09. Brain Research 101: From Human to Molecule

Hello and welcome to a chat with Uma with me, your host Uma are a strategy. On this podcast I bring together all of my roles as a neuroscientist, researcher, board certified mental health peer specialist, mental health advocate, community builder and a survivor with lived experience to bring you honest and unfiltered conversations exploring our true human experiences in their fullest form. Every week I'm bringing you conversations bridging the gap on all things neuroscience, psychology, mental health, lived experience, advocacy, psychedelics and more. This is a space for raw unfiltered truth to truly explore ourselves for who we are and how we are. I cannot wait to connect with you, answer all of your questions and co-create this with you. Welcome to a chat with Uma. Hello everyone and welcome back to a chat with Uma and I am just so excited to share this episode with you all finally because it has been a long time coming and in addition to all of the things I've shared on the podcast so far about my experiences, my story, why I am, where I am and why I do what I do. A huge part of everything I want to do with my work and the space I want to create on this podcast is to bridge the accessibility and understanding of all of the research that I'm involved in and all of the research that exists out there that is so relevant and important to people who care about psychiatric mental health, well-being, neuroscience, psychology, psychedelics, all of that research. There's so much out there and I am just on a mission to bring that to the people who care outside of the scientists themselves doing it which is the people affected by those conditions, people who want to be empowered by the understanding of where treatments are developed and what we understand about how certain things work in our systems and why we engage with research the way we do. And so much of that for me is so important because it is informed so much of why I am where I am today as a person with so much lived experience and so many conditions and how that is directly informed my very non-traditional path into science and research and starting off in psychology and then pivoting to neuroscience and really going forth with my research in neurobiology but relating it all back to humans and our experiences. I spent a really long time being very confused about how research works and not really understanding the vastness and the depth and all of the different layers and all of the different forms of research that exist and how they all come together and it really took me immersing myself into different fields to really put all this together. So rather than y'all having to do that for yourselves, I am starting all the research on this podcast off with Brain Research 101 from Human to Molecule. That is this episode and what this episode is is a primer, like a high-level overview of the types of research that go into how we understand mental health and our brains and our behavior and our conscious experience and it's really going to be presented in the form of a spectrum from you know the most obvious and intuitive parts of what we think research is like you know humans and all the ways that we study humans and then really in an intuitive way looking at the advantages and limitations to each level of research and why that leads us to the next form of research in a more specified narrowed-down way all the way down to cellular molecular just very very nitty gritty research and why that all matters and I goal with this is to just really piece together everything in a way that makes sense so that as people who may not be steeped in doing research or in the fields of academia you can get a full scope of what we are all doing at all these levels how they come together and it's just gonna make a lot of sense it didn't for a while for me and so this version of the spectrum of research and why we get to each step is what was really missing for me in conceptualizing all this so I'm just so excited to finally create this in a way that at least made sense to me so that I hope it might make sense to you and the goal with starting off all the research talk on this podcast with this is that this creates a foundation a basis for y'all to understand the conversations that will be coming because you know different researchers research at different fields and different levels of the research from the spectrum that I'm going to be bringing on especially with you know my own research so hopefully this will help put all of that in context and you can understand where in the spectrum we're talking about especially we're toggling on different parts of the spectrum and understanding how and why they all come together I especially think as someone who is a neuroscientist specifically a neurobiologist but also comes from a background of psychology and more human facing research oftentimes as soon as I mention neuroscience to anybody who's on the field or anyone who's just interested in mind or brain or mental health research the automatic assumption is that I you know look at humans and that I I'm either looking at brain scans looking at different parts of the brain in a human or I'm really just like looking at psychology and then like adding a little bit of brain speak which I can completely understand why from the outside that's what someone might think but that being said I have really been prompted to make it so much more clear to y'all what exactly brain research is how vast how diverse it is the levels of specificity that exist why people choose different forms of research and really just starting to rid ourselves of the misnomers and misconception that exists about things like neuroscience and psychology and this you know ever elusive term of research that's been kept for so long so that it can be accessible again to the people who care about it and I wish I knew this before I got into the field so I just want to add a disclaimer though all that being said my identity how I engage with research in the world will definitely shape how I share this and by no means is this the only version of a comprehensive understanding of research this is just my version of it for the purposes of how I communicate my science and my platform my podcast and how my conversations with other people and the way I view research will really parlay and overlay onto the spectrum it is not the only way to look at it and more importantly I'm speaking from my own biases and my own experiences right so I am a neuroscientist I am a neurobiologist where I am in my training and education right now is I'm about to graduate with my master's degree and I work in a lab I'm about to start my PhD in a few months I'm going to be you know full on immersed in this I have given several presentations and scientific writings on my research in layman's terms and that's the vantage point I'm speaking from I specifically do preclinical work which will get into what that means I have a background in the past of psychology research specifically psychometric and psychological testing so I do have some experience with that form of research and I am deeply immersed right now into neurobiology so I just want to make a full disclosure and disclaimer that a lot of what I'm going to be speaking about is from my experience and what I have learned so far what I have done so far and a lot of it is not from what I've done and I'm not an expert by any means any stretch of the word on any version of research I'm going to be talking about I mean I'm a lot more familiar with some than others I would not yet consider myself an expert on anything because I have not gone through my PhD program and there's so much I have to learn that being said I am far more experienced and familiar with some versions and others so there's going to be a lot of just high-level talk to illustrate the point of the spectrum I'm creating for you but by no means am I able to speak at extreme depth of any or many of the levels of this so with all of that being said there's a lot of room for interpretation and nuance and I am so excited to bring on experts of those various types of research to really fill in the gaps for everyone who's going to be interested in learning about different parts of this research but that's not the point of this podcast the point of this specific episode is to be a high-level zoomed out overview of the spectrum so that we can then have context for what? what level of research we're talking on. And I full on take responsibility for anything that I might be a little vague about or that I might get wrong. Also, of course, this episode by no means covers all