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 Desposito.

Dr. Mark Desposito is a neurologist and a professor of neuroscience and psychology at the University of California, Berkeley.

He is a world expert in the brain mechanisms controlling executive function and memory.

Executive function is the way in which we are able to designate and carry out specific cognitive strategies,

and it is fundamental to every aspect of our daily lives.

And because so much of being effective in daily life involves using specific context-relevant batches of information

in order to understand what to do and when, and what not to do and when,

and to come up with strategies that are very adaptive,

for us to move forward in the context of relationships, work, school, and athletics, and on and on,

there's really no separation between executive function and memory.

And today, Dr. Desposito explains the neural circuits controlling executive function and memory,

how they interact, the key role of dopamine in executive function and something called working memory,

and teaches us ways to optimize executive function and memory,

that is, how to optimize cognitive function.

In addition to discussing how to optimize cognitive function,

in the healthy brain,

today's discussion also centers around how to restore cognitive function

in disease or injury conditions that deplete executive function and memory,

such as traumatic brain injury, concussion, Alzheimer's, Parkinson's, and attention deficit disorders.

Dr. Desposito shares with us research findings both about behavioral and pharmacologic strategies

to enhance executive function and memory.

By the end of today's discussion, you will have learned from Dr. Desposito a tremendous amount

about the benefits of cognitive function, and how to optimize cognitive function in the healthy brain.

And you will also learn 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.

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And now for my discussion with Dr. Mark Desposito.

Dr. Desposito, welcome.

Hey, Andrew. Thank you so much for inviting me.

I'm really looking forward to our conversation.

You may not remember me, but I remember you when I was a first-year graduate student,

and you showed up at Berkeley, one of the first people to really bring functional imaging of the human brain to Berkeley,

bring a neurology and a clinical emphasis to the neuroscience studies there,

and it's really just blossomed.

And it's been a real thrill for me to see all the magnificent work out of your laboratory over the years,

and I know you also still see patients.

So the topics that are of interest to you I know are of great interest to our audience.

Maybe we'll just start off with a few of the basics and do a little functional neuroanatomy lesson for folks.

Not to scare anyone, don't worry.

This will be accessible to everyone.

And just talk about the frontal lobes and prefrontal cortex and a little bit of what those structures do,

because many times on this podcast, I've said,

okay, the neural real estate right behind your forehead is involved in context and planning, etc.

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 the frontal lobes, parietal, temporal, occipital,

and the frontal lobes probably do take up more territory than the other lobes,

probably about a third of the cortex.

And within the frontal lobes,

I don't...

I'm going to use the frontal lobes probably in our conversation a lot,

but what I really mean is the prefrontal cortex.

So within the frontal lobes,

there's also areas that are important for motor function as well.

But when we're talking about the frontal lobes and talking about its involvement in higher level cognitive abilities,

we're talking about the prefrontal cortex.

And this is what's considered sort of the highest level of cortex in the brain.

So yeah, when you think about it,

people assign it all sorts of functions.

Almost every function you think of,

people have sort of put into the brain.

So there's frontal lobes.

But I think what we've all kind of moved towards is this idea of executive function,

this ability to plan, to organize,

to really transfer our thoughts into an action

and really to be guided by goals and intentions

and not be kind of ruled by sort of just automatic behaviors.

A word we use in cognitive neuroscience is called cognitive control.

So cognitive control, executive function,

is what we attribute to it.

It's what we attribute to the frontal lobe.

And so you can think of it as the CEO of the brain

or the conductor of the orchestra,

really the part of the brain that's really controlling the rest of the brain.

So yeah, if you had to choose which part you wanted to not leave home,

it's your frontal lobes.

Speaking of which,

what are some of the symptoms of mild frontal lobe damage

and severe frontal lobe damage?

Damage brought about either through neurodegenerative disease or physical injury?

I know we're going to talk a bit about both today,

or a lot about both.

But how would lack of executive function show up,

maybe on kind of a subtle level?

Yeah, I mean, at first I should say is that it shows up all the time

because when—and frontal lobe behavior is probably much more prevalent than we realize.

Certainly we think about it when you have a—

when you have a brain injury to the frontal lobes.

And there's lots of neurological disorders like stroke and traumatic brain injury

and Alzheimer's disease that can affect the frontal lobe.

And there's a number of, you know, psychiatric disorders,

obsessive-compulsive 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 lobe seems to be the first system that's affected

because it really is involved in the highest level.

So when we're having a bad day,

when we're having difficulties sort of in our lives,

when we're setting priorities,

when we're having difficulties achieving the goal that we've set out,

when we get distract—you know, 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—

reflect that 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.

But they're rather reflexive in where they'll place their eyes.

But by the time kids are three or four,

they can certainly, you know, play with blocks

or interact with other children or their parents.

But it seems that, you know, full functionality of the frontal lobes is really gradual.

At least that's my non-clinically trained assessment.

Yeah.

Yeah, I mean, it's a really tough question to know when they're fully developed

because these studies haven't been done.

When MRI was introduced, 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 until you're 25.

That the insurance companies knew before.

Neuroscientists did as to when your frontal lobes have—

you know, when your decision-making skills are at their highest.

And so that's probably about right.

Into your 20s is probably before your frontal lobes are fully developed.

It's a really interesting question is why does it take so long?

It's the area of the brain that takes the longest to develop.

And why is that?

And I think there's a reason.

I think that this sort of slow development of frontal lobes allows us to explore,

allows us to think about novel ways of solving problems,

allows us to take in the world.

If they were shut off earlier,

it would lead to maybe a much more sort of rigid kind of, you know,

less flexible kind of behavior that we've seen things.

So I think that it helps to be—

it 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 just sit still,

but they were telling me to sit still when I was a kid—

is that somehow reflective of a slightly lagging frontal lobe function and maturity,

whereas that, you know, the kids are, like, oh, I don't understand that,

I'm going to sit still, I'm going to sit still,

that can sit still and stoic and focus.

Does that mean that they're a little bit more accelerated along that trajectory?

Yeah, it's hard to say.

I mean, the frontal lobe is a big territory, and we can get into it.

But the frontal lobe probably has 25 different sub-regions within it.

And so grossly, we think about the frontal lobes as the lateral portion of the frontal lobes,

which is involved in these executive function,

probably supports these executive function abilities.

But then we've got another part of the frontal lobes called the orbital frontal,

the cortex, which is probably involved more in social and emotional behavior.

So, you know, again, when we think about frontal lobe behaviors,

you have to break, there's so many different types of frontal lobe behaviors.

So that type of behavior, which may be involved in sort of being able to inhibit, you know,

your motor movements or maybe not being distracted,

may reflect that that system is a little bit delayed.

But it could be that another system, the one that's involved in planning and organizing,

you know, is more developed.

And I do think they develop at different,

trajectories.

So with the frontal lobes essentially serving an executive or CEO type function,

goal-directed behavior, intentions, cognitive control, these are the terms you used.

Where are the rules?

What do the rules look like?

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,

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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 are the algorithms?

How does this work? Right. Because that's a pretty common example of our patients that they

don't follow the rules. They, you know, if you're sitting in 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 Dr. Lameet, 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 rules

and just kind of pulled to their environment without having any context to it. If he put a

pair of glasses on the table and didn't ask them to put them on, they would put them on even if

they had a pair of glasses on already. Or he took them to their apartment and they saw the bed and

they'd jump into the bed and go under the covers. Or he saw it, he had a nerve, he had a nerve to

put them on. And he'd put them on and they'd go under the covers. And he saw it, he had a nerve to

put them on and they'd go under the covers. And he saw it, he had a nerve to put them on and he

put a blood pressure cuff there and she picked up the blood pressure cuff and just start taking

his blood pressure. Again, not asking him to do any of these things. And so they just don't

follow sort of the social rules, but they're there. They haven't lost rules. If you ask these

patients, was that the appropriate thing to do? They'll say no.

No, they know it's not appropriate.

They know it's appropriate. Yeah. They say, no, I'm not supposed to answer your phone, but.

Oh, wow. So they know better, but they can't control the impulse.

Exactly. So it's, it's, it's, so you,

it's not a breakdown that the rules disappear. It's that they can't apply the rule that they

can't apply the rules properly. And, and, and that's true for a lot of patients, even with

kids, you know, you tell them don't have anything to eat before dinner because we're having dinner.

And then they're sitting there having a sandwich and you say, what did I just tell you? You said,

well, don't eat, but I'm, I'm hungry. Right. Another sort of example is sort of the frontal

lobe is not completely kind of developed. So when I think about rules, I think about the brain,

you know, the brain,

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. So the most 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. And so he's storing all this information at sort of different levels of hierarchy. And he's

applying it to ultimately achieve this very simple act of, or not so simple act of hitting the golf

ball. So yeah, so I just, I think about sort of the frontal cortex is able to call upon the rule

in the appropriate context. And if you don't have your frontal lobes, it doesn't get pulled up

really. And those rules must be learned, right? There's no way I can imagine that one can be born

into the world with these rules sets intact. I think about the two marshmallow experiment,

that's sort of famous now, where kids are offered to eat one marshmallow right away or defer and

get two marshmallows, these adorable videos of the kids, the various strategies they use,

like turning away, poking the marshmallow. And, you know, there's some debate,

ongoing as to whether or not success or lack of success in deferring to the two marshmallow

reward is predictive of other things in life. But leaving that aside, am I correct in assuming that

that task is a frontal lobe task, the kids are given a novel rule, you can have one marshmallow

now or wait patiently and then with an overcome the craving for that one marshmallow, and then

you'll get two. And presumably that, 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 on 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 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, timescales, right.

And children tend to sort of act on goals that are much more short, on a shorter timescale,

you know, I'm going to have the sandwich right now, because I'm hungry, as opposed to wait till,

till dinner,

which is a longer, longer term goal. And so yeah, this default to sort of the 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? We 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 them to the goal. And

then it's a long term goal. And so, you know, we can learn that sort of the short term goal,

and then apply 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 this disaster, for reasons that aren't

interesting right now. But then when I came back my sophomore year, really spring of my freshman

year, I was like, Okay, it's on it 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 refuse to get up even if I had to use the

restroom very, very badly, I would set up all sorts of behavioral constraints. And I like to

think that I was building up my prefrontal ability to refocus on the material. And fortunately, for

me, there were no smartphones back then, it was much easier, right? Internet. Now we had email,

but no, no real internet browsing to speak of. And I like to think that the, I sometimes call it,

and this is terrible to call it this, because it's not nearly exhaustive of the underlying

function. But I call it sort of like limbic friction. It's like there's this friction that

one feels mentally, like you want to get up, you want to use the restroom, you want to eat

something, you want to call a friend, but you stay focused on the task at hand. Do you think

that that business of quote, unquote, staying focused on the task at hand can generalize

because of the sensations it generates in the body? And then you Oh, yeah, that's this is

familiar. This is just like studying.

But in a different context, one is one stays focused. Or do you think that the prefrontal

cortex is, is so context specific that it needs to learn a rule, 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, I know a number of people are

interested in how they can be more focused. And people often defer to like, what supplement,

what drug? Okay, those are interesting conversations. But I think, ultimately,

we're talking about neural circuitry.

Yeah, I mean, it absolutely can generalize it. That's been a frustrating thing into trying

to develop what we call cognitive therapy, where we 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 tasks that you've trained

them at. But it doesn't seem to generalize to 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 of Toronto, where they've been very successful in teaching patients how to

improve your executive function, and how to make that translate into your real world. But it's,

it's very hard work. It's very 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, you monitor your

brain, how you monitor what you're doing, how you don't let anxiety and procrastination get involved.

But it's a, 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 mean, the whole goal is to do things right. And, and I'm just

better at it. I don't know what it is. But I'm, 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,

you know, to people's real life.

I threw out 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's, 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, and in particular, the connections from the frontal cortex

to, let's call it circuitry that controls reflexive behaviors. What are, what is the nature of that

circuitry? And can we make any general statements like, does the frontal cortex really serve to

provide a quieting, suppressive function on reflexes?

Or is it more of an orchestra conductor where it's saying, okay, a little bit of that,

a little bit of that. And then what's, what comes out in behavior or speech is something that looks

very organized, but is actually the, the, the reflection of a lot of selective filtering.

Yeah. I mean, the prefrontal cortex, what's so fascinating about it is that it, I would say it

connects to every part of the brain, cortex and the subcortex, and almost every part of the brain

connects to it. So that, I mean, that right there tells you,

it's a pretty important area. And it has to, if it's going to be in this CEO, you know,

conductor type experience role. And so it's in this privileged position just anatomically. So

that, that gives us great insight to how important it is. And so it is connecting. And then of course,

we could talk about it, how it's connected to the body as well, how it controls heart rate

and respirations as well. So it's not just the brain. So, but it's really interesting, like you

said, is, is it really just sort of maintaining, telling you what's going on in your brain?

Yeah. I mean, I think it's, I think it's, I think it's, I think it's, I think it's, I think it's,

I think it's, I think it's, I think it's, I think it's, I think it's, I think it's, I think it's,

I think it's, I think it's, I think it's, I think it's, I think it's, I think it's, I think it's,

relevant and what's not relevant, or is it allowing you to switch? I think it does all

those things. It definitely, what we call sends these top down signals. It's sending signals to

the other brain about what you should be paying attention to and what you shouldn't be paying

attention to. So for example, if you, we've done studies with functional imaging, where we have

them look at pictures of faces and scenes, and that lights up the back of your brain, your visual

cortex has areas that 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'll, it'll, it'll sort of, it's sending a signal, say, pay attention to the faces,

ignore the scenes and, or vice versa. So it's, it's directing all of this information that we're

bombarded 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 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, of all of this control is coming from the prefrontal cortex.

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You mentioned connections between the prefrontal cortex and the body.

That's the first I've heard of that. And I'm not challenging that. To the contrary,

I'm just intrigued by it. I'm aware that the hypothalamus and some of these deeper brain

structures associated with more, let's call them primitive drives, temperature regulation,

hunger, et cetera, connect to the body. But what's the nature of some of the connections

with the frontal lobes to the body?

Yeah, I was just sort of talking in terms of

our knowledge.

Our knowledge of how changing... In one of your podcasts, you talked about how TMS to

the prefrontal cortex can slow heart rate. So I meant in that sort of way.

Got it.

That, yeah, by influencing cortical function, obviously we can influence organs like that.

Got it. So through some intermediate stations.

Yes.

Yeah. I mean, not to be hyperbolic, but it seems like the prefrontal cortex here we're referring to

is the frontal lobes.

Yeah.

And the prefrontal cortex is 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-Bucey syndrome, which has some vague similarities to how you describe frontal cortex

damage. But there, as I recall, humans or animals with that syndrome will act in a way that's not

appropriate to context. But...

Exactly.

More inappropriate. Like they'll try and eat a ceramic cup or draw with a piece of paper,

which obviously won't work. It seems like with the frontal cortex, it knows that a pen is for

writing. It just... The person might say, yeah, I know I'm not supposed to write this, but I'm just

gonna... Or write with it, but I'm gonna take your pen and write something inappropriate with it.

But it's not that they... People forget that there's a... That it's a pen. So it seems like

it's drawing on the rule sets, but that something's intact. It's like the...

It's not like Clover Busey syndrome where like animals and people can try and like mate with inanimate objects, which is one of the more salient symptoms.

I'll never forget that.

Don't forget that from my cognitive neuroscience course, which you taught, by the way.

Just throw that in there.

So how should we think about this?

And here I'm trying to get at kind of a broader understanding of brain function and context-specific behavior.

So frontal cortex is like super sophisticated, but it doesn't have all the information.

It seems like someone without a frontal cortex probably knows that you write with a pen, you don't write with a piece of paper.

Yeah.

I think it's, you know, we think about it as it's, you know, the frontal cortex allows us to take thought and move it towards action.

And there's this disconnect between the knowledge and action and the separation of action from knowledge.

And.

I guess I can reflect on my patients.

You know, when I've seen a lot of patients with damage all over the brain and all of the families of patients who have frontal lobe injury always say the same thing.

They're just no longer that person.

They're no longer my spouse.

They're no longer my best friend.

They're no longer my father.

They're just something.

They can't put it into words, but they're not them anymore.

There's something that's changed.

Whereas if you talk to a patient with Broca's aphasia who has this inability to speak, they can't get any words out.

You know, they can't get any words out.

This is a devastating problem.

They're still the same person.

They they they their personality hasn't changed.

They feel the same person.

They just can't speak.

The way they get around in the world is different.

Or if you take a patient with Proceptic Nose, which is 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 the difficult part.

Like, how does the frontal lobes allow us to sort of take take who we are and translate that into knowledge?

So we're not, I guess, another word saying it just just having knowledge isn't what makes us who we are.

Right.

It's to be able to take that knowledge and and present it in a way that allows us to live life based on our intentions and our goals and our desires.

So much of things like stoic philosophy and even online wellness.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

You know, all of those other theories of take nerede cultures are addressing the bleabydd andanniere context, right?

Like is there something like that, even, you know, in the

minds of other people, like me, who are節

But earlier you mentioned sleep deprivation can impair frontal lobe function.

It does seem that as the day progresses and certainly in the middle of the night, it just becomes much harder to control our thinking, maybe even our behavior, and certainly our emotions.

Is there a frontal lobe regulation of emotional states as well?

I know you have some recent work on this.

I'd love to hear more.

Yeah, I mean, as I was saying earlier, the frontal lobes is a big place, and half of it is involved in these high-level executive functions,

but the other half of it is part of the limbic system.

We call it the paralimic 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 areas that are kind of in the overall frontal lobe,

you will have many different impairments that we would call sort of social.

Or emotional impairments, and their executive function will be quite normal.

And then you'll have the opposite where patients with the lateral damage will have executive functions, but they seem emotionally intact.

But in real life, when we have both these intact, they're communicating with each other.

So emotion and contacts is going to influence our executive function.

We make bad decisions in stressful situations or situations we're not comfortable with.

It's where we might make a better decision if it's acquired.

So it's a quiet place.

But it is something that we can, I think you're right, you can sort of get into a routine and learn how to do things,

if you haven't very much planned out.

But what's so unique about it is how we can be flexible and adaptable, right?

When something novel comes up or 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.

But making these routines and setting all the rules when things don't go right, how to right the ship, right?

I will never ask you to demonize technology.

I certainly use a smartphone from waking till sleep.

Generally not in the middle of the night if I can avoid it, and I generally avoid it.

But I'm trying to take what we've discussed thus far and superimpose the notion of it in a way that's not going to change.

Right.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Exactly.

Yeah.

Yeah.

Yeah.

Yeah.

Yeah.

Yes.

Yeah.

Yeah.

Yeah.

And you can do it in all the virtual processes in our hospital, that is, right?

They slept and took two hadores for things.

They did an interim.

And then they did the integrated COVID vaccine which helped ourawia requests to actually

arrive.

Yeah.

So a lot of the nation's leaders have achieved have achieved schabu diesis and so we're

really beginning to vegetables these days as nearly,

have four or five different conversations very quickly while boarding a flight.

There's a task switching element that was just not present in our life prior to that.

Social media in particular, this notion of being able to scroll. So if we really step back from

this, move one's thumb and access hundreds, if not thousands of video content, each of which

has a distinct context. And so I have to imagine that kids and adults have frontal cortices that

are learning these rules. And the rule is move your thumbs, stay engaged, emotions, either positive

valence emotions or negative emotions. I mean, it's a fairly limited landscape there when you

really think about it. But the algorithm that's learned is, to me, doesn't seem exportable. It

doesn't help me.

I don't prepare for a podcast at all. I know that for sure. It doesn't help me go for a run.

Doesn't help me listen with more focused attention to a family member or a friend or a significant

other. It may make me more empathic or more angry. You know, we can speculate. But again,

with no intention of demonizing social media, does it seem that the algorithms that are being

run in our brain, I mean, are they neutral? Are they positive?

Are they negative? Should we be worried? It doesn't seem like they translate to much else.

I can't see a way in which they help us be better people in other domains. Whereas reading a book

line by line and then going back, oh, I didn't even remember anything from that page, going back

line by line, playing a game of squash or something like that, I can see the real value of the rule

sets that generalize.

Yeah. I mean, I can, you know, just historically, I grew up in a world when there was no smartphones

as a resident.

And so one of the most difficult things I do in practice is have to take care of patients in the

emergency room. And there's a real emergency. Someone's having gun control seizures or they're

having a stroke. And, you know, doing this back in the 80s or 90s and early 2000s, when you went

down there and you didn't have any smartphone, you could only rely on what's in your head.

And I could say now having the smartphone, it doesn't help me at all. I never, you know,

it does not help me at all in making the kind of decisions that I have to make in the emergency

room. I'm trying to decide.

You know, what's the problem here? What's the differential diagnosis? How should I treat it?

I'm just trying to make very, going through an algorithm, like you said, in a common sense way.

And there's nothing on my phone that I can turn to to help me do that. It has helped with giving

me knowledge. Like back in the day, I had to remember what the Dilantin dose was and have

that in my head or go look for the piece of paper in my pocket. And so I can quickly pull up, you

know, I guess I'm a little bit, you know, there's information that I can access that I don't have

to worry about keeping every day.

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 day.

So I can quickly pull up, you know, I guess I'm a little bit, you know, there's information that I can access that I don't have to worry about keeping every single dose in my head or keeping everything in my head, just facts in my head.

But outside of that, there's nothing I can turn to that it's making me, you know, better, making me make better decisions.

So I don't even need my cell phone. I don't go searching for my cell phone if I'm going to go to

a room or I'm going to take a phone call. So I don't see how it's helping sort of make your frontal lobe.

It can't be your frontal lobes. I mean, it's another way of saying it.

But on the flip side, can it help you optimize frontal lobe function technology?

Certainly it can. We can maybe talk about it later. There are certainly,

that's one way to get learned strategies is through a device that's easily accessible and,

you know, to you as opposed to a book or having a therapist in your house.

Yeah, I suppose I worry that too much of my time and other people's time and especially young

people's time is engaging in an algorithm that does not generalize.

For adaptive behavior elsewhere. And by comparison, you know, like a game of soccer with friends or something, right?

It's social. Social media is social. It's physical. Social media is not physical.

But we'll rule that portion out. But there's a rule set. There's goal-directed behavior.

Presumably some of the things that happen in a game of soccer with friends translate to some other domain of life

because it's a single context.

Game of soccer.

Whereas with social media, I don't know anybody that goes and looks at one account

and that's it and absorbs the information, maybe comments, has an interaction and goes.

It's hundreds or thousands of contexts. So is there any risk or perhaps benefit to being able to

get this very detailed portal into so many contexts per unit time? I mean,

the forebrains never had done that in the course of human history as far as I know.

Yeah. I mean,

I think there is a risk. But what pops to mind, you know, having kids is watching them navigate in their cars to places totally dependent on Google Maps.

I think you're probably old enough to remember real maps.

I still have one in my car. I love paper maps. I love maps.

Right. Where you had to really figure out, you know, you had to go to a certain place and you had to either look at the map or stop at a gas station and ask.

These skills were something that you learned and you developed.

And it was problem solving. And that's all gone now. I mean, it's I wonder even if sometimes if people even know the direction they're going,

whether it's west, north or what town they're in, because they're just following the direction.

So we'll see. I just can't imagine that that learned skill is not going to be detrimental to us at some point in generalizing the verse,

generalized in a bad way, right? As opposed to a good way.

So, yeah, it does. It does definitely worry me.

But like you said, there's nothing on the phone that helps you plan a podcast, nothing that helps me in the emergency room.

Nothing helps a professor when he's giving a lecture.

So I agree with you that that the sort of having your head buried in a cell phone, I'm not.

Yeah, it's I don't see it being healthy for your frontal lobes.

Let's talk about working memory some years back, but still now you use working memory tasks and experiments in your life.

So what are some of the things that you would like to talk about in the future?

Well, I think I would like to talk about working memory in the laboratory.

If you would be so kind as to explain what working memory is.

And then I'd love to talk about some of the work you've done exploring the role of dopamine in working memory,

because this is so critical to everyday life.

And I know dopamine is a bit of a buzzword these days, but the listeners of this podcast anyway are pretty sophisticated in terms of knowing that dopamine is not just about reward.

It's about motivation and goal directed behavior.

And I think dopamine intrigues.

For a good reason that it does govern a lot of our, you know, quality of life.

So what's working memory?

Yeah, I mean, working memory, it's interesting.

I started studying it about 30 years ago, and I don't think I realized how important it was when I started.

But what we mean by working memory is this ability to hold information in mind when it's no longer accessible to us.

So if you tell me your telephone number and I have to put it into my phone, you know, it's no longer there.

You just told me.

But I'll hold it in my working memory.

I can punch it into my phone.

It doesn't have to be something that comes from the outside world.

I could hold up, you know, I can pull up my own if I'm filling out a form and I want to pull up my Social Security number.

I can hold that in mind, too, until I put it down.

So when you think about it, it's a very important, you know, ability that we have that we do very flawlessly.

And what I've learned more about working memory is the working part of it.

It's not just this passive holding information in mind, but it's more.

Yeah.

Yeah.

Yeah.

Yeah.

It's being able to do things with the information.

It's being able to, you know, when we do a math problem, which we don't do that much now that we have calculators,

but if you do that in your head, you're able to sort of manipulate the information and do the different parts of the problem.

Or even if you're, you know, you're trying to find someone in a crowd and you're holding onto some face,

you're able to hold that face in mind and cross-check it and search.

And so there's operations to working memory.

It's not just, you know, it's not just this passive.

It's a lot of maintenance.

So when we started to think about working memory in that way, we started to realize how important it is for it's, you know, I think of it as the foundation for cognition.

Just think about reading comprehension.

You can't understand this conversation.

If you can't hold in mind what's going on, you know, earlier in the conversation or when you're reading a book, you know, remembering the sentence before it.

So it just predicts all these abilities that allows us to read, to plan, to organize, and all the sort of executive.

functions that we're doing, right?

We have to hold in mind rules.

We have to hold in mind goals.

We have to hold in mind all of these things in order to just carry out behavior.

You know, so it's really come a long way in terms of how people are thinking about it.

