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

30:23And it tastes great. If you'd like to try Athletic Greens, you can go to Athletic Greens .com slash Huberman and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road in the car on the plane, etc. And they'll give you a year supply of vitamin D3 K2. Again, that's Athletic Greens .com slash Huberman to get the five free travel packs and the year supply of vitamin D3 K2. Are there any examples of uniqueness of visual perception that come to mind? I recently did a social media post that involved, it was essentially three rings, a blue ring, a red ring and a blue ring in the center.

31:17And it's a very emotional image. And interestingly, it splits out into about thirds. Some people see the blue ring in front, quite a bit. Others see a red ring out in front. Others see them all in the same plane. And this we think has to do with differences in two things between individuals. One is the distribution of the cone photoreceptors, which we know is essentially random between individuals, maybe even between the two eyes. And then, and that gives rise to this phenomenon of chromatic aberration, 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.

31:58I'll soon do a post that hopefully distills it in a manner that's simple enough that people understand. But clearly, some people see certain colors in front of others. 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 exactly the same plane of vision. So that's the one that I know I'm guessing you know some others and perhaps some more robust ones. 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.

32:42And so kids that don't get outside are much more likely to be myopic. And it actually is not near cited. Yes. When they grow up, then kids who got outside and we now know that at least part of the story is that light seems to stimulate the expression of a class of molecules called trophic factors that you're 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 retina sits relative to the lens. And that seems to be light dependent early in life.

33:32And which gives rise to a higher incidence of myopia. And to me, this is really well, first of all, it's it's an news you can use. You should get your kids outside. Absolutely. All kinds of reason you should get outside too, especially in the mornings, yet that circadian rhythm. I know that's a famous humanist point. They're going to be putting me in the grave, David, and I'm going to be telling people to or maybe I'll be on my tombstone say get get sunlight in your eyes, especially on especially on cloudy days because there is still sunlight, even if you can't see the physical object of the sun on cloudy days.

34:13Well, 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 two. So in the early days of World War two, the Japanese army just swept through Asia, they defeated the British and Malaysia and Singapore, they over in Thailand and Burma and they were knocking on the gates of India and everything was going great except the Japanese army had a problem.

35:01There were an enormous number of their soldiers who became incapacitated with heat stroke. They got their core temperature. It got too hot. And when the army doctors examined them, they found this was much more likely to happen in soldiers who came from the northern part of Japan, Hokkaido, where it's where it snows in the winter. As opposed to the southern part of Japan, my Q -shoe, which is a semi -tropical environment. And the classical explanation, the biology like us would guess would say, oh, all right, well, this has happened genetically over many years. You have a family that's been in Q -shoe for many generations and you've selected for gene variants to allow you to tolerate the heat better.

35:49And 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 Echrine sweat glands, the sort of saltwater sweat glands, not the lipid -stinky armpit sweat glands called the apricorn ones. The Echrine 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.

36:27All right, so they say, 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. So meaning less nerve innervation of those sweat glands, as you mentioned before, just as many sweat glands, just less nerve innervation.

37:06And therefore those sweat glands could not be activated. They couldn't dump heat as well. Their heat tolerance was lower. Exactly right. And what's wonderful is that this gives an advantage that you can't get through evolution. And that it can happen right away 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 early life experience, well, then you can benefit from that early life experience within your own life. If it's not that you're great, great, great, great, great grandchildren will ultimately benefit you benefit.

37:54Another wonderful example of this comes from field mice, voles. And we were talking earlier about how we both worked with the scientist, Irv Zooker at Berkeley, who was a specialist in voles. And what people found is that if you take a wild caught field mice and you have a pregnant mothers and you have them in the lab, but you manipulate the lights so that 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 born, they will have a low density of fur anticipating summer temperatures. If you, however, put them in artificial fall, where day length is getting shorter, they will be born now with high density of fur anticipating winter temperatures.

38:58And 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 asked them when they would probably guess is heritable, but actually is not. Thanks for mentioning Irv Zooker, who as you also mentioned was an advisor to us both who's done incredible work in circadian biology, seasonal rhythms hormones and behavior. I have such reverence for Irv and the experiment you mentioned, maybe smile wide because it's but one of gosh, maybe hundreds of incredible study.

39:41So if people are interested in seasonal rhythms and circadian rhythms and biology of the most interesting kind, definitely check out Irv Zooker's work at Berkeley will provide a link to his PubMed there. Since we've been taking a tour of individual variation in olfactory perception, visual perception, and now heat tolerance. I have to ask, are you aware of any examples off the top of your head in the auditory domain that particularly intrigue you? Yeah, well, I would say one really interesting example has to do with perfect pitch. So perfect pitch as a trait that is to say you have the ability to to hear a note played and say, oh, that's a C sharp.

40:28This 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. 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, which is what we use to estimate heritability, the answer is it's kind of low.

41:11There is a heritable component, but it accounts for my recollection is on the order of 30, 40 % of the variability in perfect pitch. However, if people receive your training, starting at a young age, the chance that they will develop perfect pitch can improve drastically. In your book, unique, do you cover aspects of human individuality that extend beyond the percept, chin domain into the cognitive domain? Well, yeah, absolutely. And I think it's good to set the stage here if we're going to be talking about heritability and human individuality. And so if I can go off on a little bit of a riff for the benefit of your listeners and viewers here.

42:05So if you look at human traits, whether they are behavioral traits like shyness or very straightforward morphological traits like height, 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 variance you get from your mother and father. 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 your wex. And it turns out that this is determined by variation in the single gene, the name of the gene is boring.

42:51It's ABCC 11. It's an ion transporter. And there is 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. It doesn't matter what diseases your mother had when you were on the womb. It's 100 % heritable. Well, does this mean that ABCC 11 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.

43:38And so we have to be careful about how we refer to them in that way. For example, the wet ear wax, a variant of the ABCC 11 gene also confers a slightly higher risk for breast cancer. So clearly, it's not just for ear wax. 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 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.

44:29And there is no evidence for any degree of heritable it not 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, one thing is 0 % heritable. But where do most things fall, most things fall in the middle. 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 by what you inherit from your mother and your father.

45:15Well, 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. 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, a 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 to where they're fighting off these diseases can't live up to their genetic potential for height.

46:10If 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 decent medical care and schools in order to fulfill their genetic potential for positive traits. And 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.

47:10And much more so than say SAT tests or GRE tests or MCATs or other standardized tests. But presumably those correlate in some way. They do by do, but the IQ tests are better actually. They're talking about the classic IQ test. I am talking about the modern variants of the classic IQ test that are administered by trained psychologists and aren't just a paper form. 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 test score? Well, the answer tends to be different depending upon the population.

47:59If you look again in countries like the US or in Western Europe that are fairly affluent, where people tend to have good access to nutrition and medical care and schooling and kids get to play and they're not and they're not traumatized by war. 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 communities that face discrimination and have consistently poor, poor health care in schools, then IQ is less heritable. Why for the very same reason that it isn't height because people can't live up to their genetic potential when they don't have the basic things that everybody needs.

49:02So presumably if two identical twins and I realized they are identical, but you're familiar with twins, you have twin children. If two identical twins are raised separately, the correlation in their IQ 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. I mean, it makes perfect sense to me as to why if one of those twins went to schools that were demanding of a lot of different topic matter. And the other one went to schools where the instruction level was really deficient that one would perform far less well on an IQ test.

50:00So called intelligence or IQ. 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 a whole number of things that are all beneficial. So when you try to do epidemiology on this, you have to be aware that things are very deeply interconnected, but you bring up a good point. So it turns out that the way we get these estimates of heritability, there's two ways.

