How to Rewire Your Brain & Learn Faster | Dr. Michael Kilgard

23:10So one of the things that's most surprising to me and interesting to me is your experiments by Richardson, along and others. Recording from these areas, nucleus spasalus, releasing acetylcholine, look, it's really us, even dorsoraphae, releasing serotonin, is that they're excited the first time and then they quickly get used to it. And so they're always waiting for what the new thing is. What's the thing that's going to be informative? What's the thing that's going to have the most rewards? What's the thing that's going to have the most risk? And the problem is, we don't know what the long -term consequences are of having over and over and over activation of that pathway.

23:46We know that if you take a child and just sit in an orphanage for years upon years, they don't come out well. That's pretty clear with animals or humans that deprivation is not good, but what happens on the flip side when you stimulate and then you over stimulate? We don't really know, at least, I don't know of any clear cut, well -designed experiments. The suggestion, as you know, is maybe it increases depression and anxiety among adolescents. That appears to be what's happening, but there's no causal link because everyone is doing this experiment together. My children watched lots of videos exposed, lots of things.

24:17It's very difficult to get rid of it. It's sort of in the water. It's in the culture having a phone and having that restricted view. On the flip side, this generation is great. They got a million things they know about because they were able to time travel and look at things in the distant past, look at things in the future, look at things in other countries. They're awareness of people who are different from them is so exciting. So it's hard to balance those two, but in general, the concern for me would be if you max out that neuromodulator release, if you do things all the time, including illicit drugs that push that up, it's intuitive to me that that would then push down all your other experiences.

24:51I've had the great pleasure of taking my face from the desert world of the cyanide peninsula and putting it down into the water of the Red Sea. It's miraculous. I mean, the level of colors and movement and textures and you pull your head back up and you recalibrate like this is the moon. There's all this rock which face back down. That contrast to me is real and very exciting. Others have told me that they have taken illicit drugs and had very similar experiences. And I'm not going to say that my experience of real colors and real life forms and real waves and patterns is superior. It's just my preference.

25:24And I think we know people for thousands of years have had these kinds of experiences, looking at mountains and streams and groups of people. What we don't know is what happens when you take a lot of fentanyl, a lot of methamphetamine, a lot of cocaine or even nicotine at high levels. We don't know. But the worry is, Ben Franklin's all things in moderation. Probably better to take it slow and make sure you didn't overdo this one. But I don't know what the negative consequences are going to be other than the potential increase in depression and anxiety. You were snorkeling on a coral reef in the Dead Sea.

25:56Is that the experience you were describing? Yeah. I love Aquaria. I have some at home and I love snorkeling and done some scuba diving. And I agree when you see the richness of a coral reef and then you pop up, it's like the contrast is a big part of that experience. But it stays with you. I mean, you're out of your element down there. If you're doing scuba, you're more or less like a fish. If you're snorkeling, you're a pseudo fish. But when you come back, those experiences stay with you as an enriching experience. Watching a video of a coral reef, well, that can be relaxing. It's a completely different experience as you pointed out.

26:35I have to be careful because I'm almost 50 and I want to believe that real world experiences are better than virtual ones. And now with the huge arrival of AI, which is only going to expand, everyone's asking the same sorts of questions. What point is it true sensory deprivation? I mean, on the one end of the continuum, as you pointed out, sensory deprivation is bad, especially for a developing brain. The other end of the continuum, sensory gluttony is also bad. And we could be talking about food here. Starvation is bad and gluttony is bad. Both make you sick. One kills you faster. Starvation kills you faster.

27:11But as we've now seen with the rates of obesity in this country, gluttony is, I'm not calling people gluttons to be disparaging of them, but let's face it, people are consuming more calories than they burn for whatever reason. So I think when it comes to sensory input, I have a feeling we're going to arrive at a similar place in a few years where we are going to realize that we need to set upper limits on how much sensory input and set quality standards for sensory input. Right now, we're just kind of drinking from the fire hose. Well, and how you interact with it, what the ways you interact with are, if the only way to interact with it is flipping the screen, that's pretty limited.

27:47And what the human body does a lot of amazing things, the way we can navigate, whether it's skateboards or paragliding or whatever, people can do fantastic things with their bodies, but if you're not required to do it, we know this principle of use it or lose it. If you don't have that exposure to the sounds of Swedish vowels, when we were born, we could hear all the Swedish vowels, and then we weren't raised in a culture that used them, and they just disappeared. And the worry is that that ability, the natural predisposition of our brains to handle those kinds of inputs, that over time, when we don't use it, we'll say, I guess you don't need this.

28:17I guess swimming is not something that you're going to need to do. I guess, and a lot of adults win, which is fine, but how many of those experiences get turned off, especially at a young age, whether easier to pick up? That's one of the big questions I don't know, but it makes sense that the kinds of training, the inputs in, you know, junk in, junk out, we used to think, again, the body just grew, brains, babies just got bigger. That's all that happened. And then we started realizing the things that they saw mattered. At first, we thought, well, let's find what they like. What do they like the most?

28:46You may remember these old experiments where they found that if you give a baby a face, and you give it, and a cartoon face, it'll look more strongly at the cartoon face, the exaggerated black and white face. And some babies had trouble disengaging from it. The attention mechanisms were so cute, the two black circles and a mouth, and people sold baby mobles that were these very engaging things that the babies couldn't get their eyes off of. Now, when you go to the babies are us, or whatever store, you don't see those anymore. You see much more naturalistic kinds of things. But there was a moment when we thought, well, if the babies like it, give it to them.

29:18And then we sort of thought, maybe just because they like it is not sufficient. Maybe we should try to do a longer term read, not that short term, immediate gratification, but the longer term, what does it do that the face I've seen is an extreme face and exaggerated face. And again, we think back to individual neurons, whether retina ganglion cells are, you know, cells in fusiform face area, these are parts of the brain that are involved in visual processing. If those areas are wired normally appropriately, then we pay attention to the right cues. It's typical when I'm looking at you, when you're talking to look at your eyes, not look at your mouth, but there are a number of people who will be more interested in the movement of the mouth because it's larger than the eye movements.

30:00And that's a less effective way to look is to look at the mouth instead of looking at the eyes. These are very subtle things, but some of the microaggressions, micro gestures that are critical, not just in our culture, but in monkeys where gritting your teeth might mean one thing and winking or looking away might mean another thing. We want our children to pick those things up and know about how to interact with humans. On the flip side, social media and online culture is part of our culture now too. And so depriving them of that and having them be blocked, deprived of what their culture now is, is also seem harmful.

30:31So for me and my wife, thinking about, I don't want them to know nothing. About the internet, but I don't want them to jump in with both feet and have all of their experiences. So what proportion is that, you know, 20 % of your day on the internet, that seems reasonable. Maybe many people are 80, 90%, sometimes. I think it might be better to be at 5%, only when you're needing it to reach out or do things, but I don't know the answer to that. We're doing this big experiment. But we've done these experiments before. We did this experiments, like you said, with television, 200 channels. We did this experiment with the radio.

31:01We did this experiment with the printing press when suddenly you could go into a library and just, there were books everywhere. What would that do to people? And I'm generally an optimist, you probably already tell. Humanities done pretty good so far. The last 100 technologies didn't end things, whether it was machine guns or nuclear war or weapons. So I'm cautious optimistic. But I think we will rebalance and it won't necessarily be someone telling us. It'll be people figuring out, I don't feel good when I use this. So both my son and daughter routinely mentioned to me, when they turn off apps, remove, pick your social media, they just need a break.

31:34And I think that's again a sign that people individually have enough autonomy to figure out for themselves. What's working or what's not. But it would be good to have a body of knowledge to reinforce that and make it feel okay. You're not missing out. You're not punished because you turn this off for a few days or weeks. Yeah, the algorithms punish you for turning it off for a while. It favors a pretty consistent cadence of posting and interaction. I'm very surprised that somebody had the good sense to steer parents away from buying mobile mobiles. We should probably explain these are like things that you hang above the baby's crib, of course, and they spin around.

32:11They have kind of like branches on a tree. They're colorful. They have motion. Babies can interact with them safely. This kind of thing. I'm quite surprised, pleased, but surprised to hear that when the ideal mobile for getting babies to attend with just the simple faces was discovered that somebody intervened and said, hey, just because they like it doesn't mean it's good for them. I mean, everything else in sort of a commercial industry runs exactly the opposite way until we discover it's actually harming us. So I'm positively surprised. I don't know who made that decision, but I'm relieved to hear that if you go buy a mobile now, it's not the one that would maximally cause the baby to attend.

32:58It's the one that's best for their development of the visual system. And I immediately think of iPads. I mean, if you give a baby an iPad, they will they'll just be there all day and we think, oh, they like it. We sort of know it's not good for them. And yet, it's become the digital babysitter that the television used to be. Now, I'm not anti -technology. I'm a group in Silicon Valley after all. And I use technology, including social media. But I guess I'm concerned and struck by, you know, this question of where to draw the line. So in this instance, somebody had the good sense, but this is like the different, I mean, the food equivalent would be, sure, I'm sure kids prefer ice cream.

33:37They eat it all day long as opposed to things that are a bunch of things that brings to mind. One is how studying the brain informs how we should use our brains. One idea, as you mentioned, was language early language development, Alicin Copnick and other people have looked into, there's contrasts and sounds that we can't hear. And so my kids were young. We said, oh, we should expose them to all those sounds. As there's a company called Baby Einstein and they play Spanish or French. But we don't really know how much of these languages should they be exposed to? What is the right mix to make them better world citizens, better learners smarter, more resistant to nerds and disorders or whatever?

34:20We don't know the answer to that. So we're just running the natural experiment. I tell everybody that being an neuroscientist is way easier than being a parent. There's just too many choices. There's no control group. There's no way to run it again and tell you find out the actual answer. What's interesting was that it turns out exposing people passively, babies passively to the sounds from other languages really doesn't change very much at all because there's no interaction. So the Chinese tones or the Swedish vowels, these different sounds, when they're not really interacting with you and they're just on the screen, you don't pick them up.

34:53Which is really fascinating that your brain already knows that's a TV. And how does it know that? It knows it because your interactions with it are so limited. I took Spanish as a kid and they said you should watch Telenovelas and learn Spanish and you'll learn the culture and you'll pick it all up. You'll get the humor in the jokes. I didn't learn that much from it because no one was talking to me. I was watching passively and so we now know that when you're actively engaged, you're going to have better neuroplasticity, better generalization, you're going to better connect it than when you just sit back and watch.

35:23Here swiping is not exactly no interaction. You have some but it's pretty impoverished, pretty limited. So I suspect a lot of it isn't that bad. It just kind of comes in one ear goes out the other. But that also means those hours aren't spent doing something else. Playing in the mud, getting your immune system developed, interacting with children, hitting things with a ball. You may aren't taking as many risks. Maybe that's a good thing. Maybe not getting as many head injuries as we used to get. Maybe that's a good thing. So I think we got to take the good with the bad. But in general, the idea that neuroscience is accessible and that we learn that our experiences really matter, I think that's the exciting part.

35:59Why is chat GPT so smart? We train it on every word we ever wrote, whole species. And then that went into these billions of connections. And those billions of connections produce something that's relatively sophisticated. The same thing for a child. Here's a child. The experiences they have matter. All the kids are going to learn to walk almost all of them by a year. But a lot of things happen during that year. A lot of falls, a lot of tumbles, a lot of what's, a lot of stairs. And so I think for me, having those large fraction of experiences be what I call real, having the statistics of the natural world, things that our grandparents would have recognized and been familiar, that's likely to be something that's good for your brain.

36:36Both as a youth, as well as as a full grown adult. Then you ask the question, how about at the end of life? At the end of life, is it now okay? My brains are already done. Can I swipe to my heart's consent? Can I watch Wheel of Fortune or whatever I want all day long? The evidence suggests it also causes depression and anxiety. If your day doesn't involve other people communicating, if the heart surprises someone knocks on the door. When I was a kid, people knocked on the door a lot. It was a big surprise. That's not a surprise children have that much anymore. Someone just randomly knocking because they would have texted.

37:04And so the surprises are now coming from the donk. I got a text. Oh, Bill wants to come over. As the population ages, many people are likely to find out that having too many experiences that are disconnected from reality, that are just a show that's made to be engaging and interesting isn't as good as getting on a boat and driving some place, visiting some location, getting on a bus, driving, flying, wherever it is. So travel, gives you different experiences. You smell different smells. You hear different things. And those engage, again, those neuromodulators, those neuromodulators then help make changes because the vast majority of them puts, we take in.

37:42We just throw away. We're not memorizing every place ever was. Every place ever set my keys. Every word, everyone ever said me. None of us are tape recorders. We're picking which moments are the moments that are useful. And that's hard to know because we don't know what the future looks like. But we're making guesses based on what the past looks like. And so when the past is abnormal, robotic, exaggerated in its novelty, we make changes assuming the future is going to look like that. And the future may not be. The future may be a job. And it may not be this exciting. And it may be hard to stay focused for eight hours a day.

38:14If you're used to something exciting happening every two and a half seconds. And I don't have to do a job. For me, it's writing. We have to sit and stay focused for hours at a time, trying to put a handful of ideas together in a way that other people understand or try to develop a new treatment for someone who's suffering from a serious neurologist, I can't just water. It just takes hours and hours of focus. And for me, fishing was helpful for that. Sit there with your dad and just fish for hours. And you go, what are you doing? We're not catching or fishing. It just means we have the line of the water.

38:42And it might be a fish. There might not be. And it may only be one percent of the time you're catching a fish. It might be one tenth of a percent of the time you're catching a fish. But that's enough because the time spent in anticipation and waiting and preparation, those were meaningful times as well. So I think there's a little bit of a shift toward what are the key parts? Is it the dopamine hit, the exciting, the novelty part, or is it all other stuff? And we're now learning from the training of these networks, all of it matters. All of those inputs, all those syllables, all the junk words matter.

39:14And so I think that shift toward thinking we know what's important, the stuff we think of as important. That may not be all of it, all the rest probably plays an important role too. I'd like to take a quick break and acknowledge our sponsor, AG1. AG1 is a vitamin mineral probiotic drink that also includes prebiotics and adaptogens. As somebody who's been involved in research science for almost three decades and in health and fitness for equally as long, I'm constantly looking for the best tools to improve my mental health, physical health, and performance. I discovered AG1 back in 2012, long before I ever had a podcast, and I've been taking it every day since.

39:51I find it improves all aspects of my health, my energy, my focus, and I simply feel much better when I take it. AG1 uses the highest quality ingredients in the right combinations, and they're constantly improving their formulas without increasing the cost. In fact, AG1 just launched their latest formula upgrade. This next -gen formula is based on exciting new research on the effects of probiotics on the gut microbiome, and it now includes several clinically studied probiotic strains shown to support both digestive health and immune system health, as well as to improve bowel regularity and to reduce bloating.

40:22Whenever I'm asked if I could take just one supplement, what that supplement would be, I always say AG1. If you'd like to try AG1, you can go to drinkag1 .com slash huberman. For a limited time, AG1 is giving away a free one -month supply of omega -3 fish oil, along with a bottle of vitamin D3 plus K2. As I've highlighted before on this podcast, omega -3 fish oil and vitamin D3 K2 have been shown to help with everything from mood and brain health to heart health to healthy hormone status and much more. Again, that's drinkag1 .com slash huberman to get a free one -month supply of omega -3 fish oil plus a bottle of vitamin D3 plus K2 with your subscription.

41:01Today's episode is also brought to us by Carbon. Carbon is a diet coaching app built by nutrition expert Dr. Lane Norton. I've used Carbon for more than three years now and I have to say it's among the most powerful tools for nutrition coaching and effective weight management that I've ever encountered, especially if your goal is like mine which is to maintain or build muscle while also losing fat. Now I'm turning 50 years old this September and even though I consider myself in pretty good shape and I've been training for a long time and trying to eat right, one of my goals is to hit 50 in the absolute best shape of my life.

41:33To do that, I'm dialing in my nutrition using carbon with the goals of increasing my muscle mass, increasing my strength while also decreasing my body fat. I've been raving about the carbon app to friends and to family and to members of my huberman lab team over the last few years and everyone who's joined me in using it has found it to be tremendously useful. In fact, some of those people are going to join me in my approaching 50 fitness goals and body composition goals. My birthday is September 26th and so I'd like to invite you to join if you would like to improve your body composition and fitness to also use the carbon app.

42:05Now there are a lot of apps out there that are focused on fitness and nutrition, but what makes carbon different is that it doesn't just hand you a one size fits all plan. It actually learns your metabolism over time and it adapts your program based on your results. It also allows you total flexibility in how you eat. So if you're looking to take a smarter, more personalized approach to your nutrition, I can't recommend the carbon app enough. To try carbon, you can go to joincarbon .com slash huberman. While carbon does not typically offer trials or promotions, they've agreed to give a free seven day trial to all huberman podcast listeners.

