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

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 D'Esposito. Dr. Mark D'Esposito 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. D'Esposito 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 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. D'Esposito 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. D'Esposito 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 Newi Venison. Maui Newi Venison is the most nutrient dense and delicious red meat available.

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Hey, Andrew. Thank you so much for inviting me. Really looking forward to our conversation. 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. 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 lobes, 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 don't, I'm going to use the frontal lobes probably in our conversation a lot, but what I really mean is the prefrontal cortex.

And 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, you know, involvement higher level 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.

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 move 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 take, you know, kind of ruled by sort of just automatic behavior.

And a word we use in cognitive sciences called cognitive control. So, cognitive control executive functions, what we attribute to the frontal lobe. And so you can think of it as, you know, the CEO of the brain or the, you know, or the conductor of the orchestra, really the part of the brain that's that's really controlling the rest of the brain.

So, yeah, if you had to choose which part you wanted to not leave home, this is 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, I first I should say is that it shows up all the time because when, when, and, and frontal lobe behaviors, 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, intramac brain injury, now, time receipts that can affect the frontal lobe.

And there's a number of, you know, psychiatric disorders, obsessive cum muscle disorder and schizophrenia and depression that are thought to be frontal lobe dysfunction. 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 difficulty sort of setting priorities, when we're having difficulties achieving.

The goal that we've set out when we get distracted, you know, when we're not able to sort of adapt and be flexible, these are all the type of things that are reflected our frontal lobes are not functioning optimally. Approximately what age does the frontal lobe circuitry come online, so to speak, I mean, when I see a baby, babies can orient their eyes towards things, but they're rather reflexive in where they'll place their eyes.

But by time kids are three or four, they can certainly play with blocks or interact with other children or their parents. But it seems that, you know, full functionality, 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 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 lobes fully develop. 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 insurance companies knew before.

And it's just as interested as to when your frontal lobes have, you know, when your decision making skills 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?

I think there's a reason I think that this sort of slow developed the frontal lobes allows us to 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 sort of rigid kind of less flexible kind of behavior that we'd seen things. So I think that it helps to be take a long time to develop. But also it obviously leads to some problems sometimes in adolescence 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. Now as a kid, is that somehow reflective of a, you know, slightly lagging frontal frontal lobe function. And maturity, whereas the, you know, the kids that can sit still and still I can focus. Does that mean that they're a little bit more accelerated along that trajectory.

It's hard to say. I mean, the frontal lobe is big is a big territory and we can get into it. But there's, you know, the frontal lobe probably has 25 different sub regions within it. And so grossly we think about the frontal lobe says the lateral portion of the frontal lobes, which is involved in these executive function probably supports these executive function abilities.

But then we've got another part of the frontal lobes called the orbital frontal cortex was probably involved more in social and emotional behavior. So, you know, when we think again when we think about frontal behaviors.

They kind of you have to break. There's so many different type of frontal behavior. So that type of behavior, which may be evolved and 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, you know, is more developed. And I do think they develop a different trajectories.

So with the frontal lobes, essentially serving 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? You know, when I think about brain function, which I've spent a lot of my life thinking about, 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 that I sort of lock into a certain rule set. When I'm home, I'm in a different rule set when I'm in my friends versus when I'm with my parents, a 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 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 someone's the doctor's office and the phone rings, you know, not to pick up his phone, but the patients don't and they may pick up the phone. There's this doctor Lumea who's a neurologist from France published these beautiful papers in the 80s of all these things that patients did that just that broke the whole thing.

And so, and bring just kind of pulled to the environment without having any context to it if he put a pair of glasses on the table and didn't ask him to put them on they would put them on even if they had a pair of glasses on already or he took him to their apartment and they saw the bed and they jump into the bed and go onto 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, they just don't follow sort of the social rules, but they're there. They, 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. They know it's appropriate. Yeah, they say no, I'm not supposed to answer your phone, but. Wow. So they know better, but they can't control the impulse.

Exactly. So 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 that's true for a lot of patients, even with kids, you know, you tell them 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? Is there another sort of example sort of the frontal lobes 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, you know, off 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. The simplest one is just like where, you know, where is the flat, 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 going to do that. Right. And then another higher level rule might be if I just keep doing this, you know, this is going to be healthy for me. So he's storing all this information at sort of a different levels of hierarchy. And he's applying, he's because of applying it to ultimately achieve this very simple act of, or not so simple act of hitting the off ball. So, yeah.

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.

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. The very strategies they use like turning away and 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 to presumably that that experiment is engaging the frontal lobes. And you know, we can only speculate, but some kids are able to defer some are not.

And 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 going to have the sandwich right now because I'm hungry as opposed to wait till dinner, which is a longer, longer term goal. And so yeah, this default to sort of the short, you can, you can learn that maintaining a longer type goal can be much more beneficial than the short term goal, even though it doesn't seem obvious.

And we all learn that right as we as we get older, we keep our eye on the ball, sort of more long term goals. And that's very predictive of how successful we can we can be the farther out we can maintain a goal. And that's what the that's what the prefrontal cortex does it maintains goals and then applies those goals. And if you don't apply them, then you lose, you know, then you 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, when I, my first year of college was a disaster for reasons that are interesting right now.

But then when I came back myself more year, really spring of my freshman year, it's like, okay, it's on. I was 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, 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.

Fortunately for me, there were no smartphones back then. It was much easier. Right. Internet. Now we had 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 this because it's not nearly exhaustive of the underlying function. But I call it sort of like limbic friction.

And 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, oh, that's this is familiar. This is just like studying.

But in a different context, one is one stays focused. Where do you think that the prefrontal cortex is is so context specific that it needs to learn a route 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. No, no, no, no, interested in how they can be more focused and people often defer to like what supplement what drug. Okay, those are interesting conversations. But I think ultimately we're talking about neural circuitry.

I mean, absolutely can generalize it. That's been a frustrating thing and trying to develop what we call cognitive therapy where we teach we try to improve someone's memory ability or we try to improve someone's executive function ability that the disappointing early results was always that yeah, they get very good at the task that you've trained them at.

But it doesn't seem to generalize anything else. So if you teach them a, you know, 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 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 Toronto where they've been very successful in teaching patients how to improve your executive function and how to make that translate into real world, but it's very hard work.

And so the therapist driven it requires it requires a series of of trainings, for example, people learn they develop individual projects like planning a meal or planning a family vacation or planning a podcast and then they work through what's involved in that sort of very specific project how you 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

don't know what you're doing how you don't let anxiety and procrastination 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 to say, yeah, I'm just better at doing things.

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 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, 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 sub cortex, 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 CO, you know, conductor type experience role.

And so it's in this privileged position just anatomically so that that is a 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 this 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 sending signals to 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 are can process faces and process scenes. And 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.