forms of research and all techniques and all perspectives at all. I would never claim to be able to speak on all of that nor could that fit into one episode and be given due justice. So really, this episode is just a very high level, zoomed out basic overview for the purposes of illustrating the spectrum and so many other techniques and methods of investigation and vantage points of research and just different subfields and disciplines that people find themselves in will for sure be coming on the show to share themselves and in their research, the people doing it. And this episode serves for you to create that spectrum in your mind to be able to plug them in and have the resources and the capability of understanding where on this spectrum that falls, the level of general specificity, even if you've never done research before to really give you that information so that you can see where it falls and where it relates to research that's done on other parts of the spectrum to really get at questions that we have and that we're interested in. This episode is for you to be able to start consuming research and to start understanding things or at least to help you understand when people are bringing their research to you and just create more accessibility and equity and empowerment and understanding and I'm just so excited. All right, so let's get into brain research 101 from human to molecule. So the way I see all of this research, as I said, is a spectrum and at the perhaps top level of the spectrum for the purposes of our conversation that I see is what you would guess a human looking at a human, right? So when we're thinking about let's take a mental health question like something about people's behavior, people's symptoms, right? The intuitive thing to do when we think about doing research on a condition is to look at the human and humans who experience that. So the most top level part of this spectrum, the most like, you know, innate view of a human with symptoms is to observe them, right? So a version of observation that is perhaps the most naturalistic, the most exemplified of how they navigate the world and how they experience things is by literally observing them in their environment, living their life in a completely natural way. It's just kind of like, you know, in a creepy sense, like them being out in the world, doing whatever they do, being in school, being at work, being outside, being at home, whatever, and a researcher like literally watching them and making observations about their behavior and, you know, notating them and just like making ideas around what they're observing, right? And of course, the benefits of that is that they're getting the most natural version of a person. Perhaps if they are known that they're being watched, it's not as naturalistic as it could be if they didn't know they're being watched and sometimes that is the case. Nonetheless, it seems to be just like the most accurate way of just seeing how someone exists in their life. Now of course, there's times of limitations to this because there's no controlling of variables in this situation. There's a lot of observation and correlation with virtually no causation. And so correlation, right, is when we see something and we see something else and they happen to have some sort of pattern where they can occur together versus causation is when we can more infer that something is happening with something else and that one thing is causing the other thing. It's that there's an actual relationship of causation rather than just they happen to be existing together. So one of the prime examples that people learn in school when learning about statistics and correlation versus causation is this phenomenon of when there's a lot more ice cream that's sold, there happens to also be a lot more murder and it's really funny, right? But that's actually something that people have found. And so the correlative way of looking at it is that it happens to be that in times where more ice cream is sold, there happens to be more murders. And if you took it to a causation standpoint, that would be kind of strange, right? That how can ice cream selling cause murders or murders cause ice cream selling? Now if you think about it and take a few steps into why that might happen, you might think, oh well, maybe ice cream is sold a lot more in hotter temperatures in the summer and perhaps maybe that's something that is linked more to murder rates, right? Who knows? But that is just like a very basic example of correlation versus causation. So in the scenario of observing people completely naturalistically in their environment, like basically peeping on them, there is a lot perhaps of correlation that can be observed, but can you actually correlate anything? No, because there's no variables being controlled. What's it ever? The environment, especially let alone any factors, contributing to their environment or their behavior or anything like that. So one would think how would you narrow that down and make that a little more controlled? Well, you'd bring humans from the outside inside, perhaps inside the laboratory, so that controls for environment and being able to conduct experiments and at the very least, just taking away some variables. So still in psychological research, but now more so in a more formal setting inside of a lab. And this is where a lot of psychological research can happen. Before I move any further though, I will also say that there are parts of this spectrum that can overlap and can overlay out to different elements and vice versa. So for example, what I'm about to say is inside of a lab is where we can do things like ask questions and perform self-reports and psychological tests and psychometric tests, right? But you can also do that outside of the lab. So even in naturalistic settings, perhaps maybe you've gone through some sort of psychological evaluation or you were taking some sort of diagnosis test to see how you score as you're going through treatment. And you might be able to take that test at home, right? So when your self-report perhaps on a site, your back's depression inventory or your OCD screening test. So that can happen outside of the lab and that can also happen inside of the lab/clinic/wherever you're being tested. So there's that overlap. But generally speaking, now I'm talking about being inside of a lab, inside of a controlled setting for humans with research. So in there, you can again ask questions. You can do different psychological tests and what those are, of course, is testing for different cognitive or psychological evaluations based on a person's behavior or response or just something that is based on the way someone is consciously either behaving or speaking or reporting, right? So of course, the benefit of this again is that you are dealing with the human directly and you're getting their direct experience or at least a form of their experience that you are then interpreting, which, of course, has a lot of limitations. But nonetheless, you are getting that human perspective. And then you can also add in different variables, different manipulations, different behavioral tests to see if things change for different outcomes. So this can be anything from the more obvious parts like pharmacology, right? So when we do clinical trials for medications or for different substances, you can literally administer this either in the lab or over time. And then you can assess people's changes perhaps in behavior, changes in their symptoms for different illnesses. And again, we're talking about brain research. So very much psychiatric, mental health, things, but of course, this extends also to physical, biomedical research and medicine for very overtly physical conditions, but nonetheless, we're talking about brain research. So you can add in things like pharmacology, right? You can either acutely, like you can administer, for example, psychedelic for eight hours inside of a lab or slash clinic. clinics for this purpose, they're still like part of the lab because it's part of research. And then you can assess, you know, their response or over time antidepressant research often takes many months and, you know, of course, repeated doses for days, weeks, months. So you're still administering something and you're seeing the before and after. And of course there's placebo and there's controls, but where the purposes of the spectrum conversation we're just talking about the overt variable and manipulation. There's also doing behavioral tests and seeing if you do some sort of intervention, what changes. So that oftentimes is what found psych psychological research or psychotherapy research in