42:39Again, that's joincarbon .com slash huberman to get a seven day free trial. You and I both come from lineages of neuroscientists that focus on neuroplasticity. My lineage through hubo and visel were really about the developmental plasticity piece. Your lineage through Mike Merzenick and others, it's really about the adult plasticity piece. So I'm hoping that as we move forward, you'll be willing to do a little bit of an experiment with me as you were talking just now. What I realized is my real wish, not just for this conversation, but in life, is to come up with some real understanding of what the requirements for plasticity are.

43:21In a way that, regardless of how the world changes, AI, social media, love, scuba diving, snorkeling, etc., regardless of the inputs that we can make the best informed choices. Understanding, of course, that not all of life is about requiring ourselves, some of life is about enjoying ourselves. So if I may, I'm going to just put up a couple of things on the non -existent whiteboard here to frame in people's minds. I think we understand just by observation for thousands of years, but also now from science that from the time we're born to about 25, there's a lot of passive experience that helps reorganize the brain.

43:59Negative experiences get kind of stamped down. They can be undone through work like talk therapy and maybe some neural augmentation that we'll talk about later for PTSD. This is also true in adulthood, but that it's clear that there are at least two things that are required for plasticity at all stages of life. One is some degree of focus. Just can't be stuff in the room. Can't be classical music playing in the room. You're not going to build a Mozart or even somebody that can play even a fraction of an instrument, but if a kid learns an instrument, they can do it. If an adult really focuses and tries to learn an instrument, they can do it.

44:35It's just slower in adulthood in most cases. The other piece that I'm aware of, and tell me if I'm off here, is sleep is required. A lot of the rewiring of neural connections actually occurs during rapid eye movement sleep and deep sleep. You can't just focus and just work infinitive. You need sleep. You need rest for the rewiring to occur. But as you're telling me about these experiments, and by the way, I was not aware of this experiment that kids will attend more to a kind of a cartoon face than to a real face. I was not aware of that. As you're telling me about that or fishing or we're talking about music learning or language learning, I believe the best way to learn a language is to place yourself into an environment where it's critical that you learn it, like go to a foreign country.

45:16If you need to learn how to navigate by virtue of understanding and speaking some remnants of that language, you're going to learn it much more quickly than sitting in Spanish class back in the United States. I'm wondering in my mental model of how to change one's brain, that in addition to focus, which requires alertness, in addition to focus and periods of sleep for the rewiring to occur, maybe I can, if you have a better word, let me know, but I want to introduce this and an element of friction, that there needs to be focus and friction, right? Because with the kid looking at the face, the cartoon face, there's focus, but there's no friction to get there.

45:57With friction, like there's some element of self -generated work, like with the snorkeling, you have to get wet, you have to go under the water, you have to put the mask on. It's kind of weird to breathe through a snorkel the first time you do it. It's kind of uncomfortable. There are a bunch of things that go with it that make that experience so much more enriching in terms of how it rewires the brain. And traumatic events, unfortunately, engage focus and friction. So it meets this requirement. So I'm trying to come up with a table here and as scientists, we should try and disprove what we're putting up, right?

46:29But I feel like what one wants is just enough friction, a lot of focus, and then a period of rest in order for plasticity to occur. And maybe in a video game, there isn't enough friction. Your daughter being involved in very interested, rather, in real world human experiences, it's a pseudo -random walk. I mean, there's some regularities about how humans interact, but it's kind of a near -infinite space. And it certainly is valuable to have social, emotional intelligence. We know this. So what are your thoughts about needing to work in addition to focus in order to get meaningful? And when I say meaningful, I mean, really adaptive plasticity.

47:09Stuff that makes us smarter, makes us better. People make us feel more fulfilled. It's not all about test scores. But a really good life is one in which you feel like the things you're doing have meaning. You don't look back on the past year and go, yeah, that was just a bunch of schmooly experiences. Yeah, I mean, to start on the part you ended on, I mean, I really think reflection on these topics, this is another one that was a big surprise, is that thinking about it later, also requires your brain, not just the sleeping part when you're clearly thinking about it and turning it over your mind.

47:39But as you're on the way home from the game, as you're planning to drive to the game, or the date, or the, you know, business appointment, or whatever it might be, that idea that it's not this, all the learning doesn't happen at this one moment, but there was some preparation that went into it. There was the actual event, which often has the friction you're describing, whether some engagement and decisions are being made, whether it's information being transmitted and information being gained. And then this period of reflection, where you're wondering about it, you're thinking about, for me, often, looking back over my pictures, either of having a child or going on vacation, is helpful in reorganizing it and reframing it.

48:16For me, those are helpful things to do. But the idea that this is all happening at one snapshot, that's how we used to think of it. We used to think of it as light bulbs went off, you memorize the picture, and you're done. But that's not how any of the ideas, it's not how math is viewed, it's not how language is organized in our brain, it's a series of these memorization events. We're trying to make use of it. And what's going to be useful is hard to anticipate, hard to predict. So I like to think of it sort of from an information point of view. How many bits of information? So a bit of information is just a yes or a no.

48:46And we now live in a world where a floppy drive doesn't have a kill a bit. You know, you're not a man. You won't even know what a floppy drive is, but we're dating ourselves. Yeah, you could get gigabits. You can get terabits. So we're talking about billions, trillions of bits. And you wonder how much did you learn when you were going up to the plate and you were going to hit the ball? Well, there's this picture makes a particular look when he's going to give us lighter. This person gives a particular glint in their eye when they're about to say something mean. Each way you watch that person is giving information on what's happening in the future, but you have to be there and you have to see that person having that experience.

49:24Now as the ball is traveling down to you or as the person is about to, you know, pull the ball away from you in the Charlie Brown analogy or whatever the experience is having that sequence of events. You have a prediction. It's pretty low reliability that this is going to be a slider. Then I start to see, hey, it looks like a slider. Then I swing at it and I miss and I say, that was a slider. I miss that one. Then I think about it at the end of the day and I go back and for many of us, you dream about it. What is all that about? My original interest in neuroplasticity actually came because something happened to me, not something I chose to happen.

50:02I worked in a lab in college squeezing the salivary glands of Drosophila. So the little maggots in the fruit flies. If you squeeze them, they have these banded patterns, which were all their DNA and their chromatin, their organization of the DNA is organized. And my job was to look and find, it looked like barcodes. So it would be a thick line, thick line, thin line, thin line, thick line, thick line. In the saliva. It's actually in the cells there. It's a sensation. So about 900 cells all fused together to make one cell, all the DNA then aligns when you stain it. This is in Ron Davis's lab at Bill or College of Medicine.

50:44But when I close my eyes, I didn't see what I normally saw. What I saw were these bands because I've been staring every day at these patterns. And that happened to be several more times when I get spent a lot of time with that focus and that friction you're talking about. Suddenly you start thinking about it differently. I had a conversation with a young man a few days ago. His native language is Spanish, but he told me, I think my native language is English because I only think in English. And when I talked to my mom, I have to translate. And they told me when I took Spanish, you'd eventually dream in Spanish.

51:14And I did a few times, but I never quite got good enough. So that idea that when you have a really significant experience, you can close your eyes and see it. I believe that baseball pitchers are seeing the balls being thrown, the signs being given. I believe that someone who's playing violin really well or a neuroscientist who's doing surgery, they see those things. And that's a repetition. We now know from Olympic skiers that if you do all your time skiing, you're going to recognize. So they spend a lot of time in visualization. You spend a lot of time imagining what's going on, stepping through the motions because it's too dangerous to go down the hill at that speed too many times.

51:50You'll eventually recognize or break your back. But practicing it can be done offline. And that practicing the neurons don't know. So long as you're engaged, long as you're modified by it, that's sufficient. The problem is you're not learning anything new if you're just visualizing it. Where's the feedback from the world? There's not, but you get the repetitions. And so that idea that we can combine, and again, many, many traditions for thousands of years have had these kinds of notions. You should go back and repeat these aspects to us. We need that extra benefit. Certainly that we should sleep.

52:21There are no cultures that say don't sleep. These are well received good ideas. We're now learning how does that work? And I'm personally excited about the idea that it's about the connections. We had this idea from thousands of years ago, at four or five things that could be in balance or out of balance. They were famously blood, flim, black bile and yellow bile. And they could be in different levels. And the levels were all that were needed. And that made a lot of categories. Because with four things at several different levels, you can make lots of categories. The Myers -Briggs personality test.

52:53You take a few dimensions and you can kind of explain anything. But whether that's really how we work, where we really are too much blood, too much bile, too much flim, or even too much serotonin, too much northern African, too much dopamine, maybe there's more to us. Well, what could it be besides that? And the answer is, I think the experiments from our forefathers, from Monica Hall, Emilio Golgi said, it's the connections. And we went, what do you mean connections? What would the connections do? And now we know from some beautiful studies come out recently. It's 150 trillion of these things.

53:32Inside my brain, inside your brain, inside each of our listeners' brains. And how do they get to be the way they are? Did the genes make them? The genes? There's only three billion base pairs in the genes. Not nearly enough. We only have 20 ,000 proteins. How could 20 ,000 make 150 trillion? They couldn't. Genes are critical. They set us up to learn. But they're not enough to tell us how we work. And I think that's true. But the genes are interacting with our experiences. As we listen, as we hear, our brain is being rewired, whether it's for Japanese or English or Swedish, whatever it might be, our brains can learn anything.

54:10We can fly the space shuttle. You and I can fly the space shuttle. We can do brain surgery. All of us can. Just takes practice. That's the miraculous nature of where our neurons work. And what's surprising to me is I think we're close to figuring it out. How do the neurons work? 1949, this guy, Donald Hebs said, fire together, wire together. That's it. A lot of us went, does that make any sense? If all the neurons who fired all wired together, wouldn't everything just fired together and everything just wired together and you'd have a seizure? And the answer is that's exactly what happens. So his intuition, though, partly right, that the covariance, the co -occurring of these events is an important aspect of learning.

54:48It's not so simple. We found out that the neuron that fires a little late, they both fired together, but the neuron that fires a little bit late, instead of long -term potentiation, strength in the connection, we get long -term depression, weakening. We've been working on the brain 100 years. We really only figured this out about 25 years ago. And then the fact that none of that happens. No firing together, wiring together, no out of sync failed to link. None of that happens if the neuromodulators don't arrive. And the neuromodulators arrive a couple seconds later. So the timing, whether to strengthen a weakened, is a millisecond.

55:21A thousandth of a second says, strong or weak? Which way should I go with it? And then I've got this two -second window that says, sometime within a couple seconds, did it work? Was that a win or a loss? And if nothing happens, if it just wasn't important at all, then it all just gets flushed. In one and out the other, you just forget it. But when something exciting happens, you get released of a sealed coil in northern Africa. And these things go into the brain. They bind to receptors. They change what's happening inside the cell. And that computation is really sophisticated. And we don't have 100 billion things making that computation.

55:56We have a thousand trillion running that computation. And that computation is much more sophisticated than the computation that's happening when you train a large language network. Most of your listeners will have heard of artificial intelligence, machine learning, have some basic idea. But we know how that works because we built it. And it doesn't work how you and I work. It's a big giant global learning signal. And we just keep running around feeding it back in. And everybody learns, this is the right answer to the entire network. Right and wrong is told to every single network, neuron in the network, is something called gradient descent.

56:29And that process of improving the network, making it better and better and better and better, predicting has led to the revolution we've seen in artificial intelligence. What's cool is that our network is cooler. It's way bigger. Chat GPT is 540 billion weights. We're 150 trillion. So that makes us 500 times each of us. 500 times bigger in scale. And instead of requiring huge amounts of energy, a light bulb's all takes. In a hamburger day, you have plenty of food. You can learn all day long with that amount of energy. It's not that and that's miraculous. And so I think there's a lot of worry that when we learn about the brain, it will devalue humanity.

57:10We'll be less impressive. We'll be less exciting. I've just seen the opposite my whole career. If we were just genes, then you'd have eugenics, you'd have all these problems, you'd have people are valued based on whether genes are right or wrong. Turns out the 20 ,000 genes doesn't explain us. The hundreds of cell types don't explain us. It's the synapses. I think for a long time, we were hoping there'd be an easy fix. If someone had a problem, it'd be nice. If they just had too much blood, we'd give them some leeches, drain the blood out, they'd be back to good. So George Washington died. But now we're learning, most people don't have four or five things that are right or wrong.

57:44They've got billions. But they're all changeable at any stage in life. They get really hard. Don't disagree to lose an accent, for example, or to get over a traumatic event. It could be really difficult. But the fact is the brain is plastic till the very day you die. And that ability now to get our head around, what do billions of connections mean? What does all this information for? It's informing me. Not just to make us better, to be better to beat someone else on a test or anything else like that. But it's just part of who I am. When I look at a cloud, I've never seen that cloud before. When I hear a baby coup or a pedicat, all those experiences are really information rich.

58:21Different cats feel different. Different clouds look different. Different babies make different sounds. And the fact that I get my unique experience, you get your unique experience, is what our great, great, great, great grandfathers told us that we were unique and special. And then a lot of people looked at the clockwork universe and said, no, no, it's all very deterministic. It's all very fixed. It's all very rigid. You're just a machine that does what it's told. It doesn't really seem right. The math guys now tell us, if as soon as you put three things together in a nonlinear way, it's hard to predict what's going to do.

58:52And the computer scientists in the world, my brothers, one of them, have finally admitted, we don't fully understand what it's doing. We don't even know how you could understand it. It's so rich and complicated. And we're now okay with that. That kind of humility about what computers are doing and how they're working can reflect back on our own bodies where I don't know exactly why I make every decision. I say lots of things I regret. No, we shouldn't say that. All of us do. But the idea that I can change and I can make amends for that. I can say that wasn't what I meant to say. I apologize for that.

59:21That's really exciting. That there's a biological basis for it. And it's this four -factor learning rule where there's some proteins, receptors that are having binding of glutamate, serotonin, and norepinephrine. All these words you've talked about before. But they add up to something. They don't eliminate me. They add up to me. I think that's something we can really be proud of. And I think your getting this information out to audiences is really exciting because people have the right to know this. Taxpayer money is paid for all this knowledge. We've learned all this stuff. And it has real implications.

59:53Whether it's for how we treat people with disability, how we treat our elders, how we treat people who've committed crimes. All these things have implications. And I'm not saying everyone needs to become a neuroscientist by any means. But it's not just a curiosity. It's not just a laboratory trick we wanted to work out. This understanding has implications. And we've been building, as our forefathers did in other fields, physics and all the rest. They've built all the way where their model of physics is pretty good. Our model of the brain is not there yet. We're not at that level of understanding everything.

1:00:25But moving in that direction, we're eventually being able to find some child or some older person who's got a real problem. They just can't do it. We can switch from a mode of just labeling them, diagnose synodios, to a new mode of how can we assist you? And it might be changing lifestyles, changing diet, changing experiences, changing rhythms, changing friendships. But it might also be, in some cases, there's a real problem. Don't mean cells in the substantial Niagara have died. We're going to need to make this change. We need to put a stem on an electrode in where the hair cells in your ears all die.

1:00:58You can't hear. We now know why that is.

1:01:05They're not getting into their brain. So we take a cochlear implant. We take a microphone. We record the vibrations. We put it into the brain in the right way. And now many people can hear. That was a miracle not too long ago. Now it's a technology you can just go by. And moving that progress of neuroscientists, some things like schizophrenia, we've made very little progress. It's very hard for you what we do. But at least we understand the nature of the disease. It's not that they've got a germ or a bacteria or a virus. It's not there. One gene is big and bad and broken. It's not contagious. But there's some wiring challenges.

1:01:38And that most days, someone's schizophrenia is perfectly normal. Most people with neurological and psychiatric disorder spend large periods of time normal. Between periods of migraines or depression, they are acting totally reasonable. And we want to spend more time, push them more toward those times of health and satisfaction and reward and away from those times of disability engagement limitations. And I think we're moving in that direction instead of labeling and putting people off at homes more to engaging, understanding, and then eventually intervening. I agree that progress is happening fast.

1:02:11And while sometimes it might seem that we're not moving in the right direction, I think, neuroscience in particular is striving very hard. I say in particular because other fields like immunology in particular and physics have experienced great advances as you've pointed out before over the previous hundred years, whereas anytime there's been a pathogen that we've wanted to deal with and humans have put a lot of time and energy toward it, done a pretty good job of dealing with that pathogen. The same can't be said for neurologic diseases like Alzheimer's. I mean, progress is coming but it's been much more slow and we don't have cures.

