Huberman Lab - Dr. Mark D'Esposito: How to Optimize Cognitive Function & Brain Health

Episode Date: February 19, 2024

In this episode, my guest is Dr. Mark D'Esposito, M.D., a neurologist and professor of neuroscience and psychology at the University of California, Berkeley. We discuss the brain mechanisms underlying cognition and the forms of memory required for focus, productivity, planning and achieving goals, and learning. We discuss neurochemicals such as dopamine and acetylcholine and how they can be leveraged to improve cognitive functioning. We also discuss concussion, traumatic brain injury (TBI), Alzheimer's, and Parkinson's disease, and ways to restore or slow cognitive decline by using pharmacologic, lifestyle and behavioral protocols. This episode provides a modern understanding of cognition and memory and actionable tools to optimize brain health and function. For show notes, including referenced articles and additional resources, please visit hubermanlab.com. Thank you to our sponsors AG1: https://drinkag1.com/huberman Maui Nui: https://mauinuivenison.com/huberman Joovv: https://joovv.com/huberman Eight Sleep: https://www.eightsleep.com/huberman LMNT: https://drinklmnt.com/huberman Momentous: https://livemomentous.com/huberman Timestamps (00:00:00) Dr. Mark D’Esposito (00:02:08) Sponsors: Maui Nui, Joovv & Eight Sleep (00:06:23) Brain & Frontal Lobes, Prefrontal Cortex, Executive Function (00:10:31) Frontal Lobe Development, Children (00:14:12) Rules, Context & Impulse Control; Learning & Goals (00:21:45) Focus, Improving Executive Function (00:26:04) Connections & Top-Down Signals (00:29:02) Sponsor: AG1 (00:30:29) Frontal Lobe Injury; Emotional Regulation (00:37:26) Smartphones, Social Media (00:44:37) Working Memory, Dopamine (00:52:59) Sponsor: LMNT (00:54:22) Dopamine Levels & Working Memory, Cognitive Tasks, Genetics (01:00:03) Bromocriptine & Working Memory, Dopamine (01:06:21) Guanfacine, Neurotransmitter Levels, Pupil Dilation & Biomarker Tests (01:12:46) Bromocriptine, Olympics; Pharmacology & Cognitive Function, Adderall (01:19:27) Concussion, Traumatic Brain Injury (TBI) (01:25:22) Sleep, TBI, Concussion & Executive Function; BrainHQ (01:31:57) Aging & Frontal Executive System; Brain Health (01:39:26) Tools: Brain Health & Boosting Executive Function, Books (01:47:26) Alzheimer’s Disease, Genetics, Pharmacology (01:51:48) Parkinson’s Disease, L-Dopa; Coping with Alzheimer’s; Nicotine (01:58:37) Estrogen & Dopamine, Cognition; Tool: Physical Exercise (02:04:43) Tool: Mindfulness Meditation & Executive Function (02:10:31) Brain Networks; Modularity (02:17:08) Modularity, Brain Indices (02:22:53) Psilocybin; Transcranial Magnetic Stimulation (02:30:16) Zero-Cost Support, Spotify & Apple Reviews, YouTube Feedback, Sponsors, Momentous, Social Media, Neural Network Newsletter Disclaimer

Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. and Professor Mark Desposito. Dr. Mark Desposito is a neurologist and a professor of neuroscience and psychology at the University of California Berkeley. He is a world expert in the brain mechanisms controlling executive

function and memory. Executive function is the way in which we are able to designate and carry out specific cognitive strategies, and it is fundamental to every aspect of our daily lives. And because so much of being effective in daily life involves using specific context relevant batches of information in order to understand what to do and when and what not to do and when and to come up with strategies that are very adaptive for us to move forward in the context of relationships,

work, school and athletics and on and on, there's really no separation between executive function and memory. And today, Dr. Desposito explains the neural circuits controlling executive function and memory, how they interact, the key role of dopamine in executive function and something called working memory, and teaches us ways to optimize executive function and memory,

that is how to optimize cognitive function. In addition to is how to optimize cognitive function. In addition to discussing how to optimize cognitive function in the healthy brain, today's discussion also centers around how to restore cognitive function in disease or injury conditions that deplete executive function and memory, such as traumatic brain injury,

concussion, Alzheimer's, Parkinson's, and attention deficit disorders. Dr. Desposito shares with us research findings both about behavioral and pharmacologic strategies to enhance executive function and memory. By the end of today's discussion, you will have learned from Dr. Desposito a tremendous amount about the modern understanding

of cognition, that is thinking and memory, and the carrying out of specific cognitive strategies. You will also learn a tremendous amount about how to optimize brain function and brain health. Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero cost to consumer information

about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Maui Nui Venison. Maui Nui Venison is the most nutrient dense and delicious red meat available. I've spoken before on this podcast

and there's general consensus that most people should strive to consume approximately one gram of protein per pound of body weight. Now, when one strives to do that, it's important to maximize the quality of that protein intake to the calorie ratio because you don't want to consume an excess of calories when trying to get that one gram of protein

per pound of body weight. Maui Nui venison has an extremely high-quality protein to calorie ratio, so it makes getting that one gram of protein per pound of body weight extremely easy. It's also delicious. Personally, I like the ground venison. I also like the venison steaks. And then for convenience, when I'm on the road,

I like the jerky. The jerky is a very high protein to calorie ratio. So it has as much as 10 grams of protein per jerky stick, and it has something like only like 55 calories. So again, making it very easy to get enough protein without consuming excess calories. If you would like to try Maui Newi Venison, you can go to MauiNewiVenison.com slash Huberman

to get 20% off your first order. Again, that's MauiNewiVenison.com slash Huberman to get 20% off. Today's episode is also brought to us by Juv. Juv makes medical grade red light therapy devices. Now, if there's one thing I've consistently emphasized on this podcast, it's the incredible role that light can have on our biology.

And of course, I'm always telling people that they should get sunlight in their eyes as soon as possible after waking on as many days of their life as possible for sake of setting circadian rhythm, daytime mood focus, and alertness, and improve sleep. In addition to sunlight, red light and near--imp red light has been shown to have positive effects on improving numerous aspects of cellar and organ health, including faster muscle recovery, improved skin health and wound healing, even improvements in acne,

or that is removal of acne, reducing pain and inflammation, improving mitochondrial function, and even improving vision itself. What sets you apart, and why it's my preferred red light therapy device is that it has clinically proven wavelengths,

meaning it uses specific wavelengths of red light and near-infrared light in combination that trigger the optimal cellar adaptations. Personally, I use the handheld juve every day. The handheld juve is about the size of a thick piece of toast. And I also own a juve panel that allows for full body exposure and I use that one approximately five times per week

for about 10 to 15 minutes per session. If you would like to try juve, you can go to juve.com slash huberman to receive $50 off your first purchase. Again, that's juve, spell J-O-O-V-V dot com slash huberman to get $50 off your first purchase. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers

with cooling, heating, and sleep tracking capacity. I've spoken many times before in this podcast about the fact that sleep is the foundation of mental health, physical health, and performance. Now a key component of getting a great night's sleep is that in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.

And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. One of the best ways to make sure that those temperature changes occur at the appropriate times, at the beginning and throughout, and at the end of your night when you wake up, is to control the temperature of your sleeping environment.

