No one knows exactly why CSD starts. Similarly, many mysteries remain about what causes migraine pain. Previous research has proposed that migraines occur when something in the cerebrospinal fluid indirectly activates nerves in the nearby meninges (layer of membranes between the brain and skull). Masu. Rasmussen’s experiments, led by neuroscientist Maiken Nedergaardt, were initially set out to find evidence for this, but nothing came of it. “I got nothing,” he says.
So they tried a different approach, injecting fluorescent tracer substances into the cerebrospinal fluid and imaging the skulls of mice. The tracer focused on the end of the trigeminal nerve, “a large nerve bundle that lies like two sausages at the base of the skull.” It was a big surprise, he says, to discover that the substance could reach this part of the peripheral nervous system and activate pain receptors there. “So we were excited, but very perplexed: How do we get there?” This led them to the opening, the trigeminal nerve in open contact with the cerebrospinal fluid. reached the end of.
The researchers also sampled cerebrospinal fluid and found more than 100 proteins that were elevated or decreased in response to CSD, suggesting they may be involved in migraine pain. More than a dozen proteins are known to act as transmitters that can activate sensory nerves, including one called calcitonin gene-related peptide (CGRP), which is a known target for migraine drugs. Rasmussen said finding this product among them was a good sign. “But what’s most interesting to us are the 11 other proteins that have not been described so far,” he says. Because these could open the door to new treatments.
Turgay Darcala, a professor of neurology at Turkey’s Hacettepe University with an interest in the aura, says there are still reasons to be cautious. Although mouse models are useful, they are problematic due to the size differences between rodent and human skulls, particularly regarding the areas where openings are found. “The surface area-to-volume ratio is dramatically different in mice and humans,” he says. The idea that Rasmussen’s team first explored, that CSD activates nerves in the meninges and releases substances that increase their sensitivity, remains the best-supported mechanism observed in humans. he added. Rasmussen’s discovery of this undiscovered place where cerebrospinal fluid may come into contact with nerves should be considered as potentially adding to, rather than replacing, this situation.
Hadjihani agrees, but is excited to find further avenues of investigation. For doctors, the lack of understanding of how migraines work means they need to find the right combination of drugs to give patients relief. “Try one. Try a combination. Take one off,” she says. “You have to be Sherlock Holmes and find the spark to get things started.”
The fact that migraines are so diverse means there may never be a silver bullet solution. Over time, Rasmussen hopes that being able to observe changes in an individual’s cerebrospinal fluid could help minimize this speculation and lead to personalized solutions.