1:02:49We don't have pure solutions. I want to get into the neuromodulators in some degree of depth as it relates to neuroplasticity. And certainly the incredible work that you're doing with devices, vagal nerve stimulation and and so forth for treatment of everything from PTSD to tinnitus to you have a beautiful paper that came out recently. And nature, congratulations will provide a link to that paper as well as some of the others relating to restoration of motor function for people that have restricted motor function for various reasons. Before I do that, I can't help but raise once again this sort of mental model of plasticity that I'm trying to build out as we go along here, which whereby focus in friction seemed to be prerequisites.

1:03:30I mentioned sleep. You added to that reflection. And I just really want to underscore that and certainly add it to this list that I'm building here because about six months ago, I did an episode on how best to study and learn. I went into the literature. I know what my study habits and tools are and what I've used over the years. But I went to the literature, the peer reviewed literature and there were a number of takeaways but perhaps the most salient one was that students who self test learn much faster and the information they learn is much more durable over time. They forget a lot less of it than any other method.

1:04:07So tests are not just a way for others to evaluate us but for us to evaluate ourselves. And it created a whole different picture of learning and memory for me because a simple statement made by a psychologist not a neuroscientist was when something like self -testing protects against its anti -forgetting. And most of learning is just intervening in the forgetting process. Just like there are a number of stimuli in this particular interaction that unfortunately I will forget or fortunately, perhaps the irrelevant stimuli I won't remember. And so so much of what we learn is really about what we don't forget.

1:04:42It might seem like a trivial distinction to kind of flip it that way, but self -testing being key. And I think this element of reflection and a mental rehearsal is so key. I think again I don't want to demonize social media but I think that one of the downsides of smartphones and social media is that after we leave a lecture or a movie or a social interaction in the past prior to 2010 say the tendency was to walk to one's car or drive home maybe think about that interaction. Think about what was good. Think about what was bad. Maybe let it kind of stew in us a bit. And now we tend to look at our phone and start getting additional stimuli that I think collides with and and occludes the learning that would have occurred.

1:05:22So we don't get a lot of opportunity for reflection. There's a lot of sensory input, some of it's deprived, some of it's rich, but there's not a lot of time for reflection. So reflection and self -testing as kind of falling into the same bin and reinforcing learning and plasticity. The other one was that you talked about visualization and the skiers who to avoid harming themselves they used visualization as opposed to just more and more runs down the slope. We've heard before all of us that when you imagine an experience the brain doesn't know the difference between that experience and a real world experience.

1:05:56But of course a real world experience includes other things. There's vestibular feedback. There's gravity feedback. Feedback with our relationship to gravity to put in common terms. There's all sorts of stuff. The wind in our ears. And you said and I find this very interesting and very useful that visualization and mental rehearsal can be useful for reinforcing things that we've already done in the real world. But it's probably not the best way to learn new things that we haven't done in the real world. So we can pick any number of different examples, but I think people are smart enough to just leap to those on their own.

1:06:30So if they're trying to learn something and they're doing that in the real world dancing, maybe it's a physical skill, maybe it's a cognitive skill, maybe it's an emotional skill. Mental rehearsal is useful, is what I'm here you saying, provided that you're rehearsing something that you actually did as opposed to just imagining something and expecting that you're going to be able to do that something. Do I have that right? No, I think that's exactly right. I mean, if you know you're not going to need it, biology would have said you don't need this. It's a leaf that's wiggling in the air. I don't need to know where that leaf is.

1:07:01But this is the thing that cues me to where I'm going to be interested in. If this is going to help me get a mate, I'm going to learn that. If this is going to be an irrelevant fact about a cloud, I'm not going to. And I think children have a lot of trouble with that at the stage and childhood with a, they'll see a plane up there. I'm like, God, there's a little plane up there. That plane has no interaction with you at all. But they're fascinated by their cute into it. They're interested in it. We all the time have to figure out what are the things we're going to be tested on? What are the things you're going to need to know?

1:07:29And one of the ways you do that as educators, we both do, is you give them test. And a lot of people say, I can't wait to have the last test. Really? You want to have no more time when someone judges and determines how to do? What is your evaluation? I think a lot of times, many of us become lifelong learners. And we're comfortable knowing that someone else knows more of me. I'm not going to win. But that I'll be able to find out how much did I do that I know what's possible. And testing is good for us. Educators do it not just to assign and rank and distribute and give fees and season fees. But someone says, you could do better than that.

1:08:01If you got a D, you could have done better. I'm not saying you're flawed. I'm saying you didn't put in whatever was needed. And maybe that person does need to put more work in to get the B or even the A. But it's not my opinion that they can't get it. It's that they didn't get it. Explaining what's real? What percent did you know? What did you actually learn? How good are you at throwing the Tomahawk at shooting the arrow at doing rock climbing? The visualization I'm thinking about is like from free solo when he's imagined doing this. He's already done it. But he's now going through imagining it again.

1:08:32All of us do that. My children did martial arts. They're both black belts in Tecwando. And they would practice these forms. I took it at Berkeley when I was a student there. I just really enjoyed it. Is it useful? I don't have never been in a street fight. I've never needed to apply these skills. But there was a beauty to it. There was a usefulness to it. And someone came and tested me. I made it to yell about full disclosure. But I was going to need to know it. And so I knew I would stand in front of other people and admit I didn't learn it. I wanted to learn it. But I didn't learn it. Knowing that someone, a mentor you respect, a peer you value, a spouse who cares about you, whatever it is, is going to look and see how you do.

1:09:11I don't think that's harmful judgmental negative. It's not part of the culture of exceptionalism and meritocracy. That's just giving some feedback. How am I doing? And a lot of times we can do extraordinary things when people do raise the bar on us a little bit. And that can be very self -fulfilling. Certainly an over -test focused culture. My mom was a master, primary education educator. She didn't really care very much for all of the testing focused stuff. She thought, I've got to get this kid to learn how to interact with others and put away his crayons. I don't need to worry about these particular flash card -based skills.

1:09:45But we go back and forth. But the times table, is that really important? Memorizing how multiplication works? Or should you spend your time with all the state's 50 states and all their state capitals? I don't have the answer. I'm not here to tell you that I know what the right thing to do is. I don't know all the state capitals. My children do. Is that useful? I don't know whether that's going to come out. Well, that's one of the exciting things about life. You don't know what's going to be helpful. Maybe playing a lot of video games is going to turn out to be really helpful. I can't have to have enough humility.

1:10:13I think certainly one of the things I know you've experienced as a scientist is just the incredible humility that comes from recognizing this thing is way more complicated than how I'm thinking about it. It just is. We start there. We know that. And we're okay with that. We make our best model, our best explanation we've got, the explanation that fits the data that we have now that's as simple as possible. And the reason we choose the simplest one is it's the easiest to prove wrong when it's inevitably wrong. And we just make this incremental progress. Life's a lot like that too. Certainly parenting is a lot like that.

1:10:45I think this is going to be good for the kid and then no, this is not good for the kid. I think this is going to be bad for the kid. Oh, that turned out to be a really good learning experience when they're into years and there's some big crisis. So understanding that we don't know at all that things are typically neither as bad as they seem or as good as they seem and that maximizing something, that's kind of one of the key concepts I worry about a little bit, men maximizing, minimizing all the bad things, maximizing all the good things, assumes you know which things are bad and should be minimized, which things are good and should be maximized.

1:11:18And a lot of times we come to recognize later in life, oh, many of those things that I really worked hard not to have happened. Those are really valuable experiences because they taught me either how to interact with other people, had those experiences or taught me some skill that I didn't know I would need to do, how to change a tire or whatever else it is, you don't want you're tired to go flat but then you learn how to change a tire and how you learn how a scissor jack works or whatever thing that later comes in handy. So to me it's more the diversity of experiences than the better experiences and I think right now we're a little bit at a time where there's enough judgment about which experiences should you be having.

