93. Measuring Brain Health, the Link Between Inflammation and Mental Health | Austin Perlmutter, MD

Hello everyone, I'm Dr. Darsha, and I'm Dr. Altamash Raja, and welcome to Medicine Redefined. A podcast where we will explore the often overlooked but necessary components of health, what we consider to be the fundamentals. We will investigate topics and practices that can give you and your patients the best chance to optimize a healthy lifestyle. It's time to move the needle forward and put the health back in health care. Our guest today is Dr. Austin Pearlmutter. Austin is a board certified internal medicine physician, New York Times bestseller author, educator and consultant. He received his medical degree from University of Miami and completed his internal medicine residency at Oregon Health and Science University in Portland, Oregon. His focus is on helping identify and resolve the biological basis for stuckness in the body and brain, especially around decision making. He hosts the Get the Stuck Out podcast and is a co-producer of the Alzheimer's, The Science of Prevention DocuSeries. His work has often featured online on various sites including MedPageToday, Doximidi, KevinMD and PsychologyToday to name a few. In this episode we discuss Austin's background and interest in studying the brain. Subjective and objective markers to evaluate brain health. We spend a lot of time discussing the link between cognitive health and mental health. To find that Austin is very passionate about the interplay between these two and makes a compelling argument why it's not really possible to uncouple the two. If we want to consider optimizing one's cognitive health, we need to pay a lot more attention to the psychological and emotional health as well. We also touch on some tactics on how to improve or give someone the best chance to optimize their brain health and do this by discussing the science and art of behavior change. Ultimately, I think you'll find this episode to be a fascinating discussion because of Austin's unique perspective with respect to brain health. Enjoy. All right. Welcome back, everyone. Medicine Redefined. Austin, thank you so much for coming onto this show. I know UltimaSh and I. It's been a long time coming and we're super excited to have you here on Medicine Redefined. Your wealth and knowledge, just like as we said, just pretty show how there's so much that you talk about. So, thanks once again for making time to come on here. Yeah, thank you so much for having me. Yeah. So, I am interested because you know so much and you talk about psychedelics all the way to gut health, neuro, your training is an internal medicine. What made you go down that route? It's a good question. I've definitely asked myself that question a few times about health. So, you know, I guess as background, you have to understand why I went into internal medicine in the first place. And for listeners who are either international or maybe aren't necessarily with medical training in the United States, you know, there's a wide variety of things that you can specialize in after you finish your medical training, so specifically an MD training. An internal medicine is, I'd say, the most generalist of the outcomes that you can choose as far as where you go after med school. And good examples of what internal medicine's doctors will do is they would act in the hospital as a hospitalist, the person who looks after you if you get admitted with pneumonia or heart failure, but they also are in the primary care setting. So if you have a cold and you wind up needing to see your doctor to get evaluated with a chest x-ray, that's often an internal medicine doctor as well. Internal medicine doctors can also sub-specialize, which is why you get cardiologist, gastronologist, pulmonologist, et cetera. And so these are people who have kind of nailed down a system that is a particular interest to them. So with all that said, my reasoning for going into internal medicine is, first of all, I really wanted to understand chronic disease pathology. I wanted to understand, what are the major diseases that are contributing to the majority of deaths and disabilities around the country and really around the entire planet at this point? And those are the diseases that are managed by internal medicine doctors. Examples I would give would be heart disease and diabetes and obesity-related complications, as well as neurological diseases, even though neurology also participates in that. But these are the things like strokes and Alzheimer's that are often in internal medicine doctors' offices. So for all those reasons, it seemed like a good selection for me. But here's what happened. I started my internal medicine training. I loved learning about what was going wrong. I loved learning about how to manage what was going wrong. But I rapidly understood that that's what I was doing. I was managing. So I wasn't reversing disease. I certainly wasn't curing diseases. I was slowing the rate of decline of people's worsening. So if a person had diabetes, they weren't getting rid of their diabetes, but maybe their A1C would come down a bit. And if a person had hypertension, I could help to lower that blood pressure a bit. But I wasn't actually getting to any sort of root cause of what was driving the problem in the first place. Now, I want to be very clear on this because I think this is a point of contention. I am not suggesting that what internal medicines doctors do is not incredibly useful and incredibly valuable. But what I am saying is that it's not necessarily a position or a practice that has the time or resources to address root causes of disease. What are those root causes of disease? This isn't anything that people don't know. It's lifestyle factors. Depending on the study you look at, it does seem like the majority of chronic diseases are driven by preventable factors, things like diet and exercise, sleep, stress, and other kind of day-to-day decisions that kind of drive our physiology. So that was a long journey that got me to the point of asking, what could I do that would enable me to help people make the healthier choices that led them to not choosing the junk food that led them to improving their sleep quality, all these other things. And it turns out that you can't just tell people to do healthier things and expect for them to be healthier people. That is what doctors try to do. That's what everyone tries to do. This kind of incredibly unscientific idea that the only reason that people are being unhealthy is because no one has told them that they need to skip the junk food or that they need to exercise. And so I made a transition into what has become, at this point, about seven years of commitment to trying to better understand the drivers of our brains as it relates to decision-making and as it relates to mood and overall cognition. And this was in large part also spurred by the fact that as I was going through my medical training and especially as a resident, I mental health was really not good. I was stressed, I was anxious, I was feeling depressed a lot. And I had this just very negative feeling of if I'm literally doing exactly the best things I can to learn about what makes humans healthy and I'm not a happy person, something is going wrong. And so that further in my desire to understand what was kind of driving our brain state both from a mood and a cognitive perspective. And so yeah, the last years of my life have really been about trying to take that research and make it applicable for the average person. So we don't have to wait until we wind up in a doctor's office, being told that the only thing we can do is slow down what's happening and in theory and in practice, I believe we can act on some of these root cause mechanisms that are driven by our brain state. Yeah, I love that, Austin. The reason I went into PMNR was because I thought it was the closest thing to that holistic alternative medicine, you know, besides being an athlete, besides loving MSK. And I thought, you know, having those lifestyle factors, trying to increase the quality of life in your patients, I thought that would be there. And you know, the more and more you go through residency training and ultimately I think you have the same kind of view, you know, going through residency training, you're not necessarily doing that. It goes back similar to the, you know, my intern year being an intro medicine, we're just kind of on the surface of just treating and not really reversing disease. And the more and more I, you know, year after year, I kind of ammoving away towards this precision medicine alternative holistic that, you know, you've paved and a lot of other physicians have paid