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Speaker A: Welcome to the Huberman Lab podcast, where we discuss science and science based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Doctor and Professor Mark Desposito. Doctor Mark Desposito is a neurologist and ... |
Speaker B: Hey Andrew, thank you so much for inviting me. I'm really looking forward to our conversation. |
Speaker A: You may not remember me, but I remember you when I was a first year graduate student and you showed up at Berkeley. One of the first people to really bring functional imaging of the human brain to Berkeley. Bring a neurology and a clinical emphasis to the neuroscience studies there and it's really just bloss... |
Speaker B: Yeah, so there's four lobes. There's the frontal lobes, parietal, temporal, occipital, and the frontal lobes probably take up more, do take up more territory than the other lobes, probably about a third of the cortex. And within the frontal lobes, I don't. I'm going to use frontal lobes probably in our conve... |
Speaker A: Speaking of which, what are some of the symptoms of mild frontal lobe damage and severe frontal lobe damage brought about either through neurodegenerative disease or physical injury? I know we're going to talk a bit about both today or a lot about both, but how would lack of executive function show up, maybe... |
Speaker B: Yeah. First I should say is that it shows up all the time, because in frontal lobe, behavior is probably much more prevalent than we realize. Certainly, we think about it when you have a brain injury to the frontal lobes, and there's lots of neurological disorders like stroke and traumatic brain injury and A... |
Speaker A: Approximately what age does the frontal lobe circuitry come online, so to speak, when I see a baby? Babies can orient their eyes towards things, but they're rather reflexive in where they'll place their eyes. But by time, kids are three or four, they can certainly play with blocks or interact with other chil... |
Speaker B: Yeah, it's a really tough question to know when they're fully developed, because these studies haven't been done. When MRI was introduced and we were able to sort of image the brain in a noninvasive way, then studies did start to come out, trying to sort of map out at what age does your frontal lobes fully d... |
Speaker A: Sometimes can one see a lack of frontal lobe maturity in just the sheer number of physical movements that a child makes. So, for instance, in a classroom of, let's say, fourth graders, oftentimes there'll be a range of apparent ability of kids to sit still or to listen. Do we think that the kid that's having... |
Speaker B: Yeah, it's hard to say. The frontal lobe is a big territory, and we can get into it, but the frontal lobe probably has 25 different sub regions within it. And so, grossly, we think about the frontal lobes as the lateral portion of the frontal lobes, which is involved in these executive function, probably sup... |
Speaker A: So with the frontal lobes essentially serving an executive or CEO type function, goal directed behavior, intentions, cognitive control, these are the terms you used. Where are the rules? What do the rules look like? When I think about brain function, which I've spent a lot of my life thinking about, think ab... |
Speaker B: Right. Because that's a pretty common example of our patients, that they don't follow the rules. If you're sitting in someone's doctor's office and the phone rings, you know, not to pick up his phone, but the patients don't, and they may pick up the phone. There's this doctor Lamit, who's a neurologist from ... |
Speaker A: No, they know it's not appropriate. |
Speaker B: They know it's appropriate. Yeah. They say, no, I'm not supposed to answer your phone. But. |
Speaker A: Oh, wow. So they know better, but they can't control the impulse. |
Speaker B: Exactly. So it's not a breakdown that the rules disappear, it's that they can't apply the rule. They can't apply the rules properly. And that's true for a lot of patients, even with kids. You tell them, don't have anything to eat before dinner, because we're having dinner. And then they're sitting there havi... |
Speaker A: And those rules must be learned. Right. There's no way I can imagine that one can be born into the world with these rule sets. And I think about the two marshmallow experiment that's sort of famous now, where kids are offered to eat one marshmallow right away, or defer and get two marshmallows. These adorabl... |
Speaker B: Absolutely. I mean, definitely, you can learn strategies to not only sort of learn rules, but but how to apply goals. When you start to think about that task in particular, some of it has to do with sort of maintaining a goal and maintaining a goal at different, you know, time scales. Right. And children ten... |
Speaker A: Do you think that these algorithms and rules that the prefrontal cortical circuitry can learn and indeed does learn, can generalize? So, for instance, when I, my first year of college was a disaster for reasons that aren't interesting right now. But then when I came back my sophomore year, really spring of m... |
