 Thank you. So thank you very much for the invitation to speak. I actually fell in love with cultural or trans-cultural psychiatry about a decade ago when I actually met Duncan Peterson. He's the one who actually really blew my mind when he told me that cardinal directions are not perceived the same way in navigation in different cultures. So that was really new to me. And I thought, oh, wow, I really need to learn about this. And we actually had written a project together. So it means we sat through many elaborations of this grant. But unfortunately, it wasn't funded. And from the reviewer comments, it didn't seem like they wanted to fund this line of work. So we didn't end up doing the work. But before meeting him, I actually had started a project looking at the Japanese, something that we were talking about a couple of days ago. Because we had found some very strange results in a control group. And that's why I was reorganizing some slides. I thought, based on the discussion we had a couple of days ago, I wanted to add these slides here. So I'll show you what were basically the culprits that got me interested in cultural psychiatry. So all right, so what's the background? Well, the hippocampus is part of the brain. It's a structure that's involved in memory. So probably most of you know what the hippocampus does. It's involved in navigation, in episodic memory, in spatial memory. It's a lot of coincidence, because really what it does is it builds relationships. And if you're going to build relationships between items in the environment, then that's going to be your spatial memory. And then in that location, things will happen. So it will be the seat of your episodic memory. And so that's why some people call it relational memory, episodic, or spatial memory. The hippocampus is also a structure that's really vulnerable to different factors, such as stress that you just heard about, inoxia, vascular diseases, diabetes, aging. So it seems like whatever happens, if there's a vulnerability to the individual, the hippocampus seems to suffer. So it's been really a focus of interest in a lot of research studies, including studies on psychiatric disorders, where they're going to investigate whether there are any part of the brain that could predict who's going to get a psychiatric disorder. But of course, how could you do that? How could you know in advance which one of us here might get a depression or post-traumatic stress disorder when we're healthy? We can't know that. So for decades, we thought that when the hippocampus was smaller in psychiatric populations, it was the consequence of a disease. So you have a disease. You stop learning. Therefore, your hippocampus shrinks. Well, it turns out it's the other way around. At least we know for four different psychiatric disorders, and I'm going to give you specific examples. So if you take post-traumatic stress disorder, how can you know who's going to get post-traumatic stress disorder? You have a bunch of people who are going to war. You know a percentage are going to suffer some stressful event, and a percentage of those will come back home with PTSD. How could you guess who's going to get PTSD so you can scan their brains ahead of time before they go to war? Is that possible? No. So how do they solve this problem? Anyone know? That's pretty good, but that wasn't what I was looking for. Sorry? Sorry, the question was how they know. How could they know in advance who's going to get PTSD so that they could scan their brain when they're healthy? You can scan military soldiers before they go. Yeah, but it's a lot of people, right? It would cost a lot of money. How would you know who's going to get PTSD? Well, you can't. It's a trick question. What they did is they got monozygotic twins in the study, and they scanned the brains of the twins who didn't go to war, assuming that they probably had the same brain as the one who went to war and had the PTSD. And what did they find? The monozygotic twin who did not have post-traumatic stress disorder also had a small hippocampus, just like the monozygotic twin, which proves that it's not something that happened after the trauma. It was probably there before the traumatic experience. Wow, that was like a revolution in our way of thinking, right? For decades, we thought that the hippocampus shrinks because of the stress associated with PTSD or because of the fact that the patients don't learn while if they stay home and they ruminate. Well, no, it turns out that the hippocampus was small beforehand, and it's a risk factor. So now that's what we mean by saying it's a risk factor while people are healthy. It means that if any one of us has a small hippocampus, we'll be more vulnerable to getting one of these disorders that will increase of probability if you have other risk factors like genetic risk factors, epigenetics, or if you have the right environmental conditions, the stressors, et cetera. So I'll give you a few other examples. So they did the same kind of really clever studies for depression. So again, how can you know who's going to have depression? Well, you don't. So what they did is they, there's certain groups that scanned the brains of adolescents who did not have depression but had a parent with depression. And it's known that if you have a parent with depression, you're at a high risk. You have a family history, and there's a good chance you're going to get depression. Lo and behold, the adolescents with a family history of depression also have a smaller hippocampus compared to controls. So that starts to tell us, OK, well, the hippocampus is important, and it seems to be playing a role in helping us stay healthy somehow. Same thing for schizophrenia, when you scan first episodes, first episodes schizophrenics. So the very, very first time an individual has a psychotic episode, they're asked to participate in the study. They get scanned. So the idea is that there wasn't enough time for the actual schizophrenia to cause changes in the brain. So the changes that were measured were probably there before the first episode. And lo and behold, they also have a smaller hippocampus. And then for Alzheimer's disease, they can do similar types of studies, except here what they do is they'll take people who are known to have a risk because they already have memory complaints. They are documented, so they're called mild cognitive impaired individuals. We follow them for a few years, and then we see how many convert to Alzheimer's disease. And usually it's the ones that have a smaller hippocampus and neighboring enteroidal cortex. So when we say that we want to have a healthy hippocampus, a larger hippocampus, it's because it's protective against these disorders. And maybe there are others that just weren't investigated yet. Because we already know that with ADHD, with bipolar, there's a whole bunch of other disorders that involve a small hippocampus. But it's always been measured after the diagnosis. So who knows? Maybe it was there before the diagnosis as well. All right, so if we take Alzheimer's disease as an example. So as I mentioned, the hippocampus and enteroidal cortex are some of the first regions affected by Alzheimer's disease. Atrophy of the hippocampus and enteroidal cortex will lead to future clinical diagnosis. Interestingly, there's a study that looked at confirmed Alzheimer's pathology with plaques and tangles in a whole bunch of patients. Over 400 patients were analyzed. And what they looked at is whether the people had a clinical diagnosis or not. They divided people into two groups. So everybody had plaques and tangles. This is, again, the neurobiology biomarkers of Alzheimer's disease. And then they divide the two groups between who had a clinical diagnosis, who did not, and looked at what are the differences in their brains. And the differences that they measured, guess what? The ones that had a diagnosis had a small hippocampus and smaller neocortex. The ones that did not have a diagnosis. That means that they went around their lives somewhat normally. They could have had issues, but the issues were not severe enough that they got a diagnosis. They're the ones who had a larger hippocampus. So it means that even if you remove plaques and tangles, you need to have a healthy hippocampus to avoid a diagnosis. Or let me put it another way around. There were other clinical trials that were done where they successfully removed amyloid plaques, and it did not cure Alzheimer's disease. So the idea is that what causes a clinical diagnosis is the fact that the hippocampus becomes damaged. So just removing the plaques and tangles is not enough. What you need is to have the hippocampus functional again to help avoid a clinical diagnosis. So then it becomes really fundamental to figure out what causes shrinkage of the hippocampus when we're healthy. Because that's going to then have a profound impact on neuropsychiatric disorders. So