Dr. David Linden: Life, Death & the Neuroscience of Your Unique Experience | Huberman Lab Podcast

Welcome to the Huberman Lab

podcast

where we discuss science and science-based tools for everyday

life

. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. Today my guest is Dr. David Linden. Dr. David Linden is a professor of

neuroscience

at Johns Hopkins School of Medicine. His lab has studied neuroplasticity, which is how connections in the brain change in response to

experience

. Much of that work focused on a structure called the cerebellum, which is also sometimes called the minibrain because it looks like a mini brain at the bottom and back of the human brain and is responsible for a huge number of basic functions that we use. in everyday

life

, including our motor behavior, which is our ability to walk and talk, but also dance, play instruments and is responsible for a huge number of basic functions that we use in everyday life, including our sense of balance, our ability to learn new motor behaviors and our sense of time.

Today we will talk about the cerebellum and what it does, but Dr. David Linden will also teach us about the important sense of touch and what makes us different as visuals. The reason today's discussion covers so many important topics is that the laboratory Dr. David Linden has focused on many of those topics and is also the author of five excellent popular books on

neuroscience

that We focus, for example, on our sense of pleasure, where it originates and what controls it in the brain, as well as in our sense of touch, and today we begin our discussion by talking about the recent discovery of a set of neurons that are known. over a long period of time but have only recently been characterized as being involved in sensual contact in particular and it is a fascinating conversation, I further assure you that Dr.

David Linden informs us about what makes us individuals, how each and every one of us. you perceive the same things differently and it's an absolutely fascinating conversation that tells you, for example, why some of you think a smell is putrid, it actually smells like vomit, while others maybe don't mind that smell and why others are still attracted to that smell or something you see or something you hear, we also talk about nature versus nurture and how we become who we are not only through our genes and epigenetics, but also through our

experience

in early childhood and adult experience and then in the last third of our conversation.

We move on to talk about the so-called mind-body connection and the science underlying how our thoughts inform our bodily health or lack thereof, as well as how our body's organs control the chemical hormones and thoughts within our brain, then We move on to discuss Dr. David Linden himself and the fact that in 2020 he was diagnosed with a form of heart cancer which led his doctors to tell him he had six to 12 months to live, obviously because he was in our studio to record this conversation he has survived. that prognosis, but he lives day by day knowing that his

death

may come soon, although it is not clear exactly when that day will come, of course, he tells us how the initial prognosis of his cancer has changed and how he has survived that prognosis.

He reported on his daily life, as well as his thinking and relationships, and that leads to a very direct and frankly emotional conversation that includes advice on how we can all make the most of our daily lives and our lives in general. It's an extremely powerful conversation that I think everyone, regardless of age or health, can benefit from and that makes it clear that Dr. David Linden is not only a spectacular scientist but also a spectacular educator, a spectacular popular writer , a spectacular family man, including his husband and father and friend to many people and his colleagues, but he is also a brave and spectacularly generous human being.

Before I begin, I would like to emphasize that this

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is separate from my teaching and research duties at Stanford; However, it is part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public in accordance with that theme. I would like to thank the sponsors of today's podcast. Our first sponsor is Roca. Roca manufactures glasses and sunglasses that are of the highest quality. The company was founded by two American swimmers from Stanford and everything about Roca eyeglasses and sunglasses was designed with performance in mind. I have spent my entire life working on the biology of the visual system and I can tell you that

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Take a few minutes to complete the survey and help us continue to bring you the best content possible here on The Huberman Lab podcast, and as always, thank you for your interest in science and now for my conversation with Dr. David Linden. Professor Lyndon, welcome. Thank you so much. because you've been looking forward to our conversation and we have a lot to talk about, we do a lot of different aspects of science, a lot of different aspects of the personal journey and what you're facing right now as it relates to your health and your future. To start with a question that I learned from the one and only great Carl Dyseroth, who was the first guest on this podcast, my colleague at Stanford and for those of you who don't recognize Carl's name, he is an absolute phenomenon, he is an asset. clinical psychiatrist, so he's a doctor and he's also a bioengineer who has developed many of the modern tools for probing the brain, and every time I meet with Carl, the first thing he says is what are you most excited about lately, that's a good question.

So I'm going to steal that focus and say what you're most excited about lately. Well, very, lately, the most interesting thing I read in Neuroscience is the answer to a scientific problem that I think is very important for many. people's hearts and those are the nerve endings in the genitals that are responsible for sexual sensation and you know, if you think about it, people can feel sexy from being touched in many different parts of the body, but there is something special about the genitals. It doesn't matter male or female or intersex or gay or straight or bisexual or whatever you are, you know that genitals are a hot spot and why, and you would think that as biologists we would already know, this would be something we could just answer, but it has been a mystery for a long time and if we go back to 1860, there was a German neuroanatomist named Krauss and he cut out thin sections of tissue from the penis and clitoris and looked at them under the microscope and saw a particular type of nerve ending there that has since been called a corpuscle.

Kraus's and there were a lot of them in these two places, so he thought, "Well, maybe this is the cellular basis of sexual sensation, maybe these are the particular nerve endings that are there." responsible for this, um, but there were some things that were in favor of that and some things that were not, so these nerve endings are also in other places that people may find more or less sexy, like on the nipples and on the lips and they are in the anus, all places that become popular in that domain, but they are also in places like the cornea or the lining of the joints, so the distribution does not make much sense and was never known.

So if you really wanted to test as a scientist whether these nerve endings are responsible, you want to record their electrical signals while touching the genitals, you'd want to inactivate these cells and see if you can interfere with sexual sensation and This in a preprint from David Ginty's group in Harvard is just what they were able to do in mice, they found a way to tag them, record them, and artificially activate and inactivate them. Krauss corpuscles, so you see a nerve ending in the skin, could transmit types of information at an angle, could be tuned for heat or cold, itching, pain, inflammation or mechanical sensations, stretching, vibration, bleeding and, indeed, when recorded from these Kraus corpuscles, they really are. mechanical sensors, as you would expect, if they were involved in sexual sensation, that was good and then the other thing they did was they tried to turn them on artificially and the way they did it was they used genetic tricks to express one of the molecules uh uh from Carl Diceroth that activates neurons when shown blue light and they found that if they express uh uh this artificial protein in the cross cells of a male mouse and then they glow with blue light, The mouse has an erection so far, very good What happens if you turn them off?

Well if you turn them off on a male Mouse he is equally interested in females when they are in heat but he won't mount, thrust or ejaculate at most and if you turn them off on a female Mouse during the time in his cycle when he would normally be sexually receptive, you will find that she is much less interested, much less likely to let it out, much less likely to let it end like that. These are the remarkable results that finally, after all these years since 1860, we now know which are the nerve endings that transmit sexual sensation and, like all good science, then you know that there are many questions that are really interesting for our daily lives , like you.

We know that people like different things in bed and have different propensities to orgasm or like to be touched in different ways. Well, it's part of that reason, because of individual variation in the structure of your Krauss corpuscle, we know that sexual sensation decreases with aging, is part of that. because the density of Kraus corpuscles is lost in the skinof the genitals and that is a reasonable idea because we know, for example, that the fine tactile sensors in the fingertips, the so-called Merkel and Meisner endings, which are also named after German anatomists, like so many other things, They are also lost with age, so it's a reasonable idea, this finding from Ginty's lab has opened up a whole world of science and I've been my own lab doesn't work with touch, but I've been a fan of touch for many, many years. . especially because where I work, at Johns Hopkins School of Medicine, there have been a lot of fantastic touch researchers, it's been a world center for it and I found out about it over lunch and I was excited about it, so years ago I wrote a book about it.

I still follow the field and this is the most interesting thing in that field recently and as I remember, Ginty was your neighbor at Hopkins before she moved to Harvard, that's right, that's right, he was one of the queginty uh uh Stephen Shao Michael Katarina xinjiang dong There have been several world leaders in the sensation cellular base at Hopkins. Do you remember if in the preprint that you were describing there was an experiment where they activated these Kraus nucleus particles? For women, it's funny that you should mention that I sent that exact email to David Ginty and they told me that they are in the process of doing it right now and they don't know it yet, so I asked him and I told him that, for For example, it is the erection. the clitoris is even a thing in mice, he says, well, we're not really sure, so we're activating the Kraus corpuscles in female mice and we just stare at it and watch and see if something happens, just there, you know, it happens.

Know? Does the body change shape? Is there a color change? They don't even know what they're looking for because it's on the cutting edge of things, but it's a good question or maybe the mice would do it. Be more willing to mate outside the usual time frame of receptivity if these Kraus corpuscles are stimulated. That's possible. My suggestion, my assumption, would not be because I think the hormonal regulation of receptivity is like a sledgehammer and very difficult to overcome, but rather They may be more willing to continue mating or prolong their fertile time and I just want to remind people that We recently had a guest, Dr.

Rina Malik, who is an expert urologist in sexual and reproductive health, she is a doctor and she made it clear that the clitoris and the penis come from the same embryonic origin, they are analogous tissues in different individuals. I have one more question on this topic of sexual touch, these are peripheral nerves, so they are not from the brain or the spinal cord, they are in what We call it the periphery and my understanding is that peripheral neurons regenerate and can remodel themselves extensively so that Neurons within the brain and spinal cord tend to remodel less, especially as one ages after the so-called critical period.

Is it possible that these crossed corpuscles and their innervation patterns within the genitals change according to the stimulation that people experience; In other words, sexual sensation depends on experience; that's a big question, so we don't know because monitoring this in people is not technically possible. it requires cadaver tissue, so you can only do it once on animals, it will be possible and it could be for a couple of different reasons, in other words, it could be. I think what you're imagining is that there is real structural plasticity. If you looked at these Kraus corpuscles, you would actually see them changing their shape, their size or their density as a result of experience, but what can also happen is a phenomenon like desensitization, that is, when there is stimulation.

For a long time, the receptors can become temporarily less sensitive to touch and it is well known, especially in men, that chronic masturbation can produce a sensitization of sexual sensation in the penis and that could be as a result of a physical change, a morphological change in Kraus corpuscles, but it is more likely a change in their function that you couldn't see simply by looking at a schematic of their structure under the microscope. Such an interesting topic. Thanks for opening things up with that and I. I'll have to check out this preprint. I am also a big fan of the work of David Ginty and my colleagues.

There are many people involved in that line of work, of course. I'd like to talk about his recent book and the kind of underlying content. Based on what led you to write it and what intrigued you about this idea of ​​human individuality, the book is

unique

and we'll provide a link in the titles of the show notes and, um, it's a very interesting idea that We are all different, especially those who come. from a neuroscientist who was at least similarly trained to learn that the bumps and waves of the brain and the fine wiring of the brain are different and that we are all

unique

and different, we have different shapes aka morphologies, but focus on individuality human is not something that modern neuroscience or classical neuroscience has really made a lot of its focus on how people do I mean you're absolutely right so when I look at the experiments in my own lab how we do them well we work on mice we work on mice with genetic variation we don't work on highly inbred mice that are designed to be as genetically similar as possible to each other and then we raise them basically in prism in small cells, which may not be a good idea and we try to give them as similar an experience as possible.