that, that way for us. And brain health now is something that's becoming even more and more talked about. And just like you mentioned, you talk about cognition and there you talk about mood. I think it's important just to clarify what constitutes brain health when you think about it. Like, what are those elements that go to brain health at such a good question. I think when the general public thinks about brain health, what they think about tends to be, oh, my grandma has dementia, so she doesn't have good brain health. She has Alzheimer's disease. I think some people, but not all people make the connection between mental health and brain health. I mean, the fact that this is still a thing where there's an expectation that you have a disease of the mind that somehow separate from the brain is, is really a challenge for me to get my hands around because the mind and the brain are almost synonyms, right? What happens in the brain is the biology that drives your mental state. So mental health is a brain health state, even though it's not usually seen as that. But obviously beyond just Alzheimer's disease and neurodegenerative diseases, there's more to say as far as how brain health or brain state influences our day to day. An area that I've spent a lot of time focusing on is that our perception of reality, the way we make decisions, the way we interact with other people in our lives, the way that we kind of see the world as a whole is a direct reflection of our brain state. And I guess that's a bit of a challenge for people to think about because what I'm saying here is that your identity, the way that you see yourself, the way you interact with the world is a reflection of your brain state. And to take that one step further, there's nothing static about our brain state. So it's just like the rest of our body, cells are turning over, new cells are forming, it is being constantly changed as a reflection of our environment. So that means that basically anything that in my opinion is kind of a core driver of the outcome that matters, satisfaction in life, the ability to engage with, interact with and appreciate the beauty of the world is a direct manifestation of brain state. So how we make decisions, whether we make long term oriented decisions or short term oriented decisions, whether we're impulsive or reflective, whether we feel good about the day, having anxiety, depression, whether we develop a condition that makes it hard for us to think, all of these things are a reflection of brain health. And what that means for listeners who maybe haven't made the connection to what I'm trying to say here is we have an absolute loss in the way that we approach brain health, which is people don't think about it until something goes dramatically wrong, until somebody experiences a TBI, until somebody starts coming down with symptoms of dementia, until somebody has a stroke. And at that point, we say, oh, they have a brain issue. We pay almost no interest to the idea that every single day our brain health, our brain state, is driving how we experience our day. So you wake up on the right side or the wrong side of the bed, that is brain state. You make an impulsive choice and buy something that you really didn't need and now you're in the hole on your credit pills, that is brain state. You yell at your spouse unnecessarily because you were stressed at work, that is brain state. So in medicine, we talk about outcomes of interest and we talk about surrogate outcomes. In internal medicine, the outcomes we care about is bringing down people's blood pressure and making sure that their A1C is lower and making sure their LDL comes down. These are all surrogates for what really matters and what really matters is our mental health and our brain health. So there's so many different ways to slice this, but this is the conclusion that I've reached, which is no matter what you care about, in order to have your best chances of realizing it, you really need to have your brain health be your top priority. Because without that, there is no enjoyment or participation in life. Austin, I have one comment and then I've got to follow up question for you. I think what you just highlighted there in terms of people focusing more on the structural issues. I think that it's not dissimilar to really any other aspect of medicine. For instance, when we talk about musculoskeletal health and pain medicine, this biomechanical model has just persisted for such a long time and now we've started to appreciate that pain is deeper than that. You enter the biopsychosocial model of pain and we've started appreciating that a little bit more, maybe I'd say over the last five to ten years. And so people focusing on tower proteins, alpha-synucleon, CSF markers to look at brain health for a long time. That from a scientific perspective makes sense to me. But I'm also wondering, I don't know at what point the field of psychiatry was denoted in actual medical specialty, I don't know if you do, but I think that for a long time people considered our psychological or mental health was more entangled with our emotional health. We people talked about when they were sad, they had heartache, not necessarily if something was wrong with the mind, that feeling comes from the chest. And I know this is a very layman's explanation to that, but I can't help but wonder if that had something to do with that. And so, of course, as you've beautifully highlighted that the psychological aspect and the neuro aspect are so tightly coupled that maybe it doesn't even matter because it's a two-way street. But I'm wondering if you know when the field of psychiatry was actually denoted on specialty and when we started really taking mental health in the field of medicine, seriously, quote unquote. Well, I don't have the exact date as to when psychiatry became a branch out specialty, but what I will say is that you've hit on something that's super interesting, which is the separation of body and mind, right? And so now we have an emphasis on mind, body, medicine, and connecting the two things. But I just asked people, you know, when you feel like you're having a bad day, so if you're feeling anxious, if you're feeling stressed, if you're feeling low mood, what do you usually attribute it to? And I think for many people, we don't even attribute it to something. Oh, well, today is a bad day. And I woke up on the wrong side of the bed or maybe it's, I bumped into so and so on the street and they said something mean and now I'm feeling off. And that type of looking at our psychology, which our psychology is a manifestation, it's an outward reflection of our brain state, I think that's important to say. But that type of perception of how we think and feel, it's an incredibly blame-centric model because we wrap up our psychology in some version of our own identity where we can blame ourselves in each other for how we feel rather than asking what's going on. So somebody has a heart attack. We don't say, oh, they had a heart attack because they were a bad person, right? You know, they just, they didn't watch the secret and they weren't trying to manifest. We don't do that. We say, well, they had a heart attack because they had coronary plaque build up and became unstable and their LED is included, whatever it is. We talk about biology, right? And that allows us to talk about pragmatic things that we can do to work on that biology. But when it comes to how we think and feel, it's so often this kind of esoteric issue of the mind. And so there's some interesting examples of this. One that I like to talk about is how people perceive, for example, cigarette smoking and addiction. You know, there was a recent study where they asked people how much of a person's desire to kind of stop smoking was a reflection of something called willpower, which we've all heard of. And psychiatrists were better than the average person, but still there was a relatively high percentage of both that said, you know, this is really a willpower to mind issue. But if a person has schizophrenia, it's very, very odd and actually the studies have shown that really nobody says, oh, this is, this is a psychological willpower issue. They just need to not have schizophrenia. Yet both of these are manifestations of the same systems, right? They're a manifestation of brain state. So we've kind of artificially carved out this narrative where there are certain things that are within our kind of cognitive control or a willpower or our sense of self or identity. And those are things that exist independent of the biology of our brains. You know, I agree there's magic. I agree there's a ton that we don't know. But for people who have seen inside a human