Research Reels: The Neurobiology of Migraine

Welcome back to BBS Mindful Minute. My name is Brandon. Today we will sit down with Dr. Ducer, a migraine researcher and head of the neuroscience department at UTT. We discussed his journey into the world of migraine research, our evolving understanding of migraine neuropathology, current treatments, and opportunities for future treatment targets. Migraine is a debilitating disorder that affects one in six people and it's the hope that through findings made by research and labs like Dr. Ducers, we will better be able to treat and understand this disorder. Without further ado, let's get into it. Thank you so much again for being on the podcast. Could you introduce yourself and tell us a bit about your journey into neuroscience and research into migraine pathology? Sure. First of all, thank you for your time and for doing this. It's going to be fun to talk to you today. I'm Greg Ducer. I am a professor of neuroscience and also department head. I have sort of an interesting path to neuroscience because while I'm a neuroscience professor and actually head of the department, I don't have a degree in neuroscience. It's kind of amazing. A bachelor's degree in biochemistry. Then I have a PhD in pharmacology. Neither of those are neuroscience. There can be applied to neuroscience, of course, which is what we do. But it's just interesting that you don't necessarily have to have a degree in the thing that you ultimately become a professor of and even the department head of. Pharmacology is, of course, there is pharmacological application to just about anything. I was always interested in pharmacology from a neuro perspective anyway. That's really where I focused my interest in the classroom and in the laboratory. Really, I would say that I have a degree in neuro pharmacology even though it's technically not that specific. I started my research career as many students do in graduate programs where you do rotations in labs. You may not necessarily know exactly what it is that you want to work on when you start graduate school. You might have an area at neuroscience, you know, neuro pharmacology, something like that. Then you do some rotations and you try out some different projects and different research questions. That's how I started. One of the labs that I rotated in was a lab focused on pain research. That, to me, became very interesting very quickly because while I don't have pain right now, I'm very fortunate to not be a chronic pain sufferer. I do know what it's like. I have had it. I've had pain for extended periods of time and so I can at least somewhat relate to the actual subject of the research. That's not necessarily true of many other neurological disorders that one could potentially study. I don't know at least that I have them right now. People get interested in particular topics for all kinds of reasons. Maybe it's a family member that has the particular disease. How you actually get there can be quite variable between people. That's basically how I got into pain research. Then migraine sort of happened. That wasn't really anything that I was planning to do. I studied pain from the time that I started graduate school until, well, I guess I still do, but the shift to migraine, which is a form of pain, but it's a very complex form of pain, which we'll get into. That happened maybe 13 or 14 years ago. I had a colleague in my former faculty position at University of Arizona, who was working on migraine and in conversations with him. He's urging to think about migraine as a research topic to me. I started looking into it and the more I learned about it, the more fascinating it actually became, in part because we hardly know anything about it. There are hardly any people actually studying it as a disease entity. It wasn't as if I set out on my path in undergraduate schooling and in graduate training to work on migraine. I didn't actually even plan to work on pain when I was an undergraduate. It sort of happened through rotations. Then the shift into migraine happened just being in the right place at the right time and having the right people around you and being open to shifting the focus of what you do from what it had been into something new. Just being flexible and being open to allow something like that to happen is really how I got here. Well, that's actually pretty crazy. You went from biochem to pharmacology and then now you're in the neuroscience department. That's genuinely awesome because honestly, it would just like for me because I'm pre-med. I have heard all these stories about how people, like you said, you start out in your undergrad and you think you're going to go in a certain direction and then something just sparks your interest and you gain all of these new experiences and by the end of it, you could be in a completely different field. It also shows how vast the world of medicine is. You're still basically working with pharmacology by doing migraine research. I agree. The end goal of pretty much everything we do is identifying drug targets and would ideally lead to the development of new drugs in my case migraine. But you could apply a lot of what's done in the neuroscience department here and in neuroscience departments everywhere. In that context is, yes, there's a fundamental understanding of how the nervous system works. But in many cases, that often turns into therapeutic opportunities, whether it's for drugs or devices or behavioral interventions or whatever it is. I just happen to be interested in neuroscience from the context of how can we understand these