Speaker B: Yeah, I mean, it absolutely can generalize it. That's been a frustrating thing into trying to develop what we call cognitive therapy, where we try to improve someone's memory ability or we try to improve someone's executive function ability. The disappointing early results was always that, yeah, they get ver... |
Speaker A: Generalize to people's real life throughout the term limbic friction. Again, not a technical or clinical or official term in any way, but just a way to kind of capture some of the interactions of the frontal cortex with other circuitry. I mean, there's far more involved in agitation and challenges focusing t... |
Speaker B: Yes. I mean, the prefrontal cortex, what's so fascinating about it is that I would say it connects to every part of the brain cortex and the subcortex, and almost every part of the brain connects to it. So that, I mean, that right there tells you it's a pretty important area, and it has to if it's going to b... |
Speaker A: I'd like to take a brief moment and thank one of our sponsors, and that's ag one. Ag one is a vitamin, mineral probiotic drink that also contains adaptogen. I started taking ag one way back in 2012. The reason I started taking it, and the reason I still take it every day, is that it ensures that I meet all o... |
Speaker B: Yeah, I was just talking in terms of our knowledge of how changing. I wonder if your podcast, you talked about how tms to the prefrontal cortex can slow heart rate. So I meant in that sort of way. Got it. By influencing cortical function, obviously we can influence organs like that. |
Speaker A: Got it. So through some intermediate stations, yes. Not to be hyperbolic, but it seems like the prefrontal cortex, what here we're referring to as the frontal lobes, are essentially the seat of what makes us human and what makes us functional or dysfunctional in a given context. I recall there's a syndrome, ... |
Speaker B: Yeah, I think it's. We think about it as it's the frontal cortex allows us to take thought and move it towards action. And there's this disconnect between the knowledge and action and the separation of action from knowledge. And I guess I can reflect on my patients, you know, when I've seen a lot of patients... |
Speaker A: So much of things, like stoic philosophy and even online wellness culture, are about having routines overcoming reflex by just having recipes, scripts to follow each day. I certainly try to have my mornings be as what I call linear as possible. And I find it's much easier in the earlier part of the day to ju... |
Speaker B: Yeah, I mean, as I was saying earlier, the frontal lobes is a big place, and half of it is involved in these high level executive functions, but the other half of it is part of the limbic system, or we call it the paralimic system, that's involved social and emotional behavior. And so there's this intimate b... |
Speaker A: I will never ask you to demonize technology. I certainly use a smartphone from waking till sleep, generally not in the middle of the night, if I can avoid it, and I generally avoid it. But I'm trying to take what we've discussed thus far and superimpose the notion of smartphones and ask, what are the rules? ... |
Speaker B: Yeah, I mean, I can. You know, just historically, I grew up in a world when there was no smartphones as a resident. And so one of the most difficult things I do in practice is have to take care of patients in the emergency room, and there's a real emergency, someone's having gun control seizures or they're h... |
Speaker A: Yeah, I suppose I worry that too much of my time and other people's time, and especially young people's time, is engaging in an algorithm that does not generalize for adaptive behavior elsewhere. And by comparison, like a game of soccer with friends or something, it's social. Social media is social. It's phy... |
Speaker B: Mean, I think there is a risk, but what pops to mind having kids is watching them navigate in their cars to places totally dependent on Google Maps. I think you're probably old enough to remember real maps where you didn't know. |
Speaker A: I still have one in my car. I love paper maps. I love maps. |
Speaker B: Right, where you had to really figure out, you had to go to a certain place and you had to either look at the map or stop at a gas station and ask. These skills were something that you learned and you developed, and it was problem solving, and that's all gone now. I wonder even if sometimes if people even kn... |
Speaker A: Let's talk about working memory some years back, but still now you use working memory tasks and experiments in your laboratory. If you would be so kind as to explain what working memory is. And then I'd love to talk about some of the work you've done exploring the role of dopamine in working memory, because ... |
Speaker B: Yeah, I mean, working memory, it's interesting. I started studying it about 30 years ago, and I don't think I realized how important it was when I started. But what we mean by working memory is this ability to hold information in mind when it's no longer accessible to us. So if you tell me your telephone num... |
Speaker A: If we're going to think about dopamine in the context of working memory, is dopamine an accelerator on working memory? Is it a facilitator? I mean, what is dopamine doing for working memory? And maybe we could talk a little bit about the circuitry. I've talked about dopamine before on this podcast, but there... |
