Life, Death & the Neuroscience of Your Unique Experience | Dr. David Linden

1. 0:00 – 3:59

   David Linden

   1. AHAndrew Huberman0:00

      (music plays) 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 laboratory has studied neuroplasticity, that 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 referred to as the mini-brain because it looks like a mini-brain in the bottom and back of the human brain, and it's responsible for an enormous number of basic functions that we use in everyday life, including our motor behavior, that is, our ability to walk and talk, but also dance, play instruments. And it's responsible for an enormous number of basic functions that we use in everyday life, including our sense of balance, our ability to learn new motor behaviors, as well as our sense of timing. Today, we will discuss the cerebellum and what it does, but Dr. David Linden will also teach us about the important sense of touch as well as what makes us different as individuals. The reason today's discussion encompasses so many important topics is that Dr. David Linden's laboratory has focused on many of those topics, and he is also the author of five excellent popular books about neuroscience that focus on, for instance, our sense of pleasure and where it originates from and what controls it in the brain, as well as our sense of touch. And today, we start off our discussion by talking about the recent discovery of a set of neurons that have been known about for a long period of time but that only recently have been characterized that are involved in sensual touch in particular, and it's a fascinating conversation, I assure you. In addition to that, Dr. David Linden informs us about what makes us individuals, how each and every one of us perceives the same things differently, and it's an absolutely fascinating conversation which tells you, for instance, why some of you think a smell is putrid, indeed smells like vomit, whereas others perhaps are not bothered by that smell, and why others still are attracted to that smell or something that you look at or something that you hear. We also talk about nature versus nurture and how we come to be who we are, not just through our genes and epigenetics, but also through our early childhood experience and adult experience. And then in the latter third of our conversation, we shift to talking 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 the organs of our body control the chemicals, hormones, and thoughts within our brain. Then we shift to discussing Dr. David Linden himself and the fact that in 2020 he was diagnosed with a form of heart cancer that led his physicians to tell him that he had six to 12 months to live. Now, obviously because he was in our studio to record this conversation, he has outlived that prognosis, but he lives day-to-day with the knowledge that his death may very well come soon, although it isn't clear exactly when that day will come, of course. He tells us how the initial prognosis of his cancer as well as outliving that prognosis has informed his day-to-day life as well as his thinking and his relationships, and that leads to a very direct and, frankly, emotional conversation that includes advice on how all of us can get the most out of our daily living and out of our overall life. It's an extremely powerful conversation that I believe everyone, regardless of age or health status, can benefit from, and it's one that makes clear that not only is Dr. David Linden a spectacular scientist, but also a spectacular educator, a spectacular popular writer, a spectacular family man, including husband and father and friend to many people and his colleagues, but he is also a courageous and spectacularly generous human being.

2. 3:59 – 7:54

   Sponsors: ROKA & Levels; Huberman Lab Survey

   1. AHAndrew Huberman3:59

      Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is ROKA. ROKA makes eyeglasses and sunglasses that are the absolute highest quality. The company was founded by two all-American swimmers from Stanford, and everything about ROKA eyeglasses and sunglasses were designed with performance in mind. I've spent a lifetime working on the biology of the visual system, and I can tell you that your visual system has to contend with an enormous number of challenges in order for you to be able to see clearly. ROKA understands those challenges, and the biology of the visual system such that they design sunglasses and eyeglasses that always allow you to see with crystal clarity. Now initially, ROKA eyeglasses and sunglasses were designed for sports performance, and as a consequence, all of their glasses are designed to be very lightweight and to not slip off your face if you get sweaty. However, the design of the glasses include some that are specifically for sport and others whose aesthetic really allows you to use them for sport as well as out to dinner or to work, et cetera, and that's how I use them. If you'd like to try ROKA eyeglasses and sunglasses, you can go to roka.com, that's R-O-K-A .com, and enter the code Huberman to save 20% off your first order. Again, that's ROKA, R-O-K-A .com and enter the code Huberman at checkout.Today's episode is also brought to us by Levels. Levels is a program that lets you see how different foods and behaviors affect your health by giving you real-time feedback on your diet using a continuous glucose monitor. One of the most important factors impacting your immediate and long-term health is the way that your body manages its blood glucose or sometimes referred to as blood sugar levels. To maintain energy and focus throughout the day, you want to keep your blood glucose steady without big spikes or dips. Using Levels, you can monitor how different types of foods and different food combinations as well as food timing and things like exercise combine to impact your blood glucose levels. I started using Levels a little over a year ago and it gave me a lot of insight into how specific foods were spiking my blood sugar and then leaving me feeling tired for several hours afterwards, as well as how the spacing of exercise and my meals was impacting my overall energy. And in doing so, it really allowed me to optimize how I eat, what I eat, when I exercise, and so on such that my blood glucose levels and energy levels are stable throughout the day. If you're interested in learning more about Levels and trying a continuous glucose monitor yourself, go to levels.link/huberman. Right now, Levels is offering an additional two free months of membership. Again, that's levels.link, L-I-N-K/huberman to get two free months of membership. We are always striving to make the Huberman Lab Podcast better and to that end, we need your help. Over the next month, we are going to be carrying out a survey. The purpose of the survey is to improve the Huberman Lab Podcast according to your feedback. We put together a brief survey to understand what you love about the podcast, hopefully you love a few things at least or maybe just one thing, as well as what you think could be improved, or perhaps the many things that you think could be improved about the Huberman Lab Podcast. Basically what we are asking is to get your feedback so that we can improve any and all things about the Huberman Lab Podcast. The survey does not take long and every single response will be reviewed. As a thank you for completing the survey, we are offering two months free of the Huberman Lab Premium Channel. If you're already a member of the Huberman Lab Premium Channel, do not worry. You will get an additional two free months for carrying out this survey. You can find the link to the survey in the show notes for this podcast episode and on our website hubermanlab.com. So if you would be so kind as to take a few minutes to fill out the survey and help us continue with bringing you the best possible content here at the Huberman Lab Podcast and as always, thank you for your interest in science. And now for my discussion with Dr. David Linden.

3. 7:54 – 16:46

   Sensory Touch & Genitals, Krause Corpuscles

   1. AHAndrew Huberman7:54

      Professor Linden, welcome.

   2. DLDr. David Linden7:55

      Thanks so much for having me.

   3. AHAndrew Huberman7:57

      I've been looking forward to our conversation and we have a lot to talk about.

   4. DLDr. David Linden8:00

      We do.

   5. AHAndrew Huberman8:02

      Lots of different aspects of science, lots of different aspects of personal journey and what you're confronting now as it relates to your health and your future. I want to start off with a question that I learned from the one and only, the great Karl Deisseroth, who was the first guest on this podcast. My colleague at Stanford, and for those of you that don't recognize Karl's name, he is a, um, absolute phenom. He is a, uh, active clinical psych- psychiatrist, so he's an MD and he also is, um, a bioengineer who's developed a lot of the modern tools for probing the brain and, um, any time I've met with Karl, the first thing he says is, "What are you most excited about lately?" So...

   6. DLDr. David Linden8:47

      That's a good question.

   7. AHAndrew Huberman8:48

      It is. Uh, so I'm going to steal that approach and say, what are you most excited about lately?

   8. DLDr. David Linden8:55

      Well, very, very lately, the most interesting thing that I read in neuroscience is the answer to a, uh, a scientific problem that I think is really dear to a lot of people's hearts and that is, what are the nerve endings in the genitals that are responsible for sexual sensation? And, you know, if you think about it, right? People can feel sexy from being touched on lots of different parts of the body, but there's something special about the genitals. Doesn't matter male or female or intersex or gay or straight or bi or whatever you are, you know, the genitals are, are a hot spot. And why? And you, you'd think as biologists we'd know this by now. This would be something we could just answer. But, but it's been a mystery for a long time and if, if you go back to, to 1860, there was a German neuroanatomist named Krause and he cut thin sections of tissue from the penis and the clitoris and he looked at them under the microscope and he saw a particular kind of nerve ending there that has since been called the Krause corpuscle and there were lots of them in these two places and so he thought, "Well, maybe this is the cellular basis of sexual sensation. Maybe these are the particular nerve endings that are responsible, uh, for this." Um, but there were some things that, that were in favor of that and some not. So, these nerve endings are also in some other places that people can find more or less sexy, like they're in the nipples and they're in the lips and they're in the anus. All places that get popular in, uh, in that domain, but they're also in places like the cornea or the lining of the joints. So, the distribution doesn't quite make sense a- a- and so it was never known, and so in, if you wanted to really test as a scientist whether these nerve endings are responsible, you want to record their electrical signals while the genitals are being touched. You'd want to inactivate these cells and see if you could interfere with s- with, uh, sexual sensation and this, in a preprint from David Ginty's group at Harvard, is just what they have been able to do in mice. They found a way to label and record from and activate and inactivate, artificially, uh, the Krause corpuscles, and so...You see a nerve ending in the skin, it could be conveying all kinds of information. It could be tuned for hot, or for cold, or for itch, or for pain, or for in- or for inflammation, or for mechanical sensation, stretching, uh, vibration, indentation. And sure enough, when they recorded from these Kraus corpuscles, they really are, uh, mechanical sensors, as you would expect, uh, if they were involved in sexual sensation. So that was good. And then, uh, the other thing, then what they did is they- they tried to artificially turn them on. And so the way they did that is they used genetic tricks to express one of Karl Deisseroth's, uh, uh, molecules that activates neurons when they're- when blue light is shone on them. And they found that if they express, uh, uh, this artificial protein in the Kraus cells in a, uh- in a male mouse and then shine blue light, the mouse gets an erection. All right. So far so good. What happens if you turn them off? Well, if you turn them off in a male mouse, it's just as interested in females when they're in heat, but it won't mount and thrust and ejaculate as much. And if you turn them off in a female mouse during the time of her cycle where she would normally be sexually receptive, uh, you find that she is much less interested. She's much less likely to let him mount. She's much less likely to let him finish. So this is the remarkable result that, uh, finally after all these years since 1860, now we know what the nerve endings are that convey sexual sensation. And like all good science, then, you know, there are a lot of questions that are really interesting to our everyday lives like, you know, people like different things in bed and have different propensity for orgasm or- or like- like to be touched in different ways. Well, is part of that reason because of individual variation in their Kraus corpuscle structure? Um, we know that sexual sensation diminishes with aging. Is that in part because Kraus corpuscle density is lost from the skin of the genitals? And that's a reasonable idea because we know, for example, that fine touch sensors in the fingertips, uh, so-called Merkel and Meissner endings, also named after German anatomists like so many things are, uh, are also lost with age. So that's a reasonable idea. So- so this finding from Ginty's lab has opened up a whole world of science. And I've been, my la- my own lab doesn't work on touch, but I've been a fanboy of touch for- for many, many years, mostly because where I work at Johns Hopkins Medical School, there have been many terrific touch researchers, it's been a world center for it, and I hear about it over lunch and I got all fired up. So-

   9. AHAndrew Huberman14:38

      Mm-hmm.

