No one knows exactly why CSD begins. Similarly, much remains a mystery about what triggers migraine pain. 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 the skull. Rasmussen’s experiment, led by neurobiologist Maiken Nedergaard, initially set out to find evidence to support that idea—but it came up empty-handed. “We found nothing,” he says.
So they tried a different approach, injecting fluorescent tracers into the cerebrospinal fluid and imaging the skulls of mice. The tracers focused on the end of the trigeminal nerve, “these big bundles of nerves that sit like two sausages at the base of the skull.” It was a huge surprise, he says, to find that the substances could reach a part of the peripheral nervous system where they could activate pain receptors. “So we were excited and also very puzzled—how does this even get there?” That led them to the foramen—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 following CSD, suggesting a potential involvement in migraine pain. More than a dozen of the proteins that rose are known to act as messengers that can activate sensory nerves, including one called calcitonin gene-related peptide (CGRP), a known target for migraine drugs. Rasmussen says finding it in the mix was a good sign. “But what’s really interesting to us are the 11 other proteins that haven’t been described before,” he says—because they could open the door to up-to-date treatments.
There are still reasons to be cautious, says Turgay Dalkara, a professor of neurology at Hacettepe University in Turkey who studies auras. Mouse models are useful, but the differences in size rodent and human skulls are problematic—especially when it comes to the area where the hole was found. “The surface-to-volume ratio is dramatically different from mouse to human,” he says. The idea that Rasmussen’s team initially explored—that CSD releases substances that activate and sensitize nerves in the meninges—remains the best-confirmed mechanism observed in humans, he adds. Rasmussen’s discovery of this previously undiscovered site where CSF might touch nerves should be considered a possible addition to that picture, not a replacement for it.
Hadjikhani agrees, but she’s still excited about finding a path forward for research. For doctors, the lack of understanding of how migraines work means searching for the right combinations of drugs to give sufferers relief. “You try one. You try a combination. You stop one,” she says. “You have to be Sherlock Holmes, figuring out what triggers things.”
The fact that migraines are so different means there will never be a magic solution. Rasmussen hopes that in the long term, being able to observe changes in a person’s cerebrospinal fluid could minimize that guesswork and lead to personalized solutions.