You know even though it's getting the same bottom up visual input the prefrontal cortex will show greater activity to the relevant information it will it'll sort it's sending a signal say pay attention to the faces ignore the scenes and or vice versa so it's directing all of this information that we're marty with to what's what's relevant but at the same time it's also allowing us to switch if if that we now have to go switch to another task it says okay this is the same thing.

So this is not important now we're going to move over to this this other 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.

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I'm aware that the hypothalamus and some of these deeper brain structures associated with more what's called primitive drives temperature regulation hunger etc connect to the body but what what's the nature of some of the connections with the

I was just talking yeah I was just sort of talking in terms of of our knowledge of how you know changing I wondered your practice you talked about how TMS to the prefrontal cortex can slow heart rate so I meant in that in that sort of way got it that that yeah by by the by influencing

cortical function will obviously we can influence organs like that got it so through some intermediate stations yes yeah I mean it's not to not to be hyperbolic but it seems like the prefrontal cortex what here we're referring to as the frontal lobes essentially the seat of what makes us human and what makes us functional or dysfunctional in a given context right I mean I recall there's a syndrome clover bucy syndrome which has some vague

similarities to how you describe frontal cortex damage but there I 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 cop 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 not supposed to write this but I'm just

going to or write with it but I'm going to take your pen and write something inappropriate with it but it's not that they people forget that there's it that it's a pen so it seems like it's drawing on so rule sets but that something's intact it's like that it's not like clover bucy

syndrome where like animals and people can try and like mate with inanimate are objects which is one of the more salient sometimes I'll never forget that don't forget that from from my cognitive neuroscience course which you thought by the way

just throw that in there so yeah so how should we think about this and here I'm trying to get at it kind of a broader understanding of brain function and context specific behavior so frontal cortex is like super sophisticated but it doesn't have all the information

right 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 an 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 injury always say the same thing they're just no longer that person they're no longer my spouse and along my best friend and no longer my father just something they can't put it into words but they're not them anymore there's something has changed whereas if you talk to a patient with broken's aphasia who has this inability to speak they can't get any words out you know this is a devastating problem there's still the same person

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 prosa magnosic which is a this inability to recognize faces of course the way they navigate around the world is is 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 a difficult part like how does the frontal lobes allow us sort of take take who we are and translate that into knowledge

so we're not I guess another word saying or 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 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 you know overcoming reflex by just having recipes scripts to follow each day I certainly try to have my mornings be as what I call linear as possible and I find it's much easier in the earlier part of the day to just decide here's what I'm going to do right out of 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 that sort

of 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

yeah I mean as I was saying earlier the frontal lobes is a big place and and half of it is involved in these high level executive functions but the other half of it is and is part of the limbic system or that we call it the parallel limbic 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

lobe you will have many different impairments that are we would call sort of social or emotional impairments and their executive function will be quite normal and then you'll have the opposite where patients with the lateral damage will have executive functions but they seem emotionally intact but but you know in real life when we have both these

intact they're communicating with each other so right emotion and contacts and is going to influence our executive function we make bad decisions in stressful situations or situations we're not comfortable with it's it's where we might make a better decision if it's a quiet kind of quiet place but it is something that we can I think you're right you can you can sort of get into a routine and learn how to do things you

know if you have very much planned to have but what's so unique about us how we can be flexible and adaptable right when when something novel comes up or there's something something unexpected comes up we can adapt to it and that's really what the frontal cortex is really important for not just sort of making these plans routines and setting all the rules with being and when things don't go

how to 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 this 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 on the ward and and for clinic and

it's so useful right but contained in the small device there are things like for instance text messaging where unlike 20 years ago we can have four or five different conversations very quickly while boarding a flight there's a task switching element that was just not present in our life prior to that

social media in particular this notion of being able to scroll so move if we really step back from this move ones thumb and access hundreds if not thousands of video content from the stick which each of which has a distinct context

and so I have to imagine that kids and adults have frontal cordices 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 it's a fairly limited landscape there when you really think about it but 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 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 I you know we can we can speculate but again with no with no intention of demonizing social media does it seem that the algorithms

that are being run in our brain I mean are they neutral are they positive are they negative should we be worried it doesn't seem like they translate to much else they they what 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 out I didn't even remember anything from that page going back line by line playing a game of squash or something like that there I can see the real value of the rules sets that generalize

yeah I mean I can you know just historically I grew up in a world when there was no smartphones as a resident and and so one of the most difficult things I do and practices 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 go down there and you didn't have any smartphone you you could only rely on what's what's in your head

and I could say now having the smartphone it hasn't doesn't help me at all I never you know it does not help me at all and making the kind of decisions that I have to make an emergency room I'm trying to decide you know what 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 and like back in the day I had to remember what the dilanthin dose was and have it in my head or go look for the piece of paper 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 it in my head.

There's nothing I can turn to that it's it's making me you know better making me make better decisions so I don't even need my cell phone I don't go searching for myself one if I'm going to go to the emergency room I'm going to take a take a phone call so I don't see how it's helping sort of make your frontal look it can't be your frontal lobes I mean it's another way of saying it but but on the flip side can it help you optimize frontal function technologies certainly it can we can maybe talk about later there are certainly that's one way to get

to get learned strategies is through a through a device that that's easily accessible and you know to you as opposed to a book or 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 an algorithm that does not generalize for adaptive behavior elsewhere and and by comparison you know like a game of soccer with friends or something right it's social social media social it's physical social media is not physical but we'll rule that 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 it's hundreds of thousands of context so is there any risk or perhaps benefit to being able to get this very detailed portal into so many context 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 is watching them navigate in their cars to places totally dependent on on Google maps and I think you're probably old enough to remember real maps where you don't have it. I still I love paper maps I love maps.

You know you had to go to a certain place and you had to either look at the map or or ask stop at a gas station and ask if these these skills were something that you learned and you developed and it was problem solving and and that's all gone now I mean it's I wonder even if sometimes if if people even know the direction they're going whether it's west north or what sat down they're in because they're just following the direction so I will see I just can't imagine that

that learned skill is not going to be detrimental to us at some point in generalize in the worst generalize in a bad way right as opposed to a good way. So I don't I 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 else a professor when he's giving a lecture so I agree with you that the sort of having your head varied in a cell phone I'm not.

Yeah it's I don't see it being healthy for your frontal. Let's talk about working memory some years back but still now you use working memory tasks and experiments in your laboratory you would be so kind is to explain what working memory is and then I'd

like 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 buzz word these days but the listeners of this podcast anyway are are pretty sophisticated in terms of knowing that dopamine is not just about motivation and goal directed behavior and I think dopamine intrigues for good reason that it does govern a lot of our you know quality of life so what's working memory.

Yeah I mean working memory it's interesting I start 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 doesn't have to be something that comes from the outside world I could hold up you know I can pull up my own if I'm filling out a form and I want to pull up my little security number I can hold that in mind too until I put it down so when you think about it it's a very important you know ability that we have that we do very flawlessly and what I've learned more about working memory is is the working part of it it's not just this passive holding information in mind but is being able to do

things with the information it's being able to you know when we 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 on to some face you're able to hold that face in mind and cross check it and search and and so there's there's operations to working memory is not just you know it's not just this passive maintenance so we're trying to find a way to do that.

