Dr. Jack Feldman: Breathing for Mental & Physical Health & Performance

Andrew Huberman:

Welcome to The Huberman Lab podcast, where we discuss science and science-based tools for everyday life.

Andrew Huberman:

I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. Jack Feldman. Dr. Jack Feldman is a distinguished professor of neurobiology at the University of California, Los Angeles. He is known for his pioneering work on the neuroscience of breathing.

Andrew Huberman:

We are all familiar with breathing and how essential breathing is to life. We require oxygen, and it is only by breathing that we can bring oxygen to all the cells of our brain and body. However, as the work from Dr. Feldman and colleagues tells us, breathing is also fundamental to organ health and function at an enormous number of other levels. In fact, how we breathe, including how often we breathe, the depth of our breathing and the ratio of inhales to exhales actually predicts how focused we are, how easily we get into sleep, how easily we can exit from sleep.

Andrew Huberman:

Dr. Feldman gets credit for the discovery of the two major brain centers that control the different patterns of breathing. Today, you'll learn about those brain centers and the patterns of breathing they control and how those different patterns of breathing influence all aspects of your mental and physical life. What's especially wonderful about Dr. Feldman and his work is that it not only points to the critical role of respiration in disease, in health, and in daily life, but he's also a practitioner. He understands how to leverage particular aspects of the breathing process in order to bias the brain to be in particular states that can benefit us all.

Andrew Huberman:

Whether or not you are a person who already practices breathwork, or whether or not you're somebody who simply breathes to stay alive, by the end of today's discussion, you are going to understand a tremendous amount about how the breathing system works and how you can leverage that breathing system toward particular goals in your life. Dr. Feldman shares with us his own particular breathing protocols that he uses, and he suggests different avenues for exploring respiration in ways that can allow you, for instance, to be more focused for work, to disengage from work in high stress endeavors, to calm down quickly. And indeed he explains not only how to do that, but all the underlying science in ways that will allow you to customize your own protocols for your needs.

Andrew Huberman:

All the guests that we bring on the Huberman Lab podcast are considered at the very top of their fields. Today's guest, Dr. Feldman, is not only at the top of his field, he founded the field. Prior to his coming into neuroscience from the field of physics, there really wasn't much information about how the brain controls breathing. There was a little bit of information, but we can really credit Dr. Feldman and his laboratory for identifying the particular brain areas that control different patterns of breathing and how that information can be leveraged towards health, high performance and for combating disease.

Andrew Huberman:

So today's conversation, you're going to learn a tremendous amount from the top researcher in this field. It's a really wonderful and special opportunity to be able to share his knowledge with you, and I know that you're not only going to enjoy it, but you are going to learn a tremendous amount. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is however, part of my desire and effort to bring zero-cost-to-consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast.

Andrew Huberman:

One quick mention before we dive into the conversation with Dr. Feldman. During today's episode, we discuss a lot of breathwork practices, and by the end of the episode, all those will be accessible to you. However, I'm aware that there are a number of people out there that want to go even further into the science and practical tools of breathwork, and for that reason I want to mention a resource to you. There is a cost associated with this resource, but it's a terrific platform for learning about breathwork practices and for building a number of different routines that you can do or that you could teach. It's called Our Breathwork Collective. I'm not associated with the Breathwork Collective, but Dr. Feldman is an advisor to the group, and they offer daily live guided breathing sessions and an on-demand library that you can practice anytime, free workshops on breathwork. And these are really developed by experts in the field, including Dr. Feldman.

Andrew Huberman:

So as I mentioned, I'm not on their advisory board, but I do know them and their work, and it is of the utmost quality. So anyone wanting to learn or teach breathwork could really benefit from this course, I believe. If you'd like to learn more, you can click on the link in the show notes or visit ourbreathcollective.com/huberman and use the code Huberman at checkout. And if you do that, they'll offer you $10 off the first month. Again, it's ourbreathcollective.com/huberman to access the Our Breath Collective. And now for my conversation with Dr. Jack Feldman. Thanks for joining me today.

Jack Feldman:

It's a pleasure to be here, Andrew.

Andrew Huberman:

Yeah, it's been a long time coming. You're my go-to source for all things respiration. I mean I breathe on my own, but when I want to understand how I breathe and how the brain and breathing interact, you're the person I call.

Jack Feldman:

Well, I'll do my best. As you know, there's a lot that we don't understand, which still keeps me employed and engaged, but we do know a lot.

Andrew Huberman:

Why don't we start off by just talking about what's involved in generating breath, and if you would, could you comment on some of the mechanisms for rhythmic breathing versus nonrhythmic breathing?

Jack Feldman:

Okay, so on the mechanical side, which is obvious to everyone, we want to have airflow in, inhale, and we need to have airflow out. And the reason we need to do this is because for body metabolism, we need oxygen, and when oxygen is utilized through the aerobic metabolic process, we produce carbon dioxide. And so we have to get rid of the carbon dioxide that we produce, in particular because the carbon dioxide affects the acid-base balance of the blood, the pH, and all living cells are very sensitive to what the pH value is. So your body is very interested in regulating that pH. So we have to have enough oxygen for our normal metabolism, and we have to get rid of the CO2 that we produce.

Jack Feldman:

So how do we generate this airflow? Well, the air comes into the lungs. We have to expand the lungs, and as the lungs expand, basically it's like a balloon that you would pull apart. The pressure inside that balloon drops and air will flow into the balloon. So we put pressure on the lung to pull it apart. That lowers the pressure in the air sacks called alveoli, and air will flow in because pressure outside the body is higher than pressure inside the body.

Jack Feldman:

When you're doing this expansion, when you're inhaling, what produces that? Well, the principle muscle is the diaphragm, which is sitting inside the body just below the lung. And when you want to inhale, you basically contract the diaphragm, and it pulls it down and as it pulls it down, it's inserting pressure forces on the lung. The lung wants to expand. At the same time, the ribcage is going to rotate up and out and therefore expanding the cavity, the thoracic cavity.

Jack Feldman:

At= the end of inspiration, under normal conditions when you are at rest, you just relax and it's like pulling on a spring. You pulled on a spring, and you let go and it relaxes. So you inhale and you exhale. Inhale, relax, and exhale.

Andrew Huberman:

So the exhale is passive?

Jack Feldman:

At rest, it's passive. We'll get into what happens when you need to increase the amount of air you're bringing in because your ventilation, your metabolism, goes up like during exercise. Now the muscles themselves, skeletal muscles don't do anything unless the nervous system tells them to do something. And when the nervous system tells them to do something, they contract. So there are specialized neurons in the spinal cord and then above the spinal cord, the region called the brain stem, which go to respiratory muscles, in particular, for inspiration, the diaphragm and the external intercostal muscles in the ribcage, and they contract. So these respiratory muscles, these inspiratory muscles, become active, and they become active for a period of time. Then they become silent, and when they become silent the muscles then relax back to their original resting level.

Jack Feldman:

Where does that activity in these neurons that innervate the muscle, which are called motor neurons, where does that originate? Well, this was a question that's been bandied around for thousands of years, and when I was a beginning assistant professor, it was fairly high priority for me to try and figure that out because I wanted to understand where this rhythm of breathing was coming from, and you couldn't know where it was coming from until you knew where it was coming from. I didn't phrase that properly. You couldn't understand how it was being done until you know where to look.

Jack Feldman:

So we did a lot of experiments, which I can go into detail, and finally found there was a region in the brain stem that's, once again, this region sort of above the spinal cord, which was critical for generating this rhythm. It's called the pre-Bötzinger complex, and we could talk about how that was named. This small site which contains, in humans, a few thousand neurons, it's located on either side and works in tandem. And every breath begins with neurons in this region beginning to be active. And those neurons then connect ultimately to these motor neurons going to the diaphragm and to the external intercostals causing them to be active and causing this inspiratory effort. When the neurons in the pre-Bötzinger complex finish their burst of activity, then inspiration stops, and then you begin to exhale because of this passive recall of the lung and ribcage.

Andrew Huberman:

Could I just briefly interrupt you to ask a few quick questions ...

Jack Feldman:

Of course.

Andrew Huberman:

... Before we move forward in this very informative answer? The two questions are, is there anything known about the activation of the diaphragm and the intercostal muscles between the ribs as it relates to nose versus mouth breathing, or are they activated in the equivalent way regardless of whether or not someone is breathing through their nose or mouth?

Jack Feldman:

I don't think we fully have the answer to that. Clearly there are differences between nasal and mouth breathing at rest. The tendency is to do nasal breathing because the air flows that are necessary for normal breathing is easily managed by passing through the nasal cavities. However, when your ventilation needs to increase, like during exercise, you need to move more air. You do that through your mouth because the airways are much larger than, and therefore you can move much more air. But at the level of the intercostals and the diaphragm, their contraction is almost agnostic to whether or not the nose and mouth are open.

Andrew Huberman:

So if I understand correctly, there's no reason to suspect that there are particular, perhaps even nonoverlapping sets of neurons in pre-Bötzinger area of the brain stem that trigger nasal versus mouth inhales?

Jack Feldman:

No, I would say that it's not that the pre-Bötzinger complex is not concerned and cannot influence that, but it does not appear as if there's any modulation of where the air is coming from, whether it's coming through your nasal passages or through your mouth.

Andrew Huberman:

Great, thank you. And then the other question I have is that these intercostal muscles between the ribs that move the ribs up and out, if I understand correctly, and the diaphragm, are those skeletal, or as the Brits would say, skeletal muscles or smooth muscles. What type of muscle are we talking about here?

Jack Feldman:

As I said earlier, these are skeletal. I didn't say they were skeletal muscles, but they're muscles that need neural input in order to move. You talked about smooth muscles; they're specialized muscles like we have in the gut and in the heart, and these are muscles that are capable of actually contracting and relaxing on their own. So the heart beats. It doesn't need neural input in order to beat. The neural inputs modulate the strength of it and the frequency, but they beat on their own. The skeletal muscles involved in breathing need neural input.

Jack Feldman:

Now there are smooth muscles that have an influence on breathing, and these are muscles that are lining the airways. And so the airways have smooth muscle, and when they become activated, the smooth muscle can contract or relax. And when they contract inappropriately is when you have problems breathing, like in asthma. Asthma is a condition where you get inappropriate constriction of the smooth muscles of the airways.

Andrew Huberman:

So there's no reason to think that in asthma that the pre-Bötzinger, or these other neuronal centers in the brain that activate breathing, that they are involved or causal for things like asthma.

Jack Feldman:

As of now, I would say the preponderance of evidence is that it's not involved, but we've not really fully investigated that.

Andrew Huberman:

Thank you. Sorry to break your flow, but I was terribly interested in knowing answers to those questions and you provided them, so thank you.

Jack Feldman:

Now remind me again where I was.

Andrew Huberman:

Were just landing in pre-Bötzinger, and we will return to the naming of pre-Bötzinger because it's a wonderful and important story, really, that I think people should be aware of. But maybe you could march us through the brain centers that you've discovered and others have worked on as well that control breathing pre-Bötzinger, as well as related structures.

Jack Feldman:

Okay. So when we discovered the pre-Bötzinger, we thought that it was the primary source of all rhythmic respiratory movements, both inspiration and expiration. The notion of a single source is like day or night. It's like they all have the same origin, that the earth rotates, and day follows night. And we thought that the pre-Bötzinger complex would be inhalation, exhalation.

Jack Feldman:

And then in a series of experiments we did in the early part of 2000, we discovered that there seemed to be another region which was dominant in producing expiratory movements. That is the exhalation. We had made a fundamental mistake with the discovery of the pre-Bötzinger, not taking into account that at rest, expiratory muscle activity, or exhalation, is passive. So if that's the case, a group of neurons that might generate active expiration, that is to contract the expiratory muscles like the abdominal muscles of the internal intercostals, are just silent. We just thought it wasn't there. It was coming from one place. But we got evidence that in fact it may have been coming from another place. And following up on these experiments, we discovered that there was a second oscillator, and that oscillator is involved in generating what we call active expiration, that is this active ...

