Elucidating the pathophysiology of migraines

Scientists at the University of Copenhagen, Rigshospitalet and Bispebjerg Hospital are the first to show that proteins released from the brain during migraine with aura are transported with cerebrospinal fluid (CSF) to pain-signalling nerves, causing severe headaches. The new study offers promise for the development of new treatments for migraines.

In Denmark over 800,000 individuals suffer from migraines, and in about a fourth of these people, headache attacks are preceded by aura, symptoms from the brain like temporary visual or sensory disturbances five to 60 minutes before the migraine attack. Although it is understood why patients experience aura, the explanation for headaches and the one-sided nature of them was unknown.

Dr Martin Kaag Rasmussen, first author of the study and postdoc at the Center for Translational Neuromedicine at the University of Copenhagen, explained: “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.” At the trigeminal ganglion’s base, the barrier that normally stops substances in the CSF from entering the peripheral nerves is missing, which activates pain-signalling sensory nerves.

Dr Maiken Nedergaard, senior author of the study, commented: “Our results suggest that we have identified the primary channel of communication between the brain and the peripheral sensory nervous system. It is a previously unknown signalling pathway important for the development of migraine headache, and it might be associated with other headache diseases too.”

The peripheral nervous system consists of all the nerve fibres responsible for communication between the central nervous system (CNS) and the skin, organs and muscles. Part of this system is the sensory nervous system, which communicates information about touch and pain to the brain. This could explain why patients get one-sided headaches. Dr Rasmussen stated: “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”.

The researchers conducted their study on mice and included MR scans of the human trigeminal ganglion. According to the team, it is very likely that the function of the signalling pathway is the same in mice and humans, and that in humans the proteins are carried by CSF.

Mass spectrometry, among other state-of-the-art techniques, detected the wide variety of proteins released during the aura stage of the migraine attack. “The concentration of 11 percent of the 1,425 proteins we identified in the cerebrospinal fluid changed during migraine attacks. Of these, 12 proteins that had increased in concentration acted as transmitter substances capable of activating sensory nerves,” added Dr Rasmussen. “This means that when the proteins are released, they are carried to the trigeminal ganglion via the said signalling pathways, where they bind to a receptor of a pain-signalling sensory nerve, activating the nerve and triggering the migraine attack succeeding the aura symptoms.”

CGRP, a protein already linked to migraines and used in current treatments, was found in the group of proteins identified.  However, the team also discovered a series of other proteins, which could lead to novel treatment options. “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. The next step for us is to identify the protein with the greatest potential,” concluded Dr Rasmussen. He highlighted that one of the proteins identified is known to play a role in menstrual migraine.

This study was published in Science.