Tsunami-Like Mechanism In Brain May Foreshadow Migraines, Study In Mice Shows

It's what some unlucky people dread more than almost anything: the bright flashes of light, seeing shimmering stars, losing vision, or a tingling sensation in their hands or face – symptoms called an 'aura', which usually strikes before a migraine headache arrives.

Now scientists have detected in mice tsunami-like waves of a brain-signalling molecule that could explain the onset of migraines with auras. At the same time, their findings could help researchers understand other brain conditions such as stroke, epilepsy, and traumatic brain injury.

"This is something new under the Sun," said K.C. Brennan, a neurologist from the University of Utah. "Glutamate plumes are a completely new mechanism of migraine, and it's a good bet that they are players in other diseases of the nervous system."

Glutamate is a type of messenger molecule that excites nerve cells in the brain. This includes neurons, which send and receive brain signals, and star-shaped astrocytes, which are specialised support cells that lead clean-up duty in the brain.

What this new study has found is a massive outpouring of glutamate into the space between brain cells in mice, moving with shifts in brain activity already known to occur in people with migraines.

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Understanding what causes these horrendous headaches is the first step towards finding new treatments for migraines, which could help to relieve more people of their pain, nausea, and vomiting.

The role of glutamate in migraines has been suggested before. People with migraines (migraineurs) have higher levels of glutamate than unaffected individuals, both during and between migraine attacks.

But migraines are a fickle beast. Not all migraines are accompanied with an aura – only about a third of migraineurs experience them – and sometimes people have an aura with little or no headache.

Triggers also vary between migraineurs, but can include certain food and drinks, strong smells, bright lights, sun glares, stress, and fatigue.

All in all, the root cause of migraines remains poorly understood, though there are some tell-tale signs a migraine is about to occur – which leads us back to auras, and a phenomenon called spreading depolarisation.

Spreading depolarisation is a sudden shift in brain activity that has been described as "a wave of runaway excitation" in the brain. It's thought to be the basis of the migraine aura, and yet it occurs in other brain conditions too, such as stroke and other forms of brain seizures, which can be measured in people using electrodes.

It follows that over-excited brain cells might be linked to one of the most abundant excitatory neurotransmitters in the brain, glutamate, but direct evidence connecting the two in migraines specifically is lacking.

In this study, the researchers studied glutamate signalling in mice that had been designed to mimic a rare subtype of migraine (with auras), which people can inherit from their parents.

With a few genetic tweaks, the brain cells of these mice had their glutamate transport processes impaired. The researchers also used a binding protein that fluoresces when it meets glutamate, allowing the team to image levels of glutamate in the brains of these mice while they were awake.

'Plumes' of fluorescent glutamate appeared on the brain images, moving outward from a central starting point across the top layers of the brain. On average, these plumes lasted less than a second.

In theory, a surge in glutamate would set off a chain reaction, whereby the release of glutamate from one neuron triggers its neighbours to follow suit, which is what the researchers saw: a tsunami-like wave of fluorescent molecules as the glutamate swept through the mice's brains.

By measuring how often and how long the glutamate waves lasted, the researchers found that it wasn't just nerve cells pumping out too much glutamate that were the problem – astrocytes were also awfully slow at mopping up the mess.

When glutamate uptake was impaired in healthy mice, glutamate plumes popped up on the images of their brains, too, demonstrating the mechanism in play.

With further experiments, the researchers also showed that a flurry of glutamate plumes preceded the onset of chemically-induced spreading depolarisation events, while preventing plumes inhibited them from occurring.

"This shows that plumes don't just coincide with spreading depolarisations," said neuroscientist and lead author Patrick Parker, also from the University of Utah. "They are involved in their generation."

Of course, this study is only in a handful of mice that had been designed to mimic one type of migraine – and not in people who experience migraines in different ways, both with and without auras.

Still, the work is useful in that it points to a new molecular mechanism underpinning unpleasant auras – a finding that, with more research, could possibly translate into a therapy to stop migraines and auras in their tracks. However, therapies targeting glutamate receptors have not always been effective.

For now, the researchers are turning their focus towards understanding how glutamate plumes might be involved in other brain disorders, such as epilepsy and stroke, which exhibit similar waves of brain activity.

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