Neuroscience Meets Psychology | Dr. Andrew Huberman | EP 296

Epinephrine, which is also adrenaline—those are the same thing—is literally manufactured from the molecule dopamine. If you look at the biochemical cascade, it is dopamine that is converted into adrenaline, which is the basis of all energy, all neural energy, and so including thinking. And so if one is not in a place of being able to set their goal on a particular lofty goal, a graduate degree, a book, etc., yet the way one gets to that is by completing things in their immediate environment from start to finish and closing the dopaminergic loop. Those are at least micro narratives, right? So they're not integrated across a long span of time, but they're not nothing.

And so one of the things—well, I did write about this in my first book, particularly about putting your life, putting your house in perfect order. It's like, well, if you're lost, one of the things you can do is look around and see what direction you could take locally is fix something.

I'm pleased today to have with me Dr. Andrew D. Huberman. He’s a neuroscientist and tenured associate professor in the Department of Neurobiology at the Stanford University School of Medicine. Dr. Huberman and his lab have made contributions to the brain development, brain plasticity, and neural regeneration and repair fields. His work and his lab's work focuses on the visual system, elucidating the nature of neural mechanisms controlling light-mediated activation of the circadian and autonomic arousal centers in the brain, and mediating conscious vision or sight.

His lab investigates how the brain works, how it changes through experience—it's a field known as plasticity—and how it repairs itself. He and his colleagues have worked to discover strategies for halting and reversing vision loss in blinding diseases and understanding how visual perceptions and autonomic arousal states are integrated to impact behavioral responses. His lab employs a large range of state-of-the-art investigative tools—virtual reality, gene therapy, anatomy, electrophysiology, and imaging—and behavioral analysis.

In January 2021, Dr. Huberman launched the Huberman Lab podcast, concentrating on neuroscience and other scientific topics. It’s done phenomenally well for a detailed scientific podcast, attracting 1.5 million subscribers. It’s very good to see you today, Dr. Huberman, and thank you for agreeing to talk with me.

I'm delighted to be here.

Your first book, "12 Rules for Life," sits prominently on our bookshelf in our living room, and we've all read it and learned a tremendous amount from you over the years. We certainly feel a kinship because of the shared relationship between university professorship and public education as well.

Right, right. Yeah, well, we’ve got lots in common. I’m particularly interested in the neurological work that you’ve done on both anxiety and exploration, although there’s plenty of topics to talk about today and plenty of overlapping interests. But it’s been a while since I’ve reviewed the neuroscience literature pertaining to both anxiety and exploration. So maybe we could start by you laying out what you’ve discovered and how you’re thinking about what you think anxiety signifies, how it’s related to exploratory behavior, which I think you described as something approximating courageous approach, although you were talking about mice in that particular paper, and what you think—what you’re thinking about with regards to the neural basis of these different behavioral responses, behavioral and emotional responses.

Sure, I’d be happy to. And she mentioned that these days my laboratory mainly focuses on humans. We still do some mouse work, but we, in partnership with people in psychiatry, are doing essentially equivalent experiments in humans. So I’d be happy to elaborate there. You know, many people perhaps, but not everyone, have heard of the autonomic nervous system, which simply means automatic. It’s a bit of a misnomer because, without going too much into the history of that, if you look back to the origins of medicine in the time of Galen and so forth, when they were first dissecting cadavers and whatnot, there was this idea of a nervous system—or a portion of the nervous system—that eventually came to be, that could control so-called vegetative functions, meaning the rate of digestion and the really, what neuroscientists typically think of as boring stuff. But it’s anything but boring; it’s the stuff that keeps you from urinating while you’re asleep, unless you’re a very young child, right?

And it’s the stuff that keeps your digestion going as you command your attention to other things. The autonomic nervous—it’s all the things that are too complex for us to think through. That’s right, and they are, as you point out, immensely complex. And, you know, nowadays, with all this interest in the microbiome and things of that sort, I mean, these are tremendously complicated operations that are happening generally below our conscious awareness, and that are indeed vegetative. They can be controlled by emotion; you know, we’re all familiar with the idea that when we are emotionally distraught, that our digestion can be different, etc.

But typically, we can’t control, for instance, in a conscious way, the rate of our digestive or the speed of our heartbeat in any kind of direct way. We can have a particular pattern of thought to control those, but in general, those functions were thought to be vegetative and outside of our conscious control. The name autonomic nervous system sort of swallowed and overtook the vegetative part, so it includes that but also three main aspects of body-to-brain signaling.

And those three aspects are heart rate, could be quickening or slowing of heart rate—we are, and we can be very aware of that, some of us more than others—gut, and the especially the chemical composition and the extent to which our gut is empty or full. So stump—so heart, stomach, and then rate of breathing and sort of depth of breathing, meaning how much air we have available to us. And I think the three main ways to think about the way that the brain and body communicate is that they – it’s either going to be mechanical or chemical.

Let’s use the gut as an example: your stomach can feel acidic, or it can feel nice and warm and fuzzy—or whatever that is in a chemical sense. Your heart rate can feel like it’s going at a rate that’s appropriate for your circumstances. You know, if you’re running, it could be quick, and if you’re sitting in a chair quietly at the doctor’s office waiting to be called back, there—and all of a sudden your heart starts racing—then you would think, “Well that’s appropriate for that situation,” but it’s uncomfortable, right? It’s out of sync with what you are doing, which is sitting.

So there’s mechanical information and then there’s chemical information. And with respect to your lungs, you know, you can feel like you’re out of air, or you have plenty of air. You can feel like your breathing is labored, or it’s easy, or, in the chemical sense, that the air that you’re breathing, your lungs are burning, or it feels easy to breathe. So basically, there’s chemical and mechanical signaling from the body to the brain. And the brain interprets all of that, and we put all of that under the umbrella of the so-called autonomic nervous system.

And the autonomic nervous system can really be best thought of along a continuum. And here I’ll avoid complicated nomenclature, but I’ll throw it out there for the aficionados; some people have probably heard of the parasympathetic and the sympathetic—that naming is a little bit misleading. Again, what we can really think about the autonomic nervous system as is a continuum, or more like a seesaw, of at one end is alertness and at the other end is calmness, right? That is translated to the so-called sympathetic and parasympathetic nervous systems, but I’ll call it the alertness and calmness systems, just for sake of simplicity.

So it’s sort of like a seesaw, and it has different neural circuits, and basically whether or not you feel very alert or panicked, or alert but calm, or a little bit of anxiety, that's going to depend on the balance between this alertness system and the calmness system. If you're having a full-blown panic attack, then the alertness system is, you know, it's as if the seesaw is tilted all that way. If you have, um, if you're deeply asleep, well, then the calmness system is really tilted down. You could say that’s a portion of the seesaw.

This is all kind of obvious, and it dates back, you know, 100 years or so, which isn’t that long in the history of science, but we’ve known this sort of thing for a while. Okay, what’s interesting, and I think more relevant nowadays, is to think about one’s own interpretation of those signals and how that relates to anxiety and, as you pointed out, exploration. And then to think about where the nodes of control are in this seesaw model that I’m putting forward.