particular. So different modalities of psychotherapy literally administering it in a clinical research setting over time and seeing how people respond, right. And that's fantastic because you get to see how some form of intervention causes to people's experiences and how they report and how on those very same tests of sharing their experiences with their conditions or brains or whatnot, how that impacts them. In their own words, on empirical validated measures of taking the same type of test before or after to measure those outcomes. Fantastic, right. But what are the limitations? There are a lot. We can definitely see that we're getting people's experiences out from these testing modalities in more of the psychological field. Again, sometimes it's also psychiatric and involves pharmacology, but we're still in the space of looking at humans and relying on their outcomes and their ways of sharing their outcomes to assess things. Right. So we're seeing that. But we're not seeing perhaps why that this is happening. So we can't see what exactly these interventions are doing to different parts of the brain, the nervous system, the body. We don't know the exact mechanism upon which these things are acting, right. So then the natural question would be in especially brain research. Well, if some sort of intervention is working, perhaps some sort of psychotherapy that works over time and shows great results. Or if some sort of medication is working. Then what is it doing in the brain to the person? We can't see that. We can only tell what they feel. So how do we look at that? And that gets us into branching into neuroscience. So up to this point, again, this is a spectrum and there's so many levels of division and so much overlap and so many different terms and so many ways of classifying these things. But in a very, very basic sense, we started with human and we were in roughly the bubble of psychological research. And generally in terms of psychology research, there's a number of people who would be performing this. So oftentimes, if it's a sort of clinical psychotherapy intervention or some sort of research on outcomes, it oftentimes is clinical psychologists. And those are people who often are trained in both the practice of psychology and therapy as well as conducting research. So that's often clinical psychologists. There's also just different parts of psychology that are not clinical, but are much more oriented to research. So there's experimental psychology as well, neuropsychology. And there's also psychiatrists who might be doing this research and assessing outcomes of different medications and psychotherapies as well, who might be running labs or just doing research within the scope of their practice and clinic. And there's also quantitative more researchers in terms of just doing more of that observational stuff and looking at just correlations and leaning into statistics as their analysis. Of course, all research uses statistics, but in terms of more of that zoomed out approach and looking at things happening and correlations versus like specific interventions, that oftentimes can also be like people who are like doing the statistical type of analyses and are more so doing observational research. Again, mostly in the realm of psychology or related non biomedical research in that way. Then we cross into that intersection of humans, human behavior, human experiences, pharmacology, all of that with brain correlation, brain causation. So that intersection of humans and looking at the underpinning in the brain is where we start to get into neuroscience. And that specific intersection oftentimes is referred to as cognitive neuroscience. And that's a very broad term and people identify in different ways, but for now we're going to use that broad term cognitive neuroscience. So what are we transitioning into here? We're narrowing down into humans and looking at in a very broad sense their brains related to different conditions. And you know, perhaps inducing symptoms or leveraging some sort of therapy or pharmacological intervention and seeing what types of changes there might be in brains. Or just looking at a condition and looking at what happens in the brain in these conditions versus people who don't have these conditions. So very broadly speaking brain scans, brain imaging, it's what people tend to think neuroscience is. And as you're going to see is just the tip of the iceberg. It's a very beginning and a very, I mean, it's a very important part of neuroscience, but it's by no means like a big or the massive or major part of neuroscience. So generally brain scans and imaging do two types of analyses of brains, structural and functional. So structural kind of says it in the word, it's looking at the structure of the brain, structure of different parts of the brain and how it might be similar or different to a control brain. And then functional imaging is looking at what the brain is doing. So in terms of what parts of the brain are active and what brains what parts of the brain are talking to each other. And there's different forms of doing this. Some of the major ones are cat scans, cat scans, MRIs, functional MRIs are FMRIs, EEG. And those are a whole host of techniques that have different, you know, totally different strengths and weaknesses, but overall they come together to look at structural and functional parts of brain research. So strengths, of course, in looking at a human's brain is that well, you're looking at a human's brain. You're looking at, you know, kind of the very people that we're trying to help. We are looking at real people with real experiences who are able to share their symptoms and put into words and to language what they're experiencing to be able to at the very least correlate them to what we're seeing in these scans, right? And so brain scans and imaging has come a very long way. And we have some amazing technology to be able to look at different areas of the brain and to even, you know, sometimes track with tracers, like what parts of the brain are becoming active and even sometimes like tagging for different receptors and things like that. For the most part though, there are a lot of limitations. And sometimes I get a lot of surprise when I bring up that neuroscience is not just brain imaging and especially when people who are very are looking to advocate for mental health research and psychiatric illness. Like some of the easiest ways that layman's people tend to look at neuroscience or like validating like this is an actual illness, this is a brain disorder, this isn't a choice or a quirk or whatever is they really love to pull up brain scans and look and show like look this is a brain with, for example, OCD and this is a normal brain. And my OCD brain looks so different and therefore like this shows that I actually have a disorder and look that is so valid. It is so valid to want to find empirical evidence in a very, you know, easy to see sense in a very visual obvious way that there is a difference in my brain or there's a difference in this type of conditions brain versus another brain, right? At the same time though, there's a lot of danger in looking at those things without having the context around types of research and what the limitations are. And I'll give you a prime example of this actually. So a few months ago there was a whole Twitter exchange about the state of imaging research and how non-specific it is and how there is value but it is so, so, so, beyond, behind in what we need to be able to do very causational specific very, very thorough research on the central nervous system in brains and humans. And that was that there was a whole bunch of psychedelic research going on and a lot of psychedelic research includes, of course, imaging because we're looking at the effects in humans, right? And someone who's very immersed in the cognitive neuroscience field said that it's, you know, interesting that we're looking at this picture and we're making all these conclusions about what psychedelics do in the brains of humans. And actually, if you pull up a picture of a person with OCD, just like with OCD being imaged in their obsessive compulsive cycle, it looks virtually the same as someone who is on psychedelics. And so is the conclusion that people who have OCD or just people are tripping all the time, right? And of course, the answer's no. I mean, I guess maybe there's like a point, oh, a percent chance, but like, no, pretty much that's not the case, right? So given that someone is taking so much extrapolation from a picture of someone tripping on psychedelics, and then when you pull it up, dexterity picture of someone with OCD, it looks