skull, it's tissue, just like the rest of the body. Now granted, the tissue makeup is different. There's a lot more fat. There's an incredible number of cells relative to other parts of the body as far as the billions of neurons and their trillions of connections. But the bottom line is there's something physical there. And why that's so important is because if you understand that your mental and brain state or your mental and cognitive state, I should say, is a reflection of the health of that tissue. And then you understand that each decision you make, whether it's the food that you eat, the sleep that you get, the exercise you do or don't give yourself, is influencing every system that influences the brain, immune, metabolic. You basically get to tap into kind of the core OS, if you will, like the operating system of what drives our day to day function, what drives our day to day mental state. And I'm not trying to suggest that just by understanding the science that we're able to reverse or completely remove the prevalence of brain and mental health conditions today. But I do think that if the average person can start to get a little bit deeper as far as their understanding of these are reflections of brain health states, then all the sudden we are no longer acting at the end, you know, acting once somebody is had his stroke, acting once somebody has diagnosed Alzheimer's disease. And we're instead asking each day, you know, just like we'd say, you need to go exercise for your heart health, we'd say, what are you doing today for your brain health, both mental and cognitive state? And until that catches on, we're always going to be playing catch up. So there's a lot to, I guess, dissect from this, but if there's one kind of core message I've been trying to put forth, it's to tell people how much more agency they have over their brain state than they believe. And for them to understand that if you don't take control over some of your brain mechanisms, you outsource that to what's happening around you. And the modern world is by and large geared towards your brain being wired and functioning in a way that is disadvantageous to your, your health, to your brain health, to the health of your body. So it's really trying to allow people to regain some autonomy over these mechanisms by way of lifestyle. And to some extent, you could argue various pharmaceuticals could do that as well. But it's to ask this question of, you know, we have this entire range of interventions that we talk about as it relates to a condition like our cholesterol or as it relates to a condition like our blood pressure. What are we really doing that we can talk about as it relates to our day to day brain function? We have to be having that conversation because it's the one that matters most to our ability to enjoy life. I really, I really like where this is going because it's quote unquote philosophy intertwined with science. And I think we're getting to the point, especially with artificial intelligence coming out now. I mean, these are conversations I need to be had. And I love how you said that in the end, it's about the human interaction with the rest of the world, with other humans, with nature, with whatever's in front of us. And you know, when you were talking about a lot of the things, cognition, mood, even pathological states of brain health, you know, I can't help but to think, what exactly are we measuring? Right? Like are there true indicators of brain health that we can measure or are we kind of just using, you know, the indicators of sleep cardiovascular health and these other measures that we can easily measure to kind of extrapolate and say, hey, we now know we're in a good brain health. Yeah, it's an interesting point you bring up. So from what I have seen in internal medicine and it's different in certain sub specialties, you know, you only start measuring something brain related when you have concern for something going wrong. There's no annual mini mental status exam for healthy young adults. That's not recommended by any USPSTF or whatever. It's basically, if a person comes in and says, I think my thinking is off or if a person comes in, you know, with a post stroke or something, sure, you're going to do that. Or if you're concerned that they have overt pathology. So of course, you know, if a kid comes in with attention issues, they will go down a treatment algorithm or a diagnosis algorithm to evaluate for certain conditions. But what does it really look like? Most of it is talking about testing, right? So you could test a person's markers of cognition through a number of different tests. You can test everything from mental health, which is again, a reflection of brain function through questionnaires to cognitive status. As I mentioned, something like the mini mental status exam or the mocha, which are the typical ones that are done to look for cognitive issues, specifically later in life. And then there's some really interesting tests that are done primarily in an academic or a research setting to look at things like decision making levels of impulsivity based on whether a person would prefer a smaller reward today or a larger reward to tomorrow. And so I'll just couple this with saying there's tons of imaging that we can do. And really imaging of the brain is pretty recent over the last couple of decades. It's kind of gone from CT to MRI to functional MRI to PET scanning to variants on these things that allow us to see at a granular level. How are areas of the brain functioning with each other? Where is there changes in white matter, gray matter, and how that might correlate with things like diet? I think there's really one of these variables that I'm fascinated by, which is the one I described as far as decision making. So we have thought for a long time that certain people just kind of make choices impulsively or not, and that this isn't an incredibly dynamic output that changes depending on whether it's, let's say, a food or a purchase that they want to make. What we're now seeing in the research is not only that people's preferences for a smaller reward today versus a larger reward tomorrow are tethered to mental states like depression, but that it's increasingly looking like lifestyle modifications in addition to psychological interventions can modify a person's impulsivity, meaning their desire to do something not as healthy today versus something more healthy tomorrow. When I look at, I mean, I guess, the existential threats that face humanity. So whether it's resource, use outstripping our capacity or nuclear bombs or wars in other contexts, these are really a reflection of can people get along, can people plan for the future versus trying to use everything up today? And so that testing for individuals as well as at a population level, I think, is super interesting. But there are also a number of people, I'm sure you've had some of them on who are advocating for more kind of dynamic testing of brain function, and there's a number of ways you can do this. So reaction time is a test of brain function. If a person takes a cognitive test in another way, that's a reflection of brain function, where I believe that kind of the rubber meets the road is the mental health stuff. And the reason I would say that is thinking about everything as far as the surrogate or the outcome I really care about, our ability to think clearly is really important, but I think what transcends that is our ability to enjoy our days. And so if a person doesn't have good mental health, all the other stuff doesn't really matter. I have not seen a consistently administered test for the average person to get a gauge as to mental state that doesn't necessitate going into the office and doing a standard kind of depression inventory, but I really think that's where we need to be going. And to take that one step back further, if we have predictive markers of that, which from my reading, there are some that are interesting, A1C variability has some correlation with mental state, cortisol reactivity has some correlation, inflammation has gauged by a number of different markers has a correlation with mental state. What I would love for us to be able to do is come up with a predictive marker so that we can have a lifestyle intervention plan, potentially a pharmaceutical intervention plan, that predicts who's more at risk for getting the condition like depression and allows us to tailor a plan for them. So I know we're kind of diving really deep into this rabbit hole, but one of the areas that I've actually done some recent research in is to try to understand certain predictors of depression that are things like inflammation and metabolic dysfunction. And to