How to Optimize Cognitive Function & Brain Health | Dr. Mark D'Esposito

26:54But sometimes we have you just want to pay attention to the faces and not the scenes, and other times we want you to pay attention to the scenes and not the faces. Well, even though it's getting the same bottom-up visual input, the prefrontal cortex will show greater activity to the relevant information. It's sending a signal to say, pay attention to the faces, ignore the scenes, or vice versa. So it's directing all of this information that we're bombarded with to what's relevant. But at the same time, it's also allowing us to switch. If we now have to go switch to another task, it says, okay, this is not important now.

27:33We're going to move over to this other task. So there's many different components of how it can kind of control behavior, but it does all of these things in this incredible way that we still don't completely understand, but we know that's the source of all of this control is coming from the prefrontal cortex. I'd like to take a quick break and acknowledge one of our sponsors, Athletic Greens. Athletic Greens, now called AG1, is a vitamin mineral probiotic drink that covers all of your foundational nutritional needs. I've been taking Athletic Greens since 2012, so I'm delighted that they're sponsoring the podcast.

28:07The reason I started taking Athletic Greens and the reason I still take Athletic Greens once or usually twice a day is that it gets me the probiotics that I need for gut health. Our gut is very important. It's populated by gut microbiota that communicate with the brain, the immune system, and basically all the biological systems of our body to strongly impact our immediate and long-term health. And those probiotics in Athletic Greens are optimal and vital for microbiotic health. In addition, Athletic Greens contains a number of adaptogens, vitamins, and minerals that make sure that all of my foundational nutritional needs are met.

28:41And it tastes great. If you'd like to try Athletic Greens, you can go to athleticgreens.com slash Huberman, and they'll give you five free travel packs that make it really easy to mix up Athletic Greens while you're on the road, in the car, on the plane, et cetera. And they'll give you a year's supply of vitamin D3K2. Again, that's athleticgreens.com slash Huberman to get the five free travel packs and the year's supply of vitamin D3K2. You mentioned connections between the prefrontal cortex and the body. That's the first I've heard of that. And I'm not challenging that. To the contrary, I'm just intrigued by it.

29:17I'm aware that the hypothalamus and some of these deeper brain structures associated with more, let's call them primitive drives, temperature regulation, hunger, et cetera, connect to the body. But what's the nature of some of the connections with the frontal lobes to the body? Yeah, I was just sort of talking in terms of our knowledge of how, you know, changing. I wanted to do 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. That, yeah, by influencing cortical function, obviously we can influence organs like that. Got it.

29:53So through some intermediate stations. Yes. Yeah. I mean, it's, you know, not to be hyperbolic, but I mean, 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, right? I mean, I recall there's a syndrome, Kluver-Busey syndrome, which has some vague similarities to how you describe frontal cortex damage. But there, as I recall, humans or animals with that syndrome will act in a way that's not appropriate to context, but more inappropriate. Like they'll try and eat a ceramic cup or draw with a piece of paper, which obviously won't work.

30:42It seems like with the frontal cortex, it knows that a pen is for writing. It just – the person might say, yeah, I know I'm not supposed to write this, but I'm just going to – or write with it, but I'm going to take your pen and write something inappropriate with it. But it's not that people forget that it's a pen. So it seems like it's drawing on the rule sets, but that something's intact. It's not like Kluver-Busey syndrome where like animals and people can try and like mate with inanimate objects, which is one of the more salient symptoms. I'll never forget that. Don't forget that from my cognitive neuroscience course, which you taught by the way, just throw that in there.

31:23So, yeah, so how should we think about this? And here I'm trying to get at a kind of a broader understanding of brain function and context specific behavior. so frontal cortex is like super sophisticated but it doesn't have all the information right it seems like someone without a frontal cortex probably knows that you write with a pen you don't write with a piece of paper yeah i i think it's you know we think about it as it's you know 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.

32:00And I guess I can reflect on my patients. You know, I've seen a lot of patients with damage all over the brain, and all of the families of patients who have frontal lobe injury always say the same thing. They're just no longer that person. They're no longer my spouse. They're no longer my best friend. They're no longer my father. Just something. They can't put it into words, but they're not them anymore. There's something that's changed. Whereas if you talk to a patient with brocas aphasia who has this inability to speak, they can't get any words out. This is a devastating problem. They're still the same person.

32:35Their personality hasn't changed. They feel the same person. They just can't speak. The way they get around in the world is different. Or if you take a patient with proceb agnosic, which is this inability to recognize faces, of course, the way they navigate around the world is difficult. And it's not the same, but they're still the same person. And so there's something really special about the frontal cortex that allows us to be, as you said, sort of who we are. And that's the difficult part. Like, how does the frontal lobes allow us to sort of take who we are and translate that into knowledge?

33:08So we're not, I guess in other words, saying just having knowledge isn't what makes us who we are, right? It's to be able to take that knowledge and present it in a way that allows us to live life based on our intentions and our goals and our desires. 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 just decide, here's what I'm going to do, write out a list, do things in a certain sequence.

33:54If I don't do that, I go nonlinear, as I refer to it, and we'll get distracted and things of that sort. But earlier you mentioned sleep deprivation can impair frontal lobe function. it does seem that as the day progresses and certainly in the middle of the night, it just becomes much harder to control our thinking, maybe even our behavior, and certainly our emotions. Is there a frontal lobe regulation of emotional states as well? I know you have some recent work on this, so I'd love to hear more. 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 paralymic system, that's involved in social and emotional behavior.

34:41And so there's this intimate back and forth between these two areas of the cortex. If you have just damage to these areas that are kind of in the frontal lobe, you will have many different impairments that we would call sort of social or emotional impairments, and their executive function will be quite normal. And then you'll have the opposite where patients with the lateral damage will have executive functions, but they seem emotionally intact. But in real life, when we have both these intact, they're communicating with each other. So emotion and contacts is going to influence our executive function.

35:17We make bad decisions in stressful situations or situations we're not comfortable with. It's where we might make a better decision if it's a quiet place. but it is something that we can I think you're right you can you can sort of get into a routine and learn how to do things you know if you haven't very much planned out but what's so unique about is how we can be flexible and adaptable right when when something novel comes up or there's something something unexpected comes up we can adapt to it and that's really what the frontal cortex is really important for not just sort of making these plans routines and setting all the rules with being able when things don't go right how to how to right the ship right i will never ask you to um demonize technology um i certainly use a a smartphone um from waking till sleep um 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, what are the algorithms that we're learning when we use these devices?

36:32And I'm not calling them adaptive or maladaptive. They're clearly here to stay. They've assisted in medicine. I'm sure it makes it easier for doctors to communicate on the ward and for clinic and it's so useful, right? But contained in the small device, there are things like, for instance, text messaging, where unlike 20 years ago, we can have four or five different conversations very quickly while boarding a flight. There's a task switching element that was just not present in our life prior to that. Social media in particular, this notion of being able to scroll. So if we really step back from this, move one's thumb and access hundreds, if not thousands of video content from each of which has a distinct context.

37:24And so I have to imagine that kids and adults have frontal cortices that are learning these rules. And the rule is move your thumbs, stay engaged, emotions, either positive valence emotions or negative emotions. I mean, it's a fairly limited landscape there when you really think about it. But the algorithm that's learned is to me doesn't seem exportable. It doesn't help me prepare for a podcast at all. I know that for sure. It doesn't help me go for a run. It doesn't help me listen with more focused attention to a family member or a friend or a significant other. It may make me more empathic or more angry.

38:08You know, we can speculate, but again, with no intention of demonizing social media, does it seem that the algorithms that are being run in our brain, I mean, are they neutral? Are they positive? Are they negative? Should we be worried? It doesn't seem like they translate to much else. I can't see a way in which they help us be better people in other domains. Whereas reading a book line by line, and then going back, oh, I didn't even remember anything from that page, going back line by line, playing a game of squash or something like that, I can see the real value of the rule sets that generalize.

38:46Yeah. 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 control seizures or they're having a stroke. And, you know, doing this back in the 80s or 90s and early 2000s, when you went down there and you didn't have any smartphone, you could only rely on what's in your head. And I could say now having the smartphone, it doesn't help me at all. It does not help me at all in making the kind of decisions that I have to make in the emergency room.

39:21I'm trying to decide, you know, what's the problem here? What's the differential diagnosis? How should I treat it? I'm just trying to make very, going through an algorithm, like you said, in a common sense way. And there's nothing on my phone that I can turn to to help me do that. It has helped with giving me knowledge. Like back in the day, I had to remember what the Dilantin dose was and have that in my head or go look for the piece of paper in my pocket. And so I can quickly pull up, you know, I guess I'm a little bit, you know, there's information that I can access that I don't have to worry about keeping every single dose in my head or keeping everything in my head, just facts in my head.

39:57But outside of that, there's nothing I can turn to that it's making me make better decisions. So I don't even need my cell phone. I don't go searching for my cell phone if I'm going to go to Mary's room or I'm going to take a phone call. So I don't see how it's helping sort of make your frontal lobes. It can't be your frontal lobes. I mean, it's another way of saying it. But on the flip side, can it help you optimize front-to-loat function technology? Certainly it can. We can maybe talk about it later. There are certainly – that's one way to get learned strategies is through a device that's easily accessible to you as opposed to a book or having a therapist in your house.

40:37Yeah, 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, you know, like a game of soccer with friends or something, right? It's social. Social media is social. It's physical. Social media is not physical. But we'll rule that portion out. But there's a rule set. there's goal-directed behavior. Presumably some of the things that happen in a game of soccer with friends translate to some other domain of life because it's a single context game of soccer.

41:22Whereas with social media, I don't know anybody that goes and looks at one account and that's it and absorbs the information, maybe comments, has an interaction and goes. It's hundreds or thousands of contexts. So is there any risk or perhaps benefit to being able to get this very detailed portal into so many contexts per unit time? I mean, the four brains never had done that in the course of human history as far as I know. Yeah, I mean, I think there is a risk. But what pops to mind, you know, 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 have one.

42:06I still have one in my class. I love paper maps. I love maps. Right, where you had to really figure out, you know, 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 mean, I wonder even if sometimes if people even know the direction they're going, whether it's west, north, or what town they're in, because they're just following the direction. So we'll see. I just can't imagine that that learned skill is not going to be detrimental to us at some point and generalize in a bad way, right, as opposed to a good way.