Speaker B: Yeah. Let me start with the working memory, the circuitry for working memory, because one of the important things about working memory is the other type of memory is long term memory. You can. Working memory is short lived. It's only as long as you're able to rehearse it, and then it disappears, whereas what... |
Speaker A: Am I reaching too far to draw an analogy between dopamine's role in working memory, that is, to keep information online, and the other established role of dopamine, which is for movement, for the generation of smooth movement, as evidenced by conditions like Parkinson's, where people lack dopaminergic neuron... |
Speaker B: Yeah, I think that's a good way of thinking about it. And one might wonder, well, how can dopamine be important for memory, but also be important for movement? And it's really simple. It's just that it's acting on different circuits, the neurons that go to the motor areas that carry dopamine. When dopamine i... |
Speaker A: I'd like to take a quick break to acknowledge our sponsor element. Element is an electrolyte drink that has everything you need and nothing you don't. That means zero sugar and the appropriate ratios of the electrolytes, sodium, magnesium and potassium. And that correct ratio of electrolytes is extremely imp... |
Speaker B: Right? Well, most people probably have optimal dopamine, but there's a significant percentage that probably have too little or maybe too much. And unfortunately, we can't measure it in the blood. There isn't a blood test that I'm aware of that can measure dopamine because it's stuck in the brain. |
Speaker A: Peripheral dopamine in the blood is not a good readout. |
Speaker B: It's not a good readout. Yeah. And especially when you're talking about dopamine in areas like prefrontal cortex. So we don't have a good readout. There's invasive procedures like positron emission tomography, where we can inject a radioisotope that tags dopamine, and then we can measure how much we can do a... |
Speaker A: So if you were to read out a string of a few numbers or letters, and I can remember all of those a few moments later, perhaps. Perhaps my baseline dopamine levels are moderate in the normal range, whereas if I couldn't keep that online, that might be reflective of lower baseline dopamine levels. Is that righ... |
Speaker B: Yeah. It's a very strong proxy for dopamine. So if you're working marine capacity is seven letters or numbers. When I say 437-1506 if you get the. Get them all back very quickly, you probably have more baseline dopamine than someone who has five. So it's a proxy for measuring someone's opinion. So that's one... |
Speaker A: Super interesting. Maybe we could talk about bromocriptine a little bit. And I'm not encouraging people to run out and take bromocriptine. Bromocriptine, as you mentioned, is a dopamine agonist. Relatively short acting. |
Speaker B: Yeah, four or 5 hours, 6 hours. |
Speaker A: So it kicks in about 90 minutes after. As I recall you saying, I've never taken it. How do people feel when they're on bromocriptein? I mean, when I hear dopamine agonists, I mean, there are a lot of illicit drugs like cocaine, methamphetamine that are increased dopamine, but then again, chocolate, sex and f... |
Speaker B: Yeah, I mean, one of the most disappointing things to me in my career has been that pharmaceutical companies have not picked up on this idea that we could improve cognition and very specifically improve counterprocess with very specific neuromodulators. The discovery that depletion of dopamine and not other ... |
Speaker A: I mean, it's crazy for several reasons. One is that the data are clearly there, too. These drugs are already established. It's not like they have to go through safety trials again. That's already been done, but mostly because regardless of whether one is a fan of the pharmaceutical industry or hates it, the ... |
Speaker B: I'm not sure. I mean, when I realized that I could test these drugs in healthy individuals, that they were, if I gave them in low enough doses, they were safe, and I had so much experience of them in patients that I felt comfortable doing it. Then I started asking pharmaceutical companies, do you want to get... |
Speaker A: On, so they're not buzzing, thinking, oh, this feels good. They have no, my working memory is better. |
Speaker B: They have no idea. They don't even know their working memory is better until we show them that their working memory is better. Love it. Yeah. |
Speaker A: So they're truly blind to what's going on. Bromocriptine is but one of the dopamine agonists can think of a few others. Kbergoline. Like other things like that. Do any of these dopamine agonists exert this impact on working memory, or does it vary by drug because different dopamine agonists hit different rec... |
Speaker B: Yeah. No, it's not specifically the drug. The reason for bromocriptine is that it's the oldest, and it's the one I was most comfortable with. I had to be comfortable with it clinically before I'd give it to undergraduates at pan or Berkeley. So there's nothing special. But other agonists work similarly. Ther... |
