Strange Visual Auras May Hold the Key to Better Migraine Treatment

Why CSD started, no one knows. Similarly, many mysteries remain about what triggers the pain of migraines. Previous research has suggested that migraine headaches occur when something in the cerebrospinal fluid indirectly activates nerves in the nearby meninges, the membrane layers between the brain and skull. Rasmussen’s experiments, led by neuroscientist Maiken Nedergaard, initially looked for evidence to support this—but came up empty. He says: “We didn’t find anything.

So they tried a different approach, injecting fluorescent tracers into the cerebrospinal fluid and imaging the skulls of mice. The tracers were focused on the end of the trigeminal artery, “these big nerve endings that lie like two sausages at the base of the skull.” It was a big surprise, he says, to find things that were able to reach this part of the peripheral nervous system, where they were able to use pain receptors. “So we were very happy and surprised – like, how does it get there?” This led them to a hole—the end of the trigeminal nerve that was connected to the cerebrospinal fluid.

The researchers also sampled the cerebrospinal fluid and found more than 100 proteins that rose or fell after CSD, suggesting a possible involvement in migraine pain. A dozen proteins are known to act as transmitters that can activate nerves, including one called calcitonin gene-related peptide (CGRP), a known target of migraine drugs. Rasmussen says it was a good sign to find it in the mix. He says: “But for us, the most interesting are the other 11 proteins that have never been described before—as they could open the door to new therapies.”

There are still reasons for caution, said Turgay Dalkara, a neuroscience professor at Hacettepe University in Turkey who is interested in auras. Mouse models are useful, but the size difference in mouse and human skulls is a problem—especially when it comes to where the opening is found. “From mouse to human, the peak volume ratio is very different,” he said. The idea that Rasmussen’s team first investigated—that CSD releases substances that activate and sensitize neurons in the meninges—remains the best-established mechanism seen in humans, he adds. Rasmussen’s findings, of this previously undiscovered area where cerebrospinal fluid could affect the nerves, should be considered as an addition to this picture, not a substitute for it.

Hadjikhani agrees but is nevertheless happy to find another way to investigate. For doctors, the lack of understanding of how migraines work means working on the right combinations of drugs to give sufferers relief. “You try one thing. He tries a combination. He took one out,” he said. “You have to be Sherlock Holmes, find out what makes things happen.”

The fact that migraines are so variable means that there can be no silver bullet solution. Rasmussen hopes that, over time, being able to detect changes in a person’s cerebrospinal fluid can reduce this guesswork and lead to more personalized solutions.