 I'll welcome everybody to this session. It's called the Human Brain Deconstructing Mental Illness. I'm Joe Palca. I work for a radio network in the US called NPR, National Public Radio. Our speakers today are Amit Etkin. He's an assistant professor of psychiatry and behavioral sciences at Stanford University. And the Etkin lab is trying to understand the neural basis of emotional disorders in their treatment and to leverage this knowledge to develop novel treatment interventions. And to my immediate left is Tony Weiss-Corey, professor of neurology at Stanford University. And his lab is trying to study the role of immune injury and response in neurodegenerative Alzheimer's disease and understand the pathways that modulate neurodegeneration during aging and age-related changes to the brain. So deconstructing mental illness. Difficult to, oh, I mentioned before cell phones, please have them off. And there's also a hashtag, hash global health. We'll be taking questions from people watching around the world and from the room, if you prefer. And we'll be taking questions in the room. So you're welcome to chime in when the time comes. But I was thinking about a way to start, which was deconstructing, is there any way, I mean, to if, I mean, radiologists can take a picture of you and say, OK, you've got an enlarged spleen or you've got a broken femur or something like that. Is there any picture that you can take of the brain that will say that person has an emotional illness? So thank you for the question, Joan. Thank you for having us here. So let me answer that simply. No. Let me ask Tony. Yes. So the more elaborate answer is actually to take a little step back and think about what a psychiatric disorder is, right? So a psychiatric disorder is problems in thought, in emotion, in behavior, a whole bunch of things that can go together. And how are they currently defined? Well, at present, they're defined by checklist of symptoms. Those checklist of symptoms are created by committees of people and not necessarily based on an understanding of how the brain works or how we should be carving nature at its joints, so to speak. So the reason, in part, we don't have those images that say you have something wrong with you is because there's a huge overlap in the brains of people who are healthy and who are ill, even with an illness such as schizophrenia. And so part of that is really trying to, instead of having this dimension of symptoms, to move it a little bit, such that we're now talking about dimensions of brain function. And so we can talk about how much you are within or outside the normal range with brain function, just like you'd give a lab test if you're looking at your cholesterol level, right? There's a normal range, and if your level's outside the normal range, then that's a problem and that's dealt with. And that's not how we approach psychiatry right now. We approach psychiatry as something somebody tells us late in the disease that doesn't necessarily reflect all the processes we care about in the brain, and for that reason, we don't yet have that image. We are moving in that direction, and that's been a big area in the past couple of years really, that has refocused the field around an understanding of the brain as the basis of the illness, and therefore our diagnostics should be at that basis. Our treatments should be at that basis as well. So before I get off this question, I like that idea that these diseases are sort of defined by committee. Are there errors? I mean, can you go to a doctor or a psychiatrist who will say, yes, you've got this disease and you go to a different one, and a different doctor will make a different diagnosis, are the disease states sufficiently well captured by the committees to be reliable from one person to another, one therapist to another? Yes, so I wanna be careful not to knock completely our current diagnostic system, it has value, and the value is actually reliability to some degree. That is, the question you asked was, if I make a diagnosis or you make a diagnosis, do we come up with the same diagnosis? So now we have a more reliable system than we had before the diagnostic manual was introduced several decades ago, but not really where we need to go. For most illnesses that affect most people, so these things are like depression, anxiety of various forms, the reliability is actually pretty low. In fact, it is so low and in the almost questionable range of reliability that if you are looking at it blindly, you would argue maybe we should remove that diagnosis because it's not that way we make the diagnosis because it's not reliable. So there's reliability, then there's something called validity and validity just says there's something about this diagnosis having it that says something about the real physical outside world that your brain is different or something is different about you. These diagnoses were not designed to have validity in that way, they were designed to be reliable because as bad as our current system is, it was worse before. So progress is being made, but even in that reliability question, it's not really clear. It's not even checklist of symptoms like you have to have every one, you have to have five of nine for