And that's what 8Sleep allows you to do. It allows you to program the temperature of your mattress and sleeping environment, such that you fall and stay deeply asleep easily and wake up each morning feeling incredibly refreshed and energized. I've been sleeping on an 8Sleep mattress cover for almost three years now,

and it has dramatically improved the quality of my sleep. If you'd like to try 8Sleep, you can go to Aidsleep.com slash Huberman to get $150 off their Pod 3 mattress cover. Aidsleep currently ships in the USA, Canada, UK, select countries in the EU and Australia. Again, that's Aidsleep.com slash Huberman. And now for my discussion with Dr. Mark Desposito. Dr. Desposito, welcome. Hey, Andrew, thank you so much for inviting me. I'm really looking forward to our conversation. Yeah.

You may not remember me, but I remember you when I was a first-year graduate student, and you showed up at Berkeley, one of the first people to really bring functional imaging of the human brain to Berkeley, bring a neurology and a clinical emphasis to the neuroscience studies there, and it's really just blossomed. And it's been a real thrill for me to see all the magnificent work out of your laboratory over the years. And I know you also still see patients. So the topics that are of interest to you, I know are of great interest to our audience. Maybe we'll just start off with a few of the basics and do a little functional neuroanatomy lesson for folks. Not to scare anyone, don't worry. This will be accessible to

everyone. And just talk about the frontal lobes and prefrontal cortex and a little bit of what those structures do because many times on this podcast I've said, okay, the neural real estate right behind your forehead is involved in context and planning, et cetera. But you're the real expert here. How should we think about what the frontal lobes do and their various roles in health and disease? Yeah. So there's four lobes. There's a frontal lobe, parietal, temporal, occipital, and the frontal lobes probably take up more, do take up more territory than the lobes, probably about a third of the cortex. And within the frontal lobes,

I'm gonna use frontal lobes probably in our conversational app, but what I really mean is the prefrontal cortex. So within the frontal lobes, there's also areas that are important for motor function as well. But when we're talking about the frontal lobes and talking about its involvement in higher level

of cognitive abilities, we're talking about the prefrontal cortex. And this is what's considered sort of the highest level of cortex in the brain. So yeah, when you think about it, people assign it all sorts of functions, almost every function you think of, people sort of put into the frontal lobes. But I think what we've all kind of moved towards is this idea of executive function, this ability to plan, to organize, to really transfer our thoughts into an action and really to be guided by goals and intentions and not be kind of ruled by sort of just automatic behaviors. A word we use in cognitive neuroscience is called cognitive control.

So cognitive control, executive functions, what we attribute to the frontal lobe. And so you can think of it as the CEO of the brain or the conductor of the orchestra, really the part of the brain that's really controlling the rest of the brain. So yeah, if you had to choose which part you wanted to not leave home, it's your frontal

lobes. Speaking of which, what are some of the symptoms of mild frontal lobe damage and severe frontal lobe damage? A damage brought about either through neurodegenerative disease or physical injury. I know we're going to talk a bit about both today or a lot about both, but how would lack of executive function show up maybe on kind of a subtle level? Yeah. I mean, at first I should say is that it shows up all the time because when and frontal lobe

behavior is probably much more prevalent than we realize. Certainly, we think about it when you have a brain injury to the frontal lobes and there's lots of neurological disorders like stroke and traumatic brain injury and Alzheimer's disease that can affect the frontal lobe. And there's a number of psychiatric disorders, obsessive-combalist disorder and schizophrenia and depression that are thought to be frontal lobes function. But when you're sleep deprived and when you're stressed and just normal aging, the frontal lobes seems to be the first system that's affected because it really is involved in the highest level. So when we're having a bad day, when we're having difficulties sort of setting priorities, when we're having difficulties achieving the goal that we've set out,

when we get distracted, when we're not able to sort of adapt and be flexible, these are all the type of things that reflect that our frontal lobes are not functioning optimally. Approximately what age does the frontal lobe circuitry come online, so to speak? I see a baby. Babies can orient their eyes towards things, but they're rather reflexive in where they'll place their eyes. But by time kids are three or four, they can certainly play with blocks or interact with other children or their parents.

But it seems that full functionality of the frontal lobes is really gradual. At least that's my non-clinically trained assessment. Yeah, I mean, it's a really tough question to know when they're fully developed because these studies haven't been done. When MRI was introduced and we were able to sort of image the brain in a non-invasive way, then studies did start to come out trying to sort of map out at what age does your frontal lobe is fully developed.

And it seemed like it was early into your 20s. You know, I always say that it's not surprising that you can't rent a car into your 25. That the insurance companies knew before. And our scientists did as to when your frontal lobes have, when your decision-making skills are at their highest. And so that's probably about right. Into your 20s is probably before your frontal lobes are fully developed. And it's really interesting question is why does it take so long?

It's the area of the brain that takes the longest to develop and why is that? And I think there's a reason. I think that this sort of slow development of frontal lobes allows us to explore, allows us to think about novel ways of solving problems, allows us to take in the world. If they were shut off earlier, it would lead to maybe a much more rigid, less flexible behavior that we'd seen. So I think that it helps to take a long time to develop, but also it obviously leads to some problems sometimes in adolescencecence as we see sometimes. Can one see a lack of frontal lobe maturity in just the sheer number of physical movements

that a child makes? So for instance, in a classroom of, you know, let's say, you know, fourth graders oftentimes there'll be a range of apparent ability of kids to sit still or to listen. Do we think that the kid that's having a hard time focusing and listening to instructions or studying their body when they're told to sit still? I don't know if they still tell kids to sit still, but they were telling me to sit still. Right. That was a kid. Is that somehow reflective of a slightly lagging frontal lobe function and maturity, whereas that the kids that can sit still and stoic and focus, does

that mean that they're a little bit more accelerated along that trajectory? Yeah, it's hard to say. I mean, the frontal lobe is a big territory and we can get into it, but the frontal lobe probably has 25 different subregions within it. And so, grossly, we think about the frontal lobes as the lateral portion of the frontal lobes, which is involved in these executive function, probably supports these executive functionalities. But then we've got another part of the frontal lobes called the orbital frontal cortex, which is probably involved more in social and emotional behavior. So, you know, when we think of, again, when we think about frontal lobehavers, they kind

of, you have to break, there's so many different type of frontal behaviors. So that type of behavior, which may be evolved in sort of being able to inhibit, you know, your motor movements or maybe not being distracted may reflect that that system is a little bit delayed, but it could be that another system, the one that's involved in planning and organizes, is more developed. And I do think they develop at different trajectories. So with the frontal lobes, essentially, serving an executive or CEO type function, goal directed behavior, intentions, cognitive control, these are the terms you used. Where are the rules? What do the rules look like? When I think about brain function, which I've spent a lot

of my life thinking about, I think about chemical and electrical signaling between neurons, different neurons communicating more or less at a given moment, reflecting some sort of circuit as we call it, and then some behavior or some decision comes out. And if I, for instance, have to get my driver's license renewed soon. So if I go to the Department of Motor Vehicles, what a lovely experience that is. The moment I get there,

I sort of lock into a certain rule set. When I'm home, I'm in a different rule set. When I'm with my friends versus when I'm with my parents, different rule sets. And it seems that the frontal lobe is really good at drawing on context based on knowledge of where one is, and then coming up with kind of algorithms that are appropriate or inappropriate to run

in that context. But what is the nature of these algorithms? Are they of the, okay, shut down all cursing in this environment? Okay, you're free to just quote-unquote be you. I mean, when it really comes down to it, it has some interesting philosophical aspects too because just be yourself, be authentic, be vulnerable, you know, all these things make sense. But of course, one needs to be appropriate with the context. So how does this work? Like what is the, what are the algorithms? How does this work?

Right, because that's a pretty common example of our patients that they don't follow the rules. They, you know, if you're sitting in a, someone's, the doctor's office and the phone rings, you know not to pick up his phone, but the patients don't. They may pick up the phone. There's this Dr. Lumet, who's a neurologist from France, who published these beautiful papers in the 80s of all these things that patients did that broke the rules.

Just kind of pulled to their environment without having any context to it. If he put a pair of glasses on the table and didn't ask them to put them on, they would put them on even if they had a pair of glasses on already. Or he took them to their apartment and they saw the bed and they jump into the bed and go under the covers. Or he saw, he had a nurse and she,

he put a blood pressure cuff there and she picked up the blood pressure cuff and just start taking his blood pressure again, not asking him to do any of these things. And so they just don't follow sort of the social rules, but they're there. They haven't lost rules. If you ask these patients,

was that the appropriate thing to do? They'll say no. No, they know it's not appropriate. They know it's appropriate. Yeah, they say, no, I'm not supposed to answer your phone. But it's... Oh, wow. So they know, I'm not supposed to answer your phone, but. Oh, wow. So they know better, but they can't control the impulse. Exactly.

So it's, it's, it's, so it's not a breakdown at the rules disappear. It's that they can't apply the rule, they can't apply the rules properly. And, and, and that's true for a lot of patients, even with kids, you know, you tell them, uh, don't have anything to eat before dinner because we're having dinner. And then they're sitting there having a sandwich and you say, what did I just tell you? You said, well, don't eat, but I'm, I'm hungry, right? Another sort of example is sort of the frontal lobe is not completely kind of developed.

So when I think about rules, I think about the brain, you know, the brain processes information obviously, but it also stores information. The most important thing it does is store all sorts of information all over the brain. And I think what the frontal lobes do is they store rules. And what's interesting about the way it stores rules, they seem to store the rules in a hierarchical fashion. And what I mean by that is that there's different levels to rules. I like to give the example of playing golf. I tell a story a lot about my good friend Bob Knight when he hits a ball into the woods and he has to try and hit the ball out of the woods. He's holding on to all different levels of rules on how to successfully get his ball back towards the green. So the most simplest one is just like, where is the, you know, I've got to maintain the orientation to get to the flag.

You know, so he's holding that. He also had a higher level rules. He knows that if he kicks the ball, it's a penalty. So he's not gonna do that, right? And then another higher level rule might be, if I just keep doing this, you know, then this is gonna be healthy for me. And so he's storing all this information at sort of at different levels of

hierarchy and he's applying it to ultimately achieve this very simple active or not so simple active of hitting the off ball. So yeah. So I just, I think about sort of the frontal cortex is able to call upon the rule in the appropriate context. And if you don't have your frontal lobes, it doesn't get pulled up properly. And those rules must be learned, right? There's no way, I can imagine, that one can be born

into the world with these rules sets intact. I think about the two-marshmallow experiment that's sort of famous now, where kids are offered to eat one marshmallow right away or defer and get two marshmallows, these adorable videos of the kids, the various strategies they use like turning away, poking the marshmallow and you know, there's some debate ongoing as to whether or not success or lack of success in deferring

to the two-marshmallow reward is predictive of other things in life, but leaving that aside, am I correct in assuming that that task is a frontal lobe task? The kids are given a novel rule. You can have one marshmallow now or wait patiently and then with an overcome the craving for that one marshmallow and then you'll get two. Presumably that experiment is engaging the frontal lobes and we can only speculate but some kids are able to defer, some are not.

I can imagine that at that age there's a lot of neuroplasticity, strengthening and weakening of connections in the brain in an experience-dependent way. So does that mean that children and perhaps adults as well can train up their prefrontal cortical abilities to strategize and defer in a way that's adaptive? Absolutely. I mean, definitely you can learn strategies to not only sort of learn rules, but how to apply goals. When you start to think about that task in particular, some of it has to do with sort of maintaining a goal

and maintaining a goal at different, you know, time scales, right? And children tend to sort of act on goals that are much more short on a shorter time scale. You know, I'm gonna have the sandwich right now because I'm hungry as opposed to wait till, till dinner, which is a longer, longer term goal. And so yeah, this default to sort of the shorter, you can, you can learn that being tending a longer type goal can be much more beneficial than, than the short term goal, even though it doesn't seem obvious. And we all learn that, right?

We, as we, As we get older, we keep our eye on the ball of sort of long-term goals, and that's very predictive of how successful we can be. The farther out we can maintain a goal. And that's what the prefrontal cortex does. It maintains goals and then applies those goals. And if you don't apply them, then all of this executive function breaks down. Do you think that these algorithms and rules that the prefrontal cortical circuitry can learn and indeed does learn can generalize? So for instance, my first year of college was a disaster for reasons that aren't interesting right now.

But then when I came back my sophomore year, really spring of my freshman year, I was like, okay, it's on. I had to rescue myself. And so one of the things I used to do was I would study and I would set a timer. So I refused to get up. Even if I had to use the restroom very, very badly, I would set up all sorts of behavioral constraints. And I like to think that I was building up my prefrontal ability to refocus on the material. And fortunately for me, there were no smartphones back then. It was much easier internet. Now we had a email, but no real internet browsing to speak of. And I like to think that the, I sometimes call it, and this is terrible to call it this because it's not nearly exhaustive of the underlying function, but I call it sort of like limbic friction. It's like there's this friction that one feels mentally like you want to

get up, you want to use the restroom, you want to eat something, you want to call a friend, but you stay focused on the task at hand. Do you think that that business of quote unquote staying focused on the task at hand can generalize because of the sensations it generates in the body and then you go, oh, this is familiar. This is just like studying. But in a different context, one stays focused. Where do you think that the prefrontal cortex is so context specific that it needs to learn the rules for every individual situation? And then this has all sorts of implications for behavioral restraint and focus and attention deficit. So if you could just speculate, um, I know a number of people are interested in how they can be more focused and people often defer to like, what supplement,

what drug, okay, that those are interesting conversations. But I think ultimately we're talking about neural circuitry. Yeah. I mean, it absolutely can generalize it. That's been a frustrating thing into trying to develop what we call cognitive therapy where we, we teach, we try to improve someone's memory ability or we try to improve someone's executive function ability. The disappointing early results was always that, yeah, they get very good at the tasks

that you've trained them at, but it doesn't seem to generalize to anything else. So if you teach them a task, they can do amazing things like match a finger to a color to a shape and put together all sorts of rules. And then, and they're really good at that task very quickly. And then nothing's really changed in their real life. But I think we've learned on how to sort of, on how to try and make it translate to real life. And so for example, there's, there's a therapy called goal management training, which is

developed by Brian Levine and colleagues at the Rotman Research Institute at Toronto, where they've been very successful in teaching patients how to improve your executive function and how to make that translate into your real world. But it's very hard work. It's very therapist-driven. It requires a series of trainings. For example, people learn they develop individual projects It requires a series of trainings.

For example, people develop individual projects like planning a meal or planning a family vacation or planning a podcast. Then they work through what's involved in that sort of very specific project, how you stay focused, how you don't just get distracted, how you keep your eye on the ball, how you break it down to sub-goals, how you monitor what you're doing, how you keep your eye on the ball, how you break it down to sub-goals, how you monitor what you're doing, how you don't let anxiety and procrastination get involved. But it's a very active sort of process.

But when you add all that to it in a very disciplined way over the course of many hours, many weeks, it does translate. Patients and individuals just say, yeah, I'm just better at doing things. I mean, the whole goal is to do things, right? And I'm just better at it. I don't know what it is, but I'm not just better at what you taught me. I'm just better at other things. So I do have a lot of hope that these kind of therapies will generalize to the, you know, to people's real life. I, throughout the term limbic friction, again, not a technical or clinical or official term

in any way, but just a way to kind of capture some of the interactions of the frontal cortex with other circuitry. I mean, there's far more involved in agitation and challenges focusing than the limbic system, but it certainly is involved. When thinking about the frontal cortex, I often think about its connections with other areas of the brain. So maybe we could talk a little bit about those connections. And in particular, the connections from the frontal cortex to, let's call it, circuitry

that controls reflexive behaviors. What is the nature of that circuitry and can we make any general statements like does the frontal cortex really serve to provide a quieting, suppressive function on reflexes or is it more of an orchestra conductor where it's saying, okay, a little bit of that and a little bit of that. And then what comes out in behavior or speech is something that looks very organized but is actually the reflection of a lot of selective filtering. Yes. I mean, the prefrontal cortex, what's so fascinating about it is that I would say it connects to every part of the brain, cortex and the subcortex, and almost every part of

the brain connects to it. So that, I mean, that right there tells you it's a pretty important area. And it has to, if it's going to be in this CEO, you know, conductor type experience role. And so it's in this privileged position, just anatomically, so that, that gives us great insight to how important it is. And so it is connecting. And then of course we could talk about it, how it's connected to the body as well, how it controls heart rate and respirations as well.

So it's not just the brain. So, but it's really interesting. Like you said, is it really just sort of maintaining, telling you what's relevant and what's not relevant? Or is it allowing you to switch? I think it does all those things. It definitely what we call sends these top-down signals. It's sending signals to the other brain about what you should be paying

attention to and what you shouldn't be paying attention to. So for example, if you we've done studies with functional imaging where we have them look at pictures of faces and scenes and that lights up the back of your brain. Your visual cortex has areas that can process faces and process scenes. But 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'll sort of, it's sending a signal say, pay attention to the faces, ignore the scenes, or vice versa. So it's directing all of this information that we've been parted with to what's relevant. But at the same time, it's also allowing us to switch. If that, we now have to go switch to another task. It says, okay, this is not important now. We're gonna move over to this other task. So there's many different components of how it can, you know, 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 brief moment and thank one of our sponsors, and that's AG1. AG1 is a vitamin mineral probiotic drink that also contains adaptogens. I started taking AG1 way back in 2012.

The reason I started taking it and the reason I still take it every day is that it ensures that I meet all of my quotas for vitamins and minerals. And it ensures that I get enough prebiotic and probiotic to support gut health. Now gut health is something that over the last 10 years we realized is not just important for the health of our gut

but also for our immune system and for the production of neurotransmitters and neuromodulators, things like dopamine and serotonin. In other words, gut health is critical for proper brain functioning. Now of course I strive to consume healthy whole foods for the majority of my nutritional intake every single day, but there are a number of things in AG1,

including specific micronutrients that are hard to get from whole foods or at least in sufficient quantities. So AG1 allows me to get the vitamins and minerals that I need, probiotics, prebiotics, the adaptogens, and critical micronutrients. So anytime somebody asks me if they were to take just one supplement, what that supplement should be, I tell them AG1 because AG1 supports so many different systems within the body

that are involved in mental health, physical health, and performance. To try AG1, go to drinkag1.com slash huberman and you'll get a year's supply of vitamin D3K2 and five free travel packs of AG1. Again, that's drinkag1.com slash Huberman. 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. I'm aware that the hypothalamus and some of these deeper brain structures associated with more, let's call them primitive drives, temperature regulation, hunger, etc., 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 be a podcast. You talked about how TMS to the prefrontal cortex can slow heart rate. So I meant in that sort of way. That yeah, by influencing cortical function, well, obviously we can influence organs like that. Got it. So through some intermediate stations. Yes. Yeah. I mean, it's not to be hyperbolic, but it seems like the prefrontal cortex, what we're referring to as the frontal lobes, are essentially the seed of what makes us human and what makes us functional or dysfunctional in a given context.

I recall there's a syndrome, clover-buce 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 they'll try and eat a ceramic cup or draw with a piece of paper, which obviously won't work. It 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 gonna,

or write with it, but I'm gonna 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, um, so rule sets, but that something's intact. It's like that. It's not like clover, buce syndrome where, um, like animals and people can try and like mate with inanimate art objects, um, which is one of the more salient, um, symptoms. I'll never forget that. Never forget that from, from my cognitive neuroscience course, which you taught by the way.

Just throw that in there. 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. 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 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. And I guess I can reflect on my patients. You know, when 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 or 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 broke as aphasia, who has this inability to speak, they can't get any words out. Now this is a devastating problem. There's still the same person. They, they, they, their personality hasn't changed. They, 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 procephagnosic, which is an 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. 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, um, take

who we are and translate that into knowledge. So we're not, I guess another word saying of just, just having knowledge is in what makes us who we are, right? It's to be able to take that knowledge and, and, 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. 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. If I don't do that, I go non-linear 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, but and certainly our emotions. Is there a frontal lobe regulation of emotional states as well? I know you have some recent work on this. 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. And so there's this intimate back and forth between these two areas of the cortex. If you have just damage to these frontal, to these areas

that are kind of in the overfrontal lobe, you will have many different impairments that we would call social or emotional impairments, and their executive function will be quite normal. And then you'll have the opposite where patients with a lot of 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 right emotion and contacts is going to influence our executive function. We 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, kind

of a quiet place. But it is something that we can, I think you're right, you can sort of get into a routine and learn how to do things, if you have very much planned out. But what's so unique about us is how we can be flexible and adaptable, right? When something novel comes up or there's 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, and when things don't go right, how to write the ship, right? I will never ask you to demonize technology. I certainly use a smartphone from waking till sleep, generally not in the middle of the night,

if I can avoid it, and I generally avoid it. But I'm trying to take what we've discussed thus far and superimpose the notion of smartphones and ask what are the rules, what are the algorithms that we're learning when we use these devices? And 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 this 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. If we really step back from this move one's thumb and access hundreds if not thousands of video content which each of which has a distinct context. And 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. 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. 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, are they neutral?

Are they positive? 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. Yeah. I mean, I can just historically, I grew up in a world when there was no smartphones as a resident. 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 kind of 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. I never, you know it does not help me at all in making the kind of decisions that I have to make in the emergency room. I'm trying to decide, you know, what's the problem here? What's the differential diagnosis? What, 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 Dilanthin 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. But 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 much for my cell phone if I'm going to go to, or is it you remember I'm going to take a phone call. So I don't see how it's helping sort of make your front to lobe. It can't be your front to lobes. I mean, it's another way of saying

it. But on the flip side, can it help you optimize front to low function technologies? 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 and to you as opposed to a book or having a therapist in your house. Yeah, I suppose I worry that too much of my time and other people's time, and especially young people's time, is engaging in a 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 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. Whereas 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 know. I still have one of my friends. I still, 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 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 in generalizing the verse generalized in a bad way right and as opposed to a

Good way So I don't yeah, it does 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 the sort of having your head buried in a cell phone, I'm not, yeah, it's, I don't see it being healthy for your frontal loaves. Let's talk about working memory. Some years back, but still now, you use working memory tasks and experiments in your laboratory.

