If any goal that you achieved, whatever it is taking a drug, eating a food, getting a partner or whatnot if that was enough for you, right then you wouldn't keep living.
You want that system to keep tracking.
And once it gets to one place, you want it to have another place to which it could go.
Otherwise, you wouldn't live.
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. Reed Montague.
Dr. Reed Montague is the director of the Center for Human Neuroscience Research at Virginia Tech.
He is also an expert in the science of motivation, decision-making and learning and a pioneer in developing methods to directly measure levels of dopamine and other neuromodulators in humans in real time.
Today, you'll learn how dopamine really works, not just to regulate your levels of motivation we've all heard that before but also to teach you things.
Dopamine is involved in learning as well as persistence or lack of persistence.
As Reid will teach you, most of what we hear and know about dopamine is based on the idea that dopamine levels go up or down depending on our levels of expectations, and then what happens.
But, as he explains, most aspects of life work school relationships, our pursuit of money, et cetera involve multiple milestones.
We work, we wait, then we get an outcome that in turn informs the thing we do next.
Or maybe dopamine arrives suddenly with no work involved at all.
In other words, dopamine levels are constantly changing, and that shapes not just what you do now, but how you think about your recent past and what you will do next.
So when we say dopamine is involved in learning today, you are going to realize that dopamine is teaching you how to adjust your behavior.
We of course discuss how this knowledge can be leveraged for better motivation and decision-making, even better social interactions.
And we also discuss serotonin and how dopamine and serotonin work in sort of seesaw fashion and how serotonin in particular teaches you about unwanted outcomes.
We also have a discussion about SSRIs that you're going to find fascinating.
As Reid points out, SSRIs increase levels of serotonin, but often that serotonin gets used at the dopamine synapses to reduce the rewarding properties of dopamine.
So today's discussion about dopamine and serotonin is going to be vastly different than any that you've heard or read about elsewhere.
You're going to learn how those neuromodulators work and you're going to learn how they impact your everyday life and decision making.
As we all know, discussions about dopamine and serotonin are everywhere nowadays.
But in today's episode you're going to learn from a top expert in the field what these molecules truly do.
And that's going to help you better leverage your efforts, introduce what we call deliberate delays, and how to use tools like AI to improve your levels of motivation and your ability to learn through neuroplasticity.
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, today's episode does include sponsors.
And now for my discussion with Dr. Reed Montague.
Dr. Reed Montague, great to see you after all these 15 years.
15 years.
You turned us down for a job offer then.
I did.
But we both turned out okay.
Well, I hope so.
We'll see.
Well, you certainly turned out okay.
And you look great.
It's always great to see a colleague looking so fit and healthy, who also raised five children successfully and all those things.
We'll talk a little bit about your life and maybe your athletic life a little bit later.
But I want to talk about dopamine.
The world is obsessed with dopamine now.
Until very recently, people thought about dopamine as a reward.
Now slowly, people are starting to understand that dopamine is involved with things other than feeling good, such as motivation movement, et cetera.
How do you think about dopamine, the neuromodulator?
And then we'll move into the context in which you study dopamine.
But when somebody says, what does dopamine do?
How do you think and respond to that question?
Well, it used to be that dopamine was thought to equal pleasure.
Dopamine goes up, you feel good.
Dopamine goes down, you feel less good.
Okay.
It's been an explosion of work on it.
Most of the new work that's not psychological has been out of the artificial intelligence world, what's now called artificial intelligence.
It's very clearly a learning signal, number one.
So dopamine fluctuations, high and low, control learning.
It's also playing multiple roles.
It plays a role in motivation, and it may also play a role in the way you feel, okay?
It's less well understood how the sort of mechanics of what dopamine does for changing your nervous system relates to your feeling state.
You can have a feeling state that's good and see things that don't correlate with dopamine being the cause of it.
Let's talk about dopamine in the context of learning, because that's something I think most people don't associate with dopamine.
What are a few examples of what we know about dopamine and its role in learning?
That's a world I can't even summarize in a quick way.
People that work on rodents now will take a genetically modified rodent and they will study the way in which dopamine release correlates with something the animal is learning.
The animal may learn to turn left when it sees a light.
It may learn to run toward food.
It may learn to run down a maze.
All kinds of learning tasks associated with the animal are associated with dopamine fluctuations in your brain.
Now, these aren't global.
They're all over the place.
But there are different kinds of signals that you can find in different spots in your brain.
And we've begun to understand dopamine as a central player in the algorithms that your brain runs.
And that's where people like me and people like me, computational neuroscientists have made a connection.
And that's the connection between the kinds of learning rules and learning procedures that are installed in your brain, and installed in the brain of every mobile creature on the planet, and dopamine fluctuations.
So that's a strong connection that has been worked out over the last 30 years.
The algorithms are well understood.
What wasn't well understood 30 years ago was the kind of remarkable things those same algorithms can learn.
I'll come back to that.
I mean, there have been a bunch of modern breakthroughs in what's called reinforcement learning.
And reinforcement learning's main biology partner is dopamine, it's the first big hit.
Now, you know, it's an area of science.
And so what happens when you have a big finding that looks like it explains a lot of things?
Well, you know, people come rushing in to sort of beat it up.
That's their job.
That's their job to hack away.
Oh, is it really this?
Does it work the same in this context and that context?
But I think the description of what dopamine does as a learning rule is pretty much true.
Let me give you an example.
So psychologists since the time of Pavlov have understood what it means for an animal to generate a prediction and to compare it to an outcome.
Okay, the example is, so today's Wednesday.
Suppose, and this is Rich Sutton's example.
Suppose I make a prediction today that it's going to rain two inches on Saturday.
Okay, now we're going to fast forward to tomorrow and I'm going to update my prediction because I have new knowledge and it's going to say it's going to rain 10 inches on Saturday.
There's been no reinforcing feedback.
It hasn't rained yet because it's not Saturday yet.
I'm making a prediction about Saturday.
But there's a difference between this expectation and that expectation.
Those differences are encoded by dopamine.
It's called a temporal difference error.
And dopamine seems to code that.
Before you ever get to the terminal return, imagine that you were playing a game. like checkers.
You make a move in the game and you might make, I don't know, 40 moves before you win the game.
And suppose winning the game is the reward.
Well, you may have some prediction.
Your brain makes a prediction, when you play board position to board position, that you're going to win the game, and that's a fluctuating quantity.
That's a different kind of learning rule.
The kind of learning rule that psychologists talk about, that you think about in your everyday life, is it's going to rain two inches today.
Okay, how much did it rain?
So that's a comparison between an outcome and your expectation.
What Rich Sutton and Andy Bartow did was said well, what you really want to do is you want to stick between there.
Your next prediction
So you want successive predictions.
And why is that a good model for animals?
Well, because if you're an animal and you're wandering around foraging, mainly you're not finding anything.
You're going from position to position to position to position to position, but you're learning.
And dopamine is encoding those signals.
I'm so glad you said the word foraging because I want to hover on the theme of foraging in the context of human decision-making and learning and behavior.
So to stay with your description, Saturday rolls around.
Let's say it doesn't rain.
Let's say the person doesn't want it to rain.
They're not a farmer.
They want to go to the beach on Saturday.
Now we can talk about reward prediction error, right?
The difference between the expectation when it actually happens.
Okay, let me interrupt and correct that a bit.
The reward prediction error that people talk about dopamine representing is the prediction error that you get for every single step, whether or not you've received reward.
That's kind of diffused out in the psychology literature, as you have an expectation and you have a reward.
It may be positive, negative, or zero.
And what you do is you make an error there.
That was understood in the 60s and 70s.
It's called the Rescorla-Wagner rule, 1972.
That's how the system should learn.
The fact is, though, that doesn't model reality very well.
Reality doesn't give you feedback like that every time.
Reality often gives you long stretches of nothing.
The insight I think of Sutton and Bartow in their algorithm was well, a better algorithm for learning continuously is to take successive predictions and to say that's a learning rule.
Obviously, it's a learning rule of the outcome when you get an outcome, when it's not zero.
But it's successive predictions.
It's like why that should be such a deep idea is not clear to me.
What is clear to me from data is an algorithm based on that is installed in bee brains, sea slug brains, all the way up to human brains.
There are these temporal difference reward prediction errors.
And so I guess I'm sitting here trying to backwash the old version of it, which is people say in a kind of vernacular way oh, it's the difference between your expectations and reward.
Yes, when that happens, but most of the time that's not happening, in which case it's the ongoing difference between your expectation and your next expectation.
So it's fluctuations in your expectation as you move through the world.
The DeepMind guys in London who beat the world go-playing champion and made Alpha Fold and won Nobel Prizes.
I mean they're starting in 2015.
They just had this unbelievable series of hits.
They used the Sutton and Bartow algorithm.
They trained those systems where people would make – the players, the computer players would make hundreds of board –.
Position changes before you ever got to the end of the game.
And update and learn based on that.
They threw other tricks into it.
I'm not going to get technical about it.
So there's a difference.
It's not just expectation and outcome.
It's expectation, next expectation, current outcome.
And that is what rolls through.
And that is what we see installed in it when we have a paper this week coming out on honeybee brains where you can show the same sorts of learning rules in honeybee brains.
In honeybee brains it's probably octopamine, not dopamine.
But the other thing to say about dopamine is it's not just dopamine.
It's very clear that lots of neuromodulators like that are fluctuating with learning and motivation and probably the whole symphony of them that creates motivation states and things like that.
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Okay, so I want to pin up a few rules so that people can move along this because I think...
Most people, and including me, who learn about dopamine through neuroscience textbooks and lectures and papers and so forth, have been fed this overly simplistic model of expectation versus reward or lack of reward.
Expectation to outcome.
So just to remind people, dopamine reward prediction error.
The dopamine system loves novelty, especially positive novelty, right?
You don't think you're going to have a great meal someplace and it turns out to be spectacular, versus you're really expecting a place to be great.
Your friend says it's terrific and then it's okay.
And dopamine codes for a lot of the expectation reward relationship.
What you're telling us is that In most scenarios, it's more interesting than that.
There's an updating of expectation before the final answer comes in and dopamine is coding for that.
I'd like to take this word foraging. and apply it to a real world scenario in humans.
And then maybe we can use a combination of what's known.
And you'll also tell us where it might be conjecture, to kind of paint this picture in an intuitive way for people.
I have a friend and she's on the dating market now.
She will occasionally call me and ask me you know, like how do I decode this text message or this interaction?
And try and offer my support where I can.
But the conversations often go something like this.
Met so-and-so, they seem really great.
They seem really busy and they set a plan for like a month from now.
Is that weird?
I'm like, all right.
Well, you know, and I give my interpretation.
I say well, you know he's nicely set a concrete plan.
You know this and that, like person's busy, you know this and that.
I also hear the, hey, you know, met someone, they're really, really terrific.
And I say hey listen, the last time you said this, like two weeks later, it was how do I get out of seeing this person again?
So like go slow, like collect data slowly.
And I'm not going to say I'm always right, but almost inevitably it's three days later or three weeks later.
It's like, oh my goodness, how do I get out of this thing, right?
So in some sense, it's what you're saying, right?
There's a foraging for a healthy thing in life, a mate.
This has happened since the beginning of time, although not with apps.
There's updating of expectation based on experience and communication.
And I think this is a really beautiful example of forging in the context of updating expectations.
And one could argue, what is the final reward?
Is it marriage?
Is it whatever?
Okay, that's subjective.
But I think we all can intuitively understand this example, either by experience or by observation.
So for someone, this person who gets excited about someone they just met, right then meets them and is increasingly excited but it's unclear where it's going to go, then finds out as life goes that oh, they're not perfect.
There's this thing, can I live with that?
So thinking of this as like a sawtooth of dopamine going through their system.
Is that statement accurate that dopamine and other neuromodulators are encoding the sort of expectation of success or lack of success, without actually knowing what the final endpoint is?
It's exactly that, and that's the insight of Sutton and Bartow.
And when I first heard about this, I learned about it from Peter Dayan when I was a postdoc and we both arrived at the Salk Institute together.
Something about it captured me because all of a sudden it's not this...
Okay, you understand expectation and outcome.
I mean, businesses understand that.
Yeah, you're disappointed.
You expected to have a quarterly return of X and you had Y. That's less.
You expected it to be low.
It was more.
But that's really rare.
I studied hard.
I wanted an A. I got an A minus.
Yeah.
But the reality is embedded in this little simple continuous learning update rule – it's called temporal difference.
Reinforcement learning is the fact that, in the world, these expectations are going through their own trajectory.
All right,
And that's what dopamine is coding for.
Any learning rule should code for the surprising outcome.
You have an expectation for an outcome, and either high or low of that.
Every learning rule should do that, and the psychologists had that kind of figured out 40 years ago, 50 years ago.
But it doesn't quite work because it won't account for the way animals learn.
It won't let you chain events.
So, for example, if I show a light and train on a reward, an outcome, and I use the expectation outcome learning rule, it won't chain back to something that predicts a light.
Suppose a sound predicts a light and we know the light predicted the outcome.
Now I ask the question well, what happens to the sound?
Well, we know people learn, they'll associate the sound with the outcome.
It's Pavlovian.
Yeah.
But those learning rules won't do that.
They learn the wrong thing.
They just do.
It's just not well appreciated.
Now, back when we were trying to associate that learning rule with dopamine, there was...
We were mainly working on it in a kind of theoretical way.
Like if you had a signal, what would it need to look like?
Where might you find this in biology?
I remember our advisor, Terry Sanofsky, who's been on your show.
I think he said something like there are these diffuse ascending systems that deliver these transmitters.
You guys go work on that.
Sounds like Terry.
I love Terry.
And his episode was spectacularly received.
Oh, great.
Well, I mean, it was the most open, inviting environment, because all the problems given out were impossible to solve.
I remember just thinking, what?
But the first inroad was realizing that it matched what Sutton had written down not so many years before.
Sutton got his PhD I think in 84.
I think he published the paper in 88.
