Study shows how aura may lead to migraine headache

About a third of people who suffer from migraines experience a phenomenon called aura before the pain sets in. Aura includes visual disturbances and other neurological symptoms. These usually appear within the hour before migraine pain begins.

Scientists know that a widespread disruption of electrical activity in the brain called cortical spreading depression (CSD) causes aura. But how this disruption might trigger the pain of a migraine has been poorly understood. The sensory neurons that drive migraine pain sit outside the brain. It had previously been thought that the blood-brain barrier lies between the areas of the brain where CSD happens and the neurons that trigger migraine. This could prevent signaling molecules caused by CSD from reaching these neurons.

A research team led by Dr. Martin Kaag Rasmussen, formerly at NIH and now at the University of Copenhagen, and Dr. Maiken Nedergaard of the University of Rochester has been studying ways that fluids flow through and from the brain. In their new study, funded in part by NIH, they tracked the flow of cerebrospinal fluid from the brain to the peripheral nervous system in mice after CSD. Their results were published on July 5, 2024, in Science.

Using advanced imaging techniques, the researchers observed markers injected into the cerebrospinal fluid flow from the brain rapidly and directly into a peripheral nerve structure called the trigeminal ganglion. Molecules injected into the cerebrospinal fluid were able to activate receptors on cells in the trigeminal ganglion, indicating a direct route of chemical communication.

Further imaging work found that the membrane that prevents external molecules from entering the trigeminal ganglion was lacking from one end of the ganglion. This created a path for cerebrospinal fluid to flow directly from the brain into the ganglion.

The team next traced the path of molecules injected directly into the visual cortex. This part of the brain is the most common site of aura. They found that a compound injected into the visual cortex of mice made its way into the trigeminal ganglion in about half an hour. This time delay corresponds to the typical interval between aura and headache onset.

To better understand the actual substances released by the brain after aura, the researchers induced CSD in mice and then measured changes in proteins found in their cerebrospinal fluid. After CSD, levels of more than 150 proteins changed in cerebrospinal fluid. Twelve of these bound directly to receptors in the ganglion. These included proteins known to be involved in migraine headache, like calcitonin gene-related peptide, or CGRP. It also included other proteins whose potential role in headache need further study.

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

The changes in proteins observed in the cerebrospinal fluid after aura were short lived. It’s therefore likely that other processes play a role in the long duration of migraine headache. More work is needed to uncover these processes and understand how they might be targeted therapeutically.

—by Sharon Reynolds