Vagus Nerve Stimulation and the Immune System

All right. Well, I am really thrilled um for this new ground truce. live video to welcome a pioneering neurosurgeon who's the CEO of the Feinstein Institute of Medical Research at Northwell, uh Dr. Kevin Tracy. Kevin, it's great to have you. It's great to be here, Eric. Thank you for having me on. I I'm looking forward to this chat with you.

Yeah, well y your work, which has been going on for decades, culminated in this book, a part of it encapsulated in this book, The Great Nerve. If everybody doesn't know what the great nerve is, it's the Vegas nerve. uh Vegas for word Latin word for wandering and uh this nerve is like the internet throughout the whole body connecting the brain to everything and you made a seminal discovery I think it was back in nineteen eighty six with baboons, this um the idea that up till that time

the brain and the immune system were thought to be in different orbits. They weren't connected, they were firewalled, and you came up with experiments, I think, in baboons and t tumor necrosis factor and for the first time you connected the dots. Is is that a fair summary of what happened back then? It is. I I it is it is a fair summary of what happened. Back in the eighties I was part of the team here in in in a few blocks from where I'm sitting in New York City at Rockefeller and Cornell.

He first demonstrated that monoclonal antibodies Targeting TNF could s could inhibit inflammation. Now, this was published in back in Nature in 1987 in a paper I wrote with my colleague. And this paper was the first description of monoclonal anti T N F antibodies as having a therapeutic potential. And of course today those antibodies have all all kinds of commercial names like Humera and Remicate and

And and they're related ones for IL one and I and we call the whole thing cytokine storm. But back when we were doing this work, what we were actually defining was the TNF is sort of the proximal trigger of a cytokine storm. And today that's treated with with these monoclonal antibodies. But the real question that remained is if if the body has the ability to produce these molecules, cytokines, T N F, other things, that can cause so much damage through inflammation.

then then how is it normally controlled? What what is it that evolution did over millions of years to put the brakes on inflammation and prevent it from causing damage in most of us who are healthy. And that question led to the discovery of the rule of the vagus nerve acting like the brakes on your car to suppress inflammation.

Yeah, so I think this was so such a big thing because this inflammatory reflex as you label it, I think, um, really brought together uh the pathway in the brain, this great nerve, vagus nerve, as a mediator of inflammation throughout the body. uh which sets up a whole lot of ability to hack into this vagus nerve with vagus nerve stimulation.

And so uh you present in the book many anecdotes. Before I get into that, when you made that discovery back in eighty six, uh a lot of people call it a Eureka moment. You called it a holy shit moment. So the the holy shit moment came uh came in in in the nineteen nineties. We Yeah. were we were we were specifically addressing the question um how might the might the brain by by sending signals through the vagus nerve

be turning off inflammation. And and that came about because of an experiment that produced a a big surprise and you could call it an accident in the lab. We we were putting an anti-inflammatory molecule into the brains of mice and rats with the sole purpose of blocking inflammation in the brain in order to reduce the damage of a stroke, an experimental uh infarct.

And that all w went as planned. What what what what we hadn't planned is that when we put the anti inflammatory molecule in the brain and we had developed this this molecule in the lab, so it was an experimental drug, when we put put this in in the brains of these animals, it also turned off inflammation in the body. That was the that was the holy shit moment. Like how could the how could the brain be be sending signals? to control the immune system. There was no no way in nineteen ninety eight

to explain this. We went into the literature and I found an old paper, then then an old paper, now even older, that had been cited by essentially nobody, um, that Linda Watkins uh from Boulder, Colorado, had been studying sickness behavior and she showed that when when she gave I L one a a a cytokine, of course. into the abdomen of animals, they develop sickness behavior, anorexia, fatigue, behavioral withdrawal, social withdrawal.

And and when she cut the vagus nerve of those animals, it went away. Mm-hmm. And so the only way to explain that was that the vagus nerve was sending signals up into the brain that was activating the sickness behavior networks beh W I got to thinking maybe when we had put this molecule in the brain of of our animals

w maybe we had discovered the motor arc of a reflex and Linda had discovered the sensory arc of the reflex. And so so I I wrote a hypothesis paper, published it in Nature called the inflammatory reflex. And Turned out to be be correct after twenty years of mechanistic work we've connected all those dots.

Yeah, no, it's amazing. We're gonna get into the rheumatoid arthritis, both the trial that you did, remarkable trial with the sham control, and the approval by the FDA, which it really tells us that the progress is finally you passed this threshold and decades of work is really gather. But before we do that

You go through some remarkable patient anecdotes, uh, in the Great Nerve book. Um, one that is so striking is Kelly Owens. Can you tell us about her story? Kelly is a uh a remarkable a remarkable human being who as a teenager was diagnosed with inflammatory bile disease, uh uh Crohn's disease. Which uh uh was was devastating for her. Um, not only did it put her in and out of the hospital for many, many years.

It also forced her to be um subjected to you And a whole list of biologic agents like anti TNF we were just talking about, all of which have in common, many of which have in common, they have black box warnings. Which are the most serious side effects that you uh FDA will will label of a drug. I mean the side effects include sepsis, cancer, tuberculosis, fungal infection, and and they're invasive. These biologic drugs are invasive. And in Kelly's case

They didn't help her. Um, some people say she failed the drugs. I I as a physician I never say that. I say the drugs failed the patient. Right, right. And her symptoms, in addition to having GI symptoms, for many years. They also, uh, as can happen in some uh Crohn's patients, they uh it also gave her s a severe form of arthritis and arthropathy, which

intermittently required her to be in and out of wheelchairs and in and out of a cane. And this went on for many, many years. And finally her physicians told her to get used to a life of steroids And Around that point of time, she saw me on Huffington Post Live and and and I was talking about

this vagus nerve story that you've introduced and I was talking about the fact that we were launching through a company that I co founded, the company was launching a clinical trial in Europe, in Amsterdam and in Bosnia and Croatia. Well Kelly and her husband Sean talked their way into that trial somehow. They sold everything, as Kelly says, everything that wasn't tied down in New Jersey, they sold. They did a go fund me sort of.

campaign with friends and family and they moved to to Amsterdam for six months. She was implanted with what I call a gen one vagus nerve stimulator and we can talk about gen one and gen two. And and when it was turned on, within two weeks she felt a lot better and and a couple of weeks after that He gets upstairs and is looking around like where the heck is Sean? And Sean is standing at the bottom of the stairs with tears of joy running down his cheeks because he hadn't seen Kelly run in years.

Uh especially not run up a flight of stairs. So Kelly, that was um about eight years ago. Um I've been in touch with Kelly many times since. Uh she worked with us for a while, collecting a database of of patients who reach out to us. interested in in in this therapy or in clinical trials. And um she takes no medications. Her only therapy is the vagus nerve stimulator, which um sh is activated for two or three um times a day for five minutes. And um she asked me once, am I cured?

And I said, Well, Kelly, that that's a good question, but you're asking the wrong guy. Other than my conflict of interest, I'm not your physician. But it really it really raises the question if readjusting her vagus nerve activity Enabled her nervous system through neuroplasticity to reset the set point on her immune response. And it's an open question. But yes, she is uh she is symptomatically relieved and takes no medications and um is uh is doing great.

Yeah, well she attributes you to saving her life and it's pretty impressive. Now there's another story, I mean of so many but

The first person, uh, Pedro or Piero Drosh uh who was with rheumatoid arthritis, who was treated with um vagal nerve stimulation. Uh tell us a bit about him. So so so Pero was uh lives in uh um most our Bosnia in the Dinaric Alps in the west of Bosnia. And that was a trial site. And as it turned out, as you know, doing clinical trials, you you set up a multi center study and someone's first somewhere, and it happened to be Pero. So this it was back in twenty And I got words.

um through set point, uh, that that Setpoint had launched the trial and flown a neurosurgeon over to do the surgery in in Mostar and that the patient was will and I said, Can I go meet the patient? And they said the patient would love to meet you, so It was ho it was Thanksgiving week of twenty eleven. I flew over there and learned that the patient had received his Gen one vagus nerve stimulator on Labor Day of that year, so the first Monday of September.

And he had spent, he told me, um, years, uh, homebound on his couch. He was a young young guy at the time and And had young kids, but he couldn't play with his children, couldn't drive his truck, uh, couldn't work. And his doctors apologics at that time in Bosnia and so he had not responded to steroids and methotrexate. Well he had a

very significant clinical benefit from his implant, vagus nerve stimulator implant, and was out playing ping pong uh a couple of weeks later. I didn't know in until then ping pong is huge in Bosnia apparently. And uh he felt so much better playing ping pong. He he went out and started playing tennis, promptly injured his knee because he was completely deconditioned from being on the couch for years. So now because the swollen knee

uh impacts your clinical assessment in an arthritis trial. His doctor said, Take it easy, no more sports until the trial is over. So I called in the course of writing this book, The Great Nerve. to them about uh a year ago and he also is doing great. He um he's taking no medications and and has no symptoms. He's driving a truck, he's unloading cargo and he's in as I we would say he's in remicheton. Yeah.

I know it's fantastic. Now, of course these were anecdotes. They're they're really striking. But the real test, of course, the acid test is to do the randomized trial. You did that. It was published in Nature Medicine in December. uh we'll put in the links when this is archived. But that trial was impressive because it was done very rigorous with uh a sham control, hundreds of people in each arm, and this was in rheumatoid arthritis. So Um, prior to the publication even, the FDA gave approval.

uh this just last year, months ago, for the first time for a um inflammatory autoimmune disease, that vagus nerve stimulation was given FDA approval. So Can you take us through this was a big deal. Uh this was uh a culmination of many decades of effort on your part. Yeah. My yes, you're absolutely right. My part and the part of of of hundreds of people in laboratories, my laboratory and other labs around the world, but also hundreds of people

who worked directly or indirectly with Setpoint, who developed the device for the trial and raised the all the money to pay for everything and did and did all the regulatory work. So It's really important to point out that there's been um two clinical trials. The the first one was published in the proceedings of the National Academy of Sciences around twenty sixteen. I was a co author on that. And and that was a smaller open label trial.

That was led by uh Paul Peter Tack and his colleagues at Amsterdam Medical Center uh under the um support Uh in sponsorship upset point medical and the chief medical officer then was Dr. Ralph Zittnik. Now my colleague Sangeita Shavan and I studied the first patients that were implanted at our at our hospital here at Northwell Health in New York.

And Ash Mehta, the neurosurgeon, implanted these patients. And the first question in that first trial 2016 was, if we turn on the vagus nerve stimulator, can we activate the inflammatory reflex? And the answer was yes. When we when we implanted the device, measured uh collected blood before the implant and after the implant, but before it was turned on.

and then collected blood again after the implant was turned on, there was a statistically significant reduction in the T N F ability of the white blood cells of those patients to

to make TNF in response to endotoxin. So that that was really important. And then the open label trial had a positive signal in rheumatoid arthritis. That laid the groundwork for the FDA to grant set point, a breakthrough designation uh which was turns out now to be very important, as you know, uh in in these regulated times. And laid the groundwork for the um labeling trial. If if you're in the drug business, you would call it a phase three equivalent trial.

Uh this is a device. So it's it it's a it's the definitive trial that that was set up as you describe. That that trial I was not a co-author on that trial. That was an independent trial done at 40 sites. Across the United States. It was led by John Tesser from Arizona and by Dave Chernoff from the chief medical officer at Set Point.

The study enrolled, as you said, two hundred and forty-two patients, and all of them had refractory rheumatoid arthritis, which means they were having serious signs and symptoms despite the fact that they tried uh these powerful immunosuppressive drugs we talked about, the biologics or the jack the Jack inhibitors. Um, so these people were sort of out of options, and they they enrolled in the trial. Now, there's a really important point about this. Um

Two hundred and forty two patients made it into the trial. Guess how many uh created a portal, logged in and put their information in trying to get into the trial? Probably thousands, right? thirty thousand. Thirty thousand. Thir thirty thousand people tried to enroll in this trial for two hundred and fifty spots that ended up with two hundred and forty two patients in the final readout. And the reason is

The d and this is often overlooked when people talk about these kinds of things. The drugs are invasive. I mean you've already run through a couple of the people that um were d demonstrative of that. So yeah, I'm not I didn't know thirty thousand. That's amazing. But um what what is the surgery involved to put in the device?

The device um They did I'll pull on out here. Surgery involves a about an inch and a half incision in the left neck at about the level of the Adams apple, the larynx, to implant a device that's about the size of a multivitamin. uh or a fish oil pill. The device s uh sits directly on the vagus nerve at about the level of the carotid pulse. You can feel your pulse.

It is self contained with those two shiny things are the leads that sit on the vagus nerve. There is a uh a computer, a computer disc of course, there's an antenna to talk to the uh the doctor's tablet. I always drop it when I'm at the podium and that's very complicated on stage, Eric. Um it also has um

Which is really clever. Uh it sits on the vagus nerve, but it's wrapped in this this sylastic like a peapod. And so the nerve runs underneath it and then there's a stitch that goes through the top to hold the whole thing in place. that surgery take to put it in? An experienced neurosurgeon will put it in in in in under an hour, anywhere between a half hour and an hour. It's a it's an in and out surgery, outpatient.

Come in in the morning, go home in the afternoon. Um we've been doing them uh in the hospital, but uh yeah obviously this will be amenable in the future to a a full outpatient standalone facility. Right now neurosurgeons are being um trained um by the company In the procedure and so there's a there's a select group of neurosurgeons who are doing this at select sites.

But eventually, uh again I it it's possible I don't know this. I'm not an insider in set point medical, the company, but eventually I would imagine a time when these when the the the implants are brought into other specialties once the expertise has been gained. Sure. Now that device gets stimulated um a couple of times a day. So the device has a a f a rechargeable battery.

So the doctor to start,'cause the FDA has a process for rheumatoid arthritis, the rheumatologist will will program the device to to to turn itself on for one minute a day. It it nothing for the patient to do. The when the current uh is flowing, I've met many many patients They don't feel anything when it's stimulated.

other people. I met a school teacher and and and she was written about in the the New York Times, Dawn, and she told me that it wakes her up in the morning and I said, Oh, that's too bad, four thirty, waking you up at four thirty. She goes, No, I get up early anyways. I don't mind it and for years my alarm I'm a teacher and my alarm would go off at four thirty and I would uh feel the pain in my hands and wrists and I'd start to cry. And now this thing wakes me up with a little tingling.

And I wake up and I have no pain in my hands and I get a big smile on my face to start the day. So she doesn't mind the tingling. Uh well that was good because you had a sham control where you put in the device and half the They of course it wasn't getting any stimulation. It was just the device was in. That's the ultimate control in a device uh randomized trial, right?

That's right. That that's exactly right. And as you know, um the data are all in the nature medicine paper uh that uh John Tesser is the first author. And what what that that was an important factor in the sham controls. How many people in the sham group think they have the active group, think that the that they're feeling it come on for a minute a day. And that it was a small percentage.

That was um almost the exact same percentage of people in the active group who thought they could feel it. Yeah. Yeah. Yeah. So it's pretty there's no there's no perfect control for a for a procedure like this, obviously, but that's pretty darn close to perfect. Oh that that's impressive. Now one of the people was asking what's the name of the device? Is I mean it's v a V and S of a vagal nerve stimulator. Is there a name to this?

The the set point device is called an immunoregulator. Okay. And and they and they it you know, technically it goes on the vagus nerve and puts electric pulses into the vagus nerve. So yes, it's a vagus nerve stimulator, but it's very different. from what's been used for forty years to treat epilepsy and depression.

So the th that that the sign I mean, the devices are different and the signals are different, but the the biggest difference we could talk about first is that the uh the signals that are used to treat epilepsy and depression by historic precedent Those signals are on for five minutes at a time, then off for five minutes, 24 hours a day, 365 days a year. So there's a 12 hour duty cycle at 5 milliamp. As opposed to a one minute duty cycle in twenty four hours at three to four hundred microamps.

Ow. Wow. And the the re the reason is we understand the biology of how the inflammatory reflex down regulates cytokine storm and the one minute activation in the neck. drives signals down into the ganglia of the abdomen, which are relayed into the splenic nerve and the spleen, and at every step in the sequence, From the vagus nerve to the ganglia, from the ganglia to the splenic nerve, from the splenic nerve to the T cells, and from the T cells to the monocytes.

You have this thousandfold amplification of the signal, and you have a persistence of the signal that goes on for hours and hours afterwards of with neurotransmitter release. That suppresses the cytokine. So one minute gives you twelve hours of protection.

Amazing really. One minute a day. Now why don't we have for all autoimmune diseases, why isn't this become a frontline therapy instead of all the drugs? How can I get me to to say all uh all are uh or uh uh uh all for uh all for anything in medicine, right? Nothing's gonna work for everybody all the time. But you're gonna see Yeah. I think you're gonna see a lot more clinical trials. So we've seen very impressive open label trials for inflammatory bile disease. It works.

Uh, we've seen very impressive open label trials in some diabetes uh models and and uh type two diabetes uh Thank you. And and we've seen very impressive um preclinical results in um again diabetes, in multiple sclerosis. Uh we've seen we've seen pilot clinical trials in lupus arthritis. We've seen pilot clinical trials in other inflammatory conditions. So I am agreeing with you a hundred percent.

This is the tip of the iceberg. There's work to do. There's clinical trials to be done. There's there's going to be money to be raised and spent. Um, but I think You're gonna see it happen because patients are gonna demand this. I mean, we talked about the expense of biologics, we talked about their invasiveness, we talked about their immunosuppressive black box warnings. We didn't we left out the fact they only work half the time. So That much actually.

Yeah, forty percent, fifty percent if you're lucky, right? Yeah. So so the the demand is there and I wrote I wrote this book. For the simple reason of establishing a platform of basic information for patients, for doctors, and for family and friends interested in the vagus nerve. that this is what we know to be true in the lab and in the clinic. This is what we know to be false.

And these are the important things that I'm I'm urging my colleagues to double down and work harder on because we've got a lot more to do. I think we're gonna help millions of people.

Well, I think the autoimmune diseases that you just touched on, I mean, they all deserve study. Uh the rheumatoid arthritis results are so uh striking that in refractory people, no less potentially to avoid immunosuppression and all these other side effects. um has a lot of potential. Now one of the questions that one of the um listeners brought up

was about an external device. And that brings me to long COVID. So POTS, as you know very well, postural orthostatic tachycardia syndrome, very uh prominent among people with long COVID. Uh uh along the way there was a company in Canada that was uh an external vagal nerve stimulator. H has it uh has this been tested that that appears to be inflammation directly of the of this nervous system. Um w what has there been any experience with external devices and or this device in pot?

It's um there's been experience but but to m to my review of the literature and I'm speaking to the world's expert on the review of the medical literature, so that makes myself nervous. But That being said, um I my review of the literature, I am unable to find for handheld devices applied to the skin. uh any evidence that any of them directly stimulate the vagus nerve. So as as as b biomedical engineers,

Uh we've tried to do it in my lab and we've tried to do it in volunteers and biomedic we've worked with biomedical engineers. If you put electricity on the skin uh of of a of a human being or a large an animal The vagus nerve in humans in the neck where you pointed is deep in the neck. It's wrapped in its own sh sheath with the carotid artery. It's underneath several layers of fascia. It's underneath the platisma muscle. It's underneath the skin.

Electric current doesn't travel like a laser beam where you point the thing when you put it on your skin. It doesn't work that way. And so it's okay to to call things um vagus nerve stimulators, um after they've gone through FDA trials, um but it doesn't mean they are FDA. That they are at Vegas nerve symmetry. You're just not gonna get it right from an external device, is I think what you're saying. And this is uh something that has to be right. Uh on the on the Vegas.

Right. There's there's one place the vagus nerve sends a branch to the skin, and that is in the the cartilage of the external ear called the cymbaconcha, which is the part of your ear that looks like a seashell around the op Rear Simpaka. Now, if you electrically stimulate the simbaconcia with some sort of device, a tens unit or something, then arguably you've stimulated the vagus nerve.

Because you've stimulated the sensory fibers traveling from that cartil you know why it's there, right? evolutionarily the the cartilage cartilaginous gills of fish. And so it dragged the nerve with it when it when that cartilage became the cartilage of of the external ear. So so are you stimulating the vagus nerve when you when you put electricity um on your symptom? Yes, and there's some really interesting and I and I'm a fan of it, right? There's some really interesting science.

That's been done with brain imaging, fMRIs, far field evoke responses, and you can connect all kinds of dots, but you you can't say it's the same thing that setpoint is doing as putting a device on the vagus nerve to specifically activate vagus nerve fiber.

So what does that mean? It means i if you look at the typical study of a externally used device, whether it's on the neck or the ear, what you see are relatively small numbers of subjects, usually twenty or fifty, usually open label, usually not well controlled. And usually measuring some clinical effect, which often reaches statistical significance. Decreased inflammation, um, increased heart rate variability. This is interesting stuff, Eric, but it doesn't prove the mechanism.

Yeah. It doesn't prove the mechanism and and almost none of it, even some of the some of the trials that have led to FDA approvals for various devices, almost none have been replicated in a way you that would make you comfortable to recommend these things for your practice or would make your your professional societies comfortable recommending it as a as a broad scale thing, meaning they have not been subjected to large, randomized, well controlled, statistically rigorous clinical trials.

I'm not opposed to these things. I I I do it. I I use a tens unit in my ear uh most days because it might work, but but I don't but I don't recommend it to people as a therapy because I'm not sure it does work. How's that?

Yeah, no, I get that. And you know, the you're bringing up the other parts of the story here with the tens device that a lot of people are using for serious pain and um also the fact that this got its start not related to relieving inflammation. But it was back in epilepsy, nineteen eighty eight. VNS was used for epilepsy. And before we got started, you were telling me about how and it's in the book.

uh how people i it helped some people with epilepsy with their seizure control, but the people didn't want to have the device taken out who it wasn't helping. Yeah, so there there's two or three interesting stories here. Um like you I'm a fan of medical history, but the story begins at the end of the nineteenth century when a New York physician started treat treating his patients with epilepsy, serious seizure disorders.

started treating them with like a dog collar like device that he would put around put around the neck of his patients connected to a to a to a Faraday charging uh coil. And so he was shocking these people. They had to be tied down on his exam tape. So that's when this all started. And uh there's some there's some great treatises of of of that of those stories that are out there. And so skip fast forward to the nineteen eighties, as you said, and well, actually right after World War Two.

