The Mystery of Migraines

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From Our Neurons to Yours Wu Tsai Neuro Podcast

What is a migraine? And why are they so hard to treat?

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If you've ever had a migraine, you know that the symptoms — splitting headache, nausea, sensitivity to light — mean you're going to want to spend some time in bed, in a dark room.

Migraines are flat out debilitating, and the statistics back this up.

Migraines are the third most common neurological disorder. They affect as many as a billion people around the world, making them one of the world's 10 most disabling diseases according to the World Health Organization. But for all the misery for those who suffer from migraines, it's been a long haul for scientists to figure out what actually causes these episodes, and more importantly, how to provide relief.

We spoke this week with  Gabriella Muwanga, a graduate student in the Stanford lab of Viviane Tawfik, who studies what's actually going on in the brain during a migraine. And for good reason —  Muwanga has suffered from regular migraines herself since childhood and hopes to contribute to finding better treatments for them in the future.

Links

Muwanga's research profile

Learn more about the Tawfik lab at Stanford Medicine

Stanford headache specialist demystifies migraine auras (Stanford Scope Blog, 2017)

Migraine Treatment Has Come a Long Way (New York Times Well Blog, 2022)

References

Ahn, A.H. and Basbaum, A.I. Where do triptans act in the treatment of migraine? Pain. 2005 May; 115(1-2): 1–4.

Charles, A., Baca, S. Cortical spreading depression and migraine. Nat Rev Neurol 9, 637–644 (2013).

Weatherall, M.W. The diagnosis and treatment of chronic migraine. Ther Adv Chronic Dis. 2015 May; 6(3): 115–123.

Hoffmann, J.,  Baca, S. M., and  Akerman, S. Neurovascular mechanisms of migraine and cluster headache. J Cereb Blood Flow Metab. 2019 Apr; 39(4): 573–594.

Episode Transcript

Nicholas Weiler:

This is From our Neurons to Yours, a podcast from the Wu Tsai Neurosciences Institute at Stanford University. On this show, we crisscross scientific disciplines to bring you to the frontiers of brain science. I'm your host, Nicholas Weiler.

Here's the sound we created to introduce today's topic, migraines. What exactly is a migraine, and why are they so hard to study? If you've ever had a migraine, you know that the symptoms, splitting headache, nausea, sensitivity to light, I mean you're going to need to spend some time in bed, in a dark room. Missing work, missing school, migraines are flat out debilitating, and the statistics back this up.

Migraines are the third most common neurological disorder. They affect as many as a billion people around the world, making them one of the world's 10 most disabling diseases according to the World Health Organization. But for all the misery for those who suffer from migraines, it's been a long haul for scientists to figure out what actually causes these episodes, and more importantly, how to provide relief.

Even though they're so common, migraine research gets a lot less funding than other neurological diseases. One of the reasons may be that migraines, which I'll just note, affect women more than men, are often misunderstood as being little more than a really bad headache.

Gabriella Muwanga:

But it's not just a simple headache, even though headache is one of its symptoms.

Nicholas Weiler:

That's Gabriella Muwanga, a graduate student at Stanford, who studies what's actually going on in the brain during a migraine.

Gabriella Muwanga:

What I want to know is, how does migraine come about? And by knowing that, how can we treat it?

Nicholas Weiler:

And you're studying this in mice?

Gabriella Muwanga:

I am studying it in rats, which are much gentler creatures.

Nicholas Weiler:

Oh really? Why are rats gentler than mice?

Gabriella Muwanga:

Well, they fight me less. Mice are angrier, so they have worse attitudes. They're like small dogs. They're very angry creatures.

Nicholas Weiler:

Can you tell me a little bit about the lab where you work?

Gabriella Muwanga:

So I currently work in two labs. My primary mentor is Vivianne Tawfik, an anesthesiologist, so pain is her forte. And my second mentor is Dr. Raag Airan, who is a neuroradiologist and nails all things ultrasound. And I am trying to use ultrasound to target drugs in my pain models.

Nicholas Weiler:

So you're trying to use ultrasound to figure out how to get drugs to the right place in the brain to target pain?