Andrew Huberman:

Like, if I go, "Shh."

Jack Feldman:

Yeah, or when you begin to exercise and you have to go, "Ha, ha," and actually move that air out, this group of cells which is silent at rest suddenly becomes active to drive those muscles, and it appears that it's an independent oscillator.

Andrew Huberman:

Maybe you could just clarify for people what an oscillator is.

Jack Feldman:

Okay, an oscillator is something that goes in a cycle. So you can have a pendulum as an oscillator going back and forth. The earth is an oscillator because it goes around and it's day and night.

Andrew Huberman:

Some people's moods are oscillating.

Jack Feldman:

And it depends how regular they are. You can have oscillators that are highly regular that are in a watch, or you can have those that are sporadic or episodic. Breathing is one of those oscillators that, for life, has to be working continuously 24/7. It starts late in the third trimester because it has to be working when you're born and basically works throughout life. And if it stops, if there's no intervention beyond a few minutes, it will likely be fatal.

Andrew Huberman:

What is this second oscillator called?

Jack Feldman:

Well, we found it in a region around the facial nucleus. So when this region was initially identified, we thought it was involved in sensing carbon dioxide. It was what we call a central chemoreceptor. That is, we want to keep carbon dioxide levels, particularly in the brain, at a relatively stable level because the brain is extraordinarily sensitive to changes in pH. If there's a big shift in carbon dioxide, there will be a big shift in brain pH, and that'll throw your brain, if I can use the technical term, out of whack. And so you want to regulate that, and the way to regulate something in the brain is you have a sensor in the brain. And others basically identified that the ventral surface of the brain stem, that is the part of the brain stem that's on this side, was critical for that. And then we identified a structure that was near the trapezoid nucleus. It was not named in any of these, nor anatomical atlases. So we just picked a name out of the hat, and we called it the retrotrapezoid nucleus.

Andrew Huberman:

I should clarify for people, when Jack is saying trapezoid, he doesn't mean the trapezoid muscles. Trapezoid refers to the shape of this nucleus, this cluster of neurons. Perifacial makes me think that this general area is involved in something related to mouth or face. Is it an area rich with neurons controlling other parts of the face — eye blinks, nose twitches, lip curls, lip smacks?

Jack Feldman:

If you go back, in an evolutionary sense, and a lot of things that are hard to figure out begin to make sense when you look at the evolution of the nervous system. When control of facial muscles, going back to more primitive creatures because they had to take things in their mouth for eating, so we call that the face, sort of developed. The eyes were there, the mouth is there. These nuclei that contain the motor neurons, a lot of the control systems for them developed in the immediate vicinity.

Jack Feldman:

So if you think about the face, there's a lot of subnuclei around there that had various holes at various different times in evolution. And at one point in evolution, the facial muscles were probably very important in moving fluid in and out of the mouth and moving air in and out of the mouth. And so part of these many different subnuclei now seems to be, in mammals, to be involved in the control of expiratory muscles.

Jack Feldman:

But we have to remember that mammals are very special when it comes to breathing, because we're the only class of vertebrates that have a diaphragm. If you look at amphibians and reptiles, they don't have a diaphragm, and the way they breathe is not by actively inspiring and passively expiring. They breathe by actively expiring and passively inspiring because they don't have a powerful inspiratory muscle. And somewhere along the line the diaphragm developed, and there are lots of theories about how it developed. I don't think it's particularly clear. There was something you can find in alligators and lizards that could have turned into a muscle that was the diaphragm.

Jack Feldman:

The amazing thing about the diaphragm is that it's mechanically extremely efficient, and what do I mean by that? Well, if you look at how oxygen gets from outside the body into the bloodstream, the critical passage is across the membrane in the lung. It's called the alveolar capillary membrane. The alveolus is part of the lung, and the blood runs through capillaries, which are the smallest tubes in the circulatory system. And at that point oxygen can go from the air-filled alveolus into the blood.

Andrew Huberman:

Which is amazing. I find that amazing, even though it's just purely mechanical, the idea the way these little sacks in our lungs, we inhale and the air goes in and, literally, the oxygen can pass into the bloodstream.

Jack Feldman:

Passes into the bloodstream, but the rate at which it passes will depend on the characteristics of the membrane, what the distance is between the alveolus and the blood vessel, the capillary. But the key element is the surface area. The bigger the surface area, the more oxygen that can pass through. It's entirely a passive process. There's no magic about making oxygen go in.

Jack Feldman:

Now how do you get a, pack a large surface area in a small chest? Well you start out with one tube, which is the trachea. The trachea expands. Now you have two tubes. Then you have four tubes, and it keeps branching. At some point at the end of those branches, you put a little sphere, which is an alveolus. And that determines what the surface area is going to be.

Jack Feldman:

Now you then have a mechanical problem; you have the surface area. You have to be able to pull it apart. So imagine you have a little square of an elastic membrane. It doesn't take a lot of force to pull it apart. But now if you increase it by 50 times, you need a lot more force to pull it apart. So amphibians who were breathing, not by compressing the lungs and then just passively expanding it, weren't able to generate a lot of force. So they have relatively few branches. So if you look at the surface area that they pack in their lungs relative to their body size, it's not very impressive. Whereas when you get to mammals, the amount of branching that you have is you have four to 500 hundred million alveoli.

Andrew Huberman:

How, if we were to take those four to 5 million-

Jack Feldman:

Hundred million, four to 500 hundred million,

Andrew Huberman:

Hundred million, excuse me, and lay those out flat, what sort of surface area are we talking about?

Jack Feldman:

About 70 square meters, which is about a third the size of a tennis court. So you have a membrane inside of you a third the size of a tennis court that you actually have to expand every breath. And you do that without exerting much of a ... You don't feel it. And that's because you have this amazing muscle, the diaphragm, which, because of its positioning, just by moving two thirds of an inch down, is able to expand that membrane enough to move air into the lungs.

Jack Feldman:

Now at rest, the volume of air in your lungs is about two and a half liters. Do we need to convert that to quarts?

Andrew Huberman:

No.

Jack Feldman:

Right? It's about two and a half liters. When you take a breath, you're taking another 500 milliliters, or half a liter. That's the size of my fist. So you're increasing the volume by 20%, but you're doing that by pulling on this 70-square-meter membrane. But that's enough to bring enough fresh air into the lung to mix in with the air that's already there, that the oxygen levels in your bloodstream goes from a partial pressure of oxygen, which is 40 millimeters of mercury to a hundred millimeters of mercury. So that's a huge increase in oxygen, and that's enough to sustain normal metabolism. So we have this amazing mechanical advantage by having a diaphragm.

Andrew Huberman:

Do you think that our brains are larger than that of other mammals in part because of the amount of oxygen that we have been able to bring into our system?

Jack Feldman:

I would say a key step in the ability to develop a large brain that has a continuous demand for oxygen is the diaphragm. Without a diaphragm, you're an amphibian. And there's another solution to increasing auction uptake, which is the way birds breathe, but birds have other limitations and they still can't get brains as big as mammals have.

Jack Feldman:

So the brain utilizes maybe 20% of all the oxygen that we intake, and it needs it continuously. The brain doesn't want to be neglected. So this puts certain demands on breathing system. In other words, you can't shut it down for a while, which poses other issues. You're born and you have to mature. You have the small body, you have a small lung, you have a very pliant rib cage. And now you have to develop into an adult which has a stiffer rib cage, and so there are changes happening in your brain and your body where breathing, the neural control of breathing, has to change on the fly. It's not like for things like vision where you have the opportunity to sleep, and while you're sleeping, the brain is capable of doing things that are not easy to do during wakefulness, like the construction crew comes in during sleep. The change in breathing have been described as trying to build an airplane while it's flying.

Andrew Huberman:

Basically what Jack is saying is that respiration science is more complex and hardworking than vision science, which is a direct jab at me that some of you might have missed, but I definitely did not miss. And I appreciate that you always take the opportunity like a good New Yorker to give me a good healthy intellectual jab.

Andrew Huberman:

A question related to diaphragmatic breathing versus nondiaphragmatic breathing, because the way you describe it, the diaphragm is always involved. But over the years, whether it be for yoga class, or a breathwork thing, or you hear online that we should be breathing with our diaphragm. That rather than lifting our ribcage when we breathe and our chest, that it is healthier, in air quotes, or better somehow, to have the belly expand when we inhale. I'm not aware of any particular studies that have really examined the direct health benefits of diaphragmatic versus nondiaphragmatic breathing, but if you don't mind commenting on anything you're aware of as it relates to diaphragmatic versus nondiaphragmatic breathing, whether or not people tend to be diaphragmatic breathers by default, et cetera, that would be, I think, interesting to a number of people.

Jack Feldman:

Well, I think by default we are obligate diaphragm breathers. There may be pathologies where the diaphragm is compromised and you have to use other muscles, and that's a challenge. Certainly at rest, other muscles can take over, but if you need to increase your ventilation, the diaphragm is very important. It would be hard to increase your ventilation otherwise.

Andrew Huberman:

Do you pay attention to whether or not you are breathing in a manner where your belly goes out a little bit as you inhale? Because I can do it both ways. I can inhale, bring my belly in, or I can inhale, push my diaphragm and belly out, not the diaphragm out. And that's interesting, right? Because it's a completely different muscle set for each version.

Jack Feldman:

Well, in the context of things like breath practice, I'm a bit agnostic about the effects of some of the different patterns of breathing. Clearly some are going to work through different mechanisms, and we can talk about that. But at a certain level, for example whether it's primarily diaphragm or you move your abdomen or not, I am agnostic about it. I think that the changes that breathing induces in emotion and cognition, I have different ideas about what the influence is, and I don't see that primarily as which particular muscles you are choosing. But that just could be my own prejudice.

Andrew Huberman:

Okay, and we will return to that as a general theme in a little bit. I want to ask you about sighing. One of the many great gifts that you've given us over the years is an understanding of these things that we call physiological sighs. Could you tell us about physiological sighs? What's known about them, what your particular interest in them is, and what they're good for?

Jack Feldman:

Very interesting and important question. So everyone has a sense of what a sigh is. Certainly, when we're emotional in some ways, we're stressed, we're particularly happy, we'll take a little sigh. It turns out that we're sighing all the time, and when I would ask people who are not particularly knowledgeable, that haven't read my papers or James Nestor's book or listened to your podcast, they're usually off by two orders of magnitude about how frequently we sigh, on the low side. In other words, they say, "Oh, once an hour. 10 times a day."

Jack Feldman:

We sigh about every five minutes, and I would encourage anyone who finds that to be an unbelievable fact is to lie down in a quiet room and just breathe normally, just relax, just let go and just pay attention to your breathing, and you'll find that every couple of minutes you're taking a deep breath and you can't stop it. It just happens.

Jack Feldman:

Now why? Well, we have to go back to the lung again. The lung has these 500 million alveoli, and they're very tiny. They're 200 microns across, so they're really tiny. And you can think of them as fluid filled. They're fluid lined. And the reason they're fluid lined has to do with the esoterica of the mechanics of that. It makes it a little easier to stretch them with this fluid line, which is called surfactant. And surfactant is important during development. It is a determining factor when premature infants are born. If they do not have lung surfactant, then it makes it much more challenging to take care of them than after they have lung surfactant, which is sometime, if I remember correctly, in the late second, early third trimester, which it appears.

Jack Feldman:

In any case, it's fluid lined. Now think of a balloon that you would blow up, but now, before you blow it up, fill the balloon with water. Squeeze all the water out, and now when you squeeze all the water out, you notice the sides of the balloon stick to each other. Why is that? Well, that's because water has what's called surface tension. And when you have two surfaces of water together, they actually tend to stick to each other. Now, when you try and blow that balloon up, you'll notice, if you've ever done it before, that the balloon is a little harder to inflate than if it were dry on the inside. Why is that? Because you have to overcome that surface tension.