here's a summary of hundreds of studies in the different domains. So there are cognitive studies that show that stimulation of the hippocampus or competing structures like the caudate nucleus will modulate growth and shrinkage of the hippocampus. And I'm going to talk about that today. There are the studies with stress. So with stress, there's the direct toxicity of cortisol on the hippocampus, which you are familiar about. But there's also another line of studies that's really less known, which is that with stress, you get overactivation of the amygdala. When the amygdala is overactive, what you get is a silenced hippocampus, less plasticity in the hippocampus. And these are studies in rats done in Mark Packard's lab, showing that if you lesion the amygdala when you stress the rat, you don't stop plasticity in the hippocampus. So it's really through the amygdala that that's being done. But then what happens is that the stressed rat that has the overactive amygdala engages in this caudate nucleus dependent strategy. So instead of stimulating the hippocampus in a navigation task, it uses the caudate. So that could also be a reason why while we have less use of the hippocampus, which then use it or lose it, you can then get shrinkage. And then we know that there are also vascular reasons why people could have damage in the hippocampus, but also a diet. So we shouldn't neglect the impact of toxins, anti, so there's thyroid antibiotics on the microbiota. So the idea is that there are a lot of products that we can get in the pharmacy that are now known to alter the microbiota. And guess what? The microbiota is involved in producing amyloid. So it's involved in producing the Alzheimer's pathology, which then could maybe migrate and then end up leading to build up and having an impact on the incidence of Alzheimer's disease. So it's known that diet can have then an impact on plasticity. If you then look at this chain of event with the microbiota, then it can have an impact on plasticity, et cetera. Yeah, I did mention pro-inflammatory cytokines, which is a really important marker that will then directly have a negative impact on the hippocampus. All right, so as I mentioned, I'm going to now focus on more of the cognitive factors. So the hippocampus is involved early in learning. So if you take a real life example, when you're going from home to a new job, in a new city, you've just moved and you need to find your way. Often what we do, well, what we used to do in my generation was actually look at landmarks. So you would look at landmarks to orient yourself. You would want to find the right street, make sure you turn in the right place, and basically build a sort of mental map of the area so you'd know how to find your way. So the idea is that when you're doing that, you're building stimulus-stimulus relationships, relationships between different items in the environment. And here you could use various landmarks as an example, like the statue on park just below the Mont Royale. That could be a landmark for you. You could then use the old Montreal, and you know that McGill is in between. You could, if you live out west, you would know how to find your place relative to those landmarks or where to find a grocery store, et cetera. So you have a general sense in such a way that you can derive shortcuts. So a day that your road is blocked, you know how to find your way around, because you know where you are relatively speaking in your mental map. So that is a process that depends on the kind of nucleus. However, if you repeat behavior, now it's a familiar city, familiar workplace with a familiar route that you use. Every day use the same route. What happens, it becomes a habit. It becomes a habit to such an extent that sometimes you get to your target and you can't remember what you saw on your way. I mean, this used to happen to me all the time when I had, when my son was little and I was walking home with him, thinking of what I'm going to do for dinner. I was completely on autopilot. He would see all these things around and I wouldn't see anything. Oh, mom, did you see the guy with a big purple hat? No, I missed it. I was on autopilot. All right, so the autopilot is a part of the brain that relies on, is a process that relies on a part of the brain called the caudate nucleus. So it does not rely on the hippocampus. So the way that we operationalize habit autopilot is a stimulus response strategy. So what do we mean by that? When we navigate with this automated behavior, at some point, something in the environment acts as a stimulus that makes us elicit a response. So we know when we see the white building, we have to turn right. So there's this big stimulus. You don't really think about it. It's all automatic, so it's unconscious, and you can then find your way quite well with a series of stimulus response associations and then get to work fine without even really thinking about it. And you know you're engaging your caudate nucleus in stimulus response learning when on a weekend day, you're not going to work, but you still took the turn to go to work. This happens to no one. Okay, no one, no one goes out on weekends here. Okay, I'm sorry. All right, maybe no one goes to work. All right, so anyway, so there's an inverse relationship between gray matter and the hippocampus and caudate nucleus. I found that inverse relationship in both humans and rodents. That suggests that these two memory systems in a way compete against each other in the sense that you either use your hippocampus or you're caudate, but not both at the same time. And if you think about it, it makes sense. I think it's biologically adaptive to automatize repeated behavior so that you could free up your resources. You can think of what you're gonna cook for dinner and not think of how you're gonna walk and where you're gonna go. You don't have to, all that is fully automatized. You can speak automatically, you can get to your target and walk all at the same time because everything is automatized. So it's a wonderful, powerful system that is really valuable. And at the same time, if you're gonna automatize things, you don't wanna have a process that's stuck that doesn't know, oh, am I doing this automatically or am I now being cognizant and using a more of a planning cognitive strategy? So it's automatic. So the way it works actually in the rodent, they show that there's actually inhibitory processing such that when the caudate is active, the hippocampus is not active. And then it helps resolve the problem. There's not gonna be a conflict once something is automatized because it's been repeated. And that's also a very critical part of the equation. You have to have lots of repetition, right? The rodent studies that shows the most response formation dependent on the caudate nucleus of the stritem involve sometimes thousands of trials, okay? So you repeat the behavior. It's only with repetition that you get this very slow gradual learning in the caudate nucleus. And when I'm saying learning, it's because I'm equating certain biochemical processes that were measured. For example, if you measure acetylcholine, you're gonna see this gradual increase with practice in the caudate. And when the rat has automatized the behavior, then it plateaus. It's really beautiful research from Paul Gold's lab. Okay, so if we understand now that it's one structure or the other, not both at the same time, it's biologically adaptive. It makes sense. It makes us pretty good. We're a pretty good machine to be able to talk and walk and get to familiar places at the same time without thinking about it. And then we can free up our resources to do other things. That's wonderful. But then the question is, in what situations do we over-stimulate our caudate at a cost for the hippocampus? And what's going on if we get the situation where the hippocampus might be small and the caudate might be big? And I'll explain, and I'll show you this inverse relationship in a moment. But first, how did we get there? So I developed this task. I started doing this with virtual reality again because when I first started doing imaging, I thought I really needed to get these neurons in the hippocampus to work really hard. Back then in the 90s, a lot of people were using spatial memory just in a 2D display and no one was imaging the hippocampus. It was always other regions like parahippocampal cortex that were lighting up. And I had my own study from also mid-90s that showed that you really needed to create a mental map, a 3D representation of space to elicit or to require critical contribution of the hippocampus. So this is what I did. And I actually ran 10 different pilot studies that completely failed that were garbage that I never published because it turns out humans don't want to use their memory at any cost. So it's a lot easier to work with rodents, actually. And but anyways, eventually I got humans to