just put that back into the general concept of brain health without going into mental health and too much detail today, the idea would be to say whether it's ABOE4 or something that is perhaps a little bit more modifiable, what can we do on a given day that is going to allow us to decrease our chances of developing overt brain conditions, but also that will allow us to have higher functioning brains today. I don't perceive a world in which 18-year-olds in college are going to make decisions dramatically differently to prevent their chances of getting Alzheimer's when they're 70 years old. But I do see a scenario where if we can talk about lifestyle factors that will positively influence their cognitive and mental state when they're 18, right? So today that many of the same lifestyle factors that potentially could prevent their developing Alzheimer's disease become top priorities for them because it increases their academic performance, it increases their ability to bond with other people, it increases their overall life satisfaction. You mentioned specific markers that would be worth looking at if we had them. Are you aware of anything that's currently in their research that might be specific towards mental health? Well, are we talking about mental health, cognitive health, or just generally brain health? Mental health. Yeah, and so they do exist where I've spent the majority of my time is looking specifically at inflammatory predictors of depression. And so mostly what we're looking at here are going to be cytokines, as well as to some extent kind of molecules that are called acute phase reactions or things like C-reactive peptide and said rate. So basically things that tend to go up in association with inflammation. The cytokines are interesting. So cytokines are an essence proteins that are made by immune cells or act as immune signals throughout the body. So various immune cells produce various cytokines, those cytokines can have local effects, they can have kind of systemic effects. And the idea here, one of the ideas is that when our brains experience inflammation, which can be a manifestation of a number of different kind of pathways leading to this outcome of inflammation that people tend to feel more depressed. And so if you were to measure, based on several large scale studies, although there's a little bit of conflicting evidence, if you're to measure in even a healthy population, levels of these cytokines, so specifically interleukin-1 beta, interleukin-6, those tend to be some of the major ones, tumor necrosis, factor alpha, sometimes interferon gamma. But really, I all are interleukin-1 and say interleukin-6 are two of the major ones that you can predict the people who are more likely to develop depression. And similarly, if you take people with depression and measure their levels of some of these cytokines, you can predict the people who might have a treatment response versus those who would not. I think that's really interesting. Is it something that is being done as far as doctors measuring inflammatory markers and using that to predict risk for mental health disorders? I haven't necessarily seen that happen. I would also say, though, most people don't measure these cytokines. They tend to be a bit more expensive and they tend to be more used in research protocols. And so really what you get to is, or at least where I've landed is, I believe that in a certain subset of people, inflammation does drive symptoms of depression. We can talk about some of the evidence that supports that idea. But if we stick to this idea that in certain people who develop higher levels of inflammation in their bodies, they are going to develop depression. And then we understand that there are life-solid interventions that we know act on those same pathways, then it would seem to make sense if it's also beneficial for people in the whole to do these interventions that lower these markers, that that should be part of a kind of a standard protocol for mental health benefit over the course of the lifespan. That's not really the way that these things work. Again, in a typical kind of internal medicine or primary care setting, you'll have maybe a screen for depression, but until you really flag positive, which means that you get put into the treatment protocol, psychotherapy, consideration for an SSRI, there's not a lot that is necessarily done. And I think this comes back to the point we had already made, which is that psychopethology, something like depression and anxiety, is up until the point where you can say you have a DSM diagnosis, is kind of seen as something that is, well, this is what life is, or it's a reflection of your mental, or your mind, and so you're left to manage that on your own until things go really wrong. So the point here would be to, I guess, explain this in a slightly more simple way. Depression is a brain issue. We've usually looked at depression as a manifestation of one thing going wrong, usually something like serotonin. We now understand not that straightforward, many things likely contribute to a pathologist that gets described as depression, but again, it's not one universal thing. One of those things seems to be inflammation. Inflammation can be measured in the bloodstream through a variety of different ways, and inflammation also seems to be something that is both driven by and can be modified by lifestyle changes. So if we put all this together, where I believe we're going in the years to come is we are going to be increasingly able to predict who has high likelihood of getting depression and hopefully intervene ahead of time. As well as when we have people with depression, we'll measure certain markers, one of which is inflammatory markers, and based on that, we'll know who may respond to a specific drug. We now have data that people with higher levels of certain inflammatory markers may not respond to, for example, an SSRI, but they may respond to ketamine. So now we're getting into a bit of that precision where we're saying, not only do we have a census to what might be a contributor to this person's suppression, but we know that a person's markers may predict treatment response. So it does kind of tie this whole circuit together, even though we are talking several years into the future until it's probably put into practice more consistently. Is this more of a chicken or egg scenario in terms of the inflammation and depression, or do we know based off the data that it's the inflammation that's driving the depression? It's such a good question. There's always an overlap in these things, but there's a couple of pretty strong data points supporting the directionality is inflammation leading to depression. One of those is that people with elevated levels of inflammation have a higher risk for developing subsequent depression. So that kind of is one indicator that the arrow is moving that direction. But what is more convincing in my opinion is that we have interventional studies showing that when you take a healthy person and induce an intervention, or basically you give them a drug that increases inflammation in their bloodstream, that they will experience symptoms of depression, which is really interesting. And so this data primarily comes from work that's been done with people with hepatitis, as well as some cancers, but the idea is that people who are given interferons tend to develop symptoms of depression more than the average population. And that was then built into these studies, which are a little bit more recent and are fascinating, where we've isolated this part of a gram-negative bacteria called a lipopoly saccharide, and this is part of their cell membrane. It's incredibly immunogenic, meaning it induces inflammation. There's a lot of conversation around this molecule. It's also called endotoxin as to one of the correlations between what's called leaky gut and systemic inflammation. But in experiments, they will take a injection of this LPS, this lipopoly saccharide, and inject it into a healthy person, and then they will see how they feel. And people will feel many of the symptoms of depression. So there's, in my opinion, this is one of the more convincing pieces of evidence suggesting the directionality is from inflammation to depression. The other thing I just throw out that most people will have had some experience with, and we're talking earlier, I think many people at this point have come into contact with a certain type of coronavirus. We won't have to go into too many details there, but basically developing sickness. And so we all get illnesses. We all come down with whether it's the common cold or the flu or something more severe. When you experience, or when you have