virtually the same. That shows you right there so much of what I'm about to tell you in terms of limitations on imaging. So imaging can on a very, very high level show us parts of the brain that are active in certain situations and parts of the brain that might be bigger or smaller or look different than normal brains, right? But that tells us something. It tells us it gives us some type of indication into what we need to look further into from more specific, more narrow standpoints, which is like the rest of neuroscience that I'm about to get into. But a lot of people who don't understand brain research to stop there and think like that's the answer. But really, what can looking at a brain being active in a certain area tell us? I mean, it tells us that we should be looking at the mechanisms within that part of the brain. We should be looking at what is being turned on, what is being turned off. And as I'm about to get into, there is so much complexity within not just one part of a brain, but the sub parts of the brain and the different receptors that are involved to the different peptides and the different cell types and just so many things that can be happening within one area. So if we're looking at an image of a brain being just having more activity in it, we have no idea what that activity is coming from, what that's indicative of within the sometimes hundreds of different cell types you might be able to find within a part of a brain. And it's very just, it's basically a breadcrumb in the direction of where can we go. And also sometimes people talk about seeing different brain parts talking to each other in very layman's terms on a brain scan. But we don't understand the full circuit, the full picture, how this communication is being facilitated in a more specific way in terms of the different cell types, again, the different molecules, the different pathways, what is causing it. And then there's also just the, I guess, even more rudimentary version of why there's limits on brain imaging research, which is because coming back to correlation versus causation, we can try to manipulate as many variables as possible and control for as many variables as possible and just make it super, super clean. But at the end of the day, humans are messy, even if they are confined to a scan, like a little area where you have to lay, like you're in a tomb and just being in a small space. Even within that, there is so much that can happen. People can be thinking of other things, people can get distracted, people can have fear. It's just an unnatural setting, which of course natural settings also pose a lot of confounds and variables as well that could get in the way of causating things, but so can being in the setting of imaging. And so there's just a lot less control. And you might be wondering, well, if imaging is so non-specific, then why don't we just get more specific with people because people who are wanting to study, people are so complex, humans and their brains and being so much more evolved? And that is all valid. But as I'm about to get into how we actually at this point in science have the technology to be able to narrow down our questions and go from just brain part to the different circuits and the different ways that the brains are talking to each other, the different projection pathways that exist. And then even more narrow the ways that the cells themselves function and work and then how the molecules interact with the cells, the properties of the molecules. At this point, we don't really have a way of doing that in humans. And I don't think you'd want that to happen in your own brain as we'll get into. So at this point, as of March of 2023, we're talking about the general limitations of what we can do with human research, right? So that's why neuroscience is on some level, sometimes cognitive neuroscience, sometimes it's imaging, and it is also so much more. I'll also say that part of the view of neuroscience and the view of humans and imaging research, and you know, that oftentimes a trend or the inclination to want to just like talk about the brain to validate certain concerns and to try to show like the underpinning from the brain side of a illness, especially again, mental illness that faces so much stigma. And it's very well intentioned to want to speak about the brain underpinning of an illness. It's really easy for a layman's person to say, well, this part of the brain does this thing and causes this illness and that's true and not true. So take the amygdala for example and I'll come back to OCD research again. People love to say that we I have OCD because my amygdala is overactive by fear centers overactive, right? So yes, in that generally we have found that in people with OCD, in these imaging studies, we can see that the amygdala has more activity, but it doesn't do a whole lot of service to just say that because number one, that is one of many different parts of OCD that we have found so far that we're at least extrapolating to be related to OCD based on inducing symptoms by activity or inhibition of certain areas, right? But also the amygdala just like this applies to all brain parts are so complex. The amygdala is an amygdaloid complex for example. It, I mean, depending on the scientist you talk to, people could say there's like nine parts or 12 parts or like sometimes even more, but like let's say 12. There are so many subnucleus, like in my lab right now, I particularly study the central nucleus of the amygdala and within the CEA, there are three different sub-subparts of the CEA that we look at the CEC, the CEL, like it gets so narrow and there's so many different subparts that each function differently. So there's also like a hugely common part people talk about the amygdala is the basal lateral amygdala and the basal lateral amygdala versus the central amygdala have different parts that talk to different parts of the brain have different projections that sometimes talk to each other that add different implications, some of them with fear, some of them not. I mean, it's so complex. So to say that the amygdala is the center, the fear center of the brain, yeah, it is involved in fear massively. So we're other parts of the brain though and within the amygdala there's so much that goes into what we think is fear and so many different functions and that's just structurally. That's just different parts of the amygdala. That's not even accounting for the different cell types within each subpart of the amygdala and which parts of the brain they talk to and what circuit that creates and what that cascade of activity ends up resulting in and that's just one cascade but then that cascade interacting with another cascade and what that does and if that mediates or changes or counteracts, right, you're starting to see the complexity of that. So going back to cognitive neuroscience, it is valid to say that we can see the amygdala is overactive in a picture to associate with an illness. Great, but that does not tell us how we can in that same vein of the word change the illness because you can't just assume that you can just turn on or off the amygdala or just make the amygdala less active, right? That doesn't tell us what targets there are. Targets is often a term that you're going to hear in neuroscience generally speaking like brain science, especially related to mental illness, psychiatric illness, all of that. So targets basically mean if there's a part of an illness, the physiology of an illness from, you know, the standpoint of a receptor, a signaling cascade or an enzyme or a peptide or a transmitter or, you know, anything like that, like what the treatment we're doing is targeting to directly impact that part of the physiology of the illness. So we're not able to distill down to any specificity really of targets without being able to look more deeply at that part of the brain, rather than just looking at that from like a very high level zoomed out standpoint. It's kind of like looking at like lights, right? And just seeing that there's an on or off switch and when you turn it on, the lights turn on and when you turn it off, the lights turn off, right? But we can't tell by turning just someone who doesn't know electricity, which is me or anything about like wiring or anything like that. We can't turn on the lights and just like know exactly what went into turning on the lights, like all of the different parts that were turned on based on like the different wiring and the different connections and what's plugged into what and what's connected to what and you know all the different electrical processes that went into the flip to the light objectively just