depression. With the way post-traumatic stress disorder, for example, the categories have been changed basically in the new diagnostic manual in the United States, there's 600,000 different ways to have that disorder. Yeah, 600,000. So, and that's up from I think, I don't know, maybe with the previous one was maybe 1,000, 2,000, still a lot, and that engenders lack of reliability and really the patient that I'm seeing and giving a label to may not be the patient that you're seeing and giving a label to in that way. Wow, that's a great number, maybe we'll come back to that. So Tony, I know that you're more on a cellular basis, but if I hand you a tissue sample, can you say I see something in that cell that reliably tells me that there's a neurodegenerative disease in that person that that cell came from? Yes, that is the case for a number of diseases, Alzheimer's is an example, where if I get a piece of tissue from a person who has Alzheimer's disease, I could actually see that. There's certain changes that occur in the brain that lead to degenerative changes, both in neurons that communicate with each other, that some of these connections have been lost, but at the same time, there's also changes that certain proteins start to accumulate, we call those amyloid or tau proteins, and they form sort of sticky materials that the brain puts into a defined space either outside the cell or inside the cell for a reason that we don't quite understood yet, but we know these deposits are not good, so yes, we could see that. What we're trying to do really, what the field is trying to do, and this gets back to what Amit was mentioning earlier, is we're really trying to get chemical molecular signatures of all these diseases that will allow us to measure expression of certain genes, proteins, or other modifications that will tell us this person has a disease or is on the way to develop a disease, and I think there's increasing progress, again to come to the example of Alzheimer's disease, we can take the cerebrospinal fluid, so this is the fluid that is present in our brains and also in the spinal cord, is produced at a high level, it's similar to the blood, it's a different liquid, and it's localized to the central nervous tissue. So in a person with Alzheimer's disease, we can measure these two proteins that I mentioned that accumulate in the brain, we can actually measure changes in these levels. So if I took cerebrospinal fluid from a living patient, I can tell this patient has the disease. Even more interestingly and promising, I think, is that we can tell if a person is on the way to develop disease, because you can already have changes in the levels of these proteins and not yet have cognitive problems. So your brain is still functioning normally to the outside world, you may not even notice it yet, but we can chemically detect that there's something on its way to develop, and this is really the hope that we will be able to hopefully treat these diseases earlier, but the challenge also is that these changes seem to take place up to 20 years before you get dementia. So these diseases develop over very long periods of time. So if I'm 50 and I will have Alzheimer's at age 70, there's something going on in my brain right now that leads me to that disease. Now this is both sort of daunting, but it also provides hope that we will have a long time to interfere with that disease process. So again, I wanna be clear. The reason that you look in cerebral spinal fluid and not in tissue is that people generally don't like a little piece of their brain removed to be diagnosed. That is absolutely the case. But looking, but having that advantage over me in terms of being able to see something altered in a physical property, does it work the other way? Are you sometimes diagnosing people with Alzheimer's, not you, but are people being diagnosed with Alzheimer's only to find out later it wasn't Alzheimer's at all because we can now do the biopsy after they die and say, no, that's not showing. I mean, how reliably can you tell whether Alzheimer's is what's causing the symptoms that you're looking at? So I will try to answer this from a molecular perspective and maybe Amit can answer it from a clinical perspective. So these tests that we can do now with the spinal fluid, they're not that old yet, but we have probably data from five up to 10 years and they're extremely precise in predicting that you will get the disease. Not exactly when you get it. So there's still sort of an uncertainty how fast that disease will progress. But we can almost definitely say, you will get this disease. You may also get Parkinson parallel to it. So it's not going to be that this is the only disease you will have. This sounds terrible, but we can definitely say you will get Alzheimer's disease pathology because there's something wrong in the metabolism in your brain. But from the clinical perspective, and I think I want to give this to Amit, there is a diagnosis unfortunately for Alzheimer's disease and you will not have Alzheimer's disease. Maybe you can elaborate this a bit more. Yeah, and actually let me kind of generalize it a little bit as well that the diagnosis we make almost for all of the behavioral disorders. So