Maintenance so when we start to think about working memory in that way we start to realize how important it is for it's you know I think of it as the foundation for 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 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 that allows us to read to to a plant organized in all the sort of executive form.

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 carry out behavior.

You know so it's it's 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 his term while we're away working memory is is really our superpower we said it allows us to 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 I mean what is dopamine doing for working memory and maybe we could talk a little bit about the circuitry.

I've talked about dopamine before on this podcast but there's a good chance that some of the people listening to this haven't heard those episodes so maybe we could just quickly review the three major circuits for dopamine and the one that's relevant for working memory.

Yeah 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 is you can working memory 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 remember what you had for breakfast or your vacation this is information that's 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 are two completely different systems and 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 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 we get distracted they'll get less active so kind of the frontal lobes kind of track your.

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 you know the phone number well that information is in your back of the brain and so the the frontal lobes is sort of keeping information in the back of the brain active because it's connected to the visual areas it's 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.

So 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 as it's whole you know 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.

So the question is what does dopamine do well dopamine is one of the neuromodulators that are made in the brain stem and it projects up to different parts of the brain there's a system that goes up into the into the what we call the basil gangula which is important for motor function and there's another dopamine system that goes up to the frontal lobes.

So what was discovered was that if you deplete dopamine working memory drops you get a significant impairment 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.

So the reason is that the brain is not only 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 evidence by conditions like Parkinson's where people lack dopamine or neurons or have damaged the poop and energy neurons and have you know challenges in generating smooth movement.

So eventually asking is can we think of dopamine as facilitating physical movement through one circuit but also kind of mental movement thought movement kind of I'm thinking of for those just listening and not watching I'm kind of rubbing my index and middle finger against my thumb is 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.

Yeah, I think that's a good way of thinking about it and one might wonder a little how can dopamine be important for memory but also be important for movement and it's really simple. It's just that it's acting on different circuits. The neurons that go to the motor areas that carry dopamine will when dopamine is expressed there and boosted there, then it will be involved in movement and lack of dopamine and the basil gang will lead to neurological disorders like Parkinson's disease.

It 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 dopamine is that's allowing it to have different kinds of actions. That's for all transmitters. The reason why osteocoline seems to be more important for long term memories because it's projecting to the hippocampus which is so we know it's another area that's important for memory.

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So drilling a little bit more deeply into the role of dopamine and working memory, you did some really lovely experiments showing that if people who have low levels of dopamine increase their dopamine pharmacologically, I think the drug that was used was broma cryptine 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 broma cryptine didn't impart a benefit and might have even made their work in memory worse. So there's an inverted U-shaped function to this. How does one know whether or not their baseline dopamine is low, medium or high, or go how do they know whether or not they 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 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 readout. It's not a good readout, yeah. And especially when you're talking about dopamine in areas like prefrontal cortex.

So we don't have a good readout there. There's invasive procedures like positive trondamission tomography where we can inject a radioisotope that tags dopamine and then we can measure how much we can do a scan that actually shows us how much dopamine. This scan was originally developed to show Parkinson's disease that you can diagnose Parkinson's disease by showing that there's less dopamine and patients that are Parkinson's by looking at this scan. Obviously it's invasive.

You're injecting a radioisotope is 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 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 memory capacity is seven letters or numbers when I say four, three, seven, one, five, zero, six, if you get that.

So I've said six. Did them all react very quickly. You probably have more dope baseline dopamine than someone who has five. So it's a proxy for measuring. So that's one way of doing it. And that's actually how we did it in our original studies. We actually grouped individuals based on whether their capacity based on this behavioral measure was high or low.

And like you said, those who work that can only hold five or six letters, if we gave them Bremel cryptine, which was the dopernergic agonist, we improved their working memory. We got them into sort of an optimal level. But those who were already pie, we actually made them, we worked, 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, is you know, if we want to get people optimal like you were inferring, you have to know what their dopamine is. Where are you on this inverted? You curve. And the way of doing it is through genetic studies. So we have dopamine, all neurotransmitters have to be broken down and re-uptake 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 comp that is breaks down dope being in the prefrontal cortex specifically. And a large percentage of individuals, that enzyme is either overactive or underactive. Probably about 25% of individuals, it's overactive and another 25% it's underactive. So probably half the population. Now this is going to very depend on where you live and where you come from and things.

But maybe half the population either has an underactive enzyme or overactive enzyme. If you have an underactive enzyme, then actually more dope means it's around and you actually have more dope mean than others. And if you have an overactive enzyme, it's the opposite.

So we've actually shown that if you would now go and genotype people with a simple saliva test and figure out, do they have this genetic, what we call polymorphism, where it just want amino acid to get 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 dope mean, we will make them better and those who have sort of baseline high dope mean will make them worse. Super interesting.

Maybe we could talk about bromocryptine a little bit and I'm not encouraging people to run out and take bromocryptine. Bromocryptine, as you mentioned, is a dope mean agonist, relatively short acting. Yeah, four or five hours, six hours. So it kicks in about 90 minutes after, as I recall you saying, I've never taken it. How do people feel when they're on bromocryptine?

I mean, when I hear dope mean agonist, I mean there are a lot of illicit drugs like cocaine, it methamphetamine that are increased dopamine, but then again, chocolate, sex and food increased dopamine, but the kinetics, the time course and the levels are different for each of the things. Dope mean, of course, being a currency of motivation and reward, not directly related to anyone compound.

But I would think that based on the data you just described that, and given the fact that there are a number of people out there with challenges in working memory, attention, task switching, etc. But there would be a strong interest on the part of the pharmaceutical companies at least. And certainly the general public in things like bromocryptine to increase dopamine, to increase working memory, given it is our superpower.

Yeah, I mean, one of the most disappointing things to me in my career has been that pharmaceutical companies have not picked up on this idea that we could improve cognition and very specifically improve kind of process with very specific neuro modulators. The discovery that depletion of dopamine and not other transmitters and pairs of working memory was made in 1979.

When I heard Pat Glamour, 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 that just seemed impossible to me that there could be such a tight link between a single neuromodulator and single cognitive process. And just opened the door for me that this really could be an incredibly beneficial therapy for anyone with executive function or frontal function.

But unfortunately, there's never been a pharmaceutical company that's tried to develop a drug for improving cognition. That's crazy. So this is crazy. And 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.

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 want to get involved here? This should be done. I can't do this by myself. We need to have real trials and real studies of how this will help. And just there are eyes will 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?

The market for disease is an Alzheimer's disease thing. And this has been a general problem with neurology. It's very disease-centric. It's always focused on how can we develop a treatment for Alzheimer's or traumatic 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. They're not buzzing thinking, oh, this feels good. They have no idea. They have no idea. They don't even know they're working memory is better. It's always we show them that their working memory is better. So they're truly blind to what's going on.

