From aura to attack: understanding the latest insights on migraine

What is an aura like?

People with migraines can experience auras differently. Some typical symptoms include:

Visual disturbances. This is the most common symptom. The disturbance often appears as a star-shaped figure in the field of vision. This zigzag pattern gradually expands to one side of the visual field, leaving a blind spot at its center. Some people may experience only a blind spot that grows over time.

Sensory disturbances. These are the second most common manifestation. They may feel like pinpricks on the skin. Again, they typically start in a specific area of the body before gradually spreading. Sometimes only one part of the face is affected. Other times, it’s one entire side of the body. At the center, a numb area may develop. Regions of numbness can also appear on their own, however.

Speech and movement impairment. Speech impairments are rare in an aura. Some people struggle to pronounce words correctly. Occasionally, there may be one-sided impaired mobility affecting one side of the body.

With very few exceptions, these symptoms go away completely when the migraine attack begins.

A brief explainer: What is the trigeminal nerