Chapter 1: What is the vagus nerve and why is it important for health?
All right. Well, I am really thrilled for this new Ground Truths live video to welcome a pioneering neurosurgeon who is the CEO of the Feinstein Institute of Medical Research at Northwell, Dr. Kevin Tracy. Kevin, it's great to have you.
It's great to be here, Eric. Thank you for having me on. I'm looking forward to this chat with you.
Yeah, well, 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. Vegas for Latin word for wandering. And this nerve is like the internet throughout the whole body, connecting the brain to everything. And you made a seminal discovery recently.
I think it was back in 1986 with baboons, 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 tumor necrosis factor. And for the first time, you connected the dots. Is that a fair summary of what happened back then?
It is. It is a fair summary of what happened. Back in the 80s, I was part of the team here in a few blocks from where I'm sitting in New York City at Rockefeller and Cornell that identified the biological activity of TNF as a major mediator. He first demonstrated that monoclonal antibodies... targeting TNF could inhibit inflammation.
Now, this was published back in Nature in 1987 in a paper I wrote with my colleagues. And this paper was the first description of monoclonal anti-TNF antibodies as having a therapeutic potential. And of course, today, those antibodies have all kinds of commercial names like Humira and Remicade and and they're related ones for IL-1. And we call the whole thing cytokine storm.
But back when we were doing this work, what we were actually defining was that TNF is sort of the proximal trigger of a cytokine storm. And today that's treated with these monoclonal antibodies. But the real question that remained is if the body has the ability to produce these molecules, cytokines, TNF, other things, that can cause so much damage through inflammation,
then how is it normally controlled? 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 such a big thing because this inflammatory reflex, as you labeled it, I think, really brought together the pathway in the brain this great nerve, vagus nerve, as a mediator of inflammation throughout the body, which sets up a whole lot of ability to hack into this vagus nerve with vagus nerve stimulation. And so you present in the book many anecdotes.
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Chapter 2: How did Dr. Kevin Tracey's research connect the brain and immune system?
What we hadn't planned is that when we put the anti-inflammatory molecule in the brain, and we had developed this molecule in the lab, so it was an experimental drug, when we... Put this in the brains of these animals, it also turned off inflammation in the body. That was the holy shit moment. Like, how could the brain be sending signals to control the immune system?
There was no way in 1998 to explain this. We went into the literature. And I found an old paper, then an old paper, now even older, that had been cited by essentially nobody, that Linda Watkins from Boulder, Colorado, had been studying sickness behavior.
And she showed that when she gave IL-1, a cytokine, of course, into the abdomen of animals, they develop sickness behavior, anorexia, fatigue, behavioral withdrawal, social withdrawal. And when she cut the vagus nerve of those animals, it went away.
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 behind it. I got to thinking maybe when we had put this molecule in the brain of our animals, maybe we had discovered the motor arc of a reflex and Linda had discovered the sensory arc of the reflex.
And so I wrote a hypothesis paper, published it in Nature, called The Inflammatory Reflex. And it turned out to be correct. After 20 years of mechanistic work, we've connected all those dots.
Yeah, no, it's amazing. We're getting 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 the threshold and decades of work is really gathered. But before we do that, You go through some remarkable patient anecdotes in the Great Nerve book.
One that is so striking is Kelly Owens. Can you tell us about her story?
Kelly is a remarkable human being who, as a teenager, was diagnosed with inflammatory bowel disease, Crohn's disease, which was devastating for her. Not only did it put her in and out of the hospital for many, many years, it also forced her to be subjected to use drugs.
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 FDA 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.
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Chapter 3: What is the significance of the FDA approval for vagus nerve stimulation in rheumatoid arthritis?
She was implanted with what I call a Gen 1 vagus nerve stimulator, and we can talk about Gen 1 and Gen 2. And when it was turned on, within two weeks, she felt a lot better. And a couple weeks after that, she was on her way to a follow-up appointment in Amsterdam and saw the elevated triglycerides He gets downstairs 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, especially not run up a flight of stairs. He was used to her not even being able to walk up a flight of stairs. So Kelly, that was about eight years ago. I've been in touch with Kelly many times since.
She worked with us for a while collecting a database of patients who reach out to us interested in this therapy or in clinical trials. And she takes no medications. Her only therapy is the vagus nerve stimulator, which is activated for two or three days. times a day for five minutes. And she asked me once, am I cured?