50:39One way is to compare so -called identical or mono -zygotic 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 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. And 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 trade. But there is an assumption present in that, and it's called the equal environment assumption.

51:36You're saying, well, two kids raised in the same family have the same environment. Well, that's not always true, right? That can be violated by a number of different situations. So it turns out that a more powerful but much more difficult way to estimate heritability is by looking at twins' rear to part. Either identical twins or fraternal twins are a part. And there was a landmark study called the Minnesota Study of twins' rear to part, which is abbreviated MISTRA, that is really the gold standard for assessing the heritability of many different human traits, both behavioral traits, but also disease incidents.

52:28But of course, it's a small M because the population of identical twins' rear to part that you can get into the lab isn't that large. I don't remember the exact numbers, but they had something like 80s, some identicals and 50s, some fraternal in their sample. But by doing this, they were able to come up with a lot of interesting estimates. And so for example, most personality traits, what the psychologists use the acronym Ocean to mean openness, conscientiousness, empathy, agreeableness, and neuroticism. I think I got that right. That's what it's meant. Spelled right. That these traits on average tend to be about 50 % heritable.

53:20And so, okay, say, all right, well, 50 % of those personality traits is heritable. The rest is gotta be like how you were raised. It's gotta be in your family. And so everyone was shocked when they actually did the analysis and found that family has almost nothing to do with it. And what are you kidding? 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 traits. So people are much more likely to go into an occupation if their parents did.

54:09They 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 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.

55:03And I think the genome, all your DNA, all three billion basis of DNA, all 19 ,000 or so genes in a human don't make a blueprint for making your body and brain. There, it's not all 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 phalamus, you know, grow for 200 microns towards the top and then, and then cross the midline and then grow towards the ear for, you know, another distance.

55:47No, it says something like, hey, you bunch of glutamate neurons in the phalamus 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, 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 a newborn identical twins and you give them a CT scan just to measure the shape of their organs, they're not the same.

56:28You might have one twin whose spleen is 30 % larger than the other twins or whose liver is 30 % smaller than the other twins, 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 I love the armadillo because I've been told tell me I don't want to interrupt you too long, but as far as I know, the only animal in North America that carries leprosy.

57:15That is that is true and and there's a lot of twinning going on in armadillos right well what there is is actually quadding. So armadillos or the nine banded armadillo in particular and they're different armadillos and not really an armadillo specialist. I don't know if this holds for all of them, but the nine banded armadillo is born as identical quadruplets. Awesome, awesome. So you can take these identical quadruplets newly born armadillo. I don't know what a baby armadillo is called. I'm sure there's some particular word for it. Someone will tell us. I'm sure someone will comment on YouTube.

57:56What is the name of a baby armadillo? I know like a ferret baby ferrets are kits. The moms are jills, the dads are bobs. I used to be obsessed with this kind of naming it's a business of ferrets or 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. You win the pride associated with being right. That's right, right. One of my favorites is an ostentation of peacocks. Amazing. Or a murder of crows who comes up with this guy. I know. It's a bit of a raft of otters. I think that's correct. So if you have four newborn identical nine banded armadillos, then this is a great model system that biologists can use to study stochastic differences in development.

58:51And sure enough, their brains are wired slightly differently. Their bodies are slightly different. If you test them behaviorally, even very, very early in life, they have different propensities. Some are bolder when it'll explore more somewhere will tend to hide in the corner more. And you know, we know this from the lab. You get a box of mice that are in bread from the breeder and you pluck them out and they're not behaviorally identical. Some might try to bite your hand. Some will run away. Some will stand stock still. Where does this behavioral variation come from in mice that are nearly genetically identical?

59:26Well, it comes from a bunch of things. They don't always have exactly equal experience. But mostly it comes from the pseudo random stochastic nature of development. And is the pseudo random stochastic nature of development one of the 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 subservive 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.

1:00:05You 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. Right. And so genetic variation is at the heart of individuality. But there is also, there are also these other things. Right. That we've talked about. There's the effects of early life experience. And there is the stochastic nature of development because if you through the randomness of development happened to have like a particularly great variation. And you're not going to pass that on to your children, right? That isn't in your germ line. You won't pass that traits along.

1:00:45Just a brief insert here on germ line. We had Oded Rashafi on the podcast who studies epigenetic transmission and and inheritance of of it's not Lamarkey and we have to point that out. But inheritance of sort of acquired traits does happen. And the germ line is the genes that are present in the sperm and in the eggs. All the other cells of your body have genes, of course, but the best way to put this is simply going to the gym and getting fit does not make your children more fit because the germ line as far as we know is not modified in a direct way. In other words, the DNA within sperm and eggs are not modified according to your behaviors in most, but not all cases.

1:01:31That's right. And as you as you correctly said about Oded's work 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 a worms and in plants. 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.

1:02:16The evidence at presence is is poor. Actually, a lot of it comes from epidemiology, most of which came from famines in the other colleagues region of northern Sweden. And they have 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 of your male or if your grandmother went through this, then if you're if you're male, this train your female of 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 heart game or hypothesizing after the results are known.

1:03:02They 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 around them way through through luck. And you have to apply a statistical correction called a bontherone correction when you make many particularly post hoc comparisons after the experiment comparisons to set the bar much higher for accepting that data. And most of those studies, they didn't apply that correction. And I remain unconvinced of transgenerational epigenetic inheritance in mammals.

1:03:47Now, let's be clear just because it hasn't been shown convincingly now, it doesn't mean that it won't be. There are some good people working very hard on this and they may well describe a mechanism and show this convincingly in the years to come. But right now, you may well inherit your grandma's or great grandma's trauma, but you're probably doing it socially, not through marks on your DNA that changes how your genes are expressed or not expressed. Yes, so I subscribe to the idea that there is absolutely certainly transgenerational inheritance of parenting and upbringing, right? I mean your grandparents raise your parents who raise you not always people can be adopted.

1:04:35In fact, I have adopted members of my family. But by 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 far weaker. Right, and when you think about it, well, like how did that happen? That had to get into 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 or egg cell and then contribute to producing it in you. But yeah, but fragmentation of DNA and sperm is or an egg is a common thing, especially as people age, DNA sperm and eggs fragment.

1:05:31And it's possible that some of those mutations still allow for viable embryos. So it's in theory that germline could be changed by environmental events. Well, right. But now I think you're starting to talk about things that are heritable, right? You're not talking about marks on DNA. You're talking about the structure of the DNA itself. And that is its own separate issue. Now, I think 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.

1:06:19And so, for example, we know that during the 1918 pandemic flu, 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 the male children that were in utero during the winter of 1918 during the pandemic flu are on average a millimeter or two shorter. And you might say a millimeter or two, that's nothing. But in a huge statistical sample of millions of people, that's enormously significant.

1:07:13More interesting is that the incidence of schizophrenia went up about four fold from about 1 % to about 4%. And even though autism wasn't a term in 1918 yet, I don't think came along later, what we now retrospectively would call autism also went up by about four fold. 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. Do we know that it's stress and my recollection of this, I believe this was the late Paul Sternberg's work as well.

1:08:04I maybe have that name incorrect, but in any event that it is if pregnant mom gets the flu in the first trimester, you see this higher incidence of schizophrenia and autistic offspring. 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 some breakdown in the immune barrier. I just want to open up the number of variables that this could be do or do we know that it's something in the hypothalamic pituitary so called stress axis that is a dream, so hypothalamic pituitary adrenal axis. Is it elevated cortisol or could it literally be an immune neural interaction of some other sort.