Jack Feldman:

Well, your alveoli have a tendency to collapse. There's 500 million of them. They're not collapsing at a very high rate, but it's a slow rate that's not trivial. And when an alveolus collapses, it no longer can receive oxygen or take carbon dioxide out. It's sort of taken out of the equation.

Jack Feldman:

Now if you have 500 million of them and you lose 10, no big deal. But if they keep collapsing, you can lose a significant part of the surface area of your lung. Now a normal breath is not enough to pop them open, but if you take a deep breath, it pops them open-

Andrew Huberman:

Through nose or mouth.

Jack Feldman:

Doesn't matter. It's just increased that lung volume because you're just pulling on the lungs. They'll pop open about every five minutes. And so we're doing it every five minutes in order to maintain the health of our lung.

Jack Feldman:

In the early days of mechanical ventilation, which was used to treat polio victims who had weakness of their respiratory muscles, they'd be put in these big steel tubes, and the way they would work is that the pressure outside the

Jack Feldman:

And the way they would work is that the pressure outside the body would drop, that would put an expansion pressure on the ribcage. The ribcage would expand and then the lung would expand, and then the pressure would go back to normal and the lung and ribcage would go back to normal. This was great for getting ventilation, but there was a relatively high mortality rate. It was a bit of a mystery, and one solution was to just give bigger breaths. They'd get bigger breaths and the mortality rate dropped. And it wasn't until, I think it was the '50s, where they realized that they didn't have to increase every breath to be big. What they needed to do is every so often, they need to have one big breath. So you have a couple of minutes of normal breaths, and then one big breath, just mimicking the physiological sighs. And then the mortality rate drops significantly.

Jack Feldman:

And if you see someone on a ventilator in the hospital, if you watch, every couple of minutes, then you'll see the membrane move up and down. Every couple of minutes, there'll be a superbreath, and that pops it open. So there are these mechanisms for these physiological sighs. So just like with the collapse of the lungs, where you need a big pressure to pop it open, it's the same thing with alveola. You need a bigger pressure and a normal breath is not enough, so you have to take a big inhale. And what nature has done is instead of requiring us to remember to do it, it does it automatically, and it does it about every five minutes. And one of the questions we want to ... we asked is, how is this happening? Why every five minutes? What's doing it?

Jack Feldman:

And we got into it through a back door, typical of the way a lot of science gets done. There's a serendipitous event where you run across a paper and something clicks, and you just follow it up. Sometimes you go down blind ends, but this turned out to be incredibly productive. One of the guys in my lab was reading the paper about stress, and during stress, lots of things happen in the body. One of which is that the hypothalamus, which is very reactive to body state, releases peptides, which are specialized molecules, which then circulate throughout the brain and body. That particular effect's usually to help deal better with the stress. And one class of the peptides that release are called bombesin-related peptides.

Jack Feldman:

And he also realized because he was a breathing guy that when you stress, you sigh more. So we said, "All right, maybe they're related." Bombesin is relatively cheap to buy. We said, "Let's buy some bombesin, throw it in the brain stem. Let's see what happens." And one of the nice things about some experiments that we try to design, is to fail quickly. So here we had the idea. We fill bombesin in, and if bombesin did nothing, nothing lost. Maybe $50 to buy the bombesin. But if it did something, it might be of some interest. So we, one afternoon, he did the experiment.

Jack Feldman:

And he comes to me, he says ... I won't quote exactly what he said, because that might need to be censored, but he said, "Look at this." And it was in a rat. Rats sigh about every two minutes. They're smaller than we are, and they need to sigh more often. Their sigh rate from went from 20 to 30 per hour, to 500 per hour when he put bombesin into the pre-Bötzinger complex.

PART 1 OF 4 ENDS [00:35:04]

Andrew Huberman:

Amazing.

Jack Feldman:

And the way he did that is he took a very, very fine glass needle and anesthetized a rat, and inserted that needle directly into the pre-Bötzinger complex. So it wasn't a generalized delivery of the peptide, it was localized to the pre-Bötzinger, and the sigh rate went through the roof.

Andrew Huberman:

And I would add that that was an important experiment to deliver the bombesin directly to that site because one could have concluded that the injection of the bombesin increased sighing because it increased stress rather than directly increased sighing.

Jack Feldman:

Yeah. Amongst hundreds of other possible interpretations. So the precision here is very important. And that goes back to what I said at the very beginning. Knowing where this is happening allows you to do the proper investigations. If we didn't know where the inspiratory rhythm was originating, we never could have done this experiment. And so then we did another experiment. We said, "Okay, what happens if we take the cells in the pre-Bötzinger that are responding to the peptide?" So neurons will respond to a peptide because they have specialized receptors for that peptide. And not every neuron expresses those receptors. In the pre-Bötzinger complex is probably a few hundred out of thousands. So we used the technique we had used before, and this is a technique developed by Doug Lappe, down in San Diego, where you could take a peptide and conjugate it with a molecule called saporin. Saporin is a plant-derived molecule which is a cousin to ricin. And many of your listeners may have heard of ricin.

Andrew Huberman:

It's a ribosomal toxin.

Jack Feldman:

Right? It's very nasty. It's, a single stab with an umbrella will kill you, which is something that supposedly happened to a Bulgarian diplomat by a Russian operative on a bridge in London. He got stabbed. And the way ricin works is it goes inside a cell, crosses the cell membrane, goes inside a cell, kills the cell, and then it goes to the next cell and then the next cell and then the next cell. It's extremely dangerous. In fact, it's firstly impossible to work on in a lab in the United States. They won't let you touch it.

Andrew Huberman:

Ricin?

Jack Feldman:

Ricin.

Andrew Huberman:

Because we've worked with saporin many times.

Jack Feldman:

Saporin is safe because it doesn't cross cell membranes. So you get an injection of saporin, it won't do anything because it stays outside of cells.

Andrew Huberman:

Please, nobody do that, even though it doesn't cross cell membranes. Please, nobody inject saporin, whether or not you are an operative or otherwise.

Jack Feldman:

Thank you, Andrew for protecting me there. But what Doug Lappe figured out is that when a ligand binds to a receptor, there's, when a molecule binds to its receptor, in many cases that receptor-ligand complex gets pulled inside the cell. So it goes from the membrane, the cell, inside the cell.

Andrew Huberman:

So you can't go to the dance alone, but if you're coupled up, you get in the door.

Jack Feldman:

That's right. So what he figured out is he put saporin to the peptide, the peptide binds to its receptor, it gets internalized, and then when it's inside the cell, saporin does the same thing that ricin does. It kills the cell, but then it can't go into the next cell. So the only cells that get killed, or the more polite term "ablated," are cells that express that receptor. So if you have a big conglomeration of cells, you have a few thousand, and only 50 of them express that receptor, then you inject the saporin conjugated to the ligand, to the peptide, and only those 50 cells die. So we took bombesin conjugated to saporin, injected into pre-Bötzinger complex of rats. And it took about a couple days for the saporin to actually ablate cells. And what happened is that the mice started sighing less and less, excuse me, the rats started sighing less and less and less and less and essentially stopped sighing.

Andrew Huberman:

So your student, or postdoc, was it? Murdered the cells, and as a consequence, the sighing goes away. What was the consequence of eliminating sighing on the internal state or the behavior of the rats? Well, did they, in other words, if one can't sigh, generate physiological sighs, what is the consequence on state of mind? You would imagine that carbon dioxide would build up more readily or more to higher levels in the bloodstream and that the animals would be more stressed. That that's the kind of logical extension of the way we set it up.

Jack Feldman:

It was less benign than that. When the animals got to the point where they weren't sighing, then, and we did not determine this, but the presumption was that their lung function significantly deteriorated. And their whole health deteriorated significantly, and we had to sacrifice them. So I can't tell you whether they was stressed or not, but their breathing got to be significantly deteriorated that we sacrificed them at that point. Now we don't know whether that is specifically related to the fact they didn't sigh or that there was secondary damage due to the fact that some cells die. So we never determined that. Now, after we did this study, to be candid, it wasn't a high priority for us to get this out the door and publish it, so it stayed on the shelf. Then I got a phone call from a graduate student at Stanford, Kevin Yackle, who starts asking me all these interesting questions about breathing, and I'm happy to answer them, but at some point it concerned me because he was working for a renowned biochemist who worked on lung in Drosophila fruit flies. Mark Krasnow.

Andrew Huberman:

Yeah, my next door colleague,

Jack Feldman:

Right? Yeah. And I said, "Why are you asking me this?" And he said, "I was an undergraduate at UCLA, and you gave a lecture on my undergraduate class, and I was curious about breathing ever since." So that's when those things, which as a professor you love to hear, that actually is something you really affected the life of a student.

Andrew Huberman:

When you birthed a competitor, but you had only yourself to blame.

Jack Feldman:

No, I don't look at that as a competitor. I think that there's enough interesting things to go on. I know some of our neuroscience colleagues say, "You can work on my lab, but then when you leave my lab, you got to work on something different."

Andrew Huberman:

No one I ever trained with said that. It's open field. You want to work on something, you hop in the mix.

Jack Feldman:

Yeah. But there are people like that, neuroscientists like that; I never felt like that.

Andrew Huberman:

I hear that their breathing apparati are disrupted, and it causes a brain dysfunction that leads to the behavior you just described. That's actually not true. But in terms of the ... Before you, we talk about the beautiful story with Yackle and Krasnow and Feldman lab, I want to just make sure that I understand. So if physiological sighs don't happen, basically breathing overall suffers.

Jack Feldman:

Well, that would go back to the observations in polio victims in these iron lungs, where the principle deficit was there was no hyperinflation of the lungs, and they, many of them deteriorated and died.

Andrew Huberman:

And just to stay on this one more moment before we move to what you were about to describe, we hear often that people will overdose on drugs of various kinds because they stop breathing. So barbiturates, alcohol combined with barbiturates, is a common cause of death for drug users and contraindications of drugs, and these kinds of things. You hear all the time about celebrities dying because they combined alcohol with barbiturates. Is there any evidence that the sighs that occur during sleep or during states of deep, deep relaxation and sedation, that sighs recover the brain? Because you could imagine that if these sighs don't happen, as a consequence of some drug impacting these brain centers, that could be one cause of basically asphyxiation and death.

Jack Feldman:

If you look at the progression of any mammal to death, you find that their breathing slows down, a death due to, quote, natural causes. Their breathing slows down, it will stop and then they'll gasp. So we have the phrase "dying gasp," super large breaths. They're often described as an attempt to autoresuscitate, that as you take that super deep breath and that maybe it can kickstart the engine again. We do not know the degree to such things as gasp are really sighs that are particularly large. And so if you suppress the ability to gasp in an individual who is subject to an overdose, then whereas they might been able to arouse their breathing, if that's prevented, they don't get rearoused. So that is certainly a possibility. But this has not been investigated. I mean one of the things that I'm interested in is in individuals who have diseases which will affect pre-Bötzinger complex, and there's data in Parkinson's disease and multiple system atrophy, which is another form of neurodegeneration where there's loss of neurons in pre-Bötzinger. And the question is, and it also may happen in ALS, sometimes referred to as Lou Gehrig's disease and amyotrophic lateral sclerosis; these individuals often die during sleep.

Jack Feldman:

We have an idea, that we have not been able to get anyone to test, is that patients with Parkinson's, patients with MLS typically breathe normally during wakefulness. The disturbances that they have in breathing is during sleep. So Parkinson's patients at the end stages of the disease often have significant disturbances in their sleep pattern, but not during wakefulness. And we think that what could be happening is that the approximate cause of death is not heart failure, is that they become apneic; they stop breathing and don't resuscitate. And that resuscitation may or may not be due to an explicit suppression of sighs, but to an overall suppression of the whole apparatus or the pre-Bötzinger complex.

Andrew Huberman:

Got it. Thank you. So Yackle calls you up.