behave like rodents. And I'll show you the results. People at the Pavlovian Society loved that remark, which is not a joke. OK, so what I did is this is a virtual environment that's actually placed in a radial maze just like what we would use in rats. I wasn't kidding. And what I did when people were not using their memories is because when everything is open in the standard version of the radial maze, what you do is you ask the rats to go and get objects out of all the baited food rewards out of all the arms. And they have to go just once. But the young rats, they're really good at going to one and then they go to another. And then they remember not to go to those two and then they'll go to another and another. And then there's a complicated pattern that they remember. They hold all that in their memory. Humans, they just go one, two, three, four, five, six, seven, eight in a circle. They don't need memory. They don't use that memory. They try to avoid using their memory at all costs. So I had to then do something cheeky. I had to block pathways to have them do exactly what rats do. So this is what I did here. So I block four pathways. And I force people. This is S refers to start position. So the start position is always the same. By the way, it's a fundamental component of developing a habit. You always have to have exactly the same start, same target. Otherwise, if things are new, you don't develop a habit. So start is the same. You block four pathways. And what you do is you get people to go to the open pathways. Pick up here the target objects. You can't see them from the center. It's a memory task. So hide the objects where. So there's a little hole. There's a pit. And there's stairs. So they can go down the stairs and collect the object. And then go back up. And then they have to use their memory and avoid going to the four places that were open. And then guess what I do? I have everything open. And I'll say, huh, use your memory. OK, so where did you go before? The places where you already collected objects are no objects there. So you have to go to the new places. So that's what they have to do. You see, these two pathways were not visited in the previous part. And so they have to then remember that they had already gone to these two places and avoid going there. Otherwise, it would be a mistake. So how do people do this? There are several strategies that were allowed on purpose so that I could measure this hippocampus versus caudate. And if you control things too much, you only get hippocampal, right? For example, if you test people in the virtual town asking people to derive shortcuts from you start positions, well, by definition, they need a cognitive map to develop the shortcut. So that's the traditional way in which people would measure function of the hippocampus. They would force people to use their hippocampus and measure variability, right? Who's good, who's bad at using their hippocampus in that context. But that's not what I did. I confused the two strategies. The hippocampal spatial strategy and the habit-based strategy on purpose. This was never done before in humans. It was done in rodents. And it's called a dual solution task. So what do I do? So what are the two strategies here? So you could learn from the start position to hang a right, skip a pathway, go to the next one, skip the next one, and go to the next two. So you can learn a whole sequence now without a single landmark or just from your start position. From your start position, you could learn to do this. And what's going to happen is that you can get all objects perfectly well without paying attention to the environmental landmarks. So then I can then remove the landmarks and see who's doing well in that condition. That's the beauty of using virtual reality. The other strategy involves actually paying attention to the landmarks when you pick up the object. So you know that object was a little bit like in this one, it could be a little bit to the right of the tree, or there was a stone, or there was at some point like a sunset or a mountain. And you know basically where you've been in the environment. So then if I remove the environment, what happens? Then I can see who needed the environment to navigate because then people will make errors. And errors in this part is good in the sense that it's showing me who's using the hippocampus. It's not a measure of learning. In this part, it's a probe. It tells us what strategy people were using. Are they using a habit, open, closed? I shouldn't say habit. I used to call it non-spatial, but the practice of this non-spatial leads to habit. Technically, that's how we're supposed to say it. And so do they use like a series of open and closed pathways from a specific starting position? So the starting position could be their own or could be a landmark. But either way, it's just one item that's used for a whole sequence. And then what you can measure when you have the probe is that they have a whole sequence perfectly correct. So then I know who's using the sequence and who's using the landmarks. So we're gonna call the people who use the relationship between landmarks spatial. That's the cognitive map defending on the hippocampus. And we showed really nicely here in our very first FMRI study, nice FMRI activity in the hippocampus. In fact, when I presented this the first time years ago, people thought I was masking out all the activity all over the brain. I didn't. This is it. This is all the activity you're gonna get. It's really hippocampus, okay? Why? Because there's a control task where they move around in the same environment. So you remove all the motor, all the visual spatial. And all you have is a cognitive mapping. What's the difference between the two conditions? Is the cognitive mapping? And then you get this nice FMRI activity in the hippocampus. And then the ones who use the open and closed pathways as a sequence that leads to a habit that's called the stimulus response that depends on the caudate. So we knew that from the rodents. And here we go. We were able to show that in humans. Nice FMRI activity in the caudate nucleus of our response learners in this. This is really, it was really nice. I was very excited when I first got these results. You know what I mean? Imagine you take a rat task, you spend four years to try to get humans to behave like rats, and then you get the rat results. It's fun. Okay, so, and by the way, this is a comment I wanted to sit to make in another part of the course is that with FMRI, the tricky thing is you can get random effects. And I have a publication on that. We're just changing the control, modulated my FMRI activity in the hippocampus from being active to being a negative activity in the hippocampus, just by changing the control. In fact, it was the same frames. And what I did is I contrasted control before and control after, and then the same frames were leading to either significant FMRI activity in the hippocampus or significant negative activity in the hippocampus. So that's also why it was so important for me to have a rat model, because I wanted to know that what I measure is real. And that's the only way I could know it's real. With FMRI, you could never be sure. Okay. All right, so, and then what happened was we had hypothesized, so we, in our first study, we tested 50 subjects. We had hypothesized that everybody would start using a cognitive mapping strategy, and with practice, they would be using more of a serious response strategy, you know, with habit development, but that's not what happened. That was really weird. Half the people from the start used this response strategy. It's as if they completely shortcut avoided using this cognitive mapping strategy. And what I didn't say is that something that's very interesting and concurrent with the Rudin studies is that this FMRI activity that I'm showing here was in the first trial. So there was a hippocampal activity in trial one and two, and nothing in the caudate group at all, anywhere. But if you continue with training, at the end of training, you get this caudate activity. Just like in habit development. So when we run our analyses, we always run analyses, no matter how long it takes for people to learn, we'll do first trials and last trials. And then you get this very nice caudate activity when you look at the last trials. So it's really representative of habit development, but another really tricky thing that's kind of fun for you to know is that building a cognitive map is actually cognitively demanding. It takes longer, people make more errors. So maybe that's why people, they don't want to bother learning all these irrelevant details in the environment and they just want to automatize the whole thing. And that could help us explain why from the start we had like 50% not using their hippocampus. So then we were wondering, well, okay, well, if they're not using their hippocampus, what's going