1:08:53It's probably the last thing you mentioned an immune neural interaction. And the reason I say that is that Gloria Choi at MIT together with her collaborators has made a mouse model of this phenomena. So she takes pregnant female mice and she injects him with something that that it's she doesn't actually infect them with virus. She puts a chemical in that is on the code of viruses that mimics viral infection. And 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 interleukin 17 can pass through the placenta into the fetus.

1:09:48And if it's present just as you said at a particular point in development 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 disorder development of the layers of the cortex instead of it looking like layers of a cake, you see balls and clumps 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. Are those balls and clumps of cells thought to reflect alterations and cell migration. They are. Yeah, some I don't know if it's entirely known how much of it is cell division or migration, but certainly migration is a part of it.

1:10:36And it's very likely that that critical moment to disrupt this ordering of the brain and produce these increases in schizophrenia or autism vulnerability are coming at a point where neurons are migrating during development. And so what choice group did is they would did all the things you would want to do as a biologist so they gave things to block the function of 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 work, it seems that you can produce it through this immune signaling pathway.

1:11:37And so then the question is, well, like are these mice autistic? Well, how do you know if a mouse is autistic? 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, etianologist, it's a bit of a stretch, right? And it's a challenge to interpret mouse behavior in human terms, but it's a reasonable first step.

1:12:23Incredible. And I hope more will continue to be done as it surrounds the first trimester influenza hypothesis because it's been around a while. And obviously there's a spectrum of what we call autism mass burgers and 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 for that matter, there's some high functioning and low functioning people who don't have autism. But it is something that I think demands our attention and that hopefully will be resolved at some point because also influenza is, but one immune insult.

1:13:09And presumably pregnant women are being bombarded with all sorts of viruses and bacteria and fungal infections and fighting them off or not fighting them off. And who knows what the variation in neuroimmune interactions exist in there that give rise to good variation and let's call it debilitating variation. Well, that's absolutely right. And so for one example is that we don't know what the effects are on the children who were in utero while their mothers were fighting off COVID. Right? We won't know for a for a while or the home and cold and there might, I mean, there might be nothing, but or there might be something serious.

1:14:00And it's just lurking there like there was for a pandemic flu and will be very interesting and and important to find out. Agreed. 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 broad top contour understanding of the mini brain, the cerebellum. The so called mini brain. And here's why I've been a practicing neuroscientist for, you know, close to three decades. I know where the cerebellum is. I've dissected a bunch of them. I could tell you where a few things are in there. And I certainly have read about what the cerebellum does.

1:14:49But 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. There's most people here, 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 doing 50 or 1000 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?

1:15:33Because I can point to the retinas or 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 complicated structures to understand. And I know you spent some time in there. So what's the cerebellum do? Well, cerebellar researchers like to joke that the cerebellum is a counterweight to keep your head from falling forward. Well, with all the texting nowadays, people need bigger cerebellums. That's right. That's right. Probably over many generations then that will happen along with the expansion of the thumbs.

1:16:05So, but of course, everybody is going to text with their minds in about another 10 years. You'll have your lungs implant and you won't need your thumbs at all. Or maybe just five or my friend Eddie Chang is a neurosurgeon and works on the auditory system. He's been on this podcast before he was saying that in theory and actually in practice, you could just record the neural output to the muscles of the speech system essentially. And you could just amplify that and you could text without actually speaking. In fact, when we read, he told me, we are actually receiving the signals 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 -ynaptic potential.

1:16:53So you're not actually moving the vocal machinery. 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. That's right. And it's very analogous to what happens during the REM phase of sleep, right? When you have commands, your brain is issuing commands to your muscles to do things like behave in your dreams, to run away or go here, go there. But those signals actually are blocked in the brainstem and prevented from from reaching your muscles because the nerves that don't go through your brainstem like the ones that control your eye movements aren't subject to that block.

1:17:36Okay, that's why you can produce the rapid eye movements in REM sleep. But yeah, this is a general theme in the brain. A lot of times you have the output, but then you shut it down. And there are REM sleep behavior disorders where people thrash and move in their sleep during during REM. And it's because this outflow that's normally blocked isn't isn't blocked. Have you ever had the reverse happen? I have where you wake up and you're still in so called rematonia, you're still paralyzed. Yes. And there's that split second that feels like eternity where you are wide awake and you cannot move. And I'll tell you it's terrifying.

1:18:14Yeah, sleep paralysis and actually, you know, it's been known forever. You can actually find ancient Greek depictions of people lying with a demon on their chest, paralyzing them. And that is actually from sleep paralysis later Hogarth did a drawing of exactly that. So yes, there's a well known phenomenon. But to get back to the cerebellum as we started. So the cerebellum is, as you said, definitely involved in motor coordination. So people who have damage to the cerebellum aren't paralyzed, but they tend to be clumsy. They tend to not coordinate their movements. They have a disturbed gate. If they're reaching for an object, they often overshoot it and have to make successive approximating motions to get back to their target.

1:19:14So that's well understood. But if you look through evolution, the cerebellum is connected to this brain region called the phalamus and it's connected from there to many regions, including the frontal cortex where phenomena like like planning and decision making and moral sense and many aspects of personality seem to be encoded. So then the question becomes, well, that's very far away from being clumsy. What are these connections doing? And as time has gone on, I've been in this business from over 40 years now, I'm an old guy. And so initially we said, oh, yeah, cerebellum movement control motor coordination.

1:20:03That's what it's for. As time goes on, as you correctly said, the cerebellum has been implicated in more and more functions, many of which are far removed from the motor system. And if we're looking for a theme about what the cerebellum does is that it is there to predict the immediate future. It's trying to determine what's going to happen in the next second or two to best guide behavior. And as you can imagine, this kind of general computation could be applied very well. You can see why it's important for motor systems and doing sports. If you're trying to hit a baseball looking at what the picture is doing and trying to anticipate what the pitch is, but it also comes up in a social realm.

1:20:56If we're trying to read someone and predict what they are going to do is this person friend or foe, which is one of the first things that we try to assess when meeting someone. Are they competent, which is the second thing we try to assess when meeting something. A lot of this depends upon predictive circuitry and it depends in part on the cerebellum. And it seems to be at least partially impaired in people who sustain cerebellar damage. So it seems as if interestingly the cerebellum started out for prediction related for motor control and through evolution. It's basic computation has been applied to other non motor behaviors.

1:21:40Now I'm speaking in generalities and a lot of the details of this remain to be worked out and understood. But I would say that is in a nutshell the modern conception of the cerebellum. Thank you. Finally, somebody explains to me at a top contour, but highly informed way what the cerebellum does. I couldn't be more grateful. My pleasure 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, etc.

1:22:31The cerebellums in the back, the eyes are in the front, the hardwired stuff. And then the softwired 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? Yeah, I don't think there should. And I have a lot of problems with nature versus nurture as an expression. It was popularized by Francis Galton in the 19th century, a colleague 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 me in the heritability, right?

1:23:22What you inherit in the gene variations from your mother and father. And nurture means like how your parents or your community raised you. The problem I have with nurture is that it is too narrow a term that really it should be replaced with the word experience and experience in the broadest possible sense, not just social experience, but the foods your mother ate when she was carrying you in utero. The diseases you fought off or your mother fought off while she was carrying you in utero, the bacterial population of your guts. So experience meaning anything that impinges on you, starting from the earliest stages of fetal developments, continuing to the last day of your life.

1:24:24If 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 a versus because there's this idea that these things are are essentially in opposition. Well, is he that way because of of his gene variance or is that way because of what what happened to him? And I think the thing to realize is that 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 phenyl ketenuria or PKU, which is an inability to to metabolize the dietary amino acid, phenyl alanine.