42:51So, yeah, it does definitely worry me. But like you said, there's nothing on the phone that helps you plan a podcast, nothing that helps me in the emergency room, nothing helps a professor when he's giving a lecture. So I agree with you that sort of having your head buried in a cell phone, I don't see it being healthy for your frontal lobes. 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.

43:32because this is so critical to everyday life. And I know dopamine is a bit of a buzzword these days, but the listeners of this podcast anyway are pretty sophisticated in terms of knowing that dopamine is not just about reward. It's about motivation and goal-directed behavior. And I think dopamine intrigues for a good reason, that it does govern a lot of our quality of life. So what's working memory? 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.

44:12So if you tell me your telephone number and I have to put it into my phone, you know, it's no longer there. You just told me, but I'll hold it in my working memory until I can punch it into my phone. It doesn't have to be something that comes from the outside world, I could hold up, you know, I can pull up my own, if I'm filling out a form and I want to pull up my social security number, I can hold that in mind too until I put it down. So when you think about it, it's a very important, you know, ability that we have that we do very flawlessly. And what I've learned more about working memory is the working part of it.

44:48It's not just this passive holding information in mind, but it's being able to do things with the information. It's being able to, you know, when we do a math problem, which we don't do that much now that we have calculators, but if you do that in your head, you're able to sort of manipulate the information and do the different parts of the problem. Or even if you're, you know, you're trying to find someone in a crowd and you're holding onto some face, you're able to hold that face in mind and cross-check it and search. And so there's operations to working memory. It's not just, you know, it's not just this passive maintenance.

45:22So when we started to think about working memory in that way, we started to realize how important it is for, you know, I think of it as the foundation for cognition. Just think about reading comprehension. You can't understand this conversation. You can't hold in mind what's going on, you know, earlier in the conversation or when you're reading a book, you know, remembering the sentence before it. So it just predicts all these abilities that allows us to read, to plan, to organize, and all the sort of executive functions that we're doing. We have to hold in mind rules. We have to hold in mind goals.

45:55We have to hold in mind all of these things in order to just carry out behavior. So it's really come a long way in terms of how people are thinking about it. I know that Matt Walker said that sleep is our superpower, but I guess one way to sort of use this term, while we're awake, working memory is really our superpower because it It allows us to translate, as we said, sort of our knowledge into action by holding this information in mind as we're thinking about what we want to do. If we're going to think about dopamine in the context of working memory, is dopamine an accelerator on working memory?

46:32Is 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's a good chance that some of the people listening to this haven't heard those episodes. So maybe we could just quickly review the three major circuits for dopamine and the one that's relevant for working memory. 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.

47:03It's only as long as you're able to rehearse it, and then it disappears. Whereas what we call long-term memory, if I remember what you had for breakfast or your vacation, this is information that gets consolidated and gets put into a more durable form that we call long-term memory. And the interesting thing about memory is that these are separate systems. Everything from working memory just doesn't pass into long-term memory. They're two completely different systems and two completely different parts of the brain that seem to control it. So working memory, the frontal cortex seems to be very important for working memory.

47:39When we are holding information in line, the neurons, the brain cells in the frontal lobes are active, and they stay kind of active as long as we're holding on that information. And they're more active when the information is relevant. And if we get distracted, they'll get less active. So the frontal lobes kind of track the memory that you're holding in mind. Another important thing about the circuitry is that if we're holding in mind, say, digits, the phone number, well, that information is in your back of the brain. And so the frontal lobes is sort of keeping information in the back of the brain active because it's connected to the visual areas.

48:21It's able to sort of keep that information active. And so what we've learned is that there's not these buffers in the brain where, you know, if you're holding verbal information, it's in this little buffer. And if you're holding visual information, it's in another buffer. The whole brain acts as a buffer. And the frontal lobe can call up any part of the brain and keep that part of the brain active as it's trying to hold this information in line. So the mechanism for working memory is just this persistent neural activity within the frontal lobes. And so then the question is, what does dope mean?

48:54do. Well, dopamine is one of the neuromodulators that are made in the brainstem, and it projects up to different parts of the brain. There's a system that goes up into what we call the basal ganglia, which is important for motor function. And there's another dopaminergic system that goes up to the frontal lobes. And what was discovered was that if you deplete dopamine, working memory drops. You get a significant impairment in working memory if you deplete dopamine. And if you replace it, then your working memory will be improved. And so dopamine seems to be a modulator to help this persistent activity stay persistent, you know, during the time that you need to keep this information in mind.

49:38Am 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 neurons or have damage to dopaminergic neurons and have challenges in generating smooth movement. What I'm essentially asking is, can we think of dopamine as facilitating physical movement through one circuit, but also kind of mental movement, thought movement, and I'm thinking about, for those just listening and not watching, I'm kind of rubbing my index and middle finger against my thumb, just keeping something online.

50:28It's sort of a movement of thought or information, and then you kind of chuck it away and bring about the next information. Is that appropriate? 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 is expressed there and boosted there, then it will be involved in movement. And lack of dopamine in the basal ganglia will lead to neurological disorders like Parkinson's disease that has severe movement difficulty.

51:02But when it's acting in the frontal cortex and expressed in the frontal cortex, then it's going to improve working memory. So it's just the nature of where the circuits are, where the dopamine is, that's allowing it to have different kinds of actions. And that's for all transmitters. The reason why acetylcholine seems to be more important for long-term memory is because it's projecting to the hippocampus, which we know is another area that's important for memory. And that's why acetylcholine doesn't boost your working memory, but dopamine does, and vice versa. So drilling a little bit more deeply into the role of dopamine and working memory, you did some really lovely experiments showing that if people who have low levels of dopamine increase their dopamine pharmacologically, I think the drug that was used was bromocryptine, that working memory improves.

51:55Conversely, if one depletes dopamine pharmacologically, working memory gets worse. but as i recall there was an important baseline that is important because it really mattered in terms of the outcome meaning if somebody already had relatively high levels of dopamine in this circuit increasing dopamine further with bromocryptine didn't impart a benefit and might have even made their working memory worse so there's a kind of inverted u-shaped function to this. How does one know whether or not their baseline dopamine is low, medium, or high? Ergo, how do they know whether or not they would want to explore going about increasing dopamine through any number of different approaches?

52:43Right. 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. Peripheral dopamine in the blood is not a good readout. It's not a good readout, yeah. And especially when you're talking about dopamine in areas like prefrontal cortex. And so we don't have a good readout there. There's invasive procedures like positron emission tomography where we can inject a radioisotope.

53:22that tags dopamine, and then we can measure how much, we can do a scan that actually shows us how much dopamine. This scan was originally developed to show Parkinson's disease, that you can diagnose Parkinson's disease by showing that there's less dopamine in patients that have Parkinson's disease by looking at this scan. Obviously, it's invasive. You're injecting a real isotope. It's expensive, and it's not something we could all do. But we had used it to show that it correlates very strongly with your working memory capacity. So how much information you can hold online, if you can hold four or five or six letters when I do a span task correlated with how much dopamine we can see in the PET scan.

54:01So that would be a way that we could do it. 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, might be reflective of lower baseline dopamine levels. Is that right? Yeah. It's a, it's a very strong proxy for dopamine. So if you're, you're working marine capacity is seven letters or numbers when I say four, three, seven, one, five zero six if you get them all back to it very quickly. You probably have more baseline dopamine than someone who has five.

54:47So it's a proxy for measuring someone's dopamine. So that's one way to do it. And that's actually how we did it in our original studies. We actually grouped individuals based on whether their capacity based on this behavioral measure was high or low. And And like you said, those who work that can only hold five or six letters, if we gave them bromocryptine, which was the dopaminergic agonist, we improved their working memory. We got them into sort of an optimal level. But those who were already high, we actually made them, we got them worse. And the moral of that story was that more is just not better.

55:24We're trying to get people optimal. And so the real question is, you know, if we want to get people optimal, like you were inferring, you have to know what their dopamine is. Where are you on this inverted U curve? Another way of doing it is through genetic studies. So dopamine, all neurotransmitters have to be broken down and reuptaked into the brain cell in order to be used again. And there's different ways of doing it. In some cells, it gets transported back into the brain cell and other places there's an enzyme that breaks it down. Well, there's an enzyme called COMT that breaks down dopamine in the prefrontal cortex specifically.

56:09In a large percentage of individuals that enzyme is either overactive or underactive. Probably about 25 % of individuals it's overactive and another 25 % it's underactive. So probably half the population. Now this is going to They're very, depend on where you live and where you come from and things. But maybe half the population either has an underactive enzyme or overactive enzyme. If you have an underactive enzyme, then actually more dopamine sits around, and you actually have more dopamine than others. And if you have an overactive enzyme, it's the opposite. So we've actually shown that if you now go and genotype people with a simple saliva test and figure out do they have this genetic, what we call polymorphism, where just one amino acid gets changed and the enzyme becomes either active or underactive, we can do the same thing as grouping them by their capacity.

57:06Those that have the low dopamine, we will make them better, and those who have sort of baseline high dopamine will make them worse. Super interesting. Maybe we could talk about bromocryptine a little bit. and I'm not encouraging people to run out and take bromocryptine. Bromocryptine, as you mentioned, is a dopamine agonist, relatively short acting. Yeah, four or five hours, six hours. 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 bromocryptine? 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 food increased dopamine, but the kinetics, the time course and the levels are different for each of those things.

57:57Dopamine, of course, being a currency of motivation and reward, not directly related to any one compound. But I would think that based on the data you just described that, and given the fact that there are a number of people out there with challenges in working memory, attention, task switching, et cetera, that there would be a strong interest on the part of the pharmaceutical companies at least, and certainly the general public, in things like promocryptine to increase dopamine to increase working memory, given it is our superpower. 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 cognitive process with very specific neuromodulators.

58:44The The discovery that depletion of dopamine and not other transmitters impairs working memory was made in 1979. When I heard Pat Conner, he's talked about this as a resident, I was just amazed that there could be a single transmitter can change a single behavior. I was seeing very complicated behavioral deficits, and it just seemed impossible to me that there could be such a tight link between a single neuromodulator in a single cognitive process and just opened the door for me that this really could be an incredibly beneficial therapy for anyone with executive function or frontal lobe function.

