How brain conditions affect memory with Dr. Bradley Lega

[Music] Hello and welcome to the very first episode of the CVL podcast coming to you from the UT Dallas Center for Vitalongevity, which is dedicated to pursuing research that leads to cognitive health for life. Our goal is to educate you on the latest matters relating to cognition and the brain, and with each episode we'll be interviewing leading scientists and sharing the insights and suggestions to promote cognitive health throughout the lifespan. My name is Amber Kidwai, and my name is Sarah Manier, and welcome to the CVL podcast. [Music] In today's episode we're diving deep into the world of memory and your research with Dr. Bradley Lager, a renowned neurosurgeon and associate professor at UT Southwestern Medical Center. In this episode we discuss Dr. Lager's work using Stereo EEG to map brain activity in epilepsy patients. Stereo EEG is this really cool brain mapping approach which is minimally invasive, and it helps doctors find exactly where seizures start in the brain. It basically allows surgeons to target only the problematic area of the brain and avoid damage to nearby areas, which makes epilepsy treatment more precise and potentially safer for patients. We also go over some other innovative treatments for brain tumors in epilepsy and potential strategies for preserving and restoring memory function in patients with brain injuries and tumors, and the application of these strategies to age-related memory decline in healthy older adults. One of my favourite parts of this episode is where we get to learn about the discovery of time cells in the human hippocampus and their importance for memory formation. The topic of time cells is really fascinating. These are cells in the brain that logged the timing of events, and they were found in rodent brains decades ago. But Dr. Lager and his team were the first to find these in humans. And finally we discussed some practical advice for maintaining cognitive health as we age. So whether you're a science enthusiast or simply interested in keeping your mind sharp, join us as we explore the workings of our most complex organ. Today we are joined by Dr. Bradley Lager, a neurosurgeon and associate professor in the Department of Neurological Surgery at UT Southwestern Medical Center in Dallas. Dr. Lager has over 20 years of experience and specializes in neurosurgery for brain tumors and treating seizures. And he has recognised as a national expert in using advanced techniques like stereo EEG to locate the origin of epileptic seizures. His research focuses on understanding how brain conditions affect memory, with the goal of preserving and improving memory in patients with brain injuries or tumors. Dr. Lager, thank you so much for joining us today. So before we dive into the topic of memory and the conditions that affect memory function, could you tell us a bit about your background and how you got interested in neurosurgery and memory research? Sure. So in medical school at some point you have to decide the first question is whether you're interested more in medicine or surgery. So in medical school you have to decide whether you're interested in medicine or surgery. And I went into medical school without really a good sense of what I wanted to do. But once I started to have a good exposure to the different fields, I really found that I liked surgery. And then within surgery I had an opportunity to rotate with the neurosurgeons. And I found that I liked the type of surgery they're doing and I got along real well with them. I had a real good mentor in the field, a surgeon named Dr. Daniosher, who kind of explained to me how you can do interesting cognitive research as part of a career in neurosurgery also. So when I started looking for where to continue my training that was in my mind as something I wanted to work on, I had never done memory research before, but after a couple of false starts in other areas, I got connected with my kind of my research mentor in the field, the man named Mike Kahana. And he had sort of pioneered using brain recordings from patients with epilepsy to study questions that are fundamental to memory. That was it. Yeah. It's very interesting. Yeah. So as mentioned in the intro, you're one of only a handful of experts in the nation who can use a technique called stereo EEG to map brain activity, brain activity and epilepsy patients. So can you explain in simple terms what this involves and how it helps in treatment? Sure. So when you're trying to treat epilepsy, one of the questions that you have to decide is, is this a type of epilepsy that's coming from one small area, a scar area, you know, a place where there's something called a dysplasia, which is sort of like a funny way that the brain develops in one area. Or is it something that's not really coming from one area is it coming from multiple. And the different treatment option, the treatment options are different depending on that question. And so sometimes you can answer that question using what we call noninvasive data, noninvasive, just meaning something like a scan or an EEG, something that doesn't require, you know, surgery to get the information. But in other cases, you can get kind of a clue from the noninvasive data, but you can't decide definitively. And if you're trying to decide if there's a surgery that that you could potentially offer to stop the seizures, then sometimes you need a more to create a more precise map of where the seizures may be coming from. So stereo EEG is just a relatively less invasive way to get that information, placing these small 0.8 millimeter electrodes into the brain in order to figure out where the seizures may be coming from to make sure they're coming from one area to understand how they're