If you would be so kind as to explain what working memory is, and then I'd love to talk about some of the work you've done exploring the role of dopamine in working memory, because 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. So 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 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 wanna pull up

my sole 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. What I've learned more about working memory is the working part of it. It's not just this passive holding information of mine, but it's being able to do things with the information. It's being able to, when we do a bath problem, which we don't do that much now that we have

calculus, 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. So 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. If 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 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, right? We have to hold in mind rules, we have to hold in mind goals, we have to hold in mind all of these things in order to just carry out behavior. You know, so it's really come a long way in terms of how people are thinking about it. I know that Matt Walker said that like, you know, 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 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? Is it a facilitator? What is dopamine doing for working memory? 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. And 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. It's you can, working memory is short lived, it's only as long as you're able to rehearse it and then it disappears. Whereas what we call long-term memory, if I, remembering 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 there. 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. When 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 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's in your back of the brain. And so the frontal lobes is keeping information in the back of the brain active because it's connected to the visual areas. It'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 do? Well dope mean 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 the, what we call the basal ganglia, which is important for motor function.

And there's another dopamineric 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. Am I reaching too far to draw an analogy between dopamine's role in working memory, that is to keep information online, and the other established role of dopamine, which is for movement, for the generation of smooth movement, as evidenced by conditions like Parkinson's where people lack dopaminergic neurons or have damaged 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.

It'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 dope mean 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 will, when dopamine is expressed there and boosted there, then it will be involved in movement. And lack of dopamine and the basal ganglion will lead to neurological disorders like Parkinson's

disease that has severe movement difficulty. But when it's acting in the frontal cortex and expressing the frontal cortex, then it's going to improve working memory. So it's just the nature of where the circuits are, where the don't mean 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 memories 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 in vice versa. I'd like to take a quick break to acknowledge our sponsor, Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means zero sugar

and the appropriate ratios of the electrolyte, sodium, magnesium and potassium. And that correct ratio of electrolytes is extremely important because every cell in your body, but especially your nerve cells, your neurons, relies on electrolytes in order to function properly. So when you're well hydrated and you have the appropriate amount of electrolytes

in your system, your mental functioning and your physical functioning is improved. I drink one packet of element dissolved in about 16 to 32 ounces of water when I wake up in the morning, as well as while I exercise. And if I've sweat a lot during that exercise, I often will drink a third element packet dissolved

in about 32 ounces of water after I exercise. Element comes in a variety of different flavors, all of which I find really tasty. I like the citrus, I like the watermelon, I like the raspberry, frankly, I can't pick just one. It also comes in chocolate and chocolate mint, which I find taste best if they are put into water dissolved and then heated up.

I tend to do that in the winter months because of course you don't just need hydration on hot days and in the summer and spring months but also in the winter when the temperatures are cold and the environment tends to be dry. If you'd like to try Element you can go to drinkelementspelled.com.com. To try a free sample pack again that's drinkelements.com. So drilling a little bit more deeply into the role of dopamine in 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. Conversely, 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 bromo-cryptine 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? Right. Well, most people probably have optimal dopamine, but there's a significant percentage that probably have too little or maybe too much.

And it's 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 doesn't, is not a good read out. It's not a good read out, yeah. And especially when you're talking about dopamine in areas like prefrontal cortex.

And so we don't have a good read out there. There's invasive procedures like positive trontomission tomography where we can inject And so we don't have a good read out there. There's invasive procedures like positron emission tomography where we can inject a radioisotope that tags don't mean and then we can measure how much, we can do a scan that actually shows us how much don't mean. This scan was originally developed to show Parkinson's disease that you can diagnose Parkinson's disease

by showing that there's less stope mean in patients that have Parkinson's disease by looking at this's less dopamine in patients that have Parkinson's disease by looking at this skin. Obviously, it's invasive. You're injecting an 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. So 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 reflective of lower baseline dopamine levels. Is that right? Yeah. It's a very strong proxy for dopamine. So if your working bearing capacity is seven letters or numbers when I say four, three, seven, one, five, zero, six, if you get them. Four, three, seven, one, five, zero, six if you get them. Four, three, seven, five, seven, six.

Did them all back very quickly. You probably have more baseline dope mean than someone who has five. It's a proxy for measuring. That's one way of doing it. That's actually how we did in our original studies. We actually grouped individuals based on whether their capacity, based on this behavioral measure, was high or low.

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 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. We're trying to get people optimal. And so the real question is, 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 Compt

that breaks down dopamine in the prefrontal cortex specifically. In 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 gonna vary, depend on other, 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 and actually more dopamine sits around and 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. Those 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 will make them worse. Super interesting. Maybe we could talk about bromocryptin a little bit and I'm not encouraging people to run out and take bromocryptin. Bromocryptin, as you mentioned, is a dopamine agonist,

relatively short acting. Yeah, four, five hours, six hours. So kicks in about 90 minutes after, as I recall you saying. I've never taken it. Yeah. But how do people feel when they're on Roma Cryptene? 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 increase dopamine, but the kinetics, the time course and the levels are different for each of those things. Dopamine 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 and working memory, attention, task switching, etc., that there would be a strong interest on the part of the pharmaceutical companies at least, and certainly the general public

in things like promo-cryptine to increase dopamine to increase working memory, given it is our super power. 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 kind of process with very specific neuromodulators. The discovery that depletion of dopamine and not other transmitters in Pears' Working Memory was made in 1979. When I heard Pat Gormick, 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, you know, a single neuromodulator and a single cognitive process. And just opened the door for me that this really could be a incredibly beneficial therapy

for anyone with executive function or frontal lobe function. But unfortunately, there's never been a pharmaceutical company that's tried to develop a drug for improving cognition to this day. That's crazy. 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? I'm not sure. I mean, when I realized that I could test these drugs in healthy individuals, that they were, if I gave them in low enough doses, they were safe, and I had so much experience of them in patients

that I felt comfortable doing it, then I started asking pharmaceutical companies, do you wanna get involved here? We can, this should be done. I can't do this by myself. We need to have real trials and real studies 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. 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? Is it Alzheimer's disease thing? And this has been a general problem with neurology. It's very disease-centric. It's always sort of, and it's always focused on, you know, 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 help the 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. And my working memory is better. They have no idea. They don't even know their working memory is better. It's always, we show them that their working memory is better. Love it. Yeah. They don't even know their working memory is better. It's always, we show them that their working memory is better. So yeah.

So they're truly blind to what's going on. Bromocryptine is but one of the dopamine agonists can think of a few other, kibregoline, 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 specifically the drug. The reason for bronocryptine is that it's the oldest and it's the one I was most comfortable with. I had to be comfortable with it clinically before I'd give it to undergraduates at Penn or Berkeley, so there's nothing special, but other agonists work similarly. There's a drug that's developed for Parkinson's, which is a Compt 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 future work that Norepinephrine also seems to be helpful with working memory. It's not as 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. You know, I wrote a paper as a resident, you know, sometimes you're attending say, hey, can you write this review paper for us? And I wrote one as a resident called the pharmacology cognition where I just looked

at all the animal literature on, you know, giving neuromodulators, acetylcholine, bronch, dopamine 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, don't mean,

and it wouldn't do anything. You give acid to a choline, it wouldn't do anything. But if you gave a low dose of both, it would be really effective. So these, you know, these neurotransmitter 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, these stress 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 things. 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 different interactions. Maybe we could talk about a couple of other drugs that are legal and have FDA approval or are known to be safe in the right context that it seems would fit the bill here for improving working memory. One 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 wellbutrin can improve working memory? Yeah, and 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 brain fog for COVID showing that improved symptoms with it. So there's actually some trials now that are looking at guanfacine. And so I would say anything that boosts norepinephrine would be helpful. seen. 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. Serotonin, increasing serotonin, increasing acetylcholine boosts other cognitive processes. And then 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 working memory. So what I'm really pushing for is not just a single, you know, it's going to be one drug, you know, 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 so that everyone's don't be norp and nephron 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. You're not actually doing it. We're not actually doing it, but it seems that way. 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 acid 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. Most 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, etc. 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 dopaminer system is complicated because it's not only just the prefrontal cortex, as we talked about, it's also the