whether you're talking about psychiatry or neurology. So things like certain types of dementias in neurology can actually present like psychiatric disorders and like other types of dementias. They're all basically presumptive diagnoses. So clinical diagnosis based on experience and certain patterns, which of course become more reliable as the person gets more ill and is more terminal, right? Which is not so helpful in terms of you'd like to have more certainty earlier on. So these are presumptive, as Tony was saying. You really only know when you look at their brains what happens. So you do make misdiagnoses in that way. Something like traumatic brain injury, TBI, which we see for example is very prominent now from NFL issues in terms of chronic traumatic encephalopathy. Warfighters in Iraq and Afghanistan getting a lot of improvised explosive devices driven TBI's. The kinds of changes induced by those injuries look like changes you see in Alzheimer's and in fact put you at greater risk. Psychiatric diagnoses themselves change the structure of certain brain areas and put you at risk for dementias. So you have to actually start now thinking about these things as more of a continuum across these different pathologies and different brain regions and systems. And so there is a lot of misdiagnoses for if you will good reason, right? Because there's a confluence of mechanisms around things like the hippocampus which underlies your ability to form memory and is impacted in dementia but also in a lot of other disorders. So that's just one example. But before we leave this point, I'm just, I'm struck by the possibility, again, at least at this juncture, maybe you can tell me that there are more things you can do. But if you find out, or if I should find out that in 20 years I will have Alzheimer's disease, that's a kind of a burdensome thing to me as an individual because I'm not sure what things I can do about that with that knowledge. Is that a, are we in that funny stage now where we can diagnose better than we can treat? Or funny isn't maybe the right word. Yeah, right. Not sure that we can diagnose better than we can treat. We know there's a lot of things that can be done for a range of these conditions. Well, that we should all be doing now, like your diet, your exercise, all these things that are modifiable risk factors. So smoking is a risk factor for a lot of stuff that can go wrong with the brain. So you don't have to actually know that you're gonna have a disease to be able to do those things so people don't do them anyway, even though we know we should, including doctors. I think our problem is actually in many ways the opposite, that we only get certainty about diagnosis far too late. So if you think about psychiatric diagnoses and Alzheimer's being kind of the extreme, right, where we can really only diagnose once it's really gone too far, and a psychiatric diagnosis, typically the person's been ill for a long time before they ever come into your office to get diagnosed. If it's something like autism or schizophrenia, it's affected their brains and them throughout their development. And so you kind of miss the window to really have the biggest impact. So I think our problem is too late diagnoses where symptoms are obvious instead of getting to the point which is what we'll get through through the science of early diagnosis, risk factors, and so forth. And then we'll worry about is that a burden? Can we modify it? We're nowhere near there yet, I think. But it does occur to me that to change behavior, we could just tell everyone that they're gonna get Alzheimer's and see if that doesn't change. Sorry. Tony, I'm sitting here also wondering, do you think, I mean, we talked about this that, I mean, it said we need to look at the brain because that's gotta be, do you think that every, even Alzheimer's, but any other kind of neurodegenerative disease will show some sort of modification in cells or could it just be that the connections between cells are altered and you won't see it in an individual cell? I think if we use the right tools, we will see changes always at the cell or the level because the cells respond to their environment. There's different types of cells in the brain and one of the most sensitive cells in the brain, it's called a microglia. This is an immune cell and these cells basically survey sort of the state of the brain, as soon as anything goes wrong, they get activated, they get alerted like the police, they will go in and try to fix things. Sometimes they do the wrong thing, I'm stopping making analogies. But they're clearly very sensitive to anything that changes. So if connections between nerve cells start changing, these cells will react to it. But even in the neurons, if we have good enough tools and we can measure the expression of genes in these neurons, we will be able to see that there's something wrong in how they fire, how they're responding to their environment. Actually, it's interesting that you talked about glia. Maybe you could tell people, it used to be that people thought that neurons where all the action was in the brain, but the brain has got a lot of different kinds of cells and maybe you could tell us a little bit about what people have