In Pisa, Italy, a uh a physiologist um worked on an epilepsy model in in his lab, in C I believe it was in Cat. And and show that it i if he electric if he induced seizure activity in the brain of the cats and measured it by EEG, but apply electric current, a l just brief electric pulses to the vagus nerve of those cats, that it would stop the the epileptic spikes. In the nineteen eighties, a a uh uh a Philadelphia neuroscientist patented that, cited that Italian's work in his patent.

And led to the first clinical trials by a company called Cyberonyx. The f the first device was implanted by a neurosurgeon named Bill Bell, who was actually my chief resident when I was an intern here at the New York hospital on Neurosurge. And it turned out to have very significant benefit um Helping some patients who would go from having ten or twenty or fifty seizures an hour to having none or or very few. I mean putting some people who were homebound back at work and out out out Thank you.

And today we don't know why. I pretty much just told you most of the science that we know about vagus nerve stimulation and epilepsy. It seems to work in half the people, but we don't know why. The other half, uh that it didn't work in in this back in the early days, the surgeons would say, Well, this isn't helping you

Well, when I just take it out. The patient's like, You're not taking out my device. Surprised, surprising the doctors and and and they asked why and the patient says,'Cause I feel better. It makes me happy. It makes me f Based on that, that led to Uh clinical trials of using vagus nerve stimulation to treat treatment refractory epilepsy uh sorry, depression patients.

patients who are out of options with talk therapy, patients who are out of options with medical therapy. And as it turns out in years and years of work, it works again about fifty percent of the time, about half

And and people say, Oh, well, I wish it was more than fifty percent. Well, some of the people that have benefited from these vagus nerve implants for treatment resistant depression have gone from being suicidal or unable to care for their families or unable to work to being back in uh uh uh b back back in the mainstream.

And so I I I I wish there was I wish there was a lot more talk about this, Eric. I wish a lot more people knew about this. I wish we knew a lot more about the mechanism and I w I wish we had a had really better analysis of the cost benefit ratio.'Cause I think I think more people should know about this and more should be done. Yeah, I think it's important to point out there the randomized trial in refractory depression

was just published uh this month. Um and it's as you say, uh a half the people derive substantial benefit with severe refractory depression. So this whole idea of hacking the vagus nerve. whether it's to reduce inflammation or maybe not so clear cut as far as the mechanism for benefit, it's pretty striking the diverse um

uh be b beneficial potential use cases, if you will, clinical applications. Now, one of the things that is hot these days, which I don't understand, are cold plunges. You have these people advocating, like, you know, Peter Atia and others of the broscience, you should go for cold plunges. And these people are going from cold plunges to hot saunas. Uh there's a diving reflex. What's going on here? Is there anything too cold? Plunges.

We could talk about this for two hours, Eric. I'm not sure uh we could do that. Um I think you have to be really careful um when You talk about what we understand about these physiological responses, uh, because it's complicated. So maybe we could back up for one second to the Vegas nerve. M many of your many of your listeners are physicians and and

Many of your listeners are scientists and well versed in all this, but for those that are not, we say ver vagus nerve, but you have two of them. You have one on each side of your neck.

Uh, and we say two vagus nerves, but inside of each of them you have a hundred thousand fibers. So you have two hundred thousand vagus nerves, technically, and each and every one of those individual fibers uh was selected for and and and and subjected to evolutionary pressure for millions and millions of years to have a specific origin, a specific destination from the brain to the body or the body to the brain, and to do a specific function.

And the idea when we stimulate in the lab and and with our limited clinical um uh evidence, uh the the the evidence suggests that when when the idea is to control inflammation We're stimulating a few hundred fibers, and that's sufficient to control inflammation. Those are not the same fibers that control your response to the cold. Those are not the same fibers that control the your response to your heart. Those are not the same fibers that control your response to breathing.

So the question is when someone tells me I want to do this, that, or the other thing to stimulate my vagus nerve, I say, oh really, which one are you going to stimulate? And how are you going to do that? That's where it gets complicated. It's incredibly complicated. So cold plunge. You know, everyone remembers their first cold plunge, right?

And and because it's awful. I mean, it might might happen by accident. My brother tricked me in the uh on a on a on a warm spring day. My brother tricked me into running into the freezing cold ocean by s he was standing at his ankles and he told me to do a running dive. And when you go into that fifty degree water, um, you come up and you can't breathe. All the air goes out of your lungs and and you can't inhale. And that is a massive fight or flight response.

That is a massive fight-of-flight response. You have a surge of of epinephrine and norepinephrine, your heart rate goes up, your blood pressure goes up. And that's the opposite, allegedly, of a parasympathetic fighter a rest and digest response. But what happens if you stay in the cold water and you cold adapt? And here, Eric, it's very hard to find well-controlled. Oh, really? Yeah. Clinical studies. I found a few and they're in the book. But but it's very hard. Usually it's uh so military.

type soldiers, um in Iceland or something, or in the in the in in in the Baltic States getting sprayed with water in a cold room and with you know, dressed in a a bathing suit. And Then they give their blood and so there's some data like If you cold adapt to some point for some period of time, uh you will actually feel your heart rate slow down. At which point you can say my my Vegas response has exceeding my fight or flight response. They're both still active, by the way.

