 Josh is a neurologist. He practices currently in Atlanta. And he's going to talk about headaches and their relationship to the hypothalamus. We were just talking. He did his residency at University of Florida. And I think he was my TA when I was in med school there. So small world. Anyway, I'm really interested in this talk. Migraines, for those of you who practice medicine or just know anybody with migraines or even suffer from them yourself, gigantic problem. They're an enigma. And so I am waiting to be enlightened by Josh to explain exactly why we get them. So here's Josh. All right, thanks Matt for that. So despite the fact that they've plagued humankind for probably a few millennia, on the whole, we haven't made a whole lot of progress towards understanding migraine headaches. And these days are particularly at any type of fundamental or root cause level. And these days, they're a big problem. So it's estimated that about one in five women suffer from them. And that's probably an underestimate. I'm a neurologist. They're the number one reason why people are referred to me. That's true of most neurologists. But we haven't made a ton of progress, and particularly when it comes to prevention. We do have an array of pharmaceuticals that are FDA approved for use in reducing migraine headache frequency. But if you look at published clinical trials, take the best one that we have. It only reduces migraine headaches by one day a month compared to placebo. And this is in people who have baseline, 15 or more headache days per month. So that's a pretty lousy track record. And one of the issues is that with migraine, there's no real pathological signature. In fact, one of the most extraordinary features of migraines is that they occur in structurally normal brains. So there's no tissue to put under a microscope to explore, to look for clues as to its origins. We have made some progress in recent years with a mix of animal models and functional imaging studies and have worked out some of the pathophysiology for certain components of migraine. One of the things that has become clear is that at least the pain phase of migraine involves the activation of nuclei in the brainstem that are involved with sensing pain in the cranium. So those are activated by the migraine process itself, which then sends out nerve signals to the meninges, which are the coverings of the brain, causing release of inflammatory substances that are then sent back as a pain signal to the nuclei that just sent that out. So you have this self-perpetuating and amplifying feedback loop that continues over time to escalate pain until something comes along to break it or it burns itself out. And this is clearly not how our pain system is supposed to work. Pain is there to alert us when there's some sort of external threat to our survival so we can adjust our behavior accordingly. But in the case of migraine, you have sort of the brain's fire alarm system being turned on in a substantial number of people, turned on regularly in the absence of any external threat whatsoever. So you've got the fire alarm being pulled all the time and there's no flame. And this begs the question, what the fudge is going on? So in this talk, I'm actually going to propose a mechanism for understanding migraines at a root cause level and a way of understanding that points, I think, a clear path forwards towards understanding how to prevent them at their root source. So this is a personal topic for me as well. I have migraines. Mine started when I was a kid and steadily worsened into early adulthood. And this is a graphical depiction of my migraines over time and on the y-axis there is the number of days where I had to take a prescription medication. And so you'll see in 2010 that something extraordinary happened. And judging from the nature of this conference, you guys might be able to know what that was. It's when I adopted a paleo-primal ancestral nutrient dense dietary eating plan framework. And so in the year prior to doing that, I'd taken something from migraines about 60 days out of the year. And then in the year after I switched, I only needed it once. And that was on an anniversary dinner with my wife when I cheated on the diet, not her. So that experience I thought, huh, that's kind of interesting. And it's worth noting that I'm a neurologist. Migraines are my area of expertise. So I was providing myself with the state of the art care prior to this. And the best that I could do was those 60 days per year. I mean, 60 days per year. So the next question was, well, is this something that's unique to me? Or is this something other people have experienced? And lo and behold, I found that there were lots of folks, both in the ancestral health and low-carb communities, who had experienced the same exact thing. So they'd changed their diets and noted that their migraines had gone away. And the next thing I did was try to see, is this something that's been documented at all in indigenous hunter-gatherer populations? And so far, I haven't been able to find anything. No accounts of people who regularly have debilitating head pain in the absence of any cranial pathology. So we have two observations there. One is that evolutionarily appropriate diets seem to be a very effective tool at preventing migraines. And that migraines don't occur in indigenous hunter-gatherer societies, or secedes, however you want to spell. So a logical conclusion from those