They are given toys, food and water, but I agree that it feels like some kind of prison, they are not free to roam. Don't you have anything like the experience of a wild mouse? Let me put it that way, they are uh uh and yes, there are, as you rightly said, there are many experiments where there are enrichments for mice and they love it. For example, in our lab, when we put running wheels in the cages or mice and let them run overnight, they are active during the night. An average mouse will run two kilometers in a night for a while and some of the mice are so intense that they will run 20 kilometers imagine a mouse doing 20K but it will happen that they really like it, they don't like being in prison, they want to exercise and they are very bored , so yeah, to get back to your general point, uh, a lot of science is designed to try to find general principles of brain function, a physiology of genetics, and ignore individual variation, but individual variation is very important to our human experience and, in fact, is very important to the process of evolution and natural selection.

How species make their way in the world is something that requires a lot of attention and to me what's really fascinating is that when you look at the variation in the way the sense organs work, it's almost a miracle that we can agree . in a common reality even within the human species and this is true for more than some senses more than others obviously in your world on the retina we have several types of color vision loss that are well known and some other more complicated phenomena have have to do with deficiencies in the perception of movement or shape, but the place where this really happens is in the olfactory system, so we have approximately 400 functional receptors for different smells of odorant molecules in our nose and if By sequencing the genomes of In many people, the DNA that encodes these odorant receptors is found to be unusually variable from one individual to another.

In fact, if you take two different people on average, they will have functional differences 30 percent of the time. their odor receptors and if you do like Leslie Vossel and her colleagues did at Rockefeller University and do odor tests where they give people different things to smell and then they dilute them and find the threshold at which they can detect them, you will find huge changes from one person to another. People, generally speaking, some people just smell better than others, but in terms of individual smells there are also some smells that some people can't detect and other people smell one way, for example there is a secreted hormone called androstenone androstenone there some people can't smell it at all, to some people it smells quite pleasant like cut grass and to some people it smells bad like urine or sweat and it just depends on the genetic variation in a particular odor receptor, sorry. to interrupt another phenomenal researcher who studies smell, among other things, Catherine Dulock.

I once heard it said that some people have a gene that gives them the smell of microwave popcorn, they experience that smell as vomit and other people who lack this gene like the smell of microwave popcorn or at least for them it's not aversive, so it really can be a binary response. Well, it may actually be a very particular funny case, so the relevant chemical is butyric acid and also isovolic acid, so there are researchers. I think Rachel Hertz is one of them who has given a mixture of these two chemicals to people, if they say this is parmesan cheese, they say oh yeah, that's parmesan cheese and if they give it to other people and they say this It's vomit, they will do it. wow oh yeah that's vomit and if you tell people you give them a vial and they say this is parmesan cheese and they say yes and I get another one they say it's vomit oh yeah and then they say well we're actually fooling you it was the same vial.

They said no you didn't, you must have made a mistake. They are convinced that they could not have been the same, so this points out that not only is there a genetic nation that is responsible for our individual's smell perception, but we are also incredibly suggestible in terms of smells and are very dependent on them in terms of cultural context uh and this can be this can be learned and this is central to our humanity in the sense that humans are what I like Call the anti-pandas. Pandas live in a place in southern China and they eat one thing, bamboo, and that's it, humans are the opposite.

Humans can live in any ecological niche in the world, from the tropics to the poles, and humans eat a wide variety. There is a huge variety of foods and as a result it means that we have to have a very plastic factory system that there have to be very few things that we find innately aversive. They are just a handful of smells. Smells of rotten meat. uh, molecules with evocative names. such as cadaverine and putresine are things that even newborn babies find aversive, but there are other things going on that need to be learned, for example, almost all adults find the smell of poop unpleasant, but babies are happy to play happily with his own poop. learning that that's disgusting it's not because babies have a different nose it's because they have to learn culturally it's not innate it's not innate um there's just a few innate aversions to smells and some versions or innate tastes that they were born with and the other ones.

Things are culturally constructed and we can think of this in terms of how we talk about smells, so for example we could say that vanilla smells sweet, well that's weird, it's like they are two different senses, how can something smell sweet? It's like saying it sounds red right, it's a statement about synesthesia right and but how did it happen? And people say that vanilla smells sweet everywhere in the world? Well, the answer is no. In parts of the world where vanilla is used with sugar in sweet foods. like desserts, then people say that vanilla smells sweet or minty similarly, it smells sweet if it is normally used together with sugar, but if you go to a place like Vietnam, where mint is mainly used in savory dishes, people He won't say it smells like mint. sweets, then there is a Parrot Association there that at least at our level of conscious understanding feeds back with what we call olfactory or smell perception, but in reality it must be a Parrot Association at some point in development, yes, it is absolutely a Paired association. and it is something that happens continually throughout your life.

I mean, many people, for example, have stories of foods that they didn't eat as children but grew to like as adults. A good example of that is coffee. I have to overcome a bitter aversion to becoming a coffee aficionado, so you know, this feeds the more. General theme that there is no such thing as pure perception, perception is inference, it's not like there is a purely objective world that you can somehow make your way through. the senses and we can perceive that as the truth all our perception through all our senses, both the senses that point outwards to the world like smell and taste and sight and hearing and the senses that point inwards like balance and uh, is my stomach full? things like that, they are all based on experience, expectations and the situation at the time, as many of you know, I have been taking ag1 daily since 2012.

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I reply ag1 if you want to try ag1, visit Drinkag1.com Huberman to claim a special offer, they will give you five for free. travel packages plus a year's supply of vitamin D3 K2 again, that's drinkag1.com huberman, are there any examples of visual perception uniqueness that come to mind? I recently made a post on social media that involved it being essentially three rings, a blue ring and a red ring. and a blue ring in the center maybe it was the other way around excuse me, it was red blue red and um I asked which ring is in front or are they all on the same plane now, of course, it's a two-dimensional image, right? um and curiously it is divided into approximately thirds some people see the blue ring in front quite a few others see a red ring in front others see them all in the same plane and this we believe has to do with differences in two things between individuals, one is the distribution of the cone photoreceptors, which we know is essentially random between individuals, maybe even between the two eyes and then um and that gives rise to this phenomenon of chromatic aberration um which is the displacement of the visual image according to the wavelength of light and we won't get into physics now, I will soon.

Make a post that hopefully sums it up in a way that's simple enough for people to understand, but clearly some people see certain colors in front of others, and the person right next to them could see the color opposite to the front and others say what are you talking about. all the colors are in exactly the same plane of vision, so that's the one I know. I assume you know some others and maybe some more robust ones. Well, I think you know that maybe this is not what you had in mind, but one. The way experience changes the visual world has to do with the amount of light you are exposed to in the first five years of your life, so children who do not go outside are much more likely to be nearsighted and , of course. excited short-sighted yeah uh uh uh when they grow up uh that kids who went outside and now we know that at least part of the story is that light seems to stimulate the expression of a class of molecules called trophic factors that you're okay I'm familiar with that, in It actually changes the shape of the eyeball, so it is not really the structure of the retina or the lens of the cornea.

The actual degree of elongation of the eyeball changes by changing the way the retina sits in relation to the lens and that appears to be the case. dependent on light at an early stage of life and leading to a higher incidence of myopia and to me this is fine, first of all it is news that you can use, you should take your children outside for absolutely all kinds of reasons and you should go out too, especially in the mornings, yes, that circadian rhythm, yes, I know it's a famous Huber menesque, uh uh uh, period, they'll put me in the grave, David, and I'll tell him to the people to do it.

Maybe it's on my tombstone, he will say: get sunlight in your eyes, especially on cloudy days because there is still sunlight even if you can't see the physical object of the sun on cloudy days, well, you know, I think. This whole idea of ​​having traits that depend on early life experience is fascinating because there are a number of situations where you might guess that something is genetic but it isn't; It actually depends on early life experience and there's an amazing story about this that has to do with the early days of World War II, so in the early days of World War II the Japanese army just rampaged through Asia, they defeated The British, Malaysia and Singapore, invaded Thailand and Burma and were knocking on the doors of India and everything was going very well, except that the Japanese army had a problem, there was a huge number of their soldiers who were incapacitated by heat stroke, their core temperature became too high and when army doctors examined them they found this was much more likely.

This could happen in soldiers who came from the northern part of Japan, Hokkaido, where it snows in winter, as opposed to the southern part of Japan, like Kyushu, which is a semi-tropical environment and the classic explanation that biologists like us would guess would be let's say Oh, okay, this has happened genetically over many years. You have a family that has been in Kyushu for many generations and you have selected four genetic variants that allow you to tolerate heat better and we really know what this is, so if you are more tolerant to heat it is because you have more than one particular kind of sweat glands called ekrine sweat glands, the saltwater type of sweat glands, not Liberty's stinky armpit sweat glands, called alpricorn sweat glands, the echron ones, you have a higher fraction of them.

They are innervated, meaning that signals from your brain telling you that your core is too hot can make you sweat, so the total density of sweat glands between northern and southern soldiers in Japan was no different, but the Southern soldiers tend to have a higher rank. of innervation, okay, okay, this happened genetically over many generations, but if you look at those rare cases where there were soldiers from a long-established northern family and their parents moved south and then they grew up in the south location, they had a lot of sweat. sweat gland innervation, they were well tolerant, conversely, if you had a well-established family in southern Kyushu and they moved to Hokkaido and then had their child, that child developed the northern sweat gland innervation pattern , which means less nerve innervation to those sweat glands, as you mentioned before.

Since many sweat glands had less nerve innervation, therefore, those sweat glands could not activate, they could not release heat, their tolerance for heat was lower, exactly true, and the wonderful thing is that this provides an advantage that cannot be taken advantage of. Evolution and that can happen immediately in this generation, true, evolutionary change is slow, true, and you can adapt as a species and as a family over many, many generations, but when you have a phenomenon that is established in life early. experiment well then you can benefit from that early experience within your own life, it's not that your great-great-grandchildren ultimately benefit, you benefit, another wonderful example of this comes from field mice and we were talking earlier about how we both work. with scientist Irv Zucker at Berkeley, who was a specialist in involves and what people discovered is that if you take wild-caught voles and you have pregnant mothers and you have them in the laboratory, but manipulate the lights so that they have spring artificial, in other words, the length of the day lengthens day by day during pregnancy, so what happens is that when your puppies are born, they will have a low density of fur in anticipation of summer temperatures, uh, if you, however, uh put them in artificial autumn where the length of the day is shortened.

They will be born now at a high density to anticipate winter temperatures and of course you can do this no matter what the season of the world is by manipulating these lights in the lab and So, just like the sweaty Japanese soldiers, this is a great example of early life plasticity and the kind of trait that if you asked someone they would probably guess is heritable, but actually isn't. Thanks for mentioning Irv Zucker, who also mentioned that he was an advisor to both of us, who have done incredible work on circadian biology, seasonal rhythms, hormones, and behavior.