The seesaw has to include what I would call a hinge, a location in the middle in which you can voluntarily adjust the seesaw to either be more tilted toward alert or more tilted toward asleep. And for many people, they find that their overall level of autonomic arousal is either inappropriate or inadequate for the demands of their life. Inappropriate meaning their heart is racing, they feel more jittery, more as if movement would be the default and worry would be the default, and preoccupation is the default than is appropriate for their circumstances.

Waking up in the morning and feeling stressed, for instance, immediately, without any immediate cause, or maybe stress about real-life events. For other people, they feel more exhausted than they would like; they're having a hard time leaning into the pressures of daily life. Both of those, even though they have sort of polarized phenotypes, they look very different— in one case over-energized and in one case under-energized—both originate within the autonomic nervous system. And we can reliably say from work done in animals and humans that that is not the consequence of the alertness system or the calmness system being disrupted, but rather that hinge in the middle is dysregulated.

And we now know what that hinge is, and this is based on work done by colleagues of mine at Stanford, in particular, a guy named David Spiegel, who's our associate chair of psychiatry. He’s done a lot of work, and actually, his father did a lot of work in the application of clinical hypnosis—not stage hypnosis, but clinical hypnosis—for the treatment of various things. But his work and some work in our laboratory now has shown that there’s an area of the brain that you are familiar with, Dr. Peterson, which is the prefrontal cortex, and in particular, the left dorsolateral prefrontal cortex, if you really want to get down in the weeds about it, that has direct communication with two brain areas that are absolutely critical for this issue of whether or not you feel right for your circumstances, whether or not you translate that into curiosity and exploration, or whether or not you translate it into this thing that we call anxiety.

And those two areas are called the anterior cingulate cortex. Again, I apologize for all the names, but the anterior cingulate cortex and the insula. And I think if I were to make a prediction about what the buzzword is going to be in popular neuroscience in the next five years, it’s not the amygdala, it’s not the prefrontal cortex, it’s the insula. The insula has a couple of different regions, but one of its primary regions, the front end, the anterior insula, is responsible for interpreting all those bodily signals. It essentially is a funnel for all those signals about breath rate, heart rate, conditions of the gut, um whether or not your body feels ready to move or exhausted, etc.

And that all funnels into the insula. And then also coming into the insula is information from classical areas like the amygdala, which are involved in threat detection and fear, and also emotion and memory. So the insula is really this incredible hub of information about somatic signals, about bodily signals, and then the prefrontal cortex, the dorsolateral cortex in particular, is in communication with the insula and literally makes a—that's right.

Let me ask you about that. So does that mean that the body in some senses is reporting to conscious awareness? Now, it reports unconsciously in all sorts of ways too, so it might report to the hypothalamus, which is a very low-level brain control area, by the way, for those of you who are listening. It might report to the hypothalamus primarily unconsciously. But do you think it’s the insula that’s reporting on the nature of bodily states to the prefrontal cortex in a manner that allows us to be consciously aware of our body states?

That’s exactly—that part of that integration system—that’s exactly right! You’re exactly right. The insula sits as a different sort of station in that it’s reporting to the conscious areas of the brain to the prefrontal cortex, right? So we can take them into—we can take our own physiological state into account then when we’re envisioning plans because part of what the dorsolateral prefrontal cortex does is allow us to envision different possible futures, and those are plans. And you’re not going to make a plan to run two or three blocks to get to the corner store if you’re so exhausted you can’t get out of bed.

And you need a reporting mechanism that tells you what physical state you’re in so that you can predicate your plans on that. Do you think the insula, at least in part, is responsible for formulating those representations or for reporting those representations?

That is exactly right! In fact, the animal data and the human data, both lesion data and reversible inactivation data support that in humans. So you have that exactly right. And, as you mentioned, the prefrontal cortex, you know, it gets sort of thrown out there for everything. I think, you know, nowadays, people have probably heard of the prefrontal cortex and people hear about executive function, which of course is true. But if we were to really dial back and say what is the prefrontal cortex in the position to do, it’s a flexible rule-setting structure.

How do we know that? Yet I’m sure you are probably more familiar than I am with the classic Stroop task. You know, you give somebody a bunch of cards with different words on them, and those words are written in different colors, and you tell the person, “Okay, just read the words to me; ignore the color that they’re written in and just read them.” And so they’re saying, “They’re cat, dog, shelf, book, professor, student,” etc. Then you quickly change the rules and you say, “You know what? Just tell me the color that the words are written in, but ignore what the words say.” And people will do that, but there’s a portion of time in which they have—they slow down a bit.

It’s actually hard because you’ve done a rule switch. Much of life, as you know—and again, this is more your domain than mine—is about applying different rules in different contexts. Now, what we know is that the insula and the prefrontal cortex are both intimately involved in this conversation that establishes which rules are appropriate for a given situation. So for instance, if somebody were to say something that “quote unquote triggers me,” okay, I’ll use myself as the example, right? Maybe somebody will tweet something, and I’ll think, “Ah, you know,” and I immediately want to respond in a way that I know I can kind of like flip them on their back immediately.

But then I think, “Ah, you know, maybe I want to refrain from that for a number of any number of different rules or reasons,” right? Well then I have to—I’m starting to apply different rules. I’m starting to think about the context that’s outside of the autonomic response because, in a strict, very animalistic way—in other words, in the absence of an insula and a prefrontal cortex conversation—really the only thing an animal or human needs to do is just respond to their arousal. You know, it’s either—you can either retreat, you can stay put, or you can fight, right? That’s really the only three major—those are very fast responses generally.

So let me ask you about the role of the prefrontal cortex in what you described as rule switching because I would like to know what you think about whether or not the prefrontal cortex is actually, let’s say, switching rules, or if it—that what it’s doing is switching context-sensitive behavioral patterns that when we talk about, we describe as rules.

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It is the critical question that you’re asking. The prefrontal cortex, in particular the left dorsolateral prefrontal cortex, is in an incredibly unique position to not only establish different rules depending on context, and the way it does that is by accessing memory. So the hippocampus has access to the frontal cortex and vice versa. It’s almost always a reciprocal conversation, so it can pull memory, thinking, “Oh, you know, the last time I responded like that didn’t get me the result I wanted,” or “The last time I responded in this other way, I got the result I wanted.”

Again, regardless of situation, the other thing that the left dorsolateral prefrontal cortex is exquisitely positioned to do—and this is the beautiful work of a colleague of mine by the name of Nolan Williams, also in Psychiatry—is, because of its connections to some structures that then feed into the vagus nerve, it actually can slow the heart rate down.

So in other words, let’s say someone says something and your immediate impulse is to fight or to respond in a knee-jerk way. If you halt, right? I guess what the meditators and the mindfulness folks would call “the gap,” or if you can access some memory and think, “Ah,” and you might be thinking, “You know, actually, there’s a much better way to place the dart if I just kind of lean back a little bit,” or it could be, you know, silence might be the best response, right?

Or it could be that you’re going to carefully access some data from your hippocampus to respond in a way that is most effective. For instance, here I’m talking about confrontation, but it could be any situation. The left dorsolateral prefrontal cortex does two things: as it acquires a new rule set or starts to access information about a new or possible rule set, it also sends a parallel signal to slow the heart down through the vagus nerve. And that is, I think, one of the more important and fascinating discoveries in the last five years.