1:25:26And so 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 and phenyl alanine. If you don't, it doesn't matter that you inherited these things, right? So that's a way which genes and experience interact and idea of ways in which then they interact positively. Think about athletic ability, right? So a lot of athletic ability is has a heritable component. If you are born fast, for example, then you're more likely to do sports and practice them and get better at sports as a result of your experience.

1:26:18So here, genes and experience are feeding back on each other in a positive feedback loop. So there really isn't a versus 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 the 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 gloves don't fit, you must quit.

1:27:09You know, it's got that kind of snappy snare drum beat. But I think it's a more accurate. So heritability interacting with experience filtered through the randomness of development. So we can shorten that up and we'll just call it the linden hypothesis. I don't think I can take credit for that. It belongs to other people. Sure, but there's a long history and science of things being shortened up and coined. And that's as important. We're not trying to rob attribution here. And the good news is perhaps you can't call it the linden hypothesis, but I can. And what I found is as with the galpon equation, which is now out there as a hydration.

1:28:00It's a formula that gives broad, but 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 physiology and an expert in all aspects of exercise science. There's the galpon equation. There's the sobered principle. So I'm naming these things left and right. All right.

1:28:26So I'm naming these things sparingly and wear appropriate. So from here on out, heritability, interacting with experience filtered through the randomness of development as the linden hypothesis. And I'll be damned if anyone's going to rename it faster than I'm going to propagate it. All right. Well, I think all the the geneticists will be gnashing their teeth about this being named after someone who isn't actually a geneticist quite all right. And their dentists will thank me. Let's talk about mind body. Okay. I'm fascinated by this 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.

1:29:10And I got very interested in neuroscience early 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. Very little on the body. There was nothing about gut brain access in the early discussions and coursework. In parallel to all of that, I've been interested in mental health physical health and let's just call it performance and got interested in meditation, respiration based practices, things like yoga, knee, draw things that by way of experience, I understood immediately had a profound influence on the nervous system states of mind and body.

1:29:53Nowadays, there's an entire institute at the National Institutes of Health for complimentary health and medicine, essentially exploring things like yoga, knee, draw, 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 California counterculture, Estiline Institute only, you know, 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.

1:30:40And 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 aparaty, the diaphragm lungs, the heart rate variability we hear about, deliver the gut brain access 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?

1:31:23And what do you think is the potential of the mind body interaction? It seems to me we've just barely scratched the surface. Yeah, well, I'm glad you asked because I think it's a, it's a really fascinating situation and 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 that meditation can attenuate chronic pain. Well, there is a temptation to think that this operates outside the realm of science and biology that is in some very very realm and clouds that this happens.

1:32:16And, and, I mean, for good reason, there are a lot of people who will describe it in exactly that way with auras or they, they clop scientific terms like resonance and energy, but they don't actually use them in scientific way. 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 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 is, that is different like manifestation.

1:33:11Yeah. 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 psychoanalysts who have this practice in Los Angeles. And, we would have dinner together every Wednesday night. And, he would always tell me about his patients. He was very careful to keep confidentiality or he wouldn't break confidentiality. But, you know, I would say, oh, yes, how's your narcissist? Oh, we have this dream. 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.

1:34:04How 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 area, ferry 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. 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.

1:34:51And 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 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 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 extra reception, you're outward pointing senses. These are the senses that monitor your own body.

1:35:44And 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 bloodstream and that move throughout the body.

1:36:31And that can activate neurons in the brain or in other parts of the nerve system to produce changes 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 and reach many parts of the body. And we've known for a number of years that the specialized receptors for the cytokines are found throughout the brain. And yet we know very, very, very little about about what they do.

1:37:24And that's going to be an astonishingly fruitful area of scientific research. But to give one one exemplar, there are a lot of things these days suggesting 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.

1:38:15And so, you know, one of the mysteries about depression is that 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. And that's about a third 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 helped by SSRIs and will need different therapies for the other ones. That's certainly part of it.

1:39:04But part of it might actually have to do with inflammation. So if you think that inflammation is a risk factor in depression, well, you could do something very simple, right? You could you could gobble and 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, 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 we can do that. And if this really if they're depression and the answer seems to be no, it doesn't.

1:39:40Well, 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 for hepatitis C that since been superseded by more modern drugs was a pro inflammatory cytokine molecule. And when you gave it to people to treat their hepatitis C, almost everyone became depressed on the stroke. So, oh, well, this really seems like like like a link. Likewise, there are certain neurological diseases like multiple sclerosis. It turns out the incidence of depression as a comorbidity in multiple sclerosis is enormous.

1:40:25And you might think, well, there's a trivial reason for that. If you're paralyzed from MS, you're bummed out about life. And that's the reason. But if you look at people who have spinal cord injuries from accidents, they actually have major depression at a nor at a rate from people who are uninsured. So that doesn't seem to be it. It's not just that you're bummed out from being paralyzed, although, of course, it's reasonable to be bummed out about being paralyzed. But that's not it. So what happens in MS? Well, there's a bunch of cytokines, including one called interleukin six IL -6. That's elevated massively if you take a spinal tap and you look at cerebral spinal fluid.

1:41:01And so that could be causative for depression. So all these reasons to think that inflammation is involved, but yet the idea is still a little messy. So now what if instead of looking at the general population of depressed people, you look at the subset of people that don't respond to SSRI antidepressants, are they helped by anti -inflammatories? And there there's a bit of a hint that maybe they are. It's not definitive yet. There are a couple of studies. It's right on the edge. But I think this is a really good example of how we are going to see progress. Very soon in the body to mind part of mind body medicine that is going to be of enormous benefit to people.

1:41:55So interesting. Could I get your thoughts on one candidate hypothesis that I've been thinking about? I've covered depression on a few episodes. And I've had a Robin Carter Art Harris from UCSF and Dr. Matthew Johnson from your very own John Hopkins University both of whom work run laboratory studying psychedelics for the treatment of depression. The clinical trials on psilocybin. And to be clear, psilocybin is still illegal. It's been to criminalize a few places, but we're not talking about recreational use. We're talking about several therapy sessions. And then to without psilocybin, then to 2 .5 gram approximately.

1:42:35Doses of psilocybin given separately again with therapist present and then follow up therapy session seem to lead to relief of depression in approximately somewhere between 65 and 80 % of people in some cases total remission in some cases some relief without remission. Okay, so we can kind of set that result on the shelf. It's been repeated a number of different times. Compare that to the results of SSRIs which seem to help a third of people, a third minimally and a third not at all. And of course, there's a side effect profiles of the SSRIs and associated drugs, not just the SSRIs, but Buprieron and the other antidepressants that are taken in prescription drug form.

1:43:15And then there's this inflammation piece. So could we hypothesize that relief from depression has something to do with neuroplasticity rewiring of neural circuits and that psilocybin we know can encourage neuroplasticity. And that perhaps SSRIs can encourage neuroplasticity in some people, not all, and that inflammation is a barrier to neuroplasticity. To me, this is the only thing that can reconcile the current status of the results. And then there's ketamine based therapies and so we have to also kind of set that on the shelf. Let's set that aside on the shelf for now to keep it simple. So it seems to me that based on the time course over which SSRIs work, the fact that they increase serotonin very quickly, but the relief from depression comes from much later.