59:22But unfortunately, there's never been a pharmaceutical company that's tried to develop a drug for improving cognition to this day. And they, I mean, it's crazy for several reasons. One is that the data are clearly there. Two, 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 pharmaceutical industry in principle can make a ton of money doing this. So I would think that they'd be heavily incentivized to do it. So why have they turned a blind eye on this?

59:55I'm not sure. I mean, when I realized that I could test these drugs in healthy individuals, that 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 involved here? This should be done. I can't do this by myself. We need to have real trials and real studies of how this will help. And just their eyes would always cross and never got any sort of traction. It always went back to sort of disease. What disease are you curing? What's the market for it? Is it a Parkinson's disease thing?

1:00:37Is it Alzheimer's disease thing? And this has been a general problem with neurology. It's very disease-centric. It's always focused on how can we develop a treatment for Alzheimer's or traumatic brain injury or stroke as opposed to how can we develop a treatment for working memory dysfunction, which is a problem across diseases. So the answer to your earlier question is these drugs are very safe. We give them in such low doses to healthy individuals, they don't even know, they can't even tell the difference between the placebo and the drug. Really? They don't even know which one they're on. So they're not buzzing thinking like, oh, this feels good.

1:01:12And my working memory is better. 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. So they're truly blind to what's going on. Bromocryptine is but one of the dopamine agonists. You can think of a few others, cabergoline, 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 sort of hit different receptor pathways and things like that? Yeah, no, it's not specific to the drug. I mean, the reason for bromocryptine is that it's the oldest and it's the one I was most comfortable with.

1:01:52I had to be comfortable with it clinically before I'd give it to undergraduates at Penn or Berkeley, so there's nothing special. But other agonists work similarly. There's a drug that's developed with Parkinson's, which is a COMT inhibitor, which actually inhibits this enzyme that we're talking about, and that also will improve, will have the same function. There's been some work that norepinephrine also seems to be helpful with working memory. It's maybe not as potent as the dopaminergic. And that's the point I want to make, another disappointing thing about this whole field of the pharmacology of cognition.

1:02:32You know, I wrote a paper as a resident. Sometimes you're tending to say, hey, can you write this review paper for us? And I wrote one as a resident called the Pharmacology Cognition, where I looked at all the animal literature on giving neuromodulators, alstocholine, dootmine, or whatever. And there was a lot of animal literature sort of supporting that this would work in humans. But what was more striking to me was that it wasn't always just a single neurotransmitter. There were studies where you'd give dopamine and it wouldn't do anything. You'd give acetylcholine and it wouldn't do anything.

1:03:08But if you gave a low dose of both, it would be really effective. So these, you know, these gerontosis systems don't act in isolation. So we need to also study sort of how the combinations work. And that's where another, you know, where the pharmaceutical companies have the infrastructure to do these kind of studies. It's very hard to do in a single lab to do multiple drugs at one time, you know, and then try and look at trying to determine all the different interactions. Maybe we could talk about a couple of other drugs that are legal or have 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.

1:03:49One is Welbutrin, I can never pronounce that. As far as I know, it's a epinephrine or norepinephrine agonist. You just mentioned that increasing epinephrine may have a positive impact on working memory and to some extent a dopamine agonist. Is there any evidence that Welbutrin can improve working memory? 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.

1:04:29So there's actually some trials now that are looking at guanfacine. And so I would say anything that boosts norepinephrine would be helpful. But then again, I don't want to leave out the other transmitters. It's serotonin, you know, increasing serotonin, increasing acetylcholine boosts other cognitive processes. And then, you know, in a way they can help working memory. We talked about working memory being this foundation. Well, if you give acetylcholine and it kind of boosts memory, well, that can indirectly help your executive function. Or if you give a drug that improves your focus, then that can indirectly help, you know, working memory.

1:05:06So what I'm really pushing for is not just a single, you know, it's going to be one drug, it's going to be a cocktail. And we have to not only figure out what the cocktail is, but also figure out who we're giving it to, what's, you know, link it to the person's own makeup of their own neurochemistry. When we get to a point where we'll know, we can map out sort of everyone's dopamine norepinephrine serotonin levels, and then we'll make real progress in helping them. Because right now, I sort of say with my students, what we're doing is just, like cutting open the skull and just sort of pouring it onto the brain.

1:05:40We're not actually doing that. We're not actually doing it, but it seems that way. We're not... The precision is not there yet. 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 or 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 acetylcholine levels from a blood draw. I've heard of the Dutch test. I've never taken it. But a few minutes ago, you said that really one needs to do positron emission tomography imaging, which is fairly labor intensive.

1:06:22Most people don't have access to one of those. It's a clinical tool. So there are behavioral proxies. There's neuroimaging. But also to my knowledge, I don't know that there's any blood draw that will say, hey, your serotonin levels are low or your dopamine levels are moderate, et cetera. There are a lot of companies that market these, but are you aware of any clinical or other tools for getting an accurate read of neurotransmitter levels in a person's brain aside from neuroimaging? No. And it's even more complicated than it seems because the dopamineric system is complicated because it's not only just the prefrontal cortex, as we talked about, it's also the basal ganglia.

1:07:02And so not only do we have to measure dopamine just generally levels, we have to measure the balance of the dopamine in the striatum and the prefrontal cortex. There's a model of dopamine function and its relationship executive function that has to do with sort of the balance between these two systems. That dopamine in the prefrontal cortex is promoting sort of stability. It's keeping information in mind. It's keeping these representations stable. Whereas the dopamine in the basal ganglia, what it's doing is allowing you to update and refresh the information that you're holding in mind, this sort of stability versus flexibility.

1:07:43So if you have too much dopamine in front of the cortis, it could lead to a very rigid state where you don't let anything in. And if you have too much dopamine in the striatum and you get too flexible, then you can get very distractible. So there's this sort of balance of dopamine. So it's not just how much dopamine you have in your brain. It's how much, what's the balance of the dopamine. So I don't see a blood test as ever giving us that information, but I do see there being a brain test that can give us this kind of information of the two, or at least a proxy for it. So what I was thinking about when you were talking about asking this question, you know, for example, if you measure pupillary, pupil dilation, that's a pretty good proxy for the neurogenetic system.

1:08:26All right. 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, aroused somebody is, arousal is a general term here, not talking about a particular kind of arousal, then the pupil tends to be more dilated. It gets bigger the more norepinephrine is in the system. So if somebody's pupils are really big in bright light, that person's got a lot of epinephrine, adrenaline in their system.

1:09:11Do you use this clinically? Like when someone comes in and they have those big old pupils and you're like, okay, they're probably on a stimulant. 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 because really what a neuro biomarker is trying to develop something you can measure easily and simply and cheaply, you know, but gives you information about how the brain is working.

1:09:44And so that's a, you know, that's a neuroprinophane biomarker. We're in very capacities that don't mean biomarker, and we're getting better at that. But again, we're not putting enough emphasis on it, in my opinion, to really sort of help, you know, improve brain health. Have you ever tried bromocrypti? 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's so low you don't feel anything. And I should say, even with patients that take it, they rarely get any side effects. Sometimes with these drugs, because there's peripheral, don't mean they can get a nausea volume, but it's extremely well tolerated.

1:10:25You don't get anything feeling from it. Does it change reaction time? 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 sort of 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. You might find this entertaining. Some years ago, I learned that athletes were taking bromocryptine 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.

1:11:04And I'm not one of these athletes, nor was I supplying the bromocryptine. We're using it because they were sprinters and it turns out that a lot of the sprint races are won by being first out the blocks. There are other factors as well, but that reaction time, you know, hundreds of milliseconds are the difference between podium and no podium. And bromocryptine was one of the drugs used. It was not on the banned substance list. Just a reminder that every Olympics you see, there are lots of things being used that are not on the banned substance list. And I'm not trying to be disparaging. I think there's just a lot of interest in augmenting neuromodulation for nervous system function.

1:11:39Bromocryptine was top of the list at that time. I think it's on the banned list now. There's a lot of use of pharmacology now on college campuses and in high school and even in elementary schools and sometimes by parents for their kids to try and improve cognitive function. Most typically the use of Adderall, Vyvanse, Ritalin, and other stimulants, which are noradrenergic, dopaminergic agonists. Okay, so with the disclaimer, caveat, whatever you want to call it, that those decisions should always be made with a trained psychiatrist monitoring things. what are your thoughts about pharmacology for enhancing cognitive function, given that the landscape of society is challenging and people want to perform well, they need to be able to focus.

1:12:30We've got smartphones distracting us. And to some extent, you know, one could say, oh, well, it's cheating to use pharmacology, but a cup of coffee is a bit of a noradrenergic agonist. Absolutely. And certainly it improves my focus as long as I don't drink too much of it. Right. Yeah. What are your thoughts? Yeah. I think it, you know, it kind of gets back to what we talked about there being an optimal, you know, 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, then there's really no end, there's really no end.

1:13:06How do you know how much you should be taking? That experiment was run in the 80s. It's called the cocaine culture of Wall Street in the 80s. There are movies about it, and it doesn't lead to good places. Right, right. So I'm all for optimizing function. I want to optimize brain health. And if you have an underactive enzyme 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 out who is sort of on the lower end and boost them up, I'm all for that. The problem is we don't know if they're on the high end.

1:13:43And some of these athletes were actually making themselves worse. We know for sure. I mean, these are healthy Penn and Berkeley undergrads that we made them worse on working memory tests. By increasing their dopamine. Just a little amount. Just tip them over. Just a little amount. And so without the knowing, then it just seems like it's not well-informed. The other thing is if we're going to do this, we should do it right. I think drugs like Adderall and Ritalin, they were developed because they helped patients, but they weren't necessarily developed with knowing how exactly they worked. I mean, that's how the pharmaceutical company works.

1:14:23SSRIs too. Yeah. I mean, it works, so let's do it. I'm all for that as a physician. But if I had my choice, you know, drugs that boost up multiple systems, all the catecholamines, the ones that boost up dopamine, epinephrine, and norepinephrine, I would steer away from those because you have no control over how you're modulating the system. Again, I was sort of talking about a cocktail. It may be a little bit of dopamine and a little more norepinephrine, but if you take something like Ritalin-Aterol, you're just getting the same amount. So it's kind of, if I was to start to sort of experiment, then I wouldn't use Adderall or Ritalin as the drug that I think would help, even though they're clinically sort of useful.