We were doing this in 1990.
And we ran into a guy's data on dopamine signaling bull from Schultz.
We didn't know him.
And we could explain every figure in every paper he published.
And we just thought, OK, that's not an accident.
OK, fast forward.
We're in generation three.
Now we're going to come all the way forward people doing very fancy, very detailed experiments, and rodents where you can control where dopamine neurons are gonna fire.
When they're gonna fire, you can control reward.
Okay, you can just control a lot of things.
And so it's clearly more than that.
It's that and some other stuff, but that central core.
I don't see any good reason to throw away that little explanation there.
Back in 1990, The complaint was, well, that's really cool.
It matches these traces in an arcane journal of physiology paper.
What good is that?
Reinforcement learning like that can't learn anything.
The problem with that was at the time it was right.
Like there were no systems that had done anything amazing.
Now they've done everything.
And it's insane how good it was.
You're talking about the AI.
That algorithm that I just described with my hands waving –
It's the same thing that David Silver and the DeepMind guys did when they made the world champion go-playing program.
And it beat the world champion.
And that particular game had expert advice built into it.
And they removed all that.
And then they trained it from scratch.
It's called AlphaGo Zero.
And then that game was amazing.
It's an item that's never been beaten.
It basically beats the history of Go.
And so as an example, it's such an amazing—that's a breakthrough.
Anybody that knows that side—now, that's the—
That's the AI side, that's the algorithms.
But that same algorithm is installed in your head.
It's installed in the head of a songbird.
The interesting thing that's going on now is this kind of convergence, right?
There are these little gremlins in your brainstem that run that algorithm, okay?
They've now been externalized and put into a computer program that now does things that supersede us.
It's a little interesting convergence.
It's the only thing I know of that's sort of crawled out of your mind into a program, and now the program is doing things that we couldn't imagine before.
And it matches the biology.
I mean, you can see this in creatures as old as honeybees and Drosophila and whatnot.
Okay, so a couple of things.
One comment and a couple questions.
First comment I'm just going to say so that you don't feel you have to.
Everyone should know that when Reed says dopamine is responsible for X, Y and Z, there are many other chemicals in the brain likely involved as well.
Other chemicals and dopamine has multiple functions.
Yeah.
Like anything in biology.
Yeah.
We should just embed that's up on the chalkboard now so that if you want to mention it again, you can, but don't feel obligated to.
People.
We're talking about dopamine through a narrow cone here, but certainly serotonin acetylcholine norepinephrine, peptides we haven't even discovered or understand yet are contributing.
Dopamine is clearly a major player.
I want to step back to a human example, a non-AI example, with the understanding of what you just said, which is that the algorithms that AI is running are based on the same algorithms that neurons in our brainstem are using to deploy dopamine.
Which I don't know of an example like that in the world.
Do you?
I don't.
Where we've discovered the nature of an algorithm.
Once we externalize it, we write code and then it takes a few very special groups to all of a sudden have giant breakthroughs using that same algorithm.
And those breakthroughs are going to end up pumping information back into our head.
And so it's an interesting recursion there.
I don't know what will come of that.
Yeah, the fact that we took biological learning rules and gave them to a computer essentially, and the computer then can beat our own use of the biological learning rules, is pretty spectacular.
And I think it's a little scary, but I want to shelve that for later in the discussion.
I want to return to the dating example.
You're going to hang this dating example around my neck, aren't you?
No, I think that – and we can partner with another example.
Dating example is good.
You go along in an interaction with somebody.
You pick up new knowledge about them on Thursday.
You don't necessarily even see them.
It changes your expectations of them.
You pick up some new knowledge on Saturday.
You run into a coworker of theirs.
They say, oh, I hear you're seeing so-and-so.
Did you know blah, blah, blah, blah, blah?
You get a new view of it.
Changes your view.
So what I want to know is what is dopamine doing in the context of the constantly updated expectations?
We know that dopamine is involved in motivation.
Are the changes in expectation modifying motivation to either move forward, become more pessimistic, more optimistic or stay neutral?
That's a great question.
So expectations change.
Those changes in expectation are encoded by positive and negative fluctuations in dopamine.
Where does motivation come in?
Todd Braver and John Cohen had an idea about that, and I think Matt Botvinick, too.
And that is those prediction errors are perfect signals for deciding how motivated you should be.
How much should you want a thing by measuring across those kinds of signals?
And if you were doing an experiment, you were trying to look at dopamine, depending on the time scale you looked at, you might see little changes in it that correlated with fluctuating expectations and you might see something as a kind of envelope, a slower changing thing, which is the kind of experiment you might do in an experimental psychology setup.
And that would look like it correlated with motivation, with all these little wandering things going on underneath.
That's the sense in which it could do both functions.
We are told that dopamine is what we're seeking as we go through a social media environment, or we go through a dating environment, or we go through a financial environment that we're investing or investing time in.
But, as you mentioned, dopamine is not just at the finish line.
We've known this for a while now.
It's part of the neural circuitry algorithm that's driving us forward or causing us to pause.
But is it fair to say that any system, whether it's a social media platform or it's another form of business, whether they consciously realize it or not and they probably do It's built on trying to constantly update our expectations so that we keep playing the game, so that we stay in the forging mode.
Because if you think about it, it's an infinite scroll.
There is no final outcome.
If there was a final outcome, you wouldn't keep living.
You want that system to keep tracking And once it gets to one place, you want it to have another place to which it could go.
Otherwise, you wouldn't live.
Probably one insight into why it's in every mobile creature's brain on the planet.
So if any goal that you achieved, whatever it is taking a drug, eating a food, getting a partner or whatnot if that was enough for you right, then That's not the way your nervous system works.
Your nervous system keeps pushing you forward.
That's what you're working for.
You're working for this push forward drive.
Mapping that onto dopamine hits, It's not wrong.
It's just blunt.
It's just a blunt way to say it.
It's not wrong, but it is blunt.
It's a blunt way to say it.
You move around with expectations before you get any sort of big unexpected hit.
This is why I don't like the phrase or the words dopamine hits, because it implies it's like a reward that gets trickled into you.
But it is true.
You get a hit.
Mm-hmm.
It is true that there's this unexpected reward that your expectations, your series of expectations, did not anticipate and that augments
That is the learning rule.
That's what we think the dopamine fluctuations are encoding.
And so it does both jobs.
It lets you update and learn, and it codes for the kind of motivation you should have.
And when you're surprised, those are extra hits.
So it's not wrong to say that.
It's just incomplete.
I'm going to ask you to speculate a little bit here, but speculate within the context of what you know about dopamine, which is a lot.
Let's take any of the different examples that I threw out on the table for us.
And we artificially ramp up levels of dopamine with, let's not say, a drug of abuse like methamphetamine or something, but we throw a little bit of a dopaminergic stimulant into the picture.
Does that just raise the kind of the height of the sawtooth?
Does it change any of this?
For instance, if this person who goes out on a date, on the second or third date they go to something that like maybe a show that's spectacularly good, okay.
How does that change the dynamics when you know it's now there's an association with this person or an event, but let's say that they're flooded with dopamine.
Let's take a drug out of the picture.
The experience generated more dopamine.
Does it shape? their expectation and motivation around that person?
If you raise expectations and these are coded by changes in dopamine, then in fact that's sort of a tonic question.
That's sort of a tonic phasing question.
Can you explain tonic?
Most people are going to think gin and tonic.
I will.
So slower changing.
OK, so I see a show.
It makes me very excited.
I have the well fills up with a little more water.
OK, and it's sitting here.
So now the little hits are on top of that.
Or I see something that depletes it.
I take a drug and some drugs deplete dopamine.
Or they went to a play and it sucked.
Yeah.
It's disappointing or it's sad.
He's got bad taste.
Yeah.
Yeah.
It just runs in your mind.
So that can lower the levels and that changes the way in which the fluctuations have an impact on learning.
Okay.
Parkinson's disease is a condition where, by the time you show up with symptoms in the doctor's office, you've lost 70 to 75 of your dopamine neurons in your brainstem.
Those are only source of dopamine in your brain, except for a tiny pathway in your hypothalamus and pituitary.
A couple of retina.
Well, there's Sorry, the retinal biologists in me.
They're doing things totally unrelated to any of this.
They're controlling adaptation of light levels.
Yeah, light level adaptations and certainly in goldfish.
Yeah.
Um, Yeah, those are actually very interesting.
I won't talk about them.
So you had the dopaminergic brainstem neurons that degenerate in Parkinson's.
By the time you're feeling so stiff, starting to have tremors.
All the parts of the flat facey flat affect and somebody gets you to a doctor.
You're in the 70 to 75.
Okay.
So what does that mean?
Now, all of a sudden these – and dopamine neurons in your brain stem are maybe 80000 neurons per side, 160000 neurons.
That's like nothing.
They send dopamine-delivering wires, biological wires, throughout your entire brain and down your spinal cord, making hundreds of millions of connections.
But now you've shrunk those down.
And so the one thing that happens is it's very noisy now.
There's not so many neurons to cover it.
There's no smooth changes in it.
The noise floor relative to what you could generate as a signal gets really, really high.
Well, one of the things that we think dopamine is involved in in terms of information processing is valuing the world computing, if you will the value of taking this action or that action, the value of grabbing this and putting it in my mouth and drinking water, et cetera.
And the Parkinson's state is sort of like a flat value function.
You can't really see differential value in things as you look around the world.
You expect the system to fluctuate, for you to tell you if I were to do this stuff, or if I were to do that stuff, if I were to look at that, et cetera.
It gives you a fluctuation, but you can't read it.
The downstream... It's too noisy.
It's too noisy.
You can't read it.
The downstream system just has to act as it did before.
It says, oh, everything's of equal value.
Just stay put.
So I've always thought about Parkinson's as an active freezing disease.
The nervous system is doing exactly what it would do if...
Because it takes energy to transition from where you are to doing the next thing.
Why do that if there's nothing more valuable there?
This comes back to the idea of it pushing you through the world.
It doesn't habituate because it has to keep your behavior going or else you're going to die.
I don't think it's a coincidence.
In fact, I know it's not that.
Dopamine is involved in learning motivation, feelings and movement, among a few other more minor roles.
Everything about physical movement is intuitive to us.
You move forward, you move back, you move side to side, you stay put.
Okay, like movement.
The idea that levels of dopamine in a moment, and what you're referring to as the tonic kind of baseline, what I call baseline levels of dopamine, as opposed to spikes on top of that, predict whether or not you'll move forward, how much resistance there is to moving forward these kinds of things.
But I think for a lot of people it might be useful to think about dopamine in the context of thought movement, right.
And motivation is sort of a a version of forward movement.
You know, if I think about, am I motivated to do something?
I no longer like the word motivated, I decided.
I like the word a sense of urgency.
You could have a low level of urgency, moderate or high level of urgency.
Urgency I define as sort of a persistent, resilient motivation, right?
And the reason I prefer urgency to motivation is that A sense of urgency is more intuitive, I think, to most people.
We kind of know when we feel we have to do something.
We really want to do it or like we don't really want to do it or we're procrastinating.
Whereas motivation is this just kind of like catch-all term for how motivated are you?
Intrinsic motivation, extrinsic motivation.
So when I think about a sense of urgency, I think about a sense of a need and readiness to move the body and or move thoughts in a particular direction.
Do we think that dopamine is involved in moving thoughts and decision-making in a particular direction?
We exactly think that.
Thank you.
I wasn't asking you to validate my non-theory theory.
I think that dopamine is thrown around so much nowadays that we don't even really understand what motivation is, let alone how dopamine will be playing this role.
It's very clear dopamine and the other neuromodulators are involved in stabilizing and sustaining brain states.
That's why they're thought to be involved in seizures.
One thing you have to do with the brain state is kind of hold on to it a bit.
It's got to have a dwell time.
Let's call that a thought.
Boom.
And then it goes forward or changes and then it may come back to that.
So thinking and sequencing through what you would call thoughts is something that these systems are clearly intimately involved.
And there are a lot of great groups now that are exploring this and mice models and theoretical models as well.
So I think you tied the words together pretty well.
In an animal that has to keep moving to stay alive and that's all animals it has to know.
How valuable is it?
How motivated should I be?
How much should I want a thing right.
The calculations that we think the algorithms are making affecting in your brain are exactly those.
And so we can have these conversations at the level of these psychology words, which are interesting and pertinent to the way looking at an animal behave.
But now we're starting to pull it apart at the level of what is this computing?
How fast is it computing it?
How did it update it?
And now we can build artificial systems based on that.
And I think there was a paper in 2004 by David Reddish, talking about addiction as a computational disease gone awry where you keep feeding the system a level of dopamine by putting a drug in that blocks its reuptake that it can't anticipate right.
And so it keeps chasing that and it never gets there.
When people have ADHD, even low-level ADHD, or they take a drug that increases dopamine.
Do you think that it makes more things in the world sticky, meaning mentally sticky.
Like we naturally just will latch on to more things when our levels of dopamine are elevated.
We'll forage more randomly or do we forage more narrowly?
Because the whole notion of ADHD is that they the whole like oh squirrel, like that's the kind of generic example.
Is that someone with ADHD?
The theory is that their dopaminergic systems are dysregulated.
These drugs, almost all of them, right?
Whether or not it's Ritalin or Adderall or these other drugs, they raise levels of dopamine and norepinephrine and somehow put people into a more narrow trench of focus or give them a little bit more selectivity in terms of what paths they decide to forage.
Yeah.
I suspect, if you made me guess, that it's stabilizing brain states and thought sequences in a way.
That's and it doesn't divert.
Does that surprise you that increasing dopamine would do that?
No, bees do this.
Okay, so when you're a forager bee, you come back and you do a little dance in the hive and it tells the hive other forages where to go find the nectar source.
Okay, and it's a whole language.
People have worked that out.
It tells you, fly this far with the sun here, and there's a polarization.
It's an amazing phenomenon.
Yeah.
The bees go back, and they literally, they do this dance, the waggle dance.