Broma cryptine is but one of the dopamine agonists can think of a few other, um, cable or goaling, like other things like that, um, do any of these dopamine agonists exert this, uh, impact on working memory or is it, um, does it vary by drug because different dopamine agonists, uh, sort of hit different receptor pathways and things like that? Yeah, no, it's not specifically the drug. I mean, the reason for Broma cryptine 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. Um, there's a, there's a drug that's developed, which is a comp inhibitor, which actually inhibits this, this enzyme that we're talking about. And that, that also will improve, uh, will have the same, uh, function. There's been some future work that Nora Peneferin also seems to be helpful with working memory.

Uh, it's not as, uh, maybe not as, um, potent as, as the dopinergic. And that's the point I was, want to make another, another disappointing thing about this whole field of the pharmacology of cognition. Um, you know, I wrote a paper as a resident, you know, sometimes you're attending SAIC and you write this review paper for us and, and I wrote one as a resident called the pharmacology cognition where I looked at all the animal literature on, you know, uh, giving

a, a neuromodulators, acycoline, broma, um, dopamine, operative, and, and there was a lot of, there was a lot of animal literature sort of supporting that this would work in humans, but was more striking to me was that it wasn't always just a single, uh, neurotransmitter. There were studies where you'd give dopamine and it wouldn't do anything, you'd give acetylcholine and it wouldn't do anything, but if you gave a low dose of both, it would, it would be really effective.

So these, you know, these germinous 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 pharmaceuticals have the infrastructure to do these kind of studies. It's very hard to do in a single lab to, to do multiple drugs at, at one time, you know, and then try and look at, try and determine all the different interactions.

Maybe we could talk about a couple of other drugs, um, that are legal or have, and have FDA approval or known to be safe in the right context that, um, it seems would fit the bill here, uh, for improving working memory. One is, um, well butrin, broop, broop, broop, broop, broop. Uh, I can never pronounce that. Um, as far as I know, it's a, um, epinephrine or an epinephrine 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, um, well butrin can improve working memory? Yeah. Anything that, um, boosts neuropronephrine can do it. And one that we've used, that's most used is guanfacine, which is actually a blood pressure medication. So that's starting to gain some traction.

In fact, I think there was a study with COVID, with brain fog for COVID showing that improved symptoms with it. So there's actually some trials now that are looking at guanfacine. And so I would say anything that boosts neurobe and efferin would be helpful. But then again, I don't want to leave out the other transmitters. So there's serotonin, increasing serotonin, increasing acycology, and 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 acycology 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, it's going to be one drug. It's going to be a cocktail. And we have to not only figure out what the cocktail is, but also figure out who we're giving it to.

What's, you know, link it to the person's own makeup of their own neurochemistry. When we get to a point where we'll know we can map out. So everyone's don't mean no rep or never in 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. We're not actually doing it. But actually doing it. But it seems that way. We're not.

The precision is not there yet. Well, it's great that you developed this cognitive task that can be a proxy for dopamine levels. The cognitive task again being how many number, 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 cooling 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. Are moderate, yours, et cetera.

There are a lot of companies that market these, but are you aware of any clinical or other tools for getting an accurate read of neurotransmitter levels in a person's brain aside from neuroimaging? No. And it's even more complicated than it seems because the dopamine system is complicated because it's not only just a prefrontal cortex. As we talked about, it's also the basal ganglia.

So not only do we have to measure dopamine, just generally levels, we have to measure the balance of the dopamine in this triadum and the prefrontal cortex. There's a model of dopamine function and its relation to the exact function that has to do with the balance between these two systems. That dopamine in the prefrontal cortex is promoting stability. It's keeping information in mind, keeping these representations stable.

Whereas the dopamine in the basal ganglia, what it's doing is allowing you to update and refresh the information that you're holding in mind, this sort of stability versus flexibility. So if you have too much dopamine in front of a cortex, it can lead to a very rigid state where you don't let anything in. If you have too much dopamine in the straight, and then 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 what's the balance of the dopamine. So I don't see a blood test as ever giving us that information. But I do see there being a brain test that can give us this kind of information of the two, or at least a proxy for it. So what I was thinking about when you were talking about asking this question, for example, if you measure pupillary dilation, that's a pretty good proxy for a neurodegenerative system. All right.

So I'd have given people 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 pupill 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 is a general term here. Not talking about a particular kind of arousal. Then the pupill 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, they have those big old pupils. Yeah, people. 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 neuromodern laboratory 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 with, you know, but gives you information about how the brain is working. So that's a, you know, that's a norepinephrine biomarker.

Working-americ capacities that don't mean biomarker and we're getting better at that. But again, we're not putting enough emphasis on it, in my opinion, to really sort of help, you know, improve brain health. Have you ever tried broma crypti? Very early on, but it's such a low, you know, at the dose that the, my subjects were getting but like I said, it doesn't, it's so low, you don't feel anything. And I should say with even with patients that take it, they rarely get any side effects.

And with these drugs because this peripheral don't mean they can get a nausea or volume, but it's extremely well-dollerated. You don't get any, 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 broma cryptine pre-alimpyx and in the Olympics. I think it's a band 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 broma cryptine. 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, hundreds of milliseconds are the difference between podium and no podium. And broma cryptine 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.

And broma cryptine was the 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 by Vance, Ritalin and other stimulants, which are nor adjuvant or agonist.

Okay. So with the disclaimer, caveat, whatever you want to call it, that, you know, those decisions should always be made with a trained psychiatrist monitoring things. What are your thoughts about pharmacology for enhancing cognitive function given that the landscape of society is challenging? And people want to perform well. They need to be able to focus.

You'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 nor adjuvant agonist. Absolutely. And certainly can improve my focus as long as I don't drink too much of it. Right. Yeah. What are your thoughts? Yeah. I think it, you know, it kind of gets back to what we talked about there being an optimal, you know, optimal level of dopamine in your brain.

I think if you think about it as just more and more and more is better and that more is better, then there's really no, and this really no, how do you know how much you should be taking this sort of? I was running the 80s. It's called the cocaine culture of Wall Street in the 80s. There were movies about it and it doesn't lead to good places. Right. So I'm all for optimizing function. I want to optimize brain health.

And if you have an underactive, you know, enzyme that's not that that makes you don't mean levels, and 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, yeah, 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, pen and Berkeley undergraduates that we made them worse on working memory tests, you know, by increasing their dopamine. It's a little amount. Just tip them over. Just a little, little amount. And so without the knowing, then it just, it seems like it's not well informed. You know, we're going to be checking. The other thing is 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 naturally developed with knowing how exactly they worked. I mean, that's how the pharmaceutical company worked. Yes, it's a rise too. Yeah. I mean, it just works. 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 cysts, all the catacole amines, the ones that boost up dopamine, epinephrine, endormine, epinephrine, 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 neuroinephrine, but if you give it takes on 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 would use Adderall Adderall, Ritalin as the drug that I think would help, even though they're clinically sort of you. So I use things like bronchryptine 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 bring out the best in people's abilities. And I'm so glad you mentioned sleep. I would say sleep is the better. It's the foundation of mental health, physical health and performance. I mean, without that, pharmacology might bridge you for an afternoon, but you're going to pay the piper somehow. Our friend and colleague, Matt Walker, obviously, is in beating that drum for a while.