two observations is that migraines are a disease of civilization. In other words, they only occur in humans in the context of modern diets and lifestyles. So that begs the question then, how is it that modern diets and lifestyles cause migraine and where are they exerting their influence in the brain to do so? One of the most intriguing phenomenon that occurs as part of migraine physiology is something known as cortical spreading depression. This was first described, I think, in the 40s by a researcher named Aristides Liao. And it's basically an area of depressed brain or neuronal activity that typically starts out in one spot and then spreads in a wave-like fashion to encompass the rest of the brain. It oftentimes begins in the back of the brain in the occipital lobe. And it's the physiological correlate to the migraine aura, which in migraine auras are these transient disturbances in neurological function that oftentimes precede the pain phase of a migraine. And the most common are visual and origin. And what you see there on the left is the depiction of a common visual order, aura called a scintillating scatoma, starts out as a small little spot of flickering light that then expands into this half-moon-shaped object, lasts about 15 to 20 minutes, and then it goes away, and then is oftentimes followed by the pain of a migraine. What's really interesting is that you can elicit this same exact wave of spreading depression in animals, and you can do it by disturbing the brain in any manner of ways. You can just poke it with a blunt object and you'll elicit the same exact wave of spreading depression. You can stimulate it with an electrode and so forth. And it's been elicited in every mammal that it's been tested in, and it's even been shown to happen in birds and frogs. So if we consider that our last mammalian ancestor was about 60 million years ago, and if you think about birds and frogs, you go back even further, that at least this part of migraine physiology seems to come from a very ancient part of our biology. We happen to be the only animal though where it appears to be, where we can elicit it intrinsically without someone poking around inside our skull. So there are several lines of evidence that I think build a strong case to implicate the hypothalamus as the origin of migraines or the attack generator in the brain. The hypothalamus is considered to be the master of homeostasis. And homeostasis basically means the maintenance of stable internal bodily conditions. So at any given point in time, you've got zillions of chemical reactions going on inside of you. They can only unfold properly under very tight environmental parameters. And it's the job of the hypothalamus to see to it that those parameters stay within a narrow range. It's able to do this because it has influence over multiple systems. And so it can influence basically every organ system. It has direct nerve connections through the autonomic nervous system. It controls, it sits at the top of the endocrine system. So it can control physiology through hormones. And it also is responsible for evoking behaviors that promote homeostasis. So it's what makes us feel hungry or thirsty or hot or cold so that we'll adjust our behavior in a manner that promotes homeostasis. And this is just where the hypothalamus sits in the brain. So it's that little purple structure and it literally sits right on top of the pituitary gland which is the little ball-like structure underneath it and right beneath the red structure there called the thalamus. So hypo meaning below the thalamus. If you zoom in further, typically the hypothalamus is divided into multiple sub-nuclei that each of which are responsible for a different homeostatic domain. And those include things like temperature regulation, regulation of fluid balance, energy regulation, acid-base balance, mineral concentrations, circadian rhythms. So just to take one example, temperature regulation. So all of these homeostatic domains have a set point around which the hypothalamus tries to defend. So if your body temperature raises above the set point which for most of us is around 98.6, the hypothalamus will kick in the autonomic nervous system so that we sweat, so that water evaporates off the skin to cool it down. It causes vasodilation of the capillaries in the skin so that heat escapes from the blood into the atmosphere. And through the control of hormones, chiefly the thyroid hormone can reduce basal metabolic rate so that we generate less body heat. And then it also makes us feel hot so that we'll act in a way that cools us down by finding some cold or resting or getting something to drink. So now I'm gonna review the evidence that I think implicates the hypothalamus as the generator of migraine attacks. The first of these comes from what we know of of migraine triggers. So we've long known that there are certain environmental stimuli that are potent triggers of migraine. And these include things like disruption in sleep wake cycles. So too much or too little sleep or drugs like sedatives or stimulants that disrupt sleep wake cycles. Dehydration or low total body water. Stress or the inappropriate release of stress hormones. Overheating, large fluctuations in blood sugar and exogenous hormones are just some of the most potent triggers. And what's common to all of those is they're all major homeostatic challenges. So they all present the hypothalamus with an extreme challenge