I have so much reverence for Irv and the experiment you mentioned made me smile widely because he is nothing but one of God, maybe hundreds of incredible studies, so if people are interested in seasonal and circadian rhythms. rhythms and biology of the most interesting kind definitely check out Irving Zucker's work at Berkeley, we'll give you a link to his uh PubMed uh there since we've been doing a tour of individual variation in olfactory perception, visual perception and, now heat tolerance um, I have to ask, do you know of any examples that come to mind? um in the auditory domain that particularly intrigues you, yeah, well, I would say a really interesting example has to do with perfect pitch.

So perfect pitch is a trait that is, you have the ability to hear a note, play it and say, oh, that's a C sharp, right, this is a pretty rare trait, so even if you look among highly trained musicians , if you went to the Peabody Conservatory at my University at Johns Hopkins and the people tested there, they would find a higher incidence of Perfect Pitch than they would find in the general population, but still, maybe one in ten trained musicians has Perfect Pitch and Parenthetically, having Perfect Pitch doesn't necessarily make you a better musician, but it is an interesting option. phenomena and then the question is whether perfect pitch is heritable and the answer is when you look at twin studies where what is what we use to estimate heritability, the answer is that it is somewhat low if there is a hereditary component, but it takes into account , my recollection is on the order of 30-40 percent yes of the variability of imperfect pitch, however, if people receive ear training from a young age, the chance of them developing perfect pitch can improve dramatically.

In your book, unique, do you cover aspects of human individuality that extend beyond the perceptual chin domain into the cognitive domain, well, yes, absolutely, and you know, I think it's good to set the stage here if we're going to talk about heritability and human individuality, and so on, if I can continue. a little riff uh uh for the benefit of your listeners and viewers here, so if you look at human traits, whether they're behavioral traits like shyness or very simple morphological traits like height, what you tend to find is that there are There are very few traits that are completely heritable where all of their variability can be predicted based on the genetic variants that you get from your mother and father and there are some traits that are absolutely not heritable but most of them fall in between so let me give them an example.

There is wet or dry earwax in the world and it turns out that this is determined by variation in a single gene. The gene name is boring, it's abcc11. It is an ion transporter. And there is a variation in this gene that gives rise to either network. or dried earwax, no matter how your parents raised you, no matter what foods you ate growing up, no matter what diseases your mother had when you were in the womb, it is 100 percent hereditary, does this mean? We should call that abcc11 earwax-type gene, well, no, because it's not there just for that.

This gene is expressed in cells everywhere in the body and does all kinds of things. Earwax is something we notice that genes do not encode. For traits they code for proteins, so we need to be careful how we refer to them that way. For example, the wet earwax G variant of the abcc 11 gene also confers a slightly increased risk of breast cancer. So clearly it's not just for earwax it's for a lot of things, most of which we don't know yet, but in the case of earwax this exchange is 100 hereditary at the other end of the scale the speech accent is zero per percent heritable and depends entirely on the speech you experience in your childhood and interestingly it is the speech of your peers rather than the speech of your family so children of immigrants sound like where they ended up not like their parents and there is no evidence of any degree of heritability not only to be clear, I'm talking about speech accent, like whether you have a high or low voice, or whether it's nasal or more or less resonant, these are physical things that have to do with the vocal tract and are partly heritable. we have one thing that is 100 percent heritable one thing is zero percent heritable but where do most things fall? most things fall in the middle uh uh one of the most heritable traits that we know of in humans is height and in the United States height is about 85 percent is heritable 85 percent of the variation in trade height can be explained by what you inherit from your mother and father, well, what is the rest?

Well, it's nutrition, it's the diseases you fought, it's also a variationrandom, which we will talk about. much later, um, now you could say okay, well that's an estimate for people in the US, is this true worldwide? Well, not if you go to a place where people routinely don't get enough nutrition and routinely fight infectious diseases. "This has been studied in rural Bolivia, for example, or in rural India. Now height is no longer 85 percent heritable, it's only 50 percent terrible, because people in these situations in the who do not get enough food to fight these diseases cannot. If you don't live up to your genetic potential for height, if you want to make things better for the people of the world, then everyone needs to have basic things like the ability to learn, sufficient nutrition, healthcare, and decent schools to be able to meet its genetic potential.

I have used the potential for positive traits and height as an example because it is not controversial, but we could apply the same analysis to intelligence, general intelligence. Now there are people who argue about whether things like IQ tests really measure anything real and there has been a lot of fighting in the scientific literature about this, but I think that IQ tests are not perfect and sometimes they are culture-bound, but They are actually quite predictive of later success, and much more so than, say, SAT tests or GRE tests. or mcats or other standardized tests presumably correlate in some way with Baidu, but IQ tests are better they are actually talking about the classic IQ test.

I'm talking about the modern variants of the classic IQ tests that are administered by trans psychologists, uh, and they're not just a paper form, so they're not perfect and no test will be perfect, but they're pretty good, so , if you ask the question right, what is the inherited ability for the IQ test? The answer tends to be different depending on the population if we look again at countries like the United States or Western Europe that are quite prosperous, where people tend to have good access to nutrition, healthcare and education, and children can play and They are not and they are not traumatized by the war, so the IQ test score is heritable in the range of 60 to 70 percent, but if you look at the people who do not have those benefits, they are poor and this may be in the United States.

Also, if you look at communities that face discrimination and have poor health care in schools, then IQ is less heritable, for the same reason that it is high because people can't live up to their potential. genetic when they don't have the basic things that everyone needs, presumably if two identical twins and I realize they're not identical, but you're familiar with twins, you have twin children, um, if two identical twins are raised. Separately, uh, the correlation in your IQ can only be that it's only 60. I think you said that about 66 percent of your IQ can be predicted based on your genetic makeup.

I just, I mean, it makes a lot of sense to me to know why if one of those twins went to schools that required you to know a lot of different subjects and the other went to schools where the level of instruction was so poor that one would do much worse in a IQ test unless, of course, the IQ test wasn't. You're not taking advantage of school knowledge, you're taking advantage of some other thermometer of so-called intelligence or IQ, well, you know, the thing is that the Good schools correlate with many other things, so students who go to good schools are not simply benefiting from good schools, they also tend to have good health care and safer, less traumatizing neighborhoods and are more likely to have parents with books at home and uh uh and a lot of things that are beneficial, so when you try to do epidemiology on this, you have to be aware that things are deeply interconnected, but you raise a good point and it turns out that the way that We obtain these heritability estimates in two ways: one is to compare the so-called identical or monozygotic twins with the so-called fraternal or dizygotic twins, so identical twins will share almost one hundred percent of their genetic variants and, on average, fraternal twins they share 50 percent of their genetic variants and generally when people do these studies to avoid sex confusion, they will compare same-sex fraternal twins, so boys to boys and girls to girls uh uh and uh when you put these incidents into a formula called the Fischer equation, then you can get an estimate of the heritability of the trade. but there is an assumption in that and it is called the equality of environment assumption, what you are saying is that two children raised in the same family have the same environments, well that is not always true, true, it can be violated by a series of different situations, so it turns out that a more powerful but much more difficult way to estimate heritability is to look at twins raised apart, whether they are identical twins or twins raised apart, and there was a landmark study called the Minnesota Twin Study. bred separately, which is abbreviated mystra, i.e.

It really is the gold standard for assessing the heritability of many different human traits, both behavioral traits and incidents of disease, but of course it's a small M because you know that the population of identical twins raised separately that you can enter the laboratory is not. that's how big they had something, I don't remember the exact numbers, but they had something like 80, some uh, identical and 50 some fraternal, uh, in their sample, but by doing this they were able to get a lot of interesting estimates and so on. for example, most personality traits, which psychologists use the acronym ocean to mean openness, conscientiousness, empathy, agreeableness, and neuroticism.

I think I spelled it right, that these traits, on average, tend to be about 50 percent heritable, so okay, you say right. Well, fifty percent of those personality traits are hereditary, the rest has to be how you were raised, it has to be in your family, so everyone was surprised when they did the analysis and found that the family has almost nothing to do with it. see with that. What is it? Are you kidding? Parents in the world can instill many things in their children. They can demonstrate occupations, so people are much more likely to adopt an occupation if their parents did.

They can instill moral ideas and religious ideas, but in terms of these ocean personality traits, they have surprisingly little to do. So this begs the question: if 50% of the variation in these personality traits doesn't come from your genetics or your family, where does it come from, and the answer seems to be that it comes from the random nature of body and brain development. nervous system and this is a point that I think a lot of people don't understand. This is something biologists know, but we have done a very poor job of communicating the entire genome to the general public.

DNA, the three billion bases of DNA, the approximately 19,000 genes in a human being, is not a blueprint for getting your body and your brain there, it is not a schematic diagram that connects everything to everything, particularly in the nervous system, where we have these hundreds of trillions of connections, it's more of a pretty vague recipe, so the genome doesn't say, oh, okay, glutamate uses a neuron in the region of the brain called the thalamus, you know, it grows 200 microns towards the top and then, and then, and then it crosses the midline and then it grows towards the ear because you know another distance no, it says something like hey, group of glutamate neurons in the thalamus here in this area, approximately half of you crosses the midline, and so what does this mean in terms of individual variation?

Well, it means good. First, for some individuals, 40 of their axons will cross the midline of the brain and for another individual, 60 will do so in identical twins, and as you correctly said a moment ago, identical twins are not really identical in either their bodies or their temperament, so if you take newborn identical twins and give them a CT scan just to measure the shape of their organs, they are not the same. You may have a twin whose spleen is 30 times larger than the other twins or whose liver is 30 times smaller than the other twin. twins even though they have exactly the same DNA and depend on each other in utero and presumably have the same or very similar fetal environment and the reason is the random or as we say stochastic nature of neural development, a great way to study this is with nine-banded armadillos.

I know we're getting weird here, but I love the armadillo because I'm told I don't want to interrupt you too much, but as far as I know, the only one. animal in North America that carries leprosy uh that's true and um and there's a lot of twinning in Armadillos, well what there is actually quadding, so the armadillos or the nine-bounded armadillo in particular and they're different armadillos. I'm not really an armadillo specialist. I don't know if this holds true for all of them, but the nine-banded armadillo is born as identical quadruplets, amazing, amazing, so you can take these identical quadruplets, newborn armadillo.

I don't know, do you think you call him? those puppies I don't know what a baby armadillo was called, I'm sure there is a particular word for it and someone will tell us. I'm sure someone likes to comment on YouTube what the name of a baby armadillo I know is a ferret. baby ferrets are kits uh moms are jills dads are bobs I used to be obsessed with these kinds of names you know it's a ferret business or what it's like a gang of raccoons or whatever so yeah can you tell us what baby armadillos are called and what a group of armadillos are called um, you gain the pride associated with being right, that's right, one of my favorites is the ostentation of peacocks, amazing or the murder of crows that appear . with these things, I know that's a lot of otters, I think I think that's right, but if you have four newborn, nine identical founded armadillos, then this is a great model system that biologists can use to study stochastic differences in the development and Indeed, their markings are wired slightly differently, their bodies are slightly different if behavioral tests, even from very early in life, have different propensities, some are bolder, we will explore more, some will tend to hide more in the corner and you know, we.