disorders in order to make drug targets and identify drug targets and then make new drugs to treat these diseases. I'm so glad that you were able to use your formal ecological experience to kind of, in your geared neuroscience interest, to focus on something that not a lot of people are focusing on and that I know is extremely debilitating for those that do suffer with migraines. Migraines are often misunderstood or underestimated by those who have an experience them. Just so that our audience is clear kind of about what a migraine is, could you explain what a migraine is and how it differs from a regular headache? That's a great question and you're right about all of that. Migraine has a very specific diagnostic criteria and there's classification of headache disorders. This is a whole book basically of all the different kinds of headaches and how you categorize them and then how you diagnose them. So migraine is just one of many types of headache. Headache is sort of an umbrella term and under that umbrella are many different kinds of headaches and usually they're classified into primary headaches or secondary headaches. So I'll start with the other with a second one. Secondary headaches are headaches that are caused by something that is identifiable. So if you have an infection or you have a virus or you know there's something that's actually causing your headaches, maybe you have a hemorrhage inside of the brain, maybe there's a tumor that's growing. Those are going to cause headaches and those headaches are secondary because you know what the cause of the headache is. The primary headache is when the headache is the problem and you can't identify where the cause is, there's nothing on any kind of test that you can identify that is creating that headache. That is the reason that that headache is occurring and that's what migraine is. It's a primary headache disorder because we don't know what the cause of them are. The majority of the people that have migraine are entirely healthy people. There's nothing at all wrong with them other than the fact that they have migraine. So that classifies it as a primary headache disorder. So how do you diagnose it? There's a list of criteria that generally have to be met. The headache has a time component to it and so it has to last at least four hours. The cutoff in the books is 72 hours on the long end, right? But there are plenty of people who will have migraines that last way longer than 72 hours. Some people will have them that last weeks. This is part of the reason why they're so debilitating. So there's a time component to it and often you'll hear people say I have a migraine and it's only been an hour or two hours and technically that can't yet be a migraine. It doesn't mean it won't become one but it, you know, there is a minimum time component to it. There are other features that often come along with migraine that help to provide the diagnosis. So nausea, vomiting, hypersensitivity to light and sound. You can have aura which is a sensory disturbance that comes along with a migraine attack. It usually happens before the headache starts. These are most commonly visual. So people will have a blind spot in the visual field that will grow. It starts maybe as a pinpoint that'll get bigger over time. Or it's geometric patterns and flashing lights and just really, really amazing looking images that start small and then they will grow and move across the visual field. Those are classic auras. And that, if you have aura, that puts you into the migraine with aura category. You don't have to have aura. You can have migraine without aura and that's actually what most people with migraine have is they don't have aura. But if you do, it makes the diagnosis easier. So, you know, you have this time component. You have these associated features that really have to be present. But it can be very difficult to diagnose that because you don't, any given person is not necessarily going to have all of those features. And, you know, they may have had a couple of these attacks before they go see someone about them and not all of the attacks would have all of those features. So, you know, it's difficult for the clinician to diagnose this. Often it's a, you know, if you end up in the emergency department and you're having these flashing lights in your visual field and you have this intense headache, you know, the first thing to rule out really is that you're having a stroke. And so, you may go through a lot of intensive testing and you find out there's absolutely nothing wrong with you and you end up getting a diagnosis of migraine because you excluded other things that it could be. So, it's, you know, it's often a confusing situation that people get in. The physician has a problem diagnosing this, the patient, the person with the migraine has a problem getting a diagnosis for it because they're just very poorly understood and they're variable. So, you know, this is a tricky situation to be in for people. And I think that people who don't have them also misunderstand them. I, when you talk to people who have migraine, they will very commonly say that they couldn't go to work that day because the, the eight out of ten throbbing head pain that they had and the inability to get around any amount of light and sound essentially required them to sit in a dark quiet room the whole day until the migraine disappeared if it did. And they will call into work and say, you know, I have a migraine, I can't come to work today. And the response will be, oh, you just have a migraine. It sort of dismissed as, you