I know that Matt Walker said that, like, you know, sleep is our superpower.

But I guess one way to sort of use this term while we're awake, working memory is really our superpower because it allows us to translate, as we said, sort of our knowledge into action by holding.

this information in mind as we're thinking about what we want to do.

If we're going to think about dopamine in the context of working memory, is dopamine an accelerator on working memory?

Is it a facilitator?

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.

Okay.

So I think that's a good question.

So I think that's a good question.

Yeah.

Let me start with the working memory, the circuitry for working memory, because one of the important things about working memory is the other type of memory is long-term memory.

You can – working memory is short-lived.

It's only as long as you're able to rehearse it, and then it disappears.

Whereas what we call long-term memory, if I – remembering what you had for breakfast or your vacation, this is information that gets consolidated and gets put into a more durable form that we call long-term memory.

And the interesting thing about –

Yeah.

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 two completely different parts of the brain that seem to control it.

So working memory, the frontal cortex seems to be very important for working memory.

When we are holding information in line, the neurons, the brain cells in the frontal lobes are active and they stay kind of active as long as we're holding on that information.

And they're more important in the long-term memory.

Yeah.

And they're more active when the information is relevant.

And if 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, the phone number, well, that information is in your back of the brain.

And so the frontal lobes is sort of keeping information in the back of the brain active because it's connected to the –

to the visual areas.

It's able to sort of keep that information active.

And so what we've learned is that there's not these buffers in the brain where, you know, if you're holding verbal information, it's in this little buffer.

And if you're holding visual information, it's in another buffer.

The whole brain acts as a buffer.

And the frontal lobe can call up any part of the brain and keep that part of the brain active as it's – as it's – you know, as it's trying to hold this information in line.

So the mechanism for working memory is just this persistent neural activity.

Yeah.

Yeah.

Yeah.

Yeah.

So there's a lot of neural activity within the frontal lobes.

And so then the question is what does dopamine do?

Well, dopamine is one of the neuromodulators that are made in the brainstem and it projects up to different parts of the brain.

There's a system that goes up into the – into the – what we call the basal ganglia, which is important for motor function.

And there's another dopaminergic system that goes up to the frontal lobes.

And what was discovered was that if you deplete dopamine, working memory drops.

You get a significant impairment of working memory.

If you deplete dopamine and if you replace it, then your working memory will be improved.

And so dopamine seems to be a modulator to help this persistent activity stay persistent, you know, during the time that you need to keep this information in mind.

Am I reaching too far to draw an analogy between dopamine's role in working memory, that is to keep information online, and the impact of dopamine on the brain?

I think dopamine is a very important component of the brain.

And the other established role of dopamine, which is for movement, for the generation of smooth movement, as evidenced by conditions like Parkinson's where people lack dopaminergic neurons or have damage to dopaminergic neurons and have, you know, challenges in generating smooth movement.

What I'm essentially asking is can we think of dopamine as facilitating physical movement through one circuit but also kind of mental movement, thought movement?

Yeah.

I'm thinking for those just listening and not watching, I'm kind of rubbing my index and middle finger against my thumb.

So just keeping something online, it's sort of a movement of thought or information, and then you kind of chuck it away and bring out the next information.

Is that appropriate?

Yeah, I think that's a good way of thinking about it.

And one might wonder, well, how can dopamine be important for memory but also be important for movement?

And it's really simple.

It's just that it's acting on different circuits.

It's the neurons that go to the motor areas that carry dopamine.

When dopamine is expressed there and boosted there, then it will be involved in movement.

And lack of dopamine in the basal ganglia will lead to neurological disorders like Parkinson's disease that has severe movement difficulty.

But when it's acting in the frontal cortex and expressed in the frontal cortex, then it's going to improve working memory.

So it's just the nature of where the circuits are, where the dopamine is that's allowing it to have different kinds of actions.

And that's for all transmitters.

And that's the reason why acetylcholine seems to be more important for long-term memory is because it's projecting to the hippocampus, which we know is another area that's important for memory.

And that's why acetylcholine doesn't boost your working memory, but dopamine does and vice versa.

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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 bromocryptine, that working memory improves.

Conversely, if one depletes dopamine pharmacologically, working memory gets worse.

But as I recall, there was an important baseline that is important because it really mattered in terms of the outcome.

Meaning if somebody already had relatively high levels of dopamine in this circuit, increasing dopamine further with bromocryptine didn't impart a benefit and might have even made their working memory worse.

So there's a kind of inverted U-shape.

How does one know whether or not their baseline dopamine is low, medium, or high?

Ergo, how do they know whether or not they would want to explore going about increasing dopamine through any number of different approaches?

Right.

Well, most people probably have optimal dopamine, but there's a significant percentage that probably have too little or maybe too much.

And unfortunately, we can't measure it.

And the blood, there isn't a blood test that I'm aware of that can measure dopamine because it's stuck in the brain.

Peripheral dopamine in the blood is not a good readout.

It's not a good readout, yeah.

And especially when you're talking about dopamine in areas like prefrontal cortex.

And so we don't have a good readout there.

There's invasive procedures like positron emission tomography where we can inject a radioisotope 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 in patients that have Parkinson's disease by looking at this scan.

Obviously, it's invasive.

You're injecting a radioisotope.

It's expensive.

And it's not something we could all do.

But we had used it to show that it correlates very strongly with your working memory capacity.

So how much information you can hold online.

If you can hold four or five.

Or six letters when I do a span task correlated with how much dopamine we can see in the PET scan.

So that would be a way that we could do it.

So if you were to read out a string of a few numbers or letters, and I can remember all of those a few moments later, perhaps my baseline dopamine levels are moderate in the normal range.

Whereas if I couldn't keep that online, that might be.

Might be reflective of lower baseline dopamine levels.

Is that right?

Yeah, it's a very strong proxy for dopamine.

So if your working memory capacity is seven letters or numbers, when I say 4371506, if you get them all back to me very quickly, you probably have more baseline dopamine than someone who has five.

So it's a proxy for measuring someone's dopamine.

So that's one way to do it.

And that's actually how we did it in our original studies.

We.

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, we gave them bromocriptine, which was the dopaminergic agonist.

We improved their working memory.

We got them into sort of an optimal level.

But but those who were already high, we actually made them.

We were.

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 U curve?

Another way of doing it is through genetic studies.

So we have dopamine.

All neurotransmitters have to be broken down and reuptake into the into the brain cell in order to be used again.

And there's different ways of doing it in some.

There's different ways of doing it in some.

So, you know, if you're in the brain cells, it gets transported back into the brain cell and other other places.

There's an enzyme that that breaks it down.

Well, there's an enzyme called Compt that is breaks down dopamine in the prefrontal cortex specifically in a large percentage of individuals.