I know this from the lab: you get a box of mice that are inbred from the breeder and you start them off and they don't behave identically. Some might try to bite your hand, others will run away, others will stay still, where does this behavioral variation come from? they come from mice that are almost genetically identical, well it comes from a lot of things that don't always have exactly the same experience, but mainly it comes from the pseudo-random stochastic nature of development. I'd like to take a quick break and acknowledge our sponsor inside tracker inside tracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you achieve your health goals.

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I mean, if you're a fan of the X-Men, as I'm a huge fan of theIt is at the heart of variation, which is at the heart of individuality, which we are talking about, so genetic variation is at the heart. of individuality, but there are also these other things that we have talked about, there are the effects of early life experiences and there is the stochastic nature of development because if through the randomness of development you have a particularly good liver you are not going to transmit that to your children, right, that's not in your germline, you're not going to pass that trait along just a brief insert here in the germline.

We overdosed on Rashafi on the podcast that studies epigenetic transmission and, um, and a uh inheritance of is not Lamarckian, we have to point that out, but um inheritance of uh kind of acquired traits uh happens and uh the germline are the genes that are present in sperm and eggs, all the other uh cells in your body have genes, of course, but the best way to say it is just go to the gym and get in shape. It doesn't make your kids fitter because, as far as we know, the germline isn't directly changed. in other words the DNA inside sperm and eggs is not modified according to their behaviors in most cases but not all, that is correct and as you correctly said about oded work and work from other people, there is what is called transgenerational epigenetic inheritance, which means that you can have traits that are not transmitted from one generation to the next, but even from two generations to grandchildren, which do not require modification of the DNA, but until date that has been demonstrated very convincingly in worms found in plants, and the evidence in mammals is In my opinion, it is not there yet and most of the claims about it and it is very popular to say that I epigenetically inherited the trauma of my grandmother or great-grandmother.

The evidence in Presence is poor, in fact much of it comes from epidemiology. most of whom came from famines in the other colic region of northern Sweden and they had very good medical records and they said, well, if your grandfather went through the famine then you are more likely to have this trait if you are a man or if you grandmother went through this so if you are a man this train you are a woman or that trait and I mean, there are two problems, one is that there is no biological mechanism, but the other problem is that the way these things were What is discovered is something called listening or hypothesizing after the results are known.

They did a lot of statistical comparisons to try to find something significant and you know from your work in the lab that when you do a lot of comparisons you will get some things that seem significant only once in a while, randomly, luckily, and you have to apply a statistical correction called bonferoni correction when you do a lot of particularly post-hoc comparisons after the experiment, uh, comparisons to set the bar much higher for accepting those data and most of those studies. They did not apply that correction and I remain unconvinced of transgenerational epigenetic inheritance in mammals.

Let's be clear, just because it hasn't been convincingly proven now doesn't mean it won't be. There are some good people working very hard. about this and they may describe a mechanism and show it convincingly in years to come, but right now you may inherit trauma from your grandmother or great-grandmother, but you are probably doing it socially, not through marks in your DNA that changes the way your genes are expressed or not, yes, so I subscribe to the idea that there is a transgenerational inheritance of correct upbringing and education, I mean, your grandparents raise your parents, who raise you, not always people can be adopted, in fact, I have adopted members of my family, um, but I understand what you are saying correctly, the evidence that, for example, some stress-related gene was modified during trauma in my grandparents is great-grandparents and the idea that that was passed on to me through my parents than the The evidence that exists is much weaker, right?

And when you think about it, how did that thing happen that had to get into your grandparents' sperm or egg and then produce that effect in your parents' brain and then it had to get into their parents? sperm or Excel and then contribute to producing it in you, but fragmentation of DNA and sperm is um or in eggs is common, especially as people age, DNA, sperm and eggs fragment and it is possible If some of those mutations still allow for viable embryos, then in theory the germline could be changed by environmental events. Okay, but now I think you're starting to talk about things that are heritable.

You're not talking about marks on the DNA, you're talking about the structure. of the DNA itself and that is a separate topic now. I think I want to be very careful with this because what I now think is pretty well established is that you can transfer things epigenetically in a single generation, um, as a result of experiences. that the mother has during pregnancy, so, for example, we know that during the 1918 pandemic they flew, many women were pregnant and got the flu and if you look at their children, you find interesting statistical anomalies and those children, for example, the boys ended up going into the military for World War II and of course the military does a full physical exam and the records are very good so you can go into that database and find the male children that were in the womb during the winter 1918 during the pandemic. flu or on average a millimeter or two less, you could say a millimeter or two that is nothing, but in a huge statistical sample of millions of people that is enormously significant, the most interesting thing is that the incidence of schizophrenia increased approximately four times , from about one percent to about four percent and although autism was not a term in 1918 yet, I think it came later, what we would now retrospectively call autism also increased fourfold, so there is something to the fact that that mom is stressed and carrying the fetus at a particular stage.

That seems to affect brain development in a way that then makes the child more likely to be schizophrenic or autistic when they grow up. We know it's stress and what I remember about it. I believe this was also the work of the late Paul Sternberg. Maybe. I have that name um wrong, but in any case, if the pregnant mom gets the flu in the first trimester, you see this higher incidence of schizophrenia and autistic offspring um and do we know that it's stress per se because it's stressful to have the flu? but the flu is a lot of other things, it could be a fever, it could be some breakdown in the immune barrier.

I just want to open up how many variables this could be, or we know it's something in the hypothalamic pituitary, so - called the stress axis, which is the adrenal glands, so the hypothalamic, pituitary, adrenal axis, is elevated cortisol? or could it literally be an immune neural interaction of some other kind? It's probably the last thing you mentioned, an immune neural interaction and the reason I say that. is that Gloria Choi at MIT, along with her collaborators, has made a mouse model of this phenomenon, so she takes pregnant female mice and injects them with something that doesn't actually infect them with viruses, but rather gives them a limb chemistry.

That's in the code of the viruses that mimic the viral infection and then what happens is that in a way that curiously is an interaction with the bacterial content of your intestines produces an increase in an immune signaling molecule called interleukin 17. interleukin 17 it can pass through the placenta to the fetus and if it is present as you said at a particular point in development, it doesn't work anywhere during pregnancy, but during something that is sort of the mouse equivalent of the first trimester, it does. That happens, it causes disorder. development of the layers of the cortex instead of looking like layers of a cake, you see balls and clumps of cells and, parenthetically, in some, but not all, postmortem tissue from autistic people, you can also see those balls and groups of cells. of cells that are believed to reflect alterations in cell migration, yes, some, I don't know if it's entirely known how much Vision or migration is sold, but certainly migration is part of it and it's very likely that that critical moment uh to alter this order of the brain and produce these increases in schizophrenia or vulnerability to autism, they are getting to a point where neurons are migrating during development and so what the choice group did was they did all the things that We would like to do like a biologist so we gave him things to block the function of this interleukin signaling molecule and he blocked the phenomenon.

They artificially injected the signaling molecule into the fetus's brain when the mother had not been stressed and were able to reproduce it, so I'm not saying that there are no important hypothalamic-pituitary axis effects of stress hormones that you mentioned, but in this mouse model system, it looks like it can occur through this immune signaling pathway, so the question is: are these mice autistic, well how do you know if a mouse is autistic? The answer is, actually, it's a bit vague. There are behaviors that neuroscientists say are analogous to human autism, and one of them is if you give a mouse a marble in its cage.

You'll compulsively bury it over and over again or you'll bury a lot of marbles and people say that's somehow analogous to some of the compulsive behaviors seen in autism, it's a bit of a stretch right? I mean, it's challenging to interpret mouse behavior in humans. terms, but it is a reasonable, credible first step and I hope that more continues to be done around the first trimester flu hypothesis because it has been around for a while and obviously there is a spectrum of what we call autism Massive burgers and today in Nowadays people sometimes refer to this as neuroatypical, there are some people with high-functioning autism, there are some people with low-functioning autism, and in fact, there are some high-functioning and low-functioning people who don't have autism, so which, but it's something that I think demands our attention and that, hopefully, will be resolved at some point because also the flu is, but one immune, insult, and presumably pregnant women are being bombarded with all kinds of viruses, bacteria and infections fungi and we fight them. not fight them and who knows what the variation is in the neuroimmune interactions that exist there that give rise to good variation and let's call it debilitating variation, well that is absolutely correct, for example, we I don't know what the effects are on children. who were in the womb while their mothers were fighting greed, right, we won't know for a while or the common cold and I could say there might be nothing more than or there might be something serious lurking there like there's a pandemic flu and It will be very interesting and important to discover it.

Okay, I would love to talk to you about mind and body, but before I do, I would be totally remiss if I did. I'm not asking for your broad understanding of the contours of the mini brain, the cerebellum, the so-called mini brain, and here's why I've been a practicing neuroscientist for almost three decades. I know where the cerebellum is. I have dissected it. a lot of them. um, I could tell you where some things are there and I've certainly read about what the cerebellum does, but every time I do a PubMed search on the cerebellum I see a growing set of things that the cerebellum is involved in. not just balance as most people hear, but also timing and cognition.

I hear about synchronization in particular of motor behavior, but I also hear that it's involved in learning and not just motor learning and it's certainly involved in motor learning, maybe that little mini brain is involved. uh, doing 50 or a thousand different things, but how should we think about the cerebellum, what it's doing and what are some of its core operations that inform both what it's doing and maybe what other areas of the brain are doing as well? to the retinas or the auditory cortex or the thalamus and yes, there are some mysterious nuclei in the brain, but to me the cerebellum is one of the most cryptic and complicated structures to understand and I know you spent some time there, so what does well the cerebellum? uh, cerebellar researchers like to joke that the cerebellum is a counterweight to keep the head from falling forward oh perfect, with all the texting these days people need bigger ceramics, that's right, probably at over many generations, then that will happen along with an expansion of the thumbs.

Ah, so, but of course everyone will be texting their minds in about 10 more years. You'll have Elong implants and you won't need your thumbs at all, yeah, or maybe just five, or my friend Eddie Chang is a neurosurgeon and uh. He works on the auditory system, he has been on this podcast before saying yes, in theory and in thePractically, you could simply record the neural output to the muscles of the speech system, you could essentially amplify it and send text messages without actually speaking. In fact, when we were reading he told me, "We're actually receiving the signals as if we were going to say the words we're reading, but they're not getting to the place where you could get a full postsynaptic signal." potential, so you're not actually moving the vocal machinery, which means the motor signals are sent outward and then you're speaking what you're reading, but you just don't know it, it's true, it's very analogous to what happens During REM sleep, just when you have orders, your brain issues orders to your muscles to do things like behave in your dreams, run away or go here or go there, but those signals are actually blocked and the trunk is prevented from brain reaches your muscles because the nerves that do not pass through the brain stem, such as those that control eye movements, are not subject to that block, which is why you can produce rapid eye movements in REM sleep, but yes, this is a general theme in The brain often has the output but then turns it off and there are behavioral disorders in REM sleep in which people fidget and move while they sleep during the REM period and it is because this output flow that is normally blocked it is not. blocked, has the opposite ever happened to you? uh I have where you wake up and you're still in so-called rematonia, you're still paralyzed, yeah, and there's that split second that feels like an eternity where you're wide awake and you can't move and I'll tell you it's terrifying, yeah , a sleep paralysis and, in fact, you know it's been known forever.