And they feel the waggle dance on the bee, and by feeling it, they know where to go.
Wild.
Well, it's a language.
I mean, it's been decoded to some degree.
Yeah, it's very cool.
When you look at bees.
I know this because I've been working with a bee guy, Brian Smith, at Arizona State University for the last few years.
I've known him my whole career, but I now have some methodology that lets him make measurements of dopamine and serotonin and norepinephrine in bees while they do odor learning.
And he has bees on an axis, okay?
Way over here are the ADDBs, let's call them, and way over here are the concentration Bs.
And it relates to a chemical that's related to dopamine called octopamine, but it's a ratio of octopamine to tyramine.
It's like dopamine and serotonin if you were talking about primates.
The ADDBs, they feel the waggle dance.
And they start, you know, they start running for the nectar and then they get distracted.
You know, they're the four-year-old.
There are a lot of adults like that nowadays too.
Yes.
And they can't, of course, what they do by being distracted is they explore more.
Okay.
And then the ones on the far end over here, they fly right to the nectar source.
Mm-hmm.
Okay.
So you need both.
You need – that's called exploitation.
This one is exploiting where the nectar source is.
It's going to get it.
It's going to bring it back to the hive.
And the sort of ADD guys are the explorers.
They're looking for new information, new nectar sources, et cetera.
Well, your mind kind of –
As blunt as that is, your mind plays this dichotomy.
In the same individual, you think that we have this ADHD-like mode and a more focused mode.
You've got multiple Bs inside your head.
One of them is making you into the explorer, and that's really, really valuable sometimes, okay?
And companies, they keep these people around.
These are the lateral... thinkers and you just have to feed them enough.
And then you have the people that can really follow instructions and follow the best course of action and whatnot, and you need all that.
You need all that.
And this distribution of abilities is built into all of us, but it's different across us.
If I was looking at an oak leaf and I told you, what about this little wiggle?
It's the wiggle in our software design for motivation and learning.
It's very effective to sometimes be the explorer, and other times you have to be able to follow.
The chain of this is going to lead you to the thing that you want.
Stay on course.
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What you're describing is a sort of ADHD-like mode inside of all of us, as well as a highly focused mode inside all of us.
You're also I think I hear you correctly in thinking that you're also describing the fact that some people are very strongly ADHD mode and other people are very strongly focused.
They're very linear.
Or task-based.
Task-based.
They can really form a task, hold it in mind, a task stays there.
You know, lots of athletes are that way.
They set a goal and they set multiple scales of goals.
They set some goal, you know, this is where I want to be in two years.
Okay, to get there, I'm going to have to do you know I want to crawl through you know hell to get there in two years and I have to do these things and I'm going to wake up again tomorrow morning and again and again, and again.
And these goals have to be reconstituted and pursued.
If you wanted to go play in the NBA and then all of a sudden, six months into that, you decided you want to go do ice hockey.
Well, that's a problem.
That's a person who can't We all know these people.
One question I have and we can only speculate here is there's a lot of ideas now that social media.
But when I say social media I don't want to knock on.
I teach and learn on social media.
What I... mainly thinking about is short, very short form video.
There's this idea out there that it's giving everybody ADHD.
Now, I don't actually think that's true, but I could imagine that if we have this continuum of honeybee-like modes in our brains, that if we repeatedly engage in a kind of rapid turnover of stimuli, like you get when you scroll a TikTok or a YouTube Shorts or something like that
I mean there's a very frequent updating of lots of different contexts and information that those circuits might get stronger and that the circuits that allow you to move from node to node and root to a goal, updating as necessary, understanding and integrating expectations and rewards and failures and all the above right.
The athlete example, the academic example, any life navigating relation, all the stuff that we think of as building a solid life right.
You could imagine that some of that rapid updating and foraging could undermine the circuitry.
Yeah, you build your ADHD muscle.
Is there any evidence maybe from...
Related or other experiments entirely that show that if you give people a task where they have to update very quickly that you shift the sort of state of the brain toward seeking that more and doing that more easily than you do, kind of like long haul, distant reward type stuff.
I don't know the answer to that in people, but I do know about training artificial systems to do it.
And you have to be very careful to control the mix so that it doesn't overtrain on one of these two possibilities.
If we're going to divide these two possibilities.
Chase a goal, chase everything that flies along right.
And you don't want to do either one of those things.
You have to balance that.
And sometimes you have to impose constraints to make that happen in an artificial network.
It's a more complicated question. problem in people.
I mean, I can imagine, I know lots of settings for being ADD is an absolute requirement.
Can you give me a few examples?
Combat.
Combat, rapid decision-making, kind of the fighter pilot, situational knowledge.
Now, what do they do to prepare for that?
By the way, my dad was a captain in the Navy.
I have lots of combat examples in my head.
Well, they practice.
They practice.
They practice being surprised.
They practice being hungry.
They put themselves under stress, and all so that, when that happens, they don't have to run through every possibility and they're very effective.
But that requires training.
That requires an enormous amount of mental training.
It's all about the mental game.
That's a good example.
We've had a couple of experts in ADHD on here and all of them have agreed that children and adults with ADHD mild or severe can focus very intensely on things they really enjoy and are interested in.
It's not a lack of ability to focus.
It's that there's a lot of choppy terrain to get into that narrow mode of focus, unless it's something they love.
You give a kid with ADHD a video game they love, they'll drop right in as if it was the most focused you've ever seen them.
Anytime you have to do rapid fire decision making.
I think you would want somebody who is able to at least train up to that level there.
Do you worry about the overexposure to, you know, these frequent media?
Yeah, the short media.
I have a lot of kids.
And so like every parent...
My main nemesis is screen time.
I'm trying to figure out how to monitor it, measure it, restrict it, and basically my kids are smarter than me and they're more nimble and they move faster than I, So it's a battle I'm losing.
So I've decided that the only way I can combat it is to lose it, but lose it a little more effectively toward my side.
But I have to admit, when I see YouTube shorts, these little you know like oh, look at this person.
He built a house out of Jell-O and it's falling over now.
Okay, look at this other person.
There's a parakeet.
I mean, it's mind-numbing to me, right?
Well, there isn't a lot of long-term learning.
You know, one of the things that I – defined learning by as uh, useful learning is.
Did I reflect on it again at a point later in time?
You know, the other day I was on social media and I actually saw a clip.
It was on a friend of mine who has a podcast, um Stephen Bartlett, and he was interviewing a guest and um speak gets right to the heart of this conversation.
You know a lot of stuff flies by, a lot of wisdom type advice.
You know the health advice, all that you know it's constant barrage.
But this one stuck with me.
It's interesting.
He asked the guy, what's the meaning of life?
People ask this on podcasts.
I won't ask you that today.
That's a Lex Friedman question.
When you go on Lex's podcast, you can answer it to him, but I won't ask you that.
But Steven asked this guy.
I forget who it was, so forgive me.
You know what do you think the point of life is?
And the guy said, It's to learn to enjoy the passage of time.
And I thought, that's pretty awesome.
I would add to it and also engage in behaviors that buy you more time.
I said, make sure you don't undermine the time piece of it.
But it was something that flew by on social media, but stuck with me.
It is exceedingly rare that a short clip provides entertainment or information that really stays with me, that I reflect on it later.
Whereas when I read a book, it's exceedingly rare that I don't have five or ten things underlined per chapter that I go back to later.
It takes a while to read a book.
That's the thing.
It takes a deliberative set of intentional actions to read a book.
That's the difference in the modality.
So one thing that this speaks to then, is I've wondered – whether activities that require effort, that may or may not include reward, but that include effort and that are a little bit slower and effort and slower tend to go hand in hand, not always whether or not that is part of the mechanism that strengthens a circuit.
Does effort strengthen an algorithm?
In other words, if I get on social media, it's very easy to scroll scroll scroll scroll, scroll.
Short form video content
It doesn't take any effort.
And in fact, there's no learning involved.
All you have to do is move your thumb.
But there's really no learning involved.
Whereas if I have to do something, if I have to do a puzzle to get in, or if I have to solve something or think about something or grapple with something, that is where the learning occurs.
What's the relationship between, if we know, between effort and dopamine?
There is a good bit of work now where people look at the amount of effort an animal makes, has to do, to accomplish a task.
Let me just go back to something you just said, which was interesting.
When you have to do effort, it's easier to learn something because it slows you down.
I don't know whether effort is itself the cause or whether the fact that effort is slow and so it slows it down.
We could design an experiment to separate effort and speed.
Yeah, maybe slowing it down.
It may immediately give me this idea.
So that's true in simple experiments with rodents, but rodents can't read very well.
I've never seen a rodent that I admired that could manage a cell phone. very well.
And, you know, even the rodents that can read are kind of flat affectively and all.
I mean, rodent is a terrible model for this, really.
I wouldn't even do the experiment in rodent.
I'd do the experiment in human.
Yeah.
Where you can, with a few words, set a human in a certain state and you know, or you can make them hungry or you can.
You know you can put a human into a mental state by just asking them to think about X, Y and Z and have various controls to account for that.
I have to admit that when I look at The generation we're concerned about.
I've just read this book, The Anxious Generation.
Yeah, Jonathan was on this podcast.
And I was on a MacArthur network, neuroscience and law, with him for a while.
And he's just an extremely clear-headed person, really.
Always made me think about things.
On the other hand, I don't know – other than the comparison to others and the speed at which social media lets you do that – and I have girls, mainly four girls and one boy.
I don't know what it's doing to them exactly.
OK.
I don't think anybody does.
I think we all suspect there's features of it that aren't good.
And yet –
It's like we're trying to hold back a tsunami.
I mean, it's just the water is going past us.
And so I think the only way to deal with it is kind of fly by wire.
You know, when a little fire starts over here and somebody says oh, this really causes a depression in mood and it's these features of it, then we can go react to that and all.
But it's very hard to know what it's going to do. globally.
It's evolving with its own.
It feels like it's independent of anything we do.
And so I think it's going to have to be a sort of a get in front of it reaction.
You can't, for example, my kid just got a cell phone.
She's 13.
She was the last, according to her and she's the reporter here she's the last seventh grader in her school to to get a cell phone.
But the raw fact was I'm being left out of all the discussions and whatnot.
And the answer was that that is true.
She is being left out.
Their mode of choice is Snapchat now.
Well, there's a lot of downside to Snapchat.
So now I'm the I, my nervous system and my physiology is now hooked to her blizzard of time.
Requests on my phone.
I turned it off before I came in here.
On the plane flying over the country, I'm denying things and giving 15 minutes and whatnot.
So Jonathan has real prescriptions for how to fix that.
He has good suggestions for how to fix that.
But the collective action thing is –
Collected actions are hard because they're collections of humans and you just can't get people to all do something at once.
There's always a defector.
Well, I think as long as we're also training the other more slow, effortful type integration of knowledge.
I mean it would be wonderful if social media had settings where I could click entertainment.
I would just get entertainment stuff.
And then I knew how long I was doing that versus educate me, because I do learn a lot from social media and I certainly try and learn on social media.
And this, what may sound like kind of a trivial statement the other day and learn to enjoy the passage of time was what sat with me in some way that felt important to me at that moment.
And I've been reflecting on it through a couple of different lenses.
We're obviously not going to solve this problem.
I am curious about speed versus effort when foraging.
Let's take it back to the dating example.
This person's going to kill me for, I'm not going to reveal who she is.
But, you know, I said, listen, I noticed this pattern over time.
You, You discount people early or you get very excited, and then it always kind of ends up in the same place where you're like why did I do that?
And I was like, well, let's – so maybe run a different algorithm.
Maybe start to collect data a little bit more slowly, or maybe see them more frequently for like two weeks and then make a decision.
So it's not – you didn't waste so much time.
Yeah.
More frequently means more time, but not over time.
So we can change our mode of foraging.
I personally put social media on an old phone and it goes in a supermax prison lockbox that you can't code out of for 22 hours a day.
You do that to yourself.
I do.
You're like the person that can't avoid eating chocolate cake.
You lock the chocolate cake up.
No, it wasn't that.
I'd read this paper that was published recently that said that if your phone is upside down on a table or in your bag in the same room, it lowers cognitive performance, even if you're not aware of the phone.
It calls to you.
It's pulling resources.
Yeah, it's calling to you.
It's pulling resources.
If it's in another room.
It seems that your cognitive performance returns to its previously higher levels.
So I thought that's pretty good.
So I started keeping my phone in the other room.
And I thought, how much further can I take this?
So I think that the physical distance from things that's non-negotiable feels really good to somebody like me.
Out of sight, out of mind?
Maybe, although I want to bring this back to dopamine.
You know, Can the dopamine system learn to get motivation states and pleasure from resisting things?
I think, of a pathologic version of this might be.
We did an episode on anorexia where food is rewarding for most people, but for people who have true anorexia the reward system seems to enter a state where resisting food becomes the reward.
Control feels good.
Yeah, control feels good.
But there's anorexia, obviously the most dangerous and deadly psychiatric illness of all the psychiatric illnesses.
But resisting your phone to get other work done and to be more present for people in my life, including myself.
But That seems like a good thing.
So can the dopamine system encode reward for resisting behaviors as much as it can for indulging behaviors.
Yes.
I mean I think anorexia is a good example of it.
It feels good to resist.
And they do it pathologically.
It's such a dangerous disorder.
But in a healthy sense, like I'll reveal now that you were a fairly accomplished decathlete.
So that meant getting to practice, doing things.
But did you ever feel like I'm going to bed early when everybody else is staying up late?
I'm getting stronger.
Oh, I relished the whole.
I'm running this tennis court hill while all those other soft guys are, you know, asleep and I'm throwing up on top of the hill.
Yeah, that was a...
That was a thing.
And it meant when you got in a tough spot – I was a wrestler all through high school.
Yeah, they're sickos.
Yeah, they're sickos.
Yeah.
But you're never in better shape than when you're an active wrestler.
You have to put up with things that are really demanding on you like having your hair cut off.