that sickness, how is your mental state? For most people, they feel a bit socially withdrawn. They feel maybe a bit sad. They feel like they have low energy. They feel less excited about doing what they usually would. These are many of the symptoms that characterize depression. And the directionality there, again, seems to be that a person contracts an infectious disease, which increases inflammation leading to this mental state. I think it's unlikely that people start feeling sad before they contract an infectious disease. And that's the driver. So kind of what I'm saying here, a lot of data points that suggest the directionality is people who have higher levels of inflammation and not everyone, but certain people who develop higher levels of inflammation are at higher risk for developing symptoms of depression. And I just want to highlight this point because I've already made it, but it's super important. We all want to believe that these conditions that we suffer from, whether it's having a stroke or Alzheimer's disease or depression are caused by a single factor. So we'd love to think, well, the issue with stroke is, I don't know, high blood pressure or endovascular dysfunction or the issue with a person who develops Alzheimer's is emloid buildup or a person with depression has a serotonin deficiency. And I guess I'd be curious for the two of you what it's like in your practices, but it has almost never been the case that any of these chronic diseases are really the manifestation of one single thing that went wrong. I'm very seldom convinced that it's as targeted as that. And so as we're looking at a condition like depression, which we've thought about for a long time as a manifestation of a serotonin issue, that data has been strongly challenged. And in its place, we get to the nuance, which is there's probably a subset of people whose depression is inflammatory in nature. There's probably a subset of people whose depression is driven by changes in the HPA axis. There's probably a subset of people whose depression is a neuroplasticity issue. And there's probably a subset of people where metabolic dysfunction and conditions like diabetes and insulin resistance are playing a big role. And there's probably the majority of them in which multiple factors are contributing. But until you develop that nuance, you're really not able to have the conversation around how something like inflammation or insulin resistance contributes to your brain state because we're so fixated on finding the single target, which we can then manipulate with either a drug or something else that we take if and when things go really wrong. And that obviously isn't working for us. Yeah, no, I do agree. I think that, again, in the musculoskeletal world, when people come and ask me, am I having this issue? Is it because of my posture? And I say yes. And the same person can come with the same problem as me. Is it because I slept poorly in the answer? Yes. And somebody might come and have the same issue and say, did I overdo it? And the answer is yes. Again, it's a multifactorial. But of course, the issue with that becomes is that's when you start losing people, right? People don't want to hear. It's too many things. You want one problem, one thing that's the villain, the culprit. So you can attack that, put all your energy. The moment you say you have to do an overhaul on multiple things, that's where it becomes more challenging. I haven't quite figured out. I agree. But yeah, but I want to come back to the point when you were talking about the data in terms of directionality. And not being familiar with the inflammation leading to depression, I'm wondering if that data is exclusive for depression or other mental health states like anxiety, particularly I'm interested in, and then things like PTSD and things of that nature, is there a correlation there as well? Yeah. So it's a great question. From my reading, the mental health conditions with the strongest correlations for the inflammatory mental state relationship are, first and foremost, depression. PTSD, yes, anxiety, sometimes. It has not been from my reading as consistent, and so you don't have as much of that kind of directional evidence as you do in depression. Part of that is too, I think depression is a little bit more broad as far as symptoms. So as you've probably done with kind of a standard depression inventory, do you have changes in your appetite, changes in your sleep habits, changes in levels of guilt, do you feel more sad? We're kind of capturing more potential data points that contribute to what we call depression, whereas with anxiety, specifically, subtypes of anxiety that can be a little bit more nuanced. So yes, for depression, yes, for PTSD, there's some interesting evidence around schizophrenia, which is, it's kind of different in some ways as far as the psychopathology. There's some evidence for bipolar as far as inflammatory states driving potentially manic states, but I would say as far as the evidence that I'm aware of, and really one of the reasons that I've focused on depression is that that tends to be where the preponderance of the data would suggest that directionality. It's also where, of note, we have some of these a little bit more fleshed out interventions around lifestyle measures that seem to target some of that core path of physiology and can have potential reversal effects on depression itself. So from my reading, unlike conditions like PTSD, anxiety, and bipolar, we actually do have some decent data that dietary modification can have a positive impact on people with diagnosed depression, specifically around Mediterranean style diet. And so that excites me because to your earlier point, when you get too overwhelming with all the variables that influence a person's health outcomes, it's really hard to get somebody to do anything. But if you say, you know, there's actually been some randomized trials showing that people who use a Mediterranean style of eating have a higher chance of decreasing depressive symptoms than those who eat a Western pattern of eating, that becomes a little bit more tangible. So now we can say, here's the dietary pattern that may help prevent depression and may help to manage depression. And I'll just put out again, I'm not saying that is the solution for everyone, nor am I saying that is a replacement for working with a practitioner using pharmaceuticals and the like. But it is really a great thing to say that we have data suggesting that dietary modification may have a positive benefit on this disease state, where for other mental health conditions like anxiety and PTSD, I'd say the data is far less clear. Awesome. So I'm glad you brought that up. I think that you've done an awesome job kind of just painting the picture of how again, tightly these the cognitive health and mental health are linked and essentially comprised together to form brain health. Now what would be the perfect world is if we had precise markers that we've already talked about, but really we have signals is kind of what I'm getting from you, right? And stronger in some places, we hear in other places. So I'd love to spend some time talking about interventions now and really in any order that you like. But I'm curious, you know, when Darshan, I talk about kind of the pillars of lifestyle medicine or pillars of health, right? We look at exercise, sleep, nutrition, which you told us, spoke about exogenous substances in which we include our injectables and things of that nature as well. Subliments are kind of in that bucket and then of course, pharmacology. When you like to start understanding context matters, every single person would be different. But if you had to make an umbrella statement, and I apologize for putting you in a spot, I'm sure you don't like doing this, you know, in terms of you could take it either where the data is the strongest for brain health as you've defined it or where you like to consider first because you think it's low hanging fruit. Right. Yeah, that's a great question. So in a perfect world, if I was to ask, you know, what are the strongest contributors to human death and unnecessary death and disability? It's diet, it's lack of deep social connection, it's lack of exercise, it's poor sleep, it's lack of nature exposure, it's, you know, too much time on our screens, it's all the exogenous substances that we breathe in and put in our bodies. It is all of these things, I guess, the question then would be, in part, if I could wave a magic wand and solve for one of those, which one would it be? It would probably be diet because of, you know, how kind of direct those correlations seem to be, but if it comes to what I actually recommend