Jack Feldman:

So he calls us, calls me up, and he's great kid, super smart, and he tells me about these experiments that he's doing where he's looking in a database to try and find out what molecules are enriched in regions of the brain that are critical for breathing. So we and others have mapped out these regions in the brain stem, and he was looking at one of these databases to see what's enriched. And I said, "That's great, will you be willing to share our work together?" And he says, "No, my advisor doesn't want me to do that." So I said, "Okay." But Kevin's a great kid and I enjoyed talking to him and he's a smart guy. And what I found in academia is that the smartest people only want to hire people smarter than them and only want and have the preference to interact with people smarter than them. The faculty who are not at the highest level.

Jack Feldman:

And at every institution there's a distribution. There're ones above the mean, and those below the mean, those whom below the mean are very threatened by that. And I saw Kevin as a shining light, and I didn't care whether he was going to outcompete me because whatever he did was going to help me in the field. So I did wherever I can to help, to work with Kevin. So at one point I got invited to give grand rounds in neurology at Stanford. Turns out an undergraduate student who had worked with me was now head of the training program for neurologists at Stanford. Then he invited me. And at the end of my visit, I go to Mark Krasnow's office and Kevin is there and a postdoc [inaudible 00:52:59] who was also working on a project was there. And towards the end of the conversation, Mark says to me, "We found this one molecule which is highly concentrated in an important region for breathing." And I said, "Oh, that's great. What is it?" And he says, "I can't tell you because we want to work on it." So, of course I'm disappointed, but I realize that the ethic in some areas of science, or the custom in some areas of science, is that until you get a publication, you be relatively restricted in sharing the information.

Andrew Huberman:

Mark and I are going to have a chat when I come back.

Jack Feldman:

Okay. All right. Well he may remember the story differently, but I said, "Okay." And as I'm walking out the door, I remember these experiments I described to you about bombesin, and that was the only unusual molecule we're working in. So the reason I'm rushing out the door is I have a flight to catch. So I stick my head in, I said, "Is this molecule related to bombesin?" And then I run off. I don't even wait for them to reply. I get to the airport, Mark calls me and he says, "Bombesin, the peptide we found is related to bombesin. What does it do?" And I said, "I'm not telling."

Andrew Huberman:

Oh my. And I'm so glad I wasn't involved in this collaboration.

Jack Feldman:

No, no. But that was sort of a tease. Because I said, "Well, let's work together on this." And then we worked together on this-

Andrew Huberman:

A prisoner's dilemma at that point. Yeah. So Kevin Yackle is spectacular, has his own lab at UCSF. And the work that I'm familiar with from Kevin is worth mentioning now, or I'll ask you to mention it, which is this reciprocal relationship between brain state, where we could even say emotional state, and breathing. And I'd love to get your thoughts on how breathing interacts with other things in the brain. You've beautifully described how breathing controls the lungs, the diaphragm, and the interactions between oxygen and carbon dioxide, and so forth. But as we know, when we get stressed, our breathing changes. When we're happy and relaxed, our breathing changes. But also if we change our breathing, we in some sense can adjust our internal state. What is the relationship between brain state and breathing? And if you would, because I know you have a particular love of one particular aspect of this, what is the relationship between brain rhythms, oscillations, if you will, and breathing?

Jack Feldman:

This is a topic which has really intrigued me over the past decade. I would say before that, I was in my silo just interested about how the rhythm of breathing is generated and didn't really pay much attention to this other stuff. For some reason I got interested in it. And I think it was triggered by an article in The New York Times about mindfulness. Now, believe it or not, although I had lived in California for 20 years at that time, I'd never heard of mindfulness.

Jack Feldman:

It's staggering how isolated you could be from the real world. And I googled it, and there was a mindfulness institute at UCLA and they were giving courses in meditation. So I said, "Oh, this is great because I can now see whether or not the breathing part of meditation has anything to do with the purported effects of meditation." So I signed up for the course, and as I joked to you before, I had two goals. One was to see whether or not breathing had an effect, and the other was to levitate. Because I grew up in all these kung fu things, and all the monks could levitate when they meditated. So why not?

Jack Feldman:

We have a motto in the lab. You can't do anything interesting if you're afraid of failing. And if I failed to levitate, well at least I tried and I should tell you now, I still haven't done it yet. But I haven't given up.

Andrew Huberman:

Yet.

Jack Feldman:

Yet. I haven't given up. So I took this course in mindfulness and it became apparent to me that the breathing part was actually critical. It wasn't simply a distraction or a focus. They could have had you move your index finger to the same effect, but really believe that the breathing part was involved. Now, I'm not an unbiased observer. So the question is how can I demonstrate that. I didn't feel competent to do experiments in humans. And I didn't feel like I designed the right experiments in humans, but I felt maybe I can study this in rodents. So we got this idea that we are going to teach rodents to meditate, and that's laughable. But we said, "But if we can, then we can actually study how this happens." So believe it or not, I was able to get a sort of a startup grant, an R21 from NCCIH, that's the National Complementary Medicine Institute.

Andrew Huberman:

A wonderful institute, I should mention; our government puts major tax dollars toward studies of things like meditation, breathwork, supplements, herbs, acupuncture. This is, I think, not well known. And it's an incredible thing that our government does that. And I think it deserves a nod and more funding.

Jack Feldman:

I totally agree with you. I think that it's the kind of thing that many of us, including many scientists, think is too "woo woo" and unsubstantiated. But we're learning more and more. We used to laugh at neuroimmunology, that the nervous system didn't have anything to do with the immune system. And pain itself can influence your immune system. I mean, there are all these things that we're learning that we used to dismiss. And I think there's, there's real nuggets to be learned here. So they went out in the limb and they funded this particular project, and now I'm going to leap ahead because for three years we threw stuff up against the wall that didn't work. And recently we had a major breakthrough. We found a protocol by which we can get mice to breathe slowly, awake mice to breathe slowly. I won't tell you.

Andrew Huberman:

Normally they don't breathe slowly.

Jack Feldman:

No. In other words, whatever their normal breath is, we could slow it down by a factor of 10, and they're fine doing that. So we could do that for 30 minutes a day for four weeks, like a breath practice.

Andrew Huberman:

Do they levitate?

Jack Feldman:

We haven't measured that yet. I would say a priori. We haven't seen them floating to the top of their cage, but we haven't weighed them. Maybe they weigh less. Maybe levitation is graded. And so maybe if you weigh less, it's sort of partial levitation. In any case, we then tested them, and we had control animals, mice, where we did everything the same except the manipulation we made did not slow down their breathing, but they went through everything else. We then put them through a standard fear conditioning, which we did with my colleague Michael Fanselow, who's one of the real gurus of fear. And we measured, a standard test is to put mice in a condition where their concerned they'll receive a shock, and their response is that they freeze, and the measure of how fearful they are is how long they freeze. This is well validated, and it's way above my pay grade to describe the validity of the test.

Jack Feldman:

But it's very valid. The control mice had a freezing time, which was just the same as ordinary mice would have. The ones that went through our protocol froze much, much less. According to Michael, the degree to which they were showed less freezing was as much as if there was a major manipulation in the amygdala, which is a part of the brain that's important in fear processing. It's a staggering change. The problem we have now is the grant ran out of money. The postdoc working on it left, and now we have to try and piece together everything, but the data is spectacular.

Andrew Huberman:

Well, I think it's, I'll just pause you for a moment there because I think that, you know, you're talking about a rodent study, but I think the benefits of doing rodent studies are that you can get deep into mechanism. And for people that might think, "Well, we've known that meditation has these benefits, why do you need to get mechanistic science?" I think that one thing that's important for people to remember is that, first of all, as many people as one might think are meditating out there or doing breathwork, a far, far, far greater number of people are not, right? I mean, the majority of people don't take any time to do dedicated breathwork nor meditate. So whatever can incentivize people would be wonderful. But the other thing is that it's never really been clear to me just how much meditation is required for a real effect. Meaning a practical effect.

Andrew Huberman:

People say 30 minutes a day, 20 minutes a day, once a week, twice a week. Same thing with breathwork. Finding minimum or effective thresholds for changing neural circuitry is what I think is the holy grail of all these practices. And that's only going to be determined by the sorts of mechanistic studies that you describe. So this is wonderful. I do hope the work gets completed, and we can talk about ways that we can ensure that that happens. But-

Jack Feldman:

Let me add one thing to what you're saying, Andrew. One of the issues I think for a lot of people is that there's a placebo effect that is in humans. They can respond to something even though the mechanism has nothing to do with what the intervention is. And so it's easy to say that the meditative response has a big component, which is a placebo effect. My mice don't believe in the placebo effect. And so if we could show there's a bonafide effect in mice, it is convincing in ways that no matter how many human experiments you did, the control for the placebo effect is extremely difficult in humans; in mice, it's a nonissue. So I think that in of itself would be a enormous message to send.

Andrew Huberman:

Excellent and indeed a better point. I think a 30-minute-a-day meditation in these mice, if I understand correctly, the meditation, we don't know what they're thinking about.

Jack Feldman:

Well, it's breath practice, really.

Andrew Huberman:

Right. So it's breath practice. So they're, because we don't, presumably they're not thinking about their third eye center, lotus position, levitation, whatever it is, they're not instructed as to what to do. And if they were, they probably wouldn't do it anyway. So 30 minutes a day in which breathing is deliberately slowed or is slowed relative to their normal patterns of breathing. Got it. What was the frequency of sighing during that 30 minutes? Unclear.

Jack Feldman:

We don't know yet. Okay. Well no, we have the data. We just, we're analyzing the data.

Andrew Huberman:

To be determined, or to be announced at some point. So the fear centers are altered in some way that creates a shorter fear response to a foot shock. What are some other examples that you are aware of from working your laboratory or work in other laboratories, for that matter, about interactions between breathing and brain state or emotional state?

Jack Feldman:

So this gets back to our prior conversation. I sort of went off on that tangent. I think we need to think separately of the effect of volitional changes of breathing on emotion versus the effect of brain state on breathing. So the effect of brain state on breathing, like when you're stressed, is a effect presumably originating in higher centers, if I can use that term, affecting breathing. It's, the reciprocal is that when you change breathing, it affects your emotional state. I think of those two things as different that may ultimately be tied together. So there's a landmark paper published in the '50s where they stimulate it in the amygdala of cats. And depending on where they stimulated, they got profound changes in breathing. There's every pattern of breathing could possibly imagine. They found a site in the amygdala which could produce that. So there's clearly a powerful descending effect coming from the amygdala, which is a major site for processing emotion, fear, stress and whatnot that can affect breathing.

Jack Feldman:

And clearly we have volitional control over breathing. So we have profound effects there. Now I should say about emotional control over breathing, I need to segue into talking about locked-in syndrome. Locked-in syndrome is a devastating lesion that happens in a part of the brain stem where signals that controlled muscles are transmitted. So the fibers coming from your motor cortex go down to this part of the brain stem, which is called the ventral pons. And if there's a stroke there, it can damage these pathways. What happens in individuals who have locked-in syndrome is they lose all volitional movement except lateral movement of the eyes and maybe the ability to blink. The reason they're able to still blink and move their eyes is that those control centers are rostral, or closer to, are not interrupted. In other words, the interruption is below that. They continue to breathe because the centers for breathing don't require that volitional command. In any case, they're below that. So they're fine.

Jack Feldman:

So these people continue to breathe, normal intelligence, but they can't move. There's a great book called "The Diving Bell and the Butterfly" about a young man who had ... this happens to, and he describes his life and it's a real testament to the human condition that he's ... does this. It's a remarkable book, It's a short book.

Andrew Huberman:

Did he write the book by blinking to his translator?