know, something that is just so common and, you know, you just have a migraine today. And, you know, the people with migraine are very frustrated by that because, you know, just have a, it sort of minimizes the impact that the disease actually has. You just have a, what do you mean? I just have a migraine. I'm, I can't leave a quiet dark room right now because I have, you know, eight, nine, ten out of ten head pain and I can't get around any light. That's not just anything, you know, that's a completely disabling event that I'm dealing with right now and people don't take that seriously. And I think part of the reason people don't take them seriously is just because they're just so common. It's, you know, everyone you talk to and meet either knows someone that has migraine or they have them themselves. It's just, it's an incredibly common disorder and, you know, World Health Organization puts statistics on, on all diseases really. And it's the sixth most common disease worldwide and the second most disabling disease worldwide. So it's a tremendously common and a tremendously disabling thing. And for someone to say, you just have a migraine is really minimizing what the person is actually dealing with. So, you know, I think there's a lot of education that needs to happen on two people who don't have migraine, on behalf of the people who do have migraine. And that's part of what I think we try to do. That's part of what I try to do when I give a seminar, a scientific seminar, is, you know, here is what happens when you have a migraine. Here's how it can cause disability. And here's how serious they are. Oh, and by the way, it actually turns out that it's a disease that you could study in a lab. And, you know, that's a really surprising thing to me when I go give a talk somewhere to a scientific audience. And someone will come up after and say, you know, I hadn't actually thought of migraine as a disease that one could study in a laboratory. And, you know, why not? Why? We're failing somewhere if people scientists aren't actually thinking about migraine as a disease that one could study as the focus of their laboratory and their career. That's a failure somewhere of education on what it is and how big of a problem it is. Yeah, no, I'm glad that you pointed out how differently people can approach migraines from, you know, the side of the clinicians where you were talking about how hard it is for them to be able to actually pinpoint what, for instance, the aura symptom that the patient is experiencing, like what that could mean. Because, for instance, you know, you were talking about a stroke. I just got EMT certified and within my certification process, I learned about how aura is the first stage of a seizure. So just the fact that a clinician has to think about all of these different possibilities, you know, could it be a migraine, could it be a seizure, could it be a stroke? That's just crazy. But then you also brought up how, you know, people kind of just wave it off like, okay, yeah, you're having a migraine. That sucks for you, but, you know, at the end of the day, it's whatever. You know, they don't take it as seriously as you were pointing out. So, yeah, I think that's very interesting. You know, that leads me into the question about how our understanding of migraines has evolved over the years. And what advancements do you think have been made in the field recently? Yeah. So, you know, as far as we know, migraine is not a new thing for human physiology and human pathology. There's evidence of it in drawings that ancient Egyptians were doing. It's kind of interesting to go back and look at that history. If you look at people who have investigated the history of migraine and written about it, there's a lot of interesting evidence for it that you can find if you go looking. So we know they've been around for a long time. And, you know, we, we still don't understand exactly what they are and where they come from and why humans get them. The major idea, the major hypothesis for what they are still is not very specific, but it has shifted in the last, say, 10 years or so from what people classically thought migraines were, which was a vascular disorder to more of a neuronal disorder. People thought for hundreds of years that migraine is caused by blood vessels, something wrong with the blood vessel. The blood vessel is pulsing and this is what's causing the migraine pain. And, you know, you, you can see where that might come from because the throbbing nature of migraine is, you know, you would blame that on a blood vessel and it sort of makes sense. Interestingly, there was a study done, I don't know, seven or eight years ago, where the authors hooked people who were having migraines up to EKGs and they were monitoring the cardiac cycle and they were asking the person who was having the migraine to press a button in the rhythm of the throbbing of their headache and there was absolutely no correlation between the two. So that's kind of an interesting finding and it kind of makes it hard to say, well, this is entirely a blood vessel thing because there's no correlation between the rhythm of the cardiac cycle and the rhythm of the throbbing nature of the headache. Now, you know, there are complex rhythm generators in the brain that can, can create the rhythm of throbbing pain even though it might be caused by pulsing of blood vessels and so there doesn't have to be a one-on-one relationship. And I think people know, you know, if you've ever had a throbbing headache and you speed up your heart rate, the throbbing speeds up and if you slow down your heart rate, the throbbing slows down. I mean, people have done that experiment on themselves. So they kind of know that there is some relationship between the two, but it's not that simple. It's not as though, you know, one pulse of blood going through the vessel is going to equal one throb of the pain. But, you know, these are the kinds of things that ultimately created the major idea for where migraines come from, which was blood vessels. It's blood vessels. And so, you know, I think that idea still persists in the general public because I talk to people all the time who will say, you know, well, it's a blood vessel disorder and if you just can constrict the blood vessels, then the migraine goes away and that, you know, that sounds great. It's a really nice sounding, very simple hypothesis, but it's been impossible to prove that that's actually true with advanced scientific methodology. And I think really one of the nails in the coffin for that idea was a series of imaging studies that were done on people who were having migraines while they were in a scanner. And there's a whole backstory to how do you even get people in a scanner who are having migraines? You know, that's, it's, they're hard to study because you don't know when they're going to happen in people. And what the investigators found was that there was no dilation of blood vessels while these people were having migraines in this scanner. And so, you know, if this is the leading hypothesis that blood vessels are dilating and this is what's causing the problem, and we can't see that in people who are having a migraine and clearly saying they're having a mic. migraine, and we've loaded them up with a dye and we're imaging their vessels in their mini-gies and their brain. And we can't see any dilation. That's kind of a problem for the hypothesis. There's a list of caveats to doing an experiment like that. The person had to know they were about to have a migraine and they had to get into the facility and they had to get prepped for the scan. And so maybe the dilation happened earlier and it was missed by the time the actual imaging was started. So that's certainly a caveat to acknowledge. But clearly these people are having throbbing headaches at the time they're being imaged and you can't see any dilation. So that's really raised some serious questions. Along with the fact that you can give people drugs that dilate their blood vessels quite effectively, it's done all the time and that does not cause migraine and everyone that you do that too. So if it were as simple as just you dilate blood vessels and people get migraines, then everyone would get migraines as soon as you gave them a vasodilator. And that's just not true. It also would be true that if you just could constrict vessels, all migraines would go away. That's not true because we have drugs that constrict vessels and they don't work for migraine. So it's not that simple. I think this sort of shifted into the idea that the nervous system has to be contributing something important. And maybe there's still a component of the vessel. And so now it's really referred to as a neurovascular disorder because I think you need both. You need something that the vessel is doing, but you need sensitization of the nervous system that is responding to that something that the vessel is doing. That's really where the migraine comes from is that somehow the nervous system gets sensitized and it's now responding to many things that it wasn't responding to before. Normal levels of light, normal levels of sound, normal smells, pulsing of blood through vessels. It's just that the nervous system is irritated in some way and hyperactive and sensitized and it's responding to a lot of things that it wouldn't normally respond to pulsing of blood through vessels is part of it. So how do we stop the sensitization of the nervous system so that it's no longer responding to all of these things? That's really the therapeutic opportunity and that is what we need to figure out. How does the nervous system become sensitized to all of this in the first place? What are the mechanisms that it's using to respond to pulsing of blood, for example? What is it about a neuron that allows it to respond to blood coming through a vessel? What is that mechanism? We need to understand all of these things better so that we can come up with new drugs that work better than the drugs that we have and the fact that migraine is the second leading cause of disability really should tell you something about how good the drugs work that we have if they worked. They worked for large numbers of people. It wouldn't be the second leading cause of disability, but it is. So that is evidence that the drugs that we have are not working that well. That's really interesting. I loved hearing about the evolution from a surely vascular pathophysiology to something that's a little more complicated and encompasses the neuronal aspects. I've even felt victim to the vascular theory in conversations with one of your PhD students who studies the relationship between cortisol and migraine. My thinking was always that maybe as a vasoconstrictor the cortisol could provide some relief. So it was really interesting to hear kind of the ways in which that is not the full story. And that leads me into my next question, which is that your lab's website states that the most likely mechanism contributing to migraine pain is the action of peripheral no-susceptive signaling from the meninges. Can you tell us more about no-susceptive signaling and its role in migraine pathology? These