So the main thing you do when your air is cut off is don't panic.
Well, that's not, you know, you're not prebuilt to not panic.
So you have to learn how to do that.
That was the most important thing I did in wrestling.
Just learn to stay calm.
Think about where your weight was and all that.
It's the same thing for people that study a lot.
I think people that study a lot want to be better than the people that don't study a lot.
I mean, they want the idea of achieving a goal, right?
That's hard for other people to do.
And the most healthy version of that is without any regard to what anybody else is doing.
The person who just – this is the life I live and these are my standards, and I'm quiet with them and I'm going to go do this thing and it doesn't matter what anybody else thinks.
And you hope that for your children.
You hope they get to be a person like that.
Anyway, I can tell you my kid's school, just to circle back, their collective action is to completely disallow phones during the school day.
His junior high school.
They go to a school that's K through 12.
You have to put it up when you get there.
And I think 3.30 is when you can activate to call for a ride or whatever.
And it's off.
It's off.
Well, I like the head of school, but her, that's the best decision she's ever made.
I mean, that's a great decision.
And now they're wrestling with what do we do with AI in the school?
How are we going to let these kids interface with these systems that are smarter than us?
More interesting, no less.
I want to talk about AI.
But before we go there, I think you've painted a really nice picture of dopamine and the various things it does.
And even just this early statement that you made that dopamine is fluctuating according to our constant updating, not just expectation reward, but expectation, expectation, expectation, expectation.
Maybe the reward never comes.
Maybe it does.
Let's talk about serotonin because, not in every case, but at least in some cases, my understanding is that serotonin is fluctuating in the opposite direction to dopamine, at least in animal studies.
These are some interesting data.
In human studies too.
Great.
So Educate us about serotonin in this context because I know it's a huge topic.
A habit that people that work on neuromodulators.
I'll name a few dopamine serotonin norepinephrine acetylcholine histamine, probably on the order of, let's say, 15 to 20, let's say.
And then there are a lot of peptides and all.
But the big three dopamine serotonin norepinephrine, learning and motivation active inhibition attention.
That's what people would say.
Norepinephrine and epinephrine are controlling attentional states.
Serotonin tells you to get ready to wait.
Like you put an animal, you put a piece of cheese over an area of a table and there's an electrified grid on the table.
The animal knows it's electrified.
They see the cheese, they want the cheese.
There's some rodent.
They see the cheese, they want the cheese, but the light is on.
That means that the grid is active.
And they're not super hungry, so they wait.
But there's a part of their nervous system that's making that hard.
Active waiting, which also suggests another set of things for serotonin that it's learning about negative things.
Dopamine is learning about positive things or the absence of negative things.
So there's ambiguity in there because the experiments aren't all that clear yet.
There's an enormous amount of work going on.
In humans we are the only group – who record sub-second levels of dopamine and serotonin in conscious human beings while they do things.
Reward-motivated tasks, social interactions with other people, various kinds of visual perceptual tasks, looking at emotional pictures positive, negative and neutral and whatnot.
The theme that emerges from that is dopamine and serotonin are opponent to one another.
When dopamine goes up, serotonin goes down.
When serotonin goes up, dopamine goes down.
We could talk about those events as being positive events or anticipation of positive events.
Dopamine goes up and serotonin goes down in opponent.
See to that.
At your own institution.
Rob Malenka has a set of beautiful results in rodents, where the learning that they see in the animal requires that kind of oponency.
I mean it's a definitive experiment in the rodent.
It's harder to do these things in humans because you can do simple things in humans.
That's fine.
But humans can sit and have an idea and it can generate results, these kinds of signals, and they can run through the ideas.
And so that's a hard thing to both get our hands around and to do in a controlled setting.
So that's why it's been ambiguous.
But the first time we were able to measure dopamine and serotonin concurrently.
They look upon it and they look upon it all over the place.
There are old ideas from the 60s and 70s about opponent systems in this sort of affective processing space.
Dopamine has now inherited the positive part of that and serotonin the negative part of that.
Opponency, as you know, is a theme in the nervous system.
In the retina, you have color opponents.
You have light and dark opponents.
These kinds of information channels go all the way through to the visual cortex.
One other thing that's interesting is that when you put SSRIs on people, you –
Prevent selective serotonin reuptake inhibitors.
Prozac.
Fluoxetine, Luxapro.
It blocks the reuptake of serotonin in the serotonin terminals.
Over a few weeks period, you have a clinical effect.
And for some people, it's a life changer.
It's very heterogeneous.
But it pushes serotonin into the dopamine terminals too.
This is less well understood.
But if you were a system and you thought that the positive juice was dopamine and the negative juice was serotonin and you put the negative juice in the positive terminals, then the cells that control the release of that are going to chatter for positive things.
You might start negatively conditioning on things that you should actually pursue and learn about.
SSRIs have helped a great number of people.
There have also been some devastatingly tragic circumstances where SSRIs have.
The theory is that they've accelerated suicidality, they've accelerated ahedonia, they've created a lot of problems.
If we were to just take a step back in terms of serotonin as learning about negative things, if you could just summarize these results for me animals and what the expectation would be in humans.
So let's say that somebody or an animal is learning a task where they get shocked.
If one were to artificially increase serotonin, does that make somebody or an animal more or less likely to code something as negative?
Well, the idea would be it makes you less likely to code something as negative because you have less serotonin in the serotonergic terminals.
And so if they're communicating this information about More serotonin in the serotonergic terminals,
Gotcha.
So if somebody takes an SSRI, serotonin is increased and they have a tough interaction at work.
The idea is that they would encode that cognitively as less bad because there's an abundance of serotonin, or worse than it would be had they not been on this drug.
When you increase serotonin in your brain because you won't let it be vacuumed out by the normal mechanisms that clear it from your brain, then it has the opportunity to be there longer and it has the opportunity to go into the dopamine terminals.
This is something we know.
The mechanisms that suck dopamine out of the spaces of your brain will also bind to serotonin and suck it out.
Not quite as well because it's tuned, it's called a dopamine transporter.
And so depending on what the downstream...
Parts of your brain think that, in fact, increasing serotonin could decrease the serotonin in the serotonin terminals by blocking the reuptake.
I see.
So that's why you said it earlier.
I tried to correct you saying no, it's going to increase serotonin because you're blocking reuptake.
You're saying no.
It pushes serotonin into the dopamine terminals and this is why people might not get as much reward from a positive event when serotonin is elevated pharmacologically.
There was a killer paper 20 years ago on that where they've showed they gave rodents some common SSRI.
They waited this number of weeks and they went in and said where is the serotonin?
And what they showed was that the dopamine transporter pathway was the thing that was taking it into the dopamine terminals, because that's where the dopamine transporters are.
And so I don't know where that's gone since then, but that's a 20-year-old result.
It's a very clear result.
It was in a journal called Neuron.
John Danny was the senior author.
He's at Penn.
It was a remarkable paper.
I don't know that people have followed up in humans.
I actually think the only way to follow up in humans is to kind of do what we've been trying to do, which is develop methods of measuring these things in humans directly.
We've been able to do it in people that are having brain surgeries and they have an affliction.
They're going to have an electrode put in their brain for various reasons, and they let us piggyback on that.
They consent, obviously under strict ethical guidelines, but we can measure serotonin and dopamine when they do a rewarding task or they play a game that has a series of things that go on back and forth with another person, which I like better in the sense that that's a more natural reward.
Somebody does something to you and you do something back to them.
Usually in our case they're economic games.
This is encoded money or the expectation of the money that's going to come, and you can see strong opponents in dopamine and serotonin signaling in the deep structures in your brain.
These experiments, if people positively anticipate, because things are quote-unquote going well for them, you see dopamine going up and you see serotonin going down.
And if they're losing at this game or they feel like the game isn't going well for them in some way, there's more uncertainty.
Perhaps serotonin goes up and dopamine goes down.
Yes.
Interesting.
And then there's state changes in your brain that can be induced by, for example, making somebody hungry, where we don't really know how to explain what we're saying, but they still show opponents.
What would you say being hungry does to the dynamics?
For let's just take them one at a time.
Dopamine
Does dopamine still increase for positive events when people are hungry?
No, not in rodent models.
We're actually in the middle of doing something like that now, where people come in in the morning hungry.
In this case, these are people with epilepsy that have wires in their head, and we do an experiment on them right before they're going to eat, and then we repeat the experiment after they've eaten.
But in rodents it's very clear, I guess, at the level of the amygdala.
If you make a rodent hungry, then you can show that dopamine will encode something like punishment prediction errors, not reward prediction errors.
In other words, it's like it flips.
It's raw.
It's like if you're in a— How hungry do you have to be?
I don't know how it feels to be a hungry rat, but imagine that it put it in an emergency state.
Okay, so it's not just kind of like—I mean, I don't do any formal intermittent fasting, but I usually eat my first meal somewhere around— between 10 and noon.
And at 9 a.m., I'm like mildly hungry.
I could eat, but I'm not.
But by 4, you would be hungry.
I'd be really hungry.
You'd feel it.
You'd feel what we've all felt when we're hungry.
And this is a guy called Mark Anderman at Harvard.
Oh, yeah, I know Mark.
Yeah.
So he puts animals in starvation states and he shows that dopamine will encode aversive events, aversive errors.
Very clear result.
So folks- I know this because he called me.
I mean we met-.
So when your kid, boyfriend or girlfriend is hungry and you're going to a show or you're going someplace, you got to feed them if you want them to enjoy the time.
I mean, that's sort of obvious on the one hand, but I don't think we really- Oh, it's even better than that.
There's an Israeli paper from I don't know about 10 years ago where they looked at judges and the judgments that were made If you hadn't eaten, versus judgments that you made that you had eaten and you really want to judge that's had a good lunch.
Very interesting.
So general state of stress because hunger is a form of stress drives the direction of the dopamine response to either reinforce positive things or reinforce negative.
Yeah, because think about it.
If you get to a state where you're really starving, things have not been going well for a long time.
You've been making really bad decisions.
The creek dried up.
Some forest fire came through and ruined your foraging area or whatever.
Things are going really, really bad.
Are you going to really sit around and wait for the rewards?
The main thing you want to do is stay alive.
If you don't stay alive, it doesn't matter what rewards you chase.
And so in a sense, flipping dopamine's meaning is exactly what you'd want to do.
You're in an emergency state and you want to use this reinforcement system, this expectation system to stay alive.
You want to pay attention mainly to those things.
You want to pay attention to them.
You want to be motivated by them.
You want to be motivated and pay attention and avoid the negative things.
But that's an emergency state.
When I talk to people about how reinforcement learning models say, have an impact on how you should train an animal.
Typically in my case it's in the laboratory setting, but you can use this with other dogs, for example.
Training animals with really negative feedback is a really bad thing to do, because what happens when you get really negative feedback?
You're in a mall, somebody shot beside you.
That's negative feedback.
What happens you have in the extreme case, you have PTSD, but what you do is you overgeneralize.
That was so bad.
It's rational for your nervous system to think anything that looks like the mall.
The fear will start to come.
It will move out to the curb.
It will egress.
This is the whole PTSD cycle.
But that's rational.
That's rational.
That was an absolutely unexpected cataclysmic event.
You better – and you don't know what could have caused it really as far as events leading to it.
So you overgeneralize and all.
So you don't learn very well like that.
So a teacher that instead of when you mess –
When you're trying to add fractions and you don't get a common denominator.
Quite right when she takes a ruler and slaps you over the hand.
They could still do that when I was in school.
This is a generational shift, a good one.
That's a really bad way to teach me to find a common denominator.
Instead, you could just say, you know, nudge, nudge, nudge.
Anytime someone says, I have a friend, it's like code on the internet for like, it's actually you.
And that's like the, I have a friend, you know?
But so I have a friend.
People might be surprised to hear that I have friends, perhaps not.
I have a lot of friends and he's a lawyer.
And prior to becoming a lawyer, he studied torture.
In what context?
Yeah, he was going to become- Torture 101?
No, he was going to become a psychiatrist and he did a rotation with former victims of torture.
And then it took him down this rabbit hole of political torture and the history of that.
He's a real history buff.
He's a very benevolent person, very, very kind.
But he told me something interesting that I think tells me that some people figured out this thing, that if somebody is stressed enough, it contorts the dopamine reward contingency, so that dopamine no longer encodes positive things.
It just tries to prevent things from getting worse is what we're basically saying here.
He said that the way that people torture people to get information from them is actually pretty surprising at least it was to me which is they hurt them a little bit and then they tell them they're going to hurt them a lot and then they don't.
Rather than hurting them a lot somehow, by hurting them a little bit and then telling them this is going to get much worse unless people give up more information.
It's interesting.
I think it speaks exactly to this mechanism or the mechanism speaks to it.
If you hurt a person a lot, that's cataclysmic.
That's categorical.
I'm going to thank you for not breaking my arms again on Tuesday.
I mean, if you break limb and you do these cataclysmic things which leave them near death, there's nothing left.
It's a bad way to train someone.
So I mean what I'm trying to say is I understand that.
And the odd thing is when you stress someone enough, it's remarkable what becomes rewarding.
The incremental removal of threat. given that you've made good on a little promise, could be a lot.
I mean, I... Oh, I've seen that.
That doesn't even have to be as extreme as torture.
Read Dostoevsky and look at the family dynamics and go.
You know they're dialing knobs on degrees of punishment and it's very effective.
Let's take the inverse of this.
Let's shine some light in the room, so to speak.
What if dopamine gets too high?
And I'm not talking about methamphetamine, which will really skyrocket dopamine.
I would say when people are on very high levels of dopaminergic drugs like methamphetamine or cocaine.
Everything seems like a good idea to them.
And they become very self-obsessed.
In fact, there's a wonderful documentary about the Grateful Dead that I watched recently, before Bob Weir died, which someone was saying you know, at some point in the mid 80s it got a lot harder to make great music.
And someone said, what happened?
And they said, cocaine.
I said, why would cocaine do that?