1:11:52I just returned from Yellowstone National Park and there's a little platform you can look down on grand prismatic spring and there's people who are just like you are looking at a 700 foot across hot spring on top of a super volcano with rings of different colors of thermophilic bacteria and algae and you go take my picture and go and it's just difficult to say stop look at how big this is it will take more time. So I assume that the time you put into it this is back to your friction idea the time you put into it is probably proportional to the impact lasting impact it's going to have on your life and so when you're checking boxes looking for things it's probably not going to have much impact when you're playing violin for the hundredth hour not a violin player but there's a point where you eventually have changed who you are you're now a violinist I'm a neuroscientist I don't think it's something it's hard to do anyone can do it just spend all day doing experiments and that's what's neat about reading books or being a skier or being a parent everybody can get good at it but you only have so many hours and so I always think about the pie chart you only get a hundred percent coaches always say a hundred and ten percent there's no hundred and ten percent it's all a hundred percent how are you going to spend your time here I'm talking about the waking hours because I'm not going to cut corners on the sleeping hours and so you just look how am I going to spend it sometime spent working paying the bills getting the job done sometime in leisure and recreation sometime with spiritual activities and trying to make that balance I find it looks a lot like it looked for my grandparents but the proportions of that pie chart do not look like I just wanted to engage and spend all my time streaming on social media just me personally people who have done that look a lot like you'd think someone who's addicted would look they eventually realize it's just not doing it for me anymore I don't get much satisfaction um Gilbert Harvard at this great experiment looking what made people happy had these little things pop up you may know about this experiment and ask how you feeling and like people were happy when they were getting eggs it was just like I'm at the store how I said get eggs I'm getting eggs how you doing I'm pretty good I got eggs that idea that you're happiest when you're accomplishing some simple goal not some Olympic level impossible goal but just some simple thing that needs to be done what was surprising from that study was that when people were daydreaming which for years we thought the pursuit of happiness our forefathers thought if you could just sit and contemplate your navel and you know have the examined life you'd be most happy not so oftentimes contemplating our own life leads us to find someone who's got a better version of it leads us to realize we're not accomplishing every goal and so maybe humans evolved were created so that they would be actively engaged in doing something that appears to be the case and when we disengage it appears that things happen that are not good one of those typically in psychiatry they're called anxiety and oppression are different things but they may be very similar sides of coin where this is not working for me and I think we can work back to have what we go to the laundry have what we go to the grocery store and find out that that is in fact a satisfying activity even though it's pedestrian it's not something you're going to put an Instagram post on you know making a good pancakes I'm pretty good at making pancakes I flip it over it's just brown all along that's a good pancake some people are not as good at me I take a little pride in that but I'm not beating them I'm not better at pancake making I flip it it's a pancake I serve the kid the kid goes good pancake dad you're sort of done I think we devalue that by thinking I could just go to you know international have some pancake and I make a better pancake that I did it myself a lot of people during covid found out making it yourself I never made a bagel in my life and suddenly we're locked down for two whole weeks and it's like let's go make bagels kids and I went made a bagel it wasn't a good bagel I can make it get a better bagel anyplace but I made that bagel I learned a little bit about it and I appreciate better those people who master that and now when I taste a bagel I go now I see why your bagels better than my bagel and so I think those experiences are all coming into my brain I still remember obviously I wouldn't have mentioned it this thing six years ago when I'm sitting in my kitchen with my kids and a pot of water and some flour trying to figure out what I'm going to do with myself I didn't want pull world shut down but I got that gift from it that I had that better appreciation now of bagels and I just think that's a world view that we really could have gone down a path where studying the brain made us unimportant it made computers good and humans bad I'm not seeing that at all I'm super proud all my friends I don't wouldn't rather hang out with a chatbot that with my friends and I think that's going to continue to happen I don't expect there's going to be a major revolution and that's a surprise is a surprise that discovery keeps leading to good things not bad things there are a lot of dangerous things I mentioned machine guns and nuclear weapons but we mostly haven't used those things we've met all this good stuff so you can see I'm an optimist and it partly comes from studying the brain I get to study the brain while it's alive and listen to neurons where they're actually firing other people looked at it while it was in dead tissue under a microscope but they were both able to see this thing is alive and that was reflective of how I feel as a live person not as a machine not as a pawn not as a you know one vote in a democracy but as a real person and neuroscience is supporting that and that's been the history of science we didn't ruin things we found out that the Sun is not revolving around us it made it better when we found out we're revolving on the Sun we're not the only galaxy all those things were good for us but at first people were really nervous about having the answer I've just been surprised that finding the answer keeps being the good thing you'd rather have the answer there are no answers we don't want that's really surprising to me because it could have turned out we're all bad and there's nothing here and all the nihilist philosophies and all the rest would be right but that doesn't appear to be the case and all that comes from this sort of friction this reflection all these issues learning about how the brain works all the way down to the biological level all the way up to societies and groups of people who continue to be mostly prosocial mostly taking care of each other mostly not destroying the earth figure things out making adjustments ozone layer at a hole in it we made some changes that seemed very reasonable we may not be fast about it all the time but we tend to make the right path both in science as well in our species and I think that's because they're both using the same mechanism we get feedback from the world when we make the wrong choices we see it that's true as a parent true as a scientist when things don't work you're going to find out and I like that feedback from the world I'd like to take a quick break and acknowledge one of our sponsors function last year I became a function member after searching for the most comprehensive approach to lab testing function provides over 100 advanced lab tests that give you a key snapshot of your entire bodily health this snapshot offers you with insights on your heart health hormone health immune functioning nutrient levels and much more they've also recently added tests for toxins such as BPA exposure from harmful plastics and tests for PFAS or forever chemicals function not only provides testing of over a hundred biomarkers key to your physical and mental health but it also analyzes these results and provides insights from top doctors who are expert in the relevant areas for example in one of my first tests with function I learned that I had elevated levels of mercury in my blood function not only helped me detect that but offered insights into how best to reduce my mercury levels which included limiting my tuna consumption I've been eating a lot of tuna while also making an effort to eat more leafy greens and supplementing with knack and acetyl cysteine both of which can support glutathione production and detoxification and I should say by taking a second function test that approach worked comprehensive blood testing is vitally important there's so many things related to your mental and physical health that can only be detected in a blood test the problem is blood testing has always been very expensive and complicated in contrast I've been super impressed by function simplicity and at the level of cost it is very affordable as a consequence I decided to join their scientific advisory board and I'm thrilled that they're sponsoring the podcast if you'd like to try function you can go to function health dot com slash huberman function currently has a weight list of over 250 ,000 people but they're offering early access to huberman podcast listeners again that's function health dot com slash huberman to get early access to function I share and love your sense of optimism I was thinking about default settings that we arrive into the world with and it seems our deep at least to me that our default setting is to learn the young brain is poised to learn and then as we learn perhaps the only thing we need to be cautious of with respect to technology is how technologies might be kind of nudging our default settings in terms of behavior I thought a lot about this recently I thought how much time per day am I on my phone versus working on my book edits versus you know preparing for a solo podcast all of which I love preparing for podcasts and I I love being here doing podcasts and I love writing it's hard but this focus and friction thing together plus reflection I'm not trying to play psychologist here but in my mind I have this very simple mathematical formula that says that you know focus plus friction plus reflection and sleep not only give you neuroplasticity but those things combined are also what I'm hearing from you is that they they contribute to this thing called meaning like the pancake experience has meaning because there was some friction because it wasn't as good as perhaps you could go by from international house of pancakes which by the way their pancakes are not that good I'm just going to put that up there yeah come after me but like the pancakes they don't taste any they're they're deprived pancake experience in my in my view they step it up guys but that that friction of the you know your bagel I agree the bagel you made even though I didn't taste it was probably not as good as the bagel you can get in Manhattan they make pretty good bagels in Manhattan but the effort that you put into it and the thought and the fact that it it came from a mild deprivation you can go out and buy um bagels is you know that's the friction there's some focus there's a reflection it's still with you um and there's a there's a you extract meaning from it one way or the other or you discard the experience inside there was no meaning there and the and the meaning was no meaning then you just kind of go to the next thing but I think that the the human brain um as you you say it's interesting earlier you're talking about yellow bio black bio what's the other one flim and blood and blood those are the four components that for many years of people in medicine thought were like the critical elements of human experience and biology and health or lack of health and then we shifted as you point out to serotonin uh nor epinephrine aceto calling indopamine we'll go there in a moment but ultimately those are just the substrates by which we make bagels or we have a lasting experience of meaning with a advisor or more importantly a parent right um this is like the uh the alchemy of life and and neuroplasticity is really the the process right it's I always have to emphasize the to people that these things have names but they're they're not nouns their verbs plus to see as a process that that brings it together that's the the cooking of sorts so in any case I'm not trying to uh do philosophy here but there's so much richness in what what you're offering in terms of these these real real world very basic examples but they have real meaning because of what the context was and how you reflect on them now still so let's talk about those four elements not a yellow bio black bio flim and blood um gross um biologist sounds gross even though I'm sure those useful things uh I know it does useful things um let's talk about serotonin dopamine nor epinephrine and aceto calling in particular these are neuromodulators they modulate the activity of neurons they make them typically more active but sometimes less active you mentioned a few of the hubs in the brain that release these different neuromodulators I'm familiar with those but maybe you could step us through the way that you think about them uh and educate us on them because I I'm learning so much from you already today and I want to learn how you think about neuroplasticity and what these four kind of macronutrients of of neuroplasticity are yeah I mean they remind me of uh the sort of four fundamental forces of nature and then we're looking for the grand unified theory right so in physics you've got electromagnetism gravity strong nuclear force and weak nuclear force we're trying to put them all together we know they all exist but what do they all do individually how do they all work together they make tables I mean that's what all this stuff does um for me those four neurotransmitters began as a simple experiment searching for an explanation my my story of this is easy in the beginning I heard about one experiment I'm by Greg Records on the early 90s and a monkey is reaching out and having a vibration on the tip of his finger and if he pays attention to it enough he can double the number of neurons in his brain or triple or sometimes five times more neurons they respond to it touch the finger that's amazing that monkey was also listening to a sound that happened just as often but his auditory cortex did not change because he wasn't listening to the tone what was useful to him was the touch he'd pull his hand away and get a pellet reward based on the touch and the other the sound was a distraction so his brain learned touch not sound one of the other monkeys was randomized to be in the other group that monkey was also getting this finger vibrated but that vibration was a distraction and now the sounds mattered when the sound made a tiny change he had to pull his hand away not because of vibration because the sound and that monkey had no change in the way his brain processed that sense of touch on his finger but quadrupled the number of neurons in his brain that responded to that particular pitch because that particular pitch had information the time I was a biochemistry major and I thought wait I know the cellular basis of life there's all these cells it's kind of a big idea from the last century life is made of cells why who knows but that's a core idea and it's true DNA is one of the other core ideas how proteins work but how does a cell 1 100 billionth of me how does it know which I'm paying attention to it can't know everything with chat GPT it does know everything we send a signal to every cell we have a broadcast system every cell knows everything that's how it's built but with us a cell I didn't know of a way there was no biology then or now where one cell could know what is happening about everything the closest thing that was available was release of a cedar cooling we knew that if you took a drug for a hundred years we've known that blocks all these cedar cooling you won't remember anything nothing you're hearing on this podcast we remembered if you took a drug that blocked a cedar cooling he just won't remember anything it's an amnestic people used to give it to patients when they'd have surgery so they wouldn't remember all the horrible pain what is the drug the drugs anticholinergic likes cabolamine atropine these are drugs that block a cedar cooling just by preventing the receptor from the the neurotransmitter from binding the receptor these are now date rate drugs these kinds of things they're really bad because they block our memories and we need our memories and we knew a cedar cooling was responsible but that doesn't really explain how it works the fact you need it doesn't say what it's doing so the hypothesis was maybe the animals paying attention doesn't matter maybe it's simpler than that and maybe what's really happening is each time the animal tries pays attention focuses with that friction with that attention that at that moment there's a burst of a cedar cooling released so I mentioned male on the long recorded from those neurons and sure enough when animals doing this task those neurons fire so the question was if I flipped it around and said let me put an electrode in those neurons now there is no task I'm going to activate just those neurons while a tone happens can I also quadruple the number of neurons respond to that tone and it doesn't mean anything to the animal at all like I know it doesn't mean anything because there is no reward you know it was not hungry nothing is happening so that was the work I did with Mike Murray's neck and the answer is it worked was just incredible the brain the proportion of neurons respond to your finger or to a particular smell or to a orientation of light all those can be changed based on the relative timing of the release of neurotransmitters including a cedar cooling and the activity in your brain which is a very rich data source lots of information about sites and sounds and smells it has to happen a lot of times how many hundreds of times per day for many many days that's what happened to me when I squashed in those flies every day I'd go in and look at the same pattern and I close my eyes and I see it it didn't happen once it required that spaced repetition we know from psychology and neuroscience is required to change the brain and so okay I can change the brain with this one thing others came along and said what if instead of doing a cedar cooling I stimulated instead of nucleus basalus releasing a cedar cooling I stimulated locuserilius releasing over nephrine same thing happens wait a minute it's totally from brain area doesn't matter I release these neurotransmitters I also can quadruple it all right what if I did dopamine you also get an increase so the idea is I'm just labeling these things all these events I'm a wash in information everything I look every leaf that wiggles every breath of air wind against my face every bit of my shirt most that I ignore it doesn't matter but I'm learning what matters and what doesn't matter and a baby is doing it by fumbling around their fingers and hitting themselves and trying to get the bottle we're doing it by trying to figure out what gets a social cues what gets a reward or prestige or mating opportunities or safety or security and the way the neurons know the tiny tiny tiny fraction of me is this little release and this release is very transient it's not about how much there is it's about the timing of it and the psychologist knew this you ring a bell you feed the dog the bell dogs start to salivate so these classic experiments by Ivan Pavlov simply show that the brain can change why does the salivation change because of a ringing bell because that's the thing that leads to this event being useful it's useful to the dog to prepare for this activity and so you condition this particular synapse to be strengthened where normally bells just ring dogs don't care about bells bells don't matter it's just a church just the end of the hour ignore it but if over time you repeatedly teach then you make this change when we teach undergraduates what does acetylcholine do we will sometimes say it's the memory neurotransmitter and we say what does norepinephrine do will sometimes say it's the attention one and we say what does dopamine do will sometimes say it's the reward one and we say what does serotonin do will sometimes say it's the mood one and there's reasons for that and they have a lot to learn and making it simple is a good idea but the chance that any given word in english has a biological basis one molecule one cell type one rhythm is zero there's an infinite number of words we could have made there's a lot of complex biology there isn't likely in my opinion this is a rare opinion there isn't likely to be an attention thing it's just a word we made up to describe a series of phenomenon there doesn't have to be a gene for that we think there does there's a gene for everything there's lots of genes for everything so the way it works to bring this all together these forces all coming together is called the synaptic eligibility trace this is Alfredo Kirkwood's work and many others he's at Johns Hopkins but many people have contributed to this the neuron has learned the synapse has learned I need to strengthen long -term potentiation because there's a presynaptic input releasing typically glutamate on the postsynaptic cell cell is receiving it and because the order was right release glutamate and then respond I should strengthen but 99 .9999 times out of 100 I don't do it I just let it go I was going to strengthen it but then that wasn't important I just let it go a handful of seconds each hour matter and we're trying to pick which ones matter maybe it's a hundred but it's not it's not every second matters some small fraction and what we discovered is by triggering this release we're using the same way biology always works it's how you learned play violin I made a squeaky note I got something there was wrong I need to make an adjustment and what's weird is it's the same cocktail when it's a good thing or a bad thing acetylcholine or brinephrine serotonin dopamine of course changes negatively when it's bad and positively when it's good but all of these things dump onto the cell that postsynaptic cell spine is trying to figure out should I strengthen or weaken and they all work together in a very bizarre way to create that spike timing dependent plasticity and so it's a four -factor learning rule relative timing pre -post thousands of the millisecond is two of them then arrival on two G protein coupled receptors that's just the name they were given it's not a good name I don't think there's not an H protein coupled receptor that I know of but these G protein coupled receptors are running this computation super sophisticated computation way better than what AI's got and that computation means I can play pool or I can play I can learn to swim or I can learn to walk or I can speak French if I wanted to and the fact that these neurotransmitters are working together in consort is a surprise it seemed like they would likely do different things and my understanding of why we keep thinking that is because when I look inside my car everything in the car has a different purpose the brakes have nothing to do with transmission the transmission has nothing to do with power steering power steering has nothing to do with the muffler that's because the human designed it and the way we think about things is to make one thing that does one job one thing that does another job one thing that does not job biology evolution is a tinkerer and it just makes up live and die sometimes the wolf lives sometimes wolf doesn't live and we end up with this very messy thing where all these people pieces work together really well but when we try to give them labels what is the thing that's causing Alzheimer's what's the thing that's causing schizophrenia what's the thing that's causing stroke sometimes it's easy for stroke it's a blood clot causes damage to the brain but for the vast majority of things it's a whole bunch of nature nurture mumbo jumbo where a bunch of experiences stress anxiety plus a bunch of genes interacted but the part we have control over are these synopsis the brain as you know is mostly not going to get very many new neurons you get some new neurons but not very many most your neurons you got now you're going to die with but all those spines are turning over all the time just like all the cells in your face returning over every few weeks those spines are turning over and changing and reprocessing your memories and by understanding now how this works we think we can help people who are stuck so there's a large number of people in our society maybe because of social media but maybe that happened before social media who are really broken have really bad traumatic events fear of death and they just can't get over it they're stuck in a way that's not helpful it's called post -traumatic stress disorder and we're now switching this from the exciting knowledge learning the lab how fruit flies and worms and sea slugs work and finding out there's a lot of similarity how the mouse works and a lot of similarity how the monkey works and a lot of similarity how we work mostly the same the genes certainly the ones we've been talking about so far all the identical genes and all these species can we then make use of it and it's kind of scary because you think I want someone coming around and changing my brain but if I asked you and I said it was stuck just like if I said my bone is broken of course I want a doctor to put those two bones together put that cast on and help the healing process most ways we get injured we don't need a doctor scratch a wound you know get a cold doctor's not going to help you but for many of them you need someone to set that bone put it right and we're just now moving to this stage whereas first psychologists and lately now neuroscientists are learning how to reset those many people have a great fear of heights which is a smart thing to have you don't want to follow a cliff super bad you could die but for some people they can't work at a building they need to work at because their fear is so great my psychologist friends who been mastering this arcane art of cognitive behavioral therapy now claim a hundred percent cure rate for severe fear of heights people really it's ability not just afraid of high everyone's afraid of height you should be it's a smart thing that's adaptive but for maladaptive which is produced by some bad experiences typically they think it's not my field after decades of research doing it slightly differently they can make it worse which you don't want to do but they now found a path to rewire the brain and restore people people can now want airplane safely if you go get a therapy because some money got to work with a therapist but you can change your brain back and if you don't do it right you'll have that fear for the rest of your life that'll be part of your personality now we learn you can make that change for people with post -traumatic stress disorder a similar therapy cognitive processing therapy or prolonged exposure therapy will cure about 40 percent of people that's fantastic sexual assault a war go get therapy you got a good chance of being cured and never having this problem again that's fantastic they didn't use to be the case used to be 20 percent they made some changes and bumped it up to 40 percent for military it's about 20 percent chance it's a little bit worse it works less well in military populations for reason we don't really understand yet but the idea that a cure is possible that's amazing if we could have a cure that's what people want they want cures they don't be a little better they want a cure and so for some of the mental health conditions not the ones we chose necessarily some of the ones we stumbled upon we found out that that rewiring the brain is so possible that you can take symptoms and push them all the way to zero but what happens if you're in that group or you're in the 60 percent you go to the therapy you relive you work with the therapist you go through all the stuff you do all the work and you still have intrusive nightmares you still have great fear of this you still the pounding heart hypervigilance of wooden behavior all the hallmark signs the post -traumatic stress disorder what do you do there and you can't blame the psychologist you can't blame the patient they've done what they can do we now come to neuroscience and say well what are the new avenues what do you guys understand how could it get stuck how could it be broken and we usually think it was demons then we thought it was the humors that are wrong high or low now we think it's wires and the answer is those wires are hard to change neuronal wires the neuronal wires is synaptic connections it's hard to find the right one how is that there's 150 trillion of them which ones are that sexual assault which ones are that i .e.

1:38:39de attack i don't know you don't know but can we go through and develop a process to help work through and that's what we've been doing developing the tools where we use what we've learned in the lab not with a deep brain stimulating electors i did before but now switching and saying is any other way we can trigger a brief burst not of one neurotransmitter but of a bunch of neurotransmitters and one way we came upon is this way of using an electrode placed on the vagus nerve to trick the brain into thinking you're having a heart attack we only activate a few cells it's a very tiny current but normally your brain receives a signal saying my heartbeat my heartbeat my heartbeat my heart beat my lungs expanded my lungs expanded my lungs expanded and we say hope they didn't do that turns out that sends a powerful subconscious you're gonna aware of it when it happens but a very transient brief arousal signal if you got sleep out and you have to wake you up you're not breathing someone says hey wait you're not breathing we should wake you up you can wait for the hypoxia to set in or you can do it quicker this is a much faster signal and when we trigger a brief burst just half a second long that makes three out of four of those neurotransmitters active which ones?

1:39:49northern afrin acetylcholine and serotonin are all released interestingly dopamine is not inactivated rats don't like it or avoid it humans don't like it or avoid it it just doesn't matter because it's also conscious knowing what your guts are doing your heart and lungs who cares so that one is not connected to a rewarding pathway we're not aware of it but the combination of releasing those three neurotransmitters activates the appropriate chemistry it's the signal that the neuron is looking for and know it's not any one signal it's a cocktail as most things in the immune system are or bone formation or even regulating your hunger there's not one factor for anything there's 10 factors for everything now that we're learning that and embracing it we can send this signal in and at first it was just a dumb experiment repeating the one we had done with deep brain stimulation showing we could quadruple the number of neurons that produced a response to a given tone that's an ate laboratory curiosity but what's it useful for?