Jack Feldman:

He did it by blinking to his caretaker. It's pretty amazing. And there was a movie, which I've never seen with Javier Bourdain as the protagonist, but the book, I highly recommend this to anyone to read. So I had colleagues studying an individual had locked-in syndrome, and this patient breathes very robotically, totally consistent, very regular. They gave the patient a low oxygen mixture to breathe. Ventilation went up, a CO2 mixture to breathe, ventilation went up. So all the regulatory apparatus for breathing was there. They asked the patient to hold his breath or to breathe faster. Nothing happened. Just, the patient recognized the command but couldn't change it. And all of a sudden the patient's breathing changed considerably. And they said to their patient, "What happened?" They said, "You told the joke. And I laughed."

Jack Feldman:

And they went back. Whenever they told the joke that the patient found funny, the patient's breathing pattern changed. And your breathing pattern when you laugh is inhale. You go, "Haha haha." But it's also very distinctive. We have some neuroscience colleagues, who will go unnamed, who if you heard them laugh 50 yards away, you know exactly who they are. Yeah.

Andrew Huberman:

Well I'll name him. Eric Kandel.

Jack Feldman:

For one.

Andrew Huberman:

Has an inspiratory laugh. Yeah, he's famous for a [inaudible 01:09:59] As opposed to a haha.

Jack Feldman:

Exactly. exactly. So the it's very ...

Jack Feldman:

Exactly.

Andrew Huberman:

Yeah.

Jack Feldman:

So it's very stereotyped, but it's maintained in these people who lose volitional control of breathing. So there's an emotive component controlling your breathing, which has nothing to do with your volitional control, and it goes down to a different pathway because it's not disrupted by this locked-in syndrome. If you look at motor control of the face, we have the volitional control of the face, but we also have emotional control of the face, which most of us can't control. So when we look at another person, we're able to read a lot about what their emotional state is. And that's a lot about how primates, humans, communicate. And you have people who are good deceivers. Probably used car salesmen, poker players, or now poker players have tells. But many of them now wear dark glasses, because a lot of the tells you blink or whatnot.

PART 2 OF 4 ENDS [01:10:04]

Andrew Huberman:

Pupil sizes.

Jack Feldman:

Pupil size. Pupil size is a tell, which is an autonomic function, not a skeletal muscle function. But we have all these skeletal muscles which we're controlling, which give us away. I've tried to get my imaging friends to image some of the great actors that we have in Los Angeles.

Andrew Huberman:

You mean brain imagers?

Jack Feldman:

Brain imagers.

Andrew Huberman:

Yeah.

Jack Feldman:

I'm sorry.

Andrew Huberman:

No, that's all right.

Jack Feldman:

Yeah, brain images, because I think when I ask you to smile, I could tell that you're not happy, that you're smiling because I asked you to smile.

Andrew Huberman:

I think you're about to crack a joke, but we're all friends.

Jack Feldman:

No, I'm not ... When you see a picture, like at a birthday and whatnot and say "cheese," you could tell that at least half of the people are not happy they're saying cheese. Whereas a great actor, when they're able to dissemble, in the fact that they're sad or they're happy, you believe it. They're not faking it. That's great acting. And I don't think everyone could do that. I think that the individuals are able to do that, have some connection to the parts of their emotive control system that the rest of us don't have. Maybe they develop it through training and maybe not. But I think that this can be imaged. So I would like to get one of these great actors in an imager and have them go through that, and then get a normal person and see whether or not they can emulate that.

Jack Feldman:

And I think you're going to find big differences in the way they control this emotive thing. So this emotive control of the facial muscles, I think is in large part similar to emotive control of breathing. So there's that emotive control and there's that volitional control and they're different. They're different.

Jack Feldman:

Now you asked me about the Yackle stuff. The Yackle paper had to do with ascending, that the effect of breathing on emotion. What Kevin found was that there was a population of neurons in the pre-Bötzinger complex, that we're always looking to things that are projecting ultimately to motor neurons. He found the population of cells that projected to locus coeruleus. Locus coeruleus is one of those places in the brain that seemed to go everywhere.

Andrew Huberman:

It's like a sprinkler system.

Jack Feldman:

Exactly, and influence mood. And you've had a podcast about this. There's a lot of stuff going on with the locus coeruleus. So you get into the locus coeruleus, you can now spray information out throughout the entire brain. He found specific cells that projected from pre-Bötzinger to locus coeruleus, and that these cells are inspiratory modulated. Now, it's been known for a long time, since the '60s, that if you look in the locus coeruleus of cats when they're awake, you find many neurons that have respiratory modulation. No one paid much attention to him. Why bother? Not why bother paying attention, but why would the brain bother to have these inputs? So what Kevin did with Lindsay Schwarz and Liqun Luo's lab, is they killed, ablated, those cells going to locus coeruleus from pre-Bötzinger. And the animals became calmer, and their EEG levels changed in ways that are indicative that they became calmer.

Andrew Huberman:

And as I recall, they didn't just become calmer, but they weren't really capable of high arousal states. They were kind of flat.

Jack Feldman:

I don't think we really pursued that in the paper. And so we'd have to ask John Huguenard about that. But I-

Andrew Huberman:

He's on the other side of my lab, so we'll ask him. But nonetheless, that beautifully illustrates how there is a bidirectional control of-

Jack Feldman:

Well, that's ascending.

Andrew Huberman:

Emotion. Well, no, the two stories of the locked-in syndrome, plus the Yackle paper, shows that emotional states influence breathing and breathing influences emotional states. But you mentioned inspiration, which I always call inhalation, but people will follow. No, that's fine. Those are interchangeable. People can follow that. There's some interesting papers from Noam Sobel's group, and from a number of other groups, that as we inhale, or right after we inhale, the brain is actually more alert and capable of storing information than during exhales, which I find incredible. But it also makes sense. I'm able to see things far better when my eyes are open than when my eyelids are closed, for that matter.

Jack Feldman:

Maybe. I don't doubt ... Noam's work is great. Let me backtrack a bit because I want people to understand that we're talking about breathing affecting emotional cognitive state. It's not simply coming from pre-Bötzinger. There are at least ... Well, there are several other sites. And let me ... I need to go through that. One is olfaction. So when you're breathing, normal breathing, you're inhaling and exhaling. This is creating signals coming from the nasal mucosa that is going back into the olfactory bulb that's respiratory modulated. And the olfactory bulb has some profound influence and projections through many parts of the brain. So there's a signal arising from this rhythmic moving of air in and out of the nose that's going into the brain that has contained in it a respiratory modulation. So that signal is there. The brain doesn't have to be using it, but when it's discriminating odor and whatnot, that's riding on a oscillation, which is respiratory related. Another potential source is the vagus nerve. The vagus nerve is a major nerve, which is containing afferents from all of the viscera.

Andrew Huberman:

Afferents just being a-

Jack Feldman:

A signal.

Andrew Huberman:

Signals too.

Jack Feldman:

Yeah, signals from the viscera. It also has signals coming from the brain stem down, which are called efferents, but it's getting major signals from the lung, gut. And this is going up into the brain stem, so there. There are very powerful receptors in the lung that are responding to the lung volume, the lung stretch.

Andrew Huberman:

Those are baroreceptors. Oh, sorry, well, we have a number like-

Jack Feldman:

The pressure receptors.

Andrew Huberman:

Like the Piezo receptors of this year's Nobel Prize. Yeah.

Jack Feldman:

Yeah, so they're responding to the expansion and relaxation of the lung. And so if you record from the vagus nerve, you'll see that there's a huge respiratory modulation due to the mechanical changes in the lung. Now, why that is of interest is that for some forms of refractory depression, electrostimulation of the vagus nerve can provide tremendous relief. Why this is the case still remains to be determined, but it's clear that signals in the vagus nerve, at least artificial signals in the vagus nerve, can have a positive effect on reducing depression. So it's not a leap to think that under normal circumstances, that that rhythm coming in from the vagus nerve is playing a role in normal processing. Okay, let me continue. Carbon dioxide and oxygen levels. Now, under normal circumstances, your oxygen levels are fine. And unless you go to altitude, they don't really change very much. But your CO2 levels can change quite a bit with even a relatively small change in your overall breathing.

Jack Feldman:

That's going to change your pH level. I have a colleague, Alicia Meuret, who is working with patients who are anxious. And many of them hyperventilate. And as a result of that hyperventilation, their carbon dioxide levels are low. And she has developed a therapeutic treatment where she trains these people to breathe slower and to restore their CO2 levels back to normal, and she gets relief in their anxiety. So CO2 levels, which are not going to affect brain function on a breath by breath level, although it does fluctuate breath by breath, but sort of a continuous background, can change. And if it's changed chronically, we know that highly elevated levels of CO2 can produce panic attacks. And we don't know the degree to that gets exacerbated by people who have a panic attack to the degree to which their ambient CO2 levels are affecting their degree of discomfort.

Andrew Huberman:

What about people who tend to be too calm, meaning they're feeling sleepy, they're underbreathing, as opposed to overbreathing? Is there any knowledge of what the status of CO2 is in their system?

Jack Feldman:

I don't know, which doesn't mean there's no knowledge, but I'm unaware. But that's blissfully unaware. I've not looked at that literature, so I don't know.

Andrew Huberman:

And I have a feeling most of the scientific literature around breathing in humans that I'm aware of relates to these stress states because they're a little bit easier to study in the lab, whereas people feeling understimulated or exhausted all the time, it's a complicated thing to measure. You can do it, but it's not as straightforward.

Jack Feldman:

Well, CO2 is easy to measure.

Andrew Huberman:

But in terms of the measures for feeling fatigue, they're somewhat indirect, whereas stress, we can get at pulse rates and HRV, and things of that sort.

Jack Feldman:

Well, I imagine that these devices that we're all wearing will soon be able to measure. Well now they can measure oxygen levels, oxygen saturation.

Andrew Huberman:

Which is amazing.

Jack Feldman:

Yeah, but [inaudible 01:21:50] will pretty much stay above 90% unless there's some pathology or you go to altitude. But CO2 levels vary quite a bit. And in fact, because they vary, your body is so sensitive, the controller breathing, how much you breathe per minute, is determined in a very sensitive way by the CO2 level. So even a small change in your CO2 will have a significant effect on your ventilation. So this is another thing that not only changes your ventilation but affects your brain state. Now another thing that could affect, how breathing practice can affect your emotional state, is simply the descending command, because breathing practice involves volitional control of your breathing and therefore there's a signal that's originating somewhere in your motor cortex.

Jack Feldman:

Of course that's going to go down to pre-Bötzinger, but it's also going to send off collaterals to other places. Those collaterals could obviously influence your emotional state. So we have quite a few different potential sources, none of them that are exclusive. There's an interesting paper which shows that if you block nasal breathing, you still see breathing-related oscillations in the brain. And this is where I think the mechanism is occurring, is that these breathing-related oscillations in the brain, they're playing a role in signal processing. And maybe should I talk a little bit about the role that oscillations may be playing in signal processing?

Andrew Huberman:

Definitely. But before you do, I just want to ask you an intermediate question. We've talked a lot about inhalation, inspiration and exhalation. What about breath holds. In apnea, for instance, people are holding their breath, whether or not it's conscious or unconscious. They're holding their breath. What's known about breath holds in terms of how it might interact with brain state or oxygen CO2? And I'm particularly interested in how breath holds with lungs empty versus breath holds with lungs full might differ in terms of their impact on the brain. I'm not aware of any studies on this looking at a mechanistic level, but I find it really interesting. And even if there are no studies, I'd love it if you'd care to speculate.

Jack Feldman:

Well, one of the breath practices that intrigue me is where you basically hyperventilate for a minute and then hold your breath for as long as you can.

Andrew Huberman:

Tummo style, Wim Hof style.

Jack Feldman:

Exactly. Yeah.

Andrew Huberman:

We call it in the laboratory because, frankly, before tummo and before Wim, it was referred to as cyclic hyperventilation. So it's basically followed by a breath hold. And that breath hold could be done with lungs full or lungs empty.