on, is there a difference in the brains of the people who start using their hippocampus versus those who don't? And honestly, I didn't think I would find anything, but I thought, I'm a scientist, I'm supposed to investigate these things, even if I think I'm wasting my time. Turns out there are cremator differences in the hippocampus of young adults. Back then it wasn't known. I mean, we're talking, this was a discovery I made in 2003. It was published in 2007, because it got rejected everywhere, it had to be wrong, but it was replicated 12 times. But still then it had to be wrong. So, what was I saying? So there were these differences back then. People thought all young adults have a nice healthy hippocampus and the hippocampus degrades with age. That's a dogma, right? And then the hippocampus of everybody degrades with age and there were some studies already showing then that there were age-related differences, even in navigation, in terms of FMRI activity, and great matter. So, how could it be? Why is it that in young adults we see these differences? This was crazy. So here are the differences just to make sure that everybody sees them. So this is showing now a voxel-based morphometry analysis. Who knows what that is or who doesn't know? Okay, so what we do is this voxel by voxel correlation with another measure. So let's say that you know that with age the frontal cortex shrinks, right? So what you could do is take the brains of a whole bunch of people and write in your analysis algorithm their age and you see what voxel correlates with age and you do this for each voxel of the whole brain. So you take the whole brain like, okay, let's look at the one millimeter here and then the one millimeter next to it. Does it correlate to age? So if there was a shrinkage of the frontal cortex with age you would get a significant correlation by doing this voxel by voxel analysis. Okay, so that's called voxel-based morphometry. Is that clear? Okay, so then what you can do is you can then do that same voxel by voxel analysis and correlate that with what? With the probe errors. So that's the probe, remember? So people made errors, so if people made more errors it means they relied more on landmarks. So these were the people who need their hippocampus more and that's exactly what we found, that was crazy. Look at that, people who make more errors had more gray matter in their hippocampus proving that they needed landmarks. Remember that's a good thing here. This often confuses people. Okay, and then look at that, there's some people who had zero errors. That means they didn't use landmarks at all when I hit everything, zero errors, okay? And these are the ones who had the smallest hippocampus, the least gray matter in the hippocampus, okay? But look at what's below. They had the most gray matter in the caudate nucleus, like that was wild, in fact it was such a huge difference we actually completely missed it initially. There was this big blob anterior to the average caudate and normally in MRI analysis you average the whole group and then you put your statistics on the average and the statistical map was anterior to the caudate so we missed that effect. But there was this big thing and I remember with my research assistant we're like, well what's that big thing? And at some point I deviated from the standard we have running the analyses and I said, why don't we put under to visualize this statistics, we put the brain of one response learner, bang, it was the caudate. It was so far anterior that it was just beyond the average. Okay, so there are really big differences and it's not that the whole thing is shifted because there are also differences in the posterior caudate, in the tail of the caudate. So there are really big differences here between the people who really avoid using their hippocampus from the start. When they're young, like the average age is 27 years old in this group. Okay, and here are the results I was talking about in my intro on the negative correlation between the striatum and the hippocampus. So striatum includes the caudate nucleus, the reason I call it striatum here to be technically correct because rodents have the caudate merged with a putamen and nucleus accumbens together and it's formed into one structure called striatum. And it was really beautiful in the human anatomy is that with the development of the brain what you get is these structures are stretched out and then you get nice tria. So you can actually see how the brain was labeled, how that brain structure was labeled. It was named striatum because there are actually real stria there. And you'll see it in all the anatomy textbooks. Just look for that next time you see a caudate nucleus, human caudate. Okay, so anyway, so this is just to say it's not a mistake, it's meant to say here's striatum because I wanted to show in this publication that the really comparable effects in the mouse and the human showing this negative correlation between the hippocampus and striatal gray matter. And therefore it begs the question whether this is a fundamental neurobiological mechanism if we see it across species. So in other words, the hippocampus is active or the caudate may be not both at the same time and that's what the while result in something like that looks like this. All right, so then the big question is, okay, so we talked about how here when people have a smaller hippocampus, so these are the, see this is the hippocampus on the x-axis, if it's here it's smaller. So these guys here that have a smaller hippocampus larger caudate nucleus, well they might be more, these are healthy guys, but they might be more at risk of some neurological and psychiatric disorders. So then I used to say to people, these people probably shouldn't be engaging in activities that will stimulate their caudate even more because it's gonna be bad for their hippocampus. And we certainly shouldn't do that in aging because in aging we know the hippocampus is smaller so we shouldn't be engaging the caudate, right? Is that logical? Does everybody get the rationale? Do this, if you get it, no? Okay, yeah, all right, not, I can repeat. All right, so based on that I thought, hey, this is important, you know, I was telling people about it and you know what people told me? I don't believe you, you have to prove it. So I thought, what do they want me to do? They want me to shrink people's hippocampus? And the answer was yes, so you know what I did? I did it. Okay, so how do we shrink the hippocampus? Well, who read my papers here? Okay, so good, so I won't spoil it. It's not spoiled for you. You can read them after, they're actually not so bad. So okay, so these are characteristics that I've picked up from the literature what engages the hippocampus and what engages the caudate. So when I was thinking of my experimental design, I was like, okay, well how can I find something that will engage the caudate to prove that point that no one wants to believe? In fact, it's so bad that even right now there are clinical trials going on at all ages where people are stimulating the caudate, okay? Because they think that it's a good thing. So, and I'll show you some data that are interesting, I'll speak to that. Okay, so who here could guess? What would be activities that would stimulate the caudate? So it would be more like that would engage the automatization of behavior like habit that involve lots of repetition that will learn slowly where you have rapid feedback. That's an important part, right? So it's a reward. The caudate is part of the tritum which is also an area of the brain involved in addiction, right, and it's not a coincidence because to make into a habit something, you have to be successful, right? If you get up and cross your legs and fall, you don't want to do that out of habit every time you walk for the rest of your life. It would be as practical. So you want to make into habit things that are successful. So it's not the coincidence that there are actually opioid receptors in the chronic nucleus. All right, so it'll be sensitive to immediate reward and a fast feedback. This is just based on studies in literature and the stress will promote the caudate. So who can guess what's an activity that people engage that would be perfectly ethical you're not allowed to stay? So that would be perfectly ethical to practice that would stimulate the caudate. Who can guess? Oh, that's good, you got it. So that's what we did. So we train people for three months to play video games, six hours per week. It's not that much and guess what happened? Well, we did three studies. So we did two training studies. We replicated that effect twice. It's necessary now because now no one believes anything. So we did it three times. We did two training study and one cross sectional. In the cross sectional, what did we do? We recruited gamers, scanned them and looked at whether there were already differences in their