What's going on during a migraine?

Last month, we’re dipped our toes into headachey waters. And for the rest of this episode, we’re diving a bit deeper. Last time, neurologist Amanda Ellison took us through the various stages of migraine headache, and Katie Haylor wanted to find out more about what’s going on in the brain during a migraine, and what treatments are out there. So first up, here’s an interview with Anna Pace - a neurology academic and also headache doctor from Mount Sinai hospital in New York...

Anna - The most common headache syndrome that we see in the office is actually migraine. And I think primarily that's the case because the pain is so debilitating, it affects people's ability to go to work, go to school, attend social activities. And a lot of people also experience other symptoms with their migraines, aside from the debilitating pain. And that's really what brings them to the office because it makes them concerned that maybe something else is going on or they don't understand why it's happening.

Katie - What is happening in the brain of somebody who is having a migraine?

Anna - Oh, that's the million dollar question that we're all trying to figure out! What exactly happens in the brain when you have a migraine? In the past, it was thought that it was a blood vessel type of disorder or a vascular type of headache was the term that was used. Meaning that the primary reason why people had pain was because blood vessels dilated. And what we now know is that it's actually a much more complicated process than that and a very biological one. And so what we seem to understand is that for some reason, people with migraine have a very irritable or excitable brain. So their cerebral cortex is hyper-excitable. We don't understand why that is, but in the brain, the neurons are triggered to fire when they're not supposed to be doing that, or they're fired kind of inappropriately. And they set each other off kind of like a domino effect. So one neuron starts to fire, then the next one goes and the next one goes. And so all of a sudden, all of these nerves are activated and then it's followed by a wave of inactivity, or what we call cortical spreading depression. And as that happens, there are chemicals that are released in the brain that cause inflammation, which then lead to the blood vessels dilating and pain being experienced. So it's actually a very complicated interplay between the electrical activity of the brain, as well as blood flow.

Now, that's kind of the mainstay pathway that we think happens with migraine. But to be perfectly honest with you, the more and more research that we do, the more we understand that there may actually be other pathways that are a little bit redundant or they cross with this particular type of pathway, which could explain why certain people have some symptoms of migraine versus others. Or maybe why certain treatments work better for some patients than others. So I think it's a very heterogeneous type of pathway and patients really experience it differently, even though we still use the term migraine.

Katie - It sounds really complicated!

Anna - It is!

Katie - Do we know what's happening right at the beginning? When you said you have nerves firing maybe inappropriately, I think you said, why is that happening?

Anna - That we don't seem to know. I think primarily we understand migraine to be a genetic type of disorder. Or people with migraine have a genetic predisposition. So for some reason, their brain is wired in this way to be hyper-excitable. This is kind of the area of research that people are really looking into, because we don't understand why some people have this and other people don't. Obviously it does run commonly in families, but it seems to be some chemical imbalance in some of the electrolytes that flow back and forth through the nerves. But we don't understand why that is for some people and not for others.

Katie - What's going on with aura? Because when I was speaking to Amanda Ellison in a previous episode, I mentioned that I'd had, I think, only two migraines in my life, but I just felt this massive sensory overload - lights, noises - it just made me feel utterly awful. And I got all these splodges in my vision. Why does some people get this sensory overload? And why do some people not?

Anna - I actually get aura as well. And this was one of the main reasons why I wanted to go into headache medicine, because I just could not understand why this was happening. So we use the term aura to mean the neurologic symptoms that come prior to the pain that people experience. So commonly people will experience squiggly lines or zigzags in their vision. It kind of looks like a kaleidoscope. It may start in one spot, get bigger, move across their vision. Some people will get a tingling, almost kind of pins and needles sensation, followed by numbness. And some people actually notice their speech change. And that's really a result of the activation followed by the wave of depression. So depending upon which part of the brain is active, some people are a little bit more sensitive to that pathway than others because the brain is being activated. For example, in the occipital lobe, which controls your vision, you may start to see things that are not there. Then it goes away as that wave of activation starts in the back of the brain and moves forward. The occipital lobe gets activated, you see things, and then it goes away. As it hits the sensory cortex, you start to feel the pins and needles sensation, and then that goes away. If it hits the cortex involved in speech, you may have some difficulty finding your words or being able to say the word that you want to get out.

The sensory overload component, because the brain is using up all of this energy on this process, that's going on, you know, any type of stimulus, light, sound, smells, movement, almost kind of overloads the brain. And it can't function in the same way because its energy is being used up during this process. And so people often want to be in a dark quiet room and really any type of stimulus is just so incredibly uncomfortable. And as the headache continues to progress and the pain starts to resolve, people often feel what they call a migraine hangover.

Katie - When you were talking just then about speech difficulties, that seems quite scary to me because that sounds like a stroke. Is there any relationship between what's going on in a migraine compared to in a stroke? Or am I barking up the wrong tree?

Anna - No, that's actually a really great connection that you made. There is some data to suggest that people who have migraine with aura specifically, especially women, are at a slightly higher increased risk of stroke compared to the general population. The risk is still very, very low, but it is something that we do counsel our patients about. For patients who experience aura, it can be incredibly scary because it's this transient neurologic symptom, especially speech. I think my patients who have speech changes in particular always get very anxious when this happens, because sometimes you don't know, is this just my migraine? Or is this something else? Normally with migraine, it tends to be progressive. It starts, gets a little bit worse and then it goes away and it's very stereotypical. So people who have migraine with aura often report to us that they have the same type of symptom each time they get a migraine. Stroke tends to be much more quick and onset. So you're fine one second. And then all of a sudden you have a speech problem. But in certain patients, especially older ones, who've never had migraine before, who develop some kinds of symptoms like this, like a speech change or even weakness on one side or tingling or numbness. Sometimes it is important to go to the emergency room for an evaluation for stroke, because that's the thing you don't want to miss. More often than not it's not a stroke, but it can be very scary for the person who is experiencing it.