basal ganglia. And so not only do we have to measure dopamine just generally levels, we have to measure the balance of the dopamine in this triadm and the prefrontal cortex. There's a model of dopamine function and its relative 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 and refresh, you know, the information

that you're holding in mind, this sort of stability versus flexibility. So if you have too much dopamine from the cortex, it could lead to a very rigid state where you don't let anything in. And if you have too much dopamine in the straight, I mean, 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 don't mean. 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, for example, if you measure pupillary pupil dilation, that's a pretty good proxy for the neurogenetic system. All 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 it's you're in a dim room. That's sort of obvious. But at a given luminance, the more alert aroused somebody is arousal as 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. Do 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 neuromotoric systems. So that's why I've been so interested in developing biomarkers, because really what a neural biomarker is, is trying to develop something you can measure easily and simply and cheaply, but gives you information about how the brain is working. So that's a neuro-epinephrine biomarker. Work and marry 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 improve brain health. Have you ever tried bromeocryptine? Very early on, but it's such a low dose 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 it's peripheral, don't mean they can get nausea or vowing, but it's extremely well tolerated.

You don't get anything feeling from it. Does it change reaction time? It does, and that's always the question of how much of this 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 bromo-cryptine pre-Olympics and in the Olympics. I think it's a banned substance now. And the athletes that were taking it, don't ask me how I know this, but I could tell you offline. And I'm not one of these athletes, nor was I supplying the bromo kryptine.

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 band substance list.

Just a reminder that every Olympics you see, there are lots of things being used that are not on the band 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. Bromocryptine was top of the list at that time.

I think it's on the band 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 vivants, Ritalin, and other stimulants which are Noradrenergic, Dopamineergic, Agonist. 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 wanna perform well, they need to be able to focus, we'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 improves my focus as long as I don't drink too much of it. Right. Yeah, what are your thoughts? Yeah, I think it kind of gets back to what we talked about there being an optimal level of dopamine in your brain.

I think if you think about it as just more and more and more is better and that more is better, then there's really no end, there's really no end. How do you know how much you should be taking this sort of? That experiment was run in the 80s. It's called the cocaine culture of Wall Street in the 80s. There was their 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's not, that makes sure don't mean 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 and some of these athletes were actually making themselves worse. We know for sure. I mean, these are healthy Penn

and Berkeley undergraduates 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, you know, without the knowing, then it just, it seems like it's not well informed. You're going to be taking it. The other thing is, I, if we're going to do this, we should do it right. I think drugs like Adderall and Ritalin, you know, 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 worked.

That's a surprise too. Yeah. I mean, it just, 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, n noraminophen, 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 noraminophen, but if you take something like Ritalin Adderall, you just get in 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 serviced. So I use things like promo-cryptin and guanfacine 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's sleeping better and better nutrition.

All these are aiming to optimize, not reach some super human potential. Right, just bringing 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 gonna pay the piper somehow. 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 tension 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. That's why Gronel Kryptin, the Dobernurk story has been so interesting because it's a very specific effect with a very specific mechanism. I'd 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. Before we're recording a day, we were talking about football, but just want to remind people that football is just one instance of an opportunity to get a concussion or traumatic brain injury, most traumatic brain injury 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 in 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, just it's becoming more recognized. And I think we underestimated and trivialized what a concussion is. It's just something that 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 realize that there's actually quite a large percentage of people who, a year out,

there's 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 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. And 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 clearly had a concussion? Mild or severe concussion? 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, unfortunately, and you just feel off. You don't feel quite right. 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. 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 just they just want to understand their problem. They're 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 we 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 of axons. It's 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, and that angular force actually tears and stretches axons in the brain. So if you've had a concussion, you have torn 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. There's a correlation. The longer you've lost consciousness and the longer your symptoms last, the more axons you've torn, this kind of direct relationship between the two.

The mechanism is these torn axons. So now, nurses don't communicate with each other, and the brain, different brain regions are not communicating with each other. So, and it turns out the most common place for accents to tears 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 while 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 non-ability to get things done. They don't lose knowledge of who they, they don't forget their name or forget where they live or lose memories from the past or anything like that. But they just, they don't officially get things done as well as they used to. It only takes a little bit of a

drop, right? You, people think you have to have a big drop in performance to have it, have a real life impact, just a 1% drop. And you're, you're having a hard time doing your bycast or teaching a lecture or whatever you might do. A 1% drop sounds like a, or whatever you might do. A 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'd 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, this 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 picture and how fast they throw, you know, a small drop for them. Someone 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.

I don't know why tearing your cruciate 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, 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, given that sleep deprivation can compound traumatic brain injury induced deficits in working memory. 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. 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, not a lot of neurologists ask you how you're sleep, 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 to sleep last night. And it's just across the board. 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, you should don't go to work, you know, sleep, you know, just, just take it easy for a while, don't exercise.

Keep the blunt, the blunt strong. Yeah, but now it's, it's, it's the idea is that you should really get up and moving as best you got to, you got to do what you can tolerate. You don't want to give yourself what you can tolerate. So you don't want to give yourself a head. You offer it. You don't want to give yourself more of a headache or more light sensitivity, but as much as you can tolerate is, 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 and work for a couple of

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 how, 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. And then I think we need to develop therapies

that people will use. Things like gold 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.

You know about Brain HQ? So Mike Merznik, which I know you've talked about with Eddie, developed a company called Posit Science where developed these brain training games that can help improve specific cognitive functions. And they're very easy to do because they're online and they're science behind them and you can do them. So that 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 try and improve the kind of things that we think are impaired by concussion. And I'd like to see more patients get started on some of those things. Unfortunately, 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 Merzeneck and colleagues have done, and we'll provide a link to that.

I don't have any financial stake in his work or products trainings, that is. But I will say, I think Mike's work has been tremendous. I mean, he is so far ahead of the curve. 20 years ago, everyone was talking about neuroplasticity in critical periods. They gave a Nobel Prize to it to my scientific great-grandparents, David Hubel and Torrins 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 Mersennec really, I think, one of the people who deserves credit for making it clear that plasticity is ongoing, take some focus and work to access it in adulthood, but that we can all access neuroplasticity, but it takes, it's there. So I don't know. They should give MERS and IC in Nobel too, but you know, 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 goes to high school, graduates high school and then gets into a lifestyle or a 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 apparently a high degree of functionality, but they're not really pushing these forebrained circuits.

Do we imagine that some of those forebrained 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 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. For me, 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. Is that it, Seth? Yeah, I think that's fair. I think of all the systems that decline with aging, not every brain system declines, but

certainly the frontal executive system we're talking about is one that takes more of a decline than others. That's just how it is with healthy aging. Not surprising, it's the most complicated 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 not, we're maybe accelerating this decline that we know exists. And, 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. I 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, which seems and thinking about it, not just like stopping Alzheimer's disease, but promoting healthy health in a healthy brain. Neurotis 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 foraging 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's focus moves away is a way of keeping working memory and cognitive function online, maybe even strengthening it, as you said, optimizing it. I think that there's so much emphasis now on physical health, which I think is great. Sleep, thanks to Matt Walker, you really brought that torch in on sleep. And now others like myself are really trying to amplify the message of the critical role of sleep. But also, 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

or a week or more. And not just for athletes, but for elderly folks, men and women, I 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 need to do three chapters of reading fiction per week or you gotta read a,

you gotta 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 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. But what do they do for you? Outside of having a conversation with you. Yeah, no cognitive task. There's nothing. No working memory. 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 in 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, sleep, and it's well-being. 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 the first, once we develop a brain health index, that's that, then we have something to follow and to be able to measure if we are optimizing your brain health. Otherwise, how do you know if you're optimizing your brain health? You don't, your doctor's not telling you, you don't know. All these games you get on in the web don't really tell you. So 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? Again, maybe your profession and your personal life keeps you busy enough that you don't have to do those things. I 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. I'm full. My executive function is being tested to the limit. But you're like an athlete. You're like a professional athlete of the mind.

