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The Mysterious Link Between Migraine Aura and Headache

New MRI study finds no evidence for a weakened blood-brain barrier in migraine with aura patients

by Matthew Soleiman


31 May 2017


PRF News

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New MRI study finds no evidence for a weakened blood-brain barrier in migraine with aura patients

For decades, researchers have wondered if migraine attacks are somehow tied to the blood-brain barrier. According to one hypothesis, a wave of decreased activity in the cortex, known as “spreading depression,” not only underlies the aura phase of migraine but also leads to a breakdown of the blood-brain barrier. This would allow circulating inflammatory molecules to cross into the brain and rouse the neurons that trigger a migraine headache.

 

A new brain imaging study in 19 migraine with aura patients, however, finds no evidence for that hypothesis. Messoud Ashina, University of Copenhagen, Denmark, and colleagues now report that in the wake of migraine aura, the blood-brain barrier remains intact. For their analysis, the researchers focused on 10 brain areas, including those associated with visual aura symptoms and headache pain.

 

“I would like to think that the new study would put this idea to rest—that we could, as a field, agree there’s really no evidence for an opening of the blood-brain barrier, at least during the headache phase of a migraine attack,” said Gregory Dussor, University of Texas at Dallas, US. Dussor is a migraine researcher but was not involved in the study.

 

The results also have implications for understanding the therapeutic effects of migraine medications, which reportedly cannot get across the blood-brain barrier and are usually taken about the time when Ashina and colleagues scanned patients. “What’s nice about the authors catching patients during the early phase of the migraine headache is that it’s probably not the case that these drugs are gaining access to the brain,” said Dussor.

 

The study was published online April 18 in Brain.

 

No blood-brain barrier leakage

Migraine aura can manifest in a multitude of ways. People can partially lose their vision, or see illusory lines and shapes, or more rarely, feel a tingling sensation. “For some patients, aura is a warning sign that a migraine headache may come,” said Ashina.

 

In 1977, researchers proposed the idea that migraine patients might have a leaky blood-brain barrier (Harper et al., 1977). In the following decades, this idea evolved into more specific hypotheses, with one maintaining that spreading depression—perceived by patients as an aura—causes the breach in the protective barrier.

 

“The hypothesis was based on preclinical science,” explained Ashina. For example, in 2004, researchers showed that spreading depression, experimentally elicited in rats by needle pinprick, activates and boosts expression of matrix metalloproteinase 9 (MMP-9; see Gursoy-Ozdemir et al., 2004). This enzyme, in turn, cleaves proteins that compose the blood-brain barrier, increasing its permeability.

 

To test the hypothesis in migraine with aura patients, first author Anders Hougaard and colleagues used dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to measure the permeability of the blood-brain barrier. Patients alerted the researchers by telephone when they experienced an aura, and were scanned during the headache phase 1 to 22 hours later. Before being scanned, patients rated their headache pain on a scale from 0 to 10. They then returned on a day without a migraine attack for a second scanning session. Altogether, 19 men and women between the ages of 22 and 59 completed the study.

 

Comparing scans from days with and without migraine attacks, the researchers found no change in permeability in the visual cortex or the brainstem, regions previously associated with the aura and headache phases of migraine, respectively. Nor did they detect any differences in brain areas near the cerebral arteries. Even upon comparing patients who reported visual disturbances during the aura—the most common set of symptoms—with those who did not, there was no observable leak in the visual cortex.

 

“As a scientist, there’s nothing like 100 percent certainty,” said Ashina. Nonetheless, “given the method we used, with its level of sensitivity, we did not find any changes in the blood-brain barrier when the aura is over, during the headache phase.”

 

“I’m not surprised,” said Dussor. “There were some animal model studies that had shown that the blood-brain barrier could break down, but there really wasn’t much solid evidence that this absolutely happened, and certainly not in humans.”

 

Indeed, in a smaller study published last year, another group of researchers found no signs of a weakened barrier during a chemically triggered migraine attack in migraine without aura patients (Schankin et al., 2016). And while there have been reports of an increase in permeability in those with familial hemiplegic migraine, that condition is considered a severe form of migraine with aura, and so is not necessarily representative of what typically happens (Dreier et al., 2005).

 

The investigators also analyzed cerebral blood flow in the same 10 brain regions, with several seeming to show an increase in perfusion on migraine attack days. But such findings did not remain statistically significant when the researchers corrected for the multiple comparisons made in the study. That doesn’t mean the differences found are necessarily false positives, but follow-up studies are needed to be certain.

 

Where do migraine medications act?

To Ashina, the new study provides the strongest evidence to date against the hypothesis linking migraine aura to headache via blood-brain barrier disruption. Still, the investigators can’t exclude “whether other methods, or methods used during the aura phenomenon, will show something different,” Ashina said.

 

Perhaps the blood-brain barrier only becomes leaky during an aura, which lasts on average for about 20 minutes, and at most for an hour. “That’s certainly a caveat to the study,” said Dussor. Actually ruling out that possibility with brain imaging would prove to be difficult, he added, given such a narrow time window.

 

The results also touch on a related debate regarding the site of action of migraine medication. “We don’t really know where the drugs used to treat migraines work,” said Dussor. “Do they have to get into the brain to have efficacy, or are they working because they have targets in the periphery?” If the blood-brain barrier stays closed, specifically at a time when patients would take migraine medications, then it seems that the drugs can stop migraine attacks without accessing the brain.

 

As Michael Moskowitz, Harvard Medical School, Massachusetts General Hospital, Boston, US, writes in an accompanying commentary, “the findings by Hougaard and colleagues suggest that candidate tissues and cells outside the [blood-brain barrier] merit investigation to help identify therapeutically relevant target sites.”

 

So, what could connect the aura and headache phases of a migraine? “The field is still working on the molecular details of how spreading depression might actually turn into activation of nociceptors in the meninges,” said Dussor; this group of nociceptors is thought to contribute in some way to migraine headache. But not all migraine patients have aura—in fact, most do not. “How then are the meningeal nociceptors getting activated in those patients?”

 

Matthew Soleiman is a science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.

 

Image: Artist’s depiction of a zigzag visual disturbance experienced during a migraine aura. Credit: Wikimedia Commons.

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