But but but let's just say for th that you've tipped from primarily sympathetic to primarily parasympathetic. So okay, now you've stimulated your vagus nerve, but you've done a a a million other things to your nervous system. Yeah. You haven't you haven't put a device on your neck targeting a few hundred fibers to turn off inflammation. Now do the fibers

That that made that that made your blood pressure go up first and then down and your heart rate go up first and then go down. Are those the same fibers that go to your spleen and control inflammation? I don't think so. Does the whole thing act as a on block? everything at once response? I don't think so. I can play the piano and chew gum at the same time, you know? So when you break it down in a sequential way, you can understand why

why people are interested in it. And I do do cold showers several times a week at the end of my regular shower. And the reason is fight or flight, acute controlled fight or flight is anti-inflammatory. We and many others approve that, including Wim Hof, by the way. And increasing vagus activity is anti inflammatory and we prove that. So for me it's a Pascal's wager, right? My doctor says I can I'm okay in cold water. I don't

I mean I hate it for thirty seconds, but then I don't mind it. And it might be good for me. So I do it. But that's but I don't but I don't call it a vagus nerve stimulator.

Right. And a cold shower is different than going into one of these plunges. Um, you know, putting your whole body in there. Wow. I I could not do that. Plus as a cardiologist,

I got patients who if they did that they could have an MI, you know, they they could go into vasospasm and get in big trouble. So and p a lot of people don't even know they have arterial disease. So Um, okay, now another big thing these days about the vagus nerve that people with sensors are measuring, wearables, whether it's a ring or whether it's a mattress sensor or a smartwatch, is heart rate variability.

And they're equating that to, you know, everything. Uh in fact, Chat GPT Health made that like the number one thing about a pr a person's health is how is H R V and Uh, there's an article from the Washington Post about that this week. Anyway, what is your sense about this measurement that has very um z di difficult literature associated with it and obviously has a lot to do with the autonomic nervous system? Well, here we go again, right?

Let's start with what's really easy to understand and I think probably pretty important. So We can't measure the vagus nerve directly in humans. We don't have the technology. Uh we c we can put electrodes in animals and we can measure individual fibers and groups of fibers and we can get a lot of interesting data about how the vagus nerve works by recording its activity in animals.

But we we we don't have this the the tools to do that yet in people. They'll come someday. And there's some experimental tools on the West Coast that are being developed in laboratories. So it'll happen. But until then, the absolute best indicator of a person

or uh or uh or a mammal with increased vagus nerve activity is that their heart rate is slower. And and that that's because One of the branches of the vagus nerve uh that i it goes to the heart and the and the and the fibers traveling in that branch tend to s tend to slow heart rate. So that's im that's interesting and pretty easy to understand. I mean, it doesn't mean if you gargle or hum that you're s stimulating specifically those branches to your heart any more than if you

gargle or hum that you're specifically stimulating the branches to your pancreas or your spleen either. But at least we know there are branches that go to the heart and slow heart rate. So that's interesting. The second thing I find incredibly interesting is back to your your your world.

Uh the Framingham study showed that the single predictor of of longevity in a population was the population with the slowest heart rate lived longer than the population with the fastest heart rate, regardless of other other conditions.

And that study and that exact finding with a few minor tweaks was replicated in the French um study, which was what, four times bigger or something. Tens of thousands of patients. If you had a slower heart rate, Uh i if the the the population with the slower heart rate live longer than the population with the faster heart rate all cause mortality.

So that's interesting. So is it possible that those people with increased vagus activity have uh are protected against inflammation and have less less heart disease? Maybe. It's an interesting hypothesis. It's very hard to study, but it's very interesting. So what if you can't measure it and and heart rate is is confounded by all kinds of things like activity and and stress and other things. So what else can well you can measure heart rate variability. Now heart rate variability

The problem with measuring heart rate variability is comes down to a very simple understanding of what it is. It's it's it's a statistical analysis using things like Fourier transformations. of of individual bits of data, which are the um amounts of time between individual heartbeats. So you're looking at the summation of the individual heartbeats as a statistical phenomenon. And the th the reasoning is

that when the vagus nerve fires, it prolongs the time to the next heartbeat. So you get a you get a longer um duration between heartbeats. And th the more very and because the vagus nerve fires intermittently, um then the m the the more vagus nerve activity you have, then the more variability you will have in the instantaneous heartbeats. That's the fundamental principle of

of of uh the relationship of the vagus nerve to heart rate variability. And it's and it's and in opposition to this, you have the sympathetic input to the heart. accelerating heartbeat, which is also gonna be dependent on activity and your state of mind and stress and whatever else is going on. So what you do with this information and here's where it gets up to now it's easy. Up to now it's easy. What you what you do with this information is subjected to algorithms.

You know, you have a algorithm on your watch, you have a algorithm on your wearable, you have an algorithm on your arm, in your bed, you said. All we don't know what all these algorithms are, they're all proprietary. So Now you go into the billions of web impressions on vagus nerve and heart rate variability, and you come up with a lot of what I find to be um very confusing information that you alluded to.

And here it comes down to what I was pleading for a half hour ago. We we just really need more large, well controlled, well randomized, statistically meaningful clinical trials. to answer specific questions about the relationship of heart rate variability to to health. I I I don't think we have I don't think we have a good understanding of the underlying mechanism.

Yeah, and I think this is why it's so crazy that um the output uh various uh as you say, proprietary algorithm companies uh are giving people information that, you know, your heart rate variability is bad, your stress is up, you know, it may not you know I I know a lot of people using the rings and they they say they're they're constantly in stress because it's for heart rate variability. Well, I d I don't know uh if that's really true, uh but that's of course that kind of output they get.

It's using a measurement uh with um a lot of uncertainty, giving people, you know, health advice. I think we'd like to have more vagal tone. Maybe that's why you take cold showers, but have a good way of measuring it. And I would just submit that HRV, you don't want to hang your hat on that because there's a lot of uncertainties, right?

I think y I think that's very well said. And I I think the b at the end of the day you have you have devices with different algorithms that are all proprietary. So you're you're if you if you have money and you and you wanna spend it on wearable and and you think you're getting it makes you feel better to know your heart rate variability. Great. I'm I'm not it's fine. This is what makes the world go round. People do different things.