   10. DLDr. David Linden14:38

       ... years ago, I wrote a book about it and I still follow the field. And this is the most interesting thing in that field recently.

   11. AHAndrew Huberman14:44

       Yeah, and as I recall, Ginty was your neighbor at Hopkins before he moved to Harvard. So- so-

   12. DLDr. David Linden14:48

       That's right. That's right. He was one of the ones, Ginty, uh, uh, Stephen Schau, uh, Michael Cattarina, Xinzhong Dong, there have been a number of world leaders in the- in the cellular basis of touch sensation at Hopkins.

   13. AHAndrew Huberman15:04

       Do you recall if in the preprint that you were describing, there was an experiment where they activated these Kraus corpuscles in females?

   14. DLDr. David Linden15:14

       It's funny you should mention that. I sent that exact email to David Ginty. And they said they are in the process of doing that right now and they don't quite know yet. And so I asked him, I said, "So, for example, is erection of the clitoris even a thing in mice?" And he says, "Well, we're really not sure. So we're activating the Kraus corpuscles in female mice and we're just kind of staring at it and looking and see if anything happens, just their, uh, you know, does the, you know, does- does- does the- the- the body change shape? Is there a color change?" They don't even quite know what it is they're looking for because it's that much on the leading edge of things. But it's a good question.

   15. AHAndrew Huberman15:52

       Yeah, or perhaps the female mice would be more willing to mate outside of the usual timeframe of receptivity if, uh, these Kraus corpuscles are- are stimulated.

   16. DLDr. David Linden16:02

       That's possible. My suggestion, my- my guess would be not because I think that the hormonal regulation of receptivity is like a sledgehammer and very hard to overcome. But they might be more willing to continue mating or mate for longer during their, uh, fertile time.

   17. AHAndrew Huberman16:23

       And I just want to remind people because we had a- a guest recently, uh, Dr. Rena Malik, um, who's a urologist, reproductive and sexual health expert, she's a MD, and, um, uh, she made clear that the- the clitoris and the penis come from the same embryonic origin. They are analogous tissues-

   18. DLDr. David Linden16:43

       Yes.

   19. AHAndrew Huberman16:43

       ... um, in, uh, different individuals.

4. 16:46 – 19:14

   Sexual Experiences & Sensation

   1. AHAndrew Huberman16:46

      I do have one more question about this, uh, sexual touch thing. Um, these are peripheral nerves, right?

   2. DLDr. David Linden16:54

      Yes.

   3. AHAndrew Huberman16:54

      So these are not of the brain and spinal cord. They are in what we call the periphery. And my understanding is that peripheral neurons regenerate and can remodel themselves extensively in ways that, um, neurons within the brain and spinal cord, um, tend to remodel less, especially as one gets older, out of the so-called critical period. Um, is it possible that these Kraus corpuscles and their patterns of innervation within the genitals change according to the stimulation that, uh, people experience? Um, in other words, is sexual sensation experience-dependent?

   4. DLDr. David Linden17:32

      That is a great question. And so-We don't know because monitoring this in people is not technically possible, right? It requires cadaver tissue.

   5. AHAndrew Huberman17:47

      Mm-hmm.

   6. DLDr. David Linden17:48

      So, you can only do it once. In animals, it- it- it- it will be possible and it- it could be for a couple of different reasons. In other words, it could be, I think what you're imagining is that there's actual structural plasticity. If you looked at these Kraus corpuscles or, uh, that you would actually see them changing their shape or their size or their- or their density as a result of experience. But, uh, what can also happen is a phenomena like desensitization. Uh, that is to say when there's stimulation for a long time, then, uh, the receptors transiently can become less sensitive to touch and it's well-known for, uh, particularly in males that, uh, that chronic masturbation can produce desensitization of sexual sensation in the penis. And that could be as a result of a physical change, a morphological change in the Kraus corpuscles, uh, but it's more likely to be a change in their function that you wouldn't be able to simply see by looking, uh, at an outline of their structure in the microscope.

   7. AHAndrew Huberman19:00

      Mm-hmm. Such an interesting topic. Thanks for, uh, opening things up with- with that. And I'll have to check out this pre-print. I'm also a huge fan of David Ginty's work and- and colleagues. There are many people involved in, uh, that domain of work, of course.

5. 19:14 – 30:25

   Human Individuality & Variation; Senses & Odor Detection

   1. AHAndrew Huberman19:14

      I'd like to talk about your recent book and the sort of underlying basis of what led you to write it and what intrigued you about this idea of human individuality. The book, Unique, uh, is one that we'll provide a link to in the show note captions and, um, it's a very interesting idea that we are all different, um, especially coming from a neuroscientist who- who were trained at least similarly to learn that sure, the bumps and ripples of the brain and the fine wiring of the brain, um, is different and we are all unique and different, that we have different shapes, AKA morphologies, but focusing on human individuality is not something that modern neuroscience or classic neuroscience has really done much of. It's really focused on how people do X or people do Y this way. Um, tell us about Unique and tell us about human individuality.

   2. DLDr. David Linden20:11

      Yeah. Well, I mean, you're absolutely right. So when I look at the experiments in my own lab, how do we do them? Well, we work on mice. Do we work on mice with genetic variation? No. We work on highly inbred mice that are designed to be as genetically similar to each other as possible and then we raise them basically in prison, in little- little cells, which may not be a good idea, and we try to give them as similar experience as possible.

   3. AHAndrew Huberman20:39

      They are given toys and food and water, but I agree, it- it resembles, um, a prison of sorts. They aren't free to roam.

   4. DLDr. David Linden20:46

      They're- they're n- they have nothing like the experience of a wild mouse, let me put it that way. They're, uh, uh... And- and yes, there are, as you said correctly, there are plenty of experiments where there is enrichment, uh, for mice and they love it. So for example, in our lab when we put running wheels in the cages of our mice and let them run overnight, they're active at night, um, your average mouse will run two kilometers in a night for a little tiny mouse. And some of the mice are so intense, they will run 20 kilometers. Imagine a mouse doing 20K, but- but it will happen. They really, really like it. They don't like being in prison. They- they want to exercise, uh, and they're really bored. So yes, to get back to your general point, uh, so much of science is designed to try to find general principles of a function of the brain, of physiology, of genetics, uh, and to ignore individual variation. But individual variation is so important to our human experience and actually is so important to- to the process of evolution and natural selection and how- how species, uh, make their way in the world that- that it's- it's something that- that requires a lot of attention. And to me, what's really fascinating is that when you look at the variation in the way sense organs function, it's almost a miracle that we can agree on a common reality at all, even within the human species. And this is true of- of more... Of- of- of some senses more than others. Obviously in your world, in the retina, we have various kinds of- of loss of color vision, uh, that are well known and some other more complicated, uh, phenomena having to do with, uh, impairments in the perception of motion, uh, or form, but, uh, the place where this really happens is in the, uh, olfactory system. So we have approximately 400 functional receptors for different odorant molecule smells, uh, in our nose and if you, uh, sequence the genomes of many people, you find that the, uh, that the- the DNA that encodes for these odorant receptors is unusually variable from individual to individual. As a matter of fact, if you take two different people, on average, they will have functional differences in 30%......of their odor receptors. And if you do as Leslie Vosshall and her colleagues did at Rockefeller University and give 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 find enormous changes from people to people, both in term, in general terms, some people are just better smellers than others, but in terms of individual odors as well. There are some odors that some people can't detect and other people smell one way. For example, there is a, uh, there's a secreted hormone called androstenone. Androstenone, there are some people who can't smell it at all. For some people, uh, it smells like rather pleasant, like cut grass, and for some people it smells foul, like urine or sweat.

   5. AHAndrew Huberman24:34

      Hmm.

   6. DLDr. David Linden24:34

      And it just depends on genetic variation in one particular odorant receptor.

   7. AHAndrew Huberman24:41

      Uh, sorry to interrupt, uh, another, uh, phenomenal researcher who studies olfaction among other things, Catherine Dulac, um, I once heard, uh, say that some people have a gene that for them makes the smell of microwave popcorn, um, 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 can really be a binary response.