1:44:08The fact that neuromodulators like serotonin are intimately involved in neuroplasticity, they can in some cases gate neuroplasticity that are all centers back to changing neural circuits. And so what we're really trying to do, whether or not it's transcranial magnetic stimulation or now we can throw ketamine in there or psilocybin or SSRIs, that treating depression is about rewiring the brain. It's not about chemical A or B per se, although serotonin seems involved. To me, what I'd love to see is are more studies about the interaction between neuroplasticity and inflammation. And are we seeing that kind of work out there?

1:44:45And because these results sort of sit as disparate, somewhat conflicting, but it seems like inflammation is anti neuroplasticity and broadly speaking here. I realize there are many interleukins, there are many, you know, some of which are inflammatory, some of which are anti -inflammatory. But is that a meaningful hypothesis? And do you think there's any hope whatsoever to actually cure depression if we sort of start to unify the results in these different camps? Yeah, I think it's a completely reasonable hypothesis. And I would be broader. And I would say honestly the relief of any neuro psychiatric condition ultimately is from neural plasticity and some form or another.

1:45:26And I think it's worthwhile to step back a bit and talk about what neural plasticity means to date there has been a focus on synapses on the context between neurons as the site of neural plasticity. And that's warranted synapses are plastic. They changes the result of experience as a result of hormone changes as a result of exercise as a result of lots of things. But synapses are not the be all an end all of neural function. So for example, neurons work by sending electrical signals along their length and between neurons and inter converting those chemical signals. And the processes of generating those electrical signals, the ion channels that are involved that are embedded in membranes that are involved in that are also plastic.

1:46:23They can also change as a result of experience. That's what we call intrinsic plasticity as opposed to synaptic plasticity. In addition, there are literal morphological changes. So when we talk about the wiring of the brain, sometimes we're talking about literal wiring like cell A wasn't connected to cell B and now it is and that changes. And then sometimes well actually cell A was connected to cell B, but cell B wasn't responsive enough. And now there's a change in cell B. So now cell A can fire cell B. And that could have been a result of a change in its synapse making it more receptive to a transmitter release from cell A or it could be something intrinsic and cell A that makes it fire its electrical signal, it's spike more easily.

1:47:09I think that one of the key cell types that's going to be important for your hypothesis linking inflammation to synaptic plasticity is going to be a cell called a microglial cell. And microglial cells are non -inertal cells in the brain that are motile. They can crawl around, they have long processes and they can gobble things up. They can literally sort of chew away and digest bits of the extracellular scaffolding that surrounds neurons and synapses. And thereby renders them plastic, they can destroy synapses and there is a lot of indication that certain disease states may involve over exuberant microglia pruning synapses to a degree that they shouldn't.

1:48:07And we know that microglia are chock full of cytokine receptors and so are responsive to inflammatory signals. When we're talking about inflammation and we're talking about drugs, it's worthwhile to mention that there are a lot of behavioral things that also can influence the signaling. So we know, and I know you've discussed on your program, the incredibly solubrious effects of physical exercise on mental function. So exercise is about as good an antidepressant as SSRIs are. And the side effects are only good side effects as opposed to the bad side effects of SSRIs. And again, this isn't working through some area ferry realm.

1:48:56The reason that exercise works to relieve depression and the reason that exercise works to maintain your cognitive function as you age is because of biological path. And the other way is that we are now uncovering some of which will involve microglial cells and neurons and other types of cells in the brains, some of which will involve not the neurons in the brain at all, but the brains of the scar. So we know that exercise is very solubrious for keeping blood flowing to the brain. And when you're young, you have a super abundance of blood flowing to your brain. So it doesn't matter if it's reduced, transiently, you're fine.

1:49:38But as you get older, your blood vessels become more occluded and less elastic. And you're closer to the trouble spot. And if you exercise regularly, you can dilate and make your blood vessels, including those in your brain more elastic. And that is almost certainly protective against both depression and cognitive decline as we age. I am a fan of exercise, but I'm fortunate that I enjoy running in some forms of resistance training. So I always assume that the good side effects were just the positive mood effects until the recent literature that, as you mentioned, improved vascular, vascular blood flow and reduced inflammation.

1:50:29If not during the exercise, when inflammation actually increases, decreases inflammation. I'm delighted to hear you say the word microglia and my postdoc advisor, the late Ben Barris would be especially delighted. People can look up Ben. I'll provide a link to his biography in the show note captions because he really championed to the point of, I don't know if champions, even a sufficient word. I mean, Ben was beating the drum saying, we have to pay attention to glia. We have to pay attention to glia for the longest time. Glia were relegated to these other journals, even had their own journals.

1:51:03And in the last, what is it, 10 years? There's been a kind of explosion of research exploring the role of microglia and other glial cell types. And it's, it's really fantastic to see that this actually the most abundant cell type in the brain is the glial cell are getting the attention they deserve. It's absolutely true. And, you know, we scientists like to think that we're very rational creatures and we're not subject to fads, but we totally are. Right. When I started out in this field, in the early 80s, everything was about opioid peptides. And then there was a period where gaseous neurotransmitters like nitric oxide were all the rage and, you know, right now, glia are in the spotlight for a good reason.

1:51:50I'm not trying to say that it isn't worthwhile. But there is this phenomenon of things being fattish and people jumping on bound wagons. And that happens both in terms of the subject we study, but also in terms of the techniques we use. And right now, the technique that is most fattish involves single cell expression profiling that is creating a list of what genes are turned on and how strong they're turned on in single cells and seeing how that changes in different cell types. And with experience. And it's a very, it's a very valuable technique, but one could argue that it is perhaps a bit overused on that 15 years from now, people will go back and say, gosh, those folks in 2023 were really overdoing it with the single cell profiling.

1:52:46And if anyone's thinking about getting into the field of neuroscience or another area of biological or other research, I can just tell you that if you're starting your PhD or your postdoc, take a look at whatever fat is happening now and just know that in five years, it will be something different and it takes you about five years to finish your PhD or postdoc. So pick something different than what's fattish now and you'll you'll land right on the money. But there's always a lot to do. You don't have to do it. Everyone else is doing it. And indeed, the deletion test becomes relevant here. The deletion test as it was described to be by my colleague, EJ Chicholinski at Stanford is if you look around and you see one or more groups doing what you want to do very well, just pick something else.

1:53:28Your life's going to be a lot more pleasant. Absolutely, I agree with with EJ on that entirely. Let's get back to mind body. There are a bunch of different domains of mind body as you so aptly pointed out it's bi directional mind informs the body body informs the mind. But we could probably break this down into a respiration. So breathing conscious patterns of breathing, emphasizing inhales or emphasizing exhales, cyclic hyperventilating, etc. Could also be thought patterns. A little bit harder to break those down, but many not all, but many forms of meditation involve having a very still body, not all.

1:54:13There's walking meditation, etc. But still body focused mind. Kind of a not a state that we are in a lot of times unless we direct that state. There are still other mind body patterns of communication through very still body deep relaxation things like yoga, knee, jaw, non sleep, deep rest. There's hypnosis. There's touch based body, mind communication. If we're going to talk about mind body, also we should refer to as body mind. How do we dive in and think about this? Because this is involving clearly a thousand different neural pathways, not just the vagus nervous. Typically people just kind of hang their head on mind body must be vagus nerve.

1:54:57And of course it involves the vagus, but the vagus is an extensive set of pathways. So how do you like to frame up mind body and what's most intriguing to you about mind body communication both in terms of the biology and its practical applications? Well, I think just as we talked about how there are two potential pathways in conveying signals from the body to the mind, there are also two potential pathways, at least two potential pathways, to conveying signals from the brain to the body. And they are the neural signals that are conveyed by neurons that actually get there. And they are hormones and neurotransmitters and cytokines that are released from the brain.