What about drugs like Modaphanil, which are thought to be true cognitive enhancers, as opposed to drugs that just kind of 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 we're all encrypting the open-air story. It's 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.

And before we're recording a day, we were talking about football, but I 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. Then we 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 as becoming more recognized. And I think we underestimated and trivialized sort of what a concussion is.

It's just something that is, you're going to recover from it. 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 year out. They're still suffering problems.

They still feel like they're not mentally clear and they still are sensitive to light and they still feel a little dizzy and just a host of symptoms that just one year later after a concussion where they didn't even lose consciousness. 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?

Myled 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, 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. So I think in this.

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. They're just like understanding what it is, having someone to 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's basically is a tearing 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 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 neurologic, it's a real brain injury. Even if you haven't lost consciousness and you've only had symptoms for a couple of days. And there's a correlation.

The longer you've lost consciousness and the longer your symptoms last, the more axons you've torn. This kind of a direct relationship between the two. So the mechanism is these torn axons. So now, nurses don't communicate with each other and the different brain regions are not communicating with each other. And it turns out the most common place for axons 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 fogness that they're describing is just this unability to get things done. They don't lose knowledge of who they don't forget their name or forget where they live or lose memories from the past or anything like that.

But they just don't officially get things done as well as they used to. It only takes a little bit of a drop, right? People think you have to have a big drop in performance to have a real life impact. Just a 1% drop in your having a hard time doing your biceps or teaching a lecture 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 sleep? What kind of drop in prefrontal cortical function are we looking at?

Let's say I normally get seven or eight hours or six to eight hours and I suddenly only get three or four. Are we talking a significant detriment? I do think so. I do think that it is significant at a poor night sleep. And we all notice that. It's very obvious. It's hard to quantify. I'm a baseball fan so I can quantify it.

If you think about it in a picture and how fast they throw, a small drop for them, someone who's throwing 100 miles an hour, just a small drop turns them 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 work through it. That's what most doctors say. Just plow through it. Just work your way through it.

You're going to get better. 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 crucia ligament. I don't know why tearing your crucia 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. I don't know why that is either.

I think the brain is mysterious enough that most people and many clinicians are just kind of back away with hands raised. If you are in the field of neurology or psychiatry, I suppose that one has officially signed on to try and resolve these matters. 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 patient with the cushion have is their sleep is disruptive. That's true in neurology. It's fascinating.

Almost every neurological disorder patients complain of their sleep. I started asking not a lot of neurologists ask you how you sleep. I remember back from my residency, one of the first things my attending would do when we got to the ward is that I had to sleep last night. It's just a crust of the ward. Patients are not falling asleep. They're not staying asleep. We still understand why just brain injury does that.

Almost every concussion patient says I'm not sleeping well, which then compounds the problem. Optimizing sleep, optimizing nutrition. There's a question about activity. It used to be that we used to recommend you had a concussion. You should don't go to work. Just take it easy for a while. Don't exercise. Keep the blood. It's strong. Now it's the idea that you should really get up and moving, especially. You got to do what you can tolerate.

You don't want to give yourself more of a headache or more light sensitivity, but as much as you can tolerate, the thought these days about promoting recovery and then really getting your brain back working. I think a lot of my patients, they're off from work for a couple of weeks and they feel fine and they think they're pretty much normal. The first day of work is a complete disaster because until you actually test it in real life, you don't know what kind of troubles you have.

I don't recommend going back full steam, but I do recommend going back trying to build up these skills again. Then I think we need to develop therapies that people will use. Things like goal management training, which involves a therapist and health insurance doesn't pay for this. 99% of my patients don't get any help by any kind of intervention, unfortunately. Now, we talked about technology, things like brain HQ. You know about brain HQ? Mike Merzenick, which I know you've talked about with.

Develop 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. That way, you don't have a therapist in your room, but you can online do these things that are targeting specific mechanisms to try and improve the kind of things that we think are impaired by concussion.

I'd like to see more patients get started on some of those things. Of course, if you go on the web and just say, I do brain training, you'll be overwhelmed with things and you don't know what works and what doesn't work. I think the work that Merzenick 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. 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 Hewyl and Torrance and Weasel, and they deserved that Nobel Prize. But there was a kind of a central tenet of neuroscience at that time was that critical period plasticity ends around adolescents or ones early 20s and that is simply not true.

Merzenick really, I think, is one of the people who deserves credit for making it clear that plasticity is ongoing. It takes some focus and work to access it in adulthood, but we can all access neuroplasticity, but it takes, it's there. I don't know. They should give Merzenick a Nobel too, but I'm not on the committee. 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 college and graduate 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 high degree of functionality, but they're not really pushing these four brain circuits.

Do we imagine that some of those four brain circuits regress? A.K.A. 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 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. 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 looms. Right. Right. I need to do some real training, just like muscles and atrophy and cardiac fitness atrophysic if we're not doing regular resistance and cardiovascular training. Does that set? Yeah, I think that's fair.

I think, you know, of all the systems that decline with aging, not every brain system declines, but certainly the frontal executive sense of what 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. So, the more complicated system is going to take more of a hit than other systems.

Certainly, I don't know about regressing, but certainly we're not maybe accelerating this decline that we know exists. I would think about it, though, is that not just trying to prevent a decline, but what we talked about before is no reason not to optimize. 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. That's really hard for neurologists. We have a hard time thinking about brain health even though we're the brain specialists.

We think about brain disease and we're just now, as a field, start thinking about preventative neurology and thinking about it not just like stopping Alzheimer's disease but promoting healthy and healthy brain. You know, neurologists don't talk to patients about healthy patients about being healthier. I love how candid you are about the medical profession. I like to think it's changing.

I feel it's 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 starts to finish without looking at one's phone.

Even if it takes twice as long as one would like, redirecting one's focus when what 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. We really brought that torch in on sleep and now others like myself are trying to amplify the message of the critical role of sleep.

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 a week or more. Not just for athletes but for elderly folks, men and women. I feel like we need the same for cognition, for a brain function. 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 got to read a, you got to learn a few new vocabulary words and then write sentences with them. They do it in school but then we're just set into the general population and most people I think were grass. Right? Yeah, I think the big problem with brain health is trying to have a measure of what brain health is. It's interesting to me again as a physician thinking about it from an 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. No cognitive task. There's nothing. No working memory task. They don't measure your brain at all and it's not their fault. We haven't provided the field, it does not provide 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 on to something because it's not just cognition, it's cognition, it's social, it's lifestyle, sleep and it's well-being.