starting and spreading. Very interesting. And is this typically like a procedure that you conduct if something like anti-apilaptic medications not working? Is this kind of like the second step from there? That's exactly right. So if someone has seizures or one seizure, we don't call that epilepsy. If the seizures then continue, then you call that epilepsy. And in probably two thirds of people in the world who have epilepsy, medicines are enough to stop the seizures. But that still leaves a large number of people, one third of people that epilepsy in whom the medicines themselves are not enough to stop the seizures. So the first before patients really even often come to our center at UT Southwestern or certainly would see me, they've tried multiple seizure medicines and kind of already shown that they're in the group of people where the medicines aren't going to be able to stop the seizures. So kind of sing on the topic of these like treatment. So UT Southwestern is also one of the few centers that offer a treatment called laser interstitial therapy or LITT for short for brain tumors and epilepsy. So can you tell us about this procedure and it's benefits for epilepsy patients? Sure. So let's say we talked a little bit earlier about this idea of trying to map out where the seizures may be coming from. And in some cases you can localize the seizures fairly precisely to one area of the brain. As I said, maybe some a scar from an old injury or a funny way the brain developed in just one small area. And in those cases, you know, up until you know, seven or eight years ago, the only option we had is what I would call traditional or open neurosurgery, you know, open the bone and then remove this area that's causing the seizures. Laser therapy or LITT is is a great tool to have, you know, in the toolkit because it allows you to remove these areas, these relatively smaller areas less invasively using us like a three millimeter opening in the bone and then placing the laser fiber into the into the area that you want to treat rather than open surgery. It's not an option for everyone, but for certain brain tumors and certain patients with epilepsy, it's a good option. So and part of the part of what you're trying to determine now or we try to determine as part of the mapping operation as if someone may be a candidate for that. So that's really interesting to learn about those techniques. So turning now towards your research. So your research focuses on preserving and restoring memory function in patients with brain injuries or tumors. So could you tell us a little bit about any strategies or interventions that you have found to be effective for this. Well, that is this is a very challenging problem. And so, you know, we I can't say that we've we found a therapy that that is on offer, you know, or something that that's available for patients overall. But that is the ultimate goal of my research. And so the ways that we're trying to solve the problem or go go about it are to understand what we call neurophysiology, which are really like brain wave and other patterns that are going on in the brain when you successfully remember something. And the idea is that by understanding these patterns better, mapping these patterns to different types of memory functions, we can understand some of the key ones that are that appear to be supporting or helping the brain when to remember. And so then the other side, the other angle we're taking to understand it is to try to understand how different interventions may be able to modulate these patterns, sometimes called them biomarkers that are linked with with successful memory. So those are the two kind of halves of my research or two of the halves of my research and the idea is that we're going to bring these closer together so that we understand the patterns, we understand how to modulate them. And now you have the basis of a therapy. So one of the procedures, I guess, which I read about that you were involved in is closed loop neuro stimulation. Could you tell us a little bit more about that and how it relates to your research? Yeah, absolutely. So the idea of closed loop, there's basically two broad ideas when you're considering neuromodulation in general and brain stimulation in particular. And the one way is called open loop. Open loop just means you say we've identified a brain area and we're going to place a stimulating electrode and that stimulating electrode is connected to like a small computer like a battery and that battery then delivers stimulation of you know precise frequency and amplitude and everything and that's how we're going to change some abnormal brain function. And that hasn't so far using the kind of basic approaches and open loop stimulation has not proven effective for treating memory in some of the small-scale trials that have been done and things like that. Close loop neuromodulation is the idea that well you have to sense what is going on in the brain and adapt the stimulation to use the parameters meaning amplitude of the stimulation, the frequency you're using, the timing of when it's delivered that responds to what is going on in the brain on you know with some some precision in time like recording in over half a second, one full second, you know kind of in order to adapt to it. And the idea is that what's happening in the brain is always dependent on what's going on in the environment when it's related to memory and that means that I think that these closed loop approaches are going to be more effective. And so when I was saying earlier about the idea of trying to understand how brain stimulation may modulate these biomarkers, these patterns that are linked to memory, part of it is understanding how to sense and then use stimulation to respond on these