In fact, you can find ancient Greek depictions of people lying down with a demon on their chest paralyzing them and that is actually due to sleep paralysis. Later, Hogarth did a drawing of exactly that, so yes, this is a well-known phenomenon, but going back to the cerebellum, as we started, the cerebellum, as you said, is definitely involved in motor coordination, so people who have damage to the cerebellum is not. They are paralyzed but tend to be clumsy, they tend not to coordinate their movements, they have a disturbed gate, if they are reaching for an object they often overtake it and have to make successive approach movements to return to their target, so that is well understood . but if you look through evolution, the cerebellum is connected to this region of the brain called the thalamus and from there it is connected to many regions, including the frontal cortex, where phenomena like planning and decision making and moral sense and many aspects of personality seem to take place. be coded so that then the question is good, that is far from being clumsy, what are these connections doing?

And as time has gone on, I've been in this business for over 40 years. I'm an older guy and at first we were like oh. yes, cerebellar movement control, motor coordination, that's what it's for as time goes on, as you correctly said, the cerebellum has been involved in more and more functions, many of which are very far removed from the motor system and if we're looking one thing about what the cerebellum does is it's there to predict the immediate future, it's trying to determine what's going to happen in the next second or two to achieve God's best behavior and as you can imagine, this kind of general calculation could apply very well, you can see why.

It's important that you know the motor systems and play sports and know if you're trying to hit a baseball and you're watching what the pitcher is doing and you're trying to anticipate what the pitch is, but it also comes up in the social realm if we're trying to read people. someone and predict what this person is going to do, friend or enemy, which is one of the first things we try to evaluate when we meet someone, whether they are competent, which is the second thing we try to evaluate when we encounter something. Much of this depends on predictive circuits and depends in part on the cerebellum and appears to be at least partially impaired in people who suffer cerebellar damage, so it seems that, interestingly, the cerebellum began for predictive purposes related to motor control and , through evolution, its basic calculation has been applied to other non-motor behaviors.

Now I'm speaking in generalities and many of the details of this are still to be worked out and understood, but I would say that it is, in a nutshell, the modern conception of the cerebellum. Thank you, finally someone explains to me that, in an excellent and highly informed way, what the cerebellum does, could not be more I appreciate my enjoyment in all aspects of biology and life, the term nature versus nurture is relevant, but never as much as when I think about the nervous system and I know it firsthand because I have studied neuronal development, both the nature side and the so-called hard-wired things. that genes just set up the neurons that connect to that neuron, etc., the cerebellum is in the back, the eyes are in the front, hard-wired things and then soft-wired things, parenting things are things that can be changed through experience, what are your thoughts? about nature versus nurture and there should even be a versus there, yeah I don't think there should be and I have a lot of problems with nature versus nurture as an expression that was popularized by Francis Galton in the 19th century.

Darwin's uh colleague and I think it's wrong or misleading in many ways, so of course, nature in nature versus nurture refers in this case to me, heritability is correct, what you inherit in the genetic variations of your mother and father. and upbringing means how your parents or your community raised you. The problem I have with parenting is that it is too narrow a term that should really be replaced with the word experience and experience in the broadest possible sense, not just social experience but also. the foods your mother ate when she was carrying you in the womb, the diseases you fought or that your mother fought while carrying you in the womb, the bacterial population of your intestines, so experience means anything that affects you from the earliest possible time. stages of fetal development, uh, continuing until the last day of your life, I think it should be very expansive, much more than a social experience in the family or the community and, as you mentioned, I have a problem with a versus because there is the idea that These things are essentially in opposition, is he that way because of his genetic variants or is he that way because of what happened to him?

I think the thing to realize is that experience and heritage interact in all kinds of interesting ways. some of which are oppositional and others reinforce a classic one in genetics that has to do with a genetic disease called phenylketonuria or PKU, which is the inability to metabolize the dietary amino acid phenylalanine and, therefore, to have this. You have to inherit broken copies of this gene from both your mother and father, so it is a recessive trait and this is where experience comes in: it only matters if you eat foods rich in phenylalanine, if you don't, it doesn't matter.

It doesn't matter that you inherited these things correctly, so that's one way that genes and experience interact, an idea of ​​how they interact positively. Think about athletic ability, so a lot of athletic ability has a hereditary component if you're born. fast for example, then you are more likely to play sports and get better exports as a result of your experience, so here genes and experience feed off each other in a positive feedback loop, so there is really no versus . a versus at all and then of course the last thing is that this is not all so we talked earlier about the pseudo-random nature of stochastic development and so if I were to take the phrase nature versus nurture and reconfigure it, I would . change it to read heritability interacting with experience filtered through the random nature of development now that doesn't roll off the tongue as elegantly as nature versus nurture, you know, nature versus nurture it's like governments the gloves don't fit, you have to give up I know it has those kind of agile cash rates, but I think it's more precise, so heritability interacts with experience filtered through the randomness of development, yeah, so we can shorten it and, um, and just do it we'll call it, um, uh, the Linden hypothesis.

You know, I don't think I can take credit for it belonging to other people, sure, but there's a long history in science of things being shortened and coined and that's just as important and we're not. I'm not trying to steal attribution here, um uh, and the good news is that maybe you can't call it the Linden hypothesis, but I can, and what I've found is that with the Galpin equation, which is now available as hydration, is a formula a formula that provides broad but research-informed parameters on how much water you should drink to maintain adequate hydration for physiologists Dr.

Andy Galpin, PhD in physiology and expert in all aspects of exercise science, exists the Galpin equation the soberg principle, so I'm naming these things left and right, all right, um when appropriate and um, so I'm naming these things sparingly and when appropriate um, from here on out heritability interacting with experience filtered through the randomness of development is the Linden Hypothesis and I'll be damned if anyone's going to rename it, uh um, faster than I'm going to propagate it. Well, I think all the geneticists will gnash their teeth because it's named after someone who isn't actually one. a geneticist, very good, and your dentists will thank me, let's talk about Mind and Body, okay, this fascinates me for a couple of reasons and I promise to keep it brief, but when I was a child I was very interested in animals and biology. and my father is a scientist and I got very interested in neuroscience early on, as people may know, and a lot of neuroscience as it progressed in the mid-90s, 2000s, 2010s to 20s, was focused on the part of the brain, there was very little in the body. nothing about access to the gut brain in early discussions and coursework, um in parallel, all that.

I have been interested in mental health, physical health and let's just call it performance and I became interested in practices based on breathing and meditation, things like Yoga Nidra, things that, by the way, from experience I immediately understood had a profound influence on the states of the nervous system, mind and body, today there is a whole institute at the National Institutes of Health for complementary health and medicine that essentially explores things like Yoga Nidra breathing practices, even supplements and things like that, and there's this understanding that, oh my goodness, the nervous system extends to the body and the body sends neural signals back to the brain, so this whole notion of Mind and Body has thankfully migrated away from the Esselen Institute of Counterculture in California , just, you know, um.

By the way, that's not what I think it is, but that's what it looked like in the past and now people at all levels of science and medicine at all the major universities and in all the scientific journals are starting to publish articles . about the interactions between body organs such as the respiratory systems, the diaphragm, the lungs, the heart, heart rate variability, we hear about the liver, the intestinal axis, the brain in particular and therefore Mind, Body, the idea that our thoughts could influence our body and that our bodily state could influence our Fortunately, thoughts are not only understood, but they seem to be accepted and appreciated.

What are your thoughts on Mind and Body? What does that mean to you and what do you think is the potential of mind-body interaction? It seems to me that we've barely scratched the surface, yeah, well, I'm glad you asked because I think it's a really fascinating situation and where things are changing very, very quickly and I think for me the most important thing that people should understand is that when I have a hypothesis, let's say you have a hypothesis that meditation can alleviate chronic pain. Well, there's a temptation to think that this operates outside the realm of science and biology, that it's in some Airy fairy kingdom in the clouds where this happens and and And I mean, for good reason, there are a lot of people who do it. they'll describe exactly that way with auras or they use scientific terms like resonance and energy, but they don't actually use them scientifically, so you know there's a lot of things.

There is some very confusing language surrounding this, but it shouldn't obscure the facts that when you have a hypothesis that says that some mental state like meditation or guided breathing affects some process in the body, you should try to understand this in terms. of a biological hypothesis, not in terms of some indistinct realm, that is, it is different, like manifestation, yes, and you know, I really learned this initially from my father, my father was a psychiatrist, fromIn fact, a kind of old-fashioned talking priest psychoanalyst, how? He practices in Los Angeles and we had dinner together every Wednesday night and he always told me about his patience.

He was very careful to maintain confidentiality. He wouldn't break confidentiality, but you know, I'd say, "Oh, how are you?" narcissist oh, we had this dream, you know, so this was, you know, this was a normal conversation when I was 14 or 15 with my dad and one day I said dad, it's very clear to me that through this conversation you heal a large fraction Your patients feel better and overcome their depression or their obsessive thoughts or things that block them. How do you think it works? And he says, "Well, we don't really know the mechanics." But ultimately, when it works, it doesn't work in some area of ​​the farrier's realm.

It's working by changing the biology of the brain and when he said that it was like lightning hit my head and I thought, well, I don't have the personality type to be a talking healing psychiatrist. nice enough, but you could understand the underlying biology, maybe you do and as you have correctly pointed out, when you say the phrase Mind and Body, you are talking about two directions, you are talking about mental functions that affect the body and then you are also talking of how phenomena in the body affect the mind and we are understanding a lot more about how that happens and I think what your listeners should generally appreciate is that we have some culprits here and generally there.

There are two kinds of culprits, so if you want to send signals about the body to the mind, there are two ways to do it, one of them is through neurons that reach the body and feel things and this is known as introception. Unlike additional reception, your senses that point outward, these are the senses that monitor your own body and, while we may be aware of much of that information, much of it happens subconsciously, as if your breathing It will happen automatically most of the time without you thinking about it and that depends on the sensors about the chemistry of your blood and the state of your lungs and a series of other things that regulate that process and it all happens in the brain, usually by below the level of your conscious attention, in addition to the nerves. signals There is also a whole area of ​​diffuse hormonal or immune signals and what they are is that they are chemicals that are released into the bloodstream and that move throughout the body and that can activate neurons in the brain or in other parts of the system. highly strung. system to produce changes in mental function and I think what's really exciting a lot of people right now has to do with immune signaling molecules, so there's a class of molecules called cytokines and cytokines are basically signaling hormones. of the immune system and can flow through the bloodstream and through lymphatic fluid and reach many parts of the body.