Yeah, in a way. But then you realize there's that that's not, you know, 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 health, 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. And just listening to books or reading hard books. Yeah, I still like to read the hard covers. Yeah, likewise. Unfortunately, when I was an undergraduate 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, you know, just knowledge was, was enough, you know, like I said, our brain just stores information. That's one of its, this job. So that, that's got to be useful. But 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 scan and things like that, I think that will really boost everyone's confidence that this is really making a difference. Well, 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 audiobooks, but it's crazy to me because I'm a neuroscientist by training and I understand neuroplasticity and 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? 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, 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. This interesting conference, 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 cognitive richness. This is kind of obvious as I say this, but I feel like we're divorced from these things that really helped evolve culture and evolved individuals. And it takes some discipline,

but like Iran or going to the gym, you do it 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 gonna be a pro. I'm certainly not gonna be an English lit, I mean, you know, professor. You know, so I don't think,

obviously boosting exact functions is incredibly important, but I don't think obviously boosting executive functions is incredibly important, but I don't think it's going to happen just with technology. I 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 court, 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 an experiment and carry out the experiment, there's no technology that's gonna just be able

to teach them how to do that. You've gotta intervene sometimes and say, stop reading all those papers, they're not relevant, okay? Or 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, 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. 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, just do it this way, break it up into little pieces. It 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 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... Working memory, you got to keep information online. There's there's a bunch else there Um, I think uh, but as a tool to improve cognition

Um, I was also thinking you know, some people orient more towards the arts. My sister is really great about um, she's a therapist in San Francisco, but also um takes like theater classes and she said, you know like improv is like forces you to like keep on your toes Keep the context there. You're up on your feet like, 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, 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, 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 into sub goals and you've got to do it simultaneously and you got to filter out distractions and, you know, you know, for example, my, my kids got me one of these pizza ovens for, for Christmas. And, you know, you think it's easy to sort of make some pizza and throw it in the oven and done. That's where I'm on my third time and it's easy just sort of make some pizza and throw it in the oven and done. That's where I'm on my third time and it's still not even round.

I'll come over and test that sounds good. It sounds good and you're in a city with great food. So the standard is really high. Attempted to make a reference to the cheeseboard pizza, but I want to keep the lines as short as possible because they're already too long. a cheeseboard 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. Parkinson'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 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 their, one's risk for getting Alzheimer's? It's not that straightforward as other diseases. There's diseases like Huntington's 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 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 a case that you're increased your risk of getting it. There are families where there is something special about the family where it just runs in families, but I try to not scare my patients' 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 nerves-generated 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 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 sub-seller structures and buildup, and 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. 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 allergic 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? I 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, it's very frustrating because the neurodegenerative disorders, it's just, it's so, so many factors that are probably involved in the pathology that there's not one single transmitter. The 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 acetylcholine in the brains and the only approved treatment for Alzheimer's disease is a drug that boosts acetylcholine. It's called the neppazil. There's a few of them. They're anti-colonase-trace 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, the wide range of cognitive behavioral issues. And there doesn't seem to be at least one neurotransmitter that can make the difference.

And so now the push has been, is there one, is there something else that we can do? Can 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 saved 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, 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 a cure. Parkinson's, you mentioned, is a deficit in dopaminergic function due largely to degeneration

of dopaminergic neurons. There, there's some effective treatments, right? Eldopa. 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 Macuna Prurin. It's the velvety bean. Yeah, I've heard of it. It's 99% L-dopa.

I hover it, yeah. It's present in like some energy drinks and supplements and people can go buy it. I'm not suggesting they do that. I actually tried it. Boy, feel, being really dopamine out does not, to me, doesn't feel that good. Yeah, 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 al-dopa to get enough into your brain.

That happened early in neurology when it was discovered we couldn't give our patients enough al-dopa without them feeling bad because it's also metabolized in the periphery and so it wasn't until we Cynomet came along which has this deboxylase, decarboxylase inhibitor that blocks sort of the breakdown of dopamine that we were able to sort of get enough dopamine into the brain. So 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 al-dopa or bromocryptine or drugs like that. Going back to Alzheimer's for a moment, I mean, what do you tell it? 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 inducement or aplasticity, but we're just gonna 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 toto-day basis. A 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. So there's still those memories that 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 in a symptomatically. I've seen a number of videos on social media, 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. Yeah, it's a tragic situation for Alzheimer's right now. It seems like if ever there was a

call to arms for the neurology community and biotech and behavioral tech would be for Alzheimer's, for the treatment of Alzheimer's. Yeah, absolutely. I will never ask, I guess, 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 Nicaragum. And I said, I gotta ask, what's this about? By the way, he's extremely sharp still. And he said, oh yeah, yeah, yeah, you know, I used to be a smoker, but smoking is really bad for you because you can get lung cancer, dipping is bad for you because you can get lung cancer. Dipping is 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. Well, he's not, he is an MD actually. And I thought, well, 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. I 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 and it was used in a number of early Alzheimer's studies just because of its effect on the colonergic system. So there is some truth to that. The colonergic system is dysfunctional in Alzheimer's disease and boosting the colon allergic system probably is beneficial. I mean, the patients that we give the anticholinesceraries 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. It doesn't really slow the course of the disease. That's the problem that disease just carries on, even though we're symptomatically improving the symptoms. But again, I think it's gonna take both acetylcholine and something else. I think we don't know. Should we give dopamine with the nicotine or the acetylcholine? Are we gonna have enough for it?

I think it's gonna be a cocktail, which again, pharmaceutical companies have not tried a cocktail of neuromodulators for Alzheimer's disease. They've just tried hasocoline. Sounds like you should be running the FDA. No disrespect to the current people in charge, by the way. But maybe, actually, 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 maybe there's more susceptibility in one case, maybe less susceptibility, maybe certain neurotransmitters are more effective in improving symptoms in men

versus women. Do 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 and dobernurgic 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.

And 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. She did this amazing study where she studied healthy Berkeley undergraduates at two points in time during their menstrual cycle. One estrogen was at its lowest and one was its highest. She studied healthy Berkeley undergraduates at two points in time during their mental cycle. One estrogen was at its lowest and one 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. When they were low estrogen, they were low dopamine. And if they were low estrogen and low dopamine at 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, you know, 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. I think people mistakenly hear, okay, testosterone, men, 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 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 them 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?

It's 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 mental cycle we can think about how much it fluctuates in an individual

woman over 30 days, but then you can think across individuals, you can think about how much it can account for individual differences. So not only sort of knowing your dopamine level, but just knowing sort of how it's level, but just knowing cell rest and cell lungs 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 a 45 45 minute bout of exercise, pick your favorite exercise, and then doing cognitive work immediately afterward when presumably the catacolamines, dopamine, norepinephrine, and epinephrine are going to be circulating at least in the blood at higher levels? Has 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. So for example, the group at University of Illinois Champaign Archimere'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. And so, you know, the hard part in the real world is how do you get a seven-year-old to do the kind of aerobic, etc. But now with recombin bicycles and now there has been studies with seven-year-olds with just putting them in, mostly with the recombin bicycles, it's sort of designing, we 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, 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, no neurologist would say you got'm hearing, you know, you hear more neurologists talk about that, you know, 30 years ago, no neurologist would say you got exercise more, you know, or just now it's sort of 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 they were like, I guess, it's super interesting and I think it's going to be, you know, that kind of made me think that what we didn't talk about was mindfulness. And so when we add a lot of these studies also if they add mindfulness training to the Chard Quark 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 they sort of stereotypical meditation of 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. I think of meditation of that sort as a focus exercise. Right. It's not so much a perceptual exercise because thoughts are kind of, you know, 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, you know, to stop and relax and refocus is an important strategy for boosting executive function. So and that, 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 tell her the mindfulness, but most forms of mindfulness will work up the type you're talking about. That's similar, what I described is similar to what you guys explored.

