Researchers identify unknown signaling pathway in the brain responsible for migraine with aura

A previously unknown mechanism by which proteins are transported from the brain to a specific group of sensory nerves triggers migraine attacks, a new study suggests, potentially paving the way for new treatments for migraine and other types of headaches.

The work appears in Science.

More than 800,000 Danes suffer from migraine, a condition characterized by severe headaches on one side of the head. In about a quarter of all migraine sufferers, headache attacks are preceded by aura, brain symptoms such as temporary visual or sensory disturbances that precede the migraine attack by 5-60 minutes.

Although we know with some certainty why patients experience aura, it has been a mystery why they get headaches and why migraines are one-sided.

A new study in mice, conducted by researchers from the University of Copenhagen, Rigshospitalet and Bispebjerg Hospital, shows for the first time that proteins released from the brain in migraine with aura are transported via cerebrospinal fluid to the pain nerves responsible for the headache.

“We found 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,” said postdoc Martin Rasmussen from the Center for Translational Neuromedicine at the University of Copenhagen, who is the first author of the study.

At the base of the trigeminal ganglion, the barrier that normally prevents substances from entering the peripheral nerves is missing. This allows substances in the cerebrospinal fluid to enter and activate the pain-signaling sensory nerves, leading to headaches.

“Our results suggest that we have identified the primary communication channel between the brain and the peripheral sensory nervous system. It is a previously unknown signaling pathway that is important for the development of migraine headaches, and it may also be associated with other headache disorders,” says Professor Maiken Nedergaard, who is the lead author of the study.

The peripheral nervous system consists of all the nerve fibers responsible for communication between the central nervous system (the brain and spinal cord) and the skin, organs and muscles. The sensory nervous system, which is part of the peripheral nervous system, is responsible for transmitting information about, for example, touch, itch and pain to the brain.

The research findings provide insight into why migraines are usually one-sided, something that has puzzled scientists until now.

“Most patients experience unilateral headaches, and this signaling pathway may help explain why. Our study of how proteins are transported out of the brain shows that the substances are not transported to the entire intracranial space, but mainly to the sensory system on the same side, causing unilateral headaches,” Rasmussen says.

The study was conducted on mice, but also included MRI scans of the human trigeminal ganglion. According to the scientists, there is every indication that the function of the signaling pathway is the same in mice and humans, and that the proteins are also transported via cerebrospinal fluid in humans.

Proteins could lead to new treatment options

Using advanced techniques such as mass spectrometry, which can detect a wide selection of proteins in a given sample, the researchers analyzed the cocktail of substances released during the aura phase of a migraine attack, that is, during the phase of visual disturbances.

“The concentration of 11 percent of the 1,425 proteins we identified in the cerebrospinal fluid changed during migraine attacks. Of these proteins, 12 proteins that were increased in concentration acted as transmitters that could activate sensory nerves,” Rasmussen says. “This means that when the proteins are released, they are transported via the aforementioned signaling pathways to the trigeminal ganglion, where they bind to a receptor on a pain-signaling sensory nerve, activate the nerve, and cause the migraine attack after the aura symptoms.”

The group of proteins the researchers identified included CGRP, a protein already linked to migraines and used in existing treatments. However, the researchers also discovered a range of other proteins that could pave the way for new treatment options.

“We hope that the proteins we identified, apart from CGRP, can be used to design new preventive treatments for patients who do not respond to available CGRP antagonists. The next step for us is to identify the protein with the greatest potential,” says Rasmussen.

He explains that one of the identified proteins plays a role in menstrual migraine.

“Initially, we hope to identify the proteins that trigger migraine phenotypes. Then we will do provocation tests in people to determine whether exposure to any of the identified proteins can trigger a migraine attack,” Rasmussen says. “It’s a good idea to test whether these and other proteins can trigger migraine attacks in people, because if so, they can be used as targets in treatment and prevention.”