And he said, because it's a me drug.
Dopamine and cocaine are synonymous with one another.
But there are a lot of situations where people are overindulging themselves with food, overindulging themselves with dopaminergic activities.
What does that do to the reward?
If you look at it on the average, it resets expectations where very few, if any, natural events can exceed them.
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So I rescued a dog once back when I was a kid.
I kept lots of animals when I was a kid.
I had My father told me in the end, oh, no, you had over 30 cats.
Oh, my God.
They stayed outside.
Why?
That was back when animals – oh, I just kind of – 30 cats?
I had a cat.
The cat had litter.
There were seven in the litter.
They all survived.
Then – good for you, man.
I wasn't really a budding scientist then, but I realized in retrospect that I really watched them.
Okay.
I understood the behavior.
And there was this dog, this little dog that I rescued that had been beat up and stuff.
And that dog was never right.
It had been so abused that basically it started out by biting you, right?
And that's what happens when you hurt an animal, you know, when you take it past the edge.
Of course, then you take it even further and you have learned helplessness where you just...
Sit and don't do anything.
It was tragic.
I couldn't get that dog to lighten up those cats.
But her world was inverted permanently.
Had just been completely inverted.
Up was down, down was up.
Basic safety was reward.
Everything else...
You were in an emergency state.
It's just a lot easier, as a behavioral commitment, to just start out by biting, because you're going to have to bite at some point anyway.
Yeah, well, I think we've all known some people like this.
It's tragic to see.
Hurt people have a – and it's interesting as we get more and more knowledge about how to hack that and intervene on that, that –.
It would be nice to be able to fix people like that.
I think they would like to be fixed.
I think of some people I know, a cousin in particular.
Drugs of abuse do this to people.
They just – they get people into these states where they just – people make decisions that they know are going to lead to – they've done it before and they're just going to go down the hole again.
Lots of family members where that would be true.
I think nowadays we all know or are aware of people that did that because of the incredible expansion of availability of drugs of abuse, including prescription drugs.
I think if I may, I just want to just to make sure that I'm staying oriented here.
Here's where we've gotten it seems.
Dopamine encodes positive expectation and rewards, and it's graded.
You can have low levels, medium or high levels, depending on how much positive anticipation.
Serotonin seems to encode negative events.
If a human or an animal, sadly is raised in conditions or spends enough time in conditions where true rewards aren't there and survival itself becomes the reward, the dopamine system will adjust its baseline so that it's just fighting for the survival.
And it's important when you're fighting for survival to recognize and anticipate negative events.
And so Anderman's work shows that it does prediction on the outcome.
That's going to be negative, and it gives you a positive pulse for that.
You better go learn about that thing.
You better learn about this thing because you're in a negative state.
I don't know how you got here, but you're in an emergency state.
This is what stress would put you in.
And so positive becomes negative.
You need to have positive prediction errors to the prediction of negative – because that's what's going to keep you alive by paying attention to that.
I keep going back to relationships, but there's so many examples from friends in my life.
I have a really good friend who had had a series of very, very challenging relationships.
I mean, just brutal.
And then has entered a phase of his life where things are really good and really peaceful.
And for about the first three years of that new healthy relationship I'd be like hey, how's it going?
And he'd be like, and he used to say, I'm like a cat in a room full of rocking chairs.
He'd say, and I go, why, it's tense?
And he goes, no, it's so calm.
And I would say only recently has that message changed.
And now he's like really, I mean, He's really flourishing.
The relationship is flourishing.
The whole landscape around it is flourishing and it's really cool to see.
But it's exactly what you're talking about.
You know, it takes some time of feeling safe for somebody to stop just thinking they need to fight for survival and safety.
And then it seems that the dopamine system can then adjust its baseline so that it can now work for rewards again.
Pretty incredible.
It makes good sense that the dopamine system would be adaptive in this way, and not just for rewards, because throughout human evolution I mean people have had to deal with tremendous hardship and stress.
When things are really shitty, what is the serotonin system doing?
Much less has been done on that.
The thing that we know for sure in humans is that in all these probes that we have done, it's opponents its opponent.
It is going the opposite direction.
Some of the best data is from humans, not rodents.
It's a minority observation in rodents.
I mean, it's scattered.
It's quite hard to engineer the behavior in a rodent.
I think it's... Oh, I love that we're talking about humans.
I mean, most people listening are interested in humans.
I am totally fascinated, to the point of being blown away by this SSRI thing that if serotonin reuptake inhibitors drive up serotonin, which they do, they prevent reuptake, that some of that serotonin gets into the dopamine synapses.
A lot of it does.
A lot of it does.
Why haven't we been told this?
And then it lowers the rewarding properties of good stuff.
That's the best way to explain it.
And, you know, it's science.
Somebody doesn't think that's the explanation.
But the fact is, when you put an SSRI on the serotonin that's released due to activity in serotonin neurons, it's not going back into serotonin terminals.
Where does it go?
This paper by John Danny in 2005 showed it goes into the dopamine system and he knows that because he could block the dopamine reuptake and it was a 40 difference.
So there's all the serotonin sitting there in these terminals they're going to be releasing.
Now it's the negative juice.
Let's say that on the other side of this signaling pathway, electrical activity comes through.
You release this transmitter, it has an impact and the receiver goes oh, I'm getting a lot of negative stuff here.
But in fact, it's because it's sitting in neurons that chatter for positive things.
You would have a hard time learning about positive things.
You might also register negative events as being rewarding.
You'd learn yourself into a kind of depression that way.
That's an interesting set of possibilities, physical possibilities.
Yeah, that was a fantastic paper.
I don't know why it didn't sort of catch on.
I think there.
I don't remember, but I know John Danny quite well and he did hard experiments and they took a long time.
We'll put a reference to the paper.
I think I'll answer my own question by saying that I think that really good scientific findings and theories need advocacy to get legs.
They need a shepherd.
They need a shepherd.
I mean, it's part of the reason I started the podcast and invite amazing guests like you and like Terry on and people who really think deeply about the whole field.
And you're changing the way that I think about serotonin SSRIs, dopamine.
You're expanding all of it, truly.
And I know for those listening, that's also true.
I know you're chomping at the bit to talk about learning algorithms and AI, but I want to know first about the experiments where you stuck wires up people's noses and recorded dopamine signals in their noses.
Because
These are wild and cool experiments.
They are.
And they're not wild and cool because of me.
They're wild and cool because of Christina Zolano at Northwestern.
But let me say one thing about how we do measure dopamine in human brains.
We do it in very specialized circumstances where you are having a deep brain stimulating electrode put into your brain to treat a movement disorder like Parkinson's disease or essential tremors.
So when you have that and a minority of patients choose to have a small burr hole put in their head and under careful operating room procedures it's put down into different structures in your brain we won't name them and then turned on.
And it's symptom relieving.
Essential tremors is like Parkinson's disease you have and you have difficulty with movement and whatnot.
I don't think you have the emotional problems the Parkinson's patients do, but it's not Parkinson's.
You have not lost dopamine.
If you give an essential tremor patient dopamine drugs like they do Parkinson's patients, they get much worse okay.
The tremors are typically just really irritating for people, and so they do elective neurosurgery to have microwires put in their brain, and it's a very active area of clinical neuroscience and clinical treatment.
Parkinson's disease also you can have a stimulating electrode put in.
When you do that, you put a little tiny and I mean tiny guide tube down and they drop the electrodes in there.
And under those circumstances, we ask to put an electrode in equipped with a neural network model that knows how to interpret electrical signals on the electrode as dopamine serotonin norepinephrine, pH and peroxide fluctuations.
This isn't exactly, you know, you don't go into Walmart and find this kind of stuff.
I mean, the reason nobody's heard about it is because it's a very specialized area right on the edge of translational neuroscience.
And so it's there that we've gotten recordings from deep in the brain.
What's amazing is when you ask people would you let us piggyback on your electrodes, because the electrodes that they use have research contacts and we can make measurements of these transmitters without sitting on any of the clinical bandwidth.
In other words, we don't eat up any of the ability of the neurologist to use the electrode output to make decisions about the treatment.
Okay, there are a lot of moving parts in that.
I've been doing this for a while.
And so for about the last 12 years, I got very motivated to measure dopamine in human beings at time scales that were physiological and during cognitive events that we find meaningful.
Okay, so I thought the method was very clever.
I won't even go into talking about the method.
It kind of worked right away.
But the entire process didn't work right away and it's taken way over a decade.
I mean it took a lot of work.
So we have sites set up around the world where we do these things.
OK.
It's in that context that we have got knowledge about how to use these depth electrodes to – instead of just measuring electrical activity to do neurochemistry.
Then I ran into Christina Zolano, who's an olfactory physiologist, full professor at Northwestern University.
Very gifted.
What Christina was doing was taking these depth electrodes that are FDA approved, normally used to be put carefully down into the tissue of your brain They're basically just rubbery little tubes about a millimeter in diameter and snaking it up people's nose and just laying it up against a region of the olfactory epithelium, the part of your tissue inside your nose, way up high, basically around here.
Near your eyeball.
Near your eyeball, above your eyeball.
Above and northwest of your eyeball.
Okay, and doing electrophysiology, listening to the electrical activity, and she already had rodent model stuff.
And I went, I can totally get the chemistry off of that.
Why is that important?
Well, other than being weird, you can consent healthy people into doing this.
You can snake this thing up there and clip it to their nostril, set up the electronics beside them and then you can do all kinds of stuff, including letting them eat, letting them do mindfulness meditation, breathing exercises, letting them do decision-making tasks, with and without other people.
You can do simple things like just a stimulus and then squirt odor in there, a rewarding smell.
And measure dopamine and serotonin.
Oh, yeah.
And so we're giddy about this, mainly because we can consent healthy people into doing this.
One of the complaints, of course, of doing it in – people with epilepsy and Parkinson's and whatnot, is they have epilepsy and Parkinson's.
They have an affliction on board.
Could you just share with us?
Are there any top contour statements that we can make about brain state, dopamine and serotonin as measured off through the nose?
Like for instance, if you see a fluctuation in dopamine through one of these nasal probes.
Okay, what we see in the nasal recordings looks very much like exactly what we would expect if we were recording from the neurons in the midbrain.
Based on what people have recorded on the simple experiments you know.
There's a cue, there's a reward, there's this, it went up, it went down, that kind of thing.
This is a positive picture.
This is a negative picture.
This is positive affect.
This is negative affect.
Okay, so dopamine increases when there's a positive expectation, serotonin increases when there's a negative expectation.
And you're recording that from the nose, essentially non-invasively, except somebody has to put a wire.
Apparently the language is minimally invasive.
All right, well...
Cool.
I can live with minimally invasive.
So I haven't done it yet myself, because when I was scheduled to do it we realized we'd clipped the age at 65 and I had a birthday on Sunday and I aged out.
How old are you now?
I'm 66.
You're looking good, man.
People are going to be like, what are your protocols?
You know, raise five kids, run a big lab.
Never sleep.
Do you not sleep?
Never sleep.
Not really.
Do you not sleep well or you just work all the time?
You know, my dad, who died at 91 in 2021, he didn't sleep.
Take that, Matt Walker, Brian Johnson.
You don't have to sleep to live to 99.
A lot of that's genetics.
It's a setting.
I'm just teasing.
A lot of that's genetics.
I think I do fine on six hours.
I prefer seven, but I don't need eight.
I definitely do not need eight.
It's really variable with people.
And then there's the cognitive people, the people that develop an opinion about how well or long they slept.
And that idea circulates in their mind.
I didn't get much sleep last night.
How much do you sleep per night?
I know we're taking a tangent here, but people will find this interesting and I certainly do.
Okay.
When I was younger, it would be like four.
Okay.
I know another person like that.
Okay.
Now, because I get up really, really early.
What time do you get up?
I get up 3.30, 4 in the morning.
I really enjoy quiet.
What time do you go to sleep?
Well, I go to sleep twice.
You know, I'll fall asleep in the evening and then I wake up.
What time in the evening, like 8, 9?
8.
I might sleep till 10.
But if I do that, I feel good.
And then I have to pretend like I need to go to bed.
And so I'll lie down and then, you know, when everything's quiet, I'll move back downstairs.
The way I do science is I have to get quiet.
That part I can't do with other people.
I have to do it in dead quiet.
The data would say that that first round of short sleep, you're grabbing your deep sleep, you're getting your growth hormone surge, which is great bodily repair sufficient to keep you healthy enough.
And the second phase probably you're getting some REM sleep enough to seem like an emotionally stable guy.
Well, that's not true.
But you know my mom, who died in 2023 at almost 90.
She used to complain to me as a child you're up because I'd wander outside.
And back when I was a kid, no one was scared of anything.
And so I'd walk out in the door and I might walk a mile away from home or something.
I mean, we just weren't scared of anything then.
You know, now we're scared of everything.
And I worried about it until I got a little older, until I was 12 or 13 years old.
And then I just realized I'm just going to decide how I think I feel and that's it.
And everybody else is different than me.
And I was raised in a community where there was clearly something wrong with me compared to everybody else, right.
Or maybe someone was wrong with all of them.
Yeah, well, maybe.
I mean it's cool that you learned to trust that, because we get a lot of messages about we need X, Y and Z And I mean you clearly are, you know, you're a competitive athlete.
Your lab's done spectacularly well.
I mean, it works for you.
So you know if it works for you.
It probably also helped with raising kids, because having all that energy to raise five kids is Well.
I've had Two marriages, so maybe it worked or didn't work.
So you have some conditioning too.
So you know what?
You can delete that.
We'll delete that if you want me to.
When I hear you talk about people, I just think to myself oh, you know, I have this person, they have a relationship, da-da-da.
The one thing that does for you is you back off people a little bit.
What does for you?
Divorce.
You kind of go, if you think at all about it, you just go...
Nobody is one thing.
Everybody is a little complicated.
Nobody is Mother Teresa 99.9% of the time.
They were a jerk last Thursday or they were this.