like beating down at us and vice versa turning it off as well. So it's that level of specificity that's often missing for imaging and that's a huge opportunity problem opportunity whatever you want to call it in neuroscience and it's something that's really being worked on because ideally again, we would like to do our research in humans and be able to see things and be able to make a difference with that because these are just subjects we're ultimately interested in yet we're not at that point and that's so complicated and hard. I have no idea what goes into the engineering and the bioengineering, the mechanics like all of it of developing technology like that like props and kudos to those people, they have a huge task in front of them. And the final thought I'll leave you with to really hone in on the limitations of cognitive neuroscience and imaging and kind of the point I'm trying to make with the specificity and kind of reimagining what people think neuroscience is and only focusing on imaging neuroscience is have you ever gone and gotten a brain scan to diagnose or assess treatment of your psychiatric illness like have you gone to a therapist or psychiatrist and part of the diagnosis process was a brain scan to tell you what your brain looked like and if it looked different than normal people's brains quote unquote or if it functioned differently like as the method or part of diagnosis I can all but bet that the answer is no and that's because that doesn't happen and why does it not happen because it's not used as a reliable measure to be able to see in depth what's going on in someone's brain for psychiatric mental illnesses it is used like I said as a frame of reference when doing trials and when looking for potential correlates or things that seem to be similar in people with certain illnesses versus healthy controls but it's not used for diagnosis and that's because it's just not there in terms of reliability and specificity and truly being able to encapsulate what an illness can look like in terms of a brain and the imaging of it so that's my tangent on on cognitive neuroscience and what people think neuroscience is but as you're about to see we're going to get far more complex with this so because of everything I listed before the way to narrow down and the way to address some of the limitations of that imaging research is to cross over to the zoomed out term is preclinical research so preclinical kind of says it in the word it's before clinical which means really before people so if it's not people then who is it in? Well at this next level if we're not looking at the images of brains of humans then we are looking at the brains and systems of animals and that I know seems like kind of counterintuitive and if you're like super unfamiliar with research then you're probably just like well how can you compare an animal to a human and there's a lot packed into that that's like an entire semester's worth of topic to understand and like get on board with the idea that animals are worth doing research in but something that up into a few sentences we do the best we can and there are models of different animals most used often are rodents so rats and mice that have been found to have the most general similarity to human structure function and behavior and then there's also different forms of research that are rodents so non-human primate research so that's oftentimes in monkeys and they often especially in psychiatric research are much more close to child like models like human child models because of their function and structure once again and their behavior you know there's also for different purposes of looking at different parts of the brain and different functions so like for visual research in the past historically cats have been used because of their high visual acuity and that's just a few examples there's so many there's believe it or not there's a whole subset of neuroscience that does a lot of research in drosophila which is flies and you will never catch me doing that ever that I'm like I cannot imagine doing flyers but props and total kudos to everybody who does that is so valid it's so important but that's just to show you the areas of ple- they're just the scope of preclinical research that exists and it gets even more complex but we're starting with this level right so in preclinical research if we're transitioning from human brains to animal brains then what is it that we can do in animal brains and how do we start narrowing down from the question of just brain parts and what lights up in the brain right well then we're going to look at how brains parts communicate with each other and not just like this part talks to this part but what part within that part talks to which part and leveraging what neurotransmitters what neurons what cell types what peptides and so many other things that create that pathway and those different pathways how do they create a circuit perhaps so you think of the word circuit in you know regular life and electricity and all of that that I'm very unfamiliar with it's basically what we're calling a circuit in a human brain so like this thing causes this thing which then causes this thing which then causes this thing and that's a very reliable pattern of communication that happens generally speaking as a cascade because of a certain you know electrical event or percept the perceived event in a human's life just related to behavior and affect and motion all of those things right so we're talking about systems neuroscience that's basically what this is referring to when we're looking at different systems within the brain and how they communicate with each other but from a specified way of looking at different again cell types and what's contributing to this system so that we have a much more detailed accurate picture of this connectivity pattern and how we can perhaps interrupt it or facilitate more of it depending on what your goal is so you might be wondering okay well how do you look at this system in a preclinical model in effectively in animal model brain well the differences between looking at a human brain and an animal brain is that we are able to actually go look at the animal brain by like manipulating things and injecting things and cutting into them and looking at the actual activity right so we have far more flexibility in being able to induce behavior and doce conditions induce the activation or suppression of different neurons or cell types in their brain through super cool experimental techniques that exist and we're able to directly manipulate certain things so in a human brain we don't have a way and even if we have a way of activating for example like a receptor it's going to be global and it's going to go wherever the receptor is in the brain so we're seeing like a whole network effect of one thing if it's even that specific but in an animal brain we have the technology to be able to literally go into just one part of the brain and activate through tons of you know cool scientific magic techniques like optogenetics and using just you know different basically virus constructs to be able to target specific cell types within one part of a brain and we can then turn them on and the pathway to which they go to this next part of the brain on, but not turn on like the other cell types that exist around it or just turn on that part of the brain and not other parts of the brain and look at how it affects that next part of the brain and that's circuit and then perhaps like a multi a multi faceted circuit and we can just be very specific and get more to that causation rather than the correlation and that's really only possible with the more invasive techniques that we at this point don't and can't do in humans. So that's systems neuroscience and a very very basic nutshell, right? It's so complex but just in a nutshell. But then going on the spectrum of narrowing down questions, if we're looking at how brain parts talk to each other then the natural next question is well what exactly are the cells doing? Why is it causing this communication in the first place? What are the properties of these cells? Are these cells themselves acting differently in certain circumstances or conditions than other than others specifically in the context of again like psychiatric brain mental health research because that's our jam, right? I mean you could apply it to really any type of neuroscience or research but in this context like we're once we look at systems we're going to wonder about the cells within that system and then that takes us more to cellular neuroscience and again like this is a spectrum and things overlap all the time but