are all great questions. One of the things that you have to ask when trying to figure out where a headache comes from is what are the pain-sensitive structures that exist in the relevant location? And we're really thinking about pain-sensitive structures in and around the skull if we're talking about headaches. And it turns out that the brain is not sensitive to pain. The brain itself is not sensitive to pain. Obviously, you need a brain to respond to the input that comes in and to interpret that and to create the whole experience that is pain. The brain is needed for that. There's no question. But the brain itself, if you stimulate the brain itself, you cut it or you put chemicals onto it or you probe it mechanically, there's no anatomy that exists that allow you to be able to feel that because there are no sensory neurons that innervate the brain itself. It's an interesting anatomical fact. So that's tricky. How does a headache coming from the brain? If you can literally cut the brain itself and there's no way to feel that, that causes you to make a different hypothesis. It turns out that the meninges that cover the brain, those are very, very, very densely innervated by neurons, sensory neurons. And as far as we know, the only sensation that you can feel when you stimulate the meninges is pain. And this has been done in humans. There are some very famous studies in the field that were done in 1940 on patients who were having open skull surgery for another reason. And while the skull was open, you know, often open skull surgery patients are conscious. They're clearly anesthetized to some level, but they're conscious and someone is talking to them and, you know, just making sure that everything is okay as the procedure is progressing. But in those patients that were having open skull surgery, a team of neurologists went in to where the skull was open and probed around on the meninges with various kinds of stimuli and then asked the people, does this hurt? And is there any other sensation that you can feel? The only thing that was reported was pain. So there's no sensation to temperature. Your meninges don't feel warm and, you know, people sort of know this just from their own life. That what is the sensation that you can feel that you think you can feel from within your skull? Pain is really the only thing. It doesn't, it's not as if your meninges ever feel warm or cold. They don't itch. I mean, you wouldn't be able to scratch them anyway, even if they did itch. So why would they itch? Pain is the only thing. And so, you know, that creates a hypothesis. You know, sometimes the simplest answer to the question is the correct one. The only really pain-sensitive structure inside of the skull is the meninges and a couple of vessels. There's this, you know, really interesting vascular formation in the brain called the circle of willis. It turns out if you probe that, it's painful, but most of the actual vessels or themselves are not painful. The areas around the vessels might be painful, but the vessel itself is not. So, this leads to the hypothesis that the meninges are the source of the headache. I'm sort of ignoring the skull here. Of course, the skull is painful if you fracture it or you, you know, you do something noxious to the skull. You feel that certainly, but many, in many cases, in most cases, a migraine does not feel like skull pain. It's inside of the skull. There's sort of interesting ways that people will describe the sensation of their migraine. Some people describe them as it's exploding, as if there's pressure from the inside of the head pushing out. And other people describe it as imploding where there's pressure from the outside pushing in. We don't actually know if those are different kinds of headaches with different mechanisms to them, but they're both categorized as a migraine. So really, the leading hypothesis is that the meninges are the location where the headache is coming from. But then the primary question is, well, okay, what's happening to the meninges in a person who's having a migraine to generate this sensation that they are having this head pain? And that, we have no idea what the answer to that question is. So we know that if you get an infection of the meninges meningitis, that is incredibly painful. People have very intense headaches when that happens. And so we know that that's another piece of evidence that stimulating the meninges can cause the headache. But people who are having migraine don't have an infection. They don't have bacteria in their meninges. They don't have a virus. So it's not that. There has to be something that is activating these nerve endings in the meninges natively by something that's just not coming from the outside and that's happening within the skull that leads to pain. And we just don't know what that is. That I think is really one of the fundamental questions in the field is what exactly is it that is activating these pain-sensing neurons that integrate the meninges to cause the headache? I wouldn't say that the migraine attack itself because as we've discussed, there are a lot of different things that come along with the migraine. There's the aura. There's the nausea in the vomiting. There's a lot of things that are the brain. Something is happening in the brain along with the headache and might be happening before the headache ever starts. But somehow those things that are happening in the brain turn into a headache at some point and that probably requires communication between what's going on in the brain and what's on the brain. top of the brain, the