for most people, it's generally not diet. And the reason for this is in my sojourn to try to understand drivers of human behavior, I happened upon the research inhabit formation and I've had the opportunity to speak with people who are expert in this, I had a chance to do an interview with Wendy Wood who is really one of the world's foremost researchers on habit formation. And the takeaway from all of this is that humans do things they enjoy, which is a really stupid thing to say, but is so important when you understand why that matters. And so let me break that down. If a person comes into the clinic and you see that this person would benefit from exercise, diet, better stress management, sleep, which is basically all the people. And you say, well, here's what you need to do. You need to start eating healthier, you need to start exercising, you need to start going to bed on time, you need to start meditating for 30 minutes a day. All of that is true, but is it actually helpful? And I would argue that most of it is not helpful. And part of the reason for that is that the reason that people don't eat healthy food isn't that, well, at least the larger reason isn't that they don't know it's healthy. It's that unhealthy food tastes better. I hate to say that, but I think it's true, right? So sugar tastes good for most people. As much as we want to say, oh, yes, it's toxic and I would never eat it, most people, I believe, would actually enjoy a sweetened ice cream as opposed to a bland ice cream. And similarly, many, if not most people would enjoy being sedentary, rather than going out and jogging the 5K every day. And this isn't anything mind-blowing as it relates to what humans would think they would do from an evolutionary kind of perspective. I mean, I have a dog. If I gave that dog the option of eating food that tastes really good, but it's bad for them, or running around on the track all day versus hanging it on the couch, she's going to choose often the stuff that's a little bit more unhealthy because it makes sense from kind of an energy conservation mechanism and also evolutionarily, there's a signal that they get that we get from eating certain foods that are hyper-palatable. So that is a long-winded way of me saying humans tend to do the things that they enjoy. And as it relates to habit formation, which habits are these unconscious loops in our brains that drive up to 40% of our decisions in a given day, habits are formed when we do the same thing repeatedly. And we're far more likely to do the same thing repeatedly if we enjoy it. Great example would be pulling out your smartphone and checking your emails or social media. Many people, if not most people, do something like this. First thing when they wake up in the morning, the first 15 minutes, that becomes a habit loop where we're not even thinking about why am I taking out my phone, we do it because it's a virtual because we enjoyed it and because now we don't even think about it. So we do things that we enjoy and when we do things that we enjoy, they become habits and they become automatic and they are things that we do without even thinking about them. If I want somebody to become healthy and I tell them you need to stop eating sugar, you need to eat a whole lot more whole foods, try to make sure you're eating foods with very few ingredients and so on and so forth. There's very little about that that is intrinsically enjoyable because you're actually cutting out the things that the brain has been evolutionary program to enjoy and that modern society has set up to be convenient. Similarly if I'm telling somebody, hey listen, you need to start exercising. There's not much that people would necessarily say, oh, I really can't wait to start exercising. People know it's good for them. So what people can get on board with and why, again, very long-winded way of getting to this point, what I recommend for people to do first and foremost as it relates to protecting their brain health is to prioritize sleep and the reason for this is that unlike eating healthier food and unlike exercising, almost everybody feels better after a good night of sleep. So it's something that we can say is number one, really good for your body and your brain and number two, you will enjoy if you actually give yourself access to that seven to eight hour window of sleep each night. So you start there. What I also tell people is I think diet makes a huge difference for brain health but it's not necessarily something where everyone's going to feel it immediately. So sure if you completely cut out sugar and you're drinking two liters of coca-cadae, you'll probably feel a little bit clear-headed or you might be feeling some sugar withdrawals but you might feel that. But for the average person, you start mixing in some whole foods into the diet, you might not feel cognitively clear right away. But based on the research, if you skip one night of sleep, you will statistically or I should say there will be a statistically significant output of worse cognition. You'll have worse focus, you'll have worse attention, you'll be more irritable, you'll make worse decisions as it relates to the food that you eat. On average, people eat several hundred extra calories a day and it tends to be from highly caloric unhealthy sources when they're sleep deprived. You get that good night of sleep, it actually sets your brain up for a place where you're thinking clear, you're feeling better and you're more likely then to make all the other decisions that would have been really challenging if not impossible the night before. So I can talk about, I guess some of my top tips is that it's interesting as far as how to actually get better sleep. But to answer the question here, I will almost always tell people if there's one thing you can do today that is going to significantly positively augment your brain health, it is granting yourself that seven to eight hour window of high quality sleep tonight. It's making that your objective for the day because tomorrow, you'll think better, you'll feel better and you'll make healthier decisions. I absolutely love that. I got to tell you, I've asked some variation of that question to almost any guest who's been on here before and really anybody who's had the patience to have this type of conversation with me. And of course, my bias is exercise, but because I'm habituated and I've been an athlete my entire life and when I go two to three days without exercise or a really good quality movement of some sort, I'm having withdrawal effects and we can talk about whether or not that's a good thing. You know, a recent guest who's a sleep expert just talked about her hierarchy, of course. Again, if we just talk about how many days could you go without sleep or how many days could you go without even food or the effects you're going to have, it's going to be demonstrated in your pathophysiology, we should say pretty profoundly. So that's maybe another way for people to look at it. But I really love that. I mean, you know, you talk a lot about habits. I mean, we're fans of James Clear, BJFog, all those folks who, you know, James Clear talks about decreasing the amount of friction, you know, when you're having between a good habit and increasing the amount of friction when it is bad habit. So just the fact that when you're having a conversation with a patient to decrease the amount of friction that that's going to be between them receiving your quote unquote advice, I think just, you know, just engaging in something that they're more likely to enjoy. I really love that approach. So I'm going to steal that if that's okay with you. But yeah, of course, you spoke to something right there that I think is incredibly important to pause on, which is you mentioned kind of the friction between what the patient wants and what you want. And this is the lesson that I have learned so many times and for it to stick, it really requires a re-conceptualization of how behavior change works. You know, as much as we want to believe otherwise, the things that we care about as doctors are not the same things that patients care about. You know, your blood pressure is elevated. We need to bring your weight down, your cholesterol is too high. Sometimes they care and often they don't. I cannot tell you how many times a person came in. I said, I really want you to work on X, Y or Z and they came back to the clinic and I said, how did it go? And they said, oh, I didn't do it. And so I would say, I don't understand, right? We talked about this. We talked about you getting out and walking every day. We talked about you not drinking soda, but you still drank the soda and you still sat on the couch. And the delta