generally speaking cellular neuroscience is looking at the properties of the cells the neurons or the yeah just the cells in general themselves. So like the actual channels that the cells used to be able to activate or not activate and the properties of how they are you know growing and how they are being instigated to communicate or being suppressed and the receptors and the synapses and the dendrites and just looking at just like a very zoomed in version of the cell itself and then there's tons of forms of research in neuroscience and then preclinical neurobiology where you're able to like specifically like go into a cell and you're able to watch it act and you're able to see how it acts in response to different stimuli and it's really called electrophysiology and you're able to do this in so many different ways but effectively you're like looking straight at a cell which is absolutely wild and that gives you more understanding of the actual like fundamental properties of the cell and why you know that can contribute to the more network effect and perhaps going back to targets give you a target to act upon in a more specific way in terms of developing treatments right and then molecular neuroscience is looking at the molecules involved with those cells so it's again very very very specific and you're able to once again develop therapeutic targets for these very things right so we've gotten super super narrow and now I'm gonna go more lateral so rather than getting even more specific I'm gonna go kind of if we've been going down this whole time I'm gonna go take one step to the right I'm picking right like subjectively but going to the right of cellular molecular research and that's because I want to talk about stem cell research in a very very layman's high level sense so at this point I've been talking all about preclinical neurobiology and by the way I should specify that when people talk about neurobiology that is a part of neuroscience it's not not neuroscience sometimes people are like oh you're a neurobiologist you're not a neuroscientist like no neurobiology is effectively looking at the biology of the nervous system so specifically more of exactly what I said like looking at the cellular molecular systems level like biological properties of the brain rather than more so like how that's translating directly to you know like humans and more of like that zoomed out like correlational aspects so oftentimes neurobiology refers to working in what's called a wet lab so wet labs are when you're I mean so that's kind of gross but like really your hands are directly doing experiments and are like working with cells and media and doing experiments that are directly manipulating thing and then what's not wet lab is dry lab the exact opposite which is working not with basic biological things in your hands it's doing more of the human side more of the imaging or computational which we're going to get into computational in a second but just you know what's not wet is dry so those are terms you're all up here as well wet versus dry lab so and you're also here basic science by the way so basic science is referring to this level we're at right now which is in some like very basic very fundamental very like looking at the very biological tangible underpinnings of questions that we have so again looking at cells looking at molecules looking at the very tangible ways that the brain is speaking to each other on a systems and circuit level those types of things working and looking like literally at the different transmitters and peptides and things that have been released in a brain imaging using microscopes and using chemistry and just using tons of different techniques that is very much referred to as basic research okay so we're at this place of a very fundamental part of you know very basic part of animal research and then I'm taking you laterally to a version of that research too which is stem cell research so we've been talking this whole time about like we would love to do research in humans and that would be the ideal but we can't be that invasive with them so that's why we look into animals however while we can't look at the full brain at this point again March of 2023 and I wonder how quickly this will change but while we can't like go dig into and like poke into and like you know look like take out a slice of a human brain that's alive right now we have people I'm really amazing people have figured out a way to do research in human derived stem cells and so people stem cells have had a very long reputation for many types of reasons and ways but like what it kind of looks like now is being able to take just like like a skin punch or a saliva swab and use what's within that to develop different types of cells from that DNA that information and it's super super cool and basically you can differentiate and develop different types of cells and parts you know that are not cells as well part of the nervous system like glia and astrocytes and whatnot and then study the properties of those types of cells coming from a specific human being with a specific genetic makeup so that is super super revolutionary and being able to do more human targeted more bio individual research right but what are the limitations the limitations are that were one looking at cells and not how that necessarily is a part of a full natural picture of a brain and a system and how that has like a network effect and just all the connectivity parts of how it communicates with other cells we're not there yet I mean there's different levels of this and there's you know different forms of like brain organoids and kind of like many versions of brains there's something called a neurosphere and that stuff is in process and exists but it's not exactly like we're we have like a cell or we have like human tissue that we then like turn into a human brain I mean that's in the pipeline and that's going to be amazing but not yet so limitations but also benefits and directly from humans rather than animal models and animal models obviously like I said the limitations are they're not humans that's intuitive right and they have so many strengths which are discounted oftentimes and are not fully understood by people who are not in research and it's totally valid and that so with that they have tons of strengths and they're very important and it made a huge difference and I mean what if you've ever taken a medication or had a some form of a procedure or anything I mean animal models thank you for that right and generally like I did this spectrum from human to molecule to illustrate a point and narrow down down down to a question but research oftentimes goes bi-directionally and starts from observation in humans and then looking into the animal and starting from a very very basic molecular cellular level looking at the circuit level seeing how that plays out in behavior of animals and then determining that it might be a good candidate it might be safe for humans and then moving it up the human pipeline so it's very very bi-directional and animals play a huge role in that right but of course there's limitations of it not being a human and having different needs being on different cycles having just differences in each animal model has their own benefits and uh i i advantages and disadvantages right now the less we're taking all this and creating a full picture of everything and then to kind of round this whole spectrum out I'm going to throw in computation neuroscience and the reason I didn't say that in imaging research because, you know, computational neuroscience, that's its own like massive field and is so complex and so fascinating. And you would think, again, computational immediately would look or sound like, you know, taking imaging data and like doing a whole bunch of computer stuff with it, right? This is the most like layman's way of thinking about it. But the reason I didn't bring it up there is because computational neuroscience really spans so many levels of what I just talked about in that spectrum. It really spans the whole thing to my understanding. And what computational neuroscience is is developing through computational techniques and coding and logic and math and all of those foreign things to me, developing a model to be able to predict the effects of different types of manipulations on all levels of that spectrum and really kind of expedite the scientific process by creating models of different parts of the brain and taking all of and aggregating all the data and the functionality that we have and that we've learned about so far to be able to make a predictive, reliable model so that we can expedite research and