Invest Like the Best with Patrick O'Shaughnessy
00:27:04 · Patrick O'Shaughnessy
[00:27:04] S0: I have a stupid basic question. What is the method by which we can read and how precise is our ability to read activity, and what does activity even mean in different parts of the brain?
00:27:13 · Andrew Huberman
[00:27:13] S1: Great questions. So it depends on how invasive you want to get. So most people understand, or if you have it, no big deal, that neurons communicate through action potentials, electrical signals. And we were taught, and it's still in the textbooks, that they're always the same size and shape for a given neuron. It turns out that's not even true. So there's a variability there, but we sort of have this all or none, a neuron either fires or it doesn't, but there are graded potentials. You get to a threshold, the neuron fires, communicates with the next neuron, depending on the milieu there, how many other inputs, what they're doing, the next neuron fires, you sort of set off a chain or not. So, you can record from neurons by putting an electrode close to them, extracellular recordings, you can put a bed of nails nearby, record lots of those extracellular signals, you can impale a neuron, record intracellularly, all of that requires breaching the skull, sticking wires basically down into the brain. The methods that are really exciting are things like ultrasound, transcranial magnetic stimulation, which is used for the treatment of depression and other things. The spatial control there, that's for stimulation, is not great. The recording from the nervous system, you can go from what I just described, intracellular recording at the most extreme, then extracellular recording, and then you go all the way to, like, fMRI, or EEG, when people see these, like, heat maps of the brain, where you really can only measure signals in the surface, like at the cortex, which is interesting, but you're not gonna get to the deeper layers. A big problem now is how important is it to understand the natural patterns of activity in detail before we start poking around and stimulating with writing? And obviously there are two ways to write, at least two. You can use pharmacology. So what does most pharmacology do? Whether it's alcohol, barbiturates, sedatives of some kind, what are you doing? You're increasing the threshold for activation. You're quieting the brain by just increasing the threshold for activation. You're doing it indirectly, by increasing inhibitory release. So there's less excitation overall.
00:29:10 · Andrew Huberman
You think about Adderall, caffeine, nicotine, speed, modafinil, and you're talking about lowering the threshold because those generally work by increasing neuromodulators that increase the likelihood that neurons will fire. So you're just kind of ramping up that baseline. So creating higher RPM across the brain and body. That's why they lead to some shaking, some agitation, like everything's like primed to move, primed to fire, primed to think. It's hard to shut off your mind when you're under the influence of stimulants. Easier when you're under the influence of these other drugs that increase inhibition. So the real question for trying to get to better reading and writing to the nervous system is about spatial and temporal precision and how willing you are to put something underneath the skin. I say skin because you don't necessarily have to go under the skull. Like, let's take vagal stimulation, for example. Vagal stimulation, most people think about as a way to calm down, but most of the vagal pathways are excitatory. And so common treatments for depression now, if somebody's willing, is to put a small, a little smaller than a penny size stimulator under the skin of the neck and stimulate the vagus in order to overcome this sort of sedation that accompanies depression. So vagal stimulation increases alertness. Neuroscientists have known this for a long time, and a lot of people are getting pretty good results in their treatment of their depression by increasing vagal stimulation. And it's dynamic. You can say, How do you I feel okay. You can actually see this in real time. There's an amazing thing that my colleague Karl Deisseroth, one of the greatest bioengineers alive, has talked about where he's talking to a patient and she's suicidally depressed, and then he starts increasing the stimulation on her vagus, and she starts moving from that to a discussion about how she feels willing enough to go out and apply for a job in real time. It just tells you that these excitatory mechanisms and these depressive mechanisms, or inhibitory mechanisms, are profound in terms of our perception of the outside world, our perception of ourself. So this would be very nice to have. The question is, are you willing to go under the skin? I am.
00:31:09 · Andrew Huberman
A guy that came up, not mainly through my lab, but he spent some time in my lab, he's now the head neurosurgeon at Neuralink, Matt McDougall, amazing guy, has a little receiver implanted under his skin of his hand between his thumb and his index finger. And his wife does too, and it opens their door to their home, to keys. Like, I was like, what are you doing? He's like, it's a sort of biohacking Bay Area ish kind of stuff. He's like, yeah, like, I'm just playing with the idea of what is it like to have a small device under your skin that can do stuff in the world for you. That's very neural link ish, and obviously they have much bigger aspirations than that. But I think within twelve months, 20% of the entrepreneur real world will be asking, if it's only as invasive as getting a piercing, yeah, maybe I want a little vagal stimulator. And that's coming next. People are thinking like peptides, what are we gonna do? I'm not worried about peptides. I'm thinking implantable devices is where it's gonna go next. The commercially available vagal stimulators, some have shown some promise. They're not super impressive. To my neurosurgeon colleagues who like to get it under the skin and under the skull. But I will say there's some interesting results there, but we're not quite there. But think about ten years ago, if I told you, listen, you're going be wearing a ring or a band on your wrist that measures your sleep and HRV, that's pretty out there.
00:32:25 · Patrick O'Shaughnessy, Andrew Huberman
[00:32:25] S0: I'm so fascinated by this. So there's reading the underlying activity of the brain at different levels of fidelity. There's writing. You talked about ultrasound stimulation, I think there's electrical, I think there's magnetic stimulation potentially of these areas of the brain. One central part that I don't really know much about is the model of the brain itself. [00:32:43] S1: How [00:32:44] S0: far along in our understanding of that we even are. I know there's some things that we can say activation of this area produces this thing. But like, it feels like we need those three things, like good input modalities, good reading methods, and a model. [00:32:55] S1: Yeah. I'm glad you're asking. Yeah. I mean, these are my favorite topics. It's just that usually people are like, what peptide should I take? [00:33:01] S0: Which peptide should we take by the way?
00:33:03 · Andrew Huberman
[00:33:03] S1: I mean, it depends on what your pain points are. So at the periphery, the retina, the cochlea, the tongue, the olfactory system, the skin, neuromuscular control, which isn't at the periphery, but I think we know pretty darn well how the nervous system works. And we know how different wavelengths of light are transformed into visual images at a, not even a first approximation, but we understand that in significant detail, how motion is processed. We understand a fair amount about memories, although I want to put that on the shelf for a moment because there's an important finding in the memory field that will make you feel like it's in kind of twilight zone, perhaps in neuroscience. It worries me all the time. The hypothalamus. So circuits that are deep in the brain that control hunger, anger, sexual appetite, lack thereof hormone secretion. Those are switches. So do we understand those? Yes. Do we understand everything? No, but we understand them. I mean, one of the reasons the GLPs are so effective and one of the reasons they got so much velocity is because we understand where they bind in the brain and they bind to these hypothalamic and other areas, of course, that activate neurons that are involved in the suppression of appetite. And so it's a very simple equation, really. Ramp these GLP levels up a thousand fold, people aren't as hungry. But it turns out they're not as driven for other things too if you get beyond a certain level. I think Sam Altman talked about his experience with that at one point, and why he decided to either back off the dosage or stop taking them. So as you move in from the periphery of the sensory organs, right? And as you move up from the base of the brain, the deeper limbic structures and hypothalamic structures to the prefrontal cortex, we can say, yeah, like your prefrontal cortex, know based on lesion studies in humans, activation studies is really important for contextual learning, for strategy setting in different environments, for suppression of impulse, what we call top down suppression. So do we understand what the prefrontal cortex is doing? Yeah. The place where it starts to get murky is at the level of memory. We'll talk about that in a moment. And at the level of thoughts, you won't find a chapter in a neuroscience textbook that says, this is how thoughts are made.