And I said, well, Kelly, 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 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 symptomatically relieved and takes no medications and is doing great.
Yeah, well, she attributes you to saving her life, and it's pretty impressive. Now, there's another story. I mean, there's so many, but the first person, Pedro, or Piro, who was with rheumatoid arthritis, who was treated with vagal nerve stimulation. Tell us a bit about him.
So Pero lives in Mostar, 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 set up a multicenter study and someone's first somewhere, and it happened to be Pero. So this was back in 2011.
And I got word through Setpoint that Setpoint had launched the trial and flown a neurosurgeon over to do the surgery in Mostar. And I said, can I go meet the patient? And they said, the patient would love to meet you. So it was Thanksgiving week of 2011.
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Chapter 4: What patient anecdotes highlight the effectiveness of vagus nerve stimulation?
I flew over there and learned that the patient had received his Gen 1 vagus nerve stimulator on Labor Day of that year. So the first Monday of September. And he had spent, he told me, years homebound on his couch. He was a young guy at the time. And and had young kids, but he couldn't play with his children, couldn't drive his truck, couldn't work.
And his doctors 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 a couple weeks later. I didn't know until then. Ping pong is huge in Bosnia, apparently.
And he felt so much better playing ping pong, 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 of the swollen knee, 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, I called his doctors, and I spoke to them about a year ago, and he also is doing great. He's taking no medications and has no symptoms. He's driving a truck. He's unloading cargo, and he's in, we would say he's in remission.
You know, it's fantastic. Now, of course, these are anecdotes. 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. We'll put in the links when this is archived. But that trial was impressive because it was done very rigorous with a sham control, hundreds of people in each arm.
And this was in rheumatoid arthritis. So prior to the publication even, the FDA gave approval. This just last year, months ago, for the first time for a inflammatory autoimmune disease, that vagus nerve stimulation was given FDA approval. So can you take us through? This was a big deal. This was a culmination of many decades of effort on your part. Yeah.
Yes, you're absolutely right. My part and the part of hundreds of people in laboratories, my laboratory and other labs around the world, but also hundreds of people who work directly or indirectly with Setpoint, who developed the device for the trial and raised all the money to pay for everything and did all the regulatory work. So, yeah.
It's really important to point out that there's been two clinical trials. The first one was published in the Proceedings of the National Academy of Sciences around 2016. I was a co-author on that. And that was a smaller open-label trial that was led
by Paul Peter Tack and his colleagues at Amsterdam Medical Center under the support and sponsorship of Setpoint Medical and the chief medical officer then was Dr. Ralph Zittnick. Now, my colleague Sangeeta Shivan and I studied the first patients that were implanted at our hospital here at Northwell. Health in New York. And Ash Mehta, the neurosurgeon, implanted these patients.
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Chapter 5: How does vagus nerve stimulation work in treating autoimmune conditions?
So these people were sort of out of options, and they enrolled in the trial. Now, there's a really important point about this. 242 patients made it into the trial. Guess how many created a portal, logged in, and put their information in trying to get into the trial? Probably 1,000, right? It's 30,000. 30,000, wow.
30,000 people tried to enroll in this trial for 250 spots that ended up with 242 patients in the final readout. And the reason is, and this is often overlooked when people talk about these kinds of things, the drugs are invasive.
All the biologics are injected. I mean, my goodness, yeah. And these are very expensive, have just potentially very serious side effects. I mean, you've already run through a couple of the people that were demonstrative of that. So, yeah, I didn't know 30,000. That's amazing. But what is the surgery involved to put in the device?
The device, I'm pulling out here. Surgery involves about an inch and a half incision in the left neck at about the level of the Adam's apple, the larynx, to implant a device that's about the size of a multivitamin. or a fish oil pill. The device sits directly on the vagus nerve at about the level of the carotid pulse. You can feel your pulse.
And it is self-contained with those two shiny things are the leads that sit on the vagus nerve. There is a computer disk, of course. There's an antenna to talk to the doctor's tablet. I always drop it when I'm at the podium, and that's very complicated on stage, Eric. It also has, which is really clever, it sits on the vagus nerve, but it's wrapped in this silastic, 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. How long did that surgery take to put it in? An experienced neurosurgeon will put it in in under an hour, anywhere between a half hour and an hour. It's an in-and-out surgery, outpatient, come in in the morning, go home in the afternoon.