we can expedite hypotheses and we can test things out on a computational model before going through months and years of testing out an experiment or experiments on animals because they take so long. I mean, hello, why does a PhD in neuroscience think I'm about to perhaps embark on take like four to eight years? It's not for laziness, it's not for slowness, it's because there's so much that goes into the variables and the controlling of everything, right? So computational neuroscience serves to be able to expedite that process and kind of narrow down directions to go forth because a lot of times there's hypotheses and then they don't end up panning out and there, which is valid, and that's so important in science, but that took so much time at effort to get to that answer when maybe computational neuroscience can give us an expedited way of looking at that and also give us, you know, more targeted hypotheses of things that us as humans have not thought of yet. So that's kind of something that kind of ties all of this whole spectrum together and with preclinical research at large, right? We just talked about the advantages and disadvantages, but huge advantage that is perhaps like maybe the most important outside of being able to actually do these invasive techniques and get so specific in animals in a way that we can't do in humans is also the controlling of variables, right? So we cannot control humans in their, all the variables that contribute to everything we're looking at, like, you know, we can try to control for some that we can for see, like perhaps diet and sleep and, you know, exercise the medications that they are taking the stimuli whatever, but we cannot control for hardly like anything relative to the scope of what humans experience and even the variables that we try to control for can be not fully controlled because like can someone really control all of their sleep even though we might be expecting them and telling them they need to sleep eight hours a day for a certain pharmacological experiment, right? Like we can't actually do that and there's also just so many things like in terms of their unique makeups and their backgrounds and if we're talking psychiatric research, life experiences and comorbidities and so many things that are so important to consider when moving forth with the claim in humans and seeing how much a hypothesis or an intervention generalizes to the complexity of humans and their differences, right? But for the purposes of really testing the effect and really getting to causality about certain functions of different receptors or networks, different circuits, different interventions, different, you know, receptor agonists or antagonists or properties of cells and all of those things, it is so much easier to do in animals who are very very very controlled and even within that we have to work so hard to control for variables, but nonetheless it's so much easier to control like the environment that they're in, the literal like cages or the environments that they live in, what they're eating, who they're interacting with, when they were born, the exact conditions into which they were born, you know, like just so many things and making it super consistent across the entire population, that's a huge part of scientific integrity and we get to do that with animals, we get to do that with ourselves of course and so that's a probably the most like in my opinion the biggest benefit of preclinical research outside of the invasiveness that we can't do in humans and also because we talked about who generally does psychological research like what kind of vocation someone generally has in terms of neuroscience, there's a wide variety of people who might be doing that research, but generally speaking, again, this aren't, these are the rules but not the exceptions at all, the people doing cognitive like more imaging neuroscience tend to be people who went and got their formalized training generally through a PhD, also sometimes through an MD or MD PhDs of physician scientists as well in either psychology because that oftentimes includes like the neuroimaging human facing side of things, more like experimental psychology, sometimes even clinical psychology but mostly experimental cognitive sides of things or sometimes depending on the program, they do join the neuroscience PhD programs at university and then they go specialized in cognitive neuroimaging techniques and their project through their PhD so they can be quote-unquote neuroscientists if they can be psychologists and then in terms of the preclinical neurobiology side of who does that research, typically they're people who are in straight up a neuroscience PhD program and they are then join a lab and develop their skills in preclinical neurobiology research that can also include people who are physician scientists so doing MD PhDs as well but they typically are in a PhD program doing their preclinical like neurobiology research as well as opposed to in cognitive neuroscience oftentimes a solely an MD student, solely like a medical student can also engage in that imaging research just because of the techniques and the way one engages with the lab and the way the training goes so preclinical research very much tends to be neuroscience PhD students yet also within neuroscience and science and biomedical sciences in general there's some overlap with other departments and other programs so sometimes it could be someone from a bioengineering major who's doing neurobiology research or from pharmacology because pharmacology is very closely interrelated has their own unique set of skills and focuses as well but oftentimes pharmacology PhD students and neuroscience students are working on virtually the exact same project it just depends on like what program and what track that they picked and maybe what department or program that their advisor of choice is in but nonetheless the commonality the theme here of how people do this research is as students and people who oftentimes are at the front lines of doing these research projects and these experiments through their PhD their graduate students they're also postdoctoral associates so what people typically might be doing after a PhD or they're a full-fledged principal investigator where they have their own lab and they're running you know either running their own experiments at the beginning or they're leading a team of said students and postdocs and research scientists that might be doing these experiments as well and then there's also people who have these titles neuroscientists like colleges pharmacologists like bioengineer like those people doctors all of them who also work in pharmaceutical companies or external companies who are also doing those experiments as well so the setting you know can defer but generally the title and the skill set doesn't and then really the other caveat to that as well is there's computational neuroscientists who might be in either some sort of computer science program or have developed computer science skills and then now are in a neuroscience program sometimes people will do some of their you know their first part of their training in one field and then do their postdoctoral fellowship or further training and another field to really bridge their interests it just all depends and there's so many paths and we can we will be talking all about the different paths and upcoming episodes of different people who have taken those different paths and then that also lends itself to people who have done their degrees their training and things like you know very very closely related fields like biology or chemistry biochemistry even physics and then they decide that they want to go into neuroscience and neurobiology and they will bring that training and that information and apply it to specifically neuroscience neurobiology to do that more preclinical work in their again postdoctoral fellowships or you know pivoting into that in their later faculty career or you know in industry or just different companies there's different paths but generally speaking There's in within those realms of training is how people end up doing this type of research and I really want to take you through A example that comes to mind of a question or a general subject and how this would apply and narrow down the spectrum of Research that I just shared with you. So let's take a question. Well that really interests me, which is the effects of psychedelics. Let's say specifically psilocybin on OCD, right? So in the most naturalistic sense that we talked about the very beginning at that top level That would look like someone who has obviously this is not recommendation