learned about what the brain is made up of. Yeah, that's a great point. I'm glad you're bringing that up. This is sort of my pet peeve. I'm actually an immunologist by training, so I studied initially the immune system and then got into neuroscience. So there was really a time where people studied only neurons. That was what the brain is about. And maybe 10, 20 years ago, really people started to say there are other cells in the brain. They were actually termed glue from the Greek word glia, means glue, and they were just thought to stick the neurons together. But we now know that these cells are equally important. They're not as electrically active, at least not. There's some that also have electrical activity, but they're not the main sort of the computer network, but they're the maintenance system. And I mentioned one type that is actually an immune cell, these microglia. So there's cells in the brain that have very important function, like isolating the wires, the axons, and that neurons are used to communicate with each other. That's also fulfilled by these other cells, the glue cells. But even beyond that, if we look outside the brains, certainly we have a vasculature in the brain. The brain consumes 20% of the blood supply, the energy supply in our body. This is facilitated by a very elaborate vascular network. So if anything goes wrong with the blood vessels in your brain, you might get a stroke, or you don't get enough energy to the brain, that will have an effect. And then beyond that, we know now that the rest of the body communicates with the brain. So there is a much more intricate system of how the brain responds to what is going on in our body. So it's really a multi-level system. And we start to explore this interaction at all levels now. So when you hear, I mean, this kind of complicated multi-level structure that you're dealing with on the inside, but you've got somebody sitting in your office, I mean, how does that make you feel? And how do you tackle that? Are you the psychiatrist? Oh, sorry. I'll just, I'll just. So I guess you can answer that question in a couple of different ways, which is in part, how do people want to hear about what is going on, right? And how do I as a psychiatrist in the clinical interaction, which is limited by the tools I have, versus I as a neuroscientist, perhaps less limited by the tools I have, kind of make sense of that. My sense is that the patients I interact with tend to appreciate understanding more about their illness, as well as they should, right? We're trying to create more of a consumer understanding from patients in general. And so it's good to be able to understand that your disease is biological. There's nothing at fault. Often there's a lot of stigma associated with mental illness. So being able to even explain that biology, if it's not their biology, at least it's the general biology that we're understanding about psychiatric disorders. That helps de-stigmatize. Putting it in the context of the body, as Tony was saying, helps explain why it's not just mental content. It's how your physical brain health, your general cardiovascular health, what you're doing in terms of exposure to light, the amount of sleep you get. All of these things are not your mental content that you might feel like you're wrestling with all the time, but the way that you then influence the organ that is the basis of the disorder. So that actually, it's helpful. I've not really had too much of an issue with people feeling like it's biological and not my fault you fix it if you educate them sufficiently. There's a tweet that came in from someone named Zebulon Carlander who asks what would be the most effective single measure possibly taken to combat mental illness? Would you offer one? Or would you say it's a constellation? Because you did mention exercise, diet. This is a, but is there something beyond that? Yeah. So among those, it's the most important. So I'd actually say awareness, awareness of yourself and your emotions and know that there is a problem and that it can be fixed to some degree in some people. So our treatments are not perfect, a lot of trial and error for sure, but our biggest problem globally is actually that people don't know that they have a psychiatric disorder, don't know that there's something wrong that can be helped. And then because of stigma and all the other things that happened throughout the world, they never actually get treatment. So even in places where there's a horrendous ratio of psychiatrists to population even asking for help in the community level to a priest or somebody who isn't even trained that itself is the barrier. So, you know, I would stack that is the biggest global impact. And then in places where there are care, it's an entirely different nation in terms of developing new interventions, but most of the depression in the world is untreated. Here's another question, which I may modify slightly, but it comes from Eileen Nora Vitarelli, who says it's important for understanding how the normal brain works to support cognition and motion sensory function. And I guess the twist on that was yes, you can see when things are abnormal, but what is normal, essentially? Is there a good understanding