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.