Gabriella Muwanga:

Yes. So ultrasound can be used to ease delivery of drugs into the brain because we have what we call the blood-brain barrier. And a lot of drugs don't really cross this barrier and yet we need to get it in there. Another thing is that usually, we want drugs to do a particular thing. But because they don't bind this one place, you have all these side effects, these things happening that you don't want to happen. But with the technology that's developed in his lab, you can use these ultrasound responsive nanoparticles, put a drug inside the particle, shine some ultrasound on it, and release a drug in only a particular spot that you want it to go to.

Nicholas Weiler:

That is super cool.

Gabriella Muwanga:

Yeah. Yeah.

Nicholas Weiler:

It's like science fiction neuroscience.

Gabriella Muwanga:

Right? I was like, "This can't be real."

Nicholas Weiler:

Okay. So fundamentally, what is a migraine?

Gabriella Muwanga:

A migraine is a neurological disorder. It presents usually with pain and a headache. It's hugely a moderate to severe headache. So usually, when you get this headache, it's going to be like, "Ooh, this is close to the worst pain I have ever felt." And it's going to stop you from doing things that you would usually do, go to work, go to school. In addition to the headache, you have other symptoms, like nausea and vomiting, sensitivity to light, to sound, to touch. So migraine is a serious issue.

Nicholas Weiler:

What makes it classified as a neurological disorder?

Gabriella Muwanga:

The root of it is in the nervous system. There are different theories for how migraine comes about, but there's no definitive answer for how it does. One group thinks that it's due to changes in the vasculature in the brain.

Nicholas Weiler:

By vasculature, meaning?

Gabriella Muwanga:

Blood vessels. Changes in the way blood flows in the brain and how this change in blood flow interacts with the nervous system or nerves in your head and in your face. And other people think it's a change in electrical activity. They think a wave of spreading electrical activity goes over your cortex, especially over your visual cortex, to form photophobia or sensitivity to light, which is one of the symptoms of migraine. So they believe this must be what's behind the migraine disorder.

Nicholas Weiler:

Okay. So there are a couple of theories, has something to do with blood vessels in your brain or some sort of electrical activity spreading over your brain. Is that right?

Gabriella Muwanga:

Yeah.

Nicholas Weiler:

If you can study someone who has a migraine, can you actually see this happening in someone's brain?

Gabriella Muwanga:

If you study someone who has a migraine, you can't. They have actually done some imaging studies where they show changes in the brain that are specific to people that suffer from migraines compared to people that do not. But we don't have enough of those studies to make conclusions about, okay, this is exactly what is happening, which is why they can't use it to diagnose migraine.

Nicholas Weiler:

So sometimes people talk about an aura that comes with a migraine. What does that involve?

Gabriella Muwanga:

So the aura is, in a lot of people, it's a visual disturbance that comes before your headache. And it is one of the phases of migraine. So migraine usually happens in four phases. You have your prodrome, your aura, the headache phase, and the postdrome. So the prodrome, you have exhaustion. You're just tired for no reason. And then you have the aura, where you have visual disturbances. You might see color. Other people have auditory disturbances, where they hear things that aren't there. And other people, although this is the rarer kind of aura, might smell things that just aren't there. And it usually shows up a few hours before the headache begins.

Nicholas Weiler:

What are some of the things people might experience with the aura?

Gabriella Muwanga:

Well, I smell fish, which is very uncomfortable, because I used to like fish before that started happening. And now, we just don't work. And other people, they become very dizzy and it could be blurry. It could be like little pinpoints of color. The general understanding is that you are perceiving something that is not there, and it can only be classified as aura.

Nicholas Weiler:

Okay. So then after the aura, then you get the big deal, the headache and everything else. What is that like?

Gabriella Muwanga:

It can be very severe. The headache can last anywhere from a few hours to days. If you're lucky, it'll last three days. If it becomes much longer than that, it's moving into what they call status migrainosus, or it's an intractable migraine.

Nicholas Weiler:

So what does that mean, a migraine that just goes on indefinitely?

Gabriella Muwanga:

Yeah. And is not responsive to medication, to any sort of intervention. But usually, in the aura phase, you can take the acute medications for a migraine to prevent the pain from coming on, or to reduce how long the migraine lasts. And to prevent the migraine in general, we also have preventative medications. But they're not mechanism-based, so it doesn't work for everyone.

Nicholas Weiler:

Okay. So it's more complex and probably more painful than your typical headache. I've had headaches where I had to lie down and go into a dark room, and I didn't want to see any light or hear anyone talking to me. I guess, how do you know if that's a bad headache or that's a migraine? How would you know that oh, I just had my first migraine, or I just had a bad headache because I was stressed out?