Those aren’t data from my laboratory; I wish they were. But it’s very clear that when we start accessing alternate rule sets, there’s a signal that quiets the body in some ways. And it positions. Is that partly how you calm yourself down?

That’s right, it is how you calm yourself down. And again, you have the clinical background, not I, but I’ll confess I’ve been in therapy enough to know that occasionally, you know, one feels as if you’re accessing some piece of info—as the patient side I can only report from the patient side, you know—accessing some what feels like important piece of information. You’re pulling on a thread of some sort, but then the therapist will say something, and it literally gives you that alternate view.

And this notion of looking at things through a different perspective—we often think about that as a switch in our cognitive frame, in our thinking, but also we now know there’s this parallel signal that’s sent to the body in which—in order to access these alternate rule sets, new ways of looking at things, there’s a calming signal literally sent to the body as well.

And I find this conversation fascinating because normally we just think about anxiety and exploration and rule setting and rule responses or responses to rules, etc., as a kind of the body send signals and the brain does all this. What neuroscientists have always talked about is top-down processing, right? Just sort of suppress the hypothalamus, control the limbic system, right? And that’s true to some extent, but there’s also—it’s clear there are signals being sent to the body in parallel.

And rather than looking at the signals more like conducting than suppressing. Exactly, like conducting, like an orchestra conductor. Exactly!

And there’s a very interesting phenomenon that takes place in people that have chronic anxiety or for people who essentially stop accessing alternate rules and responses to these signals. And this is, I think, what is showing up in chronic anxiety, certainly in certain forms of depression, and when people enter states of rage and dysregulation is that normally we know based on neuroimaging that the prefrontal cortex is essentially leading the response of this anterior cingulate cortex in the insula. So information is coming up from the body into the insula, and then being fed to the prefrontal cortex. But then the prefrontal cortex is actually in a position to lead responses, and it essentially is acting like the coach of a team.

And the team is all these structures like the ACC and the anterior cingular cortex and the insula, the heart rate, and so forth. What happens in individuals who have chronic anxiety or damage to the prefrontal cortex or dysregulation of these circuitries is that that order actually reverses. The insula and ACC start leading and directing the response of the prefrontal cortex. And I think, you know, we see this in—I'm sure you've seen this clinically—in individuals.

And, um, while this isn’t necessarily a discussion about society at large, I mean, we see this in dysregulated arguments and dysregulated combat where people are essentially losing themselves, and they default to one what appears to be a very primitive rule set. And it may or may not be the appropriate one, but as you and I, of course, have the good fortune of knowing a number of people who've worked in special operations and things like that, and you talk to any of those individuals, and they know from experience and from training that their ability to access multiple rule sets and options in the moments of extreme autonomic arousal is actually where their power lies.

Right. It’s the—or a combat fighter or let’s just take—or a debate, something that you’re far more versed in than I am, although I guess every academic has to deal with a bit of that coming up, the thesis defense, etc. In a really good debate, you can’t allow the autonomic response to overtake you, or you lose access to an enormous database that resides in your—one’s hippocampus, and you essentially one then defaults to the bodily state, right? And this is what we see when we see people become dysregulated in rage, etc.

So if we were to zoom out and then ask, you know, where is the line between exploration and anxiety? I think that we can check off a few boxes for sure. First of all, that autonomic arousal—this tendency to be more alert or more in action than in non-action—is a very healthy response. I mean, at the moment adrenaline is released from the adrenals and, as you know, there’s a parallel signal in the brain; you know, you get adrenaline released from the adrenals if you get in a cold shower, or somebody says something triggering, or you are afraid of heights or something, but the brain has its own kind of adrenaline system, which is this structure in the back of the brain called locus ceruleus, and it essentially has a—it essentially sprinkles the entire brain with noradrenaline and adrenaline.

It’s a very interesting system; it lacks specificity. It basically wakes up the whole brain. If I were to put a little, um, if I were to label the connections of the locus ceruleus, it’s basically connected to everything. It just kind of sprinkles a caffeine-like substance on the entire brain, wakes you up, the adrenals in the body wake up the body. So two parallel systems wake us up.

Is that associated with the orienting reflex?

Yes, if you orient, is the locus ceruleus wake up the brain? Absolutely, yeah.

So it’s a key component of the so-called reticular activating system.

Right, and incidentally, I should mention this because I was going to come to this later, but I think it’s relevant now. If somebody has a lesion in their dorsolateral prefrontal cortex, or if you transiently inactivate it with a technology, a non-invasive technology like transcranial magnetic stimulation, they can now just put a magnet on outside the skull and quiet that area of the brain transiently—in animals or humans.

What you find is that that person or human becomes incredibly accurate at any motor task. So for instance, if I were to give you a shooter game where you’re supposed to shoot targets, and I—and you’re shooting targets, you’ll have some hits and some misses, like anybody. If I inactivate your dorsolateral prefrontal cortex, your accuracy goes through the roof. It’s near 100, but the one thing you can’t do is decide whether or not you’re shooting an enemy or a friend. So you can no longer establish rules; you just become very good at execution of the motor behavior.

Similarly, in an animal or person without a dorsolateral prefrontal cortex, you see a trade-off there, right? Between specificity and flexibility, that’s right. And so we see this theme over and over again where—as a purely, you know, sensory-motor response machine, the prefrontal cortex isn’t even necessary. In fact, if you get rid of it entirely, people become like machines.

If I click over here, somebody has no prefrontal cortex, basically everything becomes a stimulus, a puppy. Everything’s a stimulus. You know, I used to have a bulldog when he was a puppy, you had to worry about leaving cords out and everything went into his mouth. By the time he was, you know, a year old, in part because he was a bulldog, he just kind of laid there, like you could put a toy in front of him, and he wasn’t into playing, and just leave it alone. A baby, everything’s a stimulus. Many adults become infant-like in their responses, right?

When anxiety is high, in fact, I have a friend who’s a psychologist tell me, do you agree with this statement or not, that anxiety makes children of us all?

I don’t know if that’s true or not, but certainly, it’s been my experience that when feeling anxious—I don’t struggle with chronic anxiety, but I certainly have felt anxiety. Well, it simplifies us. I mean, all these underlying emotions and motivational states, these primordial instincts are simplification mechanisms. And so if we’re unable to compute a complex and sophisticated pathway forward that takes multiple variables into account simultaneously, we can’t just do nothing; we’re going to default to a more primordial and direct state.

And then you might say the whole panoply of emotions and motivations lies there at the weight for us to grip our behavior. If we’re—what would you say if we’re paralyzed by inability to choose between multiple options? If so, we do—to the degree that we’re simplified by an emotion, then we’re reduced to something more approximating an infantile state.

If you watch two-year-olds—and two-year-olds are particularly interesting in this regard—they basically just cycle through innate motivational states. It makes them really interesting to be around because when they’re interested in something, they’re 100 percent interested in it. And then when they’re angry, they’re 100 percent angry. And if they’re anxious, they’re 100 percent anxious. And if they’re tired, they just instantly fall into a coma. And they just cycle through these, with no overarching centralized integration.

And it’s partly because they likely don’t really manifest any integrating prefrontal cortical capacity until they hit about three, where they can start to engage in joint play states with other children, right? And then they can exercise; then they can modulate their underlying emotions in accordance with an abstract representation or goal sometimes that’s jointly shared.