This is just a totally hypothetical example someone who has OCD taking psychedelics taking specifically psilocybin and Doing it in their own environment and then somehow a researcher just getting to like watch from the outside and see what happens to that person and not ask some questions Not bother them not influence it in any way, but just watch and then make observations and come up with questions Based on the observations of how they're behaving the things that they're saying the things that look different from when They aren't on psilocybin and what happens after right and then that next level of controlling would be to bring them inside of the lab and inside of the clinic and to administer psilocybin and then just watch them inside of that setting in that more controlled setting Accounting for different stimuli and people and whatnot and seeing what effects persist and just watching and then that next level would be to actively be controlling like exactly how the psilocybin is in is ministered and Then look at the different questions you might ask the psychological psychometric testing self-report all of that and look at the effects before and after and look at more of like how that might have affected them in more of a causational wave and correlationally but still allowing for the possibility of correlation right and then taking that same person and putting them in a brain scanner and looking at them before and then looking at them during and looking at them after and looking at the different structural and functional properties of their brain in relation to psilocybin in terms of their immediate on You know like effects while they're on it as well as what happens generally to the brain after right and then coming up with questions of what parts of the brain does You know perhaps psilocybin maybe interact with and why is that the case in that specific person with OCD and how does that can you know look like compared to people who don't have OCD and also people of OCD who haven't taken psilocybin and then from there Looking at what is happening in the brain related to OCD So then you move that more into the neurobiology preclinical side and then take models of Animals that we've developed who model OCD, which is not perfect and that's never a true, you know a full translation but generally looking at Either like knocking out a certain gene that's been implicated in OCD to be able to have an animal that models OCD or you know Ins like or instigating OCD by activating a specific circuit to create that model something of that form and then administering psilocybin and looking at what Pathways are directly you know starting to be activated by putting psilocybin into an OCD animal model And then looking at what cells are involved in that and how are they changing in response to psilocybin in that OCD model that It non psilocybin animal with the OCD model has and even like animals that are just totally wild type which means that they are Completely unaffected and have not been induced with OCD or any other type of thing and then looking at the molecules involved and then looking at some sort of Computational model to be developed of a brain or the OCD and looking at how one can model the effects of psychedelics on A virtual brain and seeing how that works and then perhaps also taking you know tissue DNA whatever from someone with OCD and developing stem cells from that person to model different parts of cells from different parts of the brain and system and then seeing how a Bath of psilocybin affects that in Those cells that is kind of an illustration of these Specificity in different forms of questions and levels that one can explore with this spectrum of brain research We have now that same question. There's so many different questions to answer and they all work together So in some brain research 101 There is a spectrum of research going all the way from humans in their natural wild environment and Watching them and seeing how they're doing and Coming up with ideas and questions and then distilling that down to what we can do in humans and what we can manipulate in humans and Figure out how they feel about it how they share about it all and that's you know It's like all the psychological research all the way to what's happening in their brain and looking from a very zoomed at level into their brain with Imaging research all the way to Realizing that perhaps we can't see that much of Specificity in brains and looking for why things are happening in the brain taking that breadcrumb and going into preclinical research looking at systems level neuroscience cellular neuroscience and Molecular neuroscience and really crossing into neurobiology territory looking at cells looking at how they function with each other Looking at their properties looking at how they communicate with other parts of the brain in a very very nuanced way being able to isolate their like individual pathways and see the effects on the animals a hole in their behavior and their activity and then going into Human stem cell research and looking at cell properties in you know individualized cells from human DNA and being able to bridge that more to humans and then computational neuroscience that's looking at how we can systemize and predict things from computational modeling use leveraging the technology we have now and There's such a spectrum within that all the way from psychology to you know What we call nerve cognitive neuroscience neurobiology and Computational and there's so many subfields within that there's like pharmacology behavioral pharmacology There's affective neuroscience behavioral neuroscience Cellular physiology just tons and tons of different forms neuro pathology I mean I could go on and that's born as another conversation for another day But this spectrum is just to illustrate to you the vastness of the research the Advantage is limitations at each stage of it how they all come together and I'm so excited to now be able to share Different parts of this research with you with at different levels and how they interact with each other to come up with the Comprehensive understanding of what we have in neuroscience and in psychology and overall and brain in psychiatric research This is the exciting start of so many conversations that are coming about research from me from the amazing guests that are coming on the show Talking about so many of the questions that we have the unanswered questions that are left the Exciting findings the implications for human well-being the limitations the technology that we hope to have to continue to answer these questions and just the wide breath and depth of Incredible research that people are doing and I can't wait to be One of many conduits who bridged a gap from the people doing the research and who have invested their lives and all of their time Dedicated to these questions to the very people who want to hear from this exact people who want to learn to Empower ourselves with the information and knowledge that we have to understand ourselves better to advocate for ourselves to understand people around us To give ourselves and each other so much compassion and validation and Empowerment to heal and grow and Ultimately living the value driven beautiful lives that we have the opportunity to live and to Share that with each other. So this is the first of many. I'm so excited for everything to come on the show and Just so grateful for you taking the time to learn with me and I hope this spectrum just really illuminated all that's to come and the excitement and the beauty that is research and these conversations and If this episode resonated with you it would mean the world if you could share it on social media for anyone who is interested in brain research as well anyone who could benefit from this perspective this way of looking at brain research and all the information that I'm sharing it would mean the world for you to take a second right now to Subscribe to the show wherever you're listening to your podcasts so that you can be the first to receive episodes and you can support the show that way as well as Leaving a rating in review because that makes such a huge difference in being able to share this and space in this community with as many people as possible and to just co-create our mission together of creating a safe and validating and empowering place for excitement and research and our lived experiences and Bringing it all together for access and equity and just spreading love So it mean the world if you could share this podcast if you could rate it review it and subscribe to it and I Cannot wait to see you next week with more on a chat with you