of what that is to compare what abnormal is when you're doing on a molecular or cellular level? That's a great point. I think for certain conditions, and again, looking sort of at this continuum from healthy and then aging and then getting a degenerative disease. So I'm talking about age-related neurodegenerative diseases specifically. I think there's clearly signs where the brain is degenerated and there are clear changes that are very different from a healthy brain. But as I said, there's a continuum. So for a lot of these conditions, especially psychiatric conditions also, people are starting to look now at hundreds or thousands of individuals who have a certain disease and compare that to people who don't have the disease and try to see what are the exact differences? And can we find patterns? Not just one gene, not just one protein, but looking at a hundred or a thousand together and see there's actually a whole network that is being changed. And if that is changed, that will tell you something. Either this disease is developing or it's already has manifested. So I think there are ways to clearly delineate these changes and we're developing this as we speak, I think. All right. Oh, you knew what I was gonna say. That was quick. Yes, why don't we take a question? And I think we have microphones, but if we don't, I'll tell you what, I'll repeat the question and we'll get the microphone next. Are human beings that are stronger or different kind of environment and different situations? Different environment, different situation and cultural element, like from Asia, obviously. And but it's matter of how you perceive it, how you deal with that. This mental attitude also determine how eventually your brain cell could be trained. So let's say how we can train our brain cell mental muscle to deal with that. And that's another thing is an even higher level of spiritual muscle. You mentioned about priest. Because often we see some very weak human being physically, health-wise, but they are so resilient of a certain extreme cases, they survive. So how we can train our brain cell for that because I come from a very strong Christian family. So I often explain myself for that. So can you train your brain to be more resilient and less susceptible to mental disorder? Yeah. It's an interesting question actually from a couple of perspectives, one of which is just in general health. The other is there are certain things where you know that a stress will happen or somebody will go into combat or something bad will happen. So it'd be great to inoculate somebody in that way. And I think your question also speaks to the issue of how you interface the psychological with the biological. So how do we kind of understand our experience, which is critical to having a brain with our understanding of the brain itself. And so I trained as a basic neuroscientist, I now work primarily with people doing a range of translational basic to very applied. And so what I like to do in trying to think about that question and the way Joe has sort of expanded upon that is try to operationalize it, try to break it down to what it really is. So actually there's been a lot of talk about mindfulness, for example, at this meeting. So and that's been linked to certain spiritual practices. So what does it really mean? What is a person doing? There's nothing magical, I don't think. There's something the person is doing that you can start to bottle and you can start to operationalize it to the point where you can maybe do it on a computer. So mindfulness just being one example. You're training attention, right? You're focusing your attention and trying to shift it around to different topics. We're now doing the same kind of approach using computerized training methods where through rote practice that gets harder and harder, we can train those same brain circuits. So the message then is really trying to take these things that seem like they're different, right? The brain and the mind and all these other kind of greater things and putting them in the same language so that we can operationalize it. We can study it with science. And then the really exciting thing is you can start putting things together because now if I know how a medication works and how a brain training approach works, then they come back together because they're now speaking the same language. And I just was thinking, so in these mindfulness training things that you can sometimes wear a mask that gives you an EEG, which gives you a sense of your brain waves and when your brain is relaxed or focused, there are different patterns. But I wonder, and so that's on a macro brain. I'm measuring all the electrical activity of these billions of cells. And then you can also stick an electrode into an individual cell and measure that. But I wonder if there is gonna come a day when there will be a physiological change in an individual neuron or would it have to be a group of neurons or a group of neurons in glia that would say, yes, you have affected the change in the brain that you're looking for. And here we can measure it with this thing. Do you think that'll ever happen? Oh, it happened already. Really? Yes, yeah. No, I mean, it's amazing the progress that has been