That’s part of developing sophistication. It’s also why the idea that identity is subjectively defined is absolutely preposterous. It’s like it’s subjectively defined for two-year-olds, but it’s not subjectively defined for anyone who’s sophisticated enough to negotiate with someone else.

And so tell me about—tell me what you think about this. My understanding of the prefrontal cortex is that over the course of evolutionary time, it grew out of the frontal cortex and that out of the motor cortex, more specifically. And so the best way to think about what the prefrontal cortex does in some sense is that it generates potential abstract patterns of action. It generates them in abstraction so that they can be assessed before they’re implemented, and so it’s like it’s generating potential future selves.

That’s exactly right! You see? That’s okay; that’s exactly right. And—and I’m glad you stated it, not I, because you say that far more clearly and succinctly than I’ve heard it stated before. It’s as if it’s running, you know, running plays—I’m using a sports analogy—it’s running plays and thinking about potential outcomes. You know, I’m not a chess player, although, you know, Lex Friedman’s podcast and Lex Friedman are convincing me that perhaps I should learn because there’s a lot of discussion about chess nowadays, and there’s a lot of thinking, as I understand, about potential outcomes. You know how many moves can you anticipate; if this, then that—it’s sort of if this, then that thinking.

And if you think about its connectivity, it’s in a beautiful position based on its access to priors through the hippocampus. So memory, it can take into account current state, bodily state, it can access information, for instance, about do I have the energy? Do I have the resources to undergo a particular pattern of response? And that’s through the insula and the ACC. And then the dorsolateral prefrontal cortex, in this way of also being able to control the body, of being able to calm the body—this is a very unique pathway because typically we think of the heart rate going up if we’re excited or scared and heart rate going down if we’re calm.

But really, the default of the neural inputs to the heart and to the breathing systems, etc., are to be very activated. And then the brain provides a suppressive or kind of a braking on that entire—the vagus nerve, right? So it’s a default-on system?

It’s a default-on system. And the vagus nerve, which of course is a massive nerve pathway, again, it makes it sound like one little nerve, but it’s this huge superhighway of connections between brain and body, is classified in medical school as a parasympathetic pathway, meaning of the calming system, it kind of generically speaking—and indeed it is.

And so that the prefrontal cortex, we can think of as, remember, in the seesaw analogy, the hinge. The prefrontal cortex is more or less like the screwdriver that tightens that hinge, essentially makes sure that the seesaw stays at a level at a tilt that’s appropriate for whatever it is that you happen to be doing.

Okay, now I presume—I personally imagine, so to continue the evolutionary analogy—an animal that doesn’t have a lot of behavioral flexibility, generally its reproduction strategy is multiple copies of itself. Maybe hundreds, maybe thousands. And the reason for that is all the variability in the animal’s behavior is genetically coded. And so for it to adapt to the transforming horizon of the future, it has to produce multiple variants of itself, most of which die. With mosquitoes, for example, they produce thousands of eggs, and if they all lived, we’d be knee-deep in mosquitoes in like 10 years. But they almost all of them die because they’re not matched to the transformation that’s coming down the pipeline.

But with human beings, what we seem to have done is evolved a mechanism for manufacturing artificial selves in this game-like manner. And so we can put forward optional selves in abstraction and then kill them off when they’re not necessary without us dying.

And so the famous quote, I think it was Alfred North Whitehead, was that the purpose of thought was to let our thoughts die instead of us.

I love that, and it really makes us unique.

Yeah, it’s great! It’s absolutely great. And so—and that seems to me, too— you tell me what you think about this. Is that the abstracted artificial selves or avatars, in some sense, that the prefrontal cortex generates or that it allows these underlying motivational and emotional systems to generate? Because they can generate simple avatars by themselves, I think when we describe those, we’re describing—we’re telling stories.

When we describe one of these alternative modes of action, that’s precisely it. It’s the verbal description of that as a story! That’s right! You know, and you make a very important point, which is that the prefrontal cortex is a rule-changing, um, alternate self-accessing machine that can also calm the body, and here I’m making up a gesso story because, as I always say, I wasn’t consulted at the design phase, and so I don’t know why it’s set up this way—I just know that it is set up this way.

One reason to suppress the somatic response, the bodily response, is that it tends to be a unitary interpretation, meaning at this moment I feel alert but calm, so I feel good. But I’m guessing there’s a lot of signals coming from the body, and in fact, there are— to my brain—but I tend to just say, “I feel pretty good.” In fact, I’m very delighted to be here, so I feel good. Or if I’m very tired, I feel tired. Those tend to be very kind of binned responses, and they’re fairly generic.

Whereas your description of what the prefrontal cortex does, which is an accurate one, I should say, of imagining different selves and different outcomes almost requires that we suppress how we feel in our body in the moment. You know, I guess we can look to some of our podcasting colleagues like the Jocko Willinks or the David Goggins, you know, who are either forcing themselves or are somehow up at 4:30 in the morning and train, pushing through that what I call limbic friction.

You know, the limbic system is saying I’m tired or I’m anxious and, you know, going against that. So there’s literally a—there’s a required suppression of the bodily response in order to imagine how we would feel when we complete this, or how terrible we would—how much of that—how much of that? So let’s parse that into two parts because you can imagine there’s an inhibitory component where you’re directly in competition with an underlying urge.

So the top-down story is, so for example, if you’re responding to something in an irritable way that’s been directed to you on Twitter, there’s going to be a limbic rage response that’s associated with that, which you can then suppress. But then the question there that’s quite complex, I would say, is something like, to what degree do you think you’re directly suppressing that with the prefrontal cortex and to what degree do you think you’re spinning up an alternative self that, if embodied, wouldn’t require that physiological response, and so you’re switching to a new identity in which that limbic response is no longer germane?

Yeah, and so the reason that it disappears is not because you directly suppress it in an inhibitory manner, but because you replace what’s necessary physiologically, given your new understanding of the territory that you inhabit.

I think it’s some of both, but I’ve never been able to really wrestle that through.

Yeah, I think what you’re getting to is what we know is that the prefrontal cortex and its associated networks contain a near-infinite, if not infinite set of possibilities, right? I mean, of course, it’s bottlenecked by experience, and it’s bottlenecked by one’s imagination, but you know, the number of different possible selves that one could imagine is near-infinite if one were to spend time on it. Whereas the number of different bodily states that one can have are actually very finite.

And if you think about the autonomic nervous system—and in my laboratory, we’ve studied this typically in the context of fear and confrontation—that the simplest way to put this in a kind of a, um, in a kind of pop neuroscience way would be to say, you know, we can either be back on our heels, meaning retreating, or we can be flat-footed, sort of calm in our stance, or we can be forward center of mass. We can be in sort of pursuit and or competition. There really aren’t other motor responses for an animal, including humans, right? You can either stay put, right back up, or go forward.

You know, and this is—yeah, well, it’s useful for people to know that that’s the basic platform upon which emotions are erected, too, is that emotions are like signals of those action tendencies, and they are very simple. It’s back up, get away, stop, or move forward. And so generally, we associate positive emotion with forward movement, and that would be positive emotion that’s dopaminergically mediated fundamentally, right? And then the halting would be—well, it can be calmness because there’s nothing to do, but it can also be the paralysis that fear induces, and then panic and retreat are more; they’re sort of on the border between anxiety and pain, I suppose—pain responses.