We've been doing them in the hospital, but obviously this will be amenable in the future to a full outpatient standalone facility. Right now, neurosurgeons are being trained by the company In the procedure, and so there's a select group of neurosurgeons who are doing this at select sites. But eventually, again, it's possible. I don't know this. I'm not an insider in Setpoint Medical, the company.
But eventually, I would imagine a time when the implants are brought into other specialties once the expertise has been gained.
Sure. Now, that device gets stimulated a couple times a day.
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Chapter 6: What are the implications of vagus nerve stimulation for conditions like Long Covid and POTS?
How many people in the sham group think they have the active group, think that they're feeling it come on for a minute a day? And it was a small percentage that was almost the exact same percentage of people in the active group who thought they could feel it.
Yeah, yeah.
So it's pretty, there's no perfect control for a procedure like this, obviously, but that's pretty darn close to perfect.
That's impressive. Now, one of the people was asking, what's the name of the device? I mean, it's a VNS, a vagal nerve stimulator. Is there a name to this?
The set point device is called an immunoregulator. And 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 40 years to treat epilepsy and depression.
So the signal, I mean, the devices are different and the signals are different, but the biggest difference we could talk about first is that 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 five milliamps
as opposed to a one-minute duty cycle in 24 hours at three to 400 microamps. Oh, wow. And 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 thousand-fold amplification of the signal, and you have a persistence of the signal that goes on for hours and hours afterwards with neurotransmitter release that suppresses the cytokines.
So one minute gives you 12 hours of protection.
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Chapter 7: What role does heart rate variability play in understanding vagus nerve function?
Has this been tested? That appears to be inflammation directly of the of this nervous system. Has there been any experience with external devices and or this device in pots?
There's been experience, but 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, my review of the literature, I am unable to find for handheld devices applied to the skin, any evidence that any of them directly stimulate the vagus nerve.
So as biomedical engineers, we've tried to do it in my lab and we've tried to do it in volunteers and we've worked with biomedical engineers. If you put electricity on the skin of a human being or a large animal, The vagus nerve in humans, in the neck where you pointed, is deep in the neck. It's wrapped in its own sheath with the carotid artery. It's underneath several layers of fascia.
It's underneath the platysma muscle. It's underneath the skin. Electrocurrent 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 call things vagus nerve stimulators after they've gone through FDA trials, but it doesn't mean they are vagus nerve stimulators.
You're just not going to get it right from an external device, is I think what you're saying. And this is something that has to be right on the vagus nerve.
There's one place the vagus nerve sends a branch to the skin, and that is in the cartilage of the external ear called the simpacantia, which is the part of your ear that looks like a seashell around the open ear, simpacantia.
Now, if you electrically stimulate the Simba concha 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 cartilage. You know why it's there, right? This vagus, it's a vestigial branch of the vagus nerve that used to innervate evolutionarily the cartilaginous gills of fish.
And so it dragged the nerve with it when that cartilage became the cartilage of the external ear. So are you stimulating the vagus nerve when you put electricity on your... Yes, and there's some really interesting, 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 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 fibers. So what does that mean?
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Chapter 8: What future research is needed for vagus nerve stimulation applications?
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 that it didn't work in, back in the early days, the surgeons would say, well, this isn't helping you. Patients like, you're not taking out my device. Surprise, surprising the doctors.
And they asked why? And the patient says, because I feel better. It makes me happy. Based on that, that led to... clinical trials of using vagus nerve stimulation to treat treatment refractory epilepsy, 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 50% of the time, about half. And people say, well, I wish it was more than 50%. 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 the mainstream.
And so 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 wish we had a really better analysis of the cost-benefit ratio because 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 this month. And it's, as you say, 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 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 Attia and others of the bro science.
You should go for cold plunges. And these people are going from cold plunges to hot saunas. There's a diving reflex. What's going on here? Is there anything to cold plunges?
We could talk about this for two hours, Eric. I'm not sure we could do that. I think you have to be really careful when diving. you talk about what we understand about these physiological responses because it's complicated. So maybe we could back up for one second to the vagus nerve.
Many of your listeners are physicians and many of your listeners are scientists and well-versed in all this, but for those that are not, we say vagus nerve, but you have two of them. You have one on each side of your neck. And we say two vagus nerves, but inside of each of them, you have 100,000 fibers. So you have 200,000 vagus nerves, technically.
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