1:55:44I should mention that that hormones are actually produced by neurons, including for example, some of the hormones that you think about as being produced as sex hormones like estrogen is produced by neurons in your brain, for example. So let me give an example that I think is a bit out there, but I think is really, really fascinating. And this comes from the cancer world. And so melanoma is a bad cancer. It kills a lot of people that can spread. It's highly metastatic. And we know that melanomas often become innovative, that is to say they become contacted by neurons and wrapped and receive signals from them.

1:56:36And we also know that if a melanoma becomes innovative, then the prognosis for that patient is worse. It's more likely to grow. It's more likely to spread. Well, how does that happen? Well, recently there have been some reports that show that neurons that innovate the melanoma don't act directly onto the tumor cells. Rather what they do is they secrete a signaling molecule that has a receptor on immune cells that are patrolling the edges of the melanoma tumor and nibbling away at it. And they, when that signaling molecule is released from the neuron, it shuts down or reduces that immune patrolling function.

1:57:34And that as a consequence, the tumor can grow and spread and butt off readily. So this signal that comes from neurons is sending the ambulance home, so to speak. Yeah, exactly. And the signal is something called calcitonin gene related peptide or CGRP. I'm familiar with CGRP from the domain of touch and its involvement in, I think like it's perception, it do I have perception and it's perception. Right. Yeah. And so, all right. So if neurons can can affect the progression of cancer through their activity and these neurons in the periphery are ultimately connected to the brain through a couple of different hops.

1:58:30Then, is it reasonable to hypothesize that mental processes could affect cancer progression. So let's say we have a hypothesis and it's a wild hypothesis and I want to just emphasize that there is not evidence for this, but let's make the hypothesis that says that through meditative practice, you can slow the progression of certain tumors that tend to get interfated. Right. Well, right now, this is just kind of a wild idea, but I think the important thing, as I've said before, this is a wild idea with the biological substrate. It's not like you meditate and magic happens and force fields open in the angel saying, and then your tumor shrinks.

1:59:27This is, we are saying that activity in certain areas of the brain is increased by this meditative practice and that this sends signals to this neuron and this neuron that actually go to the tumor and make something happen through this biochemical pathway that we have defined. Right. And to me, this is speculative, but it's also extraordinarily exciting. Right. It opens a kind of investigation of mind to body signaling that has received very little attention up to now. Incredible. And I say incredible because while you're giving an example of CGRP and nerve innovation and metastatic tumors, I absolutely love the idea that a phenomenon involving some practice that could be put under the umbrella of mind body or body mind becomes something entirely different when we're trying to to hang that on the hook of a biological process.

2:00:39It's like something fundamentally changes there. Right. You know, it's amazing to me, for instance, that early on psychedelics and breath work conscious breath work were lumped together, cost people their jobs at major universities. I won't name the universities because we're all you work at one, I work at another and there's a third one called Harvard. I guess I just named them. But nowadays, there are laboratories at every single one of those institutions studying deliberate respiration on health, as well as psychedelics and meditation for that matter with the goal of understanding what cytokines, what neurotransmitters, etc.

2:01:20So I started to change through defined pathways, including Vegas, but frenic nerves and frontal cortex and all the stuff that is considered, you know, classic rigorous neuroscience. So I do think we've entered a new era. So it's not costing people their jobs anymore. It's actually giving people their jobs. And it's federally funded, which itself is also fantastic, in my opinion. So we are in a new era. What do you think needs to be done to really nail down the idea that how we think influences our biology, even though it's a total duh, because everyone knows that chronic stress, for instance, is can be detrimental.

2:02:03Short term stress can actually be beneficial, but and stress is a mental process that essentially deploys chemicals in the body that then create other issues in the body that then create shifts in mental process. So it's so obvious when it's spelled out, but it's just remarkable to me how this has just been lumped in the category of like woo science. And I can't quite figure out what needs to be done in order to convince people that their nervous system includes stuff outside the skull and spinal cord. And of course, of course, of course, it would work this way. Well, right, and I think it is the job of biomedical researchers right now to reclaim a lot of this from from the realm of nonsense.

2:02:54And the problem is there has been a lot of nonsense. And you know, there's there's sort of a visceral reaction. And when someone says, oh, yeah, well, you can do breath breath work and it'll realign your shockers. And that is, you know, what will reduce your anxiety or gut inflammation. And I'm tempted to just go, oh, shut up. But what if the shockers are collections of nerve innervation of bodily sphincter, you know, it could make sense. Right, it could, but it's got to there's got to be some some biology. In some cases, these analogies are rooted in something real. And in some cases, they're just made up bullshit.

2:03:39Right. And I think the challenge is to have really rigorous scientific tests of these things to take it back and to be willing to say, all right, there have been a lot of claims, for example, made about how mental processes can influence the body and only a subset of those are going to be true. And of that subset, it is our job to understand how they work both to rationalize them, but also to optimize them and and make them better. I mean, there's no question that mental processes affect the body. I mean, we know, for example, that if we just keep you awake and don't let you sleep long enough, you'll die.

2:04:27And what will you die from? You'll die from sepsis because the barrier between your gut contents and your peritoneum will, will, will, will break down. Right. Well, so how does that happen? Right. We're just starting to understand. Like, there's a really dramatic example, but there are going to be many more subtle examples. So you've mentioned breathwork a couple of times. And I think this is really interesting. My colleagues who are interested in respiration, tell me that you can record in many different places in the brain, many different places in the neocortex and other regions and find a signature of the breathing rhythm sort of as a background.

2:05:19And turn your own activity. You can find it in the cerebellum. You can find it in the frontal cortex. You can find it on the habanula, which is implicated in many things, including depression. You can find lots of places. So the idea that conscious modulation of your breathing could have manifold effects on neural function, I think is reasonable given that kind of observation here here. Let's talk about you a bit more. You've been so gracious in covering this wide array of topics and with such eloquence. And I must say I've been delighting in all of it. You are in a unique position these days because if I understand correctly, you've been diagnosed with a fatal illness.

2:06:17I suppose we've all been diagnosed with a fatal illness of sorts because we're all going to die sooner or later. Yes. If you're willing, could you tell us the story of how that diagnosis came to be, what your initial reaction was and where things stand now. And perhaps we can explore some of the, well, let's just say pleasant surprises that have emerged since that initial diagnosis. Well, sure, I'd be happy to. So in the summer of 2020 in the dark days of COVID, when things were looking really bad, I developed profound shortness of breath. I couldn't get up a flight of stairs without, without huffing and puffing.

2:07:07And I thought, oh, well, I've got COVID, but I took COVID vests. And there was, they were all negative. I thought, oh, I must have COVID. I've got the symptoms of COVID. I have respiratory issues. I'm feeling weak. It's got to be COVID. And after a while, and this didn't go away, my wife said, you got to go into the doctor. This is crazy. It's, you got to find out what's going on. And I did. And they, they hooked me up to an electrocardiogram. And they said, oh, you've got atrial fibrillation, meaning that your heart is doing two beats every time it should do. So I have a very high heart rate.

2:07:41And when the heart beats that fast, it can't work very effectively. There's enough time to recharge before the next beat comes. Now, it turns out that there is a very straightforward therapy for this. Atrial fibrillation comes from electrical signaling in the heart, sort of swirling about in a circle and reactivating part of a heart muscle faster than it should. And so if you thread through a catheter in your in your in your in your groin up up through blood vessels, you can put in a little needle and use that to quadrize into a blade, a tiny little strip of cells in the heart that will produce a barrier that will prevent that aberrant return of electrical activity and will cure atrial fibrillation.