1:40:47well let's take our time can we make neurons have more neurons for a low tone or a high tone yes we can can make neurons get fast or slower yes we can we even played speech sounds to rats rats don't care about English doesn't matter them it's not relevant to them but if you repeatedly pair the word dad or the word sad the neurons will shift to favor responding to a human saying dad or a human saying sad just makes sense that's the statistical probability it matters to them my dog understands some English not all of it but the ones that are walk and treat and dinner and bed all those are sit those are all things that she knows we saw the neurons making those same changes and this began to get us more and more optimistic that you could use it to treat some condition we've now shown in humans that we can use physical therapy occupational therapy cognitive behavioral therapy and sensory therapy all of which activate neurons but they don't make enough change to get people to lose their diagnosis we're still not there yet but we've now gone all the way through animal studies showing that animals with stroke benefit from physical therapy but they don't make a complete recovery when we add this brief burst they make recoveries they couldn't otherwise make we did it with hemorrhagic stroke we did with a schemic stroke we did it with peripheral nerve injury we did with spinal cord injury and we finally said this is working so well we should go try this in humans fully expecting it not to work why would it not work because it usually doesn't work lots of things work under careful laboratory conditions and you show up in the real world and your stymied you can't figure this out and one reason for that is because in the lab we can adjust the condition to be just bad enough and the treatment can be very powerful and there's no side effects and all of the doctors get patients who show up they get the car accident they get what they get they don't get to make it and adjust and so it was very humbling to try to ask the first participants first ones actually had tenonus or tenitis the ringing of the ears later participants had stroke now spinal cord injury and post traumatic stress disorder and each case it's super scary because we start off with a 99 % chance of failure that's the chance a given new idea neuroscience works don't worry we've got lots of ideas so we keep testing them and luckily the public has been very supportive of us just keep trying keep trying that amyloid things not working so good for you keep trying don't give up my grandmother died of Alzheimer's so don't give up just because something's not working maybe it's going to work tomorrow these are really hard problems and now we're to point with FDA approval three years ago of vagus nerve stimulation for the treatment of ischemic stroke that people can make gains they couldn't otherwise made they can trial they want and they just can't get those fingers to work now they make gain are they cured no you can still tell they've got a stroke but what's interesting is the gains they made in a double blindable placebo controlled trial published in a Lancet it's only in 18 days 18 days you can't play violent very well in 18 days you can't bowl very well in 18 days in 18 days they were stirring their function their hand and now we send them home and we enable them to activate their own vagus nerve while they're doing gardening activities or fishing activities or doing the dishes and what we're seeing now is although it's slower they're continuing to make progress day on day on by activating this network and telling the brain this is really important the answer is it's not really important it's just gardening but we have to kind of lie to the brain a little bit and say look you're never going to get over this because the brain is very conservative it does not want to forget all of your memories because I want to forget your childhood doesn't want to forget your language doesn't want to forget all your skills so it's very conservative of what it changes and after injury in this case a stroke there's a hole in your head neurons are dead there's a problem I got to make big changes but I wasn't expecting this because in evolution if you get a hole in your head you just die there's no I see you no one has come in to save you you just die and so we never had the chance to practice getting good at recovering we now know we could make better gains and the paper you mentioned in nature same thing happened with spinal cord injuries people have had years ago spinal cord injuries they just they can barely move that we only pick people with some movement if there's no movement we have nothing to reward nothing to condition nothing to strengthen so we chose people who had incomplete injuries mean they still have some function but they're obviously impaired then we repeatedly paired what the physical therapists they're the real experts they said this is the right muscle you should be practicing but there's different muscles in your hand that do different things they measure what you can't do but you can kind of do and we practice that and then we the neuroscientist come in with an engineering approach or a brennaker built the tiny Vegas nerve stimulator and then we found physicians and clinicians who were like mine and said let's give this a shot and we didn't think it would work it happens to have worked and now there's a Vegas nerve stimulator full disclosure I'm an inventor of and shareholder in my university requires me to disclose that so disclose that now in a company called microtransplant will spin off from my university university Texas Dallas and now you can go to your doctor and he can write a prescription for you to get an implant to help your physical therapist do their job it's not like the physical therapist wasn't trying they're working hard it's not the person didn't want to get better but the idea that you could just practice your way out of something sometimes true many people making complete recovery from injuries but many people don't and we now have this little boost this little tool I think of it like a screwdriver if you're trying to fix your car you don't have a screwdriver all the knowledge and world won't do any good it doesn't do the fixing but it gives you a new tool in the toolbox so now physical therapists and occupational therapists can give that extra boost because physical therapy is fundamentally kind of boring move your fingers move your fingers move your fingers it's not really life or death we're adding this boost so that the neurons don't give up on it it's gonna take thousands of repeats and it needs to feel important and when you're learning to ski if you don't do it right you're gonna go tell me down the mountain when you're a baby and you're trying to walk you're gonna hit your face we're doing therapy safely so no one's actually in any danger but by tricking the system hacking the vagus nerve just these small number of stretch receptors from the heart and lungs activating those which people don't typically feel by activating those we send this signal release this cocktail of these three neurotransmitters and now the synaptic eligibility to trace instead of letting that potential strengthening go away it just keeps building and building and building and we're now seeing even years later after people have been implanted they're still making continual gains and that's surprising it seemed like they had a sentence no more progress you're an adult no more plasticity but that's inconsistent with what we know I can learn new things anytime sure but why couldn't you get better from stroke the whole your head was too great evolution didn't prepare you for that kind of injury now we're fine and we can make progress even with stroke spinal cord injury tenonus and post -traumatic stress disorder amazing and I have many questions so I want to first just briefly rewind to the topic of neuromodulators and just clear one thing up for myself it's really a question I have to say I'm fascinated and surprised by the fact that whether you stimulate the release of acetylcholine or dopamine or serotonin or norepinephrine you get the same effect which is essentially you get more plasticity from fewer effort trials basically you get the kind of learning that would the changes in the brain and learning that would occur over the course of many weeks or months you can condense down to days yeah even one day and I must say and I'm not saying this just because you're sitting across from me I have ten favorite papers in all of science and your science paper stimulating nucleus basalus while exposing animals to a eight kilohertz tone I believe it was and showing this at massive rewiring of the adult auditory cortex to over represent that tone when I saw those images I can still see them in my mind they blew and purple and like I know exactly what they look like and it's just like wow that was it went against everything we had learned in our neuroscience textbooks this wasn't supposed to be possible my critical periods are over these are adult animals shouldn't happen and then when I learned about the reckons own and mercenic work of the you were talking about of detail whatever the subjects are attending to either touch or hearing that's where the plasticity occurred and just to this day blows my mind I assumed it was all governed by acetylcholine um and I have a bunch of pet theories in my mind now about why nature as a tinker might have come up with different circuits that could do that but we'll save that for um you know over over a coffee offline discussion because it would just be a wandering discussion however there is this parallel universe to the one that you exist in um with neuro stimulation which is that many many people are interested in taking drugs prescription or otherwise that they can use to open the door to and enhance neuroplasticity and I've been positively struck by the data on psychedelics traditionally the psychedelics are LSD lysergic acid diethylamide and psilocybin both of which augments serotonin active specific receptors and the data there from the clinical trials speak to pretty impressive results in some trials in relieving major depression MDMA methylene deoxine methamphetamine methamphetamine we have to remind people these are illegal drugs a schedule one drugs at least at the currently pretty impressive results for treatment of PTSD provided in all these cases that you have proper therapeutic support going into these um these sessions during and afterwards we're not talking about people just taking these recreation yeah when I saw those data I just kind of went okay well it's neuromodulators opening the window to plasticity when I think about neuro stimulation now the way you're describing it I think okay it's an electrode or micro electrode or whatever it is stimulating plasticity and when I think of somebody working to as hard as they possibly can without it ingesting any psychedelics or any neurostimulate in the therapist's office week after week where these people who have a stroke or a spinal cord injury just doing their physical therapy just working as hard as they can to try and recover any kind of movement I think the same thing they're just neuroplasticity they're trying to get that little squirt of acetylcholine out in their brain and then of course there's this other parallel universe of people who augment acetylcholine through now oral nicotine I stimulate nicotinic acetylcholine receptor and on and on and so it seems to me that the requirements this is an and gate type arrangement you need neuromodulator present you need a particular pattern of firing in the neurons so that there's a chance that they they wire together or wire apart whatever you're trying to drive the circuit to do and you need a strong intention you need that friction focus from from the person so on the one hand it seems like we need specificity and that's where we're going to go next talking about the vagal stimulators that you you work on and are getting such incredible results with but on the other side of the coin it's like you just need these chemicals present so for instance if I want to learn something and I'm going to focus as hard as I can on it I will occasionally take you know two mill these are very low doses two milligrams of nicotine I don't do this lately I just didn't experiment last year where I was I didn't like it because it it made my throat spasm a little bit when I wasn't taking the gum the muscarinic receptor business explains that so I stopped but yeah it provides a stimulant effect but here's my question if we just globally raise acetylcholine by taking a drug do you get the the opposite effect as you get from globally taking decreasing acetylcholine activity by taking a drug which you said makes you forget if you just globally raise acetylcholine by taking I don't know what's a good example of a drug that will do that for NAL simers patient or for um I mean all of the drugs have been nicotine yeah all of the drugs have been useful increase acetylcholine as well as increasing there's a lot more dopamine apomorphine apomorphine you know people take apomorphine for various reasons it improves working memory we know this at least in the short term for people that have modest low dopamine going in if you already have high dopamine probably not going to do much but sounds like you just need to boost a neuromodulator or some small cocktail of of these forward neuromodulators and the opportunity for plasticity does indeed expand regardless of the entry point that you take is that your view as well because you're working in an area where and by the way I brought along one of these stimulators uh uh to this recording it Michael was kind enough to give me one I don't know he did you give this to me or are you taking it back to Texas with you okay this thing is smaller this is a little chip that is smaller than my pinky nail I hold it up for the camera um we can probably provide a link to an image of it in the show no captions for those of you're listening it tiny tiny yeah this would be inserted about three centimeters deep in an outpatient thing in and out of the clinic probably less than it less painful than a dental cleaning um if you especially if you like going to the dentist as little as I do um this thing is all about specificity it's all about not having to take a drug yeah where's the trade off what's what are the benefits what what are the uh what are the um drawbacks of going with a microstimulator versus I don't know I'm not saying people should run out and take a psilocybin or apomorphine but by the logic that you just need an increase in a neuromodulator it works my background was in biochemistry my degree from Berkeley isn't in biochemistry I just thought let's get the biochemistry right and people will get better and then I had to learn about the brain and the brain says it's the timing the psychologist that told us at the very beginning timing timing timing timing time just back to Pavlov you can ring the bell you can feed the dog but they have to happen at the same time and if you just reward everything that's similar to rewarding nothing so the real issue that I actually spent more than five years of my life trying to do this without a device so I had had success using the deep brain stimulator I said I don't want to put deep brain stimulators I can't imagine putting hundreds of thousands of people with deep brain stimulators it seemed like too much of a true many neurosurgeon say it's not it's safe no problem but I just thought there's got to be an easier way and so I did exactly what you said I said what are the ways to increase a psilocybin or apomorphine and serotonin my catalysis may include which things do it andphetamine of course nicotine all these things very easy cocaine all these things do it and it did experiment after experiment after experiment after experiment I still feel bad for the graduate students who did all of those experiments Adderall did Adderall did all of them paired with a tone and it just didn't change anything and that's because the tone only comes on once in a while and they're just ongoing activity neurons are firing if you're recording neurons they're firing all the time only one extra potential is the tone exponential the neurons firing at four or five hertz sometimes 20 hertz just pop it along all the time and then get one more spike when you record these neurons when a drifting gradient goes by or a scene or what it's not much more spike is action potential electrical firing of neurons which is just clarified yeah thank you yeah um and so how does the brain know which thing there's a hundred and fifty trillion connections which one am I asking for more of you gotta tell me which everything make more of everything that doesn't help the network so my understanding the world that I live in is sort of a post Aristotle four humors idea that it's not that there's too little or too much of these things it's the timing that matters and when I watch a really good coach they're really into that they're going that was it that thing right there that's what I wanted to pay attention to and back to the reflection thing like let's think back that was the part were you ready is there or whatever it was there were these moments of learning and of course there's an hour of heavy working out you know whatever it is on Spanish verbs or or on rock climbing but there's these moments where you're figuring out that was the connection we sometimes call them aha moments and we think maybe the neuromodular being released at that aha moment they are I can tell you a lot of experiments been done when you're having a oh my god something just happened those neurons are having exposure to those neurotransmitters so then the question is why doesn't it work that the brain rewires for that particular tone it kind of does it's not that it doesn't work at all and as you said some conditions are so bad that you can do very non selective things in the class example would be if you have major impressive disorder and you do electric involves of therapy we're not pushing your brain toward any particular goal we're triggering a seizure in the brain it's going to change the brain but we're not telling it which way to go and somehow people tend to recover from that in a better state than they went into it because it was so bad to begin with what are the statistics on electric convulsive therapy I mean at some of us are familiar with the end of you know one flu or the kukusanas who are jack Nicholson's getting you know he's bite barred into the process and coming out of like a vegetable that's not what happens right most people emerge from it pretty intact and you're saying much better in terms of their overall mood what percentage go into remission what percentage feel significantly better so we don't know the answer to that because the randomized control trials were not done at that time my colleagues who are psychiatrists say it's the most effective thing we have for people who are treatment resistant to all the other treatments so I don't have an answer for you normally we do a sham control and these people are nested as when it happens that they would never know which one happened the study is easy to do it's just you can't do it in rats because rats don't have depression and right now no one is signing up if you have a sign up for actual therapy or a 50 percent chance getting a therapy people tend not to sign up so the answer is not known if we did we'd get a responder rate in both groups we'd say let's say it's 60 percent or 50 percent response rate whether better and we get a sham response so I say it's 25 percent get better even we don't do it you'd subtract those two it's a 25 percent take the inverse of that and you'd get a number needed to treat a four that's how we now work on these medications we think about what's the difference in the percent that you're going to get better with the double blinded placebo control that data is not available but the general idea is the symptoms are clear people that day before that happens all those memories are gone you'll have no memories whatsoever so people do this 20 times that they typically do they'll lose 20 days of their life which they never get back 20 times they have to go through the ect many people will do electric shock therapy EST three times 20 times yes yeah well I thought they just go in the woods typically sessions of three is my understanding again I'm not practicing psychiatry so take this talk with your own physician typically do a sequence of them people as you know major depression have sort of a cycling pattern as most neurological disorders and psychiatric disorders do so they'll go in during a time when they're bad and if you do nothing they'll tend to be better later because you win in when they're worse but the evidence experienced from colleagues I trust is this is really working we tried everything else and I don't know because the studies have not been done we don't have the answer what the exact probabilities are unlike the other studies we've done lots of randomized control trials with cognitive behavioral therapy but the idea is you get a benefit but it's just suggestive this is still a pretty crude technology and practitioners of it they're more than happy to acknowledge that they want the seizure not be too bad because it's too bad so they have a ways to start the seizure and then stop the seizure they've optimized it so it's more effective now than it was in Jack Nicholson days it's not painful anymore because people are nested ties when it happened you don't need to be awake you don't need to experience it that wasn't an active ingredient what was an active ingredient is the seizure which is a storm of brains it's called a brain attack or neurons are firing synchronously all over the brain and releasing massive amounts of neurotransmitters at the same time that's generally something you don't want their choice of a seizure not to have a seizure you would choose not to have a seizure your child you'd rather not have a seizure but if someone is really stuck in a severe state and they're at risk harming themselves it's been determined by powers that be that it's better to try this and many people voluntarily do it lose a few days get better for months and then come back and cycle and do it again so that idea is not a ringing endorsement the fact if you do it again it's not a cure it wasn't pushing toward any particular thing I've got a number of things in my house that work kind of well if you give them a good whack across the top of it it'll start up a motor that kind of sticks you give it a kind of a whack but I'm not really fixing it I need to grease some bearing or something I but whacking it will also work so I think this is again date me the Gilligan's Island thing I coconut would fall on your head and you'd suddenly be better that's the level of sophistication but the proof of concept is it's the plasticity that's making them better we're used to think that's like the serotonin we have to take inhibitors worked by increasing serotonin therefore we can include a people's serotonin was low at depression and yet behold they don't have low depression let's have plasticity tool is this is so so important for people to hear because I think SSR eyes have been demonized and they do indeed have side effects they've also helped a lot of people with OCD but they are a tool to induce plasticity and then it becomes a question of what what other things are you doing to try and promote plasticity in particular direction I actually think it's an unresolved question as to whether or not things like psilocybin and other psychedelics MDMA is not really a psychedelic it's an empathogen but whether or not the experience that one has during the so -called journey or trip is actually the source of the change or whether it's the augmentation and serotonin and then the things that happen afterwards I guess it's probably both because those sessions tend to be very emotionally laden and so there's a lot of talk therapy work that can be done with a qualified therapist that carries immense emotional load and it definitely includes the components of focus and friction so in any case and reprocessing later we're talking about the reflection I think many people after one of these experiences they're now thinking about in a way they weren't they're putting it away and not we're not talking about that so for PTSD in particular avoidance is a defining hallmark it's a criteria you have to have in the manual that defines what this is so avoiding it is a problem and now you you freed people from that the work though being done the rewiring is probably really work they're doing it's now they're re -entering that environment they're re -engaging that relationship they're not avoiding in part because they believe but they can do it and it isn't harmful