   8. DLDr. David Linden25:11

      Well, it can, and actually that's a very particular funny case. So the, the relevant chemical there is butyric acid and also isovaleric acid. And so, uh, there are, uh, researchers, I think Rachel Hertz, uh, is one of them, who have given a mixture of these two chemicals to people and if they say, "This is Parmesan cheese," they go, "Oh, yeah, that's Parmesan cheese." And if they give it to other people and say, "This is vomit," they'll go, "Oh, yeah, that's vomit." And if they tell people, they give them one vial and say, "This is Parmesan cheese," and they go, "Yeah." And they give them another one, they say, "It's vomit," and they go, "Yeah." And then they say, "Well, actually, we fooled you. It was the same vial." They say, "No, you didn't. You must have made a mistake." They're convinced that they couldn't have been the same thing. So this points out not only is there genetic variation that, uh, is responsible for how in- individuals perceive odor, but we are incredibly suggestible in terms of odors, and we, we are very dependent upon them in terms of cultural context, uh, and, and this can be, and this can be learned. And, and this is central to our humanity in the sense that, that we humans are what I like to call the anti-pandas. Uh, pandas live in one spot, uh, in, 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, wide, wide variety of foods. And as a result, it means that we have to have a very plastic olfactory system. There have to be very few things that we find innately aversive. There are only a handful of odors, rotting meat odors, uh, molecules with the evocative names like cadaverine and putrescine are things that even babies when they're newborn find aversive. But other things happen that they need to be learned. For example, um, pretty much every adult finds poop odors, uh, unpleasant, but babies happicl- happily play with their own poop. They have to learn-

   9. AHAndrew Huberman27:35

      Ugh. Sorry.

   10. DLDr. David Linden27:35

       ...that that's disgusting. It's not 'cause babies have a different nose.

   11. AHAndrew Huberman27:37

       Mm-hmm.

   12. DLDr. David Linden27:38

       It's because they have to learn culturally.

   13. AHAndrew Huberman27:39

       It's not innate.

   14. DLDr. David Linden27:40

       It is not innate. Um, there are only a few innate odor aversions and a few innate taste aversions that we're, we're born with, and the other things are elaborated culturally. And we can think about this in terms of how we, we, we, we talk about odors. So for example, we might say, "Vanilla smells sweet." Well, that's weird. That's like those are two different senses. How can something smell sweet? That's like saying it sounds red, right? (laughs)

   15. AHAndrew Huberman28:12

       It's like a se- it's a statement about synesthesia.

   16. DLDr. David Linden28:15

       Right, and but, but how did it come to pass? And do people say that vanilla smells sweet everywhere in the world? Well, the answer is no. So in places in the world where vanilla is used with sugar in, in sweet foods like desserts, then people say that vanilla smells sweet, or mint, similarly, uh, smells sweet if it is typically used together with sugar. But if you go to a place like, uh, uh, like Vietnam where mint is mostly used in savory dishes, people won't say that mint smells sweet.

   17. AHAndrew Huberman28:52

       So there's a paired association there that at least at our level of conscious understanding feeds back onto what we call olfactory or smell perception, but really it's a, it must be a paired association at some point in development.

   18. DLDr. David Linden29:07

       Yeah, it is. It absolutely is a paired association and it's something that goes on continually through your life, right? I mean, lots of people, for example, uh, have stories of foods that they wouldn't eat as a child but they came to like as an adult. Um, a good example of that is coffee. Uh, a lot of people have to overcome bitter aversion to, uh, to become coffee aficionados. Uh, so, uh, you know, this, this, this feeds into the more, the more general theme that...There is no pure perception. Perception is inference. It's not like there is a purely objective world that can somehow make its way through the senses and we can perceive that as the truth. All of our perception through all of our senses, both the outward pointing senses of the world like smell and taste and sight and hearing, uh, and the inward pointing senses like balance and, uh, is my stomach full, uh, and things like that, all of them are based on experience and expectation and the situation of the moment.

6. 30:25 – 31:22

   Sponsor: AG1

   1. AHAndrew Huberman30:25

      As many of you know, I've been taking AG1 daily since 2012, so I'm delighted that they're sponsoring the podcast. AG1 is a vitamin mineral probiotic drink that's designed to meet all of your foundational nutrition needs. Now, of course, I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every day, but oftentimes, I simply can't get enough servings. But with AG1, I'm sure to get enough vitamins and minerals and the probiotics that I need and it also contains adaptogens to help buffer stress. Simply put, I always feel better when I take AG1. I have more focus and energy and I sleep better and it also happens to taste great. For all these reasons, whenever I'm asked, "If you could take just one supplement, what would it be?" I answer, "AG1." If you'd like to try AG1, go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs plus a year supply of vitamin D3K2. Again, that's drinkag1.com/huberman.

7. 31:22 – 40:28

   Visual Individuality; Heat Tolerance; Early Life Experiences & Variation

   1. AHAndrew Huberman31:22

      Are there any examples of uniqueness of visual perception that come to mind? I recently did a social media post, um, that involved... i- it was essentially three rings, uh, a blue ring, um, a red ring, and a blue ring in the center. Perhaps it was the other way around, r- excuse me, it was red, blue, red. And, um, I asked which ring is in front or are they all at the, in the same plane?

   2. DLDr. David Linden31:52

      Right.

   3. AHAndrew Huberman31:52

      Um, and interestingly, it splits out into about thirds. Some people see the blue ring, i- in front quite a bit. Others see a red ring out in front. Others see them all in the same plane. And this, uh, we think has to do with, um, differences in two things between individuals. One is the distribution of the cone photoreceptors-

   4. DLDr. David Linden32:15

      Mm-hmm.

   5. AHAndrew Huberman32:15

      ... um, which we know is essentially random between individuals, maybe even between the two eyes.

   6. DLDr. David Linden32:20

      Mm-hmm.

   7. AHAndrew Huberman32:20

      And then, um, and that gives rise to this phenomenon of chromatic aberration-

   8. DLDr. David Linden32:25

      Yes.

   9. AHAndrew Huberman32:25

      ... um, which is the displacement of the visual image according to the wavelength of the light. And we won't get into the physics of it now. I'll soon do a post that hopefully distills it in a manner that's simple enough that people will understand. But clearly some people see certain colors in front of others.

   10. DLDr. David Linden32:40

       Mm-hmm.

   11. AHAndrew Huberman32:41

       Um, and the person right next to them could see the opposite color in front and others say, "What are you talking about? All the colors are in exactly the same plane of, of vision." Um, so that's the one that I know. Um, I'm guessing you know some others and, um, perhaps some more robust ones.

   12. DLDr. David Linden32:57

       Well, I think, you know, perhaps this is maybe not what you had in mind, but one way in which experience modifies the visual world has to do with how much light you're exposed to in the first five years or so of your life.

   13. AHAndrew Huberman33:16

       Mm-hmm.

   14. DLDr. David Linden33:16

       And so kids that don't get outside are much more likely to be myopic. And it actually is-

   15. AHAndrew Huberman33:26

       Near-sighted.

   16. DLDr. David Linden33:27

       Near-sighted, yes, uh, uh, when they grow up, uh, than kids who got outside. And we now know that at least part of the story is that light seems to stimulate the, um, expression of a class of molecules called trophic factors that you're well acquainted with, that actually change the shape of the eyeball. So it's not really the structure of the retina or the lens of the cornea. The actual degree of elongation of the eyeball changes, changing the way the, the retina sits relative to the lens. And that seems to be light dependent early in life and, uh, which gives rise to, uh, uh, to, uh, a higher incidence of myopia. And, and to me this is really... well, first of all, it's, it's, it's news you can use, you should get your kids outside for-

   17. AHAndrew Huberman34:21

       Absolutely.

   18. DLDr. David Linden34:22

       ... all kinds of reasons.

   19. AHAndrew Huberman34:23

       And you should get outside too, especially in the morning, set that circadian rhythm.

   20. DLDr. David Linden34:26

       Yeah, I know, that's a famous Hubermanesque, uh, uh, uh, point, yeah.

   21. AHAndrew Huberman34:31

       They're going to be putting me in the grave, David-

   22. DLDr. David Linden34:32

       (laughs)

   23. AHAndrew Huberman34:32

       ... and I'm going to be telling people to, uh... or it'll, maybe it'll be on my tombstone, it'll say, "Get, get sunlight in your eyes."

   24. DLDr. David Linden34:38

       He got, he got sunlight in his eyes. (laughs)

   25. AHAndrew Huberman34:39

       Especially on, especially on cloudy days 'cause there is still sunlight-

   26. DLDr. David Linden34:43

       Yeah.

   27. AHAndrew Huberman34:43

       ... even if you can't see the physical object of the sun on cloudy days.

   28. DLDr. David Linden34:47

       Yeah. Well, you know, I think this whole idea of having traits that are dependent upon early life experience is fascinating because there are a number of situations where you would guess that something is genetic, but it isn't. It's actually dependent on early life experience. And there's a, there's an amazing story about this having to do with the early days of World War II. So in the early days of World War II, the Japanese army just swept through Asia. They defeated the, the, the British in Malaysia and Singapore, they overrun Thailand and Burma, and they were knocking on the gates of India and everything was going great, except the Japanese army had a problem. There were an enormous number of their soldiers who became incapacitated with heat stroke. They got, their core temperature got too hot. And, uh, when the army doctors-... uh, examine them. They found this was much more likely to happen in soldiers, uh, who came from the northern part of Japan, Hokkaido, where it's, uh, you know, where it snows in the winter, as opposed to the southern part of Japan like Kyushu, which is a semi-tropical environment. And the classical explanation that biologists like us would guess, would say, "Oh, all right. Well, this has happened genetically over many years." Uh, you have a family that's been in Kyushu for many generations and you've selected for gene variants that allow you to tolerate the heat better. And we know actually what this is. So if you're more heat tolerant, it's because you have more of a particular class of sweat gland called the eccrine sweat glands, the sort of salt water sweat glands, not the lipidy, stinky armpit sweat glands called the apocrine ones. The eccrine ones, you have a higher fraction of them that are innervated, meaning that the signals from your brain that say, "Your core is too hot," can then make you sweat. So the total density of sweat glands between northern and southern soldiers in Japan wasn't different, but the southern soldiers tend to have a higher degree of innervation. All right, so we said, "Okay, well this happened genetically over many generations." But if you look at those rare cases where you have soldiers from a long-established northern family and their parents moved south and then they grew up in the southern location, they had high sweat gland innervation. They were well heat tolerant. Conversely, if you had a well-established southern Kyushu family and they moved to Hokkaido and then had their child, that child developed the northern sweat gland innervation pattern.