A 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, once we develop a brain health index that then we have something to follow and to be able to measure if we are optimizing a brain.

Now otherwise how do you know if you're optimizing your brain health? Your doctor's not telling you, you don't know all these games you get on 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 I've 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 we're I to read more fiction or learn an instrument. I mean everyone else around me would suffer if I learn 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 researching, seeing patients I've always felt that I'm maxing out on full of my executive functions being tested to the limit. You're like a professional athlete of the mind. Yeah, in a way. But then you realize that's not everything. There's so many other aspects. Everything emanates from the brain so you start to think about what should I be doing in my life as a father and a husband.

What should I be doing in terms of promoting social interactions with friends and what should I be doing for sleep and 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 reading more nonfiction books and just listening to books or reading part of art. I still like to read the hard covers.

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 all the books that I never read. I started reading my kids English literature books that I never got a chance to and started reading history. And so, yeah, I always felt just increasing knowledge. Like I said, our brain just stores information. That's one of its jobs. So 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, you know, heart disease and lung disease and skin and things like that, I think that would 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 I just, 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. It kind of, that wasn't intended to rhyme, folks.

Kind of behaviors, but clearly based on everything you've told us that if we don't exercise these working memory and other circuits for cognition, like why should they stick around? And I'm beginning to think that social media is entertaining as it is. And I learn there and I teach there, but that it's not a cohesive plot, right? It's like those baby otters, that really cool looking dog that I'd love to own. I'm thinking about kind of another dog.

This interesting conference, you know, it's like random pseudo-random tailored to me, of course, because that's what their algorithms do, but that's not following a plot, character development, antagonist, protagonist. Many of the things that provide cognitive richness is kind of obvious as I say this, but I feel like we're divorced from these things that really help to evolve culture and evolved individuals.

And it takes them discipline, but like a run or going to the gym, you do a few times for shorter amount of time with less intensity and pre-sune, you're up to speed. And there's an upper threshold unless you're going to be a pro. I'm certainly not going to be an English lit, you know, professor. You know, so I don't think obviously boosting exact functions is incredibly important, but I don't think it's going to happen just with technology. I think it's going to need human interaction.

I mean, I believe executive one should be taught in school as one of the course. As a course. This school 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 experiments and carry out the experiment, there's no technology that's going to just be able to teach them how to do that.

You've got to intervene sometimes and say, stop reading all those papers or not relevant. Okay? Or you know, you piloted this enough, get going. It's that kind of wisdom that you get when you get older that allows, that has to be on top of the technology. So that's why I think we also need to, it needs to be directed. So whether it's in school or whether it's in a patient, I think there still needs to be someone coaching us.

You know, I know that's why life coaches have been, some people have really benefited from life coaches because someone just, it sounds obvious when you tell your kids, you know, just, you know, just, just do it this way. You know, 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, 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. Yeah. Seems like a good game, right? Chess. Yeah, any, any one of the, yeah. Working memory. You got to keep information online. There's, there's a bunch else there. I think, but as a tool to improve cognition. I was also thinking, you know, some people orient more towards the arts. My sister is really great about, she's a therapist in San Francisco, but also takes like theater classes.

And she said, you know, like improv is like forces you to, like, 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 pulling the curtains and stuff till I went and did other things. But, but that whole biz is about, you know, learning the novel rule set in the moment. You know, this improv by definition. Absolutely.

I mean, anything that requires you to have that, you know, where there's a goal and you've got to break it down to sub goals and you've got to do it simultaneously and you've 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, you 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. That sounds good. And you're in a city with great food. So the standard is really high. I'm tempted to make a reference to the cheese board pizza, but I want to keep the lines as short as possible because they're already too long. Maybe we could talk a little bit about some other, unfortunately, common disease states. Parkinson's and Alzheimer's. Now, let's start with Alzheimer's.

I think a few, few things scare people more than the idea of getting Alzheimer's, especially if they have Alzheimer's in their family. First of all, what is the genetic link with Alzheimer's? If one has a parent or a 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 disease like hunting disease where it's a very strong link that if you have a parent, you have a very high chance of getting it. But there's so many factors that it's not necessarily case that you're, 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 nervous, gender disorder impacts the hippocampus among other structures. There's been some debate in recent years as to whether or not the whole amyloid hypothesis is real or not. There's a bunch of unfortunately false data accusations and that whole thing.

But my understanding is that if you look at a slice of human brain from an Alzheimer's patient that died with Alzheimer's, maybe even from Alzheimer's, that you see plaques and tangles, you see these subcellular structures and build up and that are 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. Right. All wrong. And indeed, somebody fudged data they made up data and that's terrible. But Alzheimer's is an energy gender 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? And why don't we have a treatment for Alzheimer's yet?

I feel like almost every other psychiatric disease, including Parkinson's, there are certain things you can do to at least push the system in the right way. Why is Alzheimer's and other dementia so tricky? Yeah, I mean, it's very frustrating because the neurodegenerative disorder is just, it's so, so many factors that are probably involved in the pathology that there's not once, you know, 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 acylcholine in the brains and the only approved treatment for Alzheimer's disease is a drug that boost acylcholine. What's the drug? It's called the nepazil. There's a few of them. They're anticolynecetaceous inhibitors that boost acylcholine. They've been around for 20 years or more.

And you know, 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. So 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, 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, I think 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 to largely to degeneration of dopaminergic neurons. There there's some effective treatments, right?

El Dopa. Did you know there's this over the counter, that stuff that sold that a lot of people take who don't have Parkinson's? I'm not suggesting they take it called McHughna Purine. It's the velvety bean. Yeah, I've heard of it. It's 99% El Dopa. I hope so. Yeah, it's in present in some energy drinks and supplements. I mean, people can go buy it. I'm not suggesting they do that. I actually tried it. Boy, feel, being really dopamine doubt does not, to me, doesn't feel that good.

Yeah, I felt agitated. My vision got a little twinkly. It did not feel like a high of any kind. Then I felt lousy for a couple hours after it wore off. Yeah, I don't think you can really get in enough El Dopa to get enough into your brain. What happened early in neurology when it was discovered, we couldn't give our patients enough El Dopa without them feeling bad because it's also metabolized in the periphery.

It wasn't until we, that's cinnamon came along, which has this deboxylase, decapoxylase inhibitor block 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 El Dopa or broma cryptine 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 induced neuroplasticity, but we're just going to watch the steepness of the decline. Is that really all we've got? It's all we've got is to help them with everything that comes up on a day-to-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 Pennway back that if you showed patients some family movies or family albums, it was better than any drug you could give them to sort of help their behavior. There's still those memories are in there and they were making some type of contact that was helping them emotionally that you couldn't turn off with the drugs. I think the more we do things like that, the more will be helpful for them, at least symptomatically.