that's true it isn't harmful these are pathological avoidances that people are doing the question is can we come up with something better what are the active ingredients the experiments not yet been done is to appropriately blind people so there are many drugs that make people have a trip it's possible to enroll people who've never had a psychedelic before and then they will know you can give them a lot of caffeine they might think I guess that's what you know a piety is like they wouldn't know but that's not yet been done I think it can be done usually when people say experiments can't be done properly I get nervous I just we're too smart for that we made it the moon aback we can we can do an experiment so finding out we'll know the answer on stroke which we talked about before enhancing plasticity you mentioned prozac a fluoxetine is the name of the agent selective serotonin we have to inhibitor increases serotonin and has effects on brain driving or trophic and all the rest it looked really promising in animals many many published studies did the same thing we did which is why we didn't think our thing was going to work we took the therapy which we know is helpful practice using your paw that's injured and then add the selective serotonin we had taken inhibitor and the animals made it for progress and we did it again and again we did it in monkeys we did in cats we did it in rats and then we did it in people and all the people got better and then we did a large scale randomized trial and they didn't do anything so it was 1500 people with stroke we gave them prozac and you will not be surprised that the new onset of depression was slightly lower in the group we had active antidepressant that makes sense you may or may not be surprised that the group who got the prozac also had more hip fractures because of course serotonin is critically involved in laying down bone and so this is really bad if you're an old person that had a hip fracture so taking prozac has off target effects I didn't know that it diminishes bone strength yeah yeah so serotonin is really important the conger sites are the cells in the body that make bone and when you mess with serotonin you mess with those this is a a newly discovered thing for me I didn't know about is that Ritalin has effects on growth right so most people now are aware if you take Ritalin you'll end up being about an inch shorter this is just an off target effect many many positive benefits but there are some negative and you have to weigh the pros and cons so in this case we saw all the things we knew that project didn't mean they took the drug but their functional ability their ability with their hand which wasn't any different and why is that it's because the range of problems people have is so diverse people have all kinds of other insults the rats are all perfectly situated in the cage I got exactly the lesion and all the rest why do the first few trials work because they were small randomized trials with some you know confirmation bias or some other things implicit to them the food and drug administration is serious will this really work when no one knows none of the investigator get to see the data no one gets to look at anything when you run a phase three pivotal trial it's no joke and we usually fail and that's sad for us because we wanted to work but it's the truth and we just accept it sometimes we go back through and say maybe it worked for a subset and we're still doing that maybe some people did get a benefit but if that's true that means some subset might have gotten worse good let's select these people so I think there's a lot of failed trials we can go back to and try to figure out maybe we didn't pick the right people drug companies hope that the market is as large as possible but what we find in our animal studies is there's a narrow range you've done some beautiful experiments looking at how to get retinal ganglins cells to to regrow and the conditions need to be just right not too much crush not too little crush you got to get it right I think there are a lot of things we found really do work it's just we hope they worked as a panacea and they don't they might work for 10 percent the only other therapy for stroke is called constraint induced motor training say MT and the idea is you just put a glove over the good hand and you force someone to use their bad hand yeah this is Timothy Schallert's work from years ago yeah well I love that work because it fits nicely with what we know about recovery from visual deprivation exactly your one eye you lose vision in the pathways that that eye governs you once the eye is healthy again you open it up but you have to close the other eye you can't recovery from any kind of injury you have to be careful you don't over rely on the healthy limb so this is also true in the context of stroke yeah I love the the human weasel experiment I think things in neuroscience are only useful if they're counter intuitive if they were obvious why do we need neuroscience and the idea that a kid gets a big scrape over his eye he's three years old he's got a patch on his eye for three weeks and after the patch comes off and the eye is fine you need to tell his mom hey mom what I want you to do is put a patch on the other eye she will doubtless say but that's not the eye that was hurt and you'll say I know but I have to reverse patch to rebalance the eyes that's counter intuitive these guys did experiments in cats and monkeys figured out what it was and they now saved untold number of people's vision at least in one of their eyes but it was counter intuitive to do that now we don't reverse patch anymore we give some drops the eye drops make it a little bit blurry you don't have to block the eye entirely you can just do a drop that slightly blurs the eye by opening the pupil up and now the eye that was sort of behind catches up that is super practical super cost effective at the pain cost pennies super safe it's just an eyedrop I just full disclosure I had my own amblyopia experiences a kid and when I was a very young person I sat and tried popsicle sticks I had lazy eyes for business and then that ended up causing me a double vision and trouble reading when I was a very young child so your eyes are well aligned eyes are now sitting across from you so I know and I it was many many ophthalmologist ophthalmology department's point of view there was a it's just a little bit telling too much about me but mostly about my mother it was originally believed that only adults would go through this much therapy there's actually a paper written and I'm told on me as someone who would go through this therapy and completely resolve the symptoms it just takes a lot of time following popsicle sticks I had little lenses at I don't know I guess a six years old put little lenses and that would make it hard it was like eye -building for the eye the doctor told me you don't have to do all this we could just take your eye out and we'll stretch one muscle almost drink another one and we'll pop it back in and I went oh six I don't think so yeah that sounds really scary I'll do this one how's your binocular vision now totally fine totally fine you were able to place still within the choir in depth through session still within the critical period early not because of those experiments those handful of animals made the ultimate sacrifice so that we now know how to treat things so now getting back to these counter intuitive ideas how are you going to intervene we've got a kid with Down syndrome or some with Alzheimer's and they're slipping into dementia what he's supposed to do we don't know if psilocybin is the answer let's use it it's certainly counter intuitive but it may or may not be we got to run the experiments and find out so for fluoxetine it looked really promising there was a big initiative on stem cell stem cells looked incredibly promising for stroke for stroke yeah that's right that's a 1300 person said it's a meta -analysis it just didn't help or hurt it just didn't do anything we wanted it to work I wanted to work I'm a molecular biologist I want the cells to go in there and do the good stuff release the good juices but it's a practical matter and that's what I love about working with patients is they're just very practical they don't have it all in the race this that the other thing what is the pro and con and we're now getting the point we can partly because of your work have people really understand how they work don't take an antidepressant because it's antidepressant that's just what we called it it doesn't mean that that's what it evolved for that's a label you can say anti PTSD and say this must be anti PTSD because it's called anti PTSD we have to be careful about these labels antidepressants typically are selective serotonin reuptake inhibitors but some selective norepinephrine reuptake inhibitors some are both some have kind of complex off target effects but they're all lumped because of what they do and as you said whether it's in pathogens or psychedelics these are given names because of the things we see the things we see are real people see them and this is the fact that they have on mood on whatever they all happen the question is a practical one what will the long -term outcome be and we often don't know that for many many years we think things that are very valuable initially turn out not to be so valuable I always think of the pope with a flask of god knows what but I think it was cocaine or sigma foroiter whatever else taking these substances just fully convinced I found the right thing wait the pope took cocaine is my understanding again this is one of the things I learned in catholic school but yeah there were many people who thought many of these elixirs were really really powerful agents that were going to be useful and later people just said it's not working for me most people learn yeah you can drink your way out of a bad relationship but it's not really going to solve the problem I got to do other real work so there's a lot of short -term solutions as my point and the question now is how's it going to work long -term for getting through a crisis where someone is immediately suicidal we got to get them to that point and we will do whatever it takes to get them to that point now we're in the intermediate phase but a year later how are we doing it remains to be seen we're not yet years post trying these agents we're only now trying them because their list is schedule one they cannot possibly use because we tried them in the fifties you mean the psychedelics yeah I mean I'm encouraged by the the results of the trials on psychedelics and pathogens like so siphon and MDMA in particular I'm not just being politically correct here I think people need to be very aware that the the therapeutic support going in the therapeutic support during and the therapeutic support afterwards especially for this reflection piece what's typically called integration in the psychedelic journey space is vital and there are a few or more examples of very high functioning people who have crashed their mind in their life with psychedelics using them I don't know how they were using them but you know in an unguarded way you know I think they hold great promise because of their ability to augment neuromodulators yeah yeah the the again the question about what happens in the journey is a separate matter and I'm not qualified to answer that anyway but I just find it amazing that these four chemicals serotonin dopamine norepinephrine and aceto calling a loner in combination are not the only path to plasticity but they are necessary they're not sufficient but they're necessary and you know if a small little you know pinky nail size stimulator I realize I'm holding up something that looks a little bit larger like the size of a um of a like uh reminds me of that like lip balm stuff that you probably want to go skiing like that karmic stuff it's about that big but the chip itself is the size of my pinky nail um and if that can be implanted and it can stimulate my vagus nerve in a way that the brain thinks I'm having a heart attack I think we might scare people with that discussion but as you pointed out you're not aware of that right it basically it's taking advantage of a pathway that signals something's going on in the body but nothing you're not inducing a heart attack obviously and you're getting a burst of neuromodulator release and then there's a window that opens where you can learn stuff better whether or not it's new movement new knowledge how do I I want to be a subject in an experiment where obviously I don't have a stroke well not maybe it maybe it's not obvious I don't have a stroke but I don't want to stroke but I would love to be in an experiment where you're using this uh for more rapid learning do you have any intention of doing those kinds of studies we have done a bunch of those experiments much of this work is funded by the defense advanced research projects agency DARPA uh and they're looking for ways to enhance learning um that was called the TNT program I like it to sound uh exciting was um targeted neural plasticity training uh and so under some circumstances you can improve learning but under the majority of conditions you're already so smart the rats we studied are already so smart they just didn't help didn't help or hurt doesn't help you focus more didn't help focus more didn't make it worse didn't make it better now you can always wonder maybe we didn't do the conditions right we did hundreds and hundreds of experiments so it's possible though I don't know this for sure it's possible this is one of the few technologies that helps those who are least capable among us and does not help those who are most capable and the idea is the way we're activating this is still pretty crude like I'm blasting this whole thing this used to be called the reticular activating system this arousal network that releases all these neurotransmitters it was viewed as one system back in the day we later found molecular biology and and divided it into these different neurotransmitters but they all kind of get activated a lot they're highly covarian when they fire and release relations arousing signals but the way we're doing it's still pretty crude right I'm not activating individual fibers I'm activating the whole where does it get inserted the left vagus nerve on the cervical branch just right here final increase in your skin open that out put it in close it up it right if you feel you're you're jugular your carotid artery it's running right there how long from when I walk into the clinic to when I walk out with the stimulator and again no wires right it's wireless how long is that procedure you're anesthetized for 35 minutes so from open to close that part of it is half an hour typically people you know it's shorter than a haircut yeah is the actual you know I hope short I have a short hair but yeah shorter than a haircut right but the actual showing up and getting checked in and checked out it does take two hours or whatever it is I don't actually know that's a good question you do once you do once and you're done and when it's off it's off like the medications are maybe lingering your body having effects it only you're talking about specificity which you want to get back to the specificity it doesn't activate any other nerves than the one that it's on it's a tiny bit of current and how do I activate it so we put a band around you know it looks like both headphones are you know beats headphones around it that has got a coil is a coil in that device the two coils are aligned just like your phone you put your phone on you don't plug it in the coils align that now turns it on because the device has no battery the next generation the experimental device the the device that's FDA approved does have a battery and that's how it's powered our new device is much smaller because we're giving it the power and we're also signaling now the way we do that is we measure the forces someone's making with their fingers or their hand will make it a handle will measure the forces every person's different you got to meet them where they are every educator knows this where is this kit let's get them into their best zone so if we're taking a person this is all they can turn it's all the rotation they've got of their wrist five degrees that's fine I can easily measure five degrees you can do 90 degrees 100 degrees right but they can only do five when they're doing five sometimes they do six just for whatever reason I don't know why that's when I hit the stimulator who it's the stimulator the computer does it itself it's closed loop just like your air conditioning you know when the temperature goes up you don't have to turn so they can be at home doing this they don't need to be walking around with a researcher following that's right the nature paper was done in a clinic supervised but really the therapies being delivered by the computer measuring their performance tracking each individual person looking back for the last few minutes of their activities seeing what they can produce and looking to see what's in their top 10 percent what about tinnitus by the way is that the way it's pronounced or is it tinnitus most people say tinnitus okay emphasizing the it is the inflammatory part of it there's actually nothing inflamed okay I like tinnitus tinnitus most often called tinnitus I get so many questions about tinnitus yeah clearly people suffer from it when they have it and I've seen a few papers out there that maybe low -dose melatonin before sleep can help a little bit with certain forms of tinnitus maybe it's just the consequence of improved sleep and this kind of thing in anticipation of today's discussion I put out the call for questions about brain stimulation at tons of questions about tinnitus when you treat tinnitus using this little stimulator how successful is it and also how common is tinnitus and how do you do those experiments so how common is it yeah because it seems very common based on the number of questions how successful is your treatment and then what is the experimental manipulation look like yeah so how common is it very common I mean here in loss is common it's of course highly correlated with growing old which is a good thing wait those the same thing no they're not the same thing a lot of things accumulate to cause damage to the hair cells in your ear taking on antibiotics having a viral infection a traumatic insults all those things but the number one is just growing old so if you grow old enough things start falling apart and one of the things that falls apart of these hair cells these are incredibly precise the vibrations these things are doing are the width of one atom like that's how tiny the smallest vibration you can detect the hair cells only moving back and forth by an atom it's incredibly precise and so they get damaged they're just super sensitive when they get damaged it's typically the high frequencies they get damaged whether you're going to rock concerts or shooting a gun or or you know playing your horn loud it's the high frequencies where the things vibrate the fastest they get most injured and people start noticing they can't hear as well in a crowded restaurant or whatever else you go and get an audiogram with an audiologist and they'll tell you yes above eight kilohertz or above four kilohertz you now need 20 times more sound pressure to hear it okay you can still hear just not as good the thing is the brain is plastic as we've been saying is such a good thing but the brain being plastic means if nobody high frequency ever happens and low frequency things keep happening your brain is going to shift from the high frequencies to the mid frequencies and you're now going to end up with too many neurons in the mid frequencies right at the edge of where you can hear you get too many neurons the same thing happens after an amputation so you end up with too many neurons responding to the stump because the hands not there anymore so the hands not there anymore I'm not going to keep doing that the neurons find something else to do just like the smart little neurons that they are the problem is if you exceed some threshold if I take this microphone and put it next to a speaker you'll get feedback and because the number one input to neurons in the cortex are other neurons in the cortex not the outside world neurons in the brain mostly talk to themselves not the world there's very few neurons in the eye you know this but most people are surprised you don't have megapixels of resolution you got a kind of a smallish number but you're moving around and you're using it sampling here we have a situation where the way the brain is processing is over -focused and you start to get oscillations and neurons are fired together they start to wire together then you start to pay attention to it most of us have heard it my advice for everyone is try to ignore it because when you're paying attention to it you're listening to it you're fretting about it you're worrying about it the tinnitus you're really seeing our transgenders yes I see so people self amplify their own tinnitus by paying attention to that's right and the more anxious they are about it because they think I'm dying I need to go to the doctor which is smart you should look out for new symptoms totally true they think they're dying they think they've got a brain tumor and people are relieved after four months of worrying about it to realize get a brain scan you don't have a brain tumor some people do but that's pretty rare the vast majority don't but that worrying is the food to this particular cancer oh wow that worrying in the same way that avoiding going back to the site of an assault is the thing that produces PTSD avoiding peanuts can create a severe allergy dangerous allergy to peanuts we need the exposure we need the diversity we need that context that information is useful to us when we shield ourselves as we did from peanuts many people got peanut allergies now that we've gone back to exposing children you don't have that problem nearly if I don't work with boy scouts and so we have a big giant peanut allergy warning thing oh yeah every time you board a plane now they tell you we had one person on here this peanut allergy don't eat anything containing peanuts that earlier however you said that a major reason that PTSD persists is because people avoid reflection here we're saying you want to avoid thinking about the ringing in your ears if you have tinnitus that's right because that will amplify the circuits that underlie tinnitus in some cases you need to go into the event and work with somebody to you know parse the event and uncouple the emotional load such as treatment for PTSD in other cases focusing on the problem more and more becomes an issue I guess there's probably also cases of PTSD where people are preoccupied by it it's you know it's running like a script in the background that's or just pops up randomly so for PTSD cognitive behavioral therapists do five different things because people say you're going to expose me to this I'm going to get better it doesn't make any sense I'm already exposed I think about all the time but they're not thinking about it enough they're thinking about it where they're losing control so controls you know from some classic neuroscience experiments is really important getting shocked is not bad for it's getting shocked in an uncontrollable way where you're not in charge of it if you can influence it has some agency over it then I can make a story about it when I can reflect on it I know hey bad things happen but I have a role to plan it when I'm living in an abusive home and just random stuff happens there's no agency there's no control it's just random that is what is most damaging to people they're neurons and they're psyches so here we're having a similar situation whether it's post -traumatic stress disorder which is not tennis right they're totally different things but there's a similarity there's a commonality to them that your thing that you think is make you better is making yours and there are many ways we call this the prevent defense and football I'm from Texas so we play a lot of that let's make a big or ahead of the game let's change everything wait a minute bad idea let's just keep playing the game it was working oftentimes teens will lose because they'll change their strategy here if you've got pain your finger will now switch to analogy to chronic pain and I'll get back to your question about exactly how we're treating it what the treatment is if your finger hurts you want to do something about it your mom taught you find things pay attention doctors tell you pay attention let me know what the symptoms are but sometimes that paying attention can become part of the cycle you're feeding that got it and that is then this positive feedback loop work it's worse and worse and all the rest I'm not blaming people for paying