1:15:02I use things like bromocriptine and guamfacine where they can modulate a very specific drug. And then, yeah, then the goal is to optimize. And that's what we're trying to do with cognitive therapy and everything, sleeping better and better nutrition. All of these are aiming to optimize, not reach some super human potential. Right, just bring out the best in people's abilities. Right. 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. I mean, without that, pharmacology might bridge you for an afternoon, but you're going to pay the piper somehow.

1:15:43somehow. Our friend and colleague, Matt Walker, obviously has been beating that drum for a while. What about drugs like modafinil, which are thought to be true cognitive enhancers, as opposed to drugs that just kind of are designed to ramp up levels of alertness, as many of the drugs we're discussing do? 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 this has to be more work on really understanding what specifically these drugs are doing.

1:16:28That's why the dobernerg story has been so interesting because it's a very specific effect with a very specific mechanism. And I like to see that be done with other neuromodulators. 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. You know, one subject that we haven't talked about on this podcast previously, but is of tremendous interest to people is traumatic brain injury or concussion, even mild concussion. and before we were recording today, we were talking about football, but just wanna remind people that football is just one instance of an opportunity to get a concussion or traumatic brain injury.

1:17:17Most traumatic brain injury and concussion is not due to football. It just gets a lot of the attention, but you've got bicycle accidents, car accidents, playground accidents. Maybe you could list off a few more, but how common is TBI and concussion? and maybe you could just perhaps list out some of the other situations where you see a lot of this, that it's a bit more cryptic, that people wouldn't necessarily think that sport or that population gets TBI, but they do. 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, it's just becoming more recognized.

1:17:58And I think we underestimated and trivialized sort of what a concussion is. is that it's just something that is just you're going to recover from it. I mean, still the old-school thinking by a lot of neurologists is that everyone gets better within a couple of months. Just wait it out, and you'll get better. That's just the normal time course of concussion. But as we've studied it more, we've realized that there's actually quite a large percentage of people who a year out, they're still suffering problems. They still feel like they're not mentally clear, and they still are sensitive to light and they still feel a little dizzy and just a host of symptoms that just one year later after a concussion where they didn't even lose consciousness, you know, that's something that they may not have even talked to their doctor about is lingering.

1:18:51And so it's a real, we call this persistent post-concussion syndrome, and that's the most worrisome to me because it is true that most concussions will recover. Luckily, the brain is incredibly resilient, incredibly plastic, and it will heal itself. But there are a lot of patients where it just persists, and those are the most worrisome to me because we don't have very good interventions to try and help that. And I don't think we take these patients very seriously when they're complaining of something that seems very vague and not very specific to most doctors. What do you tell a patient who comes in and has clearly had a concussion?

1:19:30um 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 you know sensitivity light just feeling not right i've had a couple of these um unfortunately and you just feel off you don't feel quite right um and some of that manifests as focus issues this was some years ago i like to think i'm through it i've had scans and i'm good um so thank thank goodness um but what do you tell them besides don't get another one? Yeah, well, first of all, 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.

1:20:13They're not walking in expecting a cure. Just understanding what it is, having someone understand what happened to them is very helpful and comforting. So what we mean by concussion, and in the clinical world we use mild traumatic brain injury kind of synonymously with concussion, it basically is a tearing of axons. The brain cells have these long fibers that communicate with each other, and they're called axons. And when the brain violently moves forward and backwards, if you're in a car accident and you have your seatbelt on and you suddenly hit, you go from 50 to zero, your head violently goes forward and violently goes backwards.

1:20:52and that angular force actually tears and stretches axons in the brain. So if you've had a concussion, you have torn some axons. I mean, luckily we have billions of them. And so if you tear a couple of thousand, you will recover, but you have torn axons. It's a real brain injury, even if you haven't lost consciousness and you've only had symptoms for a couple of days. and there's a correlation the longer you've lost consciousness and the longer your symptoms last the more axons you've torn there's kind of a direct relationship between the two so the mechanism is these torn axons so now nurses don't communicate with each other different brain regions are not communicating with each other and it turns out the most common place for axons to tear is in the frontal lobes and so now we talked about all these things that the frontal lobes do to orchestrate the rest of the brain.

1:21:52Well, it has some injured pathways. And that's why a lot of the symptoms that patients have are these kind of mild executive symptoms. This mental fogginess that they're describing is just this inability to get things done. They don't lose knowledge of who they are. They don't forget their name or forget where they live or lose memories from the past or anything like that. but they just don't officially get things done as well as they used to. It only takes a little bit of a drop, right? People think you have to have a big drop in performance to have a real-life impact. Just a 1 % drop and you're having a hard time doing your podcast or teaching a lecture or whatever you might do.

1:22:35A 1 % drop sounds like a frighteningly small change required to negatively impact life. So how about a poor night's sleep? I mean, what kind of drop in prefrontal cortical function are we looking at from, let's say, I normally get seven or eight hours or six to eight hours, and I suddenly only get three or four? Are we talking a significant detriment? I do think so. I do think that, yeah, that it is significant, a poor night's sleep. And we all notice that. I mean, it's very obvious. I mean, and you know, 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, you know, a small drop for them.

1:23:27Someone who's throwing 100 miles an hour, just a small drop turns them, you know, from really elite to someone mediocre. Maybe it's more of a 10 % drop, but it's still relatively small drop can have a huge impact. I think people think that just because you're a little bit off, that's not a big deal. You kind of work through it. And that's what most doctors say. Just plow through it. Just work your way through it. You're going to get better. And as opposed to saying, yeah, you really had a brain injury. This is what happened. We need to rehabilitate you just like we would do if you tore your anterior cruciate ligament.

1:24:03I don't know why tearing your ligament or your Achilles tendon gets more interest than tearing axons in your brain. It's amazing to me that there's more emphasis on orthopedic injuries than brain injuries. 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 that then one has officially signed on to try and resolve these matters. So for somebody that has a traumatic brain injury or low-level concussion, excuse me, would part of the primary advice be to try and get one's sleep as good as possible?

1:24:52Given that sleep deprivation can compound traumatic brain injury, induce deficits in working memory. And who knows, maybe a good portion of the deficits in working memory due to traumatic brain injury and concussion is because of the sleep deprivation that it can cause. So it can get circular. 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, you know, not a lot of neurologists ask you how you sleep, you know, but I remember back from my residency, one of the first things my attending would do when we got to the ward is, I had you sleep last night, and it just crossed the board.

1:25:37You know, patients are not falling asleep, they're not staying asleep, and we still don't understand why just brain injury does that. So almost every concussion patient says I'm not sleeping well, which then compounds the problem. So optimizing sleep, obviously optimizing nutrition. There's a question about activity. It used to be that we used to recommend, you know, you had a concussion, you should don't go to work, you know, sleep, you know, just take it easy for a while. Don't exercise. Keep the blinds drawn. But now it's the idea that you should really get up and moving. You've got to do what you can tolerate.

1:26:17You 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 promoting recovery. And then really getting your brain back working. I think, you know, a lot of my patients, they're off from work for a couple weeks, and they feel fine, and they think they're pretty much normal. And then the first day of work is a complete disaster, because until you actually test it in real life, you don't know what kind of troubles you have. So I don't recommend going back full steam, but I do recommend going back trying to build up these skills again.

1:26:53And then I think we need to develop therapies that people will use. Things like goal management training, which involves a therapist, and health insurance doesn't pay for this. So 99 % of my patients don't get any help by any kind of intervention, unfortunately. But now we talked about technology. things like Brain HQ. Do you know about Brain HQ? So Mike Merzenich, which I know you've talked about with Eddie, developed a company called Posit Science where it developed these brain training games that can help improve specific cognitive functions, and they're very easy to do because they're online and there's science behind them and you can do them.

1:27:44And so in that way, you don't have a therapist in your room, but you can online sort of do these sort of things that are targeting specific mechanisms to trying to improve the kind of things that we think are impaired by a concussion. And I'd like to see more patients get started on some of those things. Importantly, if you go on the web and just say, I won't do brain training, you'll be overwhelmed with things and you don't know what works and what doesn't work. 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.

1:28:17But 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 about neuroplasticity in critical periods. They gave a Nobel Prize to it, to my scientific great-grandparents, David Hubel and Torrance and Weasel. And they deserved that Nobel Prize. but there was a kind of a central tenet of neuroscience at that time was that critical period plasticity ends around adolescence or one's early twenties. And that is simply not true. And Merzenich really, I think one of the people who deserves credit for making it clear that plasticity is ongoing, it takes some focus and work to access it in adulthood, but that we can all access neuroplasticity, but it takes, it's there.

1:29:01So I don't know, they should give Merzenich and Nobel too, but I'm not on the committee. So just a little editorial there. The description of specific cognitive trainings that can improve working memory in people that have had traumatic brain injury or concussion, as well as our earlier discussion about the development of frontal lobe function and plasticity of frontal lobe function makes me wonder, is the working memory circuitry and frontal lobe function, a use it or lose it kind of circuit. Meaning if somebody, you know, goes to high school, graduates high school, and then gets into a lifestyle or college and then graduates college as well, and then gets into a lifestyle where they're not reading very many books, they're definitely scrolling social media, they're carrying out their daily tasks with, you know, apparently a high degree of functionality, but they're not really pushing these four brain circuits.

1:30:00do we imagine that some of those four brain circuits regress, aka use it or lose it? Seems to me that a few years back, maybe 10, 15 years back, there was a lot of interest in, you know, how to maintain cognitive function. In fact, one of the most common questions I would get, even as a neuroscientist, primarily focused on the visual and autonomic nervous system, was how do I keep my memory as I age? It seems to me that training it up and then continuing to use those circuits would be a really good way. reading books without forcing oneself to finish the chapter, even though distractions jump into one's head, things like that.

1:30:35For me, it's when I go to the gym, I try not to bring my phone. And if I do, I'll listen to one album of music, but I won't allow myself to play on my phone. I try. I mean, not interrupting a conversation with text messaging. I mean, basically the landscape I'm trying to draw here is it seems like the world is designed to disrupt, the modern world is designed to disrupt working memory and cognition of the frontal lobes. Right, right. And we need to do some real training, just like muscles and atrophy and cardiac fitness atrophies if we're not doing resistance and cardiovascular training. Does that set?