for maintaining homeostasis. There are migraine patients that tend to experience their headaches on certain cycles. These can be a certain time of day, a certain season, a certain month or time of year. And we know that the hypothalamus is tasked with controlling biological functions that occur on various time scales. I mentioned earlier that migraines are more common in women. And so if we're looking at a place in the brain where they begin, it makes sense to look for places that differ between the sexes structurally or that are sexually dimorphic. And in the brain, the most sexually dimorphic structure is the hypothalamus, chiefly the nuclei that control the release of sex hormones. There are some patients who, well before the pain of a migraine, experience what's known as a prodrome. And this is a period lasting anywhere from 24 to 48 hours where a variety of symptoms can be experienced. They include things like excessive hunger, thirst, heat or cold intolerance, fatigue, constipation, diarrhea. And in all these cases, you have behaviors that are typically in the service of homeostasis kicking in at the wrong time. So in essence, the very first clinical manifestations of a migraine that we can detect are signs of that a hypothalamus that's malfunctioning. And lastly, if we think that the hypothalamus is the generator of migraine attacks, then we would expect it to have increased activity early on in the course of a migraine. It's difficult, obviously, to get someone in a functional imaging scanner at the onset of their headache, but this has been done a few times. And you'll see in the crosshairs there is the hypothalamus lighting up. So we find that when you do image someone as early as possible in the course of the migraine, we're already seeing increased regional blood flow in the hypothalamus. So we can conclude from that, that the, or make a good case that the hypothalamus is the migraine attack generator and is the locus where we might consider modern diets and lifestyle to exert their influence. There are also clinical contexts where we see either an increase or decrease in migraine frequency. The most notable of those is obesity. So studies show that the obese are about twice as likely to experience migraine as the non-obese. We also know that weight loss or specifically fat loss is associated with a reduction in migraines. This comes primarily from the gastric bypass research. So one study, 81 patients followed for over three years. 57 had total resolution of their migraines after gastric bypass, 15 had partial resolution. Those are pretty impressive numbers. So to summarize, the obese have more migraines and fat loss leads to major migraine reductions. So put another way is that an improvement in energy homeostasis is associated with reduction in migraine frequency. We also know that there's a strong association between low-grade chronic inflammation systemically and obesity. We also know, and it's been shown in animal models of obesity that hypothalamic inflammation precedes the gain of fat. And in humans, there are signs of hypothalamic injury in the hypothalamus of the obese. So to summarize then, the points that we've made, migraines are a disease of civilization. The hypothalamus appears to be the migraine attack generator and clinical situations that are associated with improvements in energy availability and reduced systemic and presumptive hypothalamic inflammation leads to fewer migraines. So to prevent a unified theory to account for those, number one, migraines are triggered within the hypothalamus when homeostatic demands are outside the bounds of our evolutionary experience. And number two, the threshold for triggering those attacks is reduced in the presence of systemic or hypothalamic inflammation. So we can put a graphical depiction of this concept. So on the x-axis, we have time. And on the y-axis, plot out any homeostatic variable or all of them in aggregate. And so we have a set point around which the hypothalamus is trying to defend. And so over time, you'll naturally vary around that set point. We throw in the migraine threshold as if your homeostatic excursions go far enough, then you'll trigger a migraine headache. And if you're genetically susceptible, your threshold is lowered. So in this case, we see that the migraine is triggered every time we hit the threshold, which is represented by the little lighting bolts there. So we have three migraines being triggered by these homeostatic excursions. And then if we add in inflammation, we depress that set point even further. So now we've gone from having three to five times where we cross over the threshold. And then I also added in the green line for the imagined hunter-gatherer human whose variations around the set point are a lot less than the typical modern human. So they're never getting anywhere near the migraine threshold. So to summarize then, migraines are the distress signal of an overwhelmed and inflamed hypothalamus. And so understanding that helps us point the path towards prevention, which basically is to try to maintain homeostatic parameters within the bounds of our evolutionary experience and to minimize systemic inflammation. I think we all have a good idea of how best to do that. And that's it. Thank you. Thank you, Josh, that was awesome. We're gonna take 10 minute break and we'll be back with Daryl Edwards. He's gonna talk about play and physical activity and how it's good for you.