   29. AHAndrew Huberman37:34

       So meaning less nerve innervation of those sweat glands. As you mentioned before, just as many sweat glands, just less nerve innervation, therefore those sweat glands could not be activated, they couldn't dump heat as well, their heat tolerance was lower, correct?

   30. DLDr. David Linden37:45

       Exactly right. And, and what's, what's, what's wonderful is that this gives an advantage that you can't get through evolution and that it, it can happen right away in th- in, in one generation, right? Evolutionary change is slow, right? And you can adapt as a species and as a family over, over many, many, many generations. But when you have a phenomenon that is set by, uh, early life experience, well, then you can benefit from that early life experience within your own life. It's not that your great, great, great, great, great grandchildren will ultimately benefit, you benefit. Another wonderful example of this, uh, comes from field mice, voles. And we were talking earlier about how we both worked with, uh, the scientist Irve Zucker at, uh, at Berkeley, who was a, a specialist in, uh, in, in, in voles. And, uh, what people found is that if you take, uh, wild caught, uh, field mice and, uh, you have, uh, uh, pregnant mothers and you have 'em in the lab, but you manipulate the lights so that, uh, you have artificial spring, in other words, day length is getting longer day after day during the pregnancy, then what happens is when their pups were, are born, they will have a low density of fur, anticipating summer temperatures. Uh, if you, however, uh, put them in artificial fall where day length is getting shorter, uh, they will be born now with high density of fur, anticipating winter temperatures. And of course, you can do this no matter what the season actually is in the world by manipulating these lights in the lab. And so, like the sweating Japanese soldiers, this is a great example of early life plasticity and just the sort of trait that if you ask someone, they would probably guess is heritable, but actually is not.
8. 40:28 – 42:08

   Auditory Variability, Perfect Pitch

   1. AHAndrew Huberman40:28

      Since we've been taking a tour of individual variation in olfactory perception, visual perception, and, uh, now heat tolerance, um, I have to ask, are you aware of any examples off the top of your head, um, in the auditory domain that, um, particularly intrigue you?

   2. DLDr. David Linden40:46

      Yeah. Well, I would say one really interesting example has to do with perfect pitch.

   3. AHAndrew Huberman40:51

      Mm-hmm.

   4. DLDr. David Linden40:52

      So perfect pitch as a trait, that is to say, uh, you have the ability, uh, to, to hear a note played 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 Peabody Conservatory at my university, Johns Hopkins, and tested people there, you would find a higher incidence of perfect pitch than you would in the general population, but still maybe one in 10 trained musicians have perfect pitch. And parenthetically, having perfect pitch doesn't necessarily make you a better musician, uh, but it's an interesting phenomena. And so the question is, well, is perfect pitch heritable? And the answer is when you look at twin studies where, which is what we use to estimate heritability, the answer is it's kind of low. It, there's a heritable component, but it accounts for, uh, my recollection is on the, on the order of 30%, 40% of the variability in perfect pitch. However-If people receive ear training starting at a young age, the chance that they will develop perfect pitch can improve

9. 42:08 – 49:36

   Heritability & Human Individuality: Cognitive & Physical Traits

   1. DLDr. David Linden42:08

      drastically.

   2. AHAndrew Huberman42:09

      In your book, Unique, uh, do you cover aspects of human individuality that extend beyond the perception domain, um, into the cognitive domain?

   3. DLDr. David Linden42:20

      Well, yeah, absolutely. And, uh, you know, w- I think, I think it's good to set the stage here if we're going to be talking about heritability and human individuality. And, and so if I can go off on a little bit of a riff, uh, uh, for the benefit of your, of your listeners and viewers here.

   4. AHAndrew Huberman42:38

      Please.

   5. DLDr. David Linden42:39

      So, if you look at human traits, whether they are behavioral traits like shyness or very straightforward m- morphological traits like height, uh, what you tend to find is that there are very few traits that are entirely heritable, where all their variability can be predicted based on the gene variants you get from your mother and father.

   6. AHAndrew Huberman43:04

      Mm-hmm.

   7. DLDr. David Linden43:05

      And there are a few traits that are absolutely unheritable, but that most fall in between. So let me give an example. Everyone in the world has either wet or dry ear wax. And it turns out that this is determined by variation in a single gene. The name of the gene is boring, it's ABCC11. Uh, it's a ion transporter. And, uh, there's a variation in this gene, gives rise to either wet or dry ear wax. It doesn't matter how your parents raised you, it doesn't matter what foods you ate growing up, doesn't matter what, what, uh, uh, diseases your mother had when you were in the womb. It's 100% heritable. Well, does this mean that ABCC11, we should call it the ear wax type gene? Well, no, because it's not there just for that. Like this, this gene is expressed in cells in all parts of the body doing all kinds of things. Ear wax is just something that we notice. Genes don't code for traits, they code for proteins. And so we have to be careful about how we refer to them in that way. Um, for example, the wet ear wax gene, uh, variant of the ABCC11 gene also confers a slightly higher risk for breast cancer.

   8. AHAndrew Huberman44:27

      Hmm.

   9. DLDr. David Linden44:27

      Uh, so clearly it's not just for ear wax. It's, it's for a bunch of things, most of which we don't yet know about. But in the case of ear wax, this trait is 100% heritable. At the other end of the scale, speech accent is 0% heritable. It is entirely dependent upon the speech that you experience, uh, in your childhood. And interestingly, it's the speech of your peers more than the speech of your family, which is why the children of immigrants sound like the place where they wound up, not like their parents. Uh, and there is no evidence for any degree of heritability. Now, just to be clear, I'm talking about speech accent, like whether you have a high or a low voice, or it's nasal or more or less resonant. These are physical things having to do with the vocal tract and they are in part heritable. Okay, so we've got one thing that's 100% heritable and one thing that's 0% heritable, but where do most things fall? Most things fall in the middle. Uh, uh, one of the most heritable traits that we know about in humans is height and in the United States, height is about 85% heritable. 85% of the variation in the trait of height can be explained, uh, by what you inherit from your mother and your father. Well, what's the rest? Well, it's nutrition, it's the diseases you fought off, it's also random variation, which we'll talk about a lot later. Um, now you might say, "Okay, well that's an estimate for people in the US. Is this true all over the world?" Well, no. If you go to a place where people routinely don't get enough nutrition and are routinely fighting off infectious diseases, like this has been studied in rural Bolivia, for example, or rural India, now height is no longer 85% heritable, it's only 50% heritable. Why? Because people in these situations where they don't get enough nourishment, where they're fighting off these diseases can't live up to their 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 and enough nutrition and, and decent medical care and schools in order to fulfill their genetic potential for positive traits. And, uh, height I've used as an example because it is very uncontroversial, but we could apply the very same analysis to intelligence, general intelligence. Now there are people who argue about do things like IQ tests really measure anything real? And there's been a lot of fighting in the scientific literature about this, but I think intelligence tests aren't perfect and they are sometimes culture-bound, but they are actually quite predictive of, of, of, of later success. And, uh, much more so than say SAT tests or GRE tests or MCATs or other standardized tests. And, and-

   10. AHAndrew Huberman47:53

       But presumably those correlate in some way.

   11. DLDr. David Linden47:55

       They do. They do. But, but, but the IQ tests are better.... actually. They're-

   12. AHAndrew Huberman47:59

       You're talking about this, the, the classic IQ test?

   13. DLDr. David Linden48:03

       I, I am talking about the modern variants-

   14. AHAndrew Huberman48:05

       Mm-hmm.

   15. DLDr. David Linden48:06

       ... of the classic IQ tests that are administered by trained psychologists, uh, and aren't just a paper form.

   16. AHAndrew Huberman48:13

       Mm-hmm.

   17. DLDr. David Linden48:14

       And so they're not perfect and no test will be perfect, but they're pretty good. And so then if you ask the question, "Well, what is the heritability for IQ tests score?" Uh, well, the answer tends to be different depending upon the population. If you look, uh, again, in, in countries like the US or in Western Europe that are fairly affluent where, where people, uh, tend to have good access to, to nutrition and medical care and schooling and kids get to play and they're not, and they're not traumatized by war, then, uh, then IQ test score is heritable in the ballpark of 60, 70%. But if you look at people who don't have those benefits, who are poor, and this can be in the United States as well, if you look at, uh, communities that, that, uh, face discrimination and have consistently poorer, poorer healthcare and schools, then IQ is less heritable. Why? For the very same reason that it is in height, because people can't live up to their genetic potential when they don't have the basic things that everybody needs.

10. 49:36 – 1:00:12

    Heritability, Environment, Personality; Twin Studies

    1. AHAndrew Huberman49:36

       So presumably, if two identical twins, and I realize they aren't identical, but you're familiar with twins, you have twin children, um, if two identical twins are raised separately, uh, the correlation in their IQ is, can only... Is it that only 60, I think you said about 66% of their IQ can be predicted on the basis of their genetic makeup alone? Um, I mean, it makes perfect sense to me as to why if one of those twins went to schools that were demanding of, you know, a lot of different topic matter, um, and the other one went to schools where the, the instruction level was really deficient, that one would perform far less well on an IQ test. Unless, of course, the IQ test isn't tapping into school-based knowledge, it's tapping into some other, um, thermometer of, of so-called intelligence or IQ.