short time scales. So that's how it's connected. Yeah yeah great explanation thank you. So now I kind of want to like stay on the topic of memory and turn to the hippocampus, which is a brain structure that's crucial to the formation of new memories as well as for spatial navigation and orientation. And it's known to be particularly vulnerable to age-related changes, damage to this area can lead to memory impairments as we know. So can you give us an overview of some of your key research findings on the hippocampus structure and what you have explored with that? Sure, the this is a big topic and we could probably talk for an hour about you know about 10% of what I've thought about the hippocampus over the years. But I guess one of the things that's kind of been you know recently on my mind related to the hippocampus is this idea that it's not a single structure. So we think of the hippocampus, of course we have one hippocampus on the left and one on the right, but when we think about the function we think about it as being critical for memory, but one of the things I'm interested in is how different parts of the hippocampus at a simple level were dividing it into the anterior hippocampus closer to the front of the brain and the posterior hippocampus generally closer to the back of the brain are doing something slightly different when you're trying to remember something. And so I've been been using memory tasks coupled with these brain recordings to try to understand exactly what that looks like at the level of neurophysiology at the level of brain waves and you know individual neurons in the hippocampus that are responding to memory stimuli. So that's one thing. And for the memory task like how do you usually give that to patients? What does the memory task look like? Sure. Well there's a lot of memory tasks as you guys know and each one is trying to isolate a slightly different feature of what's going on with memory. So I'll just I guess I can cover a couple of broad ones. So as you said earlier the hippocampus is involved in forming memories that link together an item. So let's say an item is like okay the green cup or something like that with what we call context. Context can mean time when something happened it can mean space where something happened. For example and so I think you think of the tasks as ones that where the context is space where in this it's virtual reality where in this virtual reality environment. Did I find the green cup or you can think of it as time when when did it happen. And then another way to think of context is just an association meaning a link to another item. So let's say I tell you in the memory task the green cup is linked with you know is under the table. You have to link it with table. And if you if you never had any reason to put green cup with this you know random table together in your mind before your hippocampus is critical in order to do that. And so that those are kind of three ways that we design memory task to try to test what the hippocampus is doing. Spatial temporal and these more one item association ideas. And each of those has puts it puts slightly different demands on the hippocampus. It puts different demands on other brain structures that the hippocampus is communicating with. And so depending on the question we're asking we we would use one of those paradigms. And then the question of how they're administered well the patients that I'm often collecting data from. They're in the hospital. They we have you know they have these electrodes implanted but they spend about a week maybe a little bit longer in the hospital while they're waiting to have seizures. And so sometimes the you couldn't do a memory task because the patients are sleeping or eating or maybe they just had a seizure. But there's a lot of downtime when they're not doing any of those things and just kind of sitting there. And for patients that are willing to volunteer and to spend the time that's when we take advantage of those windows of opportunity to have them try to do one of these memory tasks. That tests these things like space and time. Yeah that's one of the really exciting things about your research is that whereas most people study memory from kind of the outside of the brain either by just asking people questions and looking at their answers or by doing scans and things you're actually able to do kind of put those electrons directly into the hippocampus and do single neural recordings which is something quite unique and really gives you really detailed information about what's going on in the hippocampus. So one of the kind of key things you're known for within the scientific community one of the things you're recognized for is finding something called time cells in the human hippocampus which basically put a time stamp on memories which sounds really cool. So can you tell us more about how you found these and why they're important for memory? Sure. So we talked just a second ago about how the hippocampus is important for linking an individual piece of information with context. We talked about how that context can be spatial where something happened or temporal when something happened. And so time cells are really very simple. It's just the idea that they are a neuron that if we take a chunk of time that the brain is always dividing our experience into what we call episodes. So the episode can be on different time skills. It can be the beginning of a podcast session. It could be a day. It can be just a two-minute block. And so the brain is always dividing up our experience into these episodes. And if the brain has some prediction about what the episode is going to be and everything, then there's these specialized neurons that are sensitive to different moments within that episode. The