Exactly, 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, breathwork, the idea that, oh, my goodness, breathing can impact your emotional state. I mean, that should have been obvious. But now that people are on board that, and now, of course, there's a lot of interest

in psychedelics as 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 as to optimize cognitive function. I mean, this conversation would have never happened. Seven 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 Nitro where you just lie down and these are free audio scripts online. We can provide links to these. 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. I 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 get re... 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, I start thinking, you know, like in the course of my lifetime, this is, you know, a relatively small, not small thing, but in relatively small time bin. And I sort of think about,

you know, best course of action given its real role in my life and what I want, etc. 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 when we're talking about what should we do besides reading fiction. I think that should be on my list. Because I guess that's one of the things we were talking about, what should we do besides reading fiction? I think that should be on my list because I guess it's just amazing that the patients tell me about it and what we've seen from our studies. A lot of this, like 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

don't mean 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, and 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 your, the state of your networks is really important factor as well, in addition to sort of your sort of neuro-modul, you know, sort of your state of your networks is really important factor as well in addition to sort

of your sort of neuro-modul, 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. Searoth taught me to ask this way back when, like, what are you most excited about now? Because I know the work you've published and we, 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, what are you really excited about? Like, like if, 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. And so it's 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 a sudden learned in neuroscience is starting to now translate into something. In sort of what's happened in the last 10 years of we've we're thinking of the brain and in a kind of a grander scale is sort of its overall organization and not so focused on just this area or that area. When I 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. And 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, an 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?

If 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 gonna get delayed because it just has this huge impact on the whole system. And if Milwaukee goes down, you don't even know it, you just fly right over that.

I'm sorry if anyone's listening from. They're probably a few. You gotta go through. But so thinking about the brain, the brain is the same way. The brain has these hubs as well. And the prefrontal cortex is a hub like Chicago. It's just an important hub that keeps the whole system going.

And 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 is that, I mean, it gets 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. What 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've really start to learn about how the brain is organized in these networks, we've also learned that learn about how the brain is organized in these networks, we've also learned that in 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.

The more segregated they are, we call that more modularity. They're kind of separate entities. They're modular. 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 advantageous to have more. So we can predict- More separateness of brain dysfunction between areas. Yeah, that the networks are sort of more independent. That 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.

Yeah. Genuine development are what we call poly-intervated. 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. Right. Look at that same kid seven months later. There's a lot more precision and movement largely due to removal, more modularity of connections. Right. Right. Interesting. So we did a study where we took 12 traumatic range repatiants and measured their modularity. So you get a number, you know, 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 more, 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, uh, different young, old patient populations. It's also predicted things like, um, 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 to behavioral therapy if they're obsessive compulsive so. There's something about this brain state that not only can measure but actually is giving us insight into. The interventions that we're doing which again is going to be much more helpful and. 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 because 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.

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 have a real verb action to them. And we haven't had so much of that for the nervous system 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. Matt Walker was just here recording this series on sleep that we'll release later this year. And stage is 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 in REM sleep are names that we made up, but there seems to be a much richer understanding of what rapid eye movement sleep is good for and what deficits and rapid eye movement sleep lead to. Then there is, for instance, how given our network, I'm gonna 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?

Is 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, this sort of thing. Well, 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. But 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, Sepeta Saragianis, 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 would 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. Maybe 80% of the time you heard it, sometimes 20% of the time you didn't hear it. Well 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 modern 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'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? And even I don't think you could even do with the EG.

I think, can we develop a proxy for modularity with some more simple way of doing it? Can we extract this maybe out of heart rate variability or for oxygen? Um, I've been, I've been working with, um, some colleagues, the former student, Brian Miller, and a post doc of Adam Gazali's West Clap, 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, we can measure the modularity in the scanner, but can we pick that up in the physiology data because they can collect oxygen and tart 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'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 in other stages of sleep. I mean, key metrics, not every metric, and 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 Cardard 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 about patients before and after macrodose psilocybin and this isn't microdosing. And 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 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. Silcyon 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 has to do with how we make these measurements.

And connectivity doesn't mean the same. 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. Because you've got to get from where your baseline is to this other state. And a lot of it has to do with like going from one state to another, not so much sort of the absolute sort of differences. So that's interesting. I didn't know about those results, but it's interesting that it does affect

sort of 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? Yeah.

So I think I have a lot of patients that I've referred for its approved use, which is depression. So I'm very excited about the of the work that's being done with it as a for depression, but we haven't really had any improved anything that's been for, you know, for cognition. So there are a bunch of studies and all small studies where you can give transcarimatic stimulation, frontal cortex and working memory improved, but they really haven't been done in ways that are, we don't know if it generalizes, if it's going to be how, you know, 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. I 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. Well, Mark, I just really wanna 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 gonna tell you a joke that was told to me. So that there are these people stranded on an island and they're really stuck and they're running out of resources. So that there are these people stranded on an island and They're 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, 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 neurologists were great at describing things, talking about the terrible conditions they could observe in great detail, but that they

conditions they could observe in great detail, but that they did not do anything about it. You 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 bromocryptine, mindfulness, exercise, and really as an exploration of what can be done

interventions. And so for all those reasons and for tolerating this terrible joke that I just told, I want to 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 pointed 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.

We're appreciating what we do. It's just so important to try and get this message apart. Like 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, what about this?

What about that? Is do you think this would help me? Because we have to be advocates for our own health. And the only one we're gonna do that is just make people understand what it is that the possibilities are. So thank you, it was a lot of fun. It 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. Please check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast.

If you have questions or comments about the podcast or topics or guests that you'd like to suggest for the Huberman Lab podcast, please put those in the comments section on YouTube. I do read all the comments. Not so much on today's episode, but on many previous episodes of the Huberman Lab Podcast, we discussed supplements.

While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like improving sleep, for improving hormone function, and for improving focus. To learn more about the supplements discussed on the Huberman Lab Podcast, visit LivMomentus, spelled O-U-S, so that's livmomentus.com slash Huberman.

If you're not already following me on social media, I am Huberman Lab on all social media platforms. So that's Instagram, Twitter, now called X, LinkedIn, Facebook, and Threads. And on all those platforms, I discuss science and science-related tools, some of which overlaps with the content of the Huberman Lab podcast, but much of which is distinct from the content covered on the Huberman Lab podcast. Again, that's Huberman Lab on all social media platforms. If you haven't already subscribed to our monthly neural network newsletter, our neural

network newsletter is a zero-cost newsletter that includes podcast summaries and protocols as short, one-to-three-page PDFs. For instance, we have zero-cost protocols for improving sleep, for improving dopamine function, for deliberate cold exposure, for fitness, for learning and neuroplasticity, and much more. To sign up for the newsletter, simply go to hubermanlab.com, go to the menu tab, scroll down to newsletter, and supply your email. Again, the newsletter is completely zero cost and I want to emphasize that we do not share your email with anybody.

Thank 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. ["Desposito"]