attention to it it is damn near impossible to not pay attention to pain it's damn near impossible not to pay attention to ringing sounds they don't all sound like sound one woman told me she heard the sounds of bird chirping and a cave that's just a very specific thing that her brain is producing the pattern of activity and it's just super annoying who wouldn't be it easy to say oh just ignore it I understand how hard that is because our attention goes to that we need to make tools to help someone like that some of the people can reach levels the commonality is like 10 20 percent of people are gonna have tennis almost every one 10 to 20 percent that's a chronic number it's a huge number it's one of the most it's why I get so many questions about it yeah and they're worrying about it and focusing on it is exacerbating it it's the number one military disability so you get a 10 percent payment for the rest of your life so it's a billion dollars per year we pay for people with tennis you can't measure it objectively just like chronic pain you can't see it they don't want it but you develop it if you're a you know aircraft carrier launch and plans or you're not you know blowing doors if you're like headphones too loud playing headphones too loud these things are really a problem those cells will get damaged the brain doesn't know if you're deaf in the natural world you just die we didn't evolve to get used to loud sounds that didn't exist for thousands and thousands years that all came on with industrial revolution you know a thunder clap was like a loud sound nowadays you can go to a concert and you know be it a hundred and twenty decibels hundred and thirty decibels for hours at a time most people interestingly well don't get tennis we see the same thing in the rats when we produce noise trauma I can make everybody deaf that's easy but only half of them show signs of tennis so the way the brain rewires itself depends upon the specifics of creating that positive feedback loop inside the brain some more things happen Charlie Gilbert do these beautiful experiments with the retina we make dual lesions in the retina and all the neurons are going jump over some crazy place we now have computational models where we understand the neurons have no inputs they will tend to do dumb things they don't tend to do smart things because you didn't tend to have simultaneously paired retinal lesions so trusting the network to do the right thing is a good idea brains are smart but in the case of pathology by definition it's not doing the right thing or would have fixed it so the same thing is happening with cancer we get cancers all the time and we fix them what's unique about cancers that cause problems the two hit hypothesis is multiple things have gone wrong and the normal tools that eliminate cancer don't work same thing with epilepsy normally you have a little epileptic circle fire together the wire together and then you go oh let's get rid of this one we make a little epileptic focian get rid of them we make a little neuroses we make a little obsessive compulsive all the time and then we eliminate them right just like my daughter saying I need to remove TikTok or whatever it is we find it to be a problem we find a solution sometimes we're aware of it make a conscious decision but more often our neurons are just doing ourselves are doing it on our behalf behind the scenes when you have flagrant cancer it's going to kill the person it's typically because multiple checkpoint inhibitors have been blocked there's a lot of problems we think the same thing is true of brain diseases whether it's mental health problems or neurological two things must have gone wrong at least not just one thing perhaps this is one of the reasons why more and more we're hearing from people like Chris Palmer out of Harvard and others who are saying you know nutrition and diet that supports metabolic health can help resolve in some cases all the symptoms but in most cases some of the symptoms of mental health issues schizophrenia bipolar depression dementia things of that sort you know there was even an attempt to create a type three diabetes nomenclature for Alzheimer's that didn't really stick because you know you can put people on a ketogenic diet doesn't always improve their Alzheimer's and it certainly doesn't cure it but the notion that you have multiple things going on to give rise to dementia have multiple things going on to give rise to it any mental health disorder and so pushing or pulling on a neuromodulator or changing your metabolic health in the way that neurons can use glucose or rely on ketones for fuel it all kind of makes sense now that we understand and we're we're observing this more and more where where it gets tricky for me as a neuroscientist is the goal the hope was always specificity yeah right that the hope was this it was a little chip that you could put in that okay you have to spend the day at the clinic but it's not 20 electric shock therapy treatments it's not a drug that makes your mood better but makes you up but you know kind of like raises your levels of apathy or or nukes your libido or or changes your appetite in a direction you didn't want you know that the hope was specificity the kind of specificity that we're seeing with you know I'm going to get some flack for this I don't take these peptides but I think a large number of people who could not lose weight any other way are seeing great success by taking wagovae and ozampic and related drugs I understand they still have to exercise and some people feel like it's cheating and there's a bunch of issues related to insurance but let's face it you know sure there's some nausea but people who for years and years just struggled with their weight are finally bringing their way down into healthier range and hopefully they'll do the behavioral things that support them as well so as neuroscientists we we always wanted specificity so for someone with tinnitus who you know it's okay I'm not gonna I'm gonna try not to think about it but if I'm hearing birds and caves chirping in the background and I'm just trying to write or read I mean it's already hard enough to focus on doing you know on focus and friction so something an impediment like tinnitus is something that one would hope you could just really just you know delete out like you could a line of script and a word document so when you stimulate the vagus nerve using this device and you want to get rid of tinnitus what are the patients doing are they are you capturing exactly what frequency the sound is yeah so we we ask them what their frequency is because we do an audiogram we can tell what their frequency where they've lost are we don't know what their brain is required to play in their head but they're saying wait I hear it at that it sounds like you're doing a tone touching yeah you do a tone actually play like a low medium high tones and then they go wait that's the one the high tone then you dial it in you first have to teach them about octave confusion if you're a music guy you know I'm not a music I'm not a music but if you get the wrong octave you can actually it's easy to confuse one octave higher than we don't know what tone they're actually hearing so it's a little bit it's a teach them about some tones sound the same but they're just double the sound is the the point but once you can figure out what they're hearing we then want all the other neurons to be important so the idea we've talked about is that set of neurons is too important it's doing something really important why because you're paying attention to it must be important you keep paying attention to it so I want to reward everybody but this set so I play a low tone lower than the thing a high tone higher than it I'm trying to strengthen all the other neurons back in that science paper back in the day by playing multiple different tones it narrows receptive fields so in this nature paper from 2020 2011 which we first treated tenetists in animals what we saw it was most correlated was actually receptive field size the neurons become non selective which means they now all respond to the same input if you're really narrow you only respond to one little bit of the cochlea if you're broad which happens after damage because you're trying to respond to something now everybody responds to every wiggle and jiggle in the ear all these neurons are now amplifying that the brain is a massive amplifier and you get feedback so what we're trying to do is narrow receptive fields and shift the maps that are found in that big blue area where everything's the same way let's make diversity so you're trying to tune the piano and take out a few keys that's right that's right and this idea of diversity is something we didn't know about back in the optimization and specificity idea we had a culture of find the thing and get the thing now mercifully we're in a much more diverse idea we're learning that the training set matters stimuli are likely to be more complicated the idea that we wanted specificity we wanted treatments and neuroscience hasn't provided that i'll take exception with that with phenoketin area we have every baby born in this country gets a heel stick and you measure the level of phenolalan hydroxylase and if they don't have it we put them on a special diet so they avoid phenolalan and they don't have severe mental retardation problem solved right this is the this is the warning that many people have seen on their diet coke cans but they probably haven't explored us to what the meaning is that PEA right is for osses harmless maybe even beneficial confession here i take 500 milligrams of it every morning makes you feel pretty good it's a little mild stimulant i've been doing that for years but if you don't have the enzyme to work with it it can cause mental retardation right and before we just called everybody retarded and now we go away there's many different ways now the fact we treated one and it was a diet change doesn't mean we've treated all of them there's many other things that cause severe problems fragile x syndrome fmr1 different gene cause a different set of thing and you can't change your diet to fix it it's not the nature of it but the example we use from human weasel where you now reverse suture i've had lots of children just working with kids and point out to their parents do you see his eyes don't go right i never notice an ophthalmology professor in neuroscience can think doesn't everybody notice eye movements no yeah some people just don't pay attention that you point it out and they go get treatment whatever it might be and they're better yeah that we should do a public health service announcement here since we're reaching some people if your child regardless of age but if your child has a quote unquote lazy eye or an eye that doesn't seem to align quite the same as the other when they're fatigued or just naturally sits that way it's very important to correct that early once you get out past a certain age their components of the brain that can become permanently blind to it which doesn't mean they're going to lose more vision it just means that they're probably only seen correctly through one one eye so these and it's normal for babies actually to the development of the ocular muscles of the eyes they don't always track so well and fixates well sometimes it's self -correcting but they should really see a pediatric ophthalmologist sorry i can't help myself no no absolutely i have a my appointment as an ophthalmology so if i don't say there's my colleagues will be angry but a lot of vision can be saved by by simple patch or as you put like i drop interventions that only have to be done early in development and it's amazing how few experiments were done i mean they didn't do thousands of and they had a handful to the smallest number at a very specific question you know very specific answer so i do think the specificity has worked on the molecular side most people i'm not one disorder is to mostly be caused by a single solution that's the smart thing to do if it's some simple like in your car usually it's something simple when your car is broken there's usually one problem but in an economic system there's probably 50 problems there's probably not one thing that's the bad thing you got to fix a lot of things in an ecosystem maybe somebody removed walls and all they got to do is put walls back and it's easy fix but typically it's some big messy situation you're trying to better understand and i think i biologist we talked about that i read a book not too long ago on kelp sea kelp macrosis and like why does kelp live worthless it's just included hundreds of grazers things adding to it the story you've heard about sea urchins and otters is way too simple but it's okay it's a way to think about it but we just come to understand to take care of the natural world it's complicated there's not going to be this one silver bullet and that's the same of our brain i like that i'm fine with that my health my diet my whatever it's about diversity try to eat a bunch of things if someone is just eating potatoes and tater tots and chicken nuggets but that's all they eat yes you're going to need to supplement something they're going to have problems and a lot of people are because they're socioeconomic status is the big one that we don't talk too much about like the neuroscience to try and understand if you're poor what things are worth it and what things aren't it's just really hard to make these judgments easy to be apparent when you've got lots of resources really hard when you're facing latch key kids and expensive food and all the rest so that's specificity thing i think we've nailed it on cooling i think we've nailed it on a lot of these stories but does that mean we've got blanket cures for most neurologists i guess disorders no for tennis we understood we had a theory of what it was we ran animal studies we reproduced it in animals and then we cured it in animals and then we did the next step and it was not as successful as we wanted to so the answer was 50 % of people got 50 % better that is called 75 % of the problem is still there not very good in addition we had that's something called sequestration where the federal government shut down in a large military trial we were going to run got canceled so we just had recently that was years ago okay we're going this a long time so that but they're just hiccups along the way political or whatever else where we were going to invest in it it was the number one disability in the military so we were going to invest in let's treat it and then we got sidelined stroke at the advantage that unlike chronic pain and tinnitus we know exactly what causes it so my team switched to stroke because there's no controversy about stroke no one's faking it i can measure it very easily i can see the whole in the head i can see their functions with tinnitus and chronic pain you can't know spinal cord injury same thing you know what causes spinal cord they had a fight car accident or fall or boating accident for PTSD it's the only mental illness we know what causes it the diagnostic criterion a trauma is what causes you to have that thing by definition the others get different theories we got genes we got factors so we chose these for three very intentionally and we're now sort of working our way back saying if synaptic plasticity rewiring of new connection to the brain if that could be used therapeutically we know it can i mean that's how rehab works that's how people get better from drug addiction or cutting or whatever else they're doing someone talks them it's just kind of inefficient takes a lot of time a lot of money can we help the therapist be better therapist love neuroplasticity if you haven't talked to therapists but neuroplasticity they love them some neuroplasticity but then they're disappointed because it's like but i can't make everybody better and i can't make anybody all the way better mostly the time so how can both be true that's just how it is hard problem we didn't evolve with we don't have a great solution but we could do something about it this was true of cancer a hundred years ago we would just say grandpa got died of old age we didn't know that we're cells ravishing his body prostate cancer colon cancer cervical cancer we didn't know that we just thought he got bad his heart stopped he died that's what happened now we took it apart but it took decade after decade or decade and we first thought there was one cell type now we know it's a whole living ecosystem of cancer cells feeding each other alive and you can't just attack it one way you got to attack it multiple ways that's how i'm coming to understand these brain disorders they're really tricky bastards when you look at HIV you go oh that's a good one that's not just some virus that's not just some bacteria with some polysaccharide you can attack that thing is really really tricky which is why we don't have an easy cure for this communicable disease which we totally understand HIV it's just a particularly sneaky one but the specificity for all kinds of viruses all kinds of bacteria we have an amazing armamentarium for the brain we've got a couple i would say Parkinson's disease we know what causes it and the symptom is you don't have enough output from your motor system and so you can disinhibit the system with the deep brain stimulating nucleus and people everyone's seen the videos if you haven't go youtube Parkinson's on and off deep brain stimulator and you'll see people who are golfing and then can barely walk now you and i know as many people do those final neurons will eventually die and they will eventually be a problem you're not changing the death that's happening in a person with Parkinson's but you're given them years of new life that's fantastic for relatively cost effective tools cochlear implants same thing people are stone deaf they're not using they don't lip reading they can pick up a phone just like you and i have a conversation they are fully restored to normal hearing and conversation but it's a small subset the list of things we've cured is small but those are proof of concepts that if we understand it we can cure more not just alleviate not just treat but cure well i hear a couple of things and i'm in agreement with you first everyone needs to appreciate that brains are made up of circuits and networks and chemicals and it's very unlikely except for rare case conditions that there will be a one pill one drug type solution or that there will be a five pill five drug type solution to any neurologic or psychiatric illness sorry folks that's the reality i think uh you know the last 50 years of research into these things has has revealed that i'm also hearing that direct circuit stimulation holds great promise your work people with spinal cord injury tinnitus enhancement of learning in non -injured people some of that work has been done um not as much uh for obvious reasons treating diseases kind of the priority brain stimulation and neural pathway stimulation from the brain to body aka nerve uh vagus stimulation works but it's not the whole picture you also need very targeted training during the stimulation to know exactly what patterns of neural firing you're trying to notch out as we say and which ones you're trying to exacerbate um to overtake the the neural territory and then the third category which is drugs whether it's through a naturally occurring compound like a mushroom that grows out of the ground or synthetically do I have psilocybin or now a lot of the psychedelics um like LSD they're trying to manufacture variations on them that don't carry the uh hallucin hallucinogenic properties but perhaps can still work as plasticity agent so there's all all this is being you know worked on but drugs i mean maybe better ways to augment serotonin that are neither psychedelic nor assessor or eyes seems like that the the tripartite approach is going to be best it's going to be devices plus training plus drugs so that um someone can really boost the plasticity in the areas they want and they can suppress neural circuit function in the areas they don't and i i think when we're talking about this i think this is going to be in the context of stroke spinal cord injury dementia whenever you say autism i always get a lot of comments saying wait what why are we trying to cure autism we're talking about people with such serious degrees so far on the on the spectrum that they they need constant care from others they're they're not functional self injurious self injurious yeah this kind of thing i'm not talking about people who are on the spectrum and and functional i know many people i work with many people that are on the spectrum and functional so um and on and on so i think that if i were in charge and i'm not in charge but if i were controlling the NIH budget for neuroscience research i would be encouraging all three of these areas yeah as well as trying to parse the various circuitries i think it's all essential i will say that i'd been surprised how long it took for the adult plasticity work that you and mercenac and Greg Reckon's own and others did to really make it into medicine i feel like it it took a while not because he weren't busy working on it but because it didn't seem like there was a big belief in brain machine interface for a long time now we have neural link we have you we've got a folks like our friend Eddie Chang who's doing remarkable work and you know taking people out of locked -in syndrome i think it's starting to happen i'm very encouraged i have a new recently a new explanation it was frustrating to me being raised by these fathers like we both were who studied neural plasticity and talked about it and trained about it it was frustrating to me at first that people didn't get it i've come around in my way of thinking about this it was smarter to hope that it was going to be simple it was smarter to hope that drugs would work it was smarter to hope that a stem cell could be added that those ones all type it's just that's actually not unreasonable if your car is broken hope it's something simple don't start off with the more complicated one it sort of outcomes razor at a societal level the question is how long do you keep doing it and i think you're making this point um you got this one nice paper with uh uh add no associated virus gene therapy changing things these are all on the table all of them now some of them are more safe than others some more challenging but the combination therapy we have a combination problem and it's a pretty big problem whether it's obesity problem or gender disorders or developmental disorders anxiety disorders mood disorders um but we don't need to medicalize everything if you're fine you're fine but if you've got a serious problem these are not subtle conditions these are people who are really really really struggling they're willing to try anything and we have this obligation to store out what works and throw them a kitchen sink at it is not so great the FDA is having to wrestle with what does it mean you're going to do four different therapy let's just take a two combination therapy do i and i have to do a four arm study where i do one group who gets both one who gets just this one who gets just that one who gets neither statistically that really increases the cost so we say now let's do it where you do all the things you think are going to need it and then none of those things so even are we doing science experiments no we're trying to treat people so i think the pieces of the puzzle are there and to my mind the um the animal literature is clear it's complicated i mean i think about the number of genes that had you know for ocular dominance plasticity the change in the visual system with two eyes how many genes play a role in that many genes many times when i said here's a new gene that plays a role a new gene that plays a role it's complicated we didn't know that we really thought it was going to be like our designed world whether something simple or you fix it this uh grind stone isn't working as the water's not flowing in right turn in this thing and when you're fixing a car cars are complicated apologies to all my friends or mechanics but by comparison to the brain where you're talking about 20 ,000 different genes you're talking about billions of different inputs coming in every hour and it's stored in a network of trillions of synapses it's just really very complicated we didn't have enough humility but i now think even if we had the humility it was still smart to spend 50 years trying what we tried it just didn't work and now the question is what do we do next and i think there will be investment i think people who are enlightened and it's interesting patients really like the cochlear implant they know how it works it's not just take a pill it's these you know eight or 20 electrodes are on my nerve which is organized like piano keys and each one pushes a different