Yeah, exactly right. It’s complicated in—yeah, yeah. So these three major categories are, I think, encompass most if not all of the possible responses. As you said, and probably form the base set for all emotions, I mean, my laboratory studied this mainly in the context of fear and confrontation, and one of the reasons we started to explore this was the following: you know, we’ve all heard a fight-or-flight or rest-and-digest, right? Those correspond to the alertness system and the calmness system of the autonomic nervous system in their kind of extreme forms.

But what we observed in animals and then now in human studies that we published about a year ago is that when people are confronted with an anxiety-provoking scenario—in our case, we do this with virtual reality because we need to do it in the laboratory—we find their pain point. Essentially, and by pain point, I don’t mean extreme fear; I mean the thing that can raise their autonomic arousal that has them in a mode of considering different options and trying to figure out what is strategic and what they’re capable of in that moment. It could be heights; it could be confrontation with a predator animal; it varies by person, do people. But everyone has their pain point.

What they do in response to that pain point is really what’s interesting, and what we found was that the pause or freeze response certainly was associated with autonomic arousal, with stress and anxiety. We measure this in the brain and body, but it was the lowest anxiety response. People always think of panic, you know, just being paralyzed in panic—that’s actually the lowest anxiety response. Retreat was the next level up in terms of levels of heart rate change and levels of change within the insula, of all places, we actually recorded from human insula through a partnership with neurosurgeons.

And then we found that there were subsets of individuals and animals—parallel animal work—that would confront a fear, not necessarily reflexively, but after some consideration, they would lean into the challenge, essentially confront the thing that was making them feel anxious. And it turned out that that response, surprisingly, was associated with the highest levels of autonomic arousal in this game, right?

So but that would be—that would be heart rate activation, particularly heart rate activation and heart rate activation, and a change in what’s called the so-called gamma wave activity in the insula. We had electrodes in the insula, and what we found was that people who were willing to lean into that challenge—their insula took on essentially a change in its activity patterns, this gamma pattern, the heart rate increased, breathing increased, sweating increased.

So these are all the marks of an anxiety attack. But here, if you were to just look at the behavior of the person or the animal, what you’d find is that they were marching forward toward their fear. This is the—you know, and so then that’s voluntary exploration, right?

So now you did an animal study with mice where you showed, if I remember correctly, that the mice that were showing tail flicking, which was a prodrome to that exploratory activity, showed a particular form of brain activity that, if you replicated with stimulation, was more potently reinforcing than sexual stimulation, right?

So here’s where the surprise came— the additional surprise came in. We thought, “Okay, wow! Well, there are animals—these mice will tail flick in response to a threat, which is essentially saying, come on, let’s go, let’s fight.” Whereas other animals would retreat, and that tail flicking—a parallel within the human studies with people being confronted with—for someone who’s scared of heights, to go through a virtual reality scenario of being up on a high beam between buildings might not sound like a big deal to the average video gamer or to you and me, but is an absolutely terrifying experience for those people. But a subset of them will just march out onto that platform where we’ll even explore jumping off the platform with the understanding that it’s not—that it’s virtual and get very scared, but they will do it, and they also show these changes in insula activity and changes in heart rate and breathing.

What was interesting to us was the mouse data told us that if you stimulate the brain area that was associated with all of this—it’s an area of the midline thalamus; I don’t get down into details of structures too much, but it was a very mysterious area that had not been explored much before, had this incredible name of nucleus reunions—why, I don’t know. The neuroanatomists name these things in peculiar ways, as you know— but if we were to stimulate that brain area in mice, we could convert a terrified, non-confrontational mouse into a mouse that was willing to confront its fears in a healthy and adaptive way. It wasn’t being foolishly running into the jaws of a predator; it was being very strategic in its confrontation.

The interesting thing was if we introduced no fear stimulus, no heights, no predator, no nothing, and we just tickle this brain area, what we found is that animals and humans love that feeling. In fact, they will work for that feeling more than they will work for other stimulation.

And how do—okay, so a bunch—I’ve got a bunch of questions about that. So the first is, how do you think that’s related to hypothalamic dopaminergic release in exploratory states and the psychomotor-stimulating effects of drugs like cocaine and amphetamine?

And then second, if you put someone in a chronic state of activating that brain area, say you did that by teaching them to approach their fears rather than to run from them, would that produce epigenetic changes that would transform them physiologically?

Okay, so both very important questions. First of all, the dopamine system is absolutely critical here. In the animal studies, we identified, because we could place tracers in the brain and measure connections, that indeed this brain area in the midline thalamus connects directly to the major hubs of dopamine release in the brain. They have names like nucleus accumbens, okay, et cetera, ventral tegmental area, right? So that was great because it confirmed for us that—so it is tapping the primary approach-related positive reward system.

That’s right, but it’s a very—it’s a very major nucleus that allows that to happen, particularly in the face of voluntary approach to feared stimuli. That’s exactly right. And you know, one thing about the dopamine system that’s so important, and also explains a lot of pathology, but also a lot of human evolution is that we have basically one major reward system, which is the dopaminergic system. You know, I sometimes like the analogy that, you know, nowadays you hear about cryptocurrency or the dollar versus the euro versus the this versus that—there’s only one currency in all of reality, actually, and that’s dopamine.

Whether or not it’s the dollar back to dopamine or it’s euro back to dopamine or bitcoin back to dopamine, in the end, whether or not someone has a billion dollars or two dollars is really—that currency resides as something that’s transacted in the real world, but their notion of power and potential is dopaminergic. And so too, the potential for mates, the potential for food—how much food you have, you know, how much meat you have stored in the freezer tells you a lot about your security and well-being for you and your family, right? And that is translated into a dopaminergic internal representation of how safe and secure you are, etc.

So this system of fear versus confrontation taps directly into the dopaminergic system. And there are beautiful sets of studies that were done in the 1960s, published in the journal Science, as you know, one of the top journals to publish in. Again, this is not work that I did, but where they gave people—human beings—the option to stimulate a number of different brain areas just sitting in the clinic.

And some brain areas would evoke feelings of drunkenness; others would evoke feelings of anger; others of sadness; others of sexual arousal. And the area that these subjects all preferred to stimulate the most—in fact, they would just sit there and lever press pretty much all day long—was this midline thalamus area. And the subjective feeling that they reported, I find this interesting and would love your thoughts on this, is one of mild frustration, anticipation of something—although they didn’t know what, anticipate.

And it’s this idea, I think, that it’s tapping into the dopamine system. And the dopamine system says something good is going to happen. That’s right! The key. So something good is going to happen. That’s right, and it’s an appetitive state in some sense. Because it doesn’t signify the acquisition of—it’s not satiating; it’s repetitious.

That’s right! And so it drives you forward, and you might think that being driven forward would be unpleasant, but if you’re, in some sense, if you’re activating the systems that drive you forward voluntarily, then that’s the most positive form of positive reinforcement you can have.

I think—I read animal researchers who said that when they watched animals who were bar-pressing to receive stimulation in those brain areas, the animals would look forward as if something was about to appear that they wanted to have appear. Incredible!

