need better maps. Yeah. My my colleague at the Feinstein Institute. Uh Stavrosanos is leading a a a very large effort.

an NIH uh funded effort to pr produce the fur first detailed maps of the human vagus nerve in history. These the this is based on cadaver dissections from I believe it's ninety-six uh I'm sorry, forty eight cadavers, ninety six vagus nerves, and they're going um um uh a a f a few microns at a time, sectioning the nerve. all along its course it in in in very detailed studies looking at individual cells and their roots and where all of the fibers uh travel.

And they're reassembling all this in uh using using very s sophisticated bioinformatics and computing to provide literally a fiber by fiber uh map. uh of the human vagus nerve. Once once we once that map is complete, we'll be able to go back and overlay function onto each fiber. And with that information, it should be possible someday to build devices the target only the f the fibers that you wanna either stimulate or inhibit uh for condition A, B, C, or D in organ A, B, C, or D.

But they've heard that there may be a role for vagus nerve stimulation and treating their rheumatoid arthritis. So this book is for them, but it's also for people who are curious about lifestyle. What what what is it that we do understand?

where there's strong evidence for for for lifestyle modifications or do it your home or do it do it yourself at home uh insights into the vagus nerve. And so the book has three parts. It has the Uh the the historical stories that g go back to Galen, uh who who was who was intrigued by the vagus nerve and and his work on the vagus nerve two thousand years ago actually was some of the earliest work imp implicating the fact that the brain

was responsible for controlling behavior. Uh and th and and the second part of the book is is really a a deeper dive into how we use vagus nerve stimulation today for for depression, for epilepsy, and and how it works to stop inflammation. And the third part of the book. is really for the the the insights for your for do it yourself and and not so much it's not a cookbook. It's not telling you how how long to hold it there's there's some tips in there but

It it it's not the it's not the answer to hold your breath for one minute or thirty seconds. It explains what happens when you hold your breath for one minute or for thirty seconds. And I and by having a common language of of evidence based explanations. I I think that there'll be a lot of people who will find that interesting.

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