or the gap here is that my goals were not aligned with the patient's goals. And I mean, just fundamentally, it's a huge mess. And I think the question that maybe all of us need to be asking, even outside of a doctor patient relationship, is how do you find alignment in something that you and the person you're working with actually care about? Because until that happens, you're just swimming upstream. That gets, I think, also to this point of how often are we just chasing surrogates. So if you argue, well, we need to bring your blood pressure down. Why is that? Well, it's because if your blood pressure is high, you might have a stroke or a heart attack. It's okay. Well, that sounds scary. But why is this scary? I mean, what is the driver of a person being concerned about that? The driver is that they won't get to spend time with their grandkids, that they won't get to go on that hiking trip they're looking forward to, that they won't get to go on the cruise with their family out of Florida. These are the things that actually drive human behavior. It's the pain that comes from not being able to do the things that we really care about. So I think trying to find, and again, I'm generalizing this outside of the doctor patient relationship, but trying to find where for us and for others, we have those pain points. And then trying to find solutions that address that directly is a whole lot more practical than just arbitrarily saying, well, we all need to be exercising. So that's the goal, or we all need to be eating healthier food and that's the goal, tethering it to something meaningful is the key. Yeah. No, that's very well said. And I think something that our audience can draw from, whether they're patients, whether they're providers, I think having the ability to have those conversations in a room where you feel you're most vulnerable and you want to see change, having those meeting for conversations absolutely, absolutely crucial. Awesome. I mean, we'd love to get into some other things here. I don't know how much time you have. Got a few more minutes. You were minutes. All right. So then, ultimately, we do want to take this. We can, I don't know if we have, if we do it part two, we can maybe do some of the life stuff. But since he brought up sleep, I'd love to get some of your tips and tools and tricks to it. So we can leave the people with some actionable stuff if that's okay. So shameless plug here, but if you go to my website, Backslash Sleep Guide, I have a free guide that people can get with all my sleep tips. So it's awesompromoter.com, Backslash Sleep Guide. But let me just run through some of the things that I think are super quick ways that people can get better sleep. So I kind of bucket these around stress, sound, light, and then let's start there. So one of the major drivers that people have around sleep is that they're stressed by the time they go to sleep. And that stress can be activation mentally. It can also be kind of stressed because they were interacting with stressful content around them. So generally speaking, I think one of the top sources of stress that comes in before bed is coming through our screens. And so trying to cut back on screen time in the hours before bed makes a ton of sense. Screens are also the source of blue light, blue light blocks melatonin production makes a harder to sleep. So generally speaking, minimize stress by reducing screen exposure in the hours before bed and try to minimize conversations with other people that are stressful in the hours before bed. I think that's really important. Another one is to think about sound. So we talk about stress. Sound is really important. When we're sleeping in loud bedrooms, it's been shown that it dramatically decreases the quality of sleep. And here's something really interesting. We are far more likely to be woken up by noises around us in the second half of the night. And the reason for that is we have kind of a sleep pressure that builds up over the course of the day. And we actually relieve a good amount of that in the first half of the night. So we're not quite as sleepy in the second half of the night. It's easier for us to wake up. So reducing noise exposure in your bedroom is really important. There's a number of ways you can do that. I have a sound machine, which I think can be really helpful for white noise. At a very basic level, trying to make sure that you close your door that if there's a lot of space between your door and the ground, consider putting some padding in there, carpets, and even kind of curtains, blinds, and those types of things can help. So reducing sound exposure before you go to sleep. Light exposure is really important. So I would say the evidence for getting early morning exposure, even though everyone's talking about this, light in your eyes, first thing, there's not as much data as to how that relates to quality of sleep. But it does seem like it's a good thing to do for maybe other reasons. It's certainly not going to hurt. It's something I try to do. But what does seem to be the case is that minimizing exposure to specifically blue spectrums of light in the two hours or so before bed is a good plan because blue light tends to be more stimulatory. And as I said before, in the context of screens, it tends to lower melatonin production. Depending on your level of biohackery, you might be somebody that considers blue light blocking glasses. I've tried them. I will use them still if I'm watching a movie or something before bed. But I think the better move for most people is just to try to have a buffer in between the time that you engage with a screen and the time you go to sleep. And if you have to interact with screens to try to use night shift or night mode versions of whatever that content is. I guess one thing I'll just say on that front is it's not just the screens and going back to the stress thing, it's any sort of digital device that can be kind of activating. And so I'm a big fan of trying to remove as many digital devices as you can from your bedroom. So if you need an alarm clock, don't use your phone, just get a standard kind of basic alarm clock. I don't think it's a good idea for us to have TVs in our room. I know that might be something people don't want to hear. But if you can get away with not having a TV in your bedroom, your sleep will thank you for it. And then one, I guess there's two more things I'll just touch on. One is temperature regulation. So our bodies tend to drop temperature a little bit when we go to sleep and we can facilitate that process and improve quality of sleep by lowering the temperature of our room in Fahrenheit degrees. That's somewhere around the 65 degree mark that seems like it's most kind of consistently cited in the literature as far as being ideal for sleep. And then the last thing I'll just mention here, which I don't think people talk about enough is substance use. So alcohol is a pretty potent inhibitor of natural sleep rhythms. And the idea of drinking right before bed, yes, it has some kind of sedative properties, but sedative is not equivalent to quality sleep. So drinking before bed and they cap to try to get sleepy is a bad plan. Having that extra glass of wine before bed, things that we should avoid if our goal is good sleep. And the last thing I'll just say on this is the coffee. So most people drink caffeine in one way, shape, or form, I'm definitely in that demographic. But what people do not usually understand is that caffeine has a six hour half life. And so if you drink a cup of coffee at 2 p.m., then at 8 p.m., you're still having half of that caffeine floating around in your bloodstream and influencing your brain function. So I find that the latest I can drink coffee is 2 p.m. Some people would have it be earlier, some people might have it be later. There's various kind of versions of people's tolerance to caffeine that in some ways is based on their genetic predispositions and how fast they metabolize the molecule. But if you are somebody that's having issues with sleep, highly recommend cutting back on afternoon caffeine. And the last thing I'll say because I've just decided to go through everything about sleep is if you are somebody who struggles with sleep and you haven't already been evaluated for it, talk to your doctor about being evaluated for your sleep. Because sleep apnea is a huge problem. There's other sleep conditions like restless legs that can be a major driver of poor sleep. But sleep apnea in particular is a massive issue affecting millions of people in the United States and millions of people who are not diagnosed. So there's some, I don't know, both of your preferences as far as whether you find a stop bang to be the most valuable tool here. But just generally speaking, especially if you have a large neck, especially if you've been told you snore, especially if you wake up in the night or have been told you wake up in the night, especially if you're feeling drowsy during the day, and especially if kind of more standard sleep hygiene measures are not working for you. I think it makes a ton of sense to ask your doctor whether you need a sleep evaluation because sleep apnea is definitely a manageable condition with proper intervention. And it's also linked to elevated levels of inflammation, higher risk of heart disease, higher risk of Alzheimer's disease, and dying early. So it's definitely something that's worth investigating if there's a chance that that's what's driving your poor sleep. 