We've known for several years that specialized receptors for these cytokines are found throughout the brain, and yet we know very, very, very little about what they do and that will be a surprisingly fruitful area of ​​scientific research, but to give a For example, there are a lot of things these days that suggest a link between inflammation in the body, whether in the gut or elsewhere to depression, well how could that work well? It could work through neurons that detect inflammation and send electrical signals to the brain or it is neither or it could be both, it could be immune signaling cytokine molecules produced at the site of inflammation that then travel. through the bloodstream and lymphatic system to then reach the brain, bind to receptors and have effects, so one of the mysteries about depression is that it is not as treatable with drug therapy, so if you look at people who suffer from depression, about a third of people see a significant benefit from modern SSRIs and related antidepressant medications, about a third see very little benefit, about a third see no benefit at all and part of the reason It's that maybe our term depression is too big, depression is actually very different.

SSRIs help biological disorders and only a subset of them and will need different therapies for the others, that's certainly part of it, but part of it could have to do with inflammation, so if you think inflammation is a factor of risk in depression, well, you could do something very simple, right? Could you? You could take an ibuprofen. There are a lot of anti-inflammatory medications that are very well understood, and what if you say it's okay? You know, let's do a study where we have a group of depressed people and we have them take anti-inflammatory medications for a few weeks and see if this relieves their depression and the answer seems to be no, it doesn't agree with them and that's a little hard to understand.

I understand this because there are definitely links between inflammation and depression, so for example, one of the first treatments for hepatitis C that has since been replaced by more modern drugs was a pro-inflammatory cytokine molecule and when given people to treat their hepatitis C. Almost everyone got depressed on this drug, so they said, well, this really seems like a link. In addition, there are certain neurological diseases such as multiple sclerosis. It turns out that the incidence of depression as a comorbidity in multiple sclerosis is enormous and one might think well. There is a trivial reason that if you are paralyzed by Mrs. you are discouraged by life and that is the reason, but if you look at people who have spinal cord injuries due to accidents, they actually have major depression at a nil percentage. in a percentage of people. that they are unharmed, so it doesn't seem like that, it's not just that you are discouraged about being paralyzed although of course it is reasonable to be discouraged about being paralyzed, but that's not all, so what happens in Ms, well, there are a lot of cytokines, including one called interleukin-6 il-6 that goes up enormously if you do a lumbar puncture and look at the cerebrospinal fluid, which could cause depression, so all these real reasons to think that Inflammation is involved, but still, the idea is still a little confusing, so what would happen if instead of looking at the general population of depressed people we looked at the subset of people who do not respond to SSRI antidepressants, if Do anti-inflammatories help them and is there a small clue? that maybe they are, it's not definitive yet, there are a couple of studies, it's right on the edge, but I think this is a very good example of how we're going to see advances very soon in the body to mind part of the mind-body medicine that is going to be of enormous benefit to people, so interesting.

Could I get your take on a candidate hypothesis I've been thinking about? I've covered depression in a few episodes and I've had Robin Cardard Harris from UCSF and Dr. Matthew Johnson from his own John Hopkins University, both of whom work in labs studying psychedelics for the treatment of depression, clinical trials with psilocybin, and to be Of course, Simon is still illegal, it has been decriminalized in some places, but we are not talking about recreational activities. use, we are talking about several therapy sessions and then two without psilocybin, then two doses of about 2.5 grams of psilocybin administered separately again with therapists present and then follow-up therapy sessions appear to lead to relief from depression by approximately 65 to 80 percent. of people in some cases complete remission in some cases some relief without remission is okay, so we can set that result on the shelf.

It has been repeated several different times. Compare that to the results of SSRIs, which seem to help a third of people. a third minimally and a third not at all and of course there are the side effect profiles of SSRIs and associated medications, not just SSRIs but also propion and the other antidepressants that are taken as prescription medications and Then there's this inflammation part, so could we hypothesize? that relief from depression has something to do with neuroplasticity, the rewiring of neural circuits and that psilocybin, which we know, can promote neuroplasticity and that perhaps SSRIs can promote neuroplasticity in some people, not all, and that inflammation is a barrier to neuroplasticity, to me, this is the only thing we can reconcile the current state of results and then there are ketamine-based therapies, so we have to put that on the shelf as well, but let's leave it Set aside for now to keep it simple, it seems to me. that, depending on the time course over which SSRIs work, the fact that they increase serotonin, very quickly, but relief from depression comes much later, the fact that neuromodulators like serotonin are intimately involved in neuroplasticity, in some cases they can recover neuroplasticity, which are all backward centers. to change the neural circuits and therefore what we are really trying to do, whether it is transcranial magnetic stimulation or not, or now we can add ketamine or psilocybin or ssris, that treating depression is about rewiring the brain, it is not deals with chemical substance A or B per se.

Although serotonin seems involved to me, what I would love to see is that there are more studies on the interaction between neuroplasticity and inflammation and if we are seeing that type of work out there and, um, because these results are somewhat disparate, somewhat contradictory, but it seems like inflammation is anti-neuroplasticity and generally speaking, I realize that there are a lot of interleukins, there are a lot of, you know, some of which are inflammatory, some of which are anti-inflammatory, but that's a significant hypothesis and can you think What is there? I hope to really cure depression if we start to unify the results in these different fields.

Yes, I think that's a completely reasonable hypothesis and I would go further and honestly say that relief from any neuropsychiatric condition ultimately comes from neuroplasticity in one form or another and I think it's worth stepping back a little bit and talking about what neuroplasticity means. . To date there has been a focus on synapses in the context between neurons as the site of neuroplasticity and that is guaranteed: synapses are plastic, they change. as a result of experience as a result of hormonal changes as a result of exercise as a result of many things, but synapses are not the be all and end all of neuronal function, so for example neurons function by sending electrical signals uh uh along their lengths and between neurons and interconvert those with chemical signals and the processes of generating those electrical signals the ion channels involved that are embedded in membranes that are also plastic can also change as a result of experience, that It is what we call intrinsic plasticity as opposed to synaptic plasticity.

In addition, there are literal morphological changes, so when we talk about the wiring of the brain we sometimes talk about literal wiring, as if cell a was not connected to cell b and now it is. this. that changes and then sometimes actually cell a was connected to cell b but cell b was not responding enough and now there is a change in cell b so now cell a can trigger cell b and That could have been the result of a change in its synapse that makes it more receptive to the release of another transmitter from cell a or it could be something intrinsic to cell a that causes it to fire its electrical signal, its spike, more easily.

I think one of the key cell types that will be important to your hypothesis, um Linking inflammation to synaptic plasticity will be a cell called a microglial cell and microglial cells are non-neuronal cells in the brain that are mobile, they can crawl, They have long processes and can devour things that they can literally chew. and digesting fragments of the extracellular scaffolding that surrounds neurons and synapses and thus renders them plastic, can destroy synapses, and there is much evidence that certain pathological states may involve excessively exuberant microglia that prunes synapses to a degree that It shouldn't and we know that microglia are packed with cytokine receptors and therefore respond to inflammatory signals.

When we talk about inflammation and we talk about medications, it's worth mentioning that there are a lot of behavioral things that can influence signaling as well. We know and I know that you have discussed on your show the incredibly healthy effects of physical exercise on mental function, so exercise is as good an antidepressant as SSRIs are and the side effects are just good side effects, unlike the bad side effects of ssris and again this is not working through some realm of Airy farrier the reason why exercise works to relieve depression and the reason why theHow exercise works to maintain your cognitive function as you age is because of biological pathways that we are now discovering, some of which will involve microgl cells and neurons and other types of cells in the brain, some of which will involve non-neurons in the brain. but to the vasculature of the brain, so we know that exercise is very healthy to maintain blood flow to the brain and when you are young.

You have a great abundance of blood flow in your brain, so it doesn't matter if it is temporarily reduced, you are fine, but as you get older, your blood vessels become more occluded and less elastic and you are closer to the problem spot and if Exercising regularly can dilate and make your blood vessels, including those in the brain, more elastic, and that almost certainly protects against depression and cognitive decline. As we age well, I am an exercise fanatic, but I am Fortunately, I enjoy running and some forms of resistance training, so I always assumed that the good side effects were just the positive effects on mood until recent literature that , as you mentioned, improved blood flow to the vascular vasculature and reduced inflammation, if not during exercise, when inflammation actually increases inflammation decreases I love hearing you say the word microglia and my postdoctoral advisor, the late Ben Barris, would be especially delighted that people can look for Ben.

I'll provide a link to his bio in the show notes titles. because he really defended it to the point of um, I don't know if Champions is even a sufficient word. I mean, Ben was overcoming the drama by saying we have to pay attention to glio, we have to pay attention to glia for a long time. relegated to these other journals, they even had their own journals and in the last 10 years there has been kind of an explosion of research exploring the role of microglia and other types of glial cells and it's really fantastic to see that this is actually the most The most abundant type of cell in the brain is the glial cell.

They are getting the attention they deserve. It is absolutely true. You know, we scientists like to think that we are very rational creatures and that we are not subject to fads, but we are absolutely right. When I started in this field in the early '80s, it was all about opioid peptides and then there was a period when gaseous neurotransmitters like nitric oxide were all the rage and, you know, now glia are in the spotlight. for good reason. I'm not trying to say for sure that it's not worth it, but there is this phenomenon of things getting bigger and people jumping on the bandwagon and it happens both in terms of the subject we study and in terms of the techniques we use and in Right now the technique that is fatter involves an expression profile of individual cells which involves creating a list of which genes are activated and how strongly they are activated in individual cells and seeing how that changes in different cell types and with experience and it is very interesting.

It's a very valuable technique, but you could argue that it may have been a little overused, because in 15 years people will go back and say: Oh my God, those people in 2023 were really going overboard with single-cell profiling. and, if anyone is thinking about entering the field of neuroscience or another area of ​​biological or other research, I can only say that if you are starting your PhD or your postdoc, look at whatever fads are happening now and know that in five years will be something different and It takes you about five years to finish your PhD or postdoc, so choose something different than what is vadish now and you will get the money that there is always a lot to do, you don't have to do what everyone else is doing .

Yes, and indeed the elimination test becomes relevant here. The elimination test as described by my colleague EJ Chuchi at Stanford is that if you look around and see one or more groups doing what you want to do very well, just pick something. Otherwise, your life will be much more pleasant. I absolutely agree with EJ on that. Let's completely go back to mind and body. There are a lot of different domains of Mind and Body, as you pointed out, it is bidirectional. the mind informs the body the body informs the mind um, but we could probably break this down into a breath, so breathing, um, conscious breathing patterns that emphasize inhalations or emphasize exhalations, cyclical hyperventilation, etc., could also be be thought patterns, um, a little harder to break down, but um.

Many, not all, but many forms of meditation involve having a very still body, not all, there is walking meditation, etc., but still, the body, a focused mind, is not a state that we often find ourselves in. unless we run that state, um, there are still others. mind-body communication patterns through deep relaxation of the very still body things like Yoga Nidra deep rest without sleep there is hypnosis there is um uh communication Body Mind based on touch if we are going to talk about Mind Body we should also refer to it as body mind um , how do we dive in and think about this?

Because this clearly involves a thousand different neural pathways, not just the vagus nerve, you know, normally people just hang their hat on Mind, Body, it must be the vagus nerve, and of course it involves the vagus. but Vegas is a long set of Paths, so how do you like to frame mind-body and what is most intriguing to you about mind-body communication, both in terms of biology and its practical applications? Well, I think just when we talked about how there are two potential pathways to transmit signals from the body to the mind. There are also two potential avenues.

At least two potential pathways. Pathways are transmission signals from the brain to the body and they are the neural signals that are transmitted by neurons that actually get there and they are hormones, neurotransmitters and cytokines that are released from the mark. I should mention that hormones are actually produced by neurons, including, for example, some of the hormones that you think of as produced as sex hormones, like estrogen, it's produced by neurons in your brain, for example, um, so let me give you an example that I think is a bit of a stretch, but I think it's really fascinating and this comes from the world of cancer, so melanoma is a bad cancer, it kills a lot of people, it can spread, it's highly metastatic and we know that Melanomas are often innervated, that is, they come into contact with neurons and receive signals from them and we also know that if a melanoma becomes innervated, then the prognosis for that patient is worse, it is more likely to grow, it is more likely to spreads well, how does that happen?

Recently, there have been some reports showing that the neurons that innervate melanoma do not act directly on the tumor cells, but instead what they do is secrete a signaling molecule that has a receptor on the immune cells that patrol the edges of the melanoma tumor and They nibble at the atoms. and when that signaling molecule is released from the neuron, it turns off or reduces that immune patrol function and then, as a consequence, the tumor can grow, spread and disappear more easily, so this signal that comes from the neurons sends the ambulances home so to talk about yeah exactly and the signal is something called calcitonin gene related peptide or CG RP uh I'm familiar with cgrp from the domain of touch and its involvement in um I think it's like the perception of itch and its perception, yes, and so, it's okay.

If neurons can affect cancer progression through their activity and these neurons in the periphery are ultimately connected to the brain through a couple of different hops, it is reasonable to hypothesize that mental processes could affect cancer progression. , so let's say we have a hypothesis and it's a crazy hypothesis and I just want to emphasize that there is no evidence for this, but let's make the hypothesis that through meditative practice you can slow the progression of certain tumors that tend to innervate well in this moment. It is a slightly crazy idea, but I think the important thing, as I said before, is that it is a crazy idea with the biological substrate, it is not as if you meditate and magic happens and the fields are forced to open and the angels They sing and then the tumor shrinks.

What we are saying is that activity in certain areas of the brain increases with this meditative practice and that this sends signals to this neuron and this neuron that actually goes to the tumor and causes something to happen through this biochemical pathway that we have correctly defined. and that To me, this is speculative but it is also extraordinarily exciting, as it opens up a kind of investigation of mind-to-body signals that has received very little attention until now. Incredible and I say incredible because while you are giving an example of cgrp and nervous and metastatic innervation. tumors I love the idea that a phenomenon involving some practice that could be included under the umbrella of Mind Body or Body Mind becomes something completely different when we try to hang that on the hook of a biological process, it's like something fundamentally changes there. um, you know, it's surprising to me, for example, that in the beginning psychedelics and breathwork got lumped together, conscious breathwork got lumped together and cost people their jobs at major universities.

I won't name the universities because we're all, you work at one, I work at another and There's a third, um, called Harvard. I guess I just named them, but today, their labs at each of those institutions study deliberate breathing for health, as well as psychedelics and meditation, with the goal of understanding what cytokines, what neurotransmitters, etc. they change. through defined pathways that include the vagus but phrenic nerves and the frontal cortex and everything that is considered, you know, classical rigorous neuroscience, so I think we have entered a new era, so it no longer costs people their jobs, it's actually giving people their jobs and it's federally funded, which in my opinion is also fantastic, so we're in a new era, what do you think needs to be done to realize the idea that the way we think influences our biology even though it's total nonsense because everyone knows chronic illness?

Stress, for example, can be harmful. Short-term stress can actually be beneficial, but stress is a mental process that essentially releases chemicals in the body that then create other problems in the body that then create changes in mental processes. It's very obvious when it's explained, but it's amazing to me how this has been lumped into the category of wooing science, um, and I can't figure out what needs to be done to convince people that their nervous system includes things. outside the skull and the spinal cord and of course, of course, of course, it would work just fine this way, and I think it's the job of biomedical researchers right now to recover a lot of this from the realm of nonsense and the problem is that There's been a lot of nonsense and you know there's kind of a gut reaction, you know when someone says, oh yeah, well you can do breath work and it will realign your chakras and that's what will reduce your anxiety or gut inflammation. and I'm tempted to say, "Shut up, but what if chakras are sets of nervous innervation of bodily sphincters and you know it might make sense, right, but there has to be some biology in some cases, these analogies?" they're rooted in something real and in some cases they're just made up lies and I think the challenge is to have really rigorous scientific testing of these things to walk back and be willing to say okay, there have been a lot of claims. for example, about how mental processes can influence the body and only a subset of them will be true and from that subset it is our job to understand how they work to rationalize them but also to optimize and improve them.

I mean, there's no doubt that mental processes affect the body. I mean, we know, for example, that if we just keep you awake and don't let you get enough sleep, you're going to die and what are you going to die of, you're going to die of sepsis because the barrier between the intestinal contents uh and your perineum is going to break down nicely, so, how does that happen? We're starting to understand that there is one really dramatic example, but there will be many more subtle examples, so I've mentioned breath work a couple of times and I think this is really interesting.

My colleagues who are interested in breathing tell me that you can record in many different places in the brain, in many different places in the neocortex and in other regions, and find a signature of the respiratory rhythm is a kind of background of the neural activity. You can find it in the cerebellum. You can find it in the frontal cortex. You can find it in the habenula, which has involved many things, including depression. You can find it in many. places, so the idea that conscious modulationof your breathing could have multiple effects on neural function, I think it's reasonable given that kind of observation here, let's talk a little more about you, you've been so kind in covering this wide range of topics. and so eloquently and I must say I have loved it all, you are in a unique position these days because, if I understand correctly, you have been diagnosed with a fatal illness.

I guess we've all been diagnosed. kind of a deadly disease because we are all going to die sooner or later yes, if you are willing, could you tell us the story of how that diagnosis came about, what your initial reaction was and where things are now and maybe we? I can explore some of the well, let's just say pleasant surprises that have arisen since that initial diagnosis, well, I sure would be happy to do so, so in the summer of 2020, in the dark days of covid, when things were looking really bad , I developed profound shortness of breath I couldn't walk up a flight of stairs without uh uh without huffing and puffing and I thought, well, I have greed, but I took covert tests and there they were all negative, but I thought, oh, I have to do it.

I have greed I have the symptoms of Kovid I have breathing problems I feel weak you have to cover it up and after a while when this didn't go away my wife said you have to go to the doctor this is crazy you have to find out what's going on and I did and they hooked me up to an EKG and they said oh uh you have atrial fibrillation which means your heart makes two beats every time it should make one so I have a very high heart rate and when the heart beats that fast it doesn't can work very effectively, there is enough time to recharge before the next beat arrives.

Now it turns out that there is a very simple therapy for this atrial fibrillation that comes from the electrical signaling in the heart spinning in a circle and reactivating part of the heart muscle faster than it should, so if you pass a catheter through your groin upwards , through the blood vessels, you can insert a little needle and use it to cauterize and remove a small strip of cells in the heart that will produce a barrier that will prevent the aberrant return of electrical activity and cure atrial fibrillation, so I have that process, that ablation surgery and, of course, that's right.

I cured my atrial fibrillation and I felt great and they said, oh, as a follow-up, come back a few months later and we'll do an echocardiogram to see what your heart looks like and they did and they said, Oh my gosh, there's this huge mass. pressing against your heart it's about the size of a Coke can uh this is what we think it is we think it's a hiatal hernia we think your stomach has protruded through the diaphragm muscle and is located next to your heart so the way we diagnose this is. With some humor they say you drink this can of Dr Pepper and then you quickly get on the table and we will do the echocardiogram and on the echocardiogram we can see a signature of the CO2 bubbles bursting in your soda and if we see those in the dough then we know it's your stomach so I did it, I broke it into pieces, I got there oh no, it's not your stomach I said oh, okay, well what we think is a teratoma and a teratoma It is a developmental anomaly that is generally carried from the fetus. life where there is a group of different cells that get to a place where they shouldn't during development and then grow.

You've probably heard of people who sometimes grow hair on their abdomen like a tooth. Sometimes women get these around their ovaries and they're not malignant they don't spread it's a pretty easy thing but I have this huge can of Coke pressing on my heart we may not know it was the source of my atrial fibrillation to begin with but To deal with this I had to have open heart surgery, so I had surgery and it was a big deal. They told me it would last about five hours. Turns out it lasted two days. Wow, they kept me on the cardiopulmonary bypass machine longer than you.

You're supposed to do this because there's a good chance a clot will form and you'll have a stroke. Fortunately, that didn't happen. I had very skilled surgeons at Johns Hopkins. He was bleeding so much that they couldn't close the chest, so they had to do it. the whole surgery and then they left me anesthetized with my chest open until the bleeding stopped and they left so the surgery was a bear and then I'm waiting to get the pathology report on the tissue they removed and it came back and it was Bad news, it sorry, it's not a teratoma, it's not benign, it's a type of cancer called synovial sarcoma and synovial sarcoma is a moderately rare cancer and it usually affects the synovial membrane, which is the lining of the joints or some other places, it's pretty rare have it. happens in the heart there are some examples if you look in the biomedical literature for common cancers like testicular cancer or breast cancer there are huge tables of statistics for millions of patients about what has been tried and what works and what is the prognosis for the synovial sarcoma of the heart your only individual case reports oh there's a man in Kenya and he got into this what happened there's a woman in Minnesota and this is what happened to her right there's no statistics because it's that rare and and the oncologist came out Well, I think you now have 6 to 18 months to live.

This was about 27 months ago, so luckily I surpassed that lifespan estimate and I think we also need to make it clear that you know being an oncologist has to be a terrible job for many reasons, but one of them is that you have to give an estimate. lifespan, even if you don't really have the data to do it in a very big way, you can't just say, "I'm not going to do it right." you have to do it, people expect it, so you know, I'm not saying that, oh, the oncologist was incompetent because I outlived my estimate, you know he was trying to do something based on very little information, he made his best guess, so So, I know I received this information and I was furious.

I was so angry. Heart cancer. Who the hell has heart cancer? Have you ever heard of someone with heart cancer? There is no heart cancer. What the hell hurts me? It's worrying this is this is a crazy time I was 59 I have a lot to do I can't have heart cancer and what I think was transformative for me is that at the same time the moment I felt burningly angry at the universe, I also felt a deep feeling of gratitude for what I had. I have had a wonderful life. I'm not that young. I have had a lot and I had Great parents, wonderful friends growing up.

I've had a good career. It was a pretty easy race. And I think the ability to have a job where you follow your own curiosity every day, there's nothing like it. So few people in the world. to get to live that way I feel incredibly grateful I feel incredibly grateful to my family and I have a wonderful wife named Dina and she is simply the best how do I deserve this? I don't deserve it, you know that honestly, so you know in Neuroscience I often think oh well there's a you know you have a state you have a set point are you anxious or are you relaxed are you running away or are you approaching you know it's like a single axis well. , but it's um you know and I think most people understand that, but, dummy, until that moment I didn't really understand that I could feel deeply grateful and deeply angry at the same moments, and you know, having cancer and getting the kind of treatments, chemotherapy and radiation.

I know it's deeply unpleasant and I had all of that and it was as unpleasant as anyone's cancer story, that you heard about the radiation burning my esophagus. I couldn't eat for weeks, it was months, it hurt to swallow, you know? Things that a lot of people have had to go through bad things like this and I realize that you know this is a deeply disempowering situation to be a medical patient, especially when there's something serious that you have, you have a limited sense of agency. they're giving you drugs that make you feel really bad and there's not much to do when I realized that for me the sense of agency came from curiosity, from being a complete nerd about things and Part of what made me curious it was about my own thought processes in relation to my cancer and my cancer diagnosis.

For example, I'm undergoing chemotherapy and I should say as background that I'm lucky because I don't have a tendency. for depression I'm a pretty optimistic guy, I don't take any credit for that, I think I was born lucky and I grew up lucky, but day after day feeling bad in my body due to chemo, it's hard to be positive, it really is. I couldn't get over it. My mood, God, was really low and I could tell myself this will end, it won't go on forever, you won't feel this way forever and you would think that as a rational person I could talk to myself.

Out of that mood, but I couldn't tell, probably because my brain had an interleukin-6 wash and I couldn't get over it. I felt very depressed, but at the same time I was kind of out of place for being a nerd. about saying huh, I bet these cytokines are ruining me right now. I bet that's what's happening and it gave me a sense of agency at a time when I wouldn't really have it otherwise. Another thing that really made me understand is this. topic we were discussing earlier about how malleable perception is and time perception in particular, if someone had told me when I was healthy before I was diagnosed, you're going to die in five years, I would have said oh no no no no no no.

I am 59 years old. It should be more than five years old. I have many things to do. Professional stuff. Personal stuff. Familiar things. I have many things to do. No, that wouldn't be like that. I would be very angry, but you. I know if you told me after my diagnosis six to 18 months, oh, you've got five years left, I'd be like five years, yeah, that's pretty good. I can do a lot in five years. I can finish in the lab and I can do it. a good job and I can spend time with my family and travel and keep the pleasures of your life and do all kinds of things five years great and of course it's the same five years, the only thing that's different is the context, but I think Lo What I really realize is that I really couldn't and still can't accept the idea of ​​my self being gone, so yes, I can do practical things.

I can update my will. I can write letters to my people in my laboratory. So if I start, you know they have that to take to their next job. You know I can do all these practical things, but in terms of genuinely engaging with my own disappearance, I really find it no matter how hard I try. I can't really do that and at first I thought, well, that's just your lack of imagination, Linden, it's just because you know you're not very good at this, but the more I thought about it, I thought, actually no, this is a human thing. .

This is a fundamental human thing and one of the things that when I look back at the 40+ years I've been doing in Neuroscience is different is that when I first trained, the brain was actually described as a reactive structure. Something happens in the brain. world, you know, it reaches your sensory organs, your eyes, your ears, it goes to your brain, it triggers some things, you think, you make decisions and then you perform an action that reaches your muscles or or or or and that is the cycle. and that's what the brain does and what we've known in more recent years is that actually when the brain is waiting for something to happen, it's not just being inactive and spaced out, but at all times the brain is subconsciously trying to predict the near future predicting in the near future is based on the idea that there will be a near future, that is, that you will not be dead and gone, that there will be a future for you, so I believe that my ability, that I think is actually a human being, I'm not talking about my ability, my failure, which I think is actually a human failure to truly engage with my own demise, is a characteristic, is a side effect of the fact that the The brain is always trying to predict the future and therefore It was interesting to me simply because my illness revealed something about the brain, but it also made me think a lot about world religions.

Religion is everywhere in the world. If you ask anthropologists, is there any society that does not have religious ideas? They'll say no, they say they don't always have the word religion, maybe they'll just say, well, yeah, everyone in this place knows you know the world is on the back of a turtle and you know this and this happened, there are these rules. We may not call it a religion, but all places in the world have religion, not all are religious, but it is a cross-cultural universal and most religions, not absolutely all, but almost all, have afterlife stories for reincarnation in those whose Consciousness endures well.

Why would that be? And in many religions they have a correct treatment: follow these rules in life and then you will be rewarded in the afterlife and that is a very general idea or punished in the afternoon or punished in the afterlife. true, and you know that in some religions you merge with the divine, in other religions you arereincarnated, it is this or that other heaven or hell, true, there are variations, but they share that your consciousness endures and so why is this so popular all over the world? Well, I would hypothesize that it is a side effect of the fact that the brain can't help but always try to predict the future, when we can't imagine the world without us, then we are forced to invent fascinating stories of the afterlife. and it makes me want to ask about this characteristic of time perception.

My undergraduate and postdoc advisors sadly died early, actually by almost any standard. And I was lucky enough to be in communication with the last two as they went. Through that process, they both described a greater sense of gratitude, especially for things they hadn't previously paid attention to, so we call this noticing the little things, yes, but that makes me conclude that something about the knowledge of impending

death

, however. away, that could be um it changes our attention, at least temporarily, it leads to this feeling of slowing down a little bit because to divert our attention to, quote, little things or things that we previously overlooked, there's this feeling of slowing down and we know by uh basic videography photography slowing down means an increase in frame rate, right, you know, you know shooting at strobe frame rates gives you the perception that strobe shots at very high frame rates give you They allow you to see things in very slow motion.

You're noticing subtle variations that you normally overlook. I'm not trying to be too reductionist about this process of enhanced gratitude which is what you describe and how it went along with intense anger, but have you noticed a change in your perception of time because you were? Given initially this You're going to be here, um, that's how most of us exist. You get the feeling that it's sooner rather than later, but you don't really know, so I'm curious how the idea that okay, you have 12 more months to live comes about. versus more than 12 months, but not infinity, but of course I know that I hope to have more than 12 months, but it is not infinity.

Yeah, you know, this idea of ​​the finish line, the cliff, leaving aside what might happen next. I don't know, I haven't been there. Change what we notice by changing our perception of time. I mean, this is a deep attunement of our perception. What are your thoughts on that? Do you notice every sip of coffee, you probably don't notice every step across the kitchen floor in the morning, you're probably paying attention to your lovely wife and kids and things that day, but presumably, it's dynamic, but what is your perception of the time now with the understanding that Yes, you made it through the door that was predicted, but what lies ahead is uncertain.

Yeah, that's really interesting and I would say my perception of time is definitely slower and it seems like an age since I was diagnosed, but I think part of it. In other words, this is because it's been action-packed since I was diagnosed. So many emotionally salient things have happened, non-trivial things, so many intense discussions with my wife, my friends, and the people in my lab. You know my wife and me. I've taken a lot more vacations than we normally do, so you know we're running around the world and there's a certain feeling of being prepared, I think that influences the perception of time, but I would say that, actually, for me Personally, Gratitude is not. about the small things Gratitude is about the bigger things Gratitude is gratitude for being a sentient being and having that blessing Gratitude is for being able to have a life where I can follow my own ideas and creativity and my gratitude is for drowning the deep love that I have felt from my wife and my children, you know, it's not the little things, it's the big things that I think about when I think about gratitude, it's not noticing the sip of tea, it's the big problems, and now You know.

For me, you know, I don't want to delay my death as much as possible, of course, but when I think about it, the part that bothers me is leaving people behind, it's not about me, I've had a great time. life, um, I've had a lot of things, I'm 61 years old. I would like to continue longer, but it is a pretty good streak. I have been able to do many things in those 61 years and I have had wonderful interconnected loving experiences and then the negative part is what I leave behind, certainly what you left behind is enormous and has been the consequence of actions long before your diagnosis, which I think it is a clear lesson for everyone.

I can't speak for you. but don't wait for the diagnosis. You've mentioned the sense of agency you felt in being able to pay attention to and explore your experience of, let's call it what it is, imminent death and at the same time, as you mentioned. I have amplified and accelerated the amount of things you have put into the world recently, writing incredible articles about your life and death experience and of course we will link them so people can read them. I've read them all and they are profound and not only do they feel important, they clearly are important, so very few people have your view of the nervous system on the mechanistic level, but also on this more holistic level that you have shown us clearly here and in your research and in your book writing and public speaking um you know, I think it's kind of risky to ask someone for advice um but I can't help it because um I think it's a real opportunity um if you had some advice um to give to each and every one of us. um based on all the experience, yeah, uh, all from the beginning, as they say, right, um, if you're willing and feel free to pass, but if you're willing, um, what's your advice?

I would say the advice that's really universal is the one that everyone already knows and it's a little trite, but I'll say it anyway and that is to appreciate what you have while you have it and know that this isn't some big secret and all. the world knows it. I would say that for a subset of people the nerd way is very empowering. I don't think that's the case for everyone. I think for a subset of people who are deeply curious because their nature turns that Curiosity into their own mortality into their own medical situation it can be enriching and helpful, but I don't think it should be broad advice.

I think it's only for a fraction of people, it's probably the worst thing they could do and there's nothing wrong with everyone being different, not everyone should do it. take the nerd way but for a fraction of people it's actually a good thing to do, it's usually the part of a conversation with a guest where I list the many things they've done and how grateful I am, and all of that is absolutely true in the The case is that you are here today and the work that you have done, but I think it is evident how much you have accomplished, not just what you have accomplished, but how much knowledge you have put into the world and not just scientific knowledge but knowledge about the human. experience of others and yourself, so I just want to extend a huge thank you on behalf of the listeners and viewers and on my own behalf, thank you for coming here today, thank you for doing what you do and it's great to have you still here and I have this conversation and I hope it lasts longer and no matter when it ends, you have done an enormous service to humanity.

Good thank you. He is very friendly. It has been a pure pleasure having this conversation with you. Thanks David, thanks for joining me. today for this discussion with Dr. David Linden, if you are learning or enjoying this podcast, please subscribe to our YouTube channel which is a great free way to support us. Also, subscribe to the podcast on Spotify and Apple and on Spotify and Apple, you can leave us a review of up to five stars if you have questions for me or comments about the podcast or guests you'd like me to consider hosting on the Huberman Lab Podcast.

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