2:08:30So I had that process, that ablation surgery, and sure enough, it cured my atrial fibrillation. I was feeling terrific. And they said, oh, as a follow up, come back a few months later and we'll do an echocardiogram to see how your heart looks. And they did. And they went, oh my god, there's this huge mass pressing against your heart. It's like the size of a coke can. Here's what we think it is. We think it's a hadle hernia. We think your stomach has poked up through the diaphragm muscle and it's nestling next to your heart. So the way we diagnose this is kind of humorous. They say, shug this can of diet, Dr.

2:09:13Pepper. And then quickly get up on the table and we'll do the echocardiogram. And in the echocardiogram, we can see a signature of the popping CO2 bubbles in your soda. And if we see those in the mass, then we know it's your stomach. So I did it. I chugged it. I got up there. Oh, no, it's not your stomach. They said, oh, okay. Well, what we think this is is a teratoma. And a teratoma is a developmental anomaly that you carry usually from fetal life, where there's a group of different cells that gets in a place where it shouldn't during development and then grows. You've probably heard about people who sometimes get like a tooth that grows hair in their abdomen.

2:09:58Sometimes women have these around their ovaries. And they're not malignant. They don't spread. It's a fairly easy thing. But I have this enormous cocan pressing on my heart. It may have. We don't know. Have been the source of my atrial fibrillation to start with. But in order to deal with this, I had to have open heart surgery. So I had the surgery. And it was a big hairy deal. I was told it would last about five hours. It turns out it lasted two days. They had me on the heart lung bypass machine longer than you're supposed to because you're very likely to throw a clot and get a stroke. Fortunately, that didn't happen.

2:10:37I had very skilled surgeons, Johns Hopkins. It was bleeding so much that they couldn't close the chest. So they had to do all the surgery and then just leave me anesthetized with my chest open until the bleeding stopped. And they go, so the surgery was a bear. And then I'm waiting to get the pathology report back on the tissue. They removed and it came back and it was bad news. Sorry. It's not a teratoma. It's not benign. It is a kind of cancer called sonovial sarcoma. And sonovial sarcoma is a moderately rare cancer. And it usually affects the sonovium, which is the lining of the joints or some other places.

2:11:16It's pretty rare to have it happen in the heart. There are a few examples. If you look in the biomedical literature for common cancers like test, test, testicular cancer or breast cancer. There are huge tables of statistics from millions of patients on what's been tried and what works and what the prognosis is for sonovial sarcoma of the heart. There are only individual case reports. Oh, there's a guy in Kenya and he got him. This is what happened. There's a woman in Minnesota. And this is what happened with her. There are no statistics because it's that rare. And the oncologist said, well, I think you've got six to 18 months to live.

2:11:57Now this was about now 27 months ago. So I've fortunately exceeded that lifespan estimate. And I think we got to be clear also that, you know, being oncologist has got to be a terrible job for many reasons. But one of them is that you got to give a lifespan estimate, even if you really don't have the data to do it in a very informed, you can't just say I won't do it. You got to do it. People expect it. So, you know, I'm not saying like, oh, the oncologist was incompetent because I've helped live my estimate. You know, he was trying to do something based on very little information made his best guess.

2:12:41So, you know, I got this information and I was furious. I was so angry. Hard cancer. Who the hell gets hard cancers? That even a thing I've ever heard of somebody with heart cancer? No, no, no. Heart cancer. What the f? I've got heart cancer. This is crazy. Time I was 59 years old. I got a lot to do. I can't have heart cancer. And what was, I think transformative for me is that at the same time that I was feeling a white hot angry with the universe. I was also feeling a deep sense of gratitude for what I've had. I've had a terrific life. I'm not that young. I've had a lot of it. And I had great parents, wonderful friends growing up.

2:13:38I've had a good career. I've had a great career. It's been a fairly easy run of it. And I think the ability to have a job where you follow your own curiosity every day. There's nothing like that. So few people in the world get to live that way. I feel incredibly grateful. I feel incredibly grateful to my family. And I have a wonderful wife named Dina. And she's just the best. How do I deserve this? I don't deserve her. You know, honestly. So, you know, in neuroscience, we often think, oh, well, there's a, you know, you have a state. You have a set point. Are you anxious or are you relaxed? Are you fleeing or are you approaching?

2:14:26You know, it's like a single axis. Well, but it isn't. You know, when I think most people understand that, but, but, but to me, I didn't until that moment really understand that I could feel profoundly grateful and profoundly angry in the very, in the very same moment. And, you know, having cancer and getting the kind of treatments, the chemo, the radiation, you know, it's famously deeply unpleasant. And I had all that. And it was just as unpleasant as anyone's cancer story that that that you've heard the radiation burn my esophagus. I couldn't eat for weeks. It was month. It was painful to swallow.

2:15:09You know, bad stuff. Lots of people have had to have bad stuff like this. And what I realize, you know, this is, it's a deeply unempowering situation to be a medical patient, particularly when there's something serious. You have, you have a limited sense of agency. Things are being done to you. Drugs go in here that make you feel really bad. And there isn't, there isn't that much to do. And I realized that for me, the sense of agency came from being curious, from being a total nerd about things. And part of what it made me curious about was my own mental processes as they related to my cancer and my cancer diagnosis.

2:16:08So for example, I'm getting in the chemo and I should just say as background, I'm fortunate. I don't have a tendency for depression. I'm a pretty upbeat guy. I don't take any credit for that. I think I was just born lucky and raised lucky. But day after day of feeling bad in your body from chemo, boy, it's hard to be positive. It really is. I could not overcome my mood, God, really, really low. And I could tell myself, this is going to be over. It's not going to go on forever. You won't feel this way forever. And you would think that as a rational person, I could talk myself out of that mood, but I couldn't.

2:16:53You know, probably because there was, my brain was a wash and interleukin six and I couldn't overcome it. I felt really low. But at the same time, I was sort of out of a remove being a nerd about going like, huh, I bet these cytokines are messing me up right now. I bet that's what's going on. And that gave me some sense of agency in a time where otherwise, I really wouldn't have that. Another thing it really brought home to me is this issue that we were discussing earlier about how malleable perception is and perception of time in particular. If someone had said to me when I was healthy before I was diagnosed, you're going to die in five years.

2:17:32I would have gone, oh, no, no, no, no, I'm 59 years old. I should get way more than five years. I got a lot of things to do. Professional things, personal things, family things, I got a lot of things to do. No, that wouldn't be right. I'd be very upset. But, you know, if you told me after my diagnosis of six to 18 months, oh, you get five years. I'd do it. Five years. Yeah, that's pretty good. I can do a lot in five years. I can finish up the lab and I can do some good work and I can spend time with my family and travel and save our lives. Pleasure. I can do all kinds of things. Five years. Great.

2:18:11And of course, it's the same five years. Right. The only thing that's different is the context. But I think the thing that really I realize the most is that I really couldn't and still can't engage with the idea of myself being gone. So, yeah, I can do practical things. I can update my will. I can write letters for my people in my lab. So, you know, if I kick off, you know, they've got that to take to their next job. You know, I can do all these nuts and bolts things. But in terms of genuinely engaging with my own demise, I really find that as much as I try, I really can't do that. And at first, I thought, well, that's just your own lack of imagination, lend them.

2:19:08It's just because, you know, you're not very good at this. But the more I thought about it, I thought, actually, no, this is a human thing. This is a fundamental human thing. And one of the things when I look back on the 40 plus years I've been doing neuroscience, that's different. Is that when I was first trained, the brain was really described as a reactive structure. Something happens in the world. You know, it comes to your sense organs, your eyes, your ears, it goes into your brain, it triggers some things. You think you make decisions and then you make an action that goes out to your muscles or, or, and that's the loop.