Nobody gets through life without making stupid, dumbass mistakes.
And it's easy to be judgmental until something bad has happened to you, like something really kind of soul-crushing, you know, like a divorce.
And you have to go—because generally, there are two people involved in that.
And so that's a learning lesson that helped me in many—it's helped me in many ways.
I appreciate my— life now for a reason and i and it wouldn't do if i didn't have those kind of scars.
Um also, science i don't know if you talk about this.
Science is a contact sport.
I haven't talked so much about this.
Science is a contact sport at the leading edge, science is a contact sport and you know um, There are a lot of smart people doing science on the world stage and certainly on the American stage.
And they're out there sort of battling at the frontier.
And the first thing that happens when you do anything good is, you know, out come the chain mail and the maces and whatnot.
And you kind of have to fight for yourself a little bit.
And so then it asks of you.
To look inside yourself, like do I – is this an important problem?
Do I really believe this result?
And our job.
The reason we're paid tax money to discover stuff is our job is to push the edge of what we know, not sit there just getting money to twiddle our thumbs.
And so if you're on the edge, you're going to make mistakes, or you're going to be wrong, or you're going to be attacked or not popular.
And that never ends.
We call it the reviewer two syndrome.
Yeah, reviewer.
Two is the one that makes your life more difficult, but maybe makes the papers better in the long run.
Maybe.
It makes us stronger.
It's the brutally hard coach of our career.
I mean, I'm no longer running a lab.
I did until a few years ago.
And I'll tell you that the other thing that's brutally hard about science is that just the work is hard.
The culture of it also has some punishing features, but...
They build us.
They make us stronger.
But it's one of the few professions where – there are others, but it's one of the few professions where you have to work exceedingly hard to get the resources just to do the work.
So it's like having two jobs wrapped into one.
And I had no idea.
That's where knowledge and textbooks came from, when I was 10, living in Macon, Georgia.
I
I don't think most people do.
Part of the reason we started this podcast is that people should interface with scientists, learn from them, understand kind of some of what it's about.
I mean, it's still an awesome endeavor, right, to discover things.
But you're right, you have to have some real fortitude.
But you're not told that when you join the club.
No, not so much.
You're not really told that.
You're generally.
Science is a.
You're an assistant, you're an apprentice.
It's an apprenticeship training.
You go sit by some person who's great at X And the main thing you do is you absorb them doing all these little things.
It's not training in X and Y and Z in school and whatnot.
It's not like that at all.
It's not like getting grades in school, but you do absorb stuff from smart people around you.
Um, I've benefited from an enormous number of firebrand intuitive people that are – but you're typically not paying for yourself then.
Then you go out and you try to do your own thing and you're like, gosh.
It's bracing in a way.
The American system I think is – I don't know how to compare to Europe.
Even though I've had European – grants, but I've never been plugged in.
We're hard on each other here.
And I've had people that have been on study review panels from Europe on American study review panels who say wow, you guys are just.
I thought you were slapping everybody on the back and Oh no.
I sat on study section review panels for a lot of years.
I was a regular member.
And you go in there knowing you're going to have to eliminate 70% of the grants that you read.
So you sort of advocate for the ones that you really like, but you have to come up with reasons why you dislike things.
And that's an unfortunate consequence of not enough funding.
I do think that things are changing now.
And there are other sources of funding, fortunately, philanthropy, foundations.
But yeah, it's not for the weak of heart at all.
And having a minimal sleep need definitely helps.
I mean, I don't know anyone that succeeds in science without working really hard.
I will also say, if you really want to get your ass kicked, just become a public facing person.
But science made all of this feel much easier.
Like there's much easier.
I mean, it's different, right?
But science I mean I don't want to get into war stories about long hours because no one's interested in that.
But Yeah, science is a thorough ass kicking with the occasional reward.
Plus it's biology, meaning even when you're right on Tuesday, eventually it's like, oh, well.
But this gets us back to dopamine and rewards, which is one thing I will say is very, in my experience, was very valuable about doing a PhD, about working in a lab doing biology experiments, is that it teaches you to set up a reward expectation motivation, contingency loop that is based on everyday things and long-term goals.
I mean, I think one of the features of being a healthy human is being able to like oh, like hey, you know it was a great cup of coffee this afternoon but also register the serotonergic like ah, that experiment failed again.
But then when things are working again, you can kind of feel like get some motivation from that and not just think about the PhD as the reward right.
So I go through life now not expecting great things to happen every day, or even every week, because I was trained in a system where the big rewards came every couple of years in terms of publishing papers.
Sometimes more frequently, but, you know, it's a long-term thing.
But what about for the more typical example in people where –
You know, you grow up and things are either really easy, really hard, or for most people it's kind of a mix.
Do you think that that's part of us learning how to navigate life going forward?
Like, you got to register your wins in order to continue to have motivation.
You also need to register your losses in order to not make the same stupid mistakes.
You have to sustain your losses, right, and get up again.
This is why I like sports for kids.
Okay.
So I've made all my kids do sports, and one of them did competitive dance.
So sports as a means to understand effort, reward, contingency over time.
And learning how to lose, even though you've brought everything you could do that day, the best you could possibly do.
Yeah, somebody's better than you.
What are you going to do now?
That is a template for a lot of lessons.
Same thing for students in science labs, especially mine.
Students do things, they come, they show me something and I go, you know, and then they feel sad.
But I watch them evolve, they evolve, you know they all get better at it, and then they do this transition.
You know, graduate students I mean, maybe this is a little academic graduate students are completely worthless to you for a long time.
Not my experience.
Well, in my world, they have so much to learn before they can do anything.
That's what I mean.
No, I mean, as people, they're valuable.
You mean in terms of data output?
Yeah, well, they don't know how to interpret the experience.
No, they don't know how to do anything at first.
No, they're very valuable to have around.
You want young people around.
You want young, fresh people around doing things and thinking great thoughts.
But then, all of a sudden, they do this transition where they're literally the most valuable person In the lab.
And then six months later, they break your heart.
They leave.
They leave.
Yeah, just like you did to your advisors.
That's what I always say.
Oh, they were all glad to see me go.
I was so blessed.
I mean, all my students did great.
One's down at UT.
One's University of Utah.
They're both kicking butt.
Another graduate student's in biotech.
And another one's on the job market now.
And I'm just glad I'm not competing with any of them.
Because I will tell you, They are phenomenal.
I don't take any credit for it.
I did what I could with them.
One was a postdoc that I just mentioned.
It's fun to be around, to watch it.
It's just so cool.
I mean the energy of youth and pouring into something with so much focus, and not for the money, because Lord knows they don't pay them very much, even as professors.
What you said about insisting that your kids play at least one sport.
I think that also gets back to removing a problem we talked about earlier, which is at least when you're playing a sport, you can't be on your phone.
Also, if you're really, really tired, it's hard to get in trouble.
It's very hard to get in trouble.
If you're a soccer player, you run – I mean you are shot at the end of the day.
It's just – you just – hey, let's go drive in the – I don't feel like it.
So it's a generic strategy I use.
And I just think sports – it's not so that they can be champions.
I mean it's great if that happens.
It's great for them.
But they challenge you in ways that other elements of your life don't.
I think of wrestling and you get your air cut off and the main thing you learn when you're a wrestler is how to manage your rising sense of panic.
Don't panic.
Think about where you are.
You're not good at that at first.
I mean when you go into an office and you face your boss or your coworker or something, nobody comes over and chokes you and says now think.
Okay.
That's the only socially acceptable setting where that kind of thing teaches you you know what are you going to do.
Losing is such an amazing, especially when you don't want to lose and you did the absolute best.
And in front of people.
Yeah.
Like track and field, you know, you run, there's only one winner, you know.
My kid has been going to these giant meets, these sort of mid-Atlantic meets.
This is a middle school.
I mean it's amazing how well-run they are.
But there will be 40 teams there.
There will be 60 kids in her event.
So if you get second, that's really, really good.
But if you want to win, there's still this little thing that eats at you and you learn how to manage it.
So I couldn't teach her that.
Sport teachers are that.
I see those as tests that we don't get put to in the modern world.
You know, it used to be different when we ran around in bands and we literally had to defend ourselves a lot.
You may have to do something that requires awful things.
You got to be ready to do an awful thing.
We're not put in that circumstance.
A lot of modern ills come from, you know, we still have that brain.
Civilization forces you to manage the stress in ways that it's just kind of not designed to do.
It's funny because when I was growing up, the sport of choice for me was skateboarding, and there weren't teams or anything like that.
I mean, you could get sponsors and some of us did, but that's not the point.
But what I learned from it was pain, pain, pain, pain, fail, pain, pain, made it.
Those guys.
Pain, pain.
And I wasn't good enough to take a career into it.
I had friends that were.
And a lot of that is done in solitude.
It was a great learning for science where I was alone in the lab.
My graduate advisor wasn't, she was available when I needed her, but I was the only one in the lab.
So I worked alone.
She said, don't burn down, don't kill yourself.
Don't drink the tetrodotoxin.
And I actually had some pretty good lab accidents from working really long hours late at night.
But it was failure, failure, discomfort, failure, failure, got something.
Failure, failure.
And it felt a lot like that.
And I remember thinking skateboarding was great because as hard as this is, it's not as hard as falling on concrete.
Same thing when I tried to learn to snowboard, everyone was like, snowboarding is pretty tough.
I was like, it's snow.
I was like, concrete hurts.
Snow is soft.
And even the ice pack is softer than, and I was like, you know, so it hurt.
It took me some time to get good at it.
But like, you're like, okay, like I get it.
So I think this actually is directly nested in everything we were talking about before, which is our expectation of whether or not our efforts are worth investing or not.
Whether or not we update the keep going or quit depends a lot on how we interpret the, how many pain episodes or rewards we expect to get before we succeed.
People have cognitive control.
People can intend to do something and inhibit your natural instincts to avoid it or to quit or to back away from it.
So the aversion signals that you would normally flee from have to be sustained, right?
When you're training to do anything like that.
And, um, It transfers when you're older.
It transfers older.
Oh, totally.
Yeah.
People that are successful at athletics.
People just tried to do it, which is why our little school, a little private school in Roanoke Virginia, has a no-cut policy.
So I think there were 45 kids on the tennis team last year.
It was almost unmanageable.
They're all out there and they compete at the level they can compete at and they win and lose.
And it's just a great – I can't teach a kid a lesson that good.
And that's training these same systems.
It is.
Expectations, disappointment, elation, recovery, do it again.
It's all built in.
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I'm going to come back to your athletic career, but I want to ask about meditation and breathing.
Um, I think of meditation as some variant on close your eyes, focus on your internal state, direct your attention to your breathing or your forehead.
I know there are walking meditations, open monitoring meditations, but I think most laboratory and most people when they think meditating, They're doing something like what I just described.
And I think of it as a perceptual exercise.
First, like you're deliberately setting your perception internally, not externally.
I understand there's these insights into consciousness, improved sleep, reduced stress, but that's all secondary and tertiary to me.
What is the consequence of doing the practice of meditation?
Directing your state inward as opposed to outward, eyes closed, focusing inward, breathing in a controlled way?
What does that do to dopamine and serotonin?
And or what are dopamine and serotonin just doing when you go from like a conversation that we're having to a meditation?
So we've been doing experiments on this with my graduate student, Nishka Raheja, who went to the Ohio State University and then worked in.
A guy called Jeff Schoenbaum's lab at the intramural program in Baltimore, NIDA National Institute of Drug Abuse, came highly recommended to me.
And so she wants to study the neural basis of mindfulness meditation.
She's herself a meditator.
There's a whole bunch of narrative that you put on top of this thing.
And I'm a little bit of a feet on the ground, real simple mind, simple.
So I said, I'll do that, but we're going to do all these breathing exercises. experiments first.
And so she's been in two settings.
One is recording from the amygdala, anterior cingulate cortex or the hippocampus while people are doing structured breathing.
This is her instructing them to breathe, you know, inhale one, two, three, four, hold, exhale.
Okay.
I sit here and I'm not instructed to do anything.
I'm just breathing, just free form, free form breathing.
So Well, cycles with it, norepinephrine and dopamine, cycle with the breathing cycle.
On inhale-exhale or overall they change as you do this?
That kind of granular detail is waiting on numbers.
But the general gist now this is from deep structures in the brain.
Is that easy breathing?
You can just see it is like a metronome.
The amplitude of the neurotransmitter fluctuations follows the inhale-exhale cycles.
It's right with it, it's very easy.
You feel like you're watching the brainstem work.
So when I tell you, breathe in, two, three, four, hold, you know, and now exhale.
All hell doesn't break loose, but it becomes hard for them to follow and the transmitters are kind of wiggling and wobbling too.
Okay, so that's in people that are in the epilepsy monitoring unit.
This is taking place at Phoenix at Benner Hospital with our colleague Robert Bina.
The most exciting stuff is, using this probe, that we can put up the nose of healthy people and do the same sort of thing.
And we see generally the same sort of thing.
The whole instructed breathing, you have to engage cognitive control over it, differentially adequate at doing that.
So they're doing structured breathing.
Does dopamine track map onto the breathing?
Yes.
But the interesting thing is we have people playing an economic exchange game.
It's called an ultimatum game.
Ultimatum game should be labeled take it or leave it.
I have $20.
I'm going to offer you a split.
Eight to you, 12 to me.
Okay.
Control passes to you.
You're going to either accept that, in which case we walk away with eight for you and 12 for me, or you're going to reject it, in which case no one gets anything.
What do people do?
Well, they tend to – they see the inequity across the players as a signal and at about 80-20, you're indifferent.
In other words, 80 to me, 20 offered to you.
50 of the time you're going to say I'll take it, 50 of the time you're going to send me a signal and say you know, go home, I'm not taking that money.
So nobody gets anything at a cost to you.
When you reject, it's at a cost to you.
The pattern that we see recording up the no's the breathing is registered cleanly with the peroxide signal which is a proxy for mitochondrial function and the dopamine signal and the norepi signal.
