It was one of those bright, but cloudy days. I was in the University library, in my usual spot by the window, trying to get my head round my lecture notes. I looked out of the window, then as I looked away, a familiar blind spot started to form.
But the blind spot wasn’t going away. Instead, the edges started to dance, and the size of the blind spot increased to fill my vision until I couldn’t see. I rested my head on the desk. Gradually, the dancing went away and I could see again. I felt weird, vague. Every sense felt heightened – sounds were too loud, smells were too strong.
As I wandered home, I was suddenly aware of pain forming behind my right eye, which seemed to spread. Then the right side of my head started to pulsate with the agonizing pain of the worst headache I had ever had. I struggled to bed, and lay there in the dark for a few hours until it went away.
I later learned that I had been experiencing a migraine, preceded by an aura (the dancing blind spot). I’ve had a few of these now, with varying symptoms. But what are migraines? The standard definitions are “severe headaches” or “recurring headaches”, but this doesn’t really begin to cover it – people are often out of action for several days or a week. One of my friends suffers from a form of migraine called a “hemiplegic” migraine – he feels the effects for several months.
Trying to explain how a migraine feels to a non-sufferer is often tricky – not helped by the fact that nobody really knows for certain what migraines are in biological terms.
Let’s start with what we do know
Migraine is the most common neurological condition in the developed world – more prevalent than diabetes and asthma combined – and is most common in females.
There are several types of migraine – about a third of sufferers will experience them as I did, with a warning aura, followed by headache, but people can have just the aura, or just the headache. There are widely accepted to be 5 main stages of a migraine, though not everyone will experience each stage. These are nicely described here, so I won’t dwell on them.
Certain “triggers” often bring about migraines, although getting to know your own personal triggers can be challenging. My migraines seem to be induced by light, but I don’t get one every time I look at a bright light, so there must be other factors at play. Triggers can be emotional (such as stress or anxiety), physical (such as lack of sleep), dietary (such as low blood sugar, dieting and alcohol), environmental (such as light, and strong smells), and even some medications.
Records of migraine go back as far as the 2nd century, when Galen described a painful disorder that affects one half of the head – he called it “hemicrania”, and believed that it was due to humors that rose from the liver. The theory of humors is now discredited; Migraines are now thought to be the result of chemical changes in certain regions of the brain, which then wreak havoc and change the way our brains respond to sensory information such as light, pain and sound. The precise details of why these chemical changes occur, and why only some people are susceptible, are still unknown – but we do have some clues.
Genetics – studies on Familial Hemiplegic Migraine
Having migraines commonly runs in families (my mother suffers from them too), which points to a genetic basis. Migraine is currently believed to be “polygenic”, meaning that it is caused by mutations in many different genes, each contributing a little to the overall result. A lot of our current understanding of the genetic basis for migraine comes from the studies on a particularly nasty type, familial hemiplegic migraine (FHM).
Hemiplegic migraine is a rare form of migraine where aura is accompanied by temporary weakness on one side of the body -“hemiplegic” means paralysis on one side of the body. Sufferers can experience speech difficulties, confusion and even coma, and is a really frightening experience, especially since the symptoms can be very similar to those of a stroke or epilepsy.
Mutations within 3 genes have been linked with FHM. Understanding how mutations in these genes might cause a migraine in FHM patients requires an understanding of neurotransmission, which in basic terms is the way the neurons in our brains communicate. When an electrical impulse passes down a neuron, it causes the release of a chemical messenger called a neurotransmitter into the synapse. This then causes an electrical impulse in the next neuron, and so on.
The 3 genes mentioned all code for proteins called ion channels that sit in the cell membrane, which are vital players in the release of neurotransmitter from neurons (see picture below – click to enlarge). The wisdom is that defects in these channels result in the increased release of glutamate (a neurotransmitter) from neurons. These then make the brain more susceptible to a phenomenon called Cortical Spreading Depression (CSD), which is essentially an intense wave of neuron activity, followed by depression of this activity. This is what is thought to initiate the aura symptoms, as CSD can spread through the areas of the cortex that control vision.
What about more common forms of migraine?
Although there is only a small amount of evidence for it, the causes of FHM might be similar to the underlying mechanisms of more common forms of migraine. For example, a study of more than 50,000 people in 2010 showed that patients with a particular variant in the sequence between two genes have a greater risk of developing migraine (journal article here and commentary here). What links it with FHM is that this region of DNA also seems to regulate the levels of glutamate (the neurotransmitter blamed for FHM). However, we know that genetics isn’t the whole story due to studies on identical twins – sometimes one twin suffers from them but the other one doesn’t.
FHM has given us an insight into the causes of aura and migraine in general, but where does the pain come from? Most areas of the brain do not register pain, but one network of nerves – the trigeminal nerve system – does. This is widely accepted to be the source of the pain during migraine, but what activates this system is unclear. One school of thought is that CSD stimulates the trigeminal nerve system directly. This would explain why it is that some migraine sufferers do not get an aura – it would depend on where the CSD occurred. If it occurred in a place unconnected to the visual side of things for example, you might not get an aura.
Another school of thought is that the trigeminal nerve system is activated not by CSD but by certain clusters of cells in the brain stem, that have been shown to be active during and after migraine. The brain stem is the central hub for information passing to and from the body. The clusters of cells mentioned normally inhibit the firing of the trigeminal nerve system (i.e. they tell the nerves not to fire). As yet unidentified changes in the behaviour of these clusters of cells might take the brakes off and allow the trigeminal nerves system to fire, causing the pain in migraine. What makes this idea attractive is that these clusters of cells control the flow of sensory information from things such as light into other regions of our brains, which would explain a migraine sufferer’s sensitivity to light, smells and noises. These cells can also be affected by our emotional state, which would explain why stress is a trigger for some people.
So we have some ideas about how the aura and the pain of migraine might arise. The neurotransmitter glutamate might be the trickster involved in causing Cortical Spreading Depression and auras, although the link has not been definitively proven in the common migraine yet. What do seem to be important are changes in the normal workings of ion channels, possibly due to genetic changes. The resulting Cortical Spreading Depression, or other factors, might then be responsible for the pain itself.
Let’s hope that the causes of the common migraine will be made clearer in the near future – it could be important for designing new treatments. At the moment, there are no treatments available that are specific to migraine – most drugs used were originally developed for other diseases. I’m willing to bet a specific treatment would be a money-spinner! Moreover, it would be nice to know what’s actually going on in my brain when I’m having a migraine, as it is downright weird.
For anyone interested in finding out more about migraine, The Migraine Trust have a selection of informative and interesting articles about various aspects of it.
Sources & Further Reading
Russell, M.B & Ducros, A. Sporadic and familial hemiplegic migraine: pathophysiological mechanisms, clinical characteristics, diagnosis and management. (2011) The Lancet Neurology 10, Issue 5 p.457-470.
Anttila et al. Genome-wide association study of migraine implicates a common susceptibility variant on 8q22.1. (2010) Nature Genetics 42, p.869-873