1:31:10Yeah, I think that's fair. I think, you know, 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 system, and it's probably the most biologically costly. And so the more complicated system is going to take more of a hit than other systems. And so certainly, I don't know about regressing, but certainly we're maybe accelerating this decline that we know exists. But a way I would think about it, though, is that not just trying to prevent a decline, but what we talked about before, there's no reason not to optimize.

1:31:57I mean, if everything is couched and I don't want to get dementia and don't want to get Alzheimer's disease and I don't want to get this and that, I think that's not the way we should be looking about it. We want to look about optimizing health and brain health and getting up to our optimal levels because otherwise we're always playing defense instead of playing offense. And that's really hard for neurologists. We have a hard time thinking about brain health even though we're the brain specialists. We think about brain disease. And we're just now, as a field, start thinking about preventative neurology and thinking about it not just like stopping Alzheimer's disease, but promoting health in a healthy brain.

1:32:36Neurologists don't talk to patients about sort of healthy patients about being healthier. 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, this 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. Maybe they had more time on their hands, but I think there was just more forging for information. I love the idea that through simple practices like forcing oneself to read a book chapter start to finish without looking at one's phone, even if it takes twice as long as one would like, redirecting one's focus when one focus moves away is a way of keeping working memory and cognitive function online, maybe even strengthening it, as you said, optimizing it.

1:33:34But, you know, I think that there's so much emphasis now on physical health, which I think is great. Sleep, thanks to Matt Walker, you know, he really, you know, brought that torch in on sleep. And now others like myself are really, you know, trying to amplify the message of the critical role of sleep. But also, you know, most people realize they should probably at least walk. The 10 ,000 steps thing is not a bad idea. getting some heart rate up a few times a week or more, maybe doing some resistance training a few times a week or more. And not just for athletes, but for elderly folks, men and women, you know.

1:34:10I feel like we need the same for cognition, for brain function. And there just isn't a structure to that. No one can say right now, you know, you need to do three chapters of reading, you know, fiction per week, or you got to read a, You got to learn a few new vocabulary words and then write sentences with them. They do it in school, but then we're just set into the general population. Right. And most people, I think, regress, right? 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 physical, they examine every organ in your body except your brain, your lungs, your heart, your skull system, your skin.

1:35:10But what do they do outside of having a conversation with you? Yeah, no cognitive task. No working memory task. 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 is their goal as a study to enroll 100 ,000 people, and they've been developing a brain health index. And that's a complicated thing to do, but I really believe they're onto something because it's not just cognition, it's cognition, it's social, it's lifestyle, like sleep, and it's well-being.

1:35:57A brain health index is going to cover all of these aspects. So they've developed quite an interesting, important index, which does try to capture all aspects of brain health and then can be used to track, where you can track your brain health over time with interventions that they've developed. So we need something like, we need to first, once we develop a brain health index, then we have something to follow and to be able to measure if we are optimizing our brain health. Otherwise, how do you know if you're optimizing your brain health? Your doctor's not telling you. You don't know. All these games you get on the web don't really tell you.

1:36:39So when we develop that, then all of the things that can promote brain health will be measurable. And I think it will take off the way physical fitness did. 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 point to learn new skills like instruments, things like that? But again, maybe your profession and your personal life keeps you busy enough that you don't have to do those things.

1:37:17I mean, for me, gathering, organizing, and disseminating the information for the podcast feels like the heavy lifting mental work for me. But I'm keenly aware of the fact that were I to read more fiction or learn an instrument, I mean, everyone else around me would suffer if I learned an instrument, but that it would probably benefit me in some real way. What are the things that you do and that you think are kind of access points that hopefully people also enjoy? 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 of my executive functions being tested to the limit.

1:38:02You're like a professional athlete of the mind. 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 should I be doing for sleep and nutrition? And it's funny you bring up books. I think I went probably 20 years where I never read any fictional book and said, this can't be good for my brain, and then just consciously started reading books and more nonfiction books.

1:38:48Listening to books or reading hard books? I still like to read the hard covers. Likewise. Unfortunately, when I was an undergraduate, you know, with pre-med, they don't let you take any courses that are interesting. So I never learned any history or, you know, all the books that I never read. I started reading my kids, you know, English literature books that I never got a chance to and started reading history. And so, yeah, I always felt just like just increasing knowledge, you know, just knowledge was, you know, like I said, our brain just stores information. That's one of its jobs. So that's got to be useful.

1:39:17But again, all of these things that I do believe help. Brain health, we need some way to measure it. I think certainly if you feel healthy, that's an important thing. If you feel like you're healthy physically or mentally, that's a good start. But if we actually had a way to sort of track it the way we can track heart disease and lung disease and skin and things like that, I think that will really boost everyone's confidence that this is really making a difference. On the basis of today's conversation, I'm going to read some fiction. I read a lot of nonfiction and I enjoy it. I listen to some audio books, but it's crazy to me because I'm a neuroscientist by training and I understand neuroplasticity.

1:40:05And I do know a bit about fitness and the key role of remaining active, kind of use it or lose it and maybe improve it, right? Kind of, that wasn't intended to rhyme, folks. Kind of behaviors, but clearly based on everything you've told us that if we don't exercise these working memory and other circuits for cognition, like why should they stick around? And I'm beginning to think that social media is entertaining as it is. And I learn there and I teach there, but that it's not a cohesive plot, right? It's like those baby otters, that really cool looking dog that I'd love to own. I'm thinking about getting another dog.

1:40:49This interesting conference, you know, it's like random, pseudo random tailored to me, of course, because that's what their algorithms do. But that's not following a plot, character development, antagonist, protagonist, any of the things that provide like cognitive richness. this is kind of obvious as i as i say this but i feel like we're divorced from these things that really helped evolve culture and evolved individuals and and it takes some discipline but like a run or going to the gym you do a few times for shorter amount of time with less intensity and pretty soon you're up to speed and there's an upper threshold unless you're going to be a pro i'm not i'm certainly not gonna be an english lit i mean you know professor you know so i don't think uh obviously boosting exact function is incredibly important but i don't think it's going to happen just with technology.

1:41:40I think it's going to need, it needs human interaction. I mean, I believe executive function should be taught in, you know, school as one of the, you know, as a course. This goal management theory that I talk about could be taught in school. It's what you do with your students. For example, when you have a graduate student and they have to learn how to read the literature and design experiment and carry out the experiment, there's no technology that's going to just be able to teach them how to do that. You've got to intervene sometimes and say, stop reading all those papers. They're not relevant.

1:42:13Okay. Or, you know, you piloted this enough, get going. It's that kind of wisdom that you get when you get older that allows, that has to be on top of the technology. So that's why I think we also need to, it needs to be directed. So whether it's in school or whether it's in a patient, I think there still needs to be someone coaching us, you know? And I know that's why life coaches have been, some people have really benefited from life coaches because someone just, it sounds obvious when you tell your kids, you know, just write, you know, just, just do it this way, you know, break it up into little pieces.

1:42:52It seems so obvious, but to them, it's not always obvious and they just need to be told something simple for it to make a big difference. And in school, we were, we were brought along step-by-step and there was context. So why wouldn't it be the same in adulthood? I'm realizing I should probably learn how to play chess. Seems like a good game, right? Chess, yeah, any one of the - Yeah, that's working memory. You got to keep information online. For sure. There's a bunch else there, I think, but as a tool to improve cognition. I was also thinking, you know, some people orient more towards the arts.

1:43:26My sister is really great about, she's a therapist in San Francisco, but also takes like theater classes And she said, you know, like improv is like forces you to keep on your toes, keep the context there. You're up on your feet. Like, you know, and I wasn't a theater kid. I did the crew. I did like the pulling the curtains and stuff till I went and did other things. But that whole biz is about being, you know, learning the novel rule set in the moment. You know, improv by definition. Absolutely. I mean, anything that requires you to have that, you know, where there's a goal and you've got to break it down to sub goals.

1:44:02and you've got to do it simultaneously and you've got to filter out distractions. And, you know, for example, my kids got me one of these pizza ovens for Christmas. And, you know, you think it's easy to sort of make some pizza and throw it in the oven and done. I'm on my third time and it's still not even round. I'll come over and test. That sounds good. That sounds good. And you're in a city with great food, so the standard is really high. I'm tempted to make a reference to the cheese board pizza, but I want to keep the lines as short as possible because they're already too long. Maybe we could talk a little bit about some other unfortunately common disease states.

1:44:46Parkinson's and Alzheimer's. Let's start with Alzheimer's. I think few things scare people more than the idea of getting Alzheimer's, especially if they have Alzheimer's in their family. First of all, what is the genetic link with Alzheimer's. If one has a parent or grandparent that got Alzheimer's, is there a known increase in one's risk for getting Alzheimer's? It's not that straightforward as other diseases. There's diseases like hunting disease where it's a very strong link that if you have a parent, you have a very high chance of getting it. But there's so many factors that it's not necessarily the case that you've increased your risk of getting it.

1:45:25There are families where there is something special about the family where it just runs in families. But I try to not scare my patient's children into worrying that they're necessarily going to get Alzheimer's because it's not that straightforward. As I understand, Alzheimer's is a neurodegenerative disorder, impacts the hippocampus, among other structures. There's been some debate in recent years as to whether or not the whole amyloid hypothesis is real or not. There's a bunch of, unfortunately, false data accusations and that whole thing. But my understanding is that if you look at a slice of human brain from a patient that died with Alzheimer's, maybe even from Alzheimer's, that you see plaques and tangles, you see these subseller structures and build up.

1:46:20And that our basic understanding of Alzheimer's that's in the textbook and that most people have heard of is still correct, right? Yes. Okay, because I think a couple of years ago, it was, unfortunately, the way social media sometimes can work is that the idea was that it was all wrong, all wrong. And indeed somebody fudged data, they made up data, and that's terrible. but Alzheimer's is an urgent disorder, includes the hippocampus, plaques and tangles are present in the neurons. Those are not good for neurons as I understand. So what's the controversy like, and why don't we have a treatment for Alzheimer's yet?