So, as this pattern of exchange is going on between the two of us, if you're going to update a model, in other words, if the signal across the two of us is such that you have to do some learning,
It's like your maximum breathing is tracking when you're going to need oxygen in the mitochondria to produce ATP, to make an update that's going to be allowed by the dopamine signal.
It's the most amazing looking data I've ever seen, and this is, in other words, your breathing and your dopamine signal in your nasal epithelium seems registered, depending on the demands of the task and the elements of the task.
Is this why you refer to dopamine as a currency?
Yes.
I refer to it as a currency mainly for the reason that a currency is used.
It's a way to take dissimilar objects and assign a common value scheme to them.
Like if I were going to trade cups for windshields.
It's easier unless we're going to haul a bunch of windshields and cups to the trading side.
It's much easier to say this is worth something in a currency.
I understand that you agree to and agree to some price.
A lot of times.
I think it doesn't matter if you're talking about the US dollar or the euro or Bitcoin.
Dopamine is the underlying currency.
It doesn't matter if you're talking about wins in sport or other kind of more evolutionarily adaptive type examples like dopamine is the currency.
It actually can provide some method for resilience in my experience.
You'll notice in human dynamics online because I spend a fair amount of time there that people will try and rob people of their sort of message by like taking like potshots at them or something.
And in science, you see legitimate critique and you see not illegitimate critique, right?
Same thing in human dynamics that you observe online.
There's real lessons to be learned from some of the critique.
But sometimes people are just trying to rob people of whatever impact they're having.
And so you can think of one's own dopamine, one's own level of motivation.
Like are you going to let somebody rob you of this currency?
We're not aware that we're using dopamine as currency.
But ultimately, like the person who's winning has more energy to go do more winning.
People who are losing sometimes dissolve into a puddle of their own tears or worse.
Other times they try and rob other people of their currency.
And, you know, this is the notion of zero sum versus non-zero sum games.
And When I step back now and I look at, like the media landscape, the political landscape, the social dynamics at large, I always think of dopamine as the currency.
If we're really honest about what's happening in the world, it's a battle over resources, and all those resources ratchet back down to this one single molecule.
It's really incredible.
Well, these same systems.
Systems, yes.
Thank you.
Yeah, because they're working as a coordinated system.
You know, dopamine turns on mitochondria.
It gives you life.
It literally turns on mitochondria.
It binds to the outside of mitochondria to monoamine oxidase and it gins up electron transport.
I mean it's a signal to make ATP available.
That's a really direct connection.
Now, what neuroscience hasn't understood very well is the connection between the algorithms that the dopamine runs, the computations and the combustion.
So like if you touch your forehead, your forehead is merely warm, right?
Now, if you touched a computer in a server center, if you could get your finger near the chip, it would burn your finger.
And if you turn the air conditioning off in a server center, within minutes, they burst into flame.
The whole thing would go up in smoke.
They're mainly generating heat, okay?
There's a big market play here to make chips that run and do the same computing, but on 40 of the power.
I mean, service centers are amazingly, and just our computing machinery is amazingly inefficient.
So there's great things to come as people take on this problem.
But we don't understand how it is that we get away to run our entire brain on 23 watts.
Well, earlier we were talking about sleep and we talked about meditation.
I want to make sure that I at least offer you the opportunity to speculate.
What do you think the kind of rejuvenative properties of sleep and meditation are –
For instance, however little you need to sleep, if you don't sleep for two days, you are a different beast altogether.
And sure, adenosine goes up and the inflammatory markers go up.
There are a lot of reasons for that, but motivation goes way down.
Dopamine dynamics change completely, right?
What do you think allows us to replenish this currency in sleep?
Like what is it?
Is it the slow breathing and meditation and sleep that allows it?
It's a combination of physiological responses and the algorithmic cleaning up.
It's a computational device.
At least we see it as a computational device.
That's the modern metaphor for how we go in and understand it.
And it has to erase stuff.
You need a time off.
You can't have information streams processing through where you need to be going.
I'm not going to save all that, or I'm going to consolidate that.
And a lot of it's about erasure and homeostasis and recovery.
I mean, that translates physically into recycling transmitters and rebuilding all that.
Because there's nothing like the kind of motivation we feel after a great night's sleep, the way we interpret events,
And all animals sleep.
It used to be thought the echidna didn't have REM sleep, but that's no longer, that's false.
It's the first time the echidna has been mentioned on this podcast.
Okay, there we go.
You may not want to go here, so feel free to say pass, but I'm very interested in the relationship between dopamine and other neuromodulators and time perception.
Could we start with some general exploration of this?
So really like in the simplest way if dopamine levels are artificially increased with a drug, What happens to time perception?
It changes.
One of the things that's latent in any description of what dopamine is doing, either from a point of view of psychology or algorithms.
That I focus on is timing.
To learn something is to suppress the statement.
You learn something about what's going to happen, when and how much.
You know what where, when and how.
And so you have to have a lot of clocks in there, okay?
As you well know, it used to be thought we had this one area, the suprachiasmatic nucleus.
It set daylight cycles, etc.
And that was one of the main sources of clocks.
Now what we know is every cell in your body has clocks in it and many multiple clocks.
This is true for using these dopamine signals too.
You not only have to have clocks, you have to be able to register the time that something was happening.
Now, I don't know exactly how that's done, but we just know that the system learns particular times and whatnot.
And so those almost certainly have to be rejuvenated and reset.
There's a whole literature in rodents called the interval timing literature, where you teach an animal to anticipate something at a particular time in the near future.
A few seconds.
And dopamine plays a critical role in that.
And there's a group in London I forget the PI's name who uses that and uses manipulations in humans of dopaminergic drugs to look at time perception changes.
But these are whole body like what did you perceive?
Is there a simple statement that we can make?
Like if we, if you increase dopamine pharmacologically and then you does your perception of time shift to it moving faster or uh, slower?
No, there's no.
I'm not saying no to that, i'm saying that there's no clear, there's no bromide for that.
All we do know is that People who smoke cannabis oftentimes think a long period of time went by and they find out that a very short period of time.
Also, people on methylphenidate, I mean people on Ritalin, will report that.
They lose time.
Now, presumably they're concentrating for longer periods of time.
It has the sound of multiple systems, not all of which you're conscious of.
But dopamine has had a...
I could start naming the people.
I know this literature on interval timing and they're beautiful relationships between the dopamine signaling and the timing, but it's not sort of they haven't been experiments where you could open up the modern understanding of it as the key and reinforcement learning.
That goes on.
Do you track time well on the order of a day, like as you move through your day, are you aware of how much time has passed?
Terrible.
I'm awful.
I'm awful with directions and time.
Can you orient well in space?
Well, I mean, if you tell me where the sun is.
Interesting.
You mean my body?
Yeah, like I know where my body is.
Well, I know you kinesthetically, I mean, you were a competitive athlete.
So that makes it, no, I mean... I am stereo blind.
Oh, yeah.
That's so weird.
Really?
Ramachandran came to New York when I was in the audience.
Your depth perception is messed up.
Well, apparently.
But you were a javelin thrower.
I pitched baseballs until I was 15.
You probably used one eye.
It's the kinetic depth effect, right, where you shake your head.
Motion parallax.
Motion parallax.
You move your head from side to side.
Maybe.
But Ramachandran was a famous visual psychophysics guy from UCSD came and he was showing all these pictures.
And he goes, can anyone in here not see the thing?
I couldn't see anything.
He goes, oh, you're stereo blind.
It's about, I don't know, 5% or something.
You probably have a hard time with barriers.
And I was a hurdler in high school and college and throwing balls.
And I also pole vaulted.
And I was left-handed until I was eight.
And my mother made me switch my hands.
Rough.
It's a right-handed world.
You go into your classroom, you count the number of left-handed desks.
I came back.
I said, there's one.
There you go.
You're going to use your right hand now.
She was horrified when I cut my food and flipped the fork over in my left hand instead of switching hands.
Well, you got some brain plasticity out of it, no doubt.
Probably.
I asked if you track time well, because I think that this is totally, you know, just observation.
I think that all the people that I know that are very driven, who have more of a I don't like to use clinical terms, non-clinically but more of a obsessive nature than more ADHD like, seem to not track time well and they're able to just throw themselves into things And discard with thoughts about the rest of the world.
And I think about this a lot because of a generation of people who grew up constantly being bombarded with information from all over the world, all day long.
It just feels and sounds so noisy to me.
And I saw an interesting article recently that the generation that grew up with social media and smartphones.
There's some interesting data that they may not track time the same way on the order of a day, but also in terms of their life arc.
And it makes it harder for them to envision long-term goals.
And I think it's an interesting but still emerging literature.
But it kind of makes sense if the dopamine system is involved in this and if it's kind of mapped to very short-term contingencies.
I grew up where there were... I would wander... forests for hours and hours and hours.
And you weren't monitored by your parents.
You left in the morning and you were supposed to show up by dark or something.
And people didn't worry about their children.
I mean, maybe this wasn't the right thing to do, but this is the way it went.
If you wanted information, you had to go find it somewhere.
And it's so much calmer than the things that our kids are embedded in.
I think it's different.
I'm not sure it's also pathological.
The adults in the room all share a worry over it, but we don't know really what to do.
I don't think we do.
And then you know these large language models.
I don't know how much you talk to them, but you know they speak 180 languages.
I use Clawed.
I love Cloud.
I love Cloud AI.
You know, I love the interface.
I think the answer is that I use it for research from time to time.
Do you ask it to summarize areas for you?
I ask it to direct me to literatures.
I guess I've asked it for some summaries here and there, but I've asked it to compare and contrast things, which is really cool because I can't do that in PubMed.
I can't go into PubMed and say compare and contrast Reed Montague's picture of dopamine to someone else's.
But Claude can do that.
It can set up a five-person panel around a topic in Claude.
I use it more and more these days, and I love it.
I also really like the interface.
It's very clean.
And I care about aesthetics, and I think it's awesome.
The game I've been in isn't the artificial intelligence end or even the neurobiology end.
I've been at the interface of those two.
So I've lived in a narrow space that shuttles people. stuff from one world into the other world.
I mean, I've used algorithms to organize biological observations, basically.
I'm the middleman in a way.
I never thought this neural network training would scale the way it has.
I would never have guessed the way it does.
And I know there are the dissenting voices.
The doomsday people.
Yeah, it doesn't really do very well.
Well, I mean, compared to who?
Does anyone know anyone else that can speak 170 languages, that can translate 170 languages?
I don't know anyone that can translate accurately 170 languages.
What do you use it for?
Things like Claude.
Do you use it as a kind of a search engine?
Well, I ask it, what's the relationship between the subjunctive mood and the use of complex numbers and non-relativistic quantum mechanics?
I asked it that recently.
Just for fun.
In quantum mechanics at least not quantum field theory, but in quantum mechanics the ways things might happen influence the probability of the way they actually turn out.
Whether or not you traverse that, you have to add up all those possibilities.
It's like a counterfactual.
It's like a mathematical rendering of a counterfactual, but it's based on experiments people have done in the real world for 100 years.
And the subjunctive mood and conditional is the same sort of thing.
Once we discovered how to speak language, we discovered how to make reference to the thing that would be if something else had happened.
They're sort of the same.
I didn't say anything, but just what's the relationship between that?
And it wrote this beautiful little essay, as it were.
And I just thought okay, I don't really care whether it maps onto some notion of consciousness or smart.
I don't know anybody that could do that.
I don't know any person that could do that.
And it's a better writer than I am.
I mean, maybe that's me, but I'm just blown away by it.
And I'm even more blown away by the reinforcement learning guys, the David Silvers and the Go and AlphaFold, and they solved the protein folding problem.
DeepMind, the company that was owned by Google, and so I guess Google won one two three, four.
They were three Nobel prizes or something this time.
The thing that happened, that AlphaFold is the program that takes DNA sequences and predicts protein structure.
And this is what Jumper and Hassabis got the Nobel Prize for.
You know that's a problem that the NIH has probably spent 100 billion on for the last 70 years.
Okay,
They've also spent money on people crystallizing proteins and seeing where the atoms are and whatnot.
And what they showed is they can develop a mapping between the sequence and the predicted protein structure, which is just amazing.
It was stunning to me.
Now, it required all that crystallography data.
But their general approach was treating it like a game, like they had treated.
Go where you do this reinforcement learning thing and you say – you take a long sequence of moves and the game ends and you get an outcome win or lose.
And that's enough to train up the best player that's ever existed in history.
And then they used AlphaGo Zero to train up to be a grandmaster chess player.
Back a few years ago, it took 30 or 40 days and I think they're down to – I mean from scratch.
So I mean, if anybody is going to write a history book on that, those are historical breakthroughs really.
And those algorithms are installed in our heads.
Biology discovered that this is the way to handle the reality that, whatever it is, given the constructs that are generated by our brains, it keeps us alive.
That's just the start, is what I think.
In other words, the neural reinforcement learning world is going to continue to grow.
It's going to explode.
We're going to really start to understand that and we may even understand how to engineer it.
Let's say somebody wants to get better at understanding where they're at in the whole learning motivation reward contingency, dopamine thing.
They're not going to drop a wire into their brain.
They may or may not be able to participate in one of these experiments, but let's say somebody wants to kind of just reflect on where they are strong and where they are weak at the level of the algorithms they're running, suggesting you necessarily have anything for them right now.
But aside from telling them to go play a competitive sport, I have a postdoc that's making a company that's going to commercialize these things up people's noses when it goes from skunk work to kinder and gentler.
And you could hack your own serotonin onto your cell phone.
You could put it up there and you could go do a thing and you could watch it on your cell phone and um, we've never had anything like that before.
Like i wonder what happens when i do this?
I know, i feel you know what happens when i solve a scrabble puzzle or what happens when i uh, you could do it yourself.
That's that's.
His goal is to take this company and put it into a commercial space where people could make personal use of it.
Oh, my god, i can give this to this person who's asking me about their dating life and they can uh, figure out how their dopamine reward expectation contingencies are running them.