hippocampus and there were. So when we recruit gamers, first of all, 83% use stimulus response strategies in the task I showed you, the radial maze, we call it the foreign aid virtual maze, 83%. Remember, I had said before that it was 50% in my first study. Here we get, so 50% were using response when I did the initial study but here if you take gamers it's 83% who use response. Already it's a significantly higher proportion are using response strategies. And look at that, the non-gamers, then if you exclude all the gamers then you get 43% using stimulus response strategies and then you get a significant reduction in gray matter in the hippocampus in the gamers. Now we don't know whether it's because gamers are already having a small hippocampus that they're interested, you know, maybe they have already a large caudate, they're reward seekers and they want this immediate reward so they're playing these video games and the video games has no impact on their brain. So we had to do the longitudinal study which I'm showing here. And what we did is we actually took non-gamers, trained them for three months, scanned them before and after and here we see shrinkage of their hippocampus and we did that in two studies with two different games. So the other one was a zombie killing game. And so what you see here is shrinkage of the hippocampus but interestingly it was only the response learners. If you look at spatial learners, so again we test them on the read-all maze, then you divide people, okay, you run the analysis separately. The ones who use spatial strategies and the ones who use response strategies to see whether the impact of video games is different. You know what happened? Spatial learners grew their hippocampus. So in other words, spatial learners were probably using a spatial strategy also in the game, okay? The problem is that generally speaking, spatial learners are not attracted to playing these games. It's 83% of the people who are attracted to play these games who will use response strategies. So in a large part, this will be detrimental to the people who want to play, right? Was it a first-person shooter game? Yeah, yeah. Okay, and the other really terrible thing that we did is we actually measured growth in the amygdala here as a result of this call of duty first-person shooter games. Like I said, it's not very good because there are some studies showing that PTSD symptoms correlate to gray matter in the amygdala. So the amygdala is important for fear and it's important for lots of things that are really great for survival, but you don't want to have too much fear in your life and you don't want to have an overactive amygdala. So yeah, so unfortunately, we tried to reverse the damage, but we didn't get the grant. No way. So they just left. Okay. So, you know, you might still be skeptical whether this is a fundamental property of the brain. Yeah? Just one quick question. What was the average A-18 sample? You know what? People were all in their 20s. It was between 18 and 35, the exact age I can't remember, but the paper is in me. Yeah, I was just thinking that, especially among the 120s, video games are so popular that that's the other thing that'd be very challenging to recruit a sample of non-gamers. Think of all the different kinds of games. Yeah. There's still a few. But yeah, no, I imagine I'm still coming out. I'm still wondering though, that there's a possible on the side of playing some little smart phone game. There could be some kind of inflator. Oh, okay. So, but here we really, in this study, we really selected the non-gamers in terms of the action video games. I can't remember now if it was also 3D platform games. I think we would have to look at the paper, but it was really, if they did a few little things, like tetrics on their phone, they would not have been excluded. Okay, well, it turns out that when I was talking to people about this, some scientists came up with this paper and said, hey, Verity, you're right. If you stimulate the caudate, the hippocampus shrinks, even in patients with Parkinson's disease that get deep brain stimulation. So in this case, they don't get the electrode in the caudate, but they get an electrode in an area that will overall enhance activity of the caudate nucleus that gets the patients to be more mobile. So it's really helpful in one way, but after 15 months, what you see in red is a decrease in the volume of the hippocampus. Okay, so this here is post-deep brain stimulation 15 months after in blue as before. So you see this huge difference that's significant. So somehow, engaging the network that involves the caudate nucleus and here actually there was growth in the putamen. So you can see there really is growth in that network, but not the caudate, but still it engages that network. It will lead to shrinkage in the hippocampus. So that was, I thought, very interesting corroborating evidence of this idea that there's this negative correlation and it's really a fundamental biological mechanism, negative correlation between the hippocampus and let's say striatum, then to be technically correct. All right, so we talked about this negative correlation between these two structures and it turns out that when people use response strategies in our studies, they also are more likely to play action video games, which I showed, but I didn't show, and I will show, they're more likely to be smoking, to drink alcohol, to, I wrote smoking and then I wrote tobacco. I think I meant to say smoking cannabis. So they smoke, they're more likely to be cannabis users. They drink double the alcohol, more lifetime use of tobacco, but in older adults there's also dietary differences. There are people who use response strategies, eat fewer green vegetables. They have higher blood LDL cholesterol. It's interesting because all of these, coincidentally, are risk factors or what's called modifiable risk factors for Alzheimer's disease. So maybe it's not a coincidence, you know? And that's important to understand what's the underlying mechanism because if it's not a coincidence, let's say that you teach people that if they stop smoking, they will decrease their risk of having Alzheimer's disease. And what do they do because they're bored? Play video games. If the fundamental reason is not the smoking, but the stimulation of reward-seeking behavior, then they're not gonna decrease their chance of having Alzheimer's disease. So we have to understand the mechanism. We have to understand what's happening if we wanna help and intervene and reduce risks of having these disorders. Response? Response, very disaster. It's more prevalent among people who have people with Alzheimer's disease being studied and see whether they have the response than spatial. So it's not spatial response, but we measured the volume of the caudate. And look at that. Patients with Alzheimer's disease have a significantly higher volume of the caudate compared to undiagnosed controls. And I'm just burning to tell you that no one cares. No one is studying the caudate in Alzheimer's besides me. Your genesis seems right, I'm right. So how long does the striatum work in a care to have more gray matter? Turns out that there is genesis actually in the striatum, but we actually don't even think we're measuring genesis. We did a rodent study that I don't think I have here, where we actually sliced up the brains of mice that were trained on a spatial task. And we looked at neurons, because they don't let us do that in humans. So, but there weren't more neurons, there were more synapses. Yeah, so it's possible that the increased gray matter is just representing more connections in the network. But if you speak to some basal gang or the other sort of urologists, they'll tell you actually there is neuron genesis in this striatum. So I haven't gone that far to dig up those papers, never found them. Yes, everyone asks me this. It seems like it would be a great target population. And I think that they would probably be. Oh, that's right. And you know what's amazing about them when they get therapy that is successful for them, whether it's pharma or cognitive, they get a decrease in pet binding in the caudate. No, but you know what? With ADHD, I found an article that said that the cognitive symptoms are identical with aging. So even though they don't have amyloid, they may have an overactive caudate, which I've shown in another study. This could come at a cost to the hippocampus. So when they get older, they may not have amyloid, but they have the same cognitive symptoms as someone who's not using their hippocampus. In other words, I think the cognitive symptoms relate to the brain that you're using, you know, like what part of the brain you're not using. The hoarding behavior is happening. Many of all the medications that they need. I don't understand your point, though. They're starting to get like the hoarding reported as kind of like a type