So that was part of that apprehension. Part of it says it’s a hope system in some sense. It’s the elicitation of hope. That’s right. You know, it’s dopamine—and here I’m robbing words from others, like my colleague Anna Lemke, who you know.

It’s not about having; it’s about wanting. It’s not about pleasure as much as it is about craving and motivation and drive and something critical about the banks—have called it seeking.

Yeah, brilliant! Brilliant! I never met Panksepp, did you?

I did! You ever met Jack?

I met him online. We were in a—we were in a neurological chat room, so to speak, for a neuropsychological chat room for about five years and I had a chance to interact with him a fair bit in that, so that was really good.

Envious! He just—he’s done beautiful work! And thank you for calling people’s attention to his work; I know you've done that many times. It’s such a key work.

The dopamine system is in touch with the autonomic system, sure, because it has to register success versus failure of some pursuit. That prefrontal cortex is actually part of the dopamine reward system.

People often overlook this, and we just think about nucleus accumbens and the ventral tegmental area, but the prefrontal cortex, because, as you pointed out before, it is generating possible outcomes—different rules, different selves are being projected into the future. You can think that the two-marshmallow tasks—the classic, you know—give kids the option to either have a marshmallow now or wait and have two marshmallows—and the cute little videos of the kids, you know, in the room with the marshmallows, sniffing it, talking to it.

Occasionally, a kid will just stuff it in his mouth. Another child will turn away, you know, delightful! Right? And all sorts of ideas have come about about how they do in life versus if they can wait or not wait.

In any case, that’s dopaminergic anticipation. The key thing with dopamine, I think that encapsulates the most of it, is this notion of reward prediction error, which is very simple. If you are excited and anticipating something, you are generating some internal sense of the probability of it happening.

We’re going to the ice cream store, kids! Let’s go; we’re gonna have ice cream! We have ice cream; it’s closed! The disappointment that they experience actually brings them far lower than they would feel—much more sad than they would feel than had you not told them you were going to get ice cream!

Which speaks exactly to what you were saying, that it’s an anticipation signal. So dopamine’s going up, up; we’re going to get ice cream and then no! So it drops below baseline.

They would have been better off being not told they were going to the ice cream store, just drive right by.

Way the danger of hope.

The danger of hope! If you anticipate that it’s going to be open, and again, this could translate to any scenario, and it’s open, there’s a dopaminergic signal upon receiving the reward, but it then drops a little bit; this is the basis of addiction, actually—drops a little bit below baseline transiently.

So we always think of the ice cream as the reward. Well, actually, the reward was right before you had that first lick of ice cream because, you know, you’re gonna get it!

This is also true of sexual behavior; it’s true of people who sell a company or they’re anticipating something exciting, or of a wedding. It’s this whole—it also sort of partially explains this notion of postpartum depression, where people are so excited about something, the delivery of a child or something in the arrival, and then for some reason they feel let down.

It’s because the anticipation was that great. So many scenarios—it might be an exhaustion component there too.

Well, it’s also the case, if I remember correctly, that that dopamine kick—so imagine what it does is backtrack the neural systems that were activated as the reward was approached. So then it feeds back reinforcement, not reward, but meditates cellular growth and maybe myelination.

It’s increasing the efficiency of the neural connections of the systems that were activated just prior to receiving that reward in the order they were prioritized— in the order they were manifested.

So the closer the behavior is to the receipt of the reward, the more it’s reinforced and more likely to be manifested in the future, and then there’s a decay function going back in time.

And so— and that’s partly how an addictive sub-personality can grow, too, right? Because you can imagine that there’s a certain state of mind that you’re in, maybe it’s a state of something approximating nihilistic hopelessness that grips you.

Every time you’re motivated to seek out your favorite drug, and that’s fairly far back in the activation chain, but it’s there every time you take a hit. So what happens is the dopaminergic reinforcement produced by the drug reinforces that nihilistic hopelessness that drives the drug-seeking behavior, and that's how, in part, you develop a monkey on your back, yeah.

I love the example, even though I am sad that it happens for people. I love the example because what you’re saying is that—and it’s exactly right—that the memory for events and states of mind and emotions that preceded a successful collection of reward or arrival at reward is set into a huge number of motor commands, some of which are subconscious.

And the ultimate dopamine signal actually—I experienced this the other day; I can give an example. My girlfriend and I decided to go to the beach. We were gonna go do this little ritual that we’ve been talking about doing for a while. And I had on a piece of paper what we had written out; we were going to do, and I had it in my back pocket.

And we got to the ocean and the sun was setting, sort of perfect timing for this, and the piece of paper was gone! And I thought, “Oh my goodness, how did I screw this up? Like, of all the things, you know, I’m supposed to— you know, I’ve been—I’m 47 years old; I should be able to do this, you know, that I blew it.”

Yeah, I blew it! So I went back to the car, long walk looking everywhere; it was not in the windy day, but I thought, “Gosh, where’s this piece of paper?” Looking around—didn’t find it. All the way back to the car, wasn’t in the car, came all the way back, and I was walking toward her; I saw her, and I thought, “Okay, this is really embarrassing. I’m gonna just have to wing it or remember. We didn't have our phones intentionally either, so we couldn’t look it up.”

And then I saw the piece of paper on the beach, and it was partially buried in the sand. I picked it up, and I was elated. What happened there was my dopamine had dropped way below baseline because I was disappointed that I’d lost it, disappointed in myself, etc.

And then I found it!

Right, and so your anticipation was for nothing!

Exactly! So you got punished by yourself for that!

Exactly! Because that should be eradicated if you’re highly anticipatory, and it doesn’t make itself manifest, then you were seriously wrong! So you’re going to take an emotional hit as a consequence of that.

I think that’s also associated—that emotional hit, that pain that you feel, I think that’s actually associated with the beginning stages of the death of the systems that mediated that initial response. Because you should eradicate systems that make you anticipate that don’t work, right?

And that means those systems, which are already instantiated and alive, in some sense, have to decay and die. And it strikes me as highly probable that you’re going to pay a price in something approximating pain for the death of those malfunctioning systems.

That’s also why—because why wouldn’t they fight for their lives to some degree? Why wouldn’t they resist the decay and death that might be necessary to keep you going?

Why there should be some pain associated with that, logically, because it is a biological transformation.

Yeah, it’s an interesting way to lend to view it through that self-image that I had in that moment of, you know, “I’m a responsible partner who can take care of a simple thing,” right? “For this nice little ritual that we’ve been talking about doing for a while, I failed!”

Well, it’s also—so interesting, you think about that. This is a depressive cascade, eh? And it’s very hard to bind because imagine you anticipate something, and then you make a mistake. Now the question then becomes how significant is the mistake?

And one view of your error would be, “Well, the paper blew out of my pocket, and that could happen to anybody.” And the more catastrophic interpretation would be—and it’s an extension of the thought path that you started to walk down— “Well, I’m near 50 years old; I should be much more responsible than this? There's something wrong with me as a person.”

And then a depressive person would go even further; they’d say, “Well, not only is there something wrong with me in this decision—this is a decision like every other decision I make right now, I never make a good decision in the past, I’ve never made a good decision, and there’s no way I’m going to change in the future.”

