A potential origin for migraines

New work in mice suggests a potential start for migraines
22 December 2020

Interview with 

K.C. Brennan, University of Utah


A X-ray image of figure clutching their head, with their brain glowing in red.


Mice that get migraines have helped scientists in the US to uncover what might be going on in the more than 10 per cent of us who suffer from the condition. What K.C. Brennan at the University of Utah has done is to make a genetic change in his mice, so they mimic the make-up of one group of humans who suffer regular migraines. By watching the brains of these animals, they’ve found that, periodically, surges appear of an excitatory nerve signal called glutamate. This, they speculate, causes overstimulation of the nearby nerve cells, starting the neurological equivalent of a Mexican wave that ripples across the brain. As it does so, it activates pain pathways that cause the ensuing headache. As K.C. Brennan explained to Chris Smith, these new insights should enable the Utah team to unpick how this happens and better ways to control it…

K.C. - We, on the most fundamental level, are trying to understand how migraine works. The approach we took was to use mice, carrying a gene that comes from a family of people who have hereditary migraine. This is a rare form of migraine, but it allows us to place the gene in the mouse, and actually ask very detailed questions that we wouldn't be able to ask with humans directly.

Chris S - But critically you can't ask a mouse if it's got a headache. So how do you know when the mouse is experiencing migraine phenomena?

K.C. - It's a very good question. For migraine with aura, this is migraine that many people will be familiar with, where you have a change in your vision, flashing lights, or sometimes people get numbness or tingling that moves, or some people lose the ability to speak, for migraine, with aura, we know that there's an event in the brain called a spreading depolarisation that underlies the migraine aura. We can look at this spreading depolarisation in the mice, and if they have the spreading depolarisation, there's other work that shows that we can assume that they have the beginnings of a migraine. So it gives us a real purchase on the subject.

Chris S - So when a person is having a migraine, there is some kind of abnormal electrical activity in at least one part of the brain to start with. And you're saying, you then get this spreading wave of changed behaviour that goes across the brain, might take in some other areas, including visual areas, which is why people see these flashing lights and so on, or experience abnormal sensations for awhile. How does that then link to the headache that comes later?

K.C. - People have found that the spreading depolarisation, this spreading wave of excitation that moves across the brain will cause pain sensing nerves to fire. And those pain sensing nerves are what generate the sensation of the headache.

Chris S - So that argues then, if we can get underneath what causes the initial wave of depolarisation, because that's upstream of the headache, we ought be able to knock the migraine on the head.

K.C. - Exactly.

Chris S - What did you actually do with these mice, that then gives us insights into that mechanism, and what might be causing it, and what might be causing it to spread in this way in the first place?

K.C. - So the mice have a little tiny window carved into their skull that allows us to look at their brain cells as they are going about their business. And this was where the surprise came. We saw these, what we call plumes, basically puffs or clouds of something called glutamate. So glutamate is the major excitatory neurotransmitter in the brain. It is used for brain cells, neurons, to communicate. It's absolutely essential, but it's kept within very, very tight bounds under normal circumstances. It's a substance that's absolutely essential for me to be talking to you right now and for you to be hearing me. And it looks like it was not kept in tight bounds in these animals.

Chris S - Putting this together, then. Would you say that a way of thinking about this is that for some reason, in individuals who are prone to migraines, that the normal rigid tight control of their glutamate occasionally gets a bit out of control in one bit of the brain, and they get this geyser goes off. And the big plume of glutamate showers a patch of brain, and the nerves there become more active than they should. And that then triggers the ones next door. And you get this sort of domino effect radiating out from where this started, spreading out that burst of activity across the brain surface. And that's the migraine kicking off. You'll see the aura, then, it's followed later by the pain. And because the brain is a bit more susceptible to not keeping control of its glutamate level, that's why it's easier for that wave of glutamate to spread across the brain in that way in those people.

K.C. - That's a lovely summation. And in being a responsible scientist, I'd have to say that's a lovely hypothesis at this point, but we can actually be as precise as you were in formulating that hypothesis about how migraines start. And that's, I think one of the exciting advances of this work,

Chris S - The problem is that glutamate is an incredibly universal transmitter, nerve transmitters, isn't it, it's an excitatory transmitter throughout the brain. So it's going to be quite tricky to turn it off without causing enormous numbers of side effects. So what do you propose to do, now you understand this a bit better for people who are prone to migraines.

K.C. - It's a very important question. So on the one hand, this does validate certain treatments that we use. We have migraine preventive drugs, for example, that suppress glutamate related excitation. So this validates, those presently used treatments, but like you said, drugs that willy nilly take glutamate levels down, have profound side effects, the best example of that is ketamine or "Special K," what we would really like to do in future is dive deeper into the very basic mechanisms of these plume events, so that we can develop more precision, fine tuned drugs that could prevent the onset of plumes, but preserve normal activity in the brain.


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