1:46:56I feel like almost every other psychiatric disease, including Parkinson's, like there are certain things you can do to at least push the system in the right way. Why is Alzheimer's and other dementias so tricky? Yeah. I mean, And it's very frustrating because the neurodegenerative disorders, it's so many factors that are probably involved in the pathology that there's not one single transmitter. In Parkinson's disease, it's a decreased dopamine, and so one transmitter can make a very big difference. Early on in Alzheimer's, it was discovered that there was low acylcholine in the brains, and the only approved treatment for Alzheimer's disease is a drug that boosts acylcholine.

1:47:38What's the drug? It's called denepazil. There's a few of them. They're anticholinesterase inhibitors that boost acetylcholine. They've been around for 20 years or more. And the reality is when you give it to your patients, they don't see much of a difference because it's not the primary deficit. So the real problem has been trying to find out what is the primary mechanism that's leading to this wide range of cognitive behavioral issues. And there doesn't seem to be at least one your transmitter that can make the difference. And so now the push has been, is there one, is there something else that we can do?

1:48:13Can we block amyloid? Can we block something in the pathology? And again, it just has not been successful. It's very frustrating because I think it was over probably 35 years ago, I saw my first Alzheimer's patients and I don't believe I say that much different to them now, you know, except that we have a lot more things we can do just on the social side of things. But unfortunately for drugs, we don't have anything that's been really transformative. But again, that's, I think, part of being a neurologist, it sounds very depressing, but I think part of what the family isn't always looking for a cure, of course, that's, they'd like to have a cure, but I think them understanding what's going on, what to expect, how to handle the behaviors is what they're really after, at least until we find, you know, a cure.

1:49:01Parkinson's, you mentioned, is a deficit in dopaminergic function due largely to degeneration of dopaminergic neurons. There, there's some effective treatments, right? L-DOPA. Did you know there's this over-the-counter stuff that's sold that a lot of people take who don't have Parkinson's? I'm not suggesting they take it, called macunipurines. It's the velvety bean. Yeah, I've heard of it. It's 99 % L-DOPA. It's present in some energy drinks and supplements. I mean, people can go buy it. I'm not suggesting they do that. I actually tried it. Boy, feel being really dopamine doubt does not, to me, doesn't feel that good.

1:49:41Yeah. I felt kind of agitated. My vision got a little, you know, twinkly. It did not feel like a high of any kind. And then I felt lousy for a couple hours after it wore off. Yeah. I don't think you can really get in enough L-DOPA to get enough into your brain. That happened early in neurology when it was discovered we couldn't give our patients enough L-dopa without them feeling bad because it's also metabolized in the periphery. And so it wasn't until we, Sinemet came along, which has this decarboxylase inhibitor that blocks sort of the breakdown of dopamine that we were able to sort of get enough dopamine into the brain.

1:50:18So I'm not sure, yeah, so that's why I think it's not going to probably get the levels up high enough in the brain. So Parkinson's patients are given L-DOPA or bromocriptine or drugs like that. Going back to Alzheimer's for a moment, I mean, what do you tell somebody who has early stage Alzheimer's? You just say, listen, try and get good sleep, try and keep people around you, stay cognitively engaged, try and keep those circuits going through behavioral-induced neuroplasticity, but we're just going to watch the steepness of the decline? Is that really all we've got? All we've got is to help them with everything that comes up on a day-to-day basis.

1:50:59A lot of the problems, the memory problems tend to be something that families can help compensate for, but you do get to a point where you can't be with someone for 24-7. It's a real burnout for caregivers. A lot of the behaviors that come up, patients get kind of delusions and agitated and some of the medications that we use for other conditions are helpful for treating that. But it's really just a purely symptomatic therapy. And the more socialization that patients get, they tend to do better. There was a study back at Penn way back that if you showed patients family movies or family albums, it was better than any drug you could give them to sort of help their behavior.

1:51:46So there's still those memories are in there, and they were making some type of contact that was helping them emotionally that you couldn't turn off with a drug. So I think the more we do things like that, the more will be helpful for them, at least symptomatically. I've seen a number of videos on social media of people with Alzheimer's who listen to a piece of music, or people with Parkinson's that hear a piece of music and that seems to resurrect some at least context-appropriate emotional state where it kind of brings the person to the surface again. Yeah, it's kind of a tragic situation for Alzheimer's right now.

1:52:26It seems like if ever there was a call to arms for the neurology community and biotech and behavioral tech, it would be for Alzheimer's, for the treatment of Alzheimer's. Absolutely. I will never ask a guest to comment on the good or bad behaviors of other people except my own. But there's a Nobel Prize winning neuroscientist and I visited him. He's in a big East Coast school back in 2010. And during the course of our one hour meeting, he consumed no fewer than four pieces of Nicorette gum. and i said i gotta ask what's this about by the way he's extremely sharp still and he said oh yeah yeah you know i used to be a smoker but smoking is really bad for you because you can get lung cancer dipping's bad for you because you can get mouth cancer but nicotine these are his words by the way is protective against parkinson's and alzheimer's and it keeps my brain sharp so i chew nicorette all day long and i thought okay well he's not he is an md actually.

1:53:37And I thought, oh, that's interesting. And I did an episode of this podcast on nicotine. It, by the way, can raise blood pressure. It's certainly smoking, vaping, dipping or snuffing, not good, bad, don't do it. But there is some interest in the use of nicotine as a cognitive enhancer. So I'd love to know your thoughts on that. And I'd love to know your thoughts on his statement about nicotine being a potential way to stave off Parkinson's and Alzheimer's with the caveat that he just kind of threw that out there. And this guy's sort of known for just kind of throwing stuff out there every once in a while.

1:54:11I have a feeling you know who this person is, but in any event, what gives? Yeah, well, I don't know anything about nicotine staving off any neurodegenerative disorder, but nicotine was used in a number of early Alzheimer's studies just because of its effect on the cholinergic system. So there is some truth to that. The cholinergic system is dysfunctional in Alzheimer's disease and boosting the cholinergic system probably is beneficial. I mean, the patients that we give the anticholinergic inhibitors, there are some families that say, yeah, he's remembering more and he's just doing better. So I've seen positive things to it.

1:54:53It doesn't really slow the course of the disease. That's the problem. The disease just carries on, even though we're symptomatically improving the symptoms. But again, I think it's going to take both acetylcholine and something else. I think we don't know, should we give dopamine with the nicotine or the acetylcholine? Should we get norepinephrine? I think it's going to be a cocktail, which again, pharmaceutical companies have not tried a cocktail of neuromodulators for Alzheimer's disease. They've just tried acetylcholine. Sounds like you should be running the FDA. No disrespect to the current people in charge.

1:55:26by the way, but maybe actually I'm, I'm a big believer that there shouldn't be individuals in charge of large organizations. There should be panels. I mean, there's so much talk about diversity, but they appoint individuals. You can't get it right. Anytime there's, when there's only one person by definition. So committees, folks, committees. Anyway, another editorial. Are there any sex differences, male, female differences in sort of these dopamine levels, working memory, injuries, concussion, like things that would direct people toward different routes of treatment, given that, you know, maybe there's more susceptibility in one case, maybe less susceptibility, maybe certain neurotransmitters are more effective in improving symptoms in men versus women.

1:56:20Do you see that in the clinic? Yeah, that's a great question. There was Emily Jacobs, who's a professor at UC Santa Barbara now in the psychology department, when she was a graduate student in my lab, studied the role of estrogen on working memory endophanergic function. And what she brought to my attention at the time, and it was embarrassing that I didn't know, was that the frontal lobes are full of estrogen receptors. There's probably more estrogen receptors in the frontal lobes than any other part of the brain. In men and women. Estrogen boosts dopamine. So higher estrogen levels correlates with increased dopamine levels.

1:56:58And there was some anecdotal evidence that in postmenopausal women who were put on estrogen that their working memory improved. And there was a kind of evolving link between estrogen and frontal lobe function. And she did this amazing study where she studied healthy Berkeley undergraduates at two points in time during the menstrual cycle when estrogen was at its lowest and what was its highest. And she also genotyped them for this enzyme they were talking about to know if they were sort of lower or higher on the dopamine level and then put them in the scanner and measured frontal lobe function and showed that there was a clear frontal lobe function was modulated by where they were in their estrogen cycle.

1:57:39When they were low estrogen, they were low dopamine. And if they were low estrogen and low dopamine to start, they really had decreased frontal lobe function and decreased working memory ability. So it fluctuated based on this interaction between estrogen and dopamine, suggesting that not only is dopamine important, but hormones are clearly important, and they work synergistically. So as we're developing this cocktail, we certainly have to bring hormones into the equation and learn more about it. There's just so little information about hormones and cognition. Yeah, one of the themes that's come out of some of the episodes we've done with MDs who specialize in endocrine health is that for both men and for women, optimizing estrogen levels is really important for cognition and vascular function.

1:58:31I think people mistakenly hear, okay, testosterone, men, you know, estrogen, women, obviously both hormones are present in men and women. In fact, I think I know that testosterone levels in women are actually higher than their estrogen levels. When you look at when you sort of use the same units of measure, it just so happens that they still have lower testosterone on average than the typical male. but that men whose estrogen levels are too low suffer cognitive defects and vascular defects. So this idea that more testosterone, lower estrogen in men is the ideal. And it just doesn't hold. It doesn't hold.

1:59:13I mean, unless you want to be dumb and have a heart attack, it just doesn't hold. Very interesting. Do we know what estrogen is doing there? Is it specifically raising dopamine? we don't have to get into the synaptic biology, but it's so interesting. Yeah, it's actually boosting dopamine activity. So it's making more dopamine available. Yeah, yeah. It's really amazing. And to think about it sort of fluctuating, certainly during the menstrual cycle, we can think about how much it fluctuates in an injured woman over 30 days, but then you can think across individuals, you can think about how much it can account for individual differences.

1:59:53So not only sort of knowing your dopamine level, but just knowing Sylvester and Sermon is really going to be important. Interesting. Is there any evidence that physical exercise can improve working memory and cognition separate from the known improvements in cardiovascular function and blood flow to the brain that occur with exercise? Like, is there anything about going for, you know, a 45-minute bout of exercise, you know, pick your favorite exercise, and then doing cognitive work immediately afterward when presumably the catecholamines, dopamine, norepinephrine, and epinephrine are going to be circulating, at least in the blood, at higher levels?