of... Oh, that's what you meant. I see. Very interesting, it's true. It could be related to an overactive caudate. Food for thought. Okay. Okay, so anyway, so this was just like a reminder that the hippocampus is involving all these disorders, so then we wanna know what leads to stimulation of the hippocampus, what leads to stimulation of the caudate nucleus. And here I have, from the literature, three factors that I've identified that will lead to, that would generate more activity in the caudate nucleus. I see time is flying so quickly. Let me see, what do I wanna do? Okay, I'm gonna have to then skip a few things compared to what's in the abstract. So, okay, I just reorganized my talk. So there's three things, three factors that are really fundamental to stimulating activity and the caudate already spoke about two of them and a little bit about the third. So the repetition, right, with routine, we get automatization of behavior and we showed it in our FMRI activity that you only get late learning caudate activity. You have stress and also reward. So when you look at the literature, reward like alcohol or amphetamine, cocaine gambling, chocolate video games, probably other things like, I don't know, sex, will also engage in, will engage the caudate nucleus. And it's also known that stress leads to relapse in addiction. So it could be by the very pathway we discussed where stress will modulate the amygdala that has this monosynaptic, you know, promotion of caudate activity. And here are just a few examples that I briefly mentioned is the fact that response learners smoke more tobacco here than spatial learners. These are the data or they're more likely to be cannabis users. These are the response learners. 67% were cannabis users and double were drinking the alcohol. This is a prenatal stress study that I did with last Schwabe. He's done a lot of beautiful work on this dual solution tasks and stress. And he is the one who had shown that if you stress individuals, you'll promote the caudate nucleus. And together we did a study where we asked people to fill out a questionnaire with their mom about the stress that the mom had when the individual was in utero. And reviewers didn't like that experimental design because they wanted to see a prospective study, but we thought, you know, it might take 20 years to answer these reviewer comments. So what we did is we just submitted the paper to another journal and these are the results. And what we showed is that 80% of the people in the prenatal stress were using response strategies. So it seems like the stress even in utero can have an impact on strategies that the individual use in their everyday life. This is also a little fun result. We found that there's a sex difference and a strategy with aging that helps explain why women are more prone to having Alzheimer's disease. So it turns out that if you look at response, if you just look at the white bars, it's the response women that have the smallest amount of gray matter in their hippocampus. And we predict that of course based on literature where other people have shown that the small hippocampus is predictive of future diagnosis, it's really gonna be the response learners that will be more vulnerable, not the spatial learners. Look at that, the spatial women have a huge hippocampus. And that's nice, when you get these kinds of fine distinctions where you show that it's not everybody behaving the same, it's really helpful because otherwise, you can't explain the data. There's a lot of variability in the ability of women to navigate in the environment and their spatial skills that represent possibly variability in their hippocampus. So it's nice to be able to show that now we can explain that variability with the response strategies. Okay, so I'm gonna skip a few slides and jump to this one. All right, so in a study of aging, oh no, I went too far, I'm gonna first show the task. Okay, so what we did is at some point, we tested children and in an initial study, we had controls of, oh yeah, I told you about it already, so I have to go back one. Okay, this is the one I told you about when I said this is the study that started getting me interested in cultural work was because what we had found is that patients with damage to the hippocampus that in, or these are epilepsy patients that had medial temporal resection that included damage to the hippocampus, the only ones who were impaired with long-term training were the people who tried to use spatial strategies. If you look here in green or in purple, these are people with damage to the hippocampus who tried to use response strategies. That's really cool because it's a completely different method, different people, different brain damage or a brain damage selective to the hippocampus and we see that you only get an impairment when people try to use their spatial memory, which is proof that these systems work independently of each other and it was actually in this study that we had found that most of the controls were using response strategies and we're like, what's going on there? I thought that everyone would have the same level of spatial response across age. This is what made us, got us interested in looking at lifespan and so we tested almost 250 subjects, children who were eight years old and look at that, most of them, about 80%, I think it's 85 actually, were using spatial strategies, completely opposite trend that I've shown you so far. So in other words, children all start by looking at landmarks in the environment and then we get the 50% I had mentioned in my initial studies and if you continue and test older adults, what you get is an increase in response strategies and a decrease in spatial strategies. So it seems like there's a decrease in spatial strategies across the whole lifespan. So then we thought, hey, wait a second, this is really important because what happens then with people who use spatial memory in aging? Do they have a larger hippocampus? Does that mean that they are more protected against dementia or Alzheimer's, you know, like, hey, and of course when we asked these questions, people back then thought this was completely ridiculous because everybody's hippocampus shrinks with age, it's a fact, I should know that. Okay, so we still decided to investigate it and we did it with a different task. So this is, we call it pairs for short because there's a pairs of pathways over here and we're gonna do this together. So let's say that you go into this pathway and your job is to find a target object, again there's a pit, you go down the stairs and you see that here there's nothing. So what your job is next time is don't go there. Okay, your job is to go to the other one. So you're always presented two. So it's a pair and when one pathway is empty, you have to go to the other one and then if you find the object, you have to keep going there, simple. So we train people on six different pairs, they have to reach criteria and then we move to another phase. So let's say in this example that the object was over here. So I'd like everyone to do it. So everyone look and try to memorize the position of the object. Over, I lost my mouse, okay. So we're here, did everybody see? Okay, so then when you reach criterion, of course this is the 3G environment so you would go and walk and see maybe more landmarks and you would do repeated training. So it's a little bit artificial what I'm doing here but I wanna give you an idea. So then when people learn to criterion, I show this. Here, this one, this image below. How many people would go to this pathway? How many people would go to this pathway? Okay, a lot of people did not answer. I want you to answer at least in your head. So we'll do it again. How many people would go here? And how many people would go here? Okay, the ones who didn't raise their hand, do you have a clear answer before I give it away? It's just because you're in a radial maze, there's walls all around blocking you to enter the other pathways. So if you were to turn around, you'd just see brick walls. That's terrible. We're so mean, you know, we confuse people on purpose. All right, so is everyone ready for me to tell you the answer? Anyone not ready? Okay, all right, so the target was actually over here. So no one, no one who answered answered wrong. Everybody who answered answered correct, some didn't answer, so I don't know what you were thinking. But, so why is it here? Someone who did it. It's all because of the peaks. Okay, because you're using the relationship between the environmental landmark and the target location. Some people don't do that. They'll say, oh, when I see the peaks, I go left. In case, in fact, I have a very funny story. One time I was invited, actually was my student, was an invited speaker and I was at the talk. And the person who invited, who was coordinating, he was a professor, he argued with everyone that the correct location was