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There is no one experience of “aura.” For some, it starts with white glitter at the edge of their vision like half-seen falling stars; others find faces distorted or words suddenly difficult to form. Science journals collect unusual cases, like Oliver Sacks’ account of waking to find his nurse had “become inorganic” and was drifting apart like a set of mosaic tiles. In rare cases, an individual can feel they are suddenly growing to an enormous size or shrinking entirely out of view—known as Alice in Wonderland Syndrome.
For most, these auras appear as if from nowhere, most commonly as a set of scintillating zigzags that grow for about 20 minutes across the edge of the field of vision. Intriguing in themselves, these phenomena are dire omens. They forewarn of the arrival, in less than an hour, of the sustained pain of a migraine.
Migraines are the world’s third most prevalent cause of disability, affecting a billion people each year by some estimates. About a third experience some form of aura beforehand, often accompanied by debilitating symptoms from vomiting to vertigo, or, in worse cases, temporary blindness or hemiplegia, a paralysis down one side of the body. But recent discoveries about mechanisms that link auras and migraines could lead to potential new treatments. Martin Kaag Rasmussen, a neuroscientist at the University of Copenhagen, says research on auras may reveal new answers to the greatest riddle of migraines: How do painful headaches arise from the brain if it has no pain receptors?
The brain, like other internal organs, is insensate, its lack of sensory receptors attested by videos of virtuoso violinists who play on unfazed as neurosurgeons go to work inside their skulls. The central nervous system, the brain and the spinal cord, is usually considered sealed off behind the so-called blood–brain barrier, explains Rasmussen. But auras—which fMRI scans have indicated originate as a sort of rolling blackout within the brain—suggest information is getting through from the brain to the pain sensors in the peripheral nervous system, the nerves outside of the central nervous system that extend across the rest of the body. “But how and where does it communicate?” asks Rasmussen. “Migraine with aura is sort of the perfect model to use to answer this question.”
Rasmussen is a coauthor of a study in mice published in July that found a tiny opening between the cerebrospinal fluid, a clear soup of nutrients that bathes the brain and spinal cord, and pain receptors in the jaw—a previously undetected point of contact where substances released in response to brain activity could activate the peripheral nervous system. This discovery sets a new direction for migraine research that could help identify new drug targets. Some neurologists think it could change how we think about headaches.
Nouchine Hadjikhani, a Harvard neuroscientist who has been researching auras for three decades, says the research is “probably the biggest advance” in 10 to 20 years about how migraines happen. Around the turn of the millennium, we learned that auras occur during a temporary shutdown of neuron activity, known as a cortical spreading depression (CSD). Hadjikhani’s team was the first to show this in humans on fMRI scans, as a slow-moving wave of cells activating anomalously, rippling across the cerebral cortex. “Imagine you throw a stone in water and you see the waves going out,” she says. Most aura symptoms are visual because more than a third of the brain is dedicated to visual processing.
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Exactly why CSD starts, nobody knows. Similarly, plenty of mysteries remain about what activates the pain of migraines. Past studies have proposed that migraine headaches occur when something in the cerebrospinal fluid indirectly activates nerves in the nearby meninges, the layers of membrane between the brain and the skull. Rasmussen’s experiment, led by neuroscientist Maiken Nedergaard, initially set out to find evidence to support this—but they came away empty-handed. “We didn’t get anything,” he says.
So they tried a different approach, injecting fluorescent tracer substances into the cerebrospinal fluid and imaging the mice’s skulls. The tracers concentrated at the end of the trigeminal nerve, “these big nerve bundles that lie like two sausages on the base of the skull.” It was a big surprise, he says, to find substances were able to reach this part of the peripheral nervous system, where they could activate pain receptors. “So we got excited and also very puzzled—like, how does it even get there?” This led them to the opening—the end of the trigeminal nerve that was in open contact with the cerebrospinal fluid.
The researchers also sampled the cerebrospinal fluid and found more than 100 proteins that rose or fell in the aftermath of CSD, suggesting potential involvement in the pain of migraine. A dozen of the proteins that increased are known to act as transmitter substances capable of activating sensory nerves, including one called calcitonin gene-related peptide (CGRP), a known target for migraine drugs. Rasmussen says it was a good sign to find it among the mix. “But for us, what is most interesting is really the 11 other proteins that have not been described before,” he says—as these could open the door for new treatments.
There are still reasons to be cautious, says Turgay Dalkara, a professor of neurology at Hacettepe University in Turkey with an interest in auras. Mouse models are useful, but the size differences in rodent and human skulls are problematic—especially when it comes to the area where the opening was found. “From the mouse to the human, the surface-volume ratio is dramatically different,” he says. The idea that Rasmussen’s team initially investigated—that CSD releases substances that activate and sensitize nerves in the meninges—remains the best supported mechanism observed in humans, he adds. Rasmussen’s finding, of this previously undiscovered spot where cerebrospinal fluid could touch nerves, should be considered a possible addition to this picture, not a replacement for it.
Hadjikhani agrees but is nevertheless excited to find a further pathway for investigation. For doctors, the lack of understanding about how migraines work means sleuthing for the right combinations of medicines to give sufferers some relief. “You try one. You try a combination. You take one off,” she says. “You have to be Sherlock Holmes, finding what triggers things.”
The fact that migraines vary so much means there may never be a silver bullet solution. Rasmussen hopes that, in the long term, being able to observe changes in an individual’s cerebrospinal fluid could minimize this guesswork and lead to personalized solutions.