Jack Feldman:

So I had a long talk with some colleagues about what they might think the underlying mechanisms are, particularly for the breath hold. And I certainly envision that there's a component with respect to the presence or absence of that with rhythmicity in your cortex, which is having effect. But the other thing with the hyperventilation, hypoventilation or the apnea, is your CO2 levels are going from low to high.

Andrew Huberman:

Anytime you're holding your breath?

Jack Feldman:

Anytime you're holding your breath.

Andrew Huberman:

Yeah.

Jack Feldman:

Okay. And those are going to have a profound influence. Now, I have to talk about episodic hypoxia because there's a lot of work going on, particularly with Gordon Mitchell, the University of Florida, is doing some extraordinary work on episodic hypoxia. So in the '80s, David Millhorn did some really intriguing work. If I gave you a low oxygen mixture for a couple of minutes, your breathing level would go up, because you want to have more oxygen.

Andrew Huberman:

You're starving for air.

Jack Feldman:

No, you're starving for oxygen.

Andrew Huberman:

All right.

Jack Feldman:

Okay. And for a couple of minutes you go up, you reach some steady state level, not so hypoxic that you can't reach an equilibrium. And then I give you room air again, your ventilation quickly relaxes back down to normal. If on the other hand, I gave you three minutes of hypoxia, five minutes of normoxia, three minutes of hypoxia, five minutes of normoxia, three minutes hypoxia, five minutes of normoxia-

Andrew Huberman:

Normoxia being normal?

Jack Feldman:

Normal air. Ventilation goes up, down, up, down, up, down, up, down. After the last episode, your breathing comes down and doesn't continue to come down, but rises again and stays up for hours. This is well validated now. This was originally done in animals, but in humans all the time. It seems to have profound benefit on motor function and cognitive function.

Andrew Huberman:

In what direction?

Jack Feldman:

Positive. I've often toyed with the idea of getting a 5%, an 8% oxygen. Don't do this listeners. Getting an 8% oxygen tank by my desk when I'm writing a grant and doing like in "Blue Velvet" and going through the episodic hypoxia to improve my cognitive function. Certainly could use improvement when I'm writing grants.

Andrew Huberman:

But you could do this without the low oxygen. You could do this through breathwork, presumably.

Jack Feldman:

It's hard to lower your oxygen enough. We're going in the experimental studies, they typically use 8% oxygen. It's hard to hold your breath long enough. And there is another difference here: That is what's happening to your CO2 levels? When you hold your breath, your oxygen levels are dropping, your CO2 levels are going up. When you are doing episodic hypoxia, your CO2 levels are going to stay pretty normal because you're still breathing. It's just the oxygen levels are gone.

Andrew Huberman:

So unlike normal conditions, which you described before, where oxygen is relatively constant and CO2 is fluctuating depending on emotional state and activity and things of that sort, in episodic hypoxia, CO2 is relatively constant, but you're varying the oxygen level coming into the system quite a bit?

Jack Feldman:

I would say CO2 is relatively constant, but it's not going to go in a direction which is going to be significantly far from normal. Whereas when you're holding your breath, you're going to become both hypoxic and hypercapnic at the same time.

Andrew Huberman:

We should explain to people what hypoxic and hypercapnic are because we haven't done that.

Jack Feldman:

Hypoxic, it's just the technical term for low levels of oxygen. Hyper — or you could say hypoxic, low — hyper is high. So hyperoxia or hypocapnia, low CO2 or hypercapnia, high levels of CO2. So when you're in episodic hypoxia, if anything, you're going to become hypocapnic, not hypercapnic. And that could play an influence on this. One example that I remember, and Gordon will have to forgive me if I'm misquoting this, is they had a patient who had a stroke and had weakness in ankle flexion, excuse me, ankle extension — to extend the ankle. And so they had the patient in a seat where they could measure ankle extension and then they measured it, and then they exposed the patient to episodic hypoxia and they measured again. The strength of the ankle extension went way up. And so Gordon is looking at this, they're looking at this now for spinal cord rehab.

Andrew Huberman:

And I imagine for all sorts of neuromuscular performance, it could be beneficial.

Jack Feldman:

Yeah, Gordon is looking into athletic performance. We have a project which we haven't been able to push to the next level, to do golf. So I think-

Andrew Huberman:

Why golf? Because you love golf.

Jack Feldman:

Well, it's because it's motor performance, coordination. So it's not simply running as fast as you can. It's coordination, concentration, a whole variety of things. And so the idea would be to get a group of golfers and give them their placebo control. So they don't know whether they're breathing a gas mixture, which is just normal air or hypoxic gas mixture, although they may be able to figure it out based on their response. Do it under controlled circumstances that do it into a net, measure their length of their drives, their dispersion and whatnot and see what happens. Look, if we could find that this works for golfers, forget about cognitive function. We could sell this for unbelievable amounts of money.

Andrew Huberman:

That sounds like a terrible idea.

Jack Feldman:

By the way. I'm not serious about selling it.

Andrew Huberman:

I know you're joking. Maybe people should know that you are joking about that. No, I think that anything that can improve cognitive and neuromuscular performance is going to be of interest for a wide range of both pathologic states like injury, TBI, et cetera. I mean one of the most frequent questions I get is about recovery from concussion or traumatic brain injury. A lot of people think sports, they think football, rugby, hockey. But if you look at the statistics on traumatic brain injury, most of it is construction workers, car crashes, bicycle accidents. The sports part of it is a tiny minuscule fraction of the total amount of traumatic brain injury out there. I think these protocols tested in the context of golf would be very interesting because of the constraints of the measures, as you mentioned. And it could be exported to a number of things.

Andrew Huberman:

I want to just try and imagine whether or not there is any kind of breathing pattern or breathwork, just to be direct about it, that even partially mimics what you described in terms of episodic hypoxia. I've done a lot of tummo, Wim Hof, cyclic hyperventilation-type breathing before; my lab studies this in humans. And what we find is that if people do cyclic hyperventilation, so for about a minute, then exhale, hold their breath for 15 to 60 seconds depending on what they can do, and just keep repeating that for about five minutes, it seems to me that it at least partially mimics the state that you're talking about because afterwards, people report heightened levels of alertness, lower levels of triggering due to stressful events. They feel comfortable at a higher level of autonomic arousal, cognitive focus. A number of improvements that are pretty impressive that any practitioner of Wim Hof or tummo will be familiar with. Is that pattern of breathing even ... Can we say that it maps to what you're describing in some general sense?

Jack Feldman:

Well, the expert in this would be Gordon Mitchell. I would say it moves in that direction, but it's not as extreme because I don't think you can get down to the levels of hypoxia that they do clinically. I know that our pals at Our Breath Collective actually just bought a machine because you can buy a machine that does this.

Andrew Huberman:

I see.

Jack Feldman:

And they bought it and they're going to do their own self-testing to see whether or not this has any effect on anything that they can measure. Of course, you have to be concerned about self-experimentation, but I applaud their curiosity in going after it.

Andrew Huberman:

Hyperbaric chambers. I hear a lot nowadays about hyperbaric chambers. People are buying them and using them. And what are your thoughts on hyperbaric chambers as it relates to any of the-

Jack Feldman:

Hyper or hypo?

Andrew Huberman:

Hyperbaric chambers.

Jack Feldman:

Okay, so you're not talking about altitude.

Andrew Huberman:

No.

Jack Feldman:

I don't really have much to say. Your oxygen levels will probably go up a little bit and that could have a beneficial effect. But that's way outside my area of comfort.

Andrew Huberman:

I think ... 2022 I think is going to be the year of two things I keep hearing a lot about, which is the deliberate use of high salt intake for performance, increasing blood volume, et cetera. And hyperbaric chambers seem to be catching on much in the same way that ice baths were and saunas seem to be right now. But anyway, a prediction we can return to at some point.

Andrew Huberman:

I want to ask you about some of the studies that I've seen out there exploring how deliberately restricting one's breathing to nasal breathing can do things like improve memory. There's a couple papers in Journal of Neuroscience, which is a respectable journal in our field. One looking at olfactory memory. So that kind of made sense because you can smell things better through your nose than your mouth, unless you're some sort of elk or something, where they can, presumably they have some sense of smell in their mouth as well. But humans generally smell with their nose. That wasn't terribly surprising. But there was a companion study that showed that the hippocampus, an area involved in encoding memories in one form or another, was more active, if you will. And memory and recall was better when people learned information while nasal breathing as opposed to mouth breathing. Does that make sense from any mechanistic perspective?

Jack Feldman:

Well, given that there are, there's a major pathway going from the olfactory system into the brain and you cut that ... And not one from many receptors in the mouth. The degree of respiratory modulation you're going to see throughout the forebrain is going to be less with mouth breathing than nose breathing, so it's certainly plausible. I think there are a lot of experiments that need to be done to distinguish between the two, that is the nasal component and the nonnasal component of these breathing-related signals. There's a tendency sometimes when you have a strong effect to be exclusive. And I think what's going on here is that there are many inputs that can have an effect.

Jack Feldman:

Now, whether they're parceled, that some affect this part of behavior and some affect that part of behavior, remains to be investigated. There's certainly a strong olfactory component. My interest is trying to follow the central component because we know that there's a strong central component in this. In fact, there's a strong central projection to the olfactory bulb. So regardless of whether or not there's any in and out of the nose, there's a respiratory input into the olfactory bulb which combines with the respiratory modulated signals coming from the sensory receptors.

Andrew Huberman:

Interesting. And as long as we are poking around, forgive the pun, the nose, what about one nostril versus the other nostril? I know it sounds a little crazy to imagine, but there have been theories in yogic traditions and others that breathing through one nostril somehow activates certain brain centers, maybe hemispherically one side of the brain versus the other, or that right nostril and left nostril breathing might differ in terms of the levels of alertness or calmness they produce. I'm not aware of any mechanistic data on that, but if there's anything worthwhile about right nostril versus left nostril breathing that you're aware of, I'd love to know.

Jack Feldman:

Well, it's certainly plausible. I don't know of any data demonstrating it except the anecdotal reports. As you know, the brain is highly lateralized, and we have speech on one side and a dominant hand is on one side. And so the notion that if you have this huge signal coming from the olfactory system, and to some degree it's lateralized, it's not perfectly symmetrical, that is one side is not going evenly to both sides, then you can imagine. And once the signal gets distributed in a way that's not uniform, that the effectiveness or the response is going to be particular to the cortex in which either the signal still remains or the signal is removed from.

Andrew Huberman:

I see. What are some of the other features of our brain and body, be it blinking or eye movements or ability to encode sounds, or any features of the way that we function and move and perceive things that are coordinated with breathing in some interesting way?

Jack Feldman:

Thank you for that question. Almost everything. So we have for, example, on the autonomic side, we have respiratory sinus arrhythmia. That is during expiration, the heart slows down. Your pupils oscillate with the respiratory cycle. I don't know what the functional basis for that is, but they do oscillate with the respiratory cycle.

Andrew Huberman:

When we inhale, our pupils constrict, presumably because there's an increase in heart rate and sympathetic tone. I would think of constriction and I'm guessing as you relax, the pupil will get ... And you exhale, and the pupil will get ...

Jack Feldman:

I think you're right, but I always get the valence of that ...

Andrew Huberman:

Well, it's counterintuitive because people wouldn't think that when the pupils get ... It depends. You can get very alert and aroused for stress or for good reasons and the pupils get wider, but your visual feel narrows and then the opposite is true. Anyway, I guess the idea is that the pupils are changing size and therefore the aperture, your visual window, is changing in coordination with breathing.

Jack Feldman:

Okay. Your fear response changes with the respiratory cycle.

Andrew Huberman:

Tell us more about that.

Jack Feldman:

Well, there's a paper by [inaudible], which I think showed rather clearly that if you show individuals fearful faces, that their measured response of fearfulness changes between inspiration, expiration. I don't know why, but it does. Your reaction time changes. So you talk about blinking; the reaction time changes between inspiration and expiration. If I ask you to punch something, that time will change between inspiration and expiration. In fact, I don't know the degree to which martial artists exploit that. You watch the breathing pattern and your opponent will actually move slower during one cycle compared to the other.