this one, whoops, this one. He couldn't see the relationship with environmental landmarks. Some people don't see it. It seems amazing, but it's true. And the ones who don't see that fine relationship, they're the ones who don't use their hippocampus. They're using seamless response. They say, when I see the peak, just go left. We tried, we thought so, but we didn't, we never found an effect. And maybe it's because in some of our studies, we find that gray matter in the right hippocampus correlates with gray matter in the left hippocampus. So it could be that it's not one or the other, but they're both somehow working and there's just variability in such a way that they don't correlate. Okay, so what happened with aging? So we replicated the other results I just showed you where there's a decrease in spatial strategies with aging. What we found, so what we do in this, and that's also the beauty of these experiments with radial mazes is you can train people to reach criteria. So if there's a learning problem because of motivation or like a lack of motivation that can happen with aging or a bit mild depression or maybe they don't see as well or like differences in affect, you control for all of that because you don't look at learning. You look at what happened after learning, right? So that's really nice. You remove a lot of confounds when you do an experiment that way. And so look, you can take then the last trading trials, you see that they all reach criteria, the young and the old, and this is the performance in the last trials of stage one, the first stage before criteria has reached. And look what happened when we shift the perspective, there's a decrease in performance in such a way that with aging, older adults use stimulus response strategies. That is dependent on what? Like Cod-8, Cod-8 nucleus and we showed it. So we show now that, so young adults have nice FM activity in the hippocampus, there was no global activity in the hippocampus of older adults that replicates the findings in the literature. Great, everyone would be happy if we just published that but no, no, we said it depends on the Cod-8. Oh, that disturbs people. It's not that there's just an impairment, that they're using a different part of the brain. And here, this was the worst, is we showed that there's nice FM activity in the hippocampus of older adults that use spatial strategies. So in other words, if you use landmarks in your environment, there will be more blood flow that we measure here, even in older adults. And this was the very first time it was demonstrated in older adults. So that's good news for all of us because it means that when we get older, if we pay attention to landmarks, we might be engaging our hippocampus. And what we see is just more focal peak in the Cod-8 if you just get the response learners in the analysis. And then we have corresponding evidence for gray matter. People who use spatial strategies have more gray matter in the hippocampus. So that's very good news for older adults and all of us. We replicated this study in a really complicated way because we wanted to look at the impact of the apoE4 gene on the brain with respect to strategies. Why was it complicated? Because the apoE4 gene has a prevalence of about 15 to 20%. So you have to test hundreds of people to be able to get a sample that's large enough for doing this study. So we tested, well, we first recruited 515 people. And out of the 515, there was 166 that had perfectly normal, healthy cognition. We excluded everybody else because they could have had confounding factors. Out of those, then we genotyped everyone, scanned everyone who wanted to be scanned and here are the results. And look at what happened. ApoE4 carriers, these are the ones that have a high risk of Alzheimer's. All of these have a high risk of Alzheimer's. You see nice FMR activity in their hippocampus when they use spatial memory. This is super good news. It means the hippocampus can be functional even if you're a apoE4 carrier. And what you see here is the response learners are using their Cod8. Same as what I've shown you lots of times before. And when we look at gray matter, look at that. ApoE4 carriers that use spatial strategies have more gray matter in the entorhinal cortex, also more in hippocampus, I'm just not showing it here, than the response learners. That is very good news, you know why? ApoE4 carriers have sometimes committed suicide when they knew their genotype for fear of getting Alzheimer's. And now what we're saying is you don't have to commit suicide. You can train your hippocampus. All right, and look at that. This is really the fun one. It's the one where you see nothing because there is nothing. The brains of apoE4 carriers that use spatial strategies are exactly the same as non-apoE4. That's like the best news. Okay, and then the effect is replicated here. The less gray matter in the entorhinal cortex of response learners is there even when you contrast to non-E4 response learners. So really there's something specific going on. Okay, so here we talked about this. The Alzheimer's patients have a larger caudate and smaller hippocampus. And here's some of the fun cultural studies that I've done. This is me in an igloo, it's a little bright. You can't see very much the bricks over here, but I actually went up north over here in iglulik. This is pretty close to the start of the expedition to the North Pole. They start about here, okay? And Montreal is over here, we're down south. Okay, so we're southerners for the Inuit. And look at what happened. So I've tested Inuit hunters who were older. These are the results. Look at that, they all use spatial strategies. Why did I do that? These are Inuit who were born before 1959. It means they were born before the white men went there and changed everything. So they were born in igloos, they were traveling with dog sleds, they didn't have store-bought food, they didn't have internet or ski dues or GPS or video games or Facebook or TV when they grew up. Okay, the young adults had everything when they grew up and look what happened. Exactly the same proportion of spatial response as us. In one generation, same genetic pool. In one generation, we see this change in strategies. What's your sample size? Oh, it's tiny, but for these studies it's huge. So it's eight and nine subjects per group. Yeah, but when you have a village of 200 that includes all ages, it's people who do these studies tell me it's amazing. Reviewers will appreciate that, but we'll see. I haven't submitted that yet. Okay, so I'm gonna skip this. I just wanted to mention, so we did a study to try to stimulate the hippercampus. So we didn't just want to shrink it, but we did all this because we thought we can actually design studies that will enhance activity in the hippercampus. And I've been working on this study since 2004 and it was inspired by a paper that I published in 1998. This is the result of my PhD work actually. We tested a very special cohort of patients that had a very small selective lesion to the hippercampus. And you can see it over here, it's very rare to get patients like that. And they were fine at all memory tasks that I gave them verbal and spatial navigation, everything except one, one that involved learning the positions of landmarks and having to then memorize the positions in relation to each other and draw an overhead map. So that was a big inspiration for me to develop a task that will really encourage activity in the hippercampus. And so we spent years developing this task that starts with very simple environments, go find the white circle and the yellow room, then there's here, go find, I don't know, the microwave in the kitchen, in this apartment, there's a museum, there's 46 different environments. So, and then it gets more and more complex then we have big cities. And in all of these situations, we encourage cognitive mapping like I explained, where you have to draw relationships between landmarks and then draw overhead maps. That seems to be critical. Placebo involved watching documentaries, so it was visual spatial. We also had the memory component, they have to answer a questionnaire. And what we find, we find that there wasn't improvement in memory, here it's just a sample, but in most memory tasks, we see an improvement in the experimental group. So this is in green, so you see from post to pre, pre to post, there's a decrease in error or increase in memory for details, things like that. So there's a significant effect in all of these conditions for the experimental, but look at the placebo here, it's really cool. There's a real placebo effect that was documented. So it's known now that there are placebo effects that are quantifiable experimentally, where all you have to do is tell people they're engaged in this amazing experiment that will, you know, heighten their functions and that will actually lead to improvement in scores. And