That enzyme is either overactive or underactive.

Probably about 25 percent of individuals.

It's overactive and another 25 percent.

It's underactive.

So probably half the population.

Now, this is going to vary.

Depend on other where you live and where you come from and things.

But but but maybe half the population either has an underactive enzyme or overactive enzyme.

If you have an underactive enzyme and actually more dopamine sits around and you actually have more dopamine than others.

And if you have an overactive enzyme, it's the opposite.

So we've actually shown that if you now go and genotype people with a simple saliva test and figure out, do they have this genetic what we call polymorphism?

Where just one amino acid gets changed and the enzyme becomes either active or underactive.

We can we can do the same thing as grouping them by their capacity.

Those that have the low dopamine, we will make them better.

And those who have sort of baseline high dopamine will will make them worse.

Super interesting.

Maybe we could talk about bromocriptine a little bit, and I'm not encouraging people to run out and take bromocriptine.

But I think it's a good idea to take it.

Bromocriptine, as you mentioned, is a dopamine agonist.

Relatively short acting.

Yeah, four or five hours, six hours.

So kicks in about 90 minutes after.

Right.

As I recall you saying, I've never taken it.

Yeah.

How do people feel when they're on bromocriptine?

I mean, when I hear dopamine agonist, I mean, there are a lot of illicit drugs like cocaine, methamphetamine that are increased dopamine.

But then again, chocolate, sex and food increased dopamine.

But the kinetics, the time course.

And the levels are different for each of those things.

Dopamine, of course, being a currency of motivation and reward, not directly related to any one compound.

But I would think that based on the data you just described that and given the fact that there are a number of people out there with challenges and working memory, attention, task switching, etc.,

that there would be a strong interest on the part of the pharmaceutical companies, at least, and certainly the general public.

But I think that there's a lot of interest in things like bromocriptine 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 neuromodulators.

The discovery that depletion of dopamine and not other transmitters impairs working memory was made in 1979.

When I heard that, I was like, oh, my God.

I heard Pat Gormer.

He used to talk about this as a resident.

I was just amazed that there could be a single transmitter can change a single behavior.

I was seeing very complicated behavioral deficits and it just seemed impossible to me that there could be such a tight link between a single neuromodulator and a single cognitive process.

And it just opened the door for me that this really could be an incredibly beneficial therapy for anyone with executive function or frontal lobe function.

So.

But unfortunately, there's never been a pharmaceutical company that's tried to develop a drug for improving cognition to this day.

That's crazy.

And they – I mean it's crazy for several reasons.

One is that the data are clearly there.

Two, these drugs are already established.

It's not like they have to go through safety trials.

Again, that's already been done.

But mostly because regardless of whether one is a fan of the pharmaceutical industry or hates it, the pharmaceutical industry in principle can make a ton of money doing this.

So I would think that they'd be heavily incentivized to do it.

Yeah.

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, you know, do you want to get involved here?

We can – this should be done.

I can't do this by myself.

We need to have real trials and we need to have real tests.

Right.

We need to have real trials and real studies of how this will help, you know.

And just it was, you know, their eyes would always cross and never got any sort of traction.

It always went back to sort of disease.

You know, what disease are you curing?

You know, what's the market for it?

Is it a Parkinson's disease thing?

Is it Alzheimer's disease thing?

And this has been a general problem with neurology.

It's very disease-centric.

It's always sort of – and it's always focused on, you know, how can we develop a treatment for Alzheimer's or traumatic brain injury or stroke?

As opposed to how can we develop a treatment for working memory dysfunction, which is a problem across diseases.

So the answer to your earlier question is these drugs are very safe.

We give them in such low doses to healthy individuals, they don't even know – they can't even tell the difference between the placebo and the drug.

Really?

They don't even know which one they're on.

So they're not buzzing thinking like, oh, this feels good and my working memory is better.

They have no idea.

They don't even know their working memory is better until we show them that their working memory is better.

Right.

They don't even know that their working memory is better.

Love it.

Yeah.

So they're truly blind to what's going on.

Bromocriptine is but one of the dopamine agonists.

You can think of a few others, cabergoline, like other things like that.

Do any of these dopamine agonists exert this impact on working memory or is it – does it vary by drug because different – a dopamine agonist sort of hit different receptor pathways and things like that?

Yeah, no, it's not specifically the drug.

I mean, the reason for bromocriptine is that it's the oldest and it's the one I was most comfortable with.

I had to be comfortable with it clinically before I'd give it to undergraduates at Penn or Berkeley, so there's nothing special.

But other agonists work similarly.

There's a drug that's developed which is a COMPT inhibitor, which actually inhibits this enzyme that we're talking about, and that also will improve – will have the same function.

There's been some future work that norepinephrine.

Norepinephrine also seems to be helpful with working memory.

It's not as – maybe not as potent as the dopaminergic.

And that's the point I want to make, another disappointing thing about this whole field of the pharmacology of cognition.

You know, I wrote a paper as a resident.

You know, sometimes you're tending to say, hey, can you write this review paper for us?

And I wrote one as a resident called the pharmacology of cognition where I just looked at all the animal literature on, you know, giving –

Norepinephrine.

Giving neuromodulators, acetylcholine, dopamine, or whatever.

And there was a lot of animal literature sort of supporting that this would work in humans.

But what was more striking to me was that it wasn't always just a single neurotransmitter.

There were studies where you'd give 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 be really effective.

So these, you know, these neurotransmitters are really effective.

You know, these neurotransmitter systems don't act in isolation.

So we need to also study sort of how the combinations work.

And that's where another – you know, where the pharmaceutical companies have the infrastructure to do these kind of studies.

It's very hard to do in a single lab to do multiple drugs at one time, you know, and then try and look at – try and determine all the different interactions.

Maybe we could talk about a couple of other drugs that are legal or have – and have FDA approval, are known to be safe in the right context.

That it seems would fit the bill here for improving working memory.

One is Welbutrin.

I can never pronounce that.

As far as I know, it's a epinephrine or norepinephrine agonist.

You just mentioned that increasing epinephrine may have a positive impact on working memory and to some extent a dopamine agonist.

Is there any evidence that Welbutrin can improve working memory?

Yeah.

Yeah.

Anything that boosts norepinephrine can do it.

The one that we've used that's most used is guanfacine, which is actually a blood pressure medication.

So that's starting to gain some traction.

In fact, I think there was a study with COVID – with brain fog for COVID showing that improved symptoms with it.

So there's actually some trials now that are looking at guanfacine.

And so I would say anything that boosts norepinephrine would be helpful.

But then again, I don't want to leave out the other transmitters.

It's a good thing.