And so they—the depressive takes that punishment response—let’s say—that’s a consequence of failed anticipation and can’t bind it. It just—it just takes out all of their potential future selves.

That’s a good way of thinking about it, yeah. And so then they’re in a depressive pit.

Yeah, it’s so—that’s too much learning from failure, right?

That’s it!

That's a—that's a—I’m really grateful for your insight on this because indeed, if I’m honest, that my thought train went to the point of, um, you know, I didn’t think, “Oh, I’m a total failure because I lost this piece of paper.” I thought to myself, “Well, you know, if it were a priority, I would have ensured I wouldn’t have lost it.”

Right, right!

Right? So the interpreter is not being a priority. Like, where are my priorities? Am I, you know, overspent? You know, what’s going on? You start to sift into the full set of questions.

And then, of course, finding the paper resurrects the sense of self.

It was, you know, I think it was in that movie Pulp Fiction, yeah.

Well, that binding problem is really tricky, eh? Because there are some good rules of thumb for that, which is one of the rules of thumb for that that’s extremely useful, that’s socially instantiated, is “innocent until proven guilty.”

That’s right!

And so you might say when those thoughts come up—because they’re adversarial and accusatory thoughts—you might say, “Well, that is part of the realm of possibility, but I shouldn’t…”

When your child does something wrong that’s minor, you don’t say you’re a rotten kid! Right? You say “You know, look kid, here’s a bunch of things you’re doing right, but in this particular example, here’s the minimal thing you did incorrectly and how to alter it.”

And it’s a really good habit of mind. It’s like to address towards yourself as well as to other people which is to say, “Well, what’s the minimum crime that I am responsible for in this moment?”

And that’s part of this miracle of the presumption of innocence; and especially without proof, a lot of what I did in my clinical practice to people who had a depressive temperament was help them make a case for themselves.

It’s like, “Well, maybe you’re as bad as you think you might be, but maybe not.” Let’s take the contrary argument. Let’s make you as innocent as you can be in this situation and only narrow the repair to the absolute minimum that needs to be manifested.

Now, some people don’t have that problem because they don’t have a depressive state of mind, let’s say. They’re somewhat resilient to the cascading effects of punishment. Those are people who are low in trait neuroticism, by the way—so you could think of trait neuroticism as an index to which the degree of failure co-activates punishment across a whole sequence of nested selves.

The more—the higher you are in neuroticism, the more likely a given error is to cascade up the hierarchy of possible selves. And it’s a trade-off because sometimes when you make one little mistake, it is actually an indicator of a flaw in your character, but most of the time, it isn’t, and it certainly can’t be responded to that all the time because then you’d never be able to make a mistake without wiping yourself completely out, and that’s obviously not helpful, is it?

Is it fair to say that, at least in the raising of children and maybe in the raising of ourselves, that we should, as much as possible, try and emphasize that errors are due to state, not trait?

You know, yes, absolutely! And you do that in an argument with your wife as well. You want to make it—you want to make it as local and precise as you possibly can.

So—and that’s also one of the advantages to removing yourself from a rage or an anxiety state because a rage or an anxiety state is low resolution and global, and so it’ll be globally accusatory.

And so you want to specify and think, “Okay, well, what’s the minimum necessary behavioral transformation to ensure that similar mistakes are not replicated in the future?”

And generally that doesn’t require like read— it’s like if your roof leaks, you don’t have to dig a new foundation. You can just fix a few shingles.

And you might think, “Well, the rain’s coming through, so you have to tear down the whole house.” It’s like, “Well no, you have to,” and you might panic and run around because the water’s coming in, but it’s still a bad idea to dig up the foundations every time some trivial maintenance problem needs to emerge.

And so one of the things that’s very useful to learn is like, “Well, is this only a trivial maintenance problem?”

And one of the advantages to that, too, is that if it’s not the collapse of your entire self, let’s say, and it’s a trivial maintenance problem, you’re much more able to activate that courageous response to anomaly that’s part and parcel of exploratory behavior and eventually success.

So—and part of the trick of many sorts of, I would say, religious training enterprises—certainly the meditative enterprises—is something like, how do you tell yourself a story, like a real story, though? A story that actually works? That’s most likely to put yourself, put yourself in a position where you can confidently approach the thing that’s blocking your path.

This notion, you brought up three points that I think immediately of, the related neurology, but I’m going to repeat them back to make sure I understand because they’re very salient in my mind right now, which is this notion of the prefrontal cortex trying different versions of self and working with, contending with bodily states in that—in those moments, and the sort of either death or, you know—or growth or resurrection of those different selves, depending on the outcomes, right?

The next—I find this notion of state or trait fascinating. You know, after I found that piece of paper, I felt like I was, like, the greatest, you know? I got this huge dopamine surge because it’s—it’s the delta—it’s the difference between your baseline and the people.

Yeah, right!

Yeah, right! So even though I lost it, right?

I mean, I should have thought, “Oh gosh, I wasted 30 minutes of our time,” but instead, I thought, “I found it! I found this amazing!”

And I felt so elated! I think there was a—it was the movie Pulp Fiction, I think it was the John Travolta character said something, I’m going to get this wrong, but you know he said, “It was almost worth losing that just to find it again.”

He was talking about something, I forget what it was, right? And I think that captured it there as well.

And then my question is, however, is, you know, we’ve been talking about if you lose something or if an outcome was not great, how that can fan out into a kind of an over-interpretation of trait and this kind of depressive neurotic interpretation.

What about the opposite, where certainly for every success that one has, you know, like for instance, if I had had not dropped this piece of paper, I wouldn’t have thought of it as a great success.

I would have just thought of it as what I was required to do in that moment, right?

It was sort of just “beauty,” right?

And I’m not somebody who celebrates with everything I check off my list. I, you know, sometimes, yes, there are bigger—bigger things than others, bigger achievements than others, but I can imagine that certain people might over-inflate their wins.

Manics!

Manics!

Exactly!

So while for a manic, every possible self is wonderful simultaneously, and so they’re completely fragmented, right? Because every possibility is 100 dopaminergically giving them a dopaminergic kick, and so it’s complete—it’s complete positive emotion catastrophe on the manic side.

So these systems, they have to exist in such tight balance, right? Because all of your potential positive selves are not to be regarded with exceptional enthusiasm; that’s a form of pathology! Even though, like, people don’t like being treated for mania often because especially going into a manic state is very enjoyable because it is associated with enthusiasm—and that’s all dopamine, dopamine-mediated positive emotion.

But there are problems with positive emotion, and one is, well—it needs to be judicious and differentiated; you shouldn’t be positive about everything, which is why you shouldn’t reward children indiscriminately. It has to be targeted.

And so when a system loses its focus and target its capacity to discriminate, then it becomes pathological, and people don’t often think of pathologies of positive emotion, but mania is definitely—that's definitely what it is.

And it makes people impulsive, too, and fragmented, even in their speech. Someone who's really manic is a different person every sentence.

That’s run-amok brain activity, and so it’s so interesting because—let’s peel that back even further. What does that mean in terms of functioning?

Well, let’s see. You could think, in some sense, that they’re hyper-engaged with the dopamine system to the exclusion of all else.

Sure!

Yeah, and to the great detriment of everything else. And part of that’s a function of disinhibition, right? Because what happens is they lose the ability to inhibit their own impulses.