    2. DLDr. David Linden50:36

       Well, you know, the thing is that good schools correlate with many other things, right? So the students that go to good schools aren't just benefiting from good schools. They tend to also have good medical care and safer, less traumatizing neighborhoods, and they're more likely to have books, parents with books in the home and, uh, uh, and, and a whole number of things that are all beneficial.

    3. AHAndrew Huberman50:58

       Sure.

    4. DLDr. David Linden50:59

       So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected, but, but you bring up a good point. So it turns out that the way we get these estimates of heritability, there's two ways. One way is to compare so-called identical or monozygotic twins with so-called fraternal or dizygotic twins. So the identical twins will share nearly 100% of their gene variants and on average, fraternal twins share 50% of their, uh, of their gene variants. And generally speaking, when people do these studies in order to avoid confounds of sex, they'll 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 Fisher's Equation then you can come up with an estimate of the heritability of the trait-

    5. AHAndrew Huberman52:03

       Okay.

    6. DLDr. David Linden52:03

       ... but there is an assumption present in that, and it's called the equal environment assumption. You're saying, well, two kids raised in the same family have the same environments. Well, that's not always true.

    7. AHAndrew Huberman52:20

       Mm-hmm.

    8. DLDr. David Linden52:20

       Right? That can be violated by a number of, uh, of different situations. So it turns out that a more powerful, but much more difficult way to estimate heritability is by looking at twins reared apart, either identical twins or fraternal twins reared apart. And there was a landmark study called the Minnesota Study of Twins Reared Apart, which is abbreviated MISTRA, that is really the gold standard for assessing the heritability of many different human traits, both behavioral traits, uh, but also disease incidents. But of course, it's a small n because, you know, the population of identical twins reared apart that you can get into the lab isn't, isn't that large.

    9. AHAndrew Huberman53:12

       Mm-hmm.

    10. DLDr. David Linden53:12

        They had something, I don't remember the exact numbers, but they had something like 80 some, uh, uh, identicals and 50 some fraternals, uh, in their, in their sample. But by doing this, they were able to come up with a lot of interesting estimates. And so for example, most, uh, personality traits, uh, what the psychologists, uh, use the acronym OCEAN to mean: openness, conscientiousness, empathy, agreeableness, and neuroticism. I think I got that right. (laughs)

    11. AHAndrew Huberman53:45

        Mm-hmm. That's it. It's, uh, spelled right. Yeah.

    12. DLDr. David Linden53:47

        Uh, that these traits on average tend to be about 50% heritable. And so, okay, you say, "Right, well, 50% of those personality traits is heritable, the rest has got to be like how you were raised. It's got to be in your family." And so everyone was shocked when they actually did the analysis.... um, and found that family has almost nothing to do with it. Andrew Huberman: Wild. And, and what? What? Are, are you kidding? It's, it's, it's, it's, it's got to. And I think the important thing to realize is these traits I just listed, you know, we call these personality traits but they are not the sum total of the way you are in the world. Parents can inculcate many things in their children. They can demonstrate trades, so people are much more likely to go into an occupation if their parents did. They can inculcate moral ideas and religious ideas. But in terms of these OCEAN personality traits, they have astonishingly little to do with it. So then this brings up the question, well, if 50% of the variation in these personality traits is not from your genetics and it's not from your family, where does it come from? And the answer seems to be is that it comes from the random nature of the development of the body and the nervous system. And this is, this is a point that I think many people don't understand. This is something that biologists know but we've done a very poor job of communicating to the general public. The genome, all your DNA, all three billion bases of DNA, all 19,000 or so genes in a human don't make a blueprint for making your body and brain. They're... It's not a schematic diagram that connects everything to everything, particularly in the nervous system where we have these hundreds of trillions of connections. Rather, it's a rather vague recipe. So the genome doesn't say, "Oh, okay, you glutamate using neuron in the brain region called the thalamus, you know, grow for 200 microns towards the top and then, and then, and then cross the midline and then grow towards the ear for, you know, another distance." No. It, it says something like, "Hey, you bunch of glutamate neurons in the thalamus over here in this area, about half of you cross the midline." And so what does this mean in terms of individual variation? Well, it means, well, for s- for, for some individuals 40% of their axons will cross the midline of the brain, and for another individual 60% will. Even in identical twins. And as you correctly said a moment ago, identical twins aren't really identical either in their bodies or their temperament. So if you take newborn identical twins and you give them a CT scan just to measure the shape of their organs, they're not the same. You might have one twin whose spleen is 30% larger than the o- than the other twin's, or whose liver is 30% smaller than the other twin's, even though they have the exact same DNA and they were lying right next to each other in the womb, and presumably had 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... (laughs)

    13. AHAndrew Huberman57:36

        I love the armadillo because I've been told... Tell me.

    14. DLDr. David Linden57:39

        Yes.

    15. AHAndrew Huberman57:39

        I don't want to, uh, uh, interrupt you too long, but, um, as far as I know the only animal in North America that carries leprosy?

    16. DLDr. David Linden57:49

        Uh, that is, that is true. Yeah.

    17. AHAndrew Huberman57:51

        And, um, and there's a lot of twinning going on in armadillos, right?

    18. DLDr. David Linden57:56

        Well, what there is is actually quadding. So armadillos, or the nine-banded armadillo in particular, and there are different armadillos, I'm not really an armadillo specialist so I don't know if this holds for all of them, but the nine-banded armadillo is born as identical quadruplets.

    19. AHAndrew Huberman58:15

        Awesome.

    20. DLDr. David Linden58:15

        Awesome. So you can take these identical quadruplet newly born armadillo, I don't know, you think you'd call them pups, I don't know what a baby armadillo is called, I'm sure there's some particular word for it. And-

    21. AHAndrew Huberman58:27

        Someone will tell us.

    22. DLDr. David Linden58:28

        I'm sure someone will tell. (laughs)

    23. AHAndrew Huberman58:28

        In the, in the comments on YouTube.

    24. DLDr. David Linden58:30

        Yes.

    25. AHAndrew Huberman58:30

        What is the name of a baby armadillo? I know like a ferret, baby ferrets are kits. Uh, uh, the moms are jills, the dads are bobs. I used to be obsessed with this kind of naming, you know, it's a, it's a business of ferrets or a, a what is like a gang of raccoons or whatever. So if you can tell us what the name is for the baby armadillos as well as what do you call a group of armadillos, um, you win the prize associated with being right.

    26. DLDr. David Linden58:55

        That's right, right? One of my favorites is an, um, an ostentation of peacocks.

    27. AHAndrew Huberman59:01

        Amazing.

    28. DLDr. David Linden59:01

        Or a murder of crows.

    29. AHAndrew Huberman59:03

        Who comes up with this stuff?

    30. DLDr. David Linden59:04

        Yeah, I know, it's, it's a bit... (laughs)
11. 1:00:12 – 1:01:19

    Sponsor: InsideTracker

    1. AHAndrew Huberman1:00:13

       I'd like to take a quick break and acknowledge our sponsor, InsideTracker. InsideTracker is a personalized nutrition platform that analyzes data from your blood and DNA to help you better understand your body and help you meet your health goals. I'm a big believer in getting regular blood work done for the simple reason that many of the factors that impact your immediate and long-term health can only be analyzed from a quality blood test. However, with a lot of blood tests out there, you get information back about blood lipids, about hormones and so on, but you don't know what to do with that information. With InsideTracker, they have a personalized platform that makes it very easy to understand your data, that is, to understand what those lipids, what those hormone levels, et cetera mean, and behavioral supplement nutrition and other protocols to adjust those numbers to bring them into the ranges that are ideal for your immediate and long-term health. InsideTracker's Ultimate Plan now includes measures of both ApoB and of insulin, which are key indicators of cardiovascular health and energy regulation. If you'd like to try InsideTracker, you can visit insidetracker.com/huberman to get 20% off any of InsideTracker's plans. Again, that's insidetracker.com/huberman to get 20% off.

12. 1:01:19 – 1:07:37

    Development, Chance; Transgenerational Epigenetic Inheritance

    1. AHAndrew Huberman1:01:19

       And is the pseudo-random stochastic nature of development one of the maging, major, excuse me, driving forces for evolution? Because, you know, we hear about mutations and we always think, or people tend to think, rather, that mutations are bad, but, of course, mutations provide the variation that can also serve adaptive traits. I mean, if you're a fan of the X-Men, as I am, huge fan of the X-Men, the entire series, every single one, including the Wolverine movies, you quickly come to learn that genetic mutation is at the heart of variation, which is at the heart of individuality, which is what we're talking about.

    2. DLDr. David Linden1:01:53

       Right, and so genetic variation is at the heart of individuality, but there is also, there are also these other things, right? (laughs) That we've talked about. There's the effects of early life experience, and there is the stochastic nature in development because if you, through the randomness of development, happen to have, like, a particularly great liver, you're not going to pass that on to your children, right?

    3. AHAndrew Huberman1:02:18

       Mm-hmm.

    4. DLDr. David Linden1:02:18

       That isn't in your germline. You won't pass that trait along.

    5. AHAndrew Huberman1:02:25

       Just qui- a brief answer here on germline. Uh, we had Oded Rechavi on the podcast who studies, um, epigenetic transmission and, um, and in- inheritance of, uh, of, of... it's not Lamarckian, we have to point that out, but, um, inheritance of, of, uh, sort of acquired traits, uh, does happen. Uh, the germline, uh, it's the genes that are present in the, the sperm and in the eggs. All the other, uh, cells of your body have genes, of course, but, um, the best way to put this is, uh, simply going to the gym and getting fit, um, does not make your children more fit because the germline, as far as we know, is not modified in a direct way. Uh, in other words, the DNA within sperm and eggs are not modified according to your behaviors in most but not all cases.