meninges, to turn on the activity in those pain-sensing neurons that are in the meninges, and that's where the headache comes from. So we don't know where any of this originates. We don't know what the reason is for any of this happening, and that I think is a major question, and that's something that we've tried to work on just asking simple questions like, "Well, what can those neurons in the meninges respond to? What kinds of receptors do they express? What are the kinds of things that could cause them to be active?" It doesn't mean those are the things that do cause them to be active. It just would allow us to make better hypotheses about what it could be if we know what they are capable of responding to. So that, I think, is really the no-susceptive signaling from the meninges concept and something that we really have to figure out. Yeah, I like how you mentioned earlier about how sometimes the answer that seems the most simplest or the most straightforward might just be the answer. Maybe it's just not that complex. Maybe we should just be looking at the fundamental basis of our knowledge and neuroscience. Maybe even your background in biochemistry could help out with this too, just knowing the basics of any of the neurotransmitters or whatever is going on in there. I just thought that was pretty interesting. Another question I have is, what are some of the other potential mechanisms that are being explored in migraine pathology in your lab? We're at another great question. So, there's a lot of interesting things that we know about migraine and people that we can't explain on top of what we've already talked about so far. One of them is that migraine is three times more common in women than it isn't men. And we don't understand why this is. It's very widely accepted. If you look across the lifespan when migraines are most common in both men and women, it's after puberty and before menopause. Across the lifespan, males and females are pretty similar before puberty and after menopause. But between those years, women are dramatically more likely to get migraines than men. And the easiest answer to that is hormones. Of course, it's hormones, right? And that's what everyone will say. Well, okay, sure. But that's a complicated, you're sort of, again, minimizing the complexity of this by just saying, oh, hormones. Well, there's a lot of hormones. And many of them can contribute to this sex and gender difference in migraine. And which one is it? Is it just one? And where is it working? And how is it working? And so, you know, people have looked at estrogen and progesterone as potential reasons for this for many years. And that's complicated because if you look across the monthly cycle in women for when they are most likely to have a migraine, it's not when estrogen and progesterone are at their peak. It's actually when they're falling. So they've already been at their peak and now they're going down. And this is when women are most likely to get migraines. And so if you are going to argue that the reason why these are happening is because of estrogen and progesterone, then why aren't women having them when they're at their highest? So it's probably not that simple, of course. Nothing is. And so we've decided to try to look at something else. And one of the major projects that we've had in the lab for a while is looking at the hormone prolactin. And this is not a hormone that people typically talk about in neuroscience and not even really in pain. But it has a very interesting physiology to it. And you know, this is something we've been looking at. The receptor expression for prolactin is different in men and women. Of course, the levels of prolactin are different in men and women. The things that prolactin might be doing in women and men are different. People know about prolactin most from its role in lactation. But that's one of only many things that it actually does in the body. And we have plenty of evidence now that it can modulate the sensitivity of pain sensing neurons. And that very differently in male neurons and female neurons. And so we think that there might be a role for prolactin in many pain disorders, but migraine being one of them. And so it might not just be estrogen and progesterone. They probably are contributing something. But we have to look at how they function in relation to how prolactin is functioning. And I think there's also an interesting question from the male perspective is, okay, males don't have the estrogen and progesterone and prolactin levels that females do. And so they may not be getting migraines because they don't have those same levels. But also they have higher testosterone levels than females do. And so it's possible that testosterone is actually protective against migraine. And so why do women have more and men have less? It could be multiple reasons. It doesn't have to be, it could be all of those, all of those could be true. But we, while we certainly have to focus on the pathophysiology of women because they are the most likely to get migraines, there's also interesting questions that can be asked in males for why they are not getting migraines. Is it just because they don't have the same thing women do or is it because they actually have something that's protecting them? I think all of those are interesting questions. And we certainly don't have them all figured out yet. I think this is an area that it's interesting to me. And I think coming back to the pharma apology discussion, if this were to lead to the identification of drug targets, there might actually be drug targets that are