2:00:34Has that stuff ever been explored? In all of the groups around the country that are trying to develop cognitive therapies, they often use aerobic exercise as another type of therapy. And so, for example, the group at University of Illinois, Champaign-Ark Gamer's group has done aerobic exercise quite a bit, and they can find it just as effective as cognitive therapy and improving executive function, just straight up aerobic exercise. Wow. And so, you know, the hard part in the real world is how do you get, you know, a seven-year-old, you know, to do the kind of aerobics. But now with, you know, recumbent bicycles, and now there has been studies with seven-year-olds with just putting them in, mostly with recumbent bicycles, sort of designing.

2:01:19We have to think about ways to design exercise that can get aerobics up. But it's – and, you know, neurologists are starting – I think, you know, my field is starting to realize that there's – we got to tackle this at all – every way we can. And so now I'm hearing – you know, you hear more neurologists talk about that. You know, 30 years ago, no neurologist would say you got to exercise more, you know. We're just – now it's talking about exercise and nutrition and sleep and, you know, it's all becoming sort of part of our package of how we're going to help our patients. But the aerobic exercise is super interesting, and I think it's going to be...

2:01:55You know, that kind of made me think that what we didn't talk about was mindfulness. And so a lot of these studies also, if they add mindfulness training to the hardcore goal management training, it's better than just the executive training alone. Just learning skills to stop, relax, refocus kind of gives this sort of boost to executive function as well. Yeah, I think of mindfulness like sort of, well, there's no such thing as traditional meditation. I have to be careful here. But the sort of stereotypical meditation of closing one's eyes, closing one's eyes, excuse me, sitting down, lying down and just focusing on one's breath and then redirecting one's focus to maybe third eye center, you know, area between the forehead, just redirecting focus, redirecting.

2:02:44I think of meditation of that sort as a focus exercise. It's not so much a perceptual exercise because thoughts are kind of doing what they're doing. It's like a focus exercise. And that's half of the problem with not achieving our goals, right, is we lose our focus. And so building into sort of strategies to main focus, to stop and relax and refocus is an important strategy for boosting executive function. And it doesn't seem to matter what, you know, I know there's all different flavors of mindfulness. So we just happened to use one when we were studying it. It doesn't yet, I don't think we know enough about how we should tailor the mindfulness, but most forms of mindfulness will work of the type you're talking about.

2:03:30That's similar, what I described is similar to what you just explored. Yeah, exactly. Yeah. I mean, it's amazing to me, you know, 20 years ago, if somebody wanted to talk about neuroscience and mindfulness on a major university campus, let's say Stanford or Berkeley was probably a little bit more tolerant of these ideas at that time, just given the kind of culture. They wouldn't have been laughed out of the room, but there was a lot of skepticism. And I feel like now mindfulness meditation, breath work, the idea that, oh my goodness, breathing can impact your emotional state. I mean, that should have been obvious.

2:04:03But now that people are on board then, And now, of course, there's a lot of interest in psychedelics. That's kind of a new emerging therapy, carrying more risk, potential risk. But it looks like it's very likely that some of those are going to make it through the FDA filters at some point. But the conversation we're having now, you know, neurologists and neurobiologists talking about mindfulness, nutrition. We're talking freely about nicotine. You know, we're not suggesting people do that. Bromocryptine to optimize cognitive function. I mean, this conversation would have never happened.

2:04:38seven years ago. No, it's just - the field has changed. Yeah. I hear neurologists talk about it all the time. So do you try mindfulness? And if you do, does it make your day? Do you feel like you perform better that day? Yeah. Thanks for asking. There are two forms of yes. The short answer is yes. There's a very specific practice that I've used since 2017 that's really benefited me so much, which is what I call it non-sleep deep rest, but it's based on a practice called yoga nidra, where you just lie down and it's, these are free audio scripts online. We can provide links to these. And you go through a body scan and you do some long exhale breathing, which emphasizes the parasympathetic, AKA relaxing aspect of the autonomic nervous system.

2:05:18I know you know this, I'm saying that for the audience. And it does involve some intentions and things like that, but it can also just be self-directed relaxation. And I emerged from that with much more mental and physical vigor than I did prior. And this only takes maybe 10 minutes. There's also a 30 minute scripts i do those and then i do mindfulness meditation the thing about mindfulness meditation that the biggest impact for me has been the problems of my life um get re um i get a different perspective i start thinking about things in different domains of time like this thing that is like a problem that i've been dealing with for instance um i start thinking like in the course of my lifetime, this is a relatively small, not small thing, but in relatively small time bin.

2:06:06And I sort of think about best course of action given its real role in my life and what I want, et cetera. So I feel like it sort of orients me in time. So that's been a major effect. For focus, the best tool I know is to, you know, put the phone in another room. That's kind of a don't. And I know our friend, Eddie Chang, neurosurgeon, chair of neurosurgery at UCSF, he's big on mindfulness meditation. So do you meditate? No, I think that's one of the things where we're talking about what should we do besides reading fiction. I think that should be on my list. Five minutes a day. No, I guess it's just amazing that the patients tell me about it and what we've seen from our studies.

2:06:47A lot of this, again, I was saying before, is if we had some measure of brain health that we could see the impact of it would sort of push us towards, you know, probably doing it more. I think another thing that we didn't sort of talk about, we talked a little about what dopamine is, are there other kind of brain states that sort of, you know, predict, you know, you know, how you're going to respond to these therapies and how, if you're going to benefit from them. And, you know, we've done a lot of work with sort of measuring sort of the large scale organization of the brain and brain networks.

2:07:19And that's sort of very popular idea in neuroscience today, sort of moving away from sort of what is this. We've talked a lot about what the frontal lobes do, but the frontal lobes are part of these networks in the brain. And really sort of the state of your networks is really an important factor as well in addition to sort of your sort of neurochemical profile. Yeah, tell me more about this. I mean, you actually preempted my next question, which is going to be, and this is my favorite question to ask. Carl D. S. Roth taught me to ask this way back when, like, what are you most excited about now?

2:07:57Because I know the work you've published and you've done a magnificent job of sharing the details of that and work of others in a really informative and in some cases actionable way. But what are you really excited about? Like if there were no financial barriers to your grants, et cetera, you had a thousand people working, what's the thing that's hitting your dopamine circuits these days? Yeah. Well, in the grand scale, I'm excited that things that we've learned over the last 30 years, not just in my lab or your lab or anyone's lab, is actually now being translated to actually helping people. I mean, when people ask me what I do, I say I'm a neurologist because that's at my core what I feel I am and I feel I got into this business to help people.

2:08:42And so when you work for years and years and years and it doesn't translate, it can be frustrating. But now I'm excited that it seems that the things we've learned, that all of us have learned in neuroscience, is starting to now translate into something. In neuroscience, what's happened in the last 10 years is we're thinking of the brain in a kind of grander scale. It's sort of its overall organization and not so focused on just this area or that area. When I talk about the frontal lobes as being the most important part, the conductor, Yes, I am talking about one brain region, but it's a brain region, like I said, that's connected to everywhere.

2:09:25And it's because it's connected to everywhere is what's really the essence of why it's so important. So some of the research I'm excited most about is sort of taking away the names of areas and just thinking about the brain as a big network, like an airline network or electrical network and how different areas communicate with each other. And when you think of it that way, so for example, in the airline network, you've got all these hubs all over the world, all over the country. In the United States, for example, you've got Chicago as a hub and there's other hubs, Milwaukee or Cincinnati. But they have very different functions in the network as a whole, right?

2:10:07If you're trying to get from New York to San Francisco, which happened to me many times, even though you're not going through Chicago, If Chicago is shut down, you're probably going to get delayed because it just has this huge impact on the whole system. And, you know, if Milwaukee goes down, you don't even know it. You just fly right over there. I'm sorry if anyone's listening from Milwaukee. There are probably a few. You got to go through. But so thinking about the brain, the brain is the same way. The brain has these hubs as well. And, you know, the prefrontal cortex is a hub like Chicago. It's just an important hub that keeps the whole system going.

2:10:46And that's why it has much more of an impact when you damage it or you stress it as opposed to some other part of the brain. And so what's exciting to me is not only does that make us thinking about disease differently, because now we're starting to think about how is diseases affecting these hubs, that the pathology seems to be like when you look at Alzheimer's disease and you look at schizophrenia and you look at a lot of diseases, it's not just that there's some microscopic change in some neuron. It seems to be affecting hubs in the brain that are affecting the whole network. And so we have a different target to go after for treatments.

2:11:23What can we do to sort of boost, you know, a hub that's been damaged as opposed to thinking about it in a less specific way? And then also, as we really start to learn about how the brain is organized in these networks, We've also learned that measuring your network structure is very predictive of your well-being and how you respond to interventions. So there's a metric called modularity, which measures how organized your brain networks are. And the brain is made up of different modules, different networks. And these networks can either be very communicating with each other or not so communicating with each other.

2:12:05And the more segregated they are, we call that more modularity. They're kind of separate entities. They're modular. And it turns out we can measure that with fMRI. We can put someone in a scanner. We can do this resting fMRI scanning. And then we can measure how modular your brain is versus my brain. And all of us are very different levels of modularity. Is it more advantageous to have more modularity as opposed to less? Yeah, it turns out that it seems to be more avatation to have more. So we can predict... More separateness of brain function between areas. Yeah, that the networks are sort of more independent.

2:12:42That doesn't mean they don't talk to each other, but at sort of baseline, they're more independent. Resting state connectivity. Yeah, they're more independent as opposed to less independent with each other. Not unlike neuromuscular junctions. Gene development are what we call poly-innervated. That's why babies can move their limbs, but not with a lot of coordination. Look at a one-year-old trying to eat spaghetti, for instance. It's hilarious. Look at that same kid seven months later. There's a lot more precision movement, largely due to removal, more modularity of connections. Right, right. Interesting.