    6. DLDr. David Linden1:03:10

       That's right, and, and as you, uh, as you correctly said about Oded's work and, and other people's work, there is what's called transgenerational epigenetic inheritance, which means that you can have traits that are passed not from one generation to the next, but even two generations to the grandchildren that don't require modification of DNA, but to date, that has been shown very convincingly in, in, uh, worms and in plants. Uh, the evidence in mammals is, is really not there yet, in, in my opinion. And most of the claims for that, and it's a very popular thing to say, "I epigenetically inherited my grandmother's or great-grandmother's trauma." Uh, the evidence at present is, is poor.

    7. AHAndrew Huberman1:04:01

       Mm-hmm.

    8. DLDr. David Linden1:04:01

       Actually, a lot of it comes from epidemiology, most of which came from famines in the Overkalix region of northern Sweden, and they had very good medical records, and they said, "Oh, well, if your grandfather went through the famine, then you're more likely to have this trait if you're male," or, "If your grandmother went through this, then if you're, if you're male, you'll have this trait, and if you're female, you'll have that trait." And, I mean, there are two problems. One is that there's not a biological mechanism, but the other problem is that the way these things were discovered is by something called HARKing, or hypothesizing after the re- results are known. Uh, they did very many statistical comparisons to try to find something significant, and you know from your work in the lab that when you do many comparisons, you're going to get some things that look significant just occasionally or randomly through, through, through luck, and you have to apply a statistical correction called a Bonferroni correction when you make many particularly post-hoc comparisons, after the experiment, uh, comparisons, to set the bar much higher for accepting that data. And most of those studies, they didn't apply-

    9. AHAndrew Huberman1:05:18

       Mm-hmm.

    10. DLDr. David Linden1:05:18

        ... that correction, and I remain unconvinced of transgenerational epigenetic inheritance in mammals. Now, let's be clear, just because it hasn't been shown convincingly now doesn't mean that it won't be. There are some good people working very hard on this, and they may well, uh, describe a mechanism and show this convincingly in the years to come, but right now, uh, you may well inherit your grandma's or great-grandma's trauma, but you're probably doing it socially-

    11. AHAndrew Huberman1:05:56

        Mm-hmm.

    12. DLDr. David Linden1:05:56

        ... not through marks on your DNA that changes how your genes are expressed or not expressed.

    13. AHAndrew Huberman1:06:03

        Yeah, so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right?

    14. DLDr. David Linden1:06:12

        (laughs)

    15. AHAndrew Huberman1:06:12

        I mean, your grandparents raised your parents, who raised you. Not always, people can be adopted.

    16. DLDr. David Linden1:06:16

        Yeah.

    17. AHAndrew Huberman1:06:16

        In fact, I have adopted members of my family, um, but...... if I understand what you're saying correctly, the evidence that, for instance, some stress-related gene was modified during a trauma in my grandparents or great-grandparents, and the idea that that was passed to me through my parents, that the evidence there is, is far weaker.

    18. DLDr. David Linden1:06:41

        Right. And when, when you think about it, well, like how did that happen? That had to get into your, your grandparents' sperm or egg cell, and then produce that effect in the brain of your parents, and then it had to get into their sperm and egg, or egg cell, and then contribute to producing it in you. And, and-

    19. AHAndrew Huberman1:07:00

        But DE- but fragmentation of DNA in sperm is, um, or in eggs is, is a, is a common, um, thing, eh, especially as people age. DNA, sperm and eggs fragment. Um, and it's possible that some of those mutations still allow for viable embryos. So, it's, in theory, the germline could be changed by, um, environmental e- events.

    20. DLDr. David Linden1:07:22

        Well, right. Uh, but now I think you're starting to talk about things that are heritable.

    21. AHAndrew Huberman1:07:26

        Mm-hmm.

    22. DLDr. David Linden1:07:27

        Right? You're not talking about marks on DNA. You're talking about the structure of the DNA-

    23. AHAndrew Huberman1:07:30

        Right.

    24. DLDr. David Linden1:07:31

        ... itself. And that is its own separate issue.

13. 1:07:37 – 1:15:52

    Single Generation Epigenetic Inheritance & Stress; Autism

    1. DLDr. David Linden1:07:37

       Now, I think I, I want to be really careful about this because what is now, I think, fairly well established is that you can transfer things epigenetically over a single generation, uh, if, as a result of experiences that the mother has during pregnancy. So, uh, for example, we know that during the 1918 pandemic flu, uh, 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 males wound up going into the Army for World War II. And of course, the Army does a complete physical and the records are very good, so you can go into that database. And you find that, uh, the male children, uh, that were, uh, in utero during the winter of 1918, during the pandemic flu, are on average a millimeter or two shorter. You might say, "A millimeter or two, that's nothing." But in a huge statistical sample of millions of people, that's enormously significant. More interesting is that the incidence of schizophrenia went up about fourfold, from about 1% to about 4%. And even though autism wasn't a term in 1918 yet, uh, I do- I think it came along later, what we now retrospectively would call autism also went up by about fourfold. So, there's something about mom being stressed and carrying the fetus at a particular stage that seems to impact brain development in a way that then makes that child more likely to be schizophrenic or autistic when they grow up.

    2. AHAndrew Huberman1:09:37

       Do we know that it's stress? And, uh, my recollection of this, and I believe this was, um, the late Paul Sternberg's work as well, uh, I maybe have that name, um, incorrect, but in any event, that it is, um, if pregnant mom gets the flu in the first trimester, you see this higher incidence of schizophrenia and, uh, autistic offspring. Um, and, but do we know that it's stress per se? Because it's stressful to have the flu, but the flu is a bunch of other things. Could be fever. Could be, um, uh, some breakdown in the immune barrier. I just want to open up the, the number of variables that this could be. D- or do we know that it's something in the hypothalamic-pituitary so-called stress axis that is, uh, adrenals, um, so hypothalamic-pituitary-adrenal axis. Um, like, is it elevated cortisol? Um, or could it literally be an immune-neural interaction of some other sort?

    3. DLDr. David Linden1:10:33

       It's probably the last thing you mentioned, an immune-neural interaction. And the reason I say that is that, uh, Gloria Choi at, uh, MIT, uh, uh, uh, together with her collaborators, has made a mouse model of this phenomena. So she takes pregnant female mice and she injects them with something that, that it's, she doesn't actually infect them with virus. She puts a chemical in that is on the coat of viruses that mimics viral infection.

    4. AHAndrew Huberman1:11:02

       Hmm.

    5. DLDr. David Linden1:11:02

       And, uh, then what happens is that in a way that interestingly is an interaction with the, with the bacterial content of her, of her gut, produces a surge of a immune-signaling molecule called interleukin 17.

    6. AHAndrew Huberman1:11:21

       Mm-hmm.

    7. DLDr. David Linden1:11:21

       Interleukin 17 can pass through the placenta into the fetus, and if it's present, just as you said, at a particular point in development, does- doesn't work anywhere during pregnancy, but during something that is sort of the mouse equivalent of the first trimester, if that occurs, it causes disordered development of the layers of the cortex. Instead of it looking like layers of a cake, you see balls and clumps-

    8. AHAndrew Huberman1:11:50

       Hmm.

    9. DLDr. David Linden1:11:51

       ... of cells. And parenthetically, in some but not all post-mortem tissue from autistic people, you can also see those balls and clumps of cells.

    10. AHAndrew Huberman1:12:00

        Are those, um, balls and clumps of cells thought to reflect, um, alterations in cell migration?

    11. DLDr. David Linden1:12:07

        They are. Yeah.

    12. AHAndrew Huberman1:12:08

        Mm-hmm.

    13. DLDr. David Linden1:12:08

        So, some, I, I don't know if it's entirely known how much of it is cell division-

    14. AHAndrew Huberman1:12:12

        Mm-hmm.

    15. DLDr. David Linden1:12:12

        ... or migration, but certainly migration is a part of it. And it's very likely that that critical moment ...... uh, to disrupt this ordering of the brain and produce these increases in schizophrenia or, or, uh, autism vulnerability, uh, are coming at a point where neurons are migrating-

    16. AHAndrew Huberman1:12:34

        Mm-hmm.

    17. DLDr. David Linden1:12:34

        ... uh, during development.

    18. AHAndrew Huberman1:12:36

        Mm-hmm.

    19. DLDr. David Linden1:12:36

        And, uh, so what Choi's group did is they w- did all the things you would want to do as a biologist. So, they gave things to block the function of, uh, you know, of this interleukin signaling molecule, and it blocked the phenomenon. They artificially injected the signaling molecule into fetal brain when the mom hadn't been stressed and they could, they could reproduce it. So I'm not saying that there aren't effects of stress hormones from the hypothalamic-pituitary axis that are important, that you mentioned, but in this mouse model system w- work, uh, it seems that, uh, you can produce it through this immune signaling pathway. And, and so then the question is, well, like, are these mice autistic? Well, how do you know if a mouse is autistic? And, and the answer is, it's actually a little vague, right? There are behaviors that neuroscientists say are analogous of human autism. And one of them is, if you give a mouse a marble in its home cage, it will bury it over and over again compulsively, or bury many marbles. And people say that that is somehow analogous to some of the compulsive behaviors you see in autism. It's a bit of a stretch, right? I mean, it's a challenge to interpret mouse behavior in, in human terms, but, um, it's a reasonable first step.