made. So for many decades, neuroscientists have been able to use what you said electrodes and sort of listen to the electrical activity, measure the electrical activity of neurons. Then they could do this in living animals, for example, and do the same thing. The animal responds to something and you can detect that electrical activity. But now we have tools that allow us to put sensors inside these cells in a living animal and they start producing light, for example. They start glowing or they become fluorescent and we can detect them. So we can actually measure the activation of a gene. We were able to do that in cell culture for a while, but we can do this now in living behaving animals. So we can train an animal to do a certain task and to respond, for example, to a circle that we show it. And if it sees this circle, a certain type of neuron will get activated and we see that a gene gets expressed in this specific neuron. So this is all still very sort of isolated and very defined settings. But what neuroscientists hope to do is that they can put this together in larger and larger ensembles that then actually relate to cognitive aspects that a psychiatrist can relate to. So by working together, we can start to put the outside world together with the molecular microscopic world. It's fascinating. Yeah, there's a lot. Can I just ask one question? Does everybody understand why there's electrical activity in the brain? Is that like, oh, yeah, I get that. You just raise your hand if you have a question about that, even a little question about that. All right, everybody gets it. No, electrical activity, it's like your heart, right? When these cells are active, they're changing electrical potentials and you can actually measure that. So that's what they mean when they're, but I'm sorry, I just got stuck on that question. Yes, we have a question. You have the microphone, so go ahead. Is age regression for real? Like in a standard world, we talk about age regression and you can go into your previous life or some of your pains can be cured through hypnosis. So what's the scientific theory behind that? So again, I think it pays to operationalize what's going on, right? So to be at the risk of being somewhat controversial, we as humans tend to scribe a lot of kind of greater causes for things and explanations for things, but ultimately we're still people and organisms and we have biology, right? So that's got to ground what we're doing in a certain way. Hypnosis has been used for a long time in different contexts and there's some thoughts that are really just research that's really starting with brain imaging to understand how different brain circuits that are especially important in attention and focus on yourself versus focus on the world are affected by these. But for pain, for example, it can definitely help. By operationalizing it and demystifying it, I think we can get more at the mechanism. Right now it's more hypotheses than anything else, but if you look actually at a phenomenon considered in that same related sphere, which is placebo, we're actually starting to understand how placebo works in very interesting ways. And placebo, by the way, for anybody who's wondering, is not nothing, right? It is actually the most powerful treatment we have for everything. And I say that without the least bit of tongue in cheek because we compare medication to placebo for everything, right? Talking about cancer treatment, HIV, psychiatric disorders, anything, we have to have a placebo, right? And oftentimes we see a little bit of a difference between our placebo and our medication. But that placebo effect is big. And that placebo effect is you're getting attention, you believe you're going to get better, and all of these things that are very biological and have a huge effect. For pain, placebo changes transmission in the brain in a way much like other drugs that you might give to relieve pain. In fact, you can quantify how much morphine equivalence a placebo intervention has. So did you show them the needle before you injected? Did you wear a white coat? Did you do all these other manipulations? You can say, well, that was eight milligrams of morphine. And this one was 12 or whatever it is and actually understand it with imaging, with all these other tools, what it's really doing. So demystifying, getting back to biology puts things in that same language, which is exciting. Someone mentioned earlier 20% of the blood supply goes to the brain. And if it goes down, let's say to 15 or 10%, then the brain faculties diminish. I guess it begs the question of what if it goes up? If it is 25 or 30%, is there a mechanism to improve the brain by improving the blood supply or the quality of the blood to the brain? Oh, that's obviously for Tony. Yeah, I think this is very tightly regulated. So you could not quickly increase the blood flow to the brain without causing a stroke or something like that. I think this is a very tight control. Now you could deliver more nutrients to the brain, more glucose maybe. The rate at which this exchange happened is dependent on how good the blood vessels, for example, are able to exchange the nutrients that are in the blood to the tissue. With age, we think that decreases, and