100%. Create tips, Austin. I know when I try to implement most of those sleep hygiene habits, I mean, my sleep, my HRV, my next day, my mental state the next day are definitely going to be way better than if I hadn't have done those things. And absolutely good point about the sleep apnea and the sleep pathology. I mean, I can't tell you how many times even in the rehab, we've almost diagnosing people with sleep apnea just because of those symptoms that you mentioned. For the listeners, I believe, I forget what episode number it is, must be in the 70s or low 80s. But we had Dr. Rajadadya come on to talk about sleep apnea and the common symptoms that manifest. Austin, I want to thank you so much for coming on here. I know you've been lightened me, Altamash with a new way of thinking, really about mental health, not one that I've really heard of before, but makes a lot of sense. And you have a really, I don't want to say simplistic, but you have a very nice way of taking us through that. So thank you so much. I do want to ask you, what, do you have any projects lined up right now or what's next? Always, always the project, right? I've got a clinical study that's wrapping up that I'm really excited to put together and share, specifically looking at how plant molecules modify epigenetics and immune function. So the basic idea there is that we've often looked at foods as healthier, unhealthy, based on their macronutrients and maybe their micronutrients. But what we haven't looked at is phytochemicals, which are the thousands of molecules contained primarily in plants that are hugely influential in a plant's health, but now we understand may influence our health. And so this study is looking at how these molecules may influence our genetic expression and therefore our immune system. So that's happening soon. Some other projects I'm involved with, I mean, definitely some interviews and summits that I'm doing soon that are coming out. But there's a study that I'm looking into putting together, which is more on some kind of nuance aspects of how psychedelics may influence health. And so if that comes to fruition, I'll be incredibly jazzed to be able to share that. But right now it's mostly about the plant molecules and the epigenetics that I'm excited about. I mean, I really hope we get to do a part too. There's so much more I want to ask and get through and understand as much of the psychedelic front as well. I know you're active on social media if you don't mind telling the listeners where they can find you, the websites and the Instagram. So I guess depending on your platform, probably the easiest way to find me is to go to my website which is austinpromotor.com. It's where I post the majority of my content. I have a newsletter there. They send out most weeks. And then Instagram and most of my social media platforms, it's Dr. Austin Prometer. So if you search for me, you will probably find me there. Cool. And we'll definitely put those in the show notes for easy link access. Last question, Austin, that we ask all our guests, it's the theme of our show, really what we try to get at. And I know a lot of it you already talked about. So how do we put the health back in health care? Well, you just dropped this question right at the very end. How do I give it? How do I give a short response to this? Yeah, I think so the question itself implies something that I totally agree with which is that health care isn't about health. It's about kind of at this stage, it's about slowing the progression of disease most of the time. It's not clear there are absolutely instances in which health care or health happens in health care systems, but by and large, health does not happen there. And so my opinion is that if a person wants to be healthy, they cannot wait for doctors to make that happen, that the actual creation of health, sustainable long term quality health for most people doesn't happen in a doctor's office. So I really have been advocating for people to take agency over wellness for themselves. If you wait until something goes wrong, you've lost your biggest chance at sustaining health over the lifespan. So that kind of questions the idea of what health care is. If we're talking about acute and reactive health care, how could that be more integrated to health? I think it needs to expand a little bit larger as far as what it means to administer health care. And the area that I'm most interested in, which we have very explosively discussed today is what is preventive mental health look like? And when have you seen that discussed in the health care setting? In my opinion, preventive mental health care is the most important thing that we could do if and when we could do it right. Because a person's mental state, as I've said already, is the most important outcome that kind of matters in life. And so how can we focus on making that a priority? Well, I think first of all, coming back to what I said about my mental health and my training, we have to define that as the priority. And if that is the priority, then it needs to be a priority for our health practitioners just as it is for our patients. So doing things to promote the mental health of health care practitioners seems essential for a system that actually wants to improve people's mental health care. I think this is a feed forward cycle whereby if people's mental health is better, they will be better able to provide good care for their patients. So one of the areas that I feel very passionate about is overhauling medical training to better enhance mental health for practitioners. We didn't talk about this too much, but for what it's worth, doctors' mental health is very bad. It's worse than the average person's suicide risk is multiple times higher, depression risk with multiple times higher, I had multiple people in my training programs that I knew who unfortunately lost their lives to mental health conditions. And so I think there's a ton that can be done for that, not the least of which is everything we've already described. How do we optimize sleep? How do we optimize diet, exercise for medical trainees? And I really think that it's starting there with creating doctors who are mentally resilient that seems like a targeted approach that allows us to then focus on what health actually means for patients because then they have the mental and cognitive bandwidth to start incorporating some of these conversations that we've already described into what the care model looks like. You can't have people who's mental state is terrible trying to look out for the mental state of other people, it's just not a sustainable model. So I know there was probably a little bit more than the question might allow, but I hope you indulge me. It's on par with everything we've talked about. It's a lot to think about. Thanks, Austin. Thank you. Thank you for listening to another episode of Medicine Read Find. Hopefully you find that to be valuable and enjoy that episode. Luckily Austin has agreed to come on for a second episode. So in the next few months, we should be able to get a part two for you guys, where we can touch a lot more about the topics that we discussed today, as well as some of the novel therapies to help address brain and emotional health as well. If you found this to be an interesting episode, please be sure to subscribe, review, and share it with anyone who you think will gain value from this. And before you sign off, please remember the important disclaimer that everything in this podcast is for educational purposes only. It does not cost you the practice of medicine, nor should it be construed as medical advice, no physician-patient related and informed, and anything discussed in this podcast does not represent the views of our employers. Please, please, please seek the guidance of your personal physician regarding any specific health related issues you have. And until next time, thank you for listening.