And that’s what leads them further into the fractures, and it’s generally a crisis-driven state, in some sense—so I guess I’m asking, how does the prefrontal cortex inhabit that?

Yeah, so if we go back to the discussion we had earlier about the prefrontal cortex being put to the test of rule changing, it looks like it’s very responsive to the immediacy of the environment, right?

So if we take the analogy of a manic state, how does that work? And I think it’s very interesting because what’s happening is the very same systems that give us nuanced input about the future—what are the consequences of my actions?

What are the best actions to take in various circumstances? So that’s not happening in a manic state, and my sense would be that everything that comes into play is in some longer-range possibilities and the future doesn’t really exist in the manic moment—everything becomes very concrete.

And once you’re inside that con-creativity, you can’t get out!

Exactly! That’s it! You go inward; you lose track of all the things you should track.

Well, and you can even see that in a simplified way. When I’ve observed someone going manic, it was almost a self-fulfilling prophecy. Whenever that person was present, everyone would gravitate toward them and often do things on their behalf, which dynamically would signal to them, you’re so important in this social interaction.

And that might be true to some degree from an external perspective.

Ultimately, though, it’s based on false precepts.

Right!

And it always results in a major crash.

But you might say then we’re speaking about testosterone or confidence-building.

Absolutely!

So how depleting all this energy applies to both men and women are interesting because even being put in a state of focus can free you from this—what would you call it?

We might even call it a positive feedback loop, right?

Yeah, that’s the fair word!

So if we think of what we’ve been discussing about reward systems, I imagine, as you point out, those aforementioned states oftentimes reflect larger systems about variability, risks, opportunities—all which lie beyond us in some kind of ideal future realm.

So I really appreciate us going down this path to understand how the risk in the future is mediated by our ability to confront anxiety head on!

And so I think that if people were to look at these neurological and psychological processes, because we’re really talking about both, as algorithms, right? These are algorithms that have been used by every animal.

Think about the animal that’s foraging for food: they go down one path; they’re surprised; they find food. They go down another path; they’re sure—they are sure; and then they get nothing! Well, what happens? They learn to remember!

They—and automatically remember everything that led to that failure. And people are very good at remembering that, but be good at remembering the things that led to successes and then ride those neurochemical waves to the next node of exploration.

You’re talking about exploration vs. anxiety. You can also do this with people in your environment; you know, this is something B.F. Skinner pointed out when he was training animals. He said you can use threat and punishment to train animals, but he said the most effective mode of training isn’t that at all.

You use sustained attention and reward.

And so imagine that you’re training a route to climb up a ladder, rung by rung, and then do a little dance on the top and then climb down the other side.

So what Skinner would do—his animals were hungry, by the way—they were starved to 75 total percent of their body weight, so they were pretty dopaminergically motivated by the provision of any food. He would watch them wander around in the cage where a ladder was, let’s say, a little rap monkey bar apparatus.

And then when the rat would get near the last matter, he’d give the food pellet. So then it was soon spending a lot of time near the ladder and now and then while it was monkeying about, it would put one foot on the first rung, and it was like food pellet! And then it would soon be doing that.

And then sooner or later, it would put the next paw on, and he’d reward it. And so Skinner trained pigeons to pilot guided missiles by pecking on photos in relationship to the ground they were watching, right?

So spectacular! You could use reward in a number—so one of the things you can do in your local environment and with yourself as well is you can watch people around you, and you can see when they make small steps towards manifesting some behaviors you’d like to see a lot more of.

And then you can tell them in this very differentiated, discriminatory manner. You can say, “Hey, look, here’s the sequence of actions you just undertook. I saw that; I noted the process, and here’s the delightful outcome. Good work!”

And man, if you do that repeatedly to people around you, and you don’t want to do this in a fake or manipulative way, but if you’re attentive to what people are doing that’s good, and you mark that with a reward, man, you produce behavioral transformations at a rate that’s just beyond belief!

I love it! And everyone feels great about it too!

Yeah, it’s really a good habit, man! It’s in giving credit. We’re not separating the wheat from the chaff in the truest sense to give credit where credit is due!

Yeah, the behavior. And you can imagine you’re facilitating growth in the manner that you just described.

And maybe what neurological or genetic transformation we didn’t get to—the gene expression part yet!

Yeah, the behaviorists like Skinner were truly brilliant. And I think one experiment that I think is worth mentioning, which is kind of speaks to the power of dopamine and why it's so vital to tap into these systems, even through menial tasks, then to build on their self-amplifying mode so that you can take on bigger things in life, so to speak.

Positive goals—that there’s a classic experiment now that’s been done in humans and in animals, where you take two rats, separate cages, or you could do this with humans where their naturalistic conditions, where one of the rats or humans actually has their dopamine depleted.

In humans, this happens through Parkinsonian things or the ingestion of drugs which accidentally depopulate the dopaminergic neurons. And what you find is that if you give them an opportunity to experience something pleasurable, like hit a lever and get a pellet of food or people to access some very tasty food, both people with dopamine and with very depleted dopamine—animals with dopamine or without dopamine will eat the food.

They will pursue the food, but only if it’s right in front of them. If you put any kind of task between a person or an animal and a reward, what you find is that a rat won’t move one rat’s life to press a lever to get the food.

So they are able to experience pleasure, but what they are unable to do is to embark on any kind of effort to achieve that pleasure.

Right, so that’s so cool! So that means that in part what the dopamine system is doing—so imagine that the purpose of the dopamine system is to elicit a satiating reward.

That’s right, fundamentally!

But then elicit a satiating reward is something that has to be approached in steps.

That’s right!

And so in order to maintain the motivation necessary to approach the satiating reward, you have to mark each of the steps with a marker of pleasure.

And so the dopamine system is marking the intermediary steps, and then it’s doing that to overcome the reluctance that you’d have to expend the energy in that micro routine that would otherwise be costly by calculating the fact that there’s a net reward that’s nested in the ultimate satiation.

That’s right!

And parsing that out across the—yeah!

Yeah!

Well, sometimes people will experience tremendous anxiety in pursuit of their rewards, you know, the social situation, or the goal, or the book. You know, people imagine failure like crazy, as I’m sure you know; we’ve all heard and seen. What’s critical, again, is this cognitive appraisal, this interpretation of that.

If you think of that anxiety as a natural system of getting you to move, of just biasing your body toward movement, toward action as opposed to inaction—because that’s what anxiety really is; it’s a bias toward action—then you can literally reshape the whole notion of what it feels like to have elevated heart rate, maybe trembling hands, maybe flushing in the face when one is doing public speaking.

You do it enough times; you get pretty comfortable! Now, there are situations in life, I should just mention, such as sleep deprivation or, uh, in particular, that tend to make this whole set of systems with prefrontal cortex and limbic stuff and ACC and insula kind of disregulated; it makes it harder to manage. That goes without saying, right? You know, the quickest way to peel somebody apart is to sleep deprive them for two or three nights!

One night you’re probably fine! Right?

Right!

So, you know, all the basics of self-care, of good nutrition, social connections, sleep, exercise, sunlight—those still apply. I just want to mention that. I want to make sure I answer your question about gene expression and permanent changes because I’ve failed to do that thus far.

One of the things that is absolutely