New mechanism #1 — selective disruption of the indirect pathway

46:48say this is all already very impressive. And just as another caveat, we're talking about Daniel specifically. This was out of the team. And this is incredible work by everybody on the team. Yeah, yeah, yeah. Everybody on the >> our friend. So, that's why we're talking about Daniel. >> Yeah. All right. So, But clearly, yeah, this is this is very I mean, there takes a lot of data. Takes a lot of like It takes a lot of brains to >> a team effort, guys. Every time we talk about it, it's always a team effort. >> Yeah. Yeah. So, let's get back to Daniel. Okay. Um here's here's what he's going to do next, okay? So, the the one part of the mesocircuit hypothesis, which is like cortical drive goes down, so the power station like the normal power grid is down, or the

47:31there's elevated firing in the pallidial population, so that's going to stop the that's going to inhibit the thalamus even more and things like that. That stuff is already corroborated. >> Yeah. Stuff we already knew. This thing is kind of confirming. Okay? >> Now, does it do anything new? Well, yes. There's something called the selective disruption of the indirect pathway. This is a new prediction from the model. Here's what's happening. So, it turns out the prediction is that the coma is actually driven by the degradation of certain medium spiny neurons. Remember those neurons that I was telling you about that like they just die if there's like any stress whatsoever? >> Or like like

48:11a little bit of oxygen deprivation immediately. >> Immediate there's like okay now I'm done. Um there's selective degradation of a certain type of medium spiny neuron in the striatum that is projecting to the part that's putting on brakes to the thalamus. Okay? And this very specific pathway is new. Okay? The classical meso circuit hypothesis is just like oh there's like striatal dysfunction, right? It's like the whole brain region, right? This thing is saying that the indirect pathway which is specifically this D2 receptor expressing medium spiny neuron, this very specific

48:52subpopulation in the striatum, that's the part that is getting weakened. Mhm. And when that gets weakened, that's going to ultimately suppress the thalamus at the end of the day. Like that thing that I was telling you about, but now it's identified a a little part. >> It's not just all of LA County, we've got it down to a street block. >> Mhm. Yeah, and a specific type of house type thing, right? Okay, so how do you Fine, that's your prediction. Predictions are only as good as the data that corroborate. Right. >> So, how do we corroborate it? We use something called diffusion tensor imaging. So, this is a advanced form of like MRI. >> Oh, this is beautiful. >> Right? What we can look at is trace This is a very cool what what you can do with MRI is MRI is magnetic resonance

49:34imaging, right? Where you look at like hydrogen molec- hydrogen atoms in whatever biological tissue and you can actually see that using this magnetic resonance imaging technique. I'm not going to get into how MRI works, but effectively we can trace hydrogen atoms, okay? Water has a bunch of hydrogen atoms. Okay? So, we can measure the directional diffusion rate of water molecules along the axons, along those fibers of those neurons, right? And we can measure in white matter, the water is going to move faster along the length of the axon than across. And so, we have a directional idea of like how diffusion of water is going. And diffusion of

50:15water is a proxy for kind of how neurons talk to one another. >> Where is it? How's the traffic and flowing? >> Right. Yeah, exactly. So, what they did was use this DTI, diffusion tensor imaging, of 51 patients with disorders of consciousness. And you can show that there's significantly lower striatum to GPE streamlines. That's the break on the thalamus. That prediction is lower in vegetative state versus minimal consciousness patients. Yeah. >> So, just to take a step back, right? The from this model, it made a prediction about where specifically in this region of the brain

50:56that is controlling the flow between the thalamus and the cortex is is the point where the degradate like the degradation of this specific area is what's actually driving the problem. Connection is is where we would find it. And so, it said this is this is the road and the house where the problems like arise out of. And then we said, "Okay, well, we have all this actual MRI data from real patients. So, can we look at this road, this house in real patients that the model predicted you would see degradation in in in an outsized ways compared to surrounding area?" Yeah. I mean, you know, they they

51:36compared vegetative versus minimally cognitive, right? Right. Right. >> Cuz we've got those two sets. Yes. And if there's a difference, there should be some statistically >> some delta between those two. The vegetative will have more of the degradation than the minimally Oh my god. >> Yeah. Yeah. And so and so on the on the on the left-hand side we see we see that significance there is a significant difference. On the right-hand side he did sneak this in. The P value is only 0.07. So it's not significant. But it's there, right? And perhaps if you were to pull the two data it would become even more significant, but it's the there's there's at least something, right? And the N is low, right? So obviously like significance is not

52:17we're not going to get like Higgs boson 10 to the minus five significance here, right? Where literally to do that they had billions of particles colliding with each other, right? So you'll never get the the significance level of traditional like physics, but the effect it seems is there, right? And with more and more data perhaps it's going to be an even bigger effect. >> Makes sense. Makes total sense. It was it was really kind of a proof of like minimally viable proof. >> Yeah. Yeah. Yeah. That this hypothesis of this little prediction that I have it's probably true. It was good enough for Nature Neuroscience. That's not bad. Exactly. Um the second thing that they did was predict this this whole AI