button these are highest these are lows they kind of get it they take ownership of it and you see kids at the pool now and they got bright pink ones they're not bothered by whatsoever that's how i hear and so i think that openness the stigma's now gone before we had lots of stigma and for me the chemical imbalance thing creates a lot of stigma you're broken the only person you can fix you is someone who has the ability to prescribe medications doctors don't want that therapy they're not looking to be the boss the world they're intimidated bothered humbled by it themselves but that's the system that we were entertaining now that we have a situation when you're saying you have a brain i'm going to help you with it whether you're a coach a parent spiritual guidance person a therapist let's work to be who you want to be i think that's just a much more healthy way i think it's much more accurate it's much more how economies ecosystems work these distributed complex networks there's not usually one size fits all and what's nice is our lived experiences really matter what you think is working for you really is valuable and we're all really different you know the kinds of fiber supplements someone uses are the kind of sleep regimen someone else needs i had someone at UCSF who got you slept like four hours a night i was like this is impossible she made amazing things happen i couldn't do it she's still there she is she's phenomenal some people need very low sleep it's amazing to know some of those or they learn to get by on it i must ask because i can't help but ask there are a bunch of domains where brain machine interface is being talked about and used not to cure disease but to increase or accelerate plasticity some years ago there was a device and i'm not trying to pick on any companies here i have no stake in this but people were excited about it it looked like a headband that you could put over your motor cortex or sensory cortex while you were practicing your golf swing or your baseball swing or studying and the idea was that you were going to boost the levels of activity in the neuron sitting below that that band and that the rationale was you're increasing the you know the likelihood that those cells were going to fire fire together wire together i mean crudely speaking that the logic was sort of there there were a lot of pieces missing like the critical spike timing dependent plasticity that you were talking about before it's unclear if it impacted neuromodulation i don't know whatever happened to those sorts of devices it seems like it just kind of went the way of nobody uses them anymore i certainly don't see people using them nowadays there are a number of things we get sent these from time to time where the idea is that you're going to get vagal stimulation with a cuff that either goes around your midsection so these are non -invasive things or an anklit tool that provides feedback by vibration i've also recently seen a growing number of companies that are developing visors for enhancing sleep there i actually think there's an opportunity because some of them can engage i -movements there's some very interesting literature about specific patterns of i -movements making it easier to fall asleep very quickly look into the center future podcast of it but this is interesting but what are your thoughts on non -invasive tools commercial devices to boost plasticity and i'm talking about in the absence of any pharmacology just put this thing over your head put this helmet on and we're not just going to measure brain activity we're going to improve learning and memory yeah i mean the key the brain is information the way chat GPT got so smart is it knows everywhere we ever wrote to each other in every great book and all that it just had a lot of information and so the question is always what information is being added to the network and so medications tend not to add a huge amount of information they may buy as they may help but experiences you have and you learn to play violin you did a lot of stuff and that richness of information which we since the early days of information theory cloud Shannon we call it bits how many bits of information is it providing if something is always on it can't be providing much information so we it was a big thing it was called trans cortical direct trans cranial direct current stimulation TDCS there was trans cranial magnetic stimulation TMS each of these things had lots of great advantages but the total amount of information they were providing to the neurons was relatively small compared to listening to my voice my voice if i write this down you're going to see it's going to be megabytes i record one a minute's worth of me talking it's going to take megabytes to write down all the vibrations if you want to hear my pitch intonation if you just write down the letters it could be much smaller but there's still a lot of information so i think that's the way i think about it is how much information is being provided is the key unit so if the thing is on all the time and not really feeding anything back it's probably not helping much it's just like taking nicotine it's just like taking some nicotine gum it's raising aceto calling that's increasing the amount of fire but there's not enough specificity there in terms of timing it sounds like it might slightly bias the probability the learning event will occur but maybe one of the reasons these devices these keep surfacing these commercial devices keep surfacing and then disappearing is that no one is raving about the result that's right you would think if something was truly awesome it would take off and that's why decides not to regulate it it's not dangerous if you want to put a stimulator on that activates your stuff you want to wear pressure point bands you want to do copper these things come they go that's totally fine we don't just don't make medical claims if you make a medical claims that's crossing a line we now have to switch gears and say we're going to have to come down like a ton of bricks on this you haven't shown that and so there've been claims about video games online and companies have had to pay big fines because they made claims that this video game will fix whatever it is stutter is a big one I have a friend down the street has got a serious study right constantly asking what can we do we have a model we think we understand but everybody's different right people study for different reasons different times but clearly there's something in the brain they'll tell you that you ask them that they don't think there's a too much blood too much bile too much flim that's not the problem it's the wiring that's wrong and I'm optimistic about that that is something you can do something about but it is not going to be easy so I would say look for things that are closed loop that connect they're providing useful information that have sensors if it sounds too good to be true it probably is I think that's the sort of easiest way to say it um electrically activating your skin providing extra feedback um having a bar let's just take you're trying to learn to drive a standard you have a techometer of course it'd be easier to if you can hear the sound of the engine revving it's more information I know what I'm doing when it stalls if I can give someone feedback how fast was that ball spinning I've got a friend who owns a golf shop and I mean it's incredible the tools they can give you of what your spin slice is that's really useful information if it's providing useful information about what you're doing that just tends to be helpful if it's not it can be greatly distracting and there are certain circumstances where adding extra simulations extra sounds extra buzzers extra whatever whether you're trying to be a running app or anything else it can make you worse because you're now focused on the running app instead of on the let's just run uh so I think people are trying to figure out when should we instrument at when should we add this extra stuff when do you need the boost and when do you not and I'm frankly pretty impressed by the consumer they tend to figure it out they tend to be pretty skeptical as they should be and they tend to draw conclusions if it's working among a lot of my friends let's try it and they're pretty smart too there's no harm when I try it they can tell what's dangerous once not if it hurts I probably shouldn't do that if it doesn't hurt I try for a while but they tend to end up in the drawer but even cochlear or hearing aids even hearing aids often end up in the drawer because they're not they didn't get a really good one they didn't get a so technology has to be really quite good to make it that level of making a clinically detectable difference or habit forming or addictive because in the case of nicotine I see a lot of people who start with one three milligram pouch or gum per day and then pretty soon they're up to six and then they're half half a canister so sometimes the in an attempt to get the boost in energy or focus or whatever or neuroplasticity people end up simply with a dependence on the tool even if the tool didn't have much of an effect yeah we haven't talked about two things just from evolutionary part why do we get used to everything why if you take morphine you just need more morphine why why are we so good at that just we live in lots of environments we're gonna expose a lot of things our biology seems to have made us really pretty tough we live in all kinds of environment people live in greenland they live it's amazing it seems like in evolution we were in lots of environments and you might have been in an environment where the only thing to eat was poppy flowers and so okay I'm always surprised how not bad these things are I mean we had the crack epidemic and it was clear that all these babies were gonna be just a bunch of wandering zombies and then you know they were impacted but not nearly as bad as the worst doomsday scenario so I'm always telling parents babies are tough they're not as fragile as you might think things we do to ourselves not as fragile because evolution is prepared us for all these pushes and pulls which is a big shock you don't want to get a bunch of trying brain injuries but exposure to drugs it's remarkable what we can tolerate and still be fine there's an interesting idea that the psychologist first came up with but we see this in neuroscience as well the inverted you where you got to get it just right not too much so more serotonin or bornephrine enhances memories but you give more and now it degrades impairments why is that I've got a pet theory no evidence for this whatsoever that because we sometimes take an agent let's say eat some berries or something like that that then send us over the moon we have all these mechanisms that then shut down and say here are conditions what we don't want to change because rewiring your brain is dangerous right you might live through the food poisoning but you might now have a rewired brain that will be bad so it seems like there's these mechanisms where you want to get in our case it's the alpha receptors the neurobrnephrine low affinity receptors the ones that are easiest to activate are the alpha receptors you want those but you don't want the beta receptors and they're not very different there's this sweet spot this Goldilocks zone and the biology is always pushing us to be right in that and everybody recognizes that people do meditation mindfulness they recognize this trying to stay in this right sweet spot which is back that optimization we've talked a lot a lot about why is that that's how you're trying to figure out which is the most important thing not the max thing that might be something that's just pathological and weird not the minimum thing that's something you could just ignore but this narrow range of things you're trying to pick out it's like shopping you don't want to buy all the things in the grocery store I'm only looking for certain things well this is essentially if we're talking about psychedelics I mean you look at the counter culture of the 60s and you know I grew up hearing story I was born in 75 I heard stories about you know people who took LSD and stared at the sun and you know burnt their retinas out and I don't know if those stories are true or not there was a lot of fear based messaging on the other hand there were a number of people who took too many drugs and there were probably a number of people who should have taken more psychedelics like we could argue it both ways and I feel like now that we're sort of returning to this notion that plant -based compounds in particular still aside then MDMA MDMA synthesized it's not plant -based could potentially be valuable therapeutics for psychiatry the idea is not to give people just as much as they want or to give them experiences the idea is that it's very targeted it's dosage targeted it's therapeutically targeted and so that getting at that sweet spot I feel like what I keep hearing from you today is that you know there've been a nut by the way I love your optimism you're optimistic even about the mistakes we've made in the past that they've led us to this place now that we need to embrace the complexity but the tools remain in my mind the same that you've got in no particular order you've got devices to measure and devices to alter neural circuits in the brain and body you've got pharmacology drive certain chemicals up and certain chemicals down and you've got talking and thinking reflecting I mean that's basically what we've got that's the kit and I can't imagine a world where there's an additional tool I would just mention gene therapy I worked on genes and moved them around a long time ago my mom asked me are you sure we want that gene moved there luckily find out genes are moving all the time anyway it's not something we're doing this special but whether it's descends muscular dystrophy or Alzheimer's if we have to do that we'll do it I mean if someone is going to lose all their memories putting in a virus that's been genetically engineered if that stops me from losing all my memories and being a burden on society and my wife I'll do that in heartbeat so the toolbox we've created is just so rich I mean we've got these places like genealogy of farms they're just making up new thing I mean it's just such a Star Trek world where you can't wait a week and someone had invented some new thing but how to use them all together that's the problem you go look at a mechanics shop they don't have five tools they have 500 tools I got a friend I just there's so many drawers I can't even pull open all the drawers to look he's just fixing one car how do they have 500 tools and we're thinking we're going to need one or two or three four so I think you're right putting the right combinations having that reflection having that societal support knowing when am I going to go into this helping people make those decisions it's just it's complicated hard we're getting better and better at it I really think we are kids got a dog phobia someone says here's what we should do first lock in the way never show them a dog again okay we tried that didn't work and now your peer groups going to start telling you if you hide from it that's not the way to get better from it whether it's abstinence right that we had this people in a lot of pain people didn't think that was a good idea doctors UCSF in other places didn't think it was a good idea to be a pain so they made a kid no one knew there would be unintended consequences certainly some people did and there's lawsuits and jail time and all the rest for a few people but most people were just doing the right thing in Catholic school I also learned that road to hell is paid with good intentions we have to own that right Thalutamide was a drug we were going to prevent women from having you know nausea during first trimester we didn't know it's going to cause birth defects but we learned that lesson we processed it we took the humility from that you can't just do the easy way out the fact that it helps today doesn't mean you're not going to later look back and regret it and so we don't make change fast in our society democracies don't make change fast all these built -in ways to change slow so we've got time to make sure it works and I think it's frustrating a lot of people who say my son went to war and needs a treatment given what they need now and there's all these people saying hey let's hold on let's wait and see I'm comfortable with that that we're waiting taking our time the process takes loads it's frustrating to me I'll be honest how slow it is to do clinical trials we're running a lot of trials a lot of people I know with a lot of serious injuries and I can't move the next thing is that the work on this one is so slow but better to be too slow than to take this lightly and think we're just going to do all these things changing people's brains and this is literally who they are this is where their personality resides this is their experiences so I've been very pleased that the federal government is doing a great job of just saying let's try all the things like you said they're not against gene therapy they're not against farm big farmer they're not in big farmers pocket they're just saying like let's what's going to work we'll know when it works we'll all know when it works and for the things that it has worked phenoketinuria and you know cochlear implants government paid eight on a money on cochlear implants just due to the next thing next thing next thing next thing and now there's multiple companies that sell those and you can have that they tried that for the retina and so far correct me if I'm wrong there's still not an awesome one of my first students is a handy forward working on the retinal prosthesis it's still hard yeah they'll get there okay just showing this key damn planker there are other people working on this they'll the neural links working on it as well artificial retina or maybe bypassing the retina and quote unquote curing blindness it's going to happen because you know what you know what inputs you need you know what's needed in the brain I think also I'm encouraged by the fact that some of the smartest people in neuroscience and engineering are working on it certainly at neural link but also in academia I mean these are some of the best minds on the planet these are really like the the astronauts of science and in a lot of fields but certainly in visual restoration the miniaturization the wireless coding I mean all the problems that we had back in the day are they're sort of just evaporated the chips get smaller and smaller the power is better and better so I too am optimistic if you were blind today you wish it was ready yesterday sure but it's gonna take investment and it's heart problem we don't know how long it's gonna take whether it's Alzheimer's or you know it's schizophrenia we just keep investing and our country keeps giving it the entire world for free we're sequencing entire genome we just gave it away who does that that's what we do so I think that kind of thing when I see something like that we can monetize it we can patent it we can say you can't use that gene I invented that gene we're not gonna do it that way so I just think we've learned some good lessons about how to just innovate and share other countries are learning let's do it together it's way better together than alone so I'm optimistic this brings us together about to visit the problems are not unsolvable and once we understand that their synopsis right they're just connections and that those things evolved to change we're not making them change I'm not frankensteining it I'm not hacking it I'm not that's how it was built to do if we need gene therapy drugs devices counseling therapy if we need five or ten things that's how my normal life was my childhood was a lot like a lot of factors diet nutrition exercise all those things were shaping who I am and we hoped it was simple it wasn't simple would have been nice and a few things were but the vast majority now are complicated and it seems like that humility and that working with patients and letting them understand what are they doing no one's trying to control anyone's brain no one is trying to put in chips and and make you do things you don't want to do that is not the future of this is just not that scary thing find serious problems and see if we can help well I love your optimism and I'm encouraged by what you've done already and I should have known that if I sat down with what the author of one of my favorite papers in science one of my top ten maybe even my top five that it would be a discussion of the sort we just had I learned a ton from you I I went into this knowing a thing or two about plasticity I have some training there indeed but I learned so much and I'm thinking about it completely differently now to be honest this notion of needing focus and friction the reflection piece that what mental rehearsal will and won't do the value of a small device like this for patients that are struggling with any number of different conditions when paired with the appropriate training and and rewiring stimuli you've also reframed the way I think about drugs that can modify neuromodulators like nicotine and of course everyone should make a choice that's best for them but you know I could go on and on but I think it's evident to anyone that's listened to this conversation now that you're really out there to to help us and to to build things that are going to help humanity and you're you're doing that I'm very excited about the recent paper I'm getting paralyzed people to access more movement once again I'll provide links to those and other resources in the in the show note captions I know you have some open clinical trials as well maybe we can direct people to the possibility that it could be subjects if that's appropriate I want to thank you for the work that you've done that you're doing and that you continue to do and for coming here today and to contribute to public science education it's been wonderful for me and I know for everyone listening so thank you ever so much thanks for helping get this complicated information out to people really appreciate it thank you for joining me for today's discussion with doctor Michael Kilgard to learn more about his work please see the links in the show note captions 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 follow the podcast by clicking the follow button on both Spotify and Apple and on both Spotify and Apple you can leave us up to a five star review and you can now leave us comments at both Spotify and Apple please also check out the sponsors mentioned at the beginning and throughout today's episode that's the best way to support this podcast if you have questions for me or comments about the podcasts or guests or topics that you'd like me to consider for the human lab podcast please put those in the comments section on YouTube I do read all the comments for those of you that haven't heard I have a new book coming out it's my very first book it's entitled protocols and operating manual for the human body this is a book that I've been working on for more than five years and that's based on more than 30 years of research and experience and it covers protocols for everything from sleep to exercise to stress control protocols related to focus and motivation and of course I provide the scientific substantiation for the protocols that are included the book is now available by pre -sale at protocolsbook .com there you can find links to various vendors you can pick the one that you like best again the book is called protocols and operating manual for the human body and if you're not already following me on social media I am huberman lab on all social media platforms so that's Instagram X threads Facebook and LinkedIn and on all those platforms I discuss science and science related tools some of which overlaps with the content of the huberman lab podcast but much of which is distinct from the information on the huberman lab podcast again it's huberman lab on all social media platforms and if you haven't already subscribed to our neural network newsletter the neural network newsletter is a zero -cost monthly newsletter that includes podcast summaries as well as what we call protocols in the form of one to three -page PDFs that cover everything from how to optimize your sleep how to optimize dopamine deliberate cold exposure we have a foundational fitness protocol that covers cardiovascular training and resistance training all of that is available completely zero cost you simply go to huberman lab .com go to the menu tab in the top right corner scroll down to newsletter and enter your email and I should emphasize that we do not share your email with anybody thank you once again for joining me for today's discussion with Dr.

3:09:25Michael Kilgard and last but certainly not least thank you for your interest in science