Speaker A: Maybe we could talk about a couple of other drugs that are legal and have FDA approval, are known to be safe in the right context. That, it seems would fit the bill here for improving working memory. One is wellbutrin. I can never pronounce that. As far as I know, it's a epinephrine or norepinephrine agonist... |
Speaker B: Yeah, anything that boosts norepinephrine can do it. The one that we've used that's most used is guanfacine, which is actually a blood pressure medication. So that's starting to gain some traction. In fact, I think there was a study with COVID with brain fog for Covid showing that improved symptoms with it. ... |
Speaker A: You're not actually doing it? |
Speaker B: We're not actually doing it, but it seems that way. The precision is not there yet. |
Speaker A: Well, it's great that you developed this cognitive task that can be a proxy for dopamine levels. The cognitive task, again being how many number letter strings somebody can remember, basically working memory performance. There are a lot of tests out there that claim they can assess dopamine and serotonin ace... |
Speaker B: No. And it's even more complicated than it seems, because the dopaminergic system is complicated because it's not only just the prefrontal cortex, as we talked about, it's also the basal ganglia. And so not only do we have to measure dopamine, just generally levels, we have to measure the balance of the dopa... |
Speaker A: So at a given, people will wonder how to do it. We're not going to go into too much detail here, but at a given brightness in the room, what we call luminance, the pupil tends to be smaller when it's bright and larger when you're in a dim room. That's sort of obvious. But at a given luminance, the more alert... |
Speaker B: Yeah, pupils. |
Speaker A: And you're like, okay, they're probably on a stimulant. |
Speaker B: Yeah. I mean, a lot of what neurology does is try to look for these windows into the brain. And so I think there are a number of windows into the brain that we're going to be able to develop that can reflect these neuromodulatory systems. So that's why I've been so interested in developing biomarkers, becaus... |
Speaker A: Have you ever tried bromocracie? |
Speaker B: Very early on, but it's such a low dose, you know, at the dose that my subjects were getting. But like I said, it doesn't. It's so low, you don't feel anything. And I should say with, even with patients that take it, they rarely get any side effects. Sometimes with these drugs, because there's peripheral, do... |
Speaker A: Does it change reaction time? |
Speaker B: It does. And that's always the question of how much of it is that we're just sort of speeding up. We're just making them faster. But for all the work we've done, it's pretty convincing that it's not just how fast you're doing it, you're doing it better. |
Speaker A: You might find this entertaining. Some years ago, I learned that athletes were taking bromocriptine pre Olympics and in the Olympics, I think it's a banned substance now, and the athletes that were taking it, don't ask me how I know this, but I could tell you offline, and I'm not one of these athletes, nor w... |
Speaker B: Absolutely. |
Speaker A: And certainly improves my focus as long as I don't drink too much of it. What are your thoughts? |
Speaker B: Yeah, I think it kind of gets back to what we talked about, there being an optimal level of dopamine in your brain. I think if you think about it as just more and more and more is better and that more is better than. There's really no end, there's really no. How do you know how much you should be taking this... |
Speaker A: That experiment was run in the eighties. It's called the cocaine culture of Wall street. In the eighties there was their movies about it and it doesn't lead to good places. |
Speaker B: Right, right. So. So I'm all for optimizing function. I want to optimize brain health. And if you have an underactive, you know, enzyme that's not that that makes your dopamine levels, then I'm all for trying to optimize that along with everything else we need to optimize in the brain. So if we could figure ... |
Speaker A: Right. Just bring out the best in people's abilities. And I'm so glad you mentioned sleep. I would say sleep is the bedrock. It's the foundation of mental health, physical health and performance. Without that, pharmacology might bridge you for an afternoon, but you're going to pay the piper somehow. And our ... |
Speaker B: Yeah, it's hard to know. I mean, I think certain drugs just improve general abilities. Either they speed how fast you can process it, or how efficient you can process or narrow the focus of your attention, and that just helps all abilities. So it's hard to say. I think just has to be more work on really unde... |
Speaker A: Maybe we could talk a bit about some of the disease conditions that you treat and the role of working memory and dopamine in those conditions, as well as other transmitter systems. One subject that we haven't talked about on this podcast previously, but is of tremendous interest to people is traumatic brain ... |