Gabriella Muwanga:

Well, where you're feeling your pain could be an indicator for whether it's a migraine or not, and whether you have other symptoms that come along with a migraine in addition to your light sensitivity. You could be vomiting. But usually, the migraine will come on one side of the face, either the right or the left. I have heard of cases where it comes in the back of the head, but usually, it should be in either side of the face and around the eye.

And so the positioning of the headache, the intensity of your headache, they make their presence known. And you don't like the light. Like you mentioned, darkness. You don't like loud noises, smells. And it usually lasts a long time. So, hard to confuse it for something else. As someone who might be getting their first migraine, if it's a headache, you feel like, "I don't feel like I've felt this before, this is torture," you might be having a migraine.

Nicholas Weiler:

You mentioned that you suffer from migraines yourself. Can you tell me a little bit about when you got your first migraine? And for you, walk me through what it's like when you get one of these.

Gabriella Muwanga:

Well, I got my first migraine when I was nine years old, and I thought I was dying. It was intense pain on the right side of my face, around my eye, and I was very nauseous. I couldn't stop vomiting as well. I couldn't eat anything or keep it down. I was sweating. I wouldn't stop sweating and it lasted like four days. And I was in boarding school, so the school nurse thought I was dying too.

I don't know why she had no idea what was going on with me, but it's possibly because I grew up in a Third-World country and there's a lot of malaria. But maybe I was dying of cerebral malaria. But no, I was having my very first migraine. And I have been diagnosed with chronic migraine. So chronic migraine is when you have 15 or more days of migraine per month. And then if you have less than 15 days, it's called episodic migraine.

Nicholas Weiler:

Always lasts seven, like a whole week?

Gabriella Muwanga:

Luckily, not anymore, because of the new medication that I have, which is very helpful. And I've been seeing great doctors. And now, the longest that it lasts now is three days. So you have a brief window within which you should take your medication for you to successfully intervene.

Nicholas Weiler:

So when you have a migraine, even if it's just three days that you've taken your medications in time, what is the effect and how does it impact you?

Gabriella Muwanga:

I'm pretty happy about it. Because sometimes I don't get the painful headache, that the aura just passes, or it lasts only a few hours. And the last option is it comes down to a level that is manageable for me, so I can continue to do my daily activities. I come to the lab or I hang out with friends, but still not be in too bright a room. But it makes everything less severe or less intense, so it makes my life better.

Nicholas Weiler:

And are there good, reliable medications that work for most people?

Gabriella Muwanga:

There are a couple of medications that work for most people. So they use Triptans, which I think act on the blood vessels in your brain. And they also use these days what they call CGRPs or CGRP antibodies and antagonists that bind to a protein that is commonly expressed on pain neurons. The exact mechanisms are still under investigation, but it works.

Nicholas Weiler:

So as you've said, this is not just a headache. This is a complex neurological disorder where there are clear different phases. Your vision gets impaired. You have nausea. You're laid out for days or a week or more, depending on the type of migraine you have. I mean, this seems like a really serious issue, but it's not one that we hear a whole lot about as far as neurological disorders go. Why do you think that is?

Gabriella Muwanga:

I think the biggest reason would be, it's dismissed a lot as a headache. Just take a painkiller, move on. But this is a very common problem. A lot of people experience migraines. If it's not chronic migraine, they've had at least one migraine in their lifetime. And so we need to know how it comes about and we need to better treat it. I'd like to say you get used to it, but you just don't. And you shouldn't have to get used to it, which is why we do research. And it's why we're trying to find ways to kick this thing.

Nicholas Weiler:

Thank you very much. I really appreciate you talking to me about this terrible thing that happens to you.

Gabriella Muwanga:

Thank you for asking.

Nicholas Weiler:

By the way, Gabbie and I emailed after the interview. She wanted to clarify that the most recent view is that migraines are caused by both abnormal brain activity and changes in blood flow. In fact, the brain could cause the changes in blood flow that lead to migraine symptoms. It's an evolving field and we'll be keeping an eye on it.

To learn more, check out the Wu Tsai Neurosciences Institute at neuroscience.stanford.edu. For more info about Gabbie's work, check out the links in the show notes. This episode was produced by Michael Osborne, with production assistance by Morgan Honiker and Christian Haigus. I'm your host, Nicholas Weiler.