Um but I think if you're if you're planning your life's medical course around it, then I I because you think people understand it, then I think that that's that's not right. Then it should be let let let the buyer be let the buyer beware.

You know, one of the things that I like to look at, um, and I like interested in your opinion, w when you do exercise, you get your heart rate, you know, really jacked up. You're doing a good day and how fast do you recover? Th to me that's a more useful because if you if it takes you a long time to get back to your basal heart rate, that's not a very good sign of your autonomic nervous system functionality.

Um, it it it's qualitative, you know, and you'll see maybe some outputs about that. But that to me is a pretty good indicator of of fitness and uh functionality of the of the autonomic nervous system. I don't know if we think that's true. I do think it's true, and I don't think there's a exercise physiologist on the planet who would disagree with you with the importance of the r the recovery to baseline and or the importance of a carefully and well measured VO2 max.

as a as a indicator of of of of uh uh of health. And I think there are various exercise advocates recommending different strategies to get more VO2 Max or to improve your VO two max or to improve your recovery. I'm not expert on that and I I don't know enough about that. That's another Because the VO two max that you get out of a smartwatch is very inaccurate and it's from walking. You know, that's not the same as going to a physiologic lab and getting a tight fit mask and getting the real deal.

And I don't even know if you wanna go bother with that, but yeah, th that's another thing that is being used a lot. Um, not not that that's connected so much with the vagal nerve per se, but these are these are misleading miscues that a lot of people are getting uh regarding their their autonomic nervous system um function. Abs absolutely. I mean and and I did specifically say a a laboratory based, well carefully controlled VO two max test. I don't know how

I don't know how my watch thinks it's getting its VO two m my VO two max when I take a when I walk the dog. I just I don't get that. Yeah. Patients are coming to me say, uh, my VO2 max is dropping. I'm getting really worried. Yeah. But there were less But Eric, Eric, can we talk about the the the far side cartoon with the sheep exercising on the treadmill in New Zealand?'Cause I think it's relevant to this.

Oh. So another, I think, huge um misnomer or misrepresentation by some, uh that when you exercise you turn on fight or flight, true, and you turn off parasympathetic, false. You don't turn off rest and digest when you turn on fight or flight. You don't turn off fight or flight when you turn on rest and digest. This is everywhere on social media and there's no evidence for it. Zero.

I mean, it's a totally subjective thing how you feel. I feel rested and digested. Great. I feel fight or flight. Great. Okay, but that doesn't have anything to do with what is happening in your nerves. And to the proof of this came just a couple of years ago, um, from a study in New Zealand.

where the uh researchers put sheep on a tr on a elevated treadmill and had them run, which I just think is a far side cartoon. I think that is a riot. If Gary Larson hasn't done one and he's listening, he should draw that, right? When the sheep are exercising, what's going on with their autonomic nervous system? And what the results showed is that as you'd expect, when they're jogging along,

The sympathetic fibers, the adrenergic fibers to the heart increase their activity, heart rate goes up, blood pressure goes up. Fine, check the box. When they looked at the vagus nerve and measured the activity, it also went up. And when they when they block that activity, either blocking the nerve with drugs or cutting the nerve.

What happened was the cardiovascular performance of the sheep declined. Cardiac output went down and coronary artery profusion went down. That that means which is what you would expect if you were designing the system. That the fight or flight and the rest and digest are acting in synergy to optimize cardiac output and cardiac function. Which is exactly how you would design it if you were the great designer. That's how you would design it.

Yeah. And that's how and that's how insulin and glucagon work. That's how how clotting and fibroanolysis work. Everything the uh opposing things work together to get a fine balance. And so that that's that's actually a really important point and leads to where you started all this is with pots. In COVID.

What we saw convincing evidence that in some from it be it started with autopsy studies actually of people who died from from COVID in in in Spain, that their vagus nerves were damaged in a number of those people. And so it raises all kinds of important questions where you began this. Um, if you have a vagus a damaged vagus nerve from COVID or some other post viral syndrome or from probably not trauma, if you if you but but if you have th this kind of problem

And the vagus nerve can't work, well there's no evidence that exercise is gonna restore it. There's no there's no exercise that a cold shower is gonna enhance it or fix it. And so it really does come back to a plea for for more research and a plea for more understanding in some who are treating POTS patients. That we don't understand that condition. And it's not a simple on and off necessarily of autonomic, whatever that is, aut on and off between autonomic balance.

But we really should be studying these neural mechanisms underlying POTS because some of those POTS patients may have damage to their vagus nerve and some of those POSP patients may have have damage to their um to their sympathetic nerves. So we we don't know. We don't know. Which could explain ultimately I hope that the study will be done with the device implant, where some people will respond, hopefully. Um and pots can be terribly uh a refractory.

difficult to treat and others might not because of that point you just uh raised. Now, just in wrapping up, um one of my colleagues here got the Nobel Prize for the piezo two receptors. Uh and uh you know, that of course is our Arnib, um Padapushin. Uh that connects with the vagal nerve. the vagus nerve uses the peas I mean the PSO two receptors are everywhere, but that is of course you might want to just comment about bringing those two things together.

Well it's been it's been brilliant work that that he did and and has been celebrated by neuroscientists and now also by immunologists and and physiologists around the world for the for the reasons that you imply. The Nerves are sensitive to vibrations through these receptors. And uh we and others are now using focused ultrasound to um w w which is a a form of ultrasound very similar, slightly different, but very similar to what is used to visualize a

A fetus in the womb, or gall stones, or or kidney stones. And this focus ultrasound can be used to go through the skin and through the tissues. And and in in contrast to a a TENS unit which stimulates and sends electricity across the skin and in all different pla directions and places, the focused ultrasound can be focused, as his name says, and you can focus it on on the vagus nerve in the liver or on the vagus nerve controlling the splenic nerve in the spleen.