Speaker B: Yeah, I think concussion is much more prevalent than we realize. And the numbers have gone up and up, not because it's becoming more common, just as becoming more recognized. And I think we underestimated and trivialized sort of what a concussion is. It's just something that is just. You're going to recover ... |
Speaker A: What do you tell a patient who comes in and has clearly had a concussion, mild or severe concussion, you know, maybe car accident, maybe a sports injury, maybe they were knocked out cold, maybe not. But they're having some headaches, some photophobia, sensitivity, light, just feeling not right. I've had a co... |
Speaker B: Yeah. Well, first of all, I. I explain what a concussion is. What I found in neurology. A lot of what patients want to know is they just want to understand their problem. Not walking in, expecting a cure, just understanding what it is. Having someone understand what happened to them is very helpful and comfo... |
Speaker A: Do a 1% drop sounds like a frighteningly small change required to negatively impact life. So how about a poor night's sleep? What kind of drop in prefrontal cortical function are we looking at from? Let's say I normally get seven or 8 hours or six to 8 hours, and I suddenly only get three or four. Are we tal... |
Speaker B: I do think so. I do think that, yeah, it is significant. A poor night's sleep, and we all notice that. I mean, it's very obvious and it's hard to sort of quantify. I'm a baseball fan, so I can quantify it. Like, if you think about it in a pitcher and how fast they throw, a small drop for them. If someone is ... |
Speaker A: Yeah, I don't know why that is either. I think the brain is mysterious enough that most people and many clinicians just kind of back away with hands raised. But if you are in the field of neurology or psychiatry, I suppose, then one has officially signed on to try and resolve these matters. So for somebody t... |
Speaker B: Not only that, but one of the most common symptoms that patients, my patients with concussion have is their sleep is disruptive. And that's true in neurology. It's fascinating. Almost every neurological disorder my patients complain of their sleep and I started asking, not a lot of neurologists ask you how y... |
Speaker A: Keep the blind blind strong. |
Speaker B: But now it's, the idea is that you should really get up and moving as best. You gotta do what you can tolerate. You don't want to give yourself a head. You don't want to give yourself more of a headache or more light sensitivity. But as much as you can tolerate is the thought these days about sort of promoti... |
Speaker A: Yeah, I think the work that Merzenich and colleagues have done, and we'll provide a link to that. I don't have any financial stake in his work or products trainings, that is. But I will say, I think Mike's work has been tremendous. I mean, he is so far ahead of the curve. 20 years ago, everyone was talking a... |
Speaker B: Yeah, I think that's fair. I think of all the systems that decline with aging, not every brain system declines, but certainly the frontal executive system we're talking about is one that takes more of a decline than others. That's just how it is with healthy aging. Not surprising. It's the most complicated s... |
Speaker A: I love how candid you are about the medical profession, and I like to think it's changing. I don't know. Something happened in the 2020, 2021 era, I feel is just my bias, but I feel that the general public started becoming more aware of the things they might do to support their mental and physical health. Ma... |
Speaker B: Yeah. I mean, I think the big problem with brain health is trying to have a measure of what brain health is. And it's interesting to me, again, as a physician, thinking about it from a neurologist standpoint, when you go to your family doctor, your primary care physician, every year, from your yearly physica... |
Speaker A: No cognitive task. |
Speaker B: There's nothing. |
Speaker A: No working memory. |
Speaker B: They don't measure your brain at all. And it's not their fault. We haven't provided, the field has not provided them with a test of brain health. And so part of the problem is we don't have a measurement of brain health. I'm involved in something called the Brain Health Project, which is at UT Dallas, which ... |
Speaker A: Perhaps you get enough of it from your work. But given what you know about brain health and approaches to brain health, what are some of the things that you do besides sleep, exercise, nutrition, in terms of trying to optimize brain function? I mean, do you make it a point to read fiction? Do you make it a p... |
Speaker B: Yeah, no, I agree with that. I think when you have a busy career and you're doing many different things like teaching and research and seeing patients, I've always felt that I'm maxing out on full, my executive function is being tested to the limit. |
Speaker A: But you're like a professional athlete of the mind. |
Speaker B: Yeah, in a way. But then you realize that's not everything. There's so many other aspects. Everything emanates from the brain. So you start to think about what should I be doing in my life as a father and a husband? What should I be doing in terms of promoting social interactions with friends, and what shoul... |
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