2:13:14So we did a study where we took 12 traumatic brain injury patients and measured their modularity. So you get a number. You just get a modularity index for each of the 12 people. And then they underwent this goal management training. and we were able to predict who was going to improve on the training. Those who had started off more modular benefited more from the training. And it's turned out that this has been a very robust finding across studies now, across different training, different young, old patient populations. It's also predicted things like whether someone in a coma is more likely to do well or if someone who's older is going to have a certain amount of cognitive decline or someone's going to respond to behavioral therapy if they're obsessive-compulsive.

2:14:02So there's something about this brain state that not only we can measure, but actually is giving us insight into the interventions that we're doing, which, again, is going to be much more helpful in determining what helps and what doesn't help if we know sort of what the state is before we start the intervention. So interesting and makes me think many things, but I'll just focus on two of them. One is I love this idea that you and others are starting to look at brain network activity as opposed to overemphasizing the role of, say, prefrontal cortex or hippocampus, understanding more that those are hubs in a larger theme of activation.

2:14:44Because if I had one wish for science communication, it's that people would, yes, learn some terms like dopamine and frontal lobes. It is important to know the nomenclature, but to understand that if you really want to be able to work with the information in a way that's beneficial, you need to think about verbs, not nouns. It's about the action states of these areas, and those action states are always involving multiple areas. Just like you can't talk about running as just like quadricep and hamstring flexion and extension and contraction. It's just, you can, you can break it down that way. And it's useful to know that, but ultimately you're talking about gait and stride and things that, that have a real verb action to them.

2:15:26And we haven't had so much of that for the nervous system at a, at a circuit level. We've been able to do that for individual neurons. That's the first piece. And then the second piece is that, you know, it occurs to me that there's so much rich understanding of the different states of sleep. You know, Matt Walker was just here recording this series on sleep that we'll release later this year. And stages one, two, three, four, deep sleep, slow wave sleep, rapid eye movement sleep. But we don't even really have a naming system for waking states. Like we say focus, we say task switching, but those are just names we made up just as stage one, two, three, and REM sleep are names that we made up.

2:16:09But there seems to be a much richer understanding of like what rapid eye movement sleep is good for and what deficits in rapid eye movement sleep lead to. Then there is, for instance, how given our network, I'm going to make this up, like calling a certain network activation state, like state A. Like I feel like neuroscience is tasked, the field of neuroscience now is tasked with giving us an understanding of the verb states and like what, like these waking states of mind are very mysterious. And for the general public, this is important because people wonder, like, is my focus poor? Or is it good?

2:16:43Is my task-switching ability good? I mean, we only tend to look at, you know, are they functional enough to do their job and manage their family, manage their lives? We don't really have metrics. But for sleep, we have metrics, and commercial products can measure that. You know, sleep tracker rings, wristbands, mattress covers, I mean, this sort of thing. Well, you know, yeah, I think modularity can actually be that metric. Some metric of your large-scale organization of your brain can be that metric. There's a number of labs that have done this, have measured modularity in real time. So what I was talking about, we're just getting a snapshot of this is what your baseline modularity is.

2:17:20But we can also look at modularity, how it changes on a second-to-second-to-minute-to-minute basis. And one of my former postdocs, Sepeda Saragliani, she just did a very simple experiment where there were sounds. And the functional MRI scanner is very loud, so you can't hear very well. But every once in a while, there'd be a sound that was just above the level of the noise of the scanner. And all you had to do was sort of press a button if you heard that sound. And you didn't pick it up all the time. You know, maybe 80 % of the time you heard it and sometimes 20 % of the times you didn't hear it.

2:17:57Well, she measured their modularity on a moment-to-moment basis, and she could predict if they were going to get that, if they were going to be correct or not and wreck the sound before they got the sound. If they were highly modular, boom, they got it. If their brain had gone into this kind of, you know, diffuse, less moderate state, they missed it. And so I could definitely see, as you're just talking about, where if we could develop a modularity metric in real time on a device, this would be game-changer. And so, and that's sort of what I'm, you know, what I've been interested in doing. What excites me is that we're not going to do with a scan, obviously you can't walk around with a scanner in your head, right?

2:18:36And even, I don't think you could even do with EEG. I think, can we develop a proxy for modularity with some more simple way of doing it? Can we extract this maybe be out of heart rate variability or for oxygen. I've been working with some colleagues, a former student, Brian Miller, and a postdoc of Adam Gazzali's, Wes Clapp, who have a company called Neuroscouting, where they are able to, they have, we've been sort of doing scanning and also collecting physiological data to try and determine if there's some problem. We can measure the modularity in the scanner, but can we pick that up in the physiology data?

2:19:20Because they can collect, you know, oxygen and heart rate variability and other metrics that may be kind of a readout of that. And then we'd have a brain state, which is what you were looking, you know, you're looking for some brain state. But it's not, I think people are thinking we need a helmet or something like that. We need just something simple, right, that reads out brain state just the way we read out other physiological information from our watch or something like that. Well, the sleep trackers of various kinds have certainly been able to pull out information about rapid eye movement and other stages of sleep.

2:19:54I mean, key metrics, not every metric, not what you would get with a person wearing an EEG probe or something, a set of probes, but certainly information that can be used. One thing that has me a little bit perplexed and I'm almost reluctant to bring it up, but I'm gonna do it, is that I did a couple episodes about psilocybin and the use of psilocybin for the treatment of depression. This is Robin Cardhart-Harris from UCSF, and I also did a solo episode emphasizing, of course, this isn't recreational use we're talking about. We're talking about for treatment of depression. But there's a lot of neuroimaging of patients before and after macrodose psilocybin, and this isn't microdosing.

2:20:38And one of the major takeaways is increased resting state connectivity. which by virtue of what you just described might not be ideal for cognitive function. It might be good for social emotional function. And I'm certainly don't want to disparage the beautiful work that's being done there. But you said that increased modularity predicted improved function, especially with cognitive interventions. Psilocybin seems to induce fairly significant increases in cross-modal talk between brain networks, in other words, less modularity. So should we be concerned? No, it's just it has to do with how we make these measurements, and connectivity doesn't mean the same.

2:21:27You know, there's different types of connectivity. And so I like to, when I think about connectivity, we talked about this connectivity of a brain state versus a brain trait. So when we're talking about you being highly modular as a trait, that's very different than what your modularity is like in different states. It actually turns out when you do these highly executive demanding tasks, you get less modular because your networks are communicating with each other. So it's important for networks to get less modular when it's a more demanding task. But that's very different than what's your baseline modularity.

2:22:11Because you've got to get from where your baseline is to this other state. And a lot of it has to do with going from one state to another, not so much the absolute differences. So that's interesting. I didn't know about those results, but it's interesting that it does affect connectivity in that way. I think the drugs that are going to be helpful are going to promote sort of networks talking to each other as opposed to networks not communicating with each other. In your clinic, do you ever combine drug therapies, cognitive training, and things like transcranial magnetic stimulation? Do you use stimulators?

2:22:47Yeah. So I think, you know, I have a lot of patients that I've referred for its approved use, which is depression. So I'm very excited about sort of the work that's being done for depression. But we haven't really had any improved anything that's been for cognition. So there are a bunch of studies, anecdotal small studies, where you can give transcranial stimulation of the frontal cortex and working memory improve. But they really haven't been done in ways that we don't know if it generalizes, if it's going to be the way it's been done in depression in a way that can really be. But again, it's just a matter of doing it.

2:23:26I think it will be part of the things we do, drugs, TMS, and all the other things we've talked about. It's not just going to be one thing. And it gets back to networks, right? What this is doing is really changing how nodes, you know, the interaction regions. It's not about sort of just increasing or decreasing activity in some mysterious part of the brain. It's just sort of restoring the balance of a network. Mark? Well, Mark, I just really want to thank you. You've given us an amazing tour of basically five fields. I threw a lot at you as a neurologist, but the way I'm slightly reluctant to do this, but I'm going to tell you a joke that was told to me.

2:24:13So that there are these people stranded on an island and they're really stuck and they're running out of resources. And by the way, this joke was told to me by a physician. And all of a sudden this hot air balloon then comes over and they're like, oh my goodness. So they start, they write help in the sand and they, you know, and hot air balloon directly over them, kind of descends almost, you know, almost to them and um and then someone in the hot air balloon says you know i'm doing the measurement and it's exactly 76 feet down to those people and then the hot air balloon takes off and goes away and the people on the beach one of them is a physician and he goes those were neurologists i tell that joke because that was the old school view of neurology that um neurologists were great at describing things, talking about the terrible conditions they could observe in great detail, but that they did not do anything about it.

2:25:19You, on the other hand, and I'm guessing others in the field, but certainly you have proven today that that joke needs to be revised, whereby there's one, at least one neurologist who casts a line down and shimmies down and assists them and pulls those stranded people on the island up to the balloon. Because today you've described the underlying nature of some of these things like working memory deficits, traumatic brain injury, concussion, Alzheimer's, Parkinson's. Again, I threw a lot at you and you've responded in thorough, clear detail. But also a number of things that clearly can assist in these situations, such as bromocriptine, mindfulness, exercise, and really as an exploration of what can be done interventions.

2:26:07And so for all those reasons and for tolerating this terrible joke that I just told, I wanna say thank you because I've learned a ton and I know the audience has learned a ton and much of what we've learned has us looking in the directions of possibility to alleviate these situations. And as you point out, for the already healthy, even to optimize brain function and health. So for all of that, thanks for sliding down the rope to the island. Well, I'd say, you know, on behalf of all the neurologists in the world, thank you for appreciating what we do. It's just so important to try and get this message apart.

2:26:49Like I said, you know, with patients, we just try to have them understand what it is that they're going through. And I think today patients have to really be advocates for themselves. And so I think the more they learn about all of these possibilities, the more they can go back to their doctors or whoever and try and ask for, you know, what about this? What about that? Do you think this would help me? Because we have to be advocates for our own health. And the only way we're going to do that is just make people understand what it is that the possibilities are. So thank you. It was a lot of fun.

2:27:22It was a great time. Well, amen to all of that. And hope to have you back again. Thanks so much. You're welcome. Thank you for joining me for today's discussion about the brain mechanisms of cognition and memory and how to optimize cognition and memory with Dr. Mark Desposito. To learn more about Dr. Desposito's 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 subscribe to the podcast on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review.

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2:29:12Thank you once again for joining me for today's discussion with Dr. and Professor Mark Desposito. And last, but certainly not least, thank you for your interest in science. you