2:19:48And that's what the brain does. And what we have known in more recent years is that actually when the brain is waiting for something to happen, it's not just idling and spacing out. That the brain is at every moment subconsciously trying to predict the near future. Predicting the near future is predicated on the idea that there will be a near future that is to say that you won't be dead and gone, right? That there'll be a future for you. And so I think that my ability, which I think is actually a human, I mean, not my ability, my failure, which I think is actually a human failure to truly engage with my own demise, is a feature.

2:20:35It is a side effect of the fact that the brain is always trying to predict the future. And so that was interesting to me just as a way that my illness was revealing something about the brain. But it also made me think a lot about the world's religions, right? Religion is everywhere in the world. If you ask anthropologists, is there any society that doesn't have religious ideas, both say no. They say they don't always have the word religion. And they might just say, well, yeah, in this place, everybody knows that the world's on the back of a turtle and this happened. There are these rules. I may not call it religion, but every place in the world has religion, not everyone is religious, but it is across cultural universal.

2:21:23And most religions, absolutely every single one, but almost every single one has stories of afterlife for reincarnation in which your consciousness endures. Well, why would that be? And in many religions, they've got a deal, right? Follow these rules in life, and then you'll be rewarded in the afterlife. And that's a very general idea, or punished in the afterlife. And in some religions, you meld with the divine, in other religions, you're reincarnated. Is this or that? You have an or hell, right? There's variants, but they share that your consciousness endures. And so why is this so popular all over the world?

2:22:11Well, I would hypothesize that it is a side effect of the fact that the brain can't help but always trying to predict the future. When we can't imagine the world without us in it, then we are forced to concoct stories of the afterlife. Fascinating. And makes me want to ask about this feature of time perception. My undergraduate, graduate, and postdoc advisors all sadly died earlier, early, really, by a pretty much any standard. And I was fortunate enough to be in communication with the last two as they were going through that process. Both of them described a heightened sense of gratitude, especially for things that previously they had not paid attention to.

2:23:13So we call this noticing the little things. But that makes me conclude that something about the knowledge of one's impending death, however far off that might be, shifts our attention, at least temporarily, leads to this sense of slowing down a bit, because in order to shift our attention to, quote unquote, the little things, or things that we previously overlooked. There's this sense of slowing down, and we know from basic videography photography that slowing down means an increase in frame rate. That, you know, shooting at strobe frame rates gives you the perception of strobe shooting at very high frame rates allows you to see things in very slow motion.

2:24:04You're noticing subtle variations that normally you overlook. I did not try to be overly reductionist about this process of enhanced gratitude that you describe and how it was alongside intense anger. But have you noticed a shift in your perception of time because you were given initially this X number of months. And then now with the, you're still here, fortunately, and with this open ended, well, it wasn't the prediction that was given to you by your oncologist, but it's unclear how long you're going to be here. Which is how most of us exist. You have the sense that it's sooner rather than later, but you don't really know.

2:24:55So I'm curious as to how the idea that, okay, you have 12 months more to live versus more than 12 months, but not infinite. But of course, I know that I have, hopefully, have more than 12 months, but it's not infinite. So, you know, this, this idea of the, the finish line, the cliff, leaving aside whatever might happen afterwards. I don't know, haven't been there. It changes what we notice by way of changing our perception of time. I mean, this is a, this is a profound tuning of our perception. What are your thoughts on that? And do you notice the each sip of coffee? You probably don't notice each step across the kitchen floor in the morning.

2:25:39You're probably paying attention to your lovely wife and kids and things that day, but presumably it's dynamic. But what is your perception of time like now with the understanding that yes, you made it through the past the gate that was predicted, but what lies ahead is uncertain. Yeah, so that's really interesting. And I would say definitely my perception of time is slower and it seems like an age since I was diagnosed. But I think part of that is because it's been action packed. In other words, since I was diagnosed so many emotionally salient things, non -trivial things have happened. So many intense discussions with my wife and my friends and the people in my lab.

2:26:33My wife and I've taken a lot more vacations than we normally do. So we're running all over the world and there's a certain sense of packing it in that I think influences time perception. But I would say actually for me personally, the gratitude isn't about the little things. The gratitude is about the very biggest things. The gratitude is gratitude for being a sentient being and having that blessing. The gratitude is for being able to have a life where I can follow my own ideas and creativity and my gratitude is for choke up.

2:27:26The profound love that I've felt from my wife and my children. It's not the little stuff. It's the big stuff that I think about when I think about gratitude. It's not noticing the sympathy. It's the big issues. And for me, I don't want to delay my death as much as possible, of course.

2:28:01But when I think about it, the part that makes me upset is leaving people behind. It's not for myself. I've had a great life. I've had a lot of it. I'm 61. I like to go longer, but that's a pretty good run. I've gotten to do lots of things in those 61 years and have wonderful loving interconnected experiences. And so the negative part is about what I leave behind. Certainly what you've left behind is enormous and has been the consequence of actions long before your diagnosis, which I think is a clear lesson to everyone. I can't speak for you, but don't wait for the diagnosis. You've mentioned the sense of agency that you felt by being able to pay attention to and explore your experience of, let's call it what it is, impending death.

2:29:14And at the same time, as you mentioned, you've amplified and accelerated the number of things that you've put into the world recently, writing incredible articles about your experience of life and death. And we will of course link to those so people can read them. I've read them all and they are profound and they don't just feel important. They clearly are important. So very few people have your insight into the nervous system at the mechanistic level, but also at this more holistic level that you've clearly displayed to us here and in your research and in your book writing and public speaking.

2:29:57I think it's a risky thing to ask somebody for advice, but I can't help myself because I think it's a real opportunity. If you had advice to give to any and all of us based on the whole experience, all of it from go, as they say, if you're willing and feel free to pass, but if you're willing, what is your advice? Well, I would say the advice that is really universal is what everybody already knows and is a bit trite, but I'll say it. Anyway, and that is appreciate what you got while you got it. And you know, this isn't any big secret and everyone knows it. I would say for a subset of people, the way of the nerd is very empowering.

2:31:02I don't think that's the case for everyone. I think for a subset of people who are deeply curious as their nature, turning that curiosity to your own mortality in your own medical situation, can be empowering and useful. But I don't think that should be broad advice. I think that's only for a fraction of people, it's probably the worst thing they could do. And there's nothing wrong with that. Everybody's, everybody's a difference, right? Not everyone should adopt the way of the nerd, but for a fraction of people, it's a really, really good thing to do. This is normally the portion of a conversation with a guest where I list off the many, many things they've done and how grateful I am.

2:32:01And all of that is absolutely true in the case of you being here today and the work you've done. But I think it's self evident how much you've not just accomplished, but how much knowledge you've put into the world and not just scientific knowledge, but knowledge about the human experience of others and of yourself. And so I just want to extend it a giant thank you on behalf of listeners and viewers and myself. Thank you for coming here today. Thank you for doing what you do. And so great to still have you here and to have this conversation. And I hope it goes longer and no matter when it ends, you've done an enormous service to humanity.

2:32:48Well, thank you. That's very kind. It's been a, it's been a pure pleasure to have this discussion with you. Thanks David. Thank you for joining me today for this discussion with Dr. David Linden. If you're learning from and or enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please subscribe to the podcast on Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five star review. If you have questions for me or comments about the podcast or guests that you'd like me to consider hosting on the Huberman lab podcast, please put those in the comment section on YouTube.

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