I've seen a number of videos on social media of people with Alzheimer's who listen to a piece of music or people with Parkinson's that hear a piece of music and that seems to resurrect some at least context appropriate emotional state where he kind of brings the person to the surface. Again, yeah, it's kind of 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 or the treatment of Alzheimer's. Yeah, absolutely. I will never ask a guest to comment on the good or bad behaviors of other people except my own, but there's a Nobel Prize winning neuroscientist and I visited him. He's in a Big East Coast school back in 2010 and during the course of our one hour meeting, he consumed no fewer than four pieces of Nicarac gum.

I said, I got to ask, what's this about? By the way, he's extremely sharp still. He said, oh, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, yeah, 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 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 Nicarac all day long.

And I thought, okay, well, he's not, he isn't empty, actually. And I thought, that's interesting. And I did an episode of this podcast on nicotine, by the way, he 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 haven't feeling you know who this person is, but in any of that, what gives?

Yeah, well, I don't know anything about nicotine staving off any neurogenitor 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 season and boosting the colonergic system probably is beneficial.

I mean, patients that would give the anticolynecerozoin inhibitors, there are some families that say, yeah, he's just 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. The disease just carries on even though we're symptomatically improving the symptoms. But again, I think it's going to take both acylocoline and something else.

I think we don't know to re-gib don't mean with the nicotine or the acylocolineceroin or we can urban that for and I think it's going to be a cocktail which again, pharmaceutical companies have not tried a cocktail of neuromodulators for Alzheimer's disease. We've just tried acylocoline. Sounds like you should be running the FDA. No disrespect to the current people in charge, by the way. But 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. I mean, there's so many committees. Another editorial.

Are there any sex differences, male-female differences in sort of these dopamine levels, working memory, injuries, concussion, 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 dopernergic 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 you hire estrogen levels correlates with increased dopamine levels. And there was some anecdotal evidence that in post-menopausal women who were put on estrogen that they're working memory and proved and there was a kind of evolving link between estrogen and frontal lobe function. And she did this amazing study where she studied healthy, Berkeley undergraduates at two points in time during their mental cycle when estrogen was at its lowest and what was the highest.

And she also genotiked 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 and they were low dopamine.

And if they were low estrogen and low dopamine to start they really had decreased frontal lobe function and decreased working memory ability. So it fluctuated based on this interaction between estrogen and dopamine. Suggesting that not only is dopamine is important but hormones are clearly important and they work synergistically. So as we're developing this cocktail we certainly have to bring hormones into the equation and learn more about it.

There's just so little information about hormones and cognition. Yeah, one of the themes that's come out of some of the episodes we've done with MDs who specialize in endocrine health is that for both men and for women optimizing estrogen levels is really important for cognition and vascular function. I think people mistakenly here, okay, testosterone men, you know, estrogen women, obviously both hormones are present in men and women.

In fact, I think I know that testosterone levels in women are actually higher than their estrogen levels when you look, when you sort of use the same units of measure. It just so happens that they still have lower testosterone on average than the typical male. And 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. 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, so the estrogen and the synapse 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 minute bout of exercise, pick your favorite exercise, and then doing cognitive work immediately afterward when presumably the catacol means dopamine or epinephrine and epinephrine are going to be circulating at least in the blood at higher levels.

Is 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 and Pain Art Cramer'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 the hard part in the real world is how do you get a seven year, eight year old through the kind of aerobic exercise? But now it's becoming bicycles and now there has been studies with seven year olds with just putting them in, mostly with a become bicycles, it's sort of designing. We have to think about ways to design exercise that can get aerobics up. And neurologists are starting, I think my field is starting to realize that we got to tackle this in all every way we can.

And so now I'm hearing more neurologists talk about that. About 30 years ago, no neurologists say you got exercise more, you know, or just now it's sort of talking about exercise and nutrition and sleep and it's all becoming sort of part of our package of how we're going to help our patients. But there were a bit of exercises, 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 at, a lot of these studies also if they had mindfulness training to the chart, core, go management training, it's better than just the executive training alone, just learning skills to stop, relax, repocus 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 stare at typical meditation of closing one's eyes, closing one's eyes, excuse me, sitting down, lying down and just focusing on one's breath and then redirecting one's focus to maybe third eye center, you know, area between the forehead, just redirecting focus, redirecting. 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 focus exercise.

And that's half of the problem with not achieving our goals, right? 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's, and it doesn't seem to matter what, you know, I know there's all different flavors of mindfulness. So we just happen to use one when we were studying it.

It doesn't yet, I don't think we know enough about how we should tell our mindfulness, but most forms of mindfulness will work of the type you're talking about. That's similar, what I described is similar to what you explored.

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, there's probably a little bit more tolerant of these ideas at that time, just given the kind of culture. They wouldn't have been laughed out of the room, but there was a lot of skepticism.

And I feel like now mindfulness meditation, breath work, the idea that, oh my goodness, breathing can impact your emotional state. Yeah. I mean, that should have been obvious. Right. But now that people are on board, then now, of course, there's a lot of interest in psychedelics. That's kind of a new emerging therapy, carrying more risk, potential risk, but it looks like it's very likely that some of those are going to make it through the FDA filters at some point.

But the conversation we're having now, you know, neurologist, neurologist, neurologist, talking about mindfulness, nutrition, we're talking freely about nicotine, you know, we're not suggesting people do that. Broma cryptine, to optimize cognitive function. I mean, this conversation would have never happened seven years ago. No, it's just the field has changed. Yeah, and 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-needra where you just lie down. And these are free audio scripts online. We can provide links to these.

And you go through a body scan and you do some long exhale breathing, which emphasizes the parasympathetic, AKK, 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, the biggest impact for me has been the problems of my life. That I get a different perspective. I start thinking about things in different domains of time. 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 a relatively small, not small thing, but a 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, et cetera. So I feel like it's orient me in time. So that's been a major effect. For focus, the best tool I know is to put the phone in another room, but 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 we're talking about.

What should we do besides reading fiction? I think that should be on my list. Because it's just amazing that the patients tell me about it. And what we've seen from our studies. You know, a lot of this, like again, I was saying before, is if we had some measure of, you know, brain health that we could see the impact of it, it would sort of push us towards just, 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, 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 brain and brain networks. And that's sort of very popular idea and neuroscience today.

So 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 factors as well. In addition to sort of your, your dope, your sort of neuromodular, you know, 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. Eseroth 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 do you, what are you really excited about?

Like if, if there were no financial barriers to your grants, et cetera, you had a thousand people working, what's the, what's the thing that's hitting your dopamine circuits these days? Well, in the grant 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 an neurologist because that's at my core what I feel I am and I feel like I got into this business to help people. And so it's, it's when you, when you work for years and years and years and it doesn't translate it, it can be frustrating. But now I'm excited that it seems that the things we've learned, that all of us have learned in neuroscience, is starting to now translate into something, isn't it?