Katie - What can you do for people then, who are experiencing migraines? I just hid until it went away. I don't know if that's a good thing to do!

Anna - We want to prevent them from coming in the first place. And then we also want to treat when a patient gets them. So the treatment really depends on how frequent the attacks are happening. Some people experience an attack once a month. Some people may experience attacks, you know, 15, 20, 30 days out of the month. And so the treatment really depends on how frequent the attacks are happening, and obviously how much they affect the person's usual routines. Medications are often commonly used, non-medication options are available as well. Often lifestyle modifications are important. So staying very well hydrated, getting good sleep, not missing meals, exercise, stress reduction. It's amazing how much some of those things can actually really affect how frequent your headaches are. They tend to reduce the frequency. There are a lot of devices that have been released that have been helpful for migraine prevention. A lot of these treatments really look to target certain parts of the pathway that we know occur in migraine. And so a multimodal approach and a multidisciplinary approach is often really important to use.

Katie - Could you target what the nerves are doing at the beginning, and maybe the vasodilation? How does it work?

Anna - Yeah, so a lot of the medications that we have work on different parts of the pathway, and we've had many new medications that have recently come out that have targeted something we newly discovered is a key part in the migraine pathway. Often combining certain treatments really give you the best benefit in terms of headache relief, especially from a prevention standpoint. Because again, since everybody experiences this a little bit differently, it may mean that certain parts of the pathway are much more active for someone than others. And so really targeting more than one area will give you the best likelihood of feeling better.

A lot of the medications that we use for migraine originally were borrowed from other classes of medicine and they essentially were found to be useful for migraine because during the trials for, say, for blood pressure or anti-depression, or anti-seizure, the patients who had had headache had noted improvement. So some of the medications that we borrow from other classes of medicines really act on kind of the later parts of the pathway. We do have four new medications that were recently approved for the treatment of migraine that have come out over the last few years, that target one specific chemical called CGRP or calcitonin gene related peptide. This is a chemical that's inflammatory and is released when you have a migraine, and it does tend to lead to vasodilation. So this particular treatment works on trying to reduce that chemical. So it's a little bit earlier on in the pathway that we tend to use and find that patients do well and have a reduction in their headache frequency when they're on these kinds of medications.

Katie - What about transcranial magnetic stimulation? We've talked about it on the podcast a little bit before, does this have any relevance to migraine?

Anna - It does. I actually find this incredibly interesting. So transcranial magnetic stimulation (TMS) has been around for a very long time, but really only started to be used for migraine, I would say probably, over the last 10, 20 years or so. It's noninvasive. For most people from a migraine perspective, it's a portable type of device. And what it does is it essentially creates an electrical current around the head and it is painless. It, we think, it helps to reduce that wave of activation and depression. The cortical spreading depression we talked about. And also helps to reduce the hyper-excitability of the brain that we know is the beginning part of the migraine. And the studies that we have for TMS found that more than half of the patients actually had a 50% reduction in their headache frequency and no side effects.

Katie - Is it safe?

Anna - Yes, it's been around for a very long time, it was originally used for anxiety and depression. And is actually still used for that purpose. It sounds kind of scary, but it actually does work very well. And I have many patients who do utilise this type of therapy and do very well. And I find in particular, and the studies have shown this as well, that patients who do have migraine with aura seem to respond well to this particular type of treatment, primarily because I think it's affecting the cortical spreading depression part of the pathway, and that's really the thing that drives the aura.

Katie - What does it look like? I'm imagining that you wear some sort of special hat and then get zapped. Maybe that's completely off! What does it look like if you're having this treatment?

Anna - So there are a lot of different kinds. The one that is used for migraine is often a single pulse and it is a portable device, kind of looks like a rectangle with two handles on the side. And people use it in the back of the head, kind of almost like, it's kind of like they're using a scarf. Like if you were to pull it around the back of your neck, except you'd put it up to the base of your head. And there are two buttons on the side that you would hit.

Katie - Looking forward, where are the areas that need work or the areas of unmet need in headache medicine specifically?

Anna - Primarily understanding a little bit more about the headache pathophysiology is important. Like we talked about, why is the brain so hyper-excitable in the first place? Why do certain patients respond to some treatments when others don't? Is there just this one pathway that we know about, are there multiple redundant pathways? And I think understanding really what happens in the brain can really help people create more targeted treatments. And we know, these last four medications, the CGRP antibodies, have really paved the way for new research, looking at targeted therapies. And coming up in the pipeline are other chemicals that we have found that really do trigger migraine attacks. So in theory, I think the areas that we really need to work on are creating more targeted therapies, maybe more individualised therapies related to the information we find as a result of this research. And also there are certain patients who aren't able to take certain medications that we have available for migraine, whether or not it's because they have another medical problem that will not allow us to use it, or if they're on other medications that will interact. And so just having some more treatment options that are safe for those patients, I think is really the other area of unmet need that we really need to address.