Exactly why CSD starts is unknown. Likewise, there’s still a lot of mystery about what triggers migraine pain. Previous studies have suggested that migraines occur when something in the cerebrospinal fluid indirectly activates nerves in the nearby meninges, the membranes between the brain and skull. Rasmussen’s experiment, led by neuroscientist Maiken Nedergaard, was originally set out to find evidence to support this—but they came up empty-handed. “We got nothing,” he says.
So they tried a different approach, injecting fluorescent markers into the cerebrospinal fluid and imaging the mice’s skulls. The markers concentrated at the ends of the trigeminal nerves, “large bundles of nerves that sit like sausages at the base of the skull.” He says it was a surprise to find that the chemicals could reach this part of the peripheral nervous system, where they could activate pain receptors. “So we were both excited and confused—like, how did it get there?” That led them to the open end—the part of the trigeminal nerve that is exposed to the cerebrospinal fluid.
The researchers also took samples of cerebrospinal fluid and found more than 100 proteins that were either increased or decreased after CSD, suggesting they might be involved in migraines. Dozens of the increased proteins are known to act as transmitters that can activate sensory nerves, including one called calcitonin gene-related peptide (CGRP), a known target of migraine drugs. It was a good sign to find it in the mix, Rasmussen said. “But for us, the most exciting thing was actually the other 11 proteins that had never been described before,” he said — because they could open the door to new treatments.
Turgay Dalkara, a professor of neuroscience at Hacettepe University in Türkiye who is interested in corona, said there are still reasons to be cautious. Mouse models are useful, but the size difference The skulls of rodents and humans are problematic.—especially when it comes to the area where the opening was found. “From mouse to human, the surface-to-volume ratio is significantly different,” he says. The idea that Rasmussen’s team originally explored—that CSD releases chemicals that activate and sensitize nerves in the meninges—remains the best-supported mechanism observed in humans, he adds. Rasmussen’s discovery of this previously undiscovered spot where cerebrospinal fluid can touch nerves should be seen as a possible addition to this picture, not a replacement for it.
Hadjikhani agrees, but is still excited to find a further avenue of investigation. For doctors, the lack of understanding of how migraines work means finding the right combination of drugs to give sufferers relief. “You try one. You try a combination. You take one off,” she says. “You have to be Sherlock Holmes, figuring out what’s causing everything.”
The fact that migraines vary so much means there may never be a one-size-fits-all solution. Rasmussen hopes that, in the long run, being able to observe changes in an individual’s cerebrospinal fluid could reduce this guesswork and lead to personalized solutions.