It would be very interesting to sit and run scenarios through your mind and run them through again and ask yourself.
Ask whether you saw something like that going on with the signaling that's available in your nose.
That's the kind of experiments we're doing now.
We have sentences playing out to people that have As each word occurs.
There's a probability that there's going to be a valence change in the sentence and we're looking at how it tracks this word by word.
We have people playing social exchange games, thinking about themselves and others.
I can imagine there's probably somebody out there that has even better ideas about how you could use it right.
I mean, I sit and work on the other end of it, but – so I'm hoping he – that's going to hit the big time for him.
Could you give me an example of something that you're particularly excited about that would make one of your kids' lives easier.
Learning how to concentrate.
Like this company, this is Seth Batten.
This company is called Nebula Neuro.
If he had a probe that we could put up there easily like the little squishy things in your ears, then
You could give them that and you could ask them to servo on their neurotransmitter release.
So they would read a passage.
You're getting real-time readout of dopamine and serotonin.
And then you make a suggestion about how to learn something about it, pay attention to a component of it, or you could do something as simple as lower this thing right here, lower this signal right here.
We just haven't had a way to measure that in real humans and in settings that are like the real world.
So you take a thousand people and you say, oh look, these people are really comprehending in a way that we want them to comprehend.
And these are in the middle and these are, wow, they're way off beam here.
And then you train a neural network who looks at the performance step by step with the transmitters there, and it generates a picture of that.
That kind of thing is going to dominate neurobiology coming up.
I mean, it's changed, whether or not people realize it or not.
So many people are getting trained in it over here, but these are the important problems.
These are the human behavior, human mind, human perception problems.
That's what you really want to get at, especially from mental illness and stuff like that.
It's not going to be a simple one thing.
So the fact that these neural networks have had a big breakthrough, and how do we train them and how do we – and there's still a ton of stuff we don't know?
These networks often learn things that the designers don't know they know.
And I think that scares a lot of people, but I think there's excitement in it to be had.
And they're very convincing.
They can make very convincing arguments and things like that.
And so I just think, letting it look at data – I can't imagine a neuroscience experiment, certainly on humans, where you wouldn't do that, where you wouldn't shine these networks on that and feed them the data.
So a lot of this is going to be how do you collect the data, how do you feed it to the networks and whatnot.
Yeah.
I'm very excited about that.
I'm excited about it because it was made fun of so much 30 years ago.
Oh, reinforcement learning can't learn anything.
Everything in science was made fun of when – now these really sound like two old guys talking about it.
But when I first started going to the annual neuroscience meeting, two things were the dregs.
Like no one attended those very few posters, which were AI – and brain machine interface.
Those were considered like the, like really just like the bottom of the pile.
Now it's the hot thing.
Yeah.
And for a while there was the you know molecular tools and genetic tools, and those are still awesome.
But now AI and brain machine interface is like all the rage.
We're going to engineer our way into the brain.
Now we're not going to just look for a pill.
Well, look, the same thing is true, if I may, I'm editorializing here, in the health space, right?
And so the same kind of what got knocked on meditation and magic carpet.
Is it like a magic carpet ride?
You know, is it woo mysticism, breath work, meditation?
Psychedelics are making a big comeback now.
That needs to be approached with caution, obviously.
It can set off psychotic episodes.
But it's being looked at seriously clinically.
Peptide the GLPs have made peptide super interesting.
I mean basically, I've lived long enough in these spaces of science and health to say whatever people are beating up on now, that's going to be the next big thing.
It's just going to take a while and you have to be discerning in how you go about it.
But I think it's wonderful that guys like Hinton and others kept hammering on this stuff when everyone thought it was like kind of backwater.
Why would you do this stuff?
Why would you do neural networks?
Because they can't learn anything.
And it was sort of true.
I mean, they weren't learning anything impressive.
And then they transitioned to learning everything.
I mean, you can ask it, what's in that picture?
And it'll answer you.
There's a woman holding a puppy dog.
The man dancing in the background looks like a painting from a Fellini movie.
It's awesome.
I mean it's proof that, whether or not you're talking about fitness or sport or science, that if you love a certain area of something, to just keep going because eventually the world kind of aligns with you and then it won't right.
Eventually it move on to something else.
He's a psychologist too.
Yeah, it's so cool.
His PhD is in psychology.
Hinton?
Yep.
Well, I'm glad to... know that you're excited.
I'm excited that you're excited.
And I'm also mostly an optimist about this stuff.
I mean, I also think when we talked a lot about social media and reward contingencies and dopamine and stuff, but I also think that the human brain is adapted to conditions over and, over and over again.
So this younger generation that we're like, how could you spend all this time on your phone?
We don't want them to destroy themselves.
On the other hand, they're doing pretty well.
Like.
There are examples of them doing spectacularly well, scrolling super fast and doing homework, playing sports, living their lives.
So you willing to answer some questions from the general public?
Sure.
Yeah.
Some great questions here.
Some of them you've already answered.
But here's one I think is worth asking.
How much of what the public hears about, quote unquote, dopamine hits is neuroscience BS, meaning it's probably not real neuroscience, And how much has an evidence base when we hear this thing dopamine hits.
Something unexpected and rewarding causes a dopamine fluctuation.
And that's true.
Okay.
But it's an incomplete story.
Do you think it's an oversimplification to assign a serotonin hypothesis of depression and a dopamine hypothesis of schizophrenia?
And if so, what other points would you add?
It's a bit of a loaded question in that both of those chemicals are fluctuating in both of those disorders.
So involved, but that's not the complete story.
You know it was.
The most conspicuous feature of schizophrenia is the fact that blocking dopamine receptors turns the symptoms down a little bit.
We discovered that a long time ago.
It was very early on seen as a hyper dopaminergic state and it is that.
I mean it is that.
If you block dopamine receptors, you don't hear voices anymore.
If you take L-Dopa and you don't have Parkinson's and you don't have schizophrenia, I can find a dose where you will start to hear voices.
I can find it as, well, you'll start to feel paranoid.
I can make you schizophreniform.
And so that's a rational assignment of dopamine, the features of schizophrenia.
Schizophrenia is pretty ill-defined.
And I think all these words are going to start getting teased apart, now that we can record things in healthy people, that we can record things in sick people and that we're recording these transmitters in people that have these actual disorders.
This person is curious about the serotonin to dopamine ratio in quitting decisions.
At what point does the neurochemical drive to persist what they're thinking of as dopamine pursuit become pathological against the valuation signal that says this isn't working?
In other words, what's the line between grit and sunk cost fallacy?
They want a lot answered in this one.
That's a great question.
I think it leaves out something that we really don't know much about, which is for these neurotransmitters to be released more or less.
You have to set expectations.
We know very little about how expectations for now are being set and being updated from state to state to state.
And that controls the fluctuations as much as anything.
And so the representations in your brain of how they're held or gotten from memory, how they control brain states and stuff that's not understood very well at all.
That's what AI is going to help us do in the next 20 years.
I love that.
I really appreciate your answer.
And guess what?
Grok AI jumped in and answered as well.
So we can see what Grok said.
It answered what?
That question?
Yeah.
So these people are asking questions.
So he has Grok running over all the... Grok just jumped in and answered.
This person didn't say, oh, no, sorry, they tagged Grok.
So Grok jumped in and answered.
I see, right.
If you ask a question on action, you tag Grok.
So I'll tell you what Grok said.
Great question.
Research shows that dopamine drives persistence grit by reinforcing effort and reward anticipation.
But high levels can trap us in sunk cost fallacies, ignoring when to quit.
Serotonin helps balance by signaling outcome valuation.
Low ratios may tip toward unhealthy persistence.
Studies, and they cite a study, link dopamine surges to overvaluing sunk efforts.
Worth exploring with the expert.
Big exclamation mark.
You.
That's funny.
Wild, right?
Yeah.
How did Grok do?
Grok did well if the brain is only a chemical machine.
Grok left off the fact that it's an electrochemical machine and that the electrical activity in the networks set things like expectations, which defines when the release is happening or not.
And so that's half the book.
What's the one thing about dopamine the public seems to always misunderstand?
Dopamine equals pleasure.
Is not true.
Is not true.
Yeah.
What's the one thing about serotonin the public always seems to misunderstand?
You know, I take drugs to increase my serotonin when I'm depressed.
What they don't understand is that those drugs are really heterogeneous, often pathological and, you know, across decades toxic.
So it's an unfortunate.
We're in an unfortunate moment there to reconfigure those, that kind of treatment.
I bet you – because I know people who swear by SSRI use.
I mean just – it transformed their life and they don't – the side effects are nominal.
It would be great to be able to identify them ahead of time the candidates for whom that would work.
A lot of this is a placebo effect.
Psychotropic meds when you have a good outcome.
Variable 50 to 80 is a placebo effect, meaning not explained by any – you can't explain the variance by anything.
But that doesn't mean it's a fake effect.
Your expectations are set by that.
Like if you believe something is going to happen.
We have very poor understanding of really how your belief that something is happening in your brain actually marshals it.
This question, I am tempted to relate to meditation, but let's see what you say.
How do dopamine responses change when you remove external rewards and rely purely on internal satisfaction?
So I think of an example like meditation, like where you're not.
Maybe you're not telling people I'm meditating to get praise, but just going into a state.
Or maybe drawing as you like drawing you're never going to show your drawings, or Is there any idea of what happens when the?
No, there's not, but it would be fantastic to measure that.
That's a fantastic question.
To what degree can you, when cut off from the world, let's say in a sensory deprivation tank, generate internal states that you chase and generate dopamine signals in that context?
That's why I mentioned these not yet published measurement schemes.
Well, I'm telling Oliver from the UK, no info, but he said yours is a superb question.
And guess what?
That's a lot of external validation.
So it kind of runs counter current to the question, but right on Oliver.
I don't know you Oliver, but it's interesting, many people are asking that same question.
What has a greater influence on dopamine levels?
Exogenous or feedback or our psychological framework?
People are thinking about this a lot.
Well, they're linked.
A little bit – my simple answer betrayed itself in a way.
They're linked.
Your ability to generate a clear expectation and hold it in mind –
I guess we're talking about consciously here, right?
It's not really clear how good you are at that.
There are a lot of questions asking about how to create a capacity for persistent motivation under conditions where things aren't going well.
You talked earlier about running up a hill and puking as a self-training.
Friday nights after the football game.
On Fridays.
I just did it because I could.
Until you actually vomited?
Oh, yeah.
I mean, I don't know.
Snot and vomit.
I would go until I couldn't go anymore.
I didn't really lift weights in high school, but I would do... I copied the Russians.
I had books, Russian books, because Caucasian sprinters in the Olympics that won were only from the Eastern Bloc countries.
Mm-hmm.
Little did I know there were all these massive steroid campaigns.
But they did a lot of plyometrics and weight box jumps and stuff.
So I would put weight vest on and do it until I just threw up.
I worked out this morning.
I felt so nauseated.
I thought, oh, my God, I don't know.
Have you ever done like a mellow workout?
No.
Your face says it all.
It's my moment every day.
That's why I don't like to work out with anybody.
It's my moment.
Yeah, same.
Unless I'm working out with Dorian Yates.
Well.
You know, because he's going to go harder than I am.
You know, when I met DeLand, he was from DeLand, Florida, Arthur Jones.
I met him at a place in Sandy Springs, which is in Atlanta.
And at the same place, I used to work out with a guy called Isaac Hayes.
You ever heard of Isaac Hayes?
Sure.
Called him Black Moses.
Yeah.
He would have this giant gold thing around.
I was 12, and I could get in the Nautilus place and do a few things.
They would let me in.
He was the nicest guy to me, Isaac Hayes.
He just died not so long ago, right?
I recognize his name, and I can see his face.
Shaped head.
Yeah.
He wore dark shades and a giant gold chain around his thing.
So cool.
Yeah.
I mean the high intensity work that Arthur Jones encouraged, I think is the best way to stimulate hypertrophy and whatnot.
The super setting.
Oh, I'm sorry.
You had to carry a bucket there.
Oh.
Because people would throw up so much.
High rep, high intensity leg day, you can definitely puke.
A lot of questions about serotonin syndrome.
I get questions about this all the time.
People who feel like because of SSRIs, they are dealing with sexual side effects.
Ahedonia motivational issues.
What do you think the cause is?
Of all those things, those drugs are binding to all kinds of receptors is what's happening.
And there are all kinds of serotonin receptors.
Okay.
You know, there's not that many different dopamine.
They're probably, what, 80 serotonin receptors or something?
There's a great number of them.
And so there's just a field of dreams of way you can sort of have side effects.
Also, just the idea that you're on them is itself an effect.
I'm on a drug.
This is a drug to manipulate my mood state.
That has an effect on your mood state and the way you feel.
Thank you for answering those questions.
I want to say a couple things.
First of all, thank you for taking time out of your very busy family and work and workout to puke, often schedule.
Despite the fact that you don't sleep much, you are very busy and It's a really wonderful opportunity that so many people can learn about dopamine and serotonin and neuromodulator dynamics from somebody who really understands the science past, present and where it's going.
These are topics that many, many people hear about and think about, and it's super important that the conversation be up-to-date and nuanced, and you've done that for us today.
I realize it's far from complete, so we'll have to have you back.
Also, I just want to say thanks for being the pioneer that you've been and forging a path that, at least to my knowledge, no one else in neuroscience is tackling.
All the technical challenges, thinking about the AI and the computational stuff, putting people into scanners, putting wires up people's nose, putting wires into people's brains
From the time I met you 15 years ago, it was very, very clear that you have a goal of solving problems, the answers to particular questions, and that you're going to do whatever it takes to get those answers.
And that's just awesome.
It's the spirit of science at its best.
And we'll put links to your work.
And I know you've written some things and given some other talks, but I'm just so grateful.
I learned a ton today and I know everyone else has.
So you've done us all a tremendous service.
So thank you.
Oh, thanks for having me.
It's a blast.
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