Key process discovered in migraines with aura

A team of Danish and US scientists has uncovered a new signalling pathway in the brain, which is linked to migraine attacks with auras – the sensory disturbances like flashing lights in vision or tingling in limbs.

The study, which was done mostly on mice, helps to explain the still poorly understood processes that trigger migraines.

The researchers found cerebrospinal fluid moves aura-causing proteins in one part of the brain to pain receptors in the nervous system, becoming the source of the sharp migraine headache.

“We have discovered that these proteins activate a group of sensory nerve cell bodies at the base of the skull, the so-called trigeminal ganglion, which can be described as a gateway to the peripheral sensory nervous system of the skull,” says Martin Kaag Rasmussen, a postdoctoral researcher at the University of Copenhagen, Denmark.

Rasmussen is first author on a paper published in Science.

“Our results suggest that we have identified the primary channel of communication between the brain and the peripheral sensory nervous system,” says senior author Maiken Nedergaard, a professor at the University of Rochester, US.

“It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too.”

Auras occur in around a quarter of migraine sufferers. They typically start happening between 5 minutes and an hour before the painful headache begins.

Scientists already knew that auras were linked with a phenomenon called “cortical spreading depression,” which usually starts in the visual processing centre of the cortex and spreads out in waves across the brain. This is why visual disturbances are the most common aura symptoms.

In this study, the researchers used a variety of experiments on mice and MRI scans on humans to establish that cerebrospinal fluid flowed to the trigeminal ganglion during a migraine, where it could then interact with the nervous system.

Then they examined 1,425 proteins in cerebrospinal fluid, looking for those that change in concentration during cortical spreading depression.

“Of these, 12 proteins that had increased in concentration acted as transmitter substances capable of activating sensory nerves,” says Rasmussen.

One of these proteins is called CGRP, and is already used in migraine treatments. But many of the other proteins provide new opportunities for treatment.

“We hope the proteins we identified – aside from CGRP – may be used in the design of new preventive treatments for patients that don’t respond to available CGRP antagonists,” says Rasmussen.

“These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies,” says Nedergaard.

The research also helps to explain why migraine sufferers often only experience pain on one side of the head.

“Our study of how proteins from the brain are transported shows that the substances are not carried to the entire intracranial space, but primarily to the sensory system in the same side, which is what causes one-sided headaches,” says Rasmussen.

In a perspective on the study, US researchers Andrew Russo and Jeffrey Iliff point out that the research could also help to explain the link between migraines and poor sleep.

They write that the possibility that sleep clears out migraine-related substances from cerebrospinal fluid and the trigeminal ganglion “would provide a potential mechanistic explanation for the clinical linkage between sleep disruption and migraine”.

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