identified that lead to the development of drugs that are only used in women or only used in men. So this isn't really something that exists right now apart from conditions where literally only men or only women get them because of the presence of maybe an organ that only women have or only men have. There aren't really drugs that are developed for conditions that both men and women get, but they only work in one or the other. I think that's an area that could be a big opportunity for new pharmacological agents. Not just for migraine, but for many diseases. I think the pathology of many diseases is probably quite different in males and females. And you know, 15, 20 years from now, maybe there will be drugs, maybe there will be a drug for migraine that is designed from the outset and to only work in women and all of the clinical trials that are done for that drug only recruit women because we think that this is a mechanism that's specific to women. So or men, you know, either way. I think that's an interesting future category of pharmacological drugs that just doesn't exist right now. And you know, it's probably because we just really haven't as a field of biology and neuroscience and biomedicine. We haven't really been good at looking at both sexes in preclinical studies and in clinical studies. We've sort of used too many males and we haven't really done enough exploring in how they're different from females. And so I think we're just behind on figuring out what those differences are. And as we figure them out, we'll figure out opportunities for therapeutics that only work in men or only work in women. Yeah, I think that's really interesting that you bring up the sex differences. I think we are as a scientific community sort of lagging behind on including women in clinical trials or research. I know like within the past two or three years it's become encouraged if not required to include both genders of rats and mice when studying different diseases and disorders. So I'm glad that we're able to look at those sex differences and be able to find targets that are not only good for everyone but also specific to each gender and recognition of their differences. As I know you are a pharmacology man and therefore you're often looking for interventions and targets or treatment. So could you discuss some of the current treatment options available for migraines and how effective they are in providing relief for sufferers? Yeah, so as we discussed, none of this is really tremendously effective. This is sort of a tricky question because we know, we think we know how many people on earth have migraines. But I'm not sure we really know that correctly because there are a lot of people who will get a migraine and when they do they take ibuprofen or something that they got at CVS or Walgreens and their migraine goes away and they never mention that to their physician because that's not why they're going to see their physician and the physician didn't ask so they never knew about it. So those people don't end up in the numbers. So I think there are a lot of people who have migraine that we don't know about because they just never get reported. And the people who do get reported are the people who told their physician about it. Maybe that's why they went to see their physician or they ended up in a headache specialist's office because the primary care physician couldn't figure it out and the drugs that were prescribed didn't work. Maybe they end up in a research study. You know, these are the people that were counting in the statistics. And I think we're underestimating how many people actually have migrained. And so that relates to the therapeutics, you know, do drugs that you can buy in CVS or Walgreens or Target or wherever. Do they work for migraine? I think they do actually work for migraine for a lot of people. And that's why we don't know about all the people, all the extra people that have migraine. But the difficult to treat people, the person who has tried the drugs that they can get over the counter and it didn't work. And now they've gone to their primary care physician and they're talking to the physician about the fact that they have migraine and they can't treat them with what they have access to over the counter. The most likely thing that the physician is going to prescribe, assuming that they come to an agreement that what the problem is likely migraine is a category of drugs called triptans. And these drugs have been around for several decades now and they're serotonin 5-HT1B and 1-D agonists. And they are the gold standard for acute migraine therapy. And so anybody who has migraine has probably tried those, at least anybody who has migraine that can't treat them with active profaner and approximate or something. They probably tried triptans and they know very well what those drugs are. I can't honestly tell you I know how they work beyond the fact that they activate serotonin 1-D and 1-D receptors. I don't know where they work. I don't know what it is they do. This is really just a fascinating thing is that these are the classic drugs that you will get prescribed if you were diagnosed with migraine and they've been the classic drugs for migraine for decades. And I can't honestly tell you how they work because people haven't figured this out yet. So interesting. So they, you know, they don't really, they work, they work really well for some people. They don't work at all for other people. You can't take them too many times per month because there's a risk that they could actually make the headaches worse in some people. And