I think the other transmitters, serotonin, increasing serotonin, increasing acetylcholine boosts other cognitive processes.

And then in a way, they can help working memory.

We talked about working memory being this foundation.

Well, if you give acetylcholine and it kind of boosts memory, well, that can indirectly help your executive function.

Or if you give a drug that improves your focus, then that can indirectly help working memory.

So what I'm really pushing for is not just a single – it's going to be one drug.

It's going to be a cocktail.

And we have to not only figure out what the cocktail is but also figure out who we're giving it to.

What's – you know, link it to the person's own makeup of their own neurochemistry.

When we get to a point where we'll know, we can map out sort of everyone's dopamine, norepinephrine, serotonin levels,

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 – it's just like cutting open the skull and just sort of pouring it onto the brain.

Right.

We're not actually doing that.

We're not actually doing it.

But it seems that way.

We're not – the precision is not there yet.

Well, it's great that you developed this cognitive task that can be a proxy for dopamine levels.

The cognitive task, again, being how many number or letter strings somebody can remember, basically working memory performance.

There are a lot of tests out there that claim they can assess dopamine and serotonin.

They can assess dopamine and serotonin, acetylcholine levels from a blood draw.

I've heard of the Dutch test.

I've never taken it.

But a few minutes ago, you said that really one needs to do positron emission tomography imaging, which is fairly labor-intensive.

Most people don't have access to one of those.

It's a clinical tool.

So there are behavioral proxies.

There's neuroimaging.

But also to my knowledge, I don't know that there's any blood draw that will say, hey, your serotonin levels are low.

Or your dopamine levels are moderate, 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 dopaminergic system is complicated because it's not only just the prefrontal cortex, as we talked about.

It's also the basal ganglia.

And so not only do we have to measure dopamine.

Just generally levels, we have to measure the balance of the dopamine in this triatom and the prefrontal cortex.

There's a model of dopamine function and its relation to executive function that has to do with sort of the balance between these two systems.

That dopamine in the prefrontal cortex is promoting sort of stability.

It's keeping information in mind.

It's keeping these representations stable.

Whereas the dopamine in the basal ganglia, what it's doing is it's keeping the information in mind.

And so what it's doing is it's 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 the frontal cortex, it could lead to a very rigid state where you don't let anything in.

And if you have too much dopamine in the striatum and you get too flexible, then you can get very distractible.

So there's this sort of balance of dopamine.

So it's not just how much dopamine you have in your brain.

It's how much, what's the balance of the dopamine.

So I don't see a blood test as ever giving us a balance.

I don't see a blood test as ever giving us that information.

But I do see there being a brain test that can give us this kind of information of the two or at least a proxy for it.

So what I was thinking about when you were talking about asking this question, you know, for example, if you measure pupillary,

pupil dilation, that's a pretty good proxy for the neurodegenerative system.

All right.

So at a given, people will wonder how to do it.

We're not going to go into too much detail here.

But at a given brightness in the room, what we call luminance, the pupil tends to be smaller when it's bright and larger when it's, you're in a dim room.

That's sort of obvious.

But at a given luminance, the more alert, aroused somebody is, arousal is a general term here.

I'm not talking about a particular kind of arousal.

Then the pupil tends to be more dilated.

It gets bigger the more norepinephrine is in the system.

So if somebody's pupils are really big in bright light, that person's got a lot of epinephrine, adrenaline in their system.

Do you use this clinically?

Like when someone comes in and they have those big old pupils and you're like, okay, they're probably on a stimulant.

Yeah.

I mean, a lot of what neurology does is try to look for these windows into the brain.

And so I think there are a number of windows into the brain that we're going to be able to develop that can reflect these neuromodulatory systems.

So that's why I've been so interested in developing this.

I've been interested in developing biomarkers because really what a neuro 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.

And so that's a neuro epinephrine biomarker.

We're comparing 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 bromoconfusion?

Have you ever tried bromocryptine?

Very early on, but it's such a low, you know, at the dose that my subjects were getting.

But like I said, it doesn't, it's so low, you don't feel anything.

And I should say with even with patients that take it, they rarely get any side effects.

Sometimes with these drugs, because there's peripheral dopamine, they can get nausea or something.

But it's extremely well tolerated.

You don't get any, anything feeling from it.

Does it change reaction?

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 bromocryptine pre Olympics and in the Olympics.

I think it's a banned substance now.

And the athletes that were taking it, don't ask me how I know this, but I could tell you offline.

And I'm not one of these athletes, nor was I supplying the bromocryptine.

We're using it because they were sprinters.

And it turns out that a lot of the sprint races are won by being first out the blocks.

There are other factors as well.

But that reaction time, you know, hundreds of milliseconds are the difference between podium and no podium.

And bromocryptine was one of the drugs used.

It was not on the banned substance list.

Just a reminder that every Olympics you see, there are lots of things being used that are not on the banned substance list.

And I'm not trying to be disparaging.

I think there's just a lot of interest in augmenting neuromodulation for nervous system function.

Bromocryptine was top of the list at that time.

I think it's on the banned list now.

There's a lot of use of pharmacology now on college campuses and in high school and even in elementary schools and sometimes by parents for their kids to try and improve cognitive function.

Most typically, the use of Adderall, Vyvanse, Ritalin and other drugs.

Which are noradrenergic, dopaminergic, agonists.

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.

We've got smartphones distracting us.

And to some extent, you know, one could say, oh, well, it's cheating to use pharmacology.

But a cup of coffee is a bit of a noradrenergic agonist.

Absolutely.

And certainly improves my focus as long as I don't drink too much of it.

Right.

Yeah.

What are your thoughts?

Yeah.

I think it, you know, it kind of gets back to what we talked about there being an optimal, you know, optimal.

Right.

Yeah.

And optimal level of dopamine in your brain.

I think if you think about it as just more and more and more is better and that more is better, then there's really no end.

There's really no end.

How do you know how much you should be taking?

There's sort of no end.

That experiment was run in 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.

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 good for you.

You know, enzyme that makes your dopamine 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 is sort of on the lower end and boost them up, I'm all for that.

The problem is we don't know if they're on the high end.

And some of these athletes were actually making themselves worse.

We know for sure.

I mean, these are healthy Penn and Berkeley undergraduates that we made them worse on working memory tests.

By increasing their dopamine.

By increasing their dopamine.

Just a little amount.

Just tipped them over just a little amount.

And so, you know, without the knowing, then it just seems like it's not well informed.

You're going to be taking it.

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 necessarily developed with knowing how exactly they worked.

I mean, that's how the pharmaceutical company works.

SSRIs too.

Yeah.

I mean, it works, so let's do it.

I'm all for that as a physician.