And neuroscience, what's sort of what's happened in the last 10 years of we've, we're thinking of the brain and in a kind of grander scale, it is sort of its overall organization and not so focused on just this area or that area. When I talk about the frontal lobes, it's being the most important part, the, you know, 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, as a big network, like an airline network or electrical network and how, 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 is a hub and there's other hub in 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's shut down, you're probably going to 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. I'm sorry if anyone's listening from there. Probably a few. You've got to 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 think it's 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, you look at schizophrenia and you look at a lot of diseases, it's not just that there's some microscopic change and 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 boost a hub that's been damaged as opposed to thinking about it in a less specific way? And then also as we really start to learn about how the brain is organized in these networks, you've also learned that measuring your network structure is very predictive of your well-being and how you respond to interventions. So there's a metric called modularity which measures how organized your brain networks are.

And the brain is made up of different modules, different networks and these networks can either be very communicating with each other or not so communicating with each other. And the more segregated they are, we call that more modularity. They're kind of separate entities, they're modular. And it turns out we can measure that with fMRI.

We can put someone in a scanner, we can do this resting fMRI scanning and then we can measure how modular your brain is versus my brain and all of us are very different levels of modularity. Is it more advantageous to have more modularity as opposed to less? Yeah, it turns out that it seems to be more 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 conics. Yeah, they're more independent as opposed to less independent with each other. Not unlike neuromuscular junctions. Genome development are what we call polyinevated. That's why babies can move their limbs but not with a lot of coordination. Look at a one-year-old trendy spaghetti, for instance. That's hilarious.

Look at that same kid seven months later, there's a lot more precision movement largely due to removal, more modularity of connections. Right, right. Interesting. So we did a study where we took 12 traumatic injury patients and measured their modularity.

So you get a number, you just get a modular index for each of the 12's people and then they underwent this go-madżrin 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. It's turned out that this has been a very robust finding across studies now, across different training, different young, old patient populations.

It's also predicted things like whether someone in a coma is more likely to do well or someone whose older is going to have a certain amount of cognitive decline or someone's going to respond to behavioral therapy if they're obsessive-compulsive.

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 in determining what helps and what doesn't help if we know sort of what the state is before we start the intervention. So interesting and makes me think many things but I'll just focus on two of them.

One is I love this idea that you and others are starting to look at brain network activity as opposed to overemphasizing the role of say prefrontal cortex or hippocampus understanding more that those are hubs in a larger theme of activation because you know 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 you know in contraction it's just you can you can break it down that way and it's useful to know that but ultimately you're talking about gate 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 you know Matt Walker was just here recording this series on sleep that we'll release later this year and your stages 1 2 3 4 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 1 2 3 and REM sleeper names that we made up but there seems to be a much richer understanding of like 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 going to make this up like calling a certain network of activation state like state a like we we that I feel like neurosciences task the field of neuroscience now is tasked with

with giving us a understanding of the verb states and like what like these waking states of mind are very mysterious and and for the general public this is important because people wonder like is my focus poor or is it is a good is my task switching ability good I mean we only

tend to look at you know it 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 that mean

the sort of thing well you know yeah I think modularity can actually be that metric some metric of of your large scale organization of your of your brain can be that metric we've there's a number of labs that have done this of 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 have changes on a second to second to minute to minute basis and one of my former postdocs separate us out of the on these she just did a very

simple experiment where there were noise that there were sounds and the functional rycec is very loud so you can't hear very well but every once in a while there'd be a sound that was just above the this the level of the noise of the the scanner and all you had to do was

sort of press a button if you heard that sound and you didn't pick it up all the time you know you maybe 80% of time you heard and sometimes 20% of times you didn't hear it well she measured their modularity at 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 and and wreck the sound before they they got the sound if there were highly modular boom they they they got it if they're brained gone into this kind of you know diffuse less modern state they they missed it and so I could

definitely see as you're talking about where if we could develop a modularity metric in real time on a device this would be game changer and so and that's sort of what I'm you know what I've been interested in do what's excites me is that we're not going to do with a skin obviously

you can't walk around with a scanner in your head right and 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

I've been working with some colleagues the former student Brian Miller and a postdoc of Adam Gazali's Westclapp who have a company called Naur Scouting where they are able to they have we've been sort of doing scanning and also collecting physiological data to to try and determine

if there's some probably we can measure the modularity and the scanner but can we pick that up in the in the physiology data because they can collect you know oxygen and heart rate variability and and other metrics that may be kind of a readout of that and then then we'd have a brain state

which is what you were looking you know you're looking for some brain state but it's not I think people are thinking we're 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 rabid eye movement and other stages of sleep I mean key metrics not every metric and not what you would get with person wearing a EEG you know 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 and I'm going to do it is that I did a couple episodes about psilocybin and the use of psilocybin for the treatment of depression this

is robin card art Harris from UCSF and I also just saw the 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 of patients before and after macrodose psilocybin this

isn't micro dosing 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 might be good for social emotional function and I'm certainly don't want to disparage the beautiful work that's

being done there but you said that increased modularity predicted improved function especially with cognitive interventions psilocybin seems to induce fairly significant increases in cross-modal talk between ring networks in other words less modularity so should we be concerned

no it's just it has to do with how we make these measurements and connectivity doesn't mean the same you know there's different types of connectivity and so I like to when I think about connectivity we're talking about this connectivity we have a brain state and 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 you do when you do these highly executive

demanding tasks you get less mod you get less modular because you have your networks are communicating with each other so it's important to be or 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 is like going from one state to another not 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 you know I have a lot of patients that I've referred for for its approved use which is depression so I'm very excited about sort of the work that's being done with it as a 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 total small studies where you can give transcranial magnetic stimulation frontal cortex and working memory improve but they really haven't been done in ways that are we don't know if it generalizes if it's 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 I but again it's just a matter of doing it I think it will be part of the things we do drugs to MS and all the other things we've talked about it's not just going to be one one thing and it gets back to networks right what

this is doing is really changing how nodes you know the interaction of 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 of a network well Mark I really want to thank you you

you're gonna give us an amazing tour of basically five fields I threw a lot at you you know as a neurologist but the way I'm I'm slightly reluctant to do this but I'm gonna tell you a joke that was told to me so that there 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

have to send 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 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 you that joke needs to be revised whereby there's one at least one neurologist who casts a line down and and shimmies down and assists them and and pulls those stranded people on on the island up to the the balloon because

today you've described the 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 you responded would in in thorough clear detail but also a number of things that that clearly can

assist in these in these in these situations such as from a cryptine 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 of possibility to to alleviate these situations and as you point out for the already healthy even to optimize brain function and health so for all of that thanks for sliding down the

rope to the 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 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 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 their doctors or whoever and try and ask for you know 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 going to do that is just make people understand what it is that the possibilities are so thank you it was a lot a lot of fun it was a great time well amen to all of that and now

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 Despazito to learn more about Dr. Despazito's work please see the links in the

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