No one knows why CSD starts; similarly, much remains a mystery about what triggers the pain of a migraine. Previous research has proposed that migraines are caused when something in the cerebrospinal fluid indirectly activates nerves in the nearby meninges, the membrane layer between the brain and the skull. Rasmussen’s experiments, led by neuroscientist Maiken Nedergaard, initially aimed to find evidence to support this, but came up with nothing. “We got nothing,” he says.
So the researchers tried a different approach: they injected a fluorescent tracer substance into the cerebrospinal fluid and imaged the skulls of mice. The tracer concentrated at the end of the trigeminal nerve, “there are two big bundles of nerves at the base of the skull, like a sausage.” It was a big surprise to find that the substance could reach this part of the peripheral nervous system and activate pain receptors, he says. “So we were excited and at the same time very puzzled: how does it get there?” This led the researchers to an opening in the trigeminal nerve ending that comes into contact with the cerebrospinal fluid.
The researchers also took samples of cerebrospinal fluid and found more than 100 proteins that were increased or decreased after CSD, suggesting they may play a role in migraine pain. Twelve 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 for migraine drugs. Finding CGRP in the mixture was a good sign, Rasmussen says. “But what’s most interesting to us are the other 11 proteins that haven’t been described before,” he says, because they could open the door to new treatments.
Turgay Darukara, a professor of neurology at Turkey’s Hacettepe University with an interest in the aura, says there’s still reason to be cautious. While mouse models are useful, differences in skull size between rodents and humans remain problematic, especially when it comes to the areas where the openings are found. “The surface area to volume ratio is dramatically different between mice and humans,” he says. The idea that Rasmussen’s team first explored – that the CSD releases a substance that activates and sensitizes nerves in the meninges – remains the best-supported mechanism observed in humans, he adds. Rasmussen’s discovery of a previously undiscovered place where cerebrospinal fluid may touch nerves should be considered a potential addition to this picture, not a replacement for it.
Hajikani agrees, but is still excited to find further avenues of investigation. For doctors, the lack of understanding about how migraines work means searching for the right combination of medications that will bring patients some relief. “Try one. Try a combination. Drop one,” she says. “You have to be Sherlock Holmes to find out what’s causing it.”
Because migraines vary widely, there may not be a one-size-fits-all solution, but Rasmussen hopes that in the long term, looking at changes in an individual’s cerebrospinal fluid may help minimize some of the guesswork and provide tailored solutions.