beginning, the middle, the end, or maybe more precise. And so you can imagine if we have an episode that's five minutes long. Maybe you have populations of a few hundred time cells, some of which are sensitive to the beginning, the middle, the end. And because they're tuned to these different moments, then the brain can reconstruct when and when a particular item was seen or when an event happened by using the information of this population of time cells. A better way to explain or maybe an easier way to explain it is by analogy to place. And that's really where the idea for time cells came from. It's been known for a long time, well, 30 years, 40 years, that there are neurons in the hippocampus that are sensitive to precise locations in space. So if you imagine entering like a football field walking onto a football field, but on this football field, someone like buried some treasure at different locations or something. And you spend some time exploring this football field. And then there's a particular location right somewhere near the 50-yard line something like that where you find some clue that leads you there. There are neurons in the hippocampus that are sensitive to precise locations within the field. And when you walk over to that space, those neurons will fire. And so your brain has a way to create the boundaries or to understand the boundaries, which seems pretty intuitive. But there's different populations of neurons that help code for the boundaries. And within this environment that the brain is defined, it breaks it up using specialized populations of neurons called play cells. And time cells are doing the same thing, but instead of a field or a physical, like a space, it's more about an episode, i.e. a chunk of time that the brain is, and you know, divided experience up into. - Yeah, I mean, that kind of makes sense, that because the thing is with Alzheimer's disease, which is known to kind of cause new generation, the hippocampus and the surrounding, MTL cortex, one of the key things that people who suffer from that have to deal with is confusion about time and space. So it kind of makes sense that those cells would be there, and that would be affected in Alzheimer's disease. So I can see how that would have a lot of impact on understanding memory and how to help people with those kinds of disorders. - So are these time cells only found in the hippocampus? - That's a good question. If we continue the analogy to play cells before, you can find play cells in many other parts of the brain. One of my areas of research is try to understand, you know, some of the other parts of the brain that may represent, you know, have these same types of time cells related to Alzheimer's, a part of the brain very related to the hippocampus called the intorinol cortex, where in your body the hippocampus, but different. They, that you can find time cells there, at least in our data, but there's also complimentary populations of neurons that are sensitive to time, but they code time in a different way. They're called ramping cells, we don't have to get into exactly what they're doing, but I think that my, if you asked me for my best guess as of now, it would be to say that, if you, if you're, you can probably find time cells in other parts of the brain, they'll probably have properties that are a little different. Maybe they'll be representing time across broaders time scales, and you see in the hippocampus, where they might represent time in a way that's complimentary to, but not exactly the same as time cells. And related to that is, I'm interested also in this population called boundary cells, which do just what they sound like, which is they mark out boundaries in space, but if we continue with this analogy that these same types of neurons can be sensitive to boundaries in time, i.e. when an episode begins, when an episode ends. - So one interesting term I've heard, I think, toluving initially cointed, endyl toluving, who is a memory researcher, the mental time travel, right? So I just kind of wanted to bring that up for our audience. So how these time cells that contribute to the role of the hippocampus allow this mental time travel in the world to recall specifically episodic memory. So the episodic memory is kind of what we're talking about here, right? So this is memory for specific events and individuals' life personal events. It's kind of a broad definition. So yeah, mental time travel is kind of an interesting concept. So it's basically our capacity to mentally reconstruct personal events from the past, which would be episodic memory, as well as to imagine possible scenarios in the future. So you're basically saying these time cells are kind of giving us that ability, correct? Yeah, certainly they would be critical for the ability, along with the other machinery that goes into it. But it would be, insofar as the time cells are helping you understand when something happened, you can imagine that time cells would be critical to be able to organize brain activity that's linked with individual parts of the memory into something that makes sense. Super interesting. So based on your research and your clinical experience, what do you think are the most promising future treatments for memory related disorders? Well, this kind of gets back to what we were talking about earlier with this idea of closed loop neuromodulation. So that it's one of the areas that I'm trying to focus on in my research because, as I said, ultimately the goal is to bring this to some, to use all this knowledge that we're gaining about the neurophysiology of memory from these brain recordings and turn it into something that could help people with memory problems. We haven't-- we've been relatively less successful at treating memory problems