But if I had my choice, you know, drugs that boost up multiple cysts, all the catecholamines,

the ones that boost up dopamine, epinephrine, and norepinephrine, I would steer away from those

because you have no control over how you're modulating the system.

Again, I was sort of talking about a cocktail.

It may be a little bit of dopamine and a little more norepinephrine.

But if you take something like Ritalin and Adderall, you just get the same amount.

So it's kind of, if I was to start to sort of experiment, then I wouldn't use Adderall or Ritalin as the drug that I think would help,

even though they're clinically sort of useful.

I use things like bromocriptine 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, sleeping better and better nutrition.

All of these are aiming to optimize, not, you know, reach some certain goal.

But I think that's where we're trying to get 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, you know, sleep is the bedrock.

It's the foundation of mental health, physical health, and performance.

I mean, without that, pharmacology might bridge you for an afternoon, but you're going to pay the piper somehow.

Our friend and colleague Matt Walker, obviously, has been beating that drum for a while.

Right.

What about drugs like modafinil, which are thought to be true cognitive enhancers,

as opposed to drugs that just kind of are designed to ramp up levels of alertness, as many of the drugs we're discussing do?

Yeah, it's hard to know.

I mean, I think certain drugs just improve general abilities.

Either they speed how fast you can process it or how efficient you can process or narrow the focus of your attention.

And that just helps all abilities.

So it's hard to say.

I think this has to be more work on really understanding what specifically, you know, these drugs are doing.

That's why the dopenerg story has been so interesting because it's a very specific effect with a very specific mechanism.

I'd like to see that be done with other neuromodulators.

Maybe we could talk a bit about some of the disease conditions that you treat and the role of working memory and dopamine in those conditions.

As well as other transmitter systems.

You know, one subject that we haven't talked about on this podcast previously, but is of tremendous interest to people, is traumatic brain injury or concussion, even mild concussion.

And before we were recording today, 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 and concussion are traumatic brain injuries.

Right.

And concussion is not due to football.

It just gets a lot of the attention.

But you've got bicycle accidents, car accidents, playground accidents.

Maybe you could list off a few more.

But how common is TBI 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 mean, concussion is much more prevalent than we realize.

And the numbers have gone up and up, not because it's becoming more common.

It's just that it's becoming more recognized.

And I think, you know, we underestimated and trivialized sort of what a concussion is.

You know, it's just something that is, you know, just you're going to recover from it.

I mean, still the old school thinking by a lot of neurologists is that everyone gets better within a couple of months.

You know?

You just wait it out and you'll get better.

That's just the normal time course of concussion.

But as we've studied it more, we've realized that there's actually quite a large percentage of people who a year out, they're still suffering problems.

They still feel like they're not mentally clear.

And they still are sensitive to light.

And they still feel a little dizzy.

And just the symptoms, you know, there's a host of symptoms that just one year later after a concussion where they didn't even lose consciousness, you know?

That's something that they may not realize.

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 has clearly had a concussion, mild or severe concussion?

You know, maybe a car accident, maybe a sports injury.

Maybe they were knocked out cold, maybe not.

But they're having some headaches, some photophobia, you know, sensitivity to 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 thank goodness.

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 not walking in expecting a cure.

Just understanding what it is, having someone understand what happened to them is very helpful and comforting.

So what we mean by concussion, and in the clinical world we use mild traumatic brain injury kind of synonymous with concussion.

It basically is a tearing of axons.

The brain cells have these long fibers that communicate with each other, and they're called axons.

And when the brain violently moves forward and backwards,

if you're in a car accident and you have your seatbelt on and you suddenly hit, you go from 50 to 0,

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 neurological, it's a real brain injury,

even if you haven't lost consciousness and you only have symptoms for a couple of days.

And there's a correlation.

The longer you've lost consciousness and the longer your symptoms last,

the more axons you've torn.

There's kind of a direct relationship between the two.

So the mechanism is these torn axons.

So now nerve cells don't communicate with each other,

and the brain, different brain regions are torn.

They're not communicating with each other.

And it turns out the most common place for axons to tear is in the frontal lobes.

And so now we talked about all these things that the frontal lobes do

to orchestrate the rest of the brain.

Well, it has some injured pathways.

And that's why a lot of the symptoms that patients have

are these kind of mild executive symptoms.

This mental fogginess that they're describing is this ability,

just this inability to get things done.

They don't lose.

They don't lose knowledge of who they are.

They don't forget their name or forget where they live

or lose memories from the past or anything like that.

But they just don't officially get things done as well as they used to.

It only takes a little bit of a drop, right?

People think you have to have a big drop in performance

to have a real-life impact.

Just a 1% drop and you're having a hard time doing your broadcast

or teaching a lecture or whatever you might do.

A 1% drop sounds like a frighteningly sad thing.

Yeah.

A frighteningly small change required to negatively impact life.

So how about a poor night's sleep?

I mean, what kind of drop in prefrontal cortical function are we looking at?

Let's say I normally get 7 or 8 hours or 6 to 8 hours

and I suddenly only get 3 or 4.

Are we talking a significant detriment?

I do think so.

I do think that, yeah, that it is significant, a poor night's sleep.

And we all notice that.

I mean, it's very obvious.

I mean, and you know, it's hard to sort of quantify.

I'm a baseball fan, so I can quantify it like if you think about it in a picture

and how fast they throw, you know, a small drop for them,

someone who's throwing 100 miles an hour,

just a small drop turns them, you know, from really elite to someone mediocre.

Maybe it's more of a 10% drop, but it's still relatively small.

Yeah.

Just a relatively small drop can have a huge impact.

I think people think that just because you're a little bit off,

that's not a big deal.

You kind of work through it.

And that's what most doctors say.

Just plow through it.

Just work your way through it.

You're going to get better.

And as opposed to saying, yeah, you really had a brain injury.

This is what happened.

We need to rehabilitate you just like we would do if you tore your anterior cruciate ligament.

I think that's why tearing your cruciate ligament or your Achilles tendon gets more interest

than tearing axons in your brain.

It's amazing to me that there's more emphasis on orthopedic injuries than brain injuries.

Yeah.

I don't know why that is either.

I think the brain is mysterious enough that most people and many clinicians just kind of back away with hands raised.

But if you are in the field of neurology or psychiatry,

I suppose then one has officially signed on to try and resolve these matters.

So for somebody that has a traumatic brain injury or low-level concussion,

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,

induce deficits in working memory.

And who knows?

Maybe a good portion of the deficits in working memory

do that.

And that's why I think the reason that we're seeing so much of a shift in the number of patients

due to traumatic brain injury and concussion is because of the sleep deprivation that it can cause.

So it can get circular.

Not only that, but one of the most common symptoms that my patients with concussion have is their sleep is disruptive.