Andrew Huberman:

Meaning as they're ... In which direction? If they're exhaling, they can punch faster?

Jack Feldman:

I have to say I don't keep a table of which is which direction things move in because I'm out of the martial arts field now.

Andrew Huberman:

My vague understanding is that exhales on strikes is the more typical way to do that. And so as people strike, they exhale in martial arts.

Jack Feldman:

As you exhale. But there are other components to striking because you want to stiffen your ribcage, you want to make a Valsalva maneuver. So that's both an inspiration and an expiration. It's at the same time, so I don't know enough about when you say during expiration. I would assume that when you make a strike, you actually want to stiffen here, which is a Valsalva-like maneuver.

Andrew Huberman:

And oftentimes, they'll clench their fist at the last moment. Anyway, there's a whole set of motor things there that we can talk to some fighters. We know people who know fighters, so we can ask them. Interesting. What are some other things that are modulated by breathing?

Jack Feldman:

I think anything anyone looks at seems to have a breathing component because it's all over your brain, and it's hard to imagine it not being effective. Now, whether it's incidental or just background and doesn't really have any behavioral advantage is possible; in other cases, there might have a behavioral advantage. This eye-opening thing for me, probably a decade ago, was digging into literature and seeing how much of cortical activity and subcortical activity had a respiratory-modulated component to it. And I think a lot of my colleagues who are studying cortex are oblivious to this.

Jack Feldman:

And they find ... I heard it talked the other day, the person will go unnamed, who find a lot of things correlated with a particular movement. And when I looked, I said, "Gee, that's a list of things that are respiratory modulated." And rather than it being correlated to the movement they were looking at, I think the movement they were looking at was modulated by breathing, as was everything else. So there wasn't that the movement itself was driving that correlation. It was that they were all correlated to something else, which is the breathing movement. And whether or not that is behaviorally relevant or behaviorally something you can exploit, I don't know.

Andrew Huberman:

I suspect you're right, that breathing is, if not the foundational driver of many, if not all of these things, that it's at least one of the foundational interactions.

Jack Feldman:

It's in the background, it's in the brain. And oscillations play an important part in brain function. And they vary in frequency from maybe a hundred hertz down to ... Well, we can get the circadian and monthly cycles, but breathing occupies a rather unusual place in all that because ... So let me talk about what the people think the oscillations are doing, particularly the faster ones. They're important in coordinating signals across neurons. Just like in a computer, a computer steps.

Jack Feldman:

Just like in a computer. A computer steps, so a computer knows when information is coming from another part of a computer, that it was originated, at a particular time. That discrete step-by-step thing is important in computer control. Now, the brain is not a digital device, it's an analog device. When I have a signal, that's coming in my ear and my eye, which is Andrew Huberman's speaking, and I'm looking at his face. I see that as a whole, but the signal is coming into different parts of my brain.

Jack Feldman:

How do I unify that? Well, my neurons are very sensitive to changes in signals arriving, by fractions of a millisecond. How do I assure that those signals coming in represent the same signal? Well, if I have, throughout my brain, an oscillation, and the signals ride on that oscillation, let's say the peak of the oscillation, I can then have a much better handle on the road of timing and say, "Those two signals came in at the same time, they may relate to the same object. Aha, I see you as one unified thing, spouting, talking."

Jack Feldman:

These oscillations come in many different frequency ranges and are important in memory formation, and all sorts of things. I don't think people pay much attention to breathing, because it's relatively slow, to this, the range when you think about — milliseconds. We have important things, that are thought to be important, in cognitive function, which are a few cycles per second, to 20, 30, 40, 50 cycles per second. Breathing in humans is maybe 0.2 cycles per second, every five seconds. Although, in rodents they're up to four per second, which is pretty fast.

Jack Feldman:

Breathing has one thing, which is special, that is, you can readily change it. The degree to which the brain is using that slow signal for anything, if that becomes part of its normal signal processing, you now change it. That signal processing has to change, and as that signal processing changes, acutely, there's a change. You asked about breath practice, how long do you have to do it? Well, a single breath will change your state. You're nervous, you take a deep breath, and it seems to help relax-

PART 3 OF 4 ENDS [01:45:04]

Andrew Huberman:

Or a sigh.

Jack Feldman:

Call it what you will. Call it what you will.

Jack Feldman:

It seems to work. Now it doesn't have a permanent change, but when I'm getting up to bat, or getting up to the first tee, or getting to give a big talk, or coming to do a podcast, get a little bit anxious, a deep breath, or a few deep breaths are tremendously effective in calming one down. You can get a transient disruption. But on the other hand, let's take something like depression. I think you can envision depression as activities going around in a circuit, and because it's continuous in the nervous system, as signals keep repeating, they tend to get stronger, and they can get so strong you can't break them. You can imagine, depression being something going on, and on, and on, and you can't break it, and so we have trouble when we get to certain levels of depression. I mean, all of us get depressed at some point, but if it's not continuous, it's not long-lasting, we're able to break it. If it's long-lasting and very deep, we can't break it.

Jack Feldman:

The question is how do we break it? Well, there are extreme measures to break it. We could do electroconvulsive shock; we shock the whole brain, that's disrupting activity in the whole brain, and when this circuit starts to get back together again, it's been disruptive. We know that the brain, when signals get disrupted a little bit, we can weaken the connections, and weakening the connections, if it's that circuit involved in depression, we may get some relief. An electroconvulsive shock does work for relieving many kinds of depression. That's pretty heroic. Focal deep brain stimulation does the same thing, but more localized, or transcranial stimulation — you're disrupting a network, and while it's getting back together, it may weaken some of the connections.

Jack Feldman:

If breathing is playing some role in this circuit and now instead of doing a one-second shock, I do 30 minutes of disruption by doing slow breathing or other breathing practice, those circuits begin to break down a little bit, and I get some relief. If I continue to do it, before the circuit can then build back up again, I gradually, can wear that circuit down. I liken this ... I tell people, it's like walking around on a dirt path. You build a rut, the rut gets so deep you can't get out of it.

Jack Feldman:

What breathing is doing is filling in the rut bit by bit, to the point that you can climb out of that rut. That is because breathing, the breathing signal, is playing some role in the way this circuit works. Then when you disrupt it, the circuit gets a little thrown off-kilter, and when, as you know, circuits get thrown off, the nervous system tries to adjust in some way or another. It turns out, at least for breathing, for some evolutionary reason or just by happenstance, it seems to improve our emotional function or our cognitive function. We are very fortunate that's the case.

Andrew Huberman:

It's a terrific segue into what I want to ask you next, and this is part of a set of questions I want to make sure we touch on before we wrap up, which is, what do you do with all this knowledge, in terms of a breathing practice? You mentioned that one breath can shift your brain state, and that itself can be powerful. I think that's absolutely, true. You've also talked about 30-minute breathwork practices, which is, 30 minutes of breathwork is a pretty serious commitment, I think, but it's doable, certainly a zero cost, except for the time, in most cases. What do you see out there in the landscape of breathwork that's being done, that you like, and why do you like it? What do you think ... or what would you like to see more of in terms of exploration of breathwork, and what do you do?

Jack Feldman:

Well, I'm a relatively, new convert to breathwork. Through my own investigation of it, I became convinced that it's real. I'm basically a beginner in terms of my own practice. I like to keep things simple. I think I've discussed this before. I liken it to someone who's a couch potato, who's told they got to begin to exercise. You don't go out and run a marathon, so couch potato, you say, "Okay, get up and walk for five minutes, then 10 minutes." Then, "Okay, now you're walking for a longer period. You begin to run." Then you reach your point, you say, "Well gee, I'm interested in this sport, and there may be particular kinds of practices that you can use that could be helpful in optimizing a performance of that sport."

Jack Feldman:

I'm not there yet. I find I get tremendous benefit by relatively short periods, between five and maybe 20 minutes of doing box breathing. It's very simple to do. I have a simple app, which helps me keep the timing.

Andrew Huberman:

Do you recall which app it is? Is it the apnea trainer? Is that the one?

Jack Feldman:

Well, I was using Calm for a long time, but I let my subscription relapse, and I have another one whose name I don't remember, but it's very simple, and it works for me. Now trying this tummo, because I'm just curious in exploring it, because it may be acting for a different way, and I want to see if I respond differently. I don't have a particular point of view. Now, I have friends and colleagues, who are into particular styles, like Wim Hof, and I think what he's doing is great, in getting people who are interested.

Jack Feldman:

I think, the notion is that I would like to see more people exploring this. To some degree, as you point out, 30 minutes a day, some of the breath patterns that some of these stars like Wim Hof, are a little intimidating to newbies. I would like to see something very simple, that people ... What I tell my friends is, "Look, just try it five or 10 minutes, see if you feel better. Do it for a few days. If you don't like it, stop. It doesn't cost anything." Invariably, they find that it's helpful. I will often interrupt my day, to take five or 10 minutes, if I find that I'm lagging.

Jack Feldman:

I think there's some pretty good data that your performance after lunch, declines. Very often what I'll do after lunch, which I didn't do today, is take five or 10 minutes and just breath practice.

Andrew Huberman:

Lately, what does that breath practice look like?

Jack Feldman:

It's just box breathing, for five or 10 minutes.

Andrew Huberman:

The duration of your inhales and holds and exhales and holds is set by the app. Is that right?

Jack Feldman:

Well, I do five seconds.

Andrew Huberman:

Five seconds inhale, five second hold, five second exhale, five second hold?

Jack Feldman:

Sometimes, I'll do doubles. I'll do 10 seconds, just because I get bored. I feel like doing it. It's very helpful. I mean, now that's not the only thing I do, with respect to trying to maintain my sanity, and my health.

Andrew Huberman:

No, I can imagine that there'd be a number of things, although you seem, because you seem very sane and very healthy. I, in fact, know that you are both those things.

Jack Feldman:

Well, you suspect that I am.

Andrew Huberman:

I suspect, but there's data. A while back, we had a conversation, a casual conversation, but you said something that really stuck in my mind, which is that it might be that the specific pattern of breathwork that one does is not as important as experiencing transitions between states, based on deliberate breathwork, or something to that extent. Which I interpreted to mean that if I were to do box breathing, with five second in, five second hold, five second exhale, five second hold, for a couple of days or maybe even a couple of minutes, and then switch to a 10 seconds, or then switch to tummo, that there's something powerful, perhaps, in the transitions, realizing the relationship between different patterns of breathing and those transitions. Much in the same way that you can get into one of these cars at an amusement park that just goes at a constant rate, and then stops.

Andrew Huberman:

Very different than learning how to shift gears. I used to drive a manual, I still can, so I'm thinking about a manual transmission. Even with an automatic transmission, you start to get a sense of how the vehicle behaves, under different conditions. I thought that was a beautiful seed for a potential breathwork practice, that at least to my awareness, nobody has really formalized, which is that you introduce some variability within the practice that's somewhat random, in order to be able to sense the relationship between different speeds and depths of inhales, exhales and holds, and so forth. Essentially, it's like driving around the track but with obstacles, at different rates, and breaking and restarting, and things of that sort. That's how you learn how to drive.

Andrew Huberman:

What do you think about that? If you like it enough, can we call it the Feldman protocol?

Jack Feldman:

Oh, please. I was asked in this BBC interview once, why didn't I name it the Feldman complex, instead of the pre-Bötzinger complex.

Andrew Huberman:

You said, I already have a Feldman complex.

Jack Feldman:

Well, it sounds like a psychiatric disorder, but I think the primary effect is this disruptive effect, which I described, but the particular responses may clearly vary depending on what that disruption is. I don't know of any particular data which are in well-controlled experiments which can actually work through the different types of breathing patterns, or simply with a box pattern, just varying the durations. I mean, pranayama is sort of similar, but the amount of time you spend going around the box is different.