so there may be a lack of active transport. So this is a way one could potentially manipulate that system. Let's take a question over here and then a question over there. I have too many questions, and I just recently read something about the positivity of gene mutation to spot family members who perhaps all of whom have Alzheimer's except one, and that one person has this gene mutation, which we've always associated with a very negative thing, but it now looks like it's gonna be a positive breakthrough and all that. But that's a different thing, sorry, to go back to, can I just say, without at the risk of getting a bit woo-woo here, I don't wanna do that. But somebody described mental diseases glibly, maybe, as life-intensified. And are there individuals who have traits that are intensified, that is part of their personality, that then doesn't go on to develop in a damaging way? And can that be spotted? One, two, sorry. We all inherit genes. Do you believe, I don't think there's evidence, but do you believe that we can inherit memories of trauma through generations before us? Yeah, so two great questions. So, let me just take the second question. So the second question is actually a really interesting phenomenon called transgenerational transmission of trauma, which actually does happen. It's been demonstrated in people and demonstrated in animals. So you can actually, and with people that it's a bit confounding because you have genetics, but you also have a common environment that you rear the child in, right? But actually with an animal, you can separate the animal. And so you can, this is work, for example, recently by Kerry Restler at Emory, who's shown that across multiple generations you can transmit kind of the risk that goes with having had that trauma exposure. So that's something just starting to understand that, but it's through what's called epigenetic modifications of genes, so not the code of the gene, but the accessibility of that genetic code to be read out. So things that happen to the DNA that either allow it to be read out more or less, which gate the code itself. And the issue about life accentuated, I think that it's a really fundamental kind of distinction I wanna make between what a mental illness is and what life is. So a mental illness being a physician is something that's impairing the person's function, right? Having a trait in a very strong way could be a huge advantage. In fact, most likely if you look around this room, the traits of conscientiousness and obsessiveness and some anxiety and fear and all these things are gonna be very different from the general population just because everybody here has been driven to succeed. Now among scientists I can tell you if you're not an obsessive scientist, you're not gonna get your job done. So those are traits that vary in the population and if you have a lot of one or the other, it may actually be quite beneficial to the point where it's impairing and you can't get your life lived in the way you would want to or you should reasonably live it. That's where the mental illness boundary kicks in. So we're not aiming to pathologize normal behavior. In fact, celebrate normal behavior. But it's when somebody comes and says, look, I need help because I can't get out of bed. I'm gonna be fired. I've been not promoted a bunch of times because I'm just not able to focus on my work. Sometimes, sometimes some traits are there through childhood and into adulthood and are fine and some traits put you at risk. Yeah, that's right. We have a question over here and then a question over here. Francis Collins from NIH. I wanna ask about schizophrenia. Here's an enormously debilitating and fairly common disorder affecting perhaps 1% of populations and across the world. And yet, we haven't had a new therapy for schizophrenia really in 50 years. And that seems so ironic given the way in which research on schizophrenia is moving forward at a pretty impressive pace, whether it's by imaging approaches, by genetic analysis, a recent study, 108 regions of the genome where there's variations that contribute to risk, whether it's understanding the cell biology by using stem cells and being able to take a skin biopsy from somebody with schizophrenia and make neurons out of that and see whether they're the same or different than somebody who doesn't have this. And yet the drug industry is pretty much runaway from any investments in this particular area for some time and there's not much going on there. Seems like such a great opportunity. What are we missing? How do we move that agenda forward more quickly? Given the enormous burden that people with this disorder and their families and friends sustain because it can be so debilitating and our treatments are really ineffective. So maybe we can answer this on kind of two levels. Again, I want to separate a bit of the sort of first world and non-first world or developing world. The developing world doesn't even have access to the treatments that we have in the first world. So that's where we start in the developing world. Let's take that just for a second off the table because I think you're asking really about, on a bigger picture, why aren't we making progress? If you look