so the physicians always nervous about how many they will prescribe per month for a person. So if you have my, maybe you have five migraine attacks a month. I mean, hopefully you have fewer than that. But let's just say you have five a month and your, your physician is going to prescribe you a trip 10 for your migraines. You know, how many of they're going to give you? They'll probably give you something like 10 to for each migraine attack. So is to not give you too many that you can take them too often and potentially make your headaches worse. That then creates a problem for the person who only has 10 pills and is now, you know, starting the month. And today they, they are developing signs that they think is going to be a migraine. And, you know, do I use one of my 10 pills on this because I'm not really sure yet whether this is a migraine. Maybe it'll become one, but maybe it won't. So I don't want to waste one of my 10 pills on this. But if I wait too long and it really turns into an obvious migraine, what people also know is that if they take the drug too late, then it doesn't work as well. And so they're constantly having to balance this, you know, do I waste one of these on this thing that might not be a migraine? Because I kind of have to do this soon. If I wait too long, it's not really going to work. You know, they're in this, this tricky situation. And this is something that people live with with the classic drug that has been given for decades for migraine. Now we have within the last five years or so, there are seven now new drugs for migraine. But they all target the same protein. It's calcitonin gene-related peptide or CGRP. That has become the hottest target for migraine drugs. And there's monoclonal antibodies that bind to the protein of the receptor. There's blockers of the receptor. So if you have the TV on ever, if you ever watch commercials on TV right now, you will see a drug for migraine that is based on targeting CGRP. And, you know, maybe serena Williams is in the commercial or maybe some Kardashian is in the commercial. You got to get a famous person on your commercial for your migraine drug. That's the game. So, but the commercials are everywhere. I mean, I don't watch TV very often anymore and don't watch commercials, but I was on a trip. Not long ago and had the TV on in the hotel room. And I mean, I think within a five minute period, I saw commercials for three of these migraines. But it's certainly they're just blasting the airwaves with this. Because it's an exciting thing and it's a new target. And it's possible that people who didn't respond to the drugs that have been around for a long time will respond to these new drugs and maybe get some relief. And in many cases, these new drugs are safer. You don't have to worry about taking them too many times a month. That's a big deal. Do they work better? We're still not really sure. But it doesn't look like these new drugs are not the end of migraine. These are these are not the cure all for migraine. They they might be helping. They might be helping the same people who got relief from the previous drugs. They might be helping some new people, but they're still not helping enough people. And they're still very large fractions of the migraine population that are not getting any relief from even these new drugs. So we still have a lot of work to do because even with all this exciting new development, there's still a lot of people that were not helping. And you know, it's because we just don't understand the disease. And until we do, we either have to get lucky and come up with a new therapeutic that we really weren't trying to come up with. It just, you know, serendipity or, you know, we're sort of trying to modify the drugs that we have already or, you know, but I think the real rational way to do this is to understand the pathophysiology. And that will lead to the identification of new drug targets and hopefully better drugs. Well, I'm so glad that we have researchers like you dedicating their career in research and their labs to finding targets and understanding the pathophysiology of migraine to hopefully provide relief and some future directions for those suffering with migrates. I just wanted to say thank you so much for being on the show and sharing all of your expertise. It was wonderful sitting down with you. Do you have any final thoughts for the audience, anything that you want to leave for them? I would, well, first of all, thank you again for your time and the great questions. I would just say to people to please understand that migraine is a seriously disabling disease and that it's very serious. And that also is something you can study. So for people who are interested in neuroscience and going into a career in research or medicine, migraines of fascinating disease from a neurological standpoint, we don't understand it. It's extremely common. Hardly anyone is working on it. How is that not an interesting career? So think about it. Think about it as something that you can, you can dedicate your life to is either studying it or treating it because people need it. Thank you again to Dr. Deuser for being on the show. We hope you enjoyed this episode and if you did share it with someone who you think will enjoy it as well. Let us know your thoughts and what you'd like to listen to next on the BBS UTD Instagram or by filling out our survey. The link to both will be in the description. If you'd like to read more about Dr. Deuser's research, his website is also linked in the description. 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