as compared to many other diseases neurological conditions. And certainly in my patients that have epilepsy, memory problems are-- it's very rare that I talk to epilepsy patients and the patient and the family don't endorse the idea that the memory problems are one of the things that they noticed early on and got worse over time as the seizures persisted. So from that perspective, me and people in my field are very motivated to try to find some kind of therapy. Ultimately, I think that there's a lot of promising approaches including what I would call non-invasive neuromodulation. And that means things like transcranial magnetic stimulation or TMS. And then up and on as a surgeon, I think more on the invasive side. And so this idea of closed loop neuromodulation precisely targeting these biomarkers, these brain wave patterns that we think our linked to memory is, I think, ultimately what will be the most promising. There's also-- I'm also interested in using what I would call adaptive or precise open loop neuromodulation and where the stimulation is not responding directly to what's going on in the brain. But how it's set up, the stimulation parameters you're using are informed by having tested how the stimulation is going to impact those brain wave patterns. And currently, where are we with this closed loop neuromodulation? Is that something that's already being brought to clinical practice? It is not. I was lucky enough to get a recent grant from the Dier Foundation, which is a charitable group at UT Southwestern. And that is one of the goals. It's to try to push this along to the point that we'd be able to then go to the bigger funding agencies and have the opportunity to test it. It's partly still understanding the basics of how it's working. And then it's also developing the-- actually, the engineering problem of developing tools that are capable of doing it. And so there are more and more devices that are used to treat other conditions that have some of the capability you would need to do closed loop neuromodulation. But the putting it together into a package that's a potential therapy-- I can't say we have done that yet or you know, gotten there. But that's kind of where you can see we want to take the research. So as a neurosurgeon, you have a unique perspective on the brain and its function. And based on your clinical and research experience, what do you think is the most important thing we can do to maintain healthy memory as we age? Well, I feel a little bit out of my element in answering that question. But because I take care of patients with who have very specific brain problems. And so I bet there are people out there who have a better qualified answer than me. But with that caveat in mind, what I often tell my patients and people that ask me questions like that is to say that at this point, the best thing we can say is to maintaining your general health is the best thing you can do to maintain your brain health. And maintaining your general health is all the things that you hear day to day are related to a healthy lifestyle. Like exercise, avoiding high blood pressure. High blood pressure can cause very small little injuries to the brain over time. And that can accumulate to lead to make the process of aging more impactful. And so things that are related to general health treating diabetes, treating high blood pressure, avoiding high cholesterol, things like that are all good. I can't say I live up to all those things all the time. But that's my best answer. Yeah, we like to say what's good for the heart is probably good for the brain. Yeah, that's right. Yeah, that's a good way to put it. Yeah, super interesting. Is there anything specific that you do in your life to maintain your cognitive health? Well, I guess you could say at some level that working at a teaching hospital where I get to train medical students and also having the research effort, I feel like keeps me a little more mentally agile. So I'm always having to think and think about these problems that are outside of my day to day routine. And I like to think at some level that helps you. I don't know if it's been proven. But I always feel like people that have-- that are the sharpest or as they get older, are ones that stay active in that way. OK, so for our listeners who want to learn more about your work and stay updated on the latest in memory research, where can they find more information? Sure. My lab is a website that's the Texas Computational Memory Lab. It's a link from the UT Southwestern O'Donnell Institute homepage. And the O'Donnell Brain Institute at UT Southwestern is puts out some reason and content related to recent research articles, some of which is stuff I've done and some of the stuff that's related that's being done YouTube. of the Western End and UT Dallas. And so that's one answer. My lab, I'm on Twitter/X at Texas Memory. And those are probably the big ones unless you want to start reading journals. - Dr. Leigham, thank you again for sharing your expertise with us today. And for the incredible work you're doing to help people maintain and improve their memory function as they age. We look forward to hearing about your future research. - Hey, thank you for listening to the CVL podcast. You can follow us on Spotify. If you would like to learn more about the Center for Vitalongevity, you can go to cvl.utdallas.edu. And here you'll find information about our research as well as information on how to volunteer to participate in our studies and how to donate to support innovative research to understand, protect, and enhance the vitality of the mind across the lifespan. Join us next time as we continue to explore the latest research and strategies for keeping our brains healthy throughout our lives. (upbeat music)