so we see that here in the placebo, but only in one of the four. So there's still fewer tasks where we see this improvement and there's no change in the hippocampus, that's what's really critical. So the no contact control and the placebo have no change, but what we saw is growth in the hippocampus of our experimental group, and you can see it over here. So everything that's highlighted shows growth, but I'm gonna focus here on the hippocampus. This is a coronal section blown up and you see nice increase in gray matter shown by these voxels. And this is showing six months later some savings. It's kind of fun because while we didn't expect to see an effect, you know, if you go to the gym for, I forgot to mention, it's a training over eight weeks, two hours per week. So imagine you went and did this at the gym. Do you expect to see still some effects six months later? Maybe not. So our explanation is maybe the fact that it involves ecologically valid environments, you know, rooms, maybe people were still engaging and that's what people told us actually, that they were engaging in visual spatial memory activities similar to what they learned. So maybe that could help explain the savings. We see an effect also in MCI patients. So here you see growth in the hippocampus of MCI. This is post minus pre six months later, no growth in the controls in the hippocampus. Look at that, there's all this shrinkage going on in the hippocampus of controls. Okay, so control MCI, so these are people at risk of Alzheimer's disease, will have quantifiable shrinkage in their brain and that shrinkage is prevented with this experimental manipulation. Okay, so now we're gonna go to the last part of the talk in the last few minutes. So I was involved in this study run by a group in London at the University College London. We got actually a pretty nice, a pretty big grant by Dutch Telecom because they wanted to promote research on Alzheimer's disease. So they got a company called Glitchers to develop spatial memory tasks that would be available for free on apps on mobile phones. And it's called C-Hero, you can go and download it for free and play it. I wrote 2.7 million because that's the last number I had but there was a VBC paper that came out, journal article that says that now that we're up to four million. So there were four million people who played the game. This paper is in your reading list. In the paper it says 2.7. We have the radial maze in there but we haven't yet analyzed the data. I'm gonna show you data from a small spatial memory task. So there are here different levels where people had to navigate and remember the turns that they made and in this one experiment they have to remember what's their start position. So to analyze the data correctly we had several components to the task. We had a visual motor skill so you can then equate the skill across people that played it all over the world. Then the path integration, that's what I was talking about where you do a series of turns and have to remember your start position and I'll show you a little video. And then there was the wayfinding task so you have to memorize a map and then find a target. Navigational strategies, that's my radial maze and then they had like a skill task where you have to take a picture of a monster and the game involved somebody running around looking for these monsters because these are monsters that were documented by the player, the player's father who had Alzheimer's disease and the documentation was all in a book that got lost so we're trying to reproduce it. That was the game, it's actually fun. I mean there's this big, fun pink monster that comes up, they look friendly even though they're monsters and they have to take a picture at the right time. Okay so we had 2.7 million players a few months ago so but that actually involves a lot of playing time, the equivalent of 63 years and 30 million dollars of research money and we had 1.3 million actually who gave their age and their country of origin and I'm gonna show some data based on that sample. Okay and it was also showcased at the United Nations. Okay and here are the questions of what happens over the lifespan, if there are differences between men and women and how it varies across the world population and this is the part where I'm supposed to find the video. So just give me a second, yeah. So you want me to skip, why don't I skip the video then? Okay so let me just, if I have to end soon I'm gonna show you the interesting results which are here, yeah and then we're done. Okay so these are the results, again you just have to point to where was your start position and then errors are measured. You had three choices and we look at errors with respect to global population across the whole world and what we see in dark are the best performance and so what you see is the best performance were actually in the northern European countries, North America and Australia, New Zealand. If you look at that same performance per country, it turns out it correlates to the GDP, to the gross domestic product of a country. So it means that the countries that were the wealthiest are the ones that actually perform best at this task and the poorest countries are the ones that perform worst. So it's very interesting and I think this is something that we need to think about, like how does it go? Is it that you have a wealthy country, therefore education and health is good, therefore people do well or is it the opposite that people do well, therefore the country is wealthy? Because, healthy, let's say here we're saying healthy like not having schizophrenia. You know but does it do well on the spatial thing that you're using cognitive mechanisms? No, we think it's a hippocampal task but it wasn't quantified, right? Because so far we just did the large studies so we need to run the imaging to validate that but it was thought that this was a spatial task, that initial task. It requires really being able to account for your spatial move. So yeah, so that's the question. Is this representative of a healthy hippocampus and decreased risk of neurological and psychiatric disorders? And the big question is how does it go? Is it that when people have fewer depression, they're better members of society and contribute and therefore we have a wealthier society or is it the opposite? A wealthier society creates individuals that are well taken care of and therefore they perform better. So are the apps representative of the larger population of the country especially in the developing world? Of course, of course. But we have some data coming up that I'm not allowed to talk about but it will come up in November. Okay, and then here we found that there was a correlation between the gender, so there are gender differences and the gap between men and women correlates also with gender gap index in terms of the difference between salaries of men and women. Okay, so countries where there's a very big difference between the salary of men and women are where there's a big difference between the performance of men and women in this task. And the Northern European countries that are egalitarian, there's very little difference between the performance of men and women. That was interesting. Okay, so. I was also counting on the question, like are people are working or not working? Because I just can't imagine if you get the data from China, that's huge demographic differences across. I don't believe like Beijing is any per capita GDP will be lower than any whatever the we're saying developed country. We can't, so the thing is we had to struggle with this because when you do an app like that the more questions you ask, the fewer people will play the game. So we had to fight all the time for every single question so we don't have as much information as we wanted. We couldn't do this as scientists because we had to work with a game company basically. It was very, very difficult at times but that's because that's how it is. The gaming company's goal is not the same as the scientist's goal. So I'm sorry, I can't answer all these questions but I did skip over the age effect which is over here. There is actually a huge effect of age and there's a significant difference at every year of age. And that's my general summary. Therefore, is that training, spatial memory increases gray matter in the hippocampus, action video games will shrink the hippocampus. Therefore, cognitive map users may be protected against Alzheimer's disease and better spatial memory seems to be associated with GDP. If you want more information, I have a free public information website called Vibo Solutions. And then there's a book that just came out on human, it's the first book on human spatial navigation where I'm a co-author. And I wanted to thank my collaborators, like three pages of collaborators because these studies were insanely difficult to run and my sponsors and thank you for listening.