    20. AHAndrew Huberman1:14:03

        Incredible. And, uh, I hope more will continue to be done, um, as it surrounds the, uh, first trimester influenza hypothesis 'cause it's been around a while. And, um, and obviously, uh, there's a spectrum, uh, of what we call autism, Asperger's, and, uh, nowadays people refer to it as, sometimes as neuroatypical. There's some high functioning people with autism, there's some low functioning people with autism, and, uh, for that matter, there's some high functioning and low functioning people who don't have autism.

    21. DLDr. David Linden1:14:35

        Right.

    22. AHAndrew Huberman1:14:35

        So, um, but it is something that I think, uh, demands our attention and, and it, that hopefully will be resolved at some point because also influenza is g- uh, but one immune, uh, insult. Um, and presumably pregnant women are being bombarded with all sorts of, uh, viruses and bacteria and fungal infections and fighting them off or not fighting them off. And who knows what the variation in, uh, neuro-immune interactions exist in there, uh, that give rise to, you know, good variation and let's call it, um, you know, uh, debilitating variation.

    23. DLDr. David Linden1:15:16

        Well, that's, that's absolutely right. And so for g- one example is that, uh, we don't know what the effects are on the children who were in utero while their m- mothers were fighting off COVID.

    24. AHAndrew Huberman1:15:31

        Mm-hmm.

    25. DLDr. David Linden1:15:31

        Right? We won't know for, uh, for a while. Um-

    26. AHAndrew Huberman1:15:35

        Or the common cold.

    27. DLDr. David Linden1:15:36

        And there might... I mean, and there might be nothing.

    28. AHAndrew Huberman1:15:38

        Mm-hmm.

    29. DLDr. David Linden1:15:38

        But... Or there might be something serious, uh, lurking there like there was for pandemic flu.

    30. AHAndrew Huberman1:15:44

        Mm-hmm.
14. 1:15:52 – 1:23:47

    Sleep Paralysis; Cerebellum, Prediction

    1. AHAndrew Huberman1:15:52

       I'd love to talk with you about mind/body, but before we do that, I would be totally remiss if I didn't ask for your, um, broad, top contour understanding of the mini brain, the cerebellum. Right?

    2. DLDr. David Linden1:16:11

       (laughs)

    3. AHAndrew Huberman1:16:11

       The so-called mini brain. And here's why. I've been a practicing-

    4. DLDr. David Linden1:16:15

       (laughs)

    5. AHAndrew Huberman1:16:15

       ... neuroscientist for, you know, close to three decades. I know where the cerebellum is. I've dissected a bunch of them. I, um, could tell you where a few things are in there. And I certainly have read about what the cerebellum does, but whenever I do a PubMed search on cerebellum, I see an ever expanding set of things that the cerebellum is implicated in. Not just balance, as most people hear, but also timing, also cognition. I hear about timing in particular of motor behavior, but then I also hear that it's involved in learning and not just motor learning, and it certainly is involved in motor learning. Perhaps that little mini brain is, uh, doing 50 or 1,000 different things, but how should we think about the cerebellum? What is it doing and what are some of its core operations that inform both what it's doing and perhaps what other areas of the brain are doing as well? Because I can point to the retinas or the auditory cortex or the thalamus, and yes, there's some mysterious nuclei in the brain, but to me, the cerebellum is one of the most cryptic and, um, complicated structures to understand. And I know you spent some time in there. So, what does the cerebellum do?

    6. DLDr. David Linden1:17:29

       Well, uh, cerebellar researchers like to joke that the cerebellum is a counterweight to keep your head from falling forward.

    7. AHAndrew Huberman1:17:36

       Oh, perfect.

    8. DLDr. David Linden1:17:36

       Yeah.

    9. AHAndrew Huberman1:17:36

       Well, with all the texting nowadays-

    10. DLDr. David Linden1:17:38

        Yeah.

    11. AHAndrew Huberman1:17:38

        ... people need b- bigger cerebellums.

    12. DLDr. David Linden1:17:39

        That's right, that's right.

    13. AHAndrew Huberman1:17:40

        Yeah.

    14. DLDr. David Linden1:17:40

        Probably over many generations then that will happen-

    15. AHAndrew Huberman1:17:42

        (laughs)

    16. DLDr. David Linden1:17:42

        ... along with the expansion of the thumbs.

    17. AHAndrew Huberman1:17:44

        (laughs)

    18. DLDr. David Linden1:17:45

        Uh, so, uh, but of course, everybody's going to text with their mind in about another 10 years, right? You'll have-

    19. AHAndrew Huberman1:17:50

        Yeah.

    20. DLDr. David Linden1:17:50

        ... Elon's implant and you won't need your thumbs at all.

    21. AHAndrew Huberman1:17:53

        Yeah, or maybe just five or-

    22. DLDr. David Linden1:17:55

        Yeah.

    23. AHAndrew Huberman1:17:55

        My friend, Eddie Chang, who's a neurosurgeon and, uh, works on the auditory system, he's been on this podcast before. He was saying that if y- i- in theory and actually in practice, you could just record the neural output to the muscles of the speech system-

    24. DLDr. David Linden1:18:09

        Yes.

    25. AHAndrew Huberman1:18:09

        ... essentially, and you could just amplify that and you could text without actually speaking.

    26. DLDr. David Linden1:18:17

        Mm-hmm.

    27. AHAndrew Huberman1:18:18

        Um, in fact, when we read, he told me, uh, we are actually receiving the signals w-... as if we were going to speak the words we're reading, but they don't quite arrive at the place where you could get a full-blown post-synaptic potential, so you're not actually moving the vocal machinery. Um, so that means the motor signals are getting sent out there, and so you're speaking what you are reading, but you just don't know it.

    28. DLDr. David Linden1:18:43

        That's right. And it's very analogous to what happens during the REM phase of sleep.

    29. AHAndrew Huberman1:18:46

        Mm-hmm.

    30. DLDr. David Linden1:18:47

        Right? When you have commands, your brain is issuing commands to your muscles to, to do things, uh, like behave in your dreams, to, to run away or go here or go there. Uh, but those signals actually are blocked in the brain stem and prevented from, from reaching your muscles. Because the, uh, nerves that don't go through your brain stem, like the ones that control your eye movements, aren't subject to that blockade. That's why you can produce the rapid eye movements-
15. 1:23:47 – 1:30:37

    Nature vs. Nature, Experience; Linden Hypothesis

    1. DLDr. David Linden1:23:47

    2. AHAndrew Huberman1:23:47

       In all aspects of biology and life, the term nature versus nurture is relevant, but never so much as when thinking about the nervous system. And I know this firsthand because I've studied neural development, both the nature side, the so-called hardwired stuff that genes just set up, neurons wire up to that neuron, et cetera. The cerebellum's in the back, the eyes are in the front, the hardwired stuff. Uh, and then the soft-wired stuff, the nurture stuff is the stuff that can be modified by experience. What are your thoughts on nature versus nurture, and should there even be a versus in there?

    3. DLDr. David Linden1:24:29

       Yeah, I don't think there should. And, and I have...... a lot of problems with nature versus nurture as, uh, as an expression. It was popularized by Francis Galton, uh, in the 19th century. A, a colleague of, uh, of, uh, of Darwin's. And I think it's wrong in, or misleading, in a lot of ways. So, of course, the nature in nature versus nurture is meant, in this case to mean heritability, right? What you inherit in the gene variations from your mother and father. And nurture means like how your parents or your community raised you. Uh, the problem I have with nurture is that it is too narrow a term. That really, it should be replaced with the word experience.

    4. AHAndrew Huberman1:25:24

       Mm-hmm.

    5. DLDr. David Linden1:25:24

       And experience in the broadest possible sense, not just social experience, but, uh, the foods your mother ate when she was carrying you in utero. Um, the diseases you fought off or your mother fought off while she was carrying you, uh, in utero. The bacterial population of your guts. Uh, so experience meaning anything that impinges on you starting from the earliest stages of fetal developments, uh, continuing to the last day of your life. I think it should be very expansive, much, much more than social experience in the family or the, or the community. And as you mentioned, I have a problem with the versus because there's this idea that these things are, are essentially in opposition. Well-

    6. AHAndrew Huberman1:26:23

       Mm-hmm.

    7. DLDr. David Linden1:26:23

       ... is he that way because of, of, of his gene variants or is that way because of what, what happened to him? And I think the thing to realize is that, uh, experience and heredity interact in all kinds of interesting ways, some of which are oppositional and some of which are reinforcing. A classic one from genetics has to do with a genetic disease called phenylketonuria, or PKU, uh, which is, uh, an inability to, uh, to metabolize, uh, the dietary amino acid phenylalanine. And, uh, so, uh, in order to have this, you have to inherit broken copies of this gene from both your mother and your father. So it's a so-called recessive trait. And here's where the experience comes in. It only matters if you eat foods rich in phenylalanine. If you don't, it doesn't matter that you inherited these things, right?

    8. AHAndrew Huberman1:27:29

       Mm-hmm.

    9. DLDr. David Linden1:27:29

       So that's a way in which genes and experience interact. An idea of, and ways in which then they interact positively, um, think about athletic ability, right? So a lot of athletic ability is... has a heritable component. If you are born fast, for example, uh, then you're more likely to do sports and practice them and get better at sports as a result of your experience. So here, genes and experience are feeding back on each other in a positive feedback loop. So there really isn't a verse- a versus at all. And then of course, the last thing is that this isn't the entirety. So we talked earlier about the pseudo-random nature of development, 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 fall off the tongue as elegantly as nature versus nurture. You know, nature versus nurture is like if the goves- the gloves don't fit, you must quit, you know? It's got that kind of snappy snare drum beat. But I think it's, it's a more accurate.

    10. AHAndrew Huberman1:28:55

        So heritability interacting with experience filtered through the randomness of development.