historically at all of psychiatry and schizophrenia is emblematic of this, we've discovered all of our interventions by chance, all of them, right? And then we've developed animal models to try to develop more drugs like that that basically are sensitive to the effects of the drugs that we found by chance. So drugs that block dopamine, for example, which is what we give as an anti-psychotic medication, if you give an animal amphetamine and it runs around the cage and acts like a mouse on speed, and you can block that with an anti-psychotic, that becomes an assay for an anti-psychotic, which means that you only are gonna find things that act in exactly the same way. You never understood the biology of the process to begin with. I think the change we're seeing now, and I actually have a lot of hope that in the next couple of years we'll start to see a lot of progress in this regard, is that by understanding things at the level of brain circuits, we can now say, look, cognition, ability to think is really important for schizophrenia. In fact, some people have suggested psychosis is not that important. It's the ability to think that is a thing that is there early, predicts outcome the best, and is very poorly targeted by current treatments. So people are developing computerized approaches at training cognition. Drug companies are developing molecules that target those functions more specifically, and the FDA has even accepted cognition as an indication, as opposed to schizophrenia per se, which is really assessed with the psychosis symptoms. So that's progress, and I think that just has to be kind of played through. The genetics has really only exploded in the past couple of years around schizophrenia, I mean really since 2011, and so that is just too early to know where that's going, but I think that for me, the moral of the story is, you take a complex disease which is probably many, many diseases, reduce it down to discrete brain systems that underlie discrete behaviors, and then there's a hope of targeting with, say, non-invasive brain stimulation, TMS, or transcradial magnetic stimulation, giving brain training, giving medications, and then best of all, combining these things because we understand what we're doing, as opposed to give one and then the other and hope for the best. Tony. Yeah, maybe if I can just add to what you alluded to, that there has been this tremendous progress in understanding genetic bases. We see changes in how neurons work in these individuals, and I think I have great hope that this will show us what is actually wrong at the molecular basis in these conditions, and as Amit mentioned, we start seeing in a number of different diseases that it's not just one type of disease, but there's variations, and that they might have different drug targets, and I think there's actually hope that pharma will see, this is a specific entity that is not the same as this other one that we used to target in the past, and so by personalizing the medicines for these individuals, you can actually start new programs which will then address diseases sort of in an individual way, and not as a big lump together where people really have not exactly the same biological disease. So let me actually present one other almost counterpoint to that, which is that there turns out to be some commonalities that are quite interesting across disorders which themselves have not been known. So we are simultaneously moving in the direction of personalizing, and I would argue asking some basic questions about what it is that that category even is. So we have a paper, for example, it's gonna come out in the next two weeks, where we just simply ask the question that nobody to my sense has thought to just ask before because the data was already there to answer it, which is, is there a common biological basis using brain imaging to all the major psychiatric disorders in adults? And so we looked at schizophrenia, depression, bipolar, obsessive-compulsive disorder, drug dependence and anxiety, and it turns out there was, and it was a single well-understood brain circuit that is important for emotion, important for cognition, and starts to identify things that exist across disorders, and then simultaneously we're taking the personalized approach to go within a disorder in a very fine way. And genetics has actually revealed the very same thing, that there's been mutations or polymorphisms that carry risk for five disorders, right? So I think we have to break our concepts to begin with of what is a disorder going back down to the individual patient, but also asking the question of the nosology to begin with, and through both of those, I think we're making tremendous progress. Well, we reached the end of the session and I'm sitting here thinking, okay, how can I sum this up? I think it's a time of actually some hope. I feel quite positive listening to both of you that this globby thing that sits inside our skulls is coming under some, even if it's not being thoroughly understood, it's being understood in enough detail to make some rather precise changes that can be helpful. So I feel pretty positive. Anyway, thank you all for coming and we'll do this again next year and see how far they've gotten. Thank you.