And as I said, we and others are are looking at this as a way to uh vibrate or activate these nerves with a non-invasive device. These are still early days, but my colleague who who runs the lab with me at the Feinstein Institute, Sangita Chavan, and our other colleague Stavrosanos, they just a couple of years ago published a paper in brain stimulation.

Showing that you can use focused ultrasound to activate the inflammatory reflex in human volunteers. And when they did this, they they they they suppressed.

inhibited cytokine storm in these volunteers using a painless noninvasive ultrasound handheld probe. You could you could imagine a a day and time they've also done it Sangita and Thomas Huerta and others in in n uh in in my lab have also done these experiments in obese animals and shown that by activating the vagus nerve with focus ultrasound you can normalize insulin resistance and blood glucose.

y you can decrease food intake and you can accelerate uh body weight loss in obese uh cafeteria fed uh mice and rats. And so the question is, can we can we learn from from these kinds of approaches to target the vagus nerve in metabolic conditions.

that may or may not be similar to or the same as targeting the vagus nerve for immunological conditions. There's there's tremendous I mean, you said it in the very beginning. What's so exciting about this, Eric, is that I'm not I'm not uh uh I'm not pushing s snake oil here or or or selling anything. Uh Yeah. that can be subjected to experiments and and to clinical trials. And and the challenge we have now

is is and sometimes this is the hardest challenge in science, isn't doing the experiments anymore and we've got all the technology certainly. The hardest challenge is asking the right question. What would be the what would be the clinical trials we could do now that would have the biggest impact? And what would be the mechanistic experiments we could do in the lab now that would get us faster into more clinical trials? That's what has me excited. That's what keeps me up at night.

Well, I mean I think uh just to pull it together, uh, you really deserve tremendous credit, Gavin, for uh uh bringing in the field of um uh the inflammatory reflex using uh a uh device that could be implanted that could knock down inflammation, as we've seen for autoimmune diseases, first one out of the block proven.

rheumatory arthritis, many more to come, likely inflammatory bowel disease and and and many others. But what you've also, I think, confronted, it's taken you decades to do this, because we live in a world of pharmaceutical Bye. And pharmaceutical companies, you know, they the the device companies that are trying to do this stuff are you know like the Rodney Dangerfields, you know, they don't get a lot of funding. They have struggle Yeah. Well,

Oh many years, it's a big slog. But I have to say, you know, if I had an autoimmune disease, i I if I had to take a drug that would mock knock down my immune system and put me in some risk versus having a an hour outpatient implant you know, I might take the implant, right? So the pro the problem is, you know, there we don't have enough interest in this bioelectronic treatment. And it's partly because the device industry

uh, you know, overall has a tougher mission. And you in a s in a way have proven that, that look, you you had this hypothesis nailed twenty, thirty years ago, and it's only taken until twenty twenty five to finally have an FDA, you know, indication and a a first, you know, tier, first

r uh rate uh randomized sham control trial. So I thought I'd just get you to comment on what's it like to try to advance a hypothesis in the world of devices because it just seems to be a much bigger um uh obstacle. I I have to say there were plenty of times when I could have quit uh in that thirty years, as you say. But the reason I I don't quit is the same reason you haven't. I mean, we we meet our patients, they need something.

And every every patient I've ever asked about this option has said, if it works, I want it. And and the and and the d and we have data now. We have thirty thousand people who tried to get into the trial for two hundred and forty two spots. So patients want this. You know, I I've been very lucky. I have a thousand scientific co-authors. And if and if you wrote and if

thirty years, but it's two thousand people that you work with over over thirty years in order to get in order to get this thing to happen. And so I'm sitting here talking to you and all along the way I've I've enjoyed this. I mean the the I love doing science. I love

you know, waking up in the middle of the night thinking maybe that experiment today will help this patient tomorrow. And y you know, I'm I'm the luckiest guy to be able to do what what I what I get to do. The patients are the ones that that are the heroes, they they don't choose to have the disease. And they sign up for clinical trials. I mean, they sign up and say, Yes, doctor, you can implant this thing in my neck and

So yeah, uh it's been it's been a long ride. There is the the There is um there is now the opportunity, I think, um, under Set Point Medical's leadership with this new immunoregulator to turn the tables on what you said on the pharma industry dominance. I mean I'm sorry, Eric, if you and I were inventing anti TNF tomorrow.

Oh, we go to the FDA and say we got a drug that's cost$100,000 a year. It's gonna have black box warnings. Some people are gonna die from it. Oh, and it's invasive, it only works forty percent of the time. What do you think the FDA would say to us with those drugs today? They would say, get out. So there's an opportun there's an opportunity now for these devices to to rewrite the book. Yeah, up until the GLP one, Ozempe, uh EMIR and the TNF blockers were the biggest drugs in the world for sale.

Uh it shows you how big a deal uh autoimmune diseases are, uh the burden in in in our population. So anyway, I I just want to say, you know, the book is is uh if phenomenal, but what's even more impressive, Kevin, is that you persevere. And you tested the hypotheses and you led to a um breaking out of f a new field. And I just think it's in the early days. I think there's gonna be a lot more autoimmune diseases

Uh, we're already seeing the uh randomized trial and refractory depression and other areas. So anyway, congrats. It's fun to discuss this with you. I um I learned a lot a and uh I know everyone else uh who joined today did as well. We'll post this with all the links that we've been talking about. and uh hopefully we'll have a chance to revisit all this progress uh in the times ahead. So thanks very much, Kevin.

Eric, thank you for having me on. Thank you for all you do to make the world more informed about science and medicine. It makes it a better place. We're grateful to you. Well, thank you. Keep up the great stuff. Bye bye now. Thanks everyone for joining. And uh we'll get this out soon.