Jack Feldman:

I don't really have much to say about this. I mean, this is why we need better controlled experiments in humans. I think this is where being able to study it in rodents, where you can have a wide range of perturbations, while you're doing more invasive studies to really get down as to which regions are affected, how is the signal processing disrupted — which is still a hypothesis — but how it's disrupted could tell us a lot about maybe there's a resonant point at which there's an optimal effect when you take a particular breathing practice.

Jack Feldman:

Then when we talked about the fact that different breathing practices could be affecting the outcome through different pathways. You have the olfactory pathway, you have a central pathway, you have a vagal pathway, you have a descending pathway; how different practices may change the summation of those things, because I think all those things are probably involved, and we're just beginning to scratch the surface. I just hope that we can get serious neuroscientists and psychologists to do the right experiments to get at this because I think there's a lot of value to human health here.

Andrew Huberman:

I do too. It's one of the reasons my lab has shifted to these sorts of things in humans. I'm delighted that you're continuing to do the hardcore, mechanistic work in mice, and probably you'll do work in humans, as well, if you're not already. There are other groups, Epel lab at UCSF and a number of ... I'm starting to see some papers out there about respiration in humans, a little bit, some more brain imaging. I can't help but ask about a somewhat, unrelated topic, but it is important, in light of this conversation, because you're here. One of the things that I really enjoy about conversations with you, as it relates to health and neuroscience, and so forth, is that you're one of the few colleagues I have who openly admits to exploring supplementation. I'm a long-time supplement fan. I think there's power in compounds, both prescription, non-prescription, natural, synthesized. I don't use these haphazardly, but I think there's certainly power in them.

Andrew Huberman:

One of the places where you and I converge is, in terms of our interest in the nervous system and supplementation, is vis-à-vis magnesium. Now I've talked at endlessly, on the podcast and elsewhere, about magnesium for sake of sleep and improving transitions to sleep, and so forth. You have a somewhat, different interest in magnesium as it relates to cognitive function and durability of cognitive function. Would you mind just sharing with us a little bit about what that interest is, where it stems from, and because it's the Huberman Lab podcast and we often talk about supplementation, what you do with that information?

Jack Feldman:

I need to disclose that I am a scientific advisor to a company called Neurocentria, which my graduate student Guosong Liu is CEO. That said, I can give you some background. Guosong, although when he was in my lab worked on breathing, had a deep interest in learning and memory. When he left my lab, he went to work with a renowned learning and memory guy at Stanford, Dick Chen. When he finished there, he was hired by Susumu Tonegawa at MIT.

Andrew Huberman:

Who also knows a thing or two about memory. I'm teasing. Susumu has a Nobel for his work on immunoglobulins, but then is a world-class memory researcher.

Jack Feldman:

And more.

Andrew Huberman:

He's many things.

Jack Feldman:

Guosong had ... very curious, very bright guy, and he was interested in how signals between neurons get strengthened, which is called long-term potentiation, or LTP. One of the questions that arose was, if I have inputs to a neuron, and I get LTP, is the LTP bigger if the signal is bigger, or the noise is less. We can imagine that when we're listening to something, if it's louder, we can hear it better, or if there's less noise, we can hear it better. He wanted to investigate this.

Jack Feldman:

He did this in tissue culture of hippocampal neurons. What he found was that if he lowered the background activity in all of the neurons, that the LTP he elicited got stronger. The way he did that was increasing the level of magnesium in the bathing solution. This gets into some esoteric electrophysiology, but basically, there's a background level of noise in all neurons, and part of it is regulated by the degree of magnesium in the extracellular bath.

Andrew Huberman:

You mean electrical noise?

Jack Feldman:

Electrical noise, I'm sorry, electrical noise. If you, in what's called the physiological range, which is between 0.8 and 1.2 millimolar, which don't worry about the number-

Andrew Huberman:

I can't believe you remember the millimolar of the magnesium.

Jack Feldman:

Well, I'm always frightened that I get, I say micro or femto, or something. I go off by several layers of magnitude. In that physiological range, there's a big difference in the amount of noise in a neuron, between 0.8 and 1.2 millimolar. He played around with the magnesium, and he found out that when the magnesium was elevated, there was more LTP. All right, that's an observation in a tissue culture.

Andrew Huberman:

I should just mention that more LTP, essentially, translates to more neuroplasticity, more rewiring of connections, in essence.

Jack Feldman:

He tested this, in mice, and basically, he offered them ... He had control mice, which got a normal diet, and one that had ... one enriched the magnesium. The ones that lived enriched with magnesium had higher cognitive function, lived longer, everything you'd want in some magic pill, those mice did that. Excuse me, rats. The problem was that you couldn't imagine taking this into humans because most magnesium salts don't passively get from the gut into the bloodstream, into the brain. They pass via what's called a transporter. A transporter is something in a membrane that grabs a magnesium molecule or atom and pulls it into the other side. If you imagine you have magnesium in your gut, you have transporters that pull the magnesium in the gut into the bloodstream.

Jack Feldman:

Well, if you had to take a normal magnesium supplement, that you can buy at the pharmacy, it doesn't cross the gut very easily. If you would take enough of it to get it in your bloodstream, you start getting diarrhea. It's not a good way to go.

Andrew Huberman:

Oh, it is a good way to go. I couldn't help myself.

Jack Feldman:

Well said. He worked with this brilliant chemist, Fei Mao, and Fei looked at a whole range of magnesium compounds, and he found that magnesium threonate was much more effective in crossing the gut blood barrier. Now, they didn't realize at the time, but threonate is a metabolite of vitamin C. There's lots of threonate in your body. Magnesium threonate would appear to be safe, and maybe part of the role — now they believe it's part of the role of the threonate — is that it supercharges the transporter to get the magnesium in. Remember, you need a transporter at the gut, into the brain and into cells.

Jack Feldman:

They gave magnesium threonate, to mice, who had... No. Let me backtrack a bit. They did a study in humans. They hired a company to do a test. It was a hands-off test. It's one of these companies that get hired by the big pharma to do their test for them. They got patients who were diagnosed as mild cognitive decline. These are people who had cognitive disorder which was age inappropriate. The metric that they use for determining how far off they were is Spearman's g factor, which is a generalized measure of intelligence that most psychologists accept. The biological age of the subjects was, I think, 51. The cognitive age was 61, based on the Spearman's g test. Oh, I should say the Spearman g factor starts at a particular level in the population, at age 20, and declines about 1% a year. Sorry to say we're not 20-year-olds anymore.

Jack Feldman:

When you get a number, from that you can put on the curve and see whether you're ... it's about your age or not. These people are about 10 years older, according to that metric. Long story short, after three months ... This is a placebo-controlled, double-blind study. The people who were in the placebo arm improved two years, which is common for human studies because of placebo effect. The people who got the compound improved eight years, on average, and some improved more than eight years. They didn't do any further diagnosis as to what caused the mild cognitive decline, but it was extraordinarily impressive.

Andrew Huberman:

It moved their cognition closer to their biological age.

Jack Feldman:

Biological age.

Andrew Huberman:

Do you recall what the doses of magnesium threonate were?

Jack Feldman:

It's in the paper, and it's basically what they have in the compound which is sold commercially. The compound which is sold commercially is handled by a nutraceutical wholesaler who sells it to the retailers, and they make whatever formulation they want. It's a dosage which is, my understanding is rarely tolerable. I take half a dose. The reason I take half a dose is that I had my blood magnesium measured, and it was low/normal for my age. I took half a dose, it became high/normal. I felt comfortable staying in the normal range. A lot of people are taking the full dose.

Jack Feldman:

At my age, I'm not looking to get smarter. I'm looking to decline more slowly. It's hard, as you know, it's hard for me to tell you whether or not it's effective, or not.

Andrew Huberman:

Well, you remembered the millimolar of the magnesium and the solution and on the high and low end. I would say it's not a well-controlled study when it's an n of one. It seems to be working.

Jack Feldman:

When I recommend it to my friends, academics who are, by nature, skeptical, if not cynical, and I insist that they try it. They usually don't report a major change in their cognitive function, although sometimes they do report, "Well, I feel a little bit more alert, and my physical movements are better." Many of them report they sleep better.

Andrew Huberman:

That makes sense. I think there's good evidence that threonate can accelerate the transition into sleep and maybe even access to deeper modes of sleep for some people there. For many people actually, a small percentage of people who take threonate, including one of our podcast staff here, have stomach issues with it. They can't tolerate it. I would say, just anecdotally, about 5% of people don't tolerate threonate well; they stop taking it, and then they're fine. It caused them diarrhea or something of that sort. Most people tolerate it well, and most people report that it vastly improves their sleep. Again, that's anecdotally.

Andrew Huberman:

There are a few studies, and there're more on the way. That's very interesting, because until you and I had the discussion about threonate, I wasn't aware of the cognitive-enhancing effects, but the story makes sense from a mechanistic perspective, and it brings it around to a bigger and more important statement, which is that I so appreciate your attention to mechanism. I guess this stems from your early training as a physicist and the desire to get numbers and to really parse things at a fine level.

Andrew Huberman:

We've covered a lot today. I know there's much more that we could cover. I'm going to insist on a part two at some point, but I really want to speak on behalf of a huge number of people and just thank you, not just for your time and energy and attention to detail and accuracy and clarity around this topic today, but also what I should have said at the beginning, which is that you really are a pioneer in this field of studying respiration and the mechanisms underlying respiration, with modern tools for many decades. The field of neuroscience was one that was perfectly content to address issues like memory, and vision, and sensation, perception, et cetera. But the respiratory system was largely overlooked for a long time. You've just been steadily clipping away and clipping away, and much ... Because of the events related to COVID, and a number of other things, and this huge interest in breathwork and brain states and wellness, the field of respiration and interest in respiration has just exploded.

Andrew Huberman:

I really want to extend a sincere thanks. It means a lot to me, and I know to the audience of this podcast, that someone with your depth and rigor in this area is both a scientist and a practitioner, and that you would share this with us, so thank you.

Jack Feldman:

Well, I want to thank you. This is actually a great opportunity for me. I've been isolated in my silo for a long time, and it's been a wonderful experience to communicate to people outside the silo who have an interest in this. I think that there's a lot that remains to be done, and I enjoy speaking to people who have interest in this. I find the interest to be quite mind-boggling, and it's quite wonderful that people are willing to listen to things that can be quite esoteric at times, but it gets down to deep things about who we are and how we are going to live our lives. I appreciate the opportunity, and I would be delighted to come back, at any time.

Andrew Huberman:

Wonderful. We will absolutely do it. Thanks again, Jack.

Jack Feldman:

Bye now.

Andrew Huberman:

Thank you for joining me for my conversation with Dr. Jack Feldman. I hope you found it as entertaining and as informative as I did. If you're learning from and/or enjoying this podcast, please subscribe to us on YouTube. That's a terrific zero-cost way to support us. In addition, please subscribe to the podcast on Spotify and Apple. On Apple, you can leave us a review, and you can leave us up to a five-star rating.

Andrew Huberman:

Please also check out the sponsors mentioned at the beginning of the podcast. That's the best way to support this podcast. In addition, if you're not already following us on Instagram and Twitter, I teach neuroscience on Instagram and Twitter. Some of that information covers information covered on the podcast. Some of that information is unique information, and that includes science and science based tools that you can apply in everyday life.

Andrew Huberman:

I also want to just mention one more time the program that I mentioned at the beginning of the episode, which is Our Breath Collective. The Our Breath Collective has an advisory board that includes people like Dr. Jack Feldman, where you can learn detailed breathwork protocols. If you're interested in doing or teaching breathwork, I highly recommend checking it out. You can find it at ourbreathcollective.com/huberman, and that will give you $10 off your first month. I want to thank you, once again, for joining me for my conversation with Dr. Jack Feldman. Last, but certainly not least, thank you for your interest in science.

PART 4 OF 4 ENDS [02:16:14]

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