Invest Like the Best with Patrick O'Shaughnessy
00:23:19 · Andrew Huberman
[00:23:19] S1: Well, think the coolest problem that's also the biggest problem is how we can non invasively write to the nervous system in So sleep and waking my best friend from childhood, Eddie Chang, is chair of neurosurgery at UCSF. He's a bioengineer. He's doing things similar ish to what Neuralink is doing, but removing brain tumors and this kind of thing. I've been with him to surgeries, like right up there next to the tumors. Patient is awake, he's probing areas of the brain, he has permission to map areas related to speech and language, etc. So breaching the skull is a big deal. The neurosurgeons say, Well, you know, a titanium plate would be better, it's stronger, it lasts longer, but most people don't want to have to do that. They do it because they need something taken out, like a tumor, or an epileptic foci. I think the big one now is who can develop, it will probably be ultrasound, but a noninvasive way of selectively activating or quieting brain areas with high amounts of temporal precision. Like getting people who are in locked in syndrome to speak, as Eddie has done, or getting people who have a spinal injury to walk, which Neuralink and Eddie and others are trying to develop technologies to do, that is heroic, right? But ultimately, and I'll go on record saying this, anyone who thinks that Meta, OpenAI, Anthropic, or Elon's got Neuralink as his stated neural interest, Anyone that thinks that those are LLM AI companies is perhaps going to be surprised at this prediction. Every single one of those is going to be a biotech company. They're all interested in the brain. You talk to any of those guys, they may not have formal training in it, but they understand a lot of neuroscience, and they will all tell you, Here's the goal, right? The goal is to be able to read and write from your brain non invasively. And there are straightforward ways to do that. So the big thing is, how can you stimulate a brain area with temporal and spatial precision? How can you quiet that brain area with spatial and temporal precision? How can you dial up or down the level of quieting? Because it's one thing to say silent versus activated, but the nervous system has a lot of graded signals in it.
00:25:15 · Andrew Huberman
Mean, we don't think about those signals, but the communication between areas is gated, it's graded, thresholds for activation change, even just for things like drive and motivation. A non invasive device where you could literally crank up your level of motivation by stimulating the nucleus accumbens and related pathways while engaging in a particular learning task or in hard work, and then turning it off so that you can capture more energy, you have more of a square wave function on your energy output, that's coming. And those companies are all about that. That's what the real arms race of AI is about. So I sort of chuckle when I think, like, okay, like the LLMs are great or terrible, depending on who you are, and I believe they're great. I'm a big fan of AI. But the dynamic modulation of your own neural activity, using non invasive technologies, not pharmacology, but then using AI to be able to understand, okay, this level of activation in this brain area for you, Patrick, is related to a hyper motivated brain state that makes it very hard for you to do anything else the rest of the day, and it will just learn to titrate. But you say, Well, that sounds kind of science fiction. How far off is that? I mean, my eight sleep changes the temperature throughout the night to give me more REM sleep or deep sleep. It's already doing that. It's just we're okay with these things in sleep, and it's doing that through a powerful but indirect method, temperature change. But it's no small thing to dynamically change and measure the degree of change in the nervous system in order to access a given state, sleep or otherwise, better. And that's what these companies want to do. So my field of neuroscience has to embrace this, and they are. That the people who are trying to figure out what are the natural signals occurring in the brain when people think, when people see, when people move their limbs in a particular way. That's been the last thirty, forty years. That's all reading from the nervous system. Now it's about writing to the nervous system non invasive.
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.