No one knows exactly why migraines occur. Likewise, many mysteries remain about what triggers migraine pain. Previous studies have proposed that migraines occur when something in the spinal 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 found nothing. “We got nothing,” he says.
So they tried a different approach: They injected fluorescent tracer substances into the spinal fluid and took images of the mice’s skulls. The tracer substances concentrated at the end of the trigeminal nerve, “those big bundles of nerves that meet like two sausages at the base of the skull.” It was a big surprise, he says, to find that the substances were able to reach this part of the peripheral nervous system, where they could activate pain receptors. “So we were excited and also very puzzled: how does it get there?” This led them to the opening, the end of the trigeminal nerve that was in open contact with the spinal fluid.
The researchers also took samples of spinal fluid and found more than 100 proteins that were increased or decreased as a result of CSD, suggesting a possible involvement in migraine pain. 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 of migraine drugs. Rasmussen says it was a good sign to find it among the mix. “But for us, what’s more interesting are really the other 11 proteins that haven’t been described before,” he says, as they could open the door to new treatments.
There are still reasons to be cautious, says Turgay Dalkara, a professor of neurology at Hacettepe University in Turkey who is interested in auras. Mouse models are useful, but size differences in Rodent and human skulls are problematic—especially when it comes to the area where the opening was found. “Between the mouse and the human, the surface-to-volume relationship is radically 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 spinal fluid might touch nerves should be seen as a potential addition to this picture, not a replacement.
Hadjikhani agrees, but is excited to find a new avenue for research. For doctors, the lack of understanding about how migraines work means they must search for the right combinations of drugs to give patients some relief. “You try one, you try a combination, you stop one,” she says. “You have to be Sherlock Holmes and figure out what triggers things.”
The fact that migraines vary so much means there may never be a silver bullet. Rasmussen hopes that, in the long term, being able to observe changes in a person’s spinal fluid could minimize this guesswork and lead to personalized solutions.