    11. DLDr. David Linden1:29:02

        Yeah.

    12. AHAndrew Huberman1:29:03

        So we can shorten that up and, um, and we'll just call it, um, uh, the Linden hypothesis.

    13. DLDr. David Linden1:29:11

        Uh, you know, I, I, I don't think I can take credit for that.

    14. AHAndrew Huberman1:29:13

        Uh, no, but-

    15. DLDr. David Linden1:29:13

        That's, it's- ... it belongs to other people.

    16. AHAndrew Huberman1:29:15

        Sure, but, um, but there's a long history in science of, of things being, uh, shortened up and, uh, coined, and that's, uh, as important. And I'm not, we're not trying to rob attribution here. Um, uh, and the good news is perhaps you can't call it the Linden hypothesis, but I can.

    17. DLDr. David Linden1:29:34

        All right then.

    18. AHAndrew Huberman1:29:35

        And what I've found is, as with the Galpin equation, which is now out there as a hydration... it's a formu- a formula that, uh, gives broad, but, um, research informed parameters as to how much water one should drink in order to maintain proper hydration. For physiologist Dr. Andy Galpin, who's a PhD in, uh, physiology and, and an expert in all aspects of exercise science. There's the Galpin equation, there's the Søberg principle. So I'm naming these things left and right-

    19. DLDr. David Linden1:30:02

        All right.

    20. AHAndrew Huberman1:30:02

        ... um, where appropriate. And, um, so I'm naming these things, uh, sparingly and where appropriate. Um, so from here on out, heritability interacting with experience filtered through the randomness of development, uh, 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. So-

    21. DLDr. David Linden1:30:25

        All right. Well, I think all the, the, the geneticists will be gnashing their teeth, uh, about this being named after someone who isn't actually a geneticist, but-

    22. AHAndrew Huberman1:30:33

        Quite all right. And their dentists will thank me.

    23. DLDr. David Linden1:30:35

        (laughs)

    24. AHAndrew Huberman1:30:36

        Let's

16. 1:30:37 – 1:39:10

    Mind-Body Interaction; Chemical Signals

    1. AHAndrew Huberman1:30:37

       talk about mind body.

    2. DLDr. David Linden1:30:38

       Okay.

    3. AHAndrew Huberman1:30:40

       I'm fascinated by this, um, for a couple of reasons, and I promise to keep this brief. But when I was growing up, I was very interested in animals and biology, and my father's a scientist, and I got very interested in neuroscience early, um, as people perhaps know. And so much of neuroscience as I was coming up through the mid-'90s, 2000s, 2010 to '20 stretch, was focused on the brain piece.

    4. DLDr. David Linden1:31:06

       Mm-hmm.

    5. AHAndrew Huberman1:31:07

       Very little on the body. There was nothing about gut-brain axis in the early discussions and coursework. Um, in parallel to all of that, I've been interested in mental health, physical health, and let's just call it performance, and, um, got interested in meditation, respiration-based practices, things like yoga nidra, things that by way of experience I understood immediately had a profound influence on the nervous system, states of mind and body.

    6. DLDr. David Linden1:31:33

       Mm-hmm.

    7. AHAndrew Huberman1:31:34

       Nowadays, there's an entire institute at the National Institutes of Health for Complementary Health and Medicine essentially exploring things like yoga nidra, respiration practices, even supplements and things of that sort. And there's this understanding that, oh my goodness, the nervous system extends into the body and the body sends neural signals back into the brain. And so this whole notion of mind-body has fortunately migrated away from kind of, um, California counterculture, Esalen Institute only, uh, you know, um, hippie new age, magic carpet stuff. By the way, that's not what I believe. That's, but that's often how it was looked at in the past.

    8. DLDr. David Linden1:32:19

       Mm-hmm.

    9. AHAndrew Huberman1:32:19

       And now people at every level of science and medicine, at every major university, and in every scientific journal are starting to publish papers about the interactions between bodily organs, like the breathing apparati, the diaphragm lungs, the heart, heart rate variability we hear about, um, the liver, the gut-brain axis in particular. And so mind-body, the idea that our thoughts could influence our body and that our bodily state could influence our thoughts, is fortunately not just understood, but it seems to be both accepted and appreciated. So what are your thoughts on mind-body? What does that mean to you? And what do you think is the potential of the mind-body interaction? It seems to me we've just barely scratched the surface.

    10. DLDr. David Linden1:33:11

        Yeah. Well, I'm glad you asked, 'cause I think it's a, it's a really fascinating, uh, situation and, uh, where things are changing very, very quickly. And I think to me, the most important thing for people to understand is that when you have a hypothesis, let's say you have a hypothesis that, uh, meditation can, uh, attenuate chronic pain, all right? Well, there is a temptation to think that this operates outside the realm of science and biology, that is in some airy-fairy realm in the clouds that this happens. And, and, and I mean, for, for good reason. There are a lot of people who will describe it in exactly that way with auras or they, they co-opt scientific terms like resonance and energy, but they don't actually use them in scientific ways. So, you know, there's a lot of very fuzzy language that surrounds this, but it shouldn't obscure the fact that when you have a hypothesis that say, some mental state like meditation or, or, or guided breathing, uh, uh, affects some process in the body, that you should be trying to understand this in terms of a biological hypothesis, not in terms of some, some, some indistinct realm that, that is, that is different.

    11. AHAndrew Huberman1:34:50

        Like manifestation.

    12. DLDr. David Linden1:34:51

        Yeah. And, you know, I really learned this initially from my father. My father was a psychiatrist. In fact, kind of a talking cure, old-fashioned psychoanalyst who had his practice in, uh, Los Angeles. And, uh, we would have dinner together every Wednesday night, and, uh, he would always tell me about his patients. He was very careful to keep confidentiality, right? He wouldn't break confidentiality, but, you know, I would say, "Oh, yes, how's your narcissist do-" "Oh, well, he had this dream." You know, so this was, you know, this was, this was normal conversation when I was 14, 15 years old with my dad. And one day I said, "Dad, it's really clear to me that through this talking cure, a large fraction of your patients feel better and they conquer their depression or, or, or their obsessive thoughts or things that are blocking them. How do you think it works?" And he says, "Well, we don't really know the mechanics, but ultimately when it works, it's not working in some airy-fairy realm. It is working by changing the biology of the brain." And when he said that, it was like a lightning bolt went off in my head and I thought, "Well, I don't have the kind of personality to be a talking cure psychiatrist. I'm not nearly nice enough, but I could understand the underlying biology. Maybe I'll do that." Uh, and so as you've correctly pointed out, when you say the phrase mind-body, you're talking about two directions. You're talking about mental functions affecting the body, and then you are also talking about how phenomena in the body affect, affect the mind. And we're understanding so much more about how that happens, and I think the general thing for your, your listeners to appreciate is that we have some culprits-... here, right? And generally speaking, there are, there are two classes of culprits. So if you want to get signals about the body to the mind, there's two ways to do that. One of them is through neurons that reach out into the body and sense things and this is referred to as interoception, right? So as opposed to exteroception, your outward-pointing senses, these are the senses that monitor your own body and, and while we can consciously be aware of a lot of that information, a lot of it is happening subconsciously. Like your breathing is happening automatically most of the time without you thinking about it and that depends upon sensors about your blood chemistry and the state of your lungs and a number of other things that are regulating that process and it's all happening in the brain usually below the level of your conscious attention. In addition to the neural signals, there is also a whole realm of hormonal or diffusible immune signals and what these are, is that these are chemicals that are released into the blood stream and that move throughout the body and that can, uh, uh, activate neurons in the brain or in other parts of the nervous system to produce changes in, uh, in mental, in mental function. And I think the real thing that is 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 the signaling hormones of the immune system and they, they can flow through the bloodstream and through lymphatic fluid, uh, and reach many parts of the body. Uh, we've known for a number of years that the specialized receptors for these cytokines are found throughout the brain and yet we know very, very, very little about, about what they do and that's going to be an astonishingly fruitful area of scientific

17. 1:39:10 – 1:43:35

    Inflammation & Depression

    1. DLDr. David Linden1:39:10

       research. But, but to give one, one exemplar, um, there are a lot of things these days suggesting a, a, a link between inflammation in the body, whether it be in the gut or in other places, to depression. Well, how might that work? Well, it could work either through inflammation sensing neurons sending electrical signals to the brain or, and it's not either/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 the lymphatic system to then reach the brain, bind receptors and have effects. And so, you know, one of the mysteries about depression is that, uh, it's not that tractable to pharmacological therapy. So if you look at people who suffer with depression, about a third of people see significant benefit from modern SSRI and related antidepressant drugs. Uh, about a third see, see very tiny benefit and about a third see no benefit at all and part of the reason is because maybe our term depression is too big a bucket. Depression is actually many different biological disorders and only a subset of those are, are helped by SSRIs and will need different therapies for the other ones. That's certainly part of it. Um, but part of it might actually have to do with inflammation. So if you think that inflammation is a, a risk factor in depression, well you could do something very simple, right? You could, you could gobble an ibuprofen, right? There's a whole bunch of anti-inflammatory drugs that are very well understood and so, well, what if you just say, "All right, you know, uh, let's have a study where we have a bunch of depressed people and we have them all eat anti-inflammatory drugs for a few weeks and we see if this relieves their depression." And the answer seems to be no, it doesn't. Well, and that's, that's a little bit hard to understand because there are definitely links between inflammation and depression. So for example, one of the early treatments for, uh, for hepatitis C that's since been superseded by more modern drugs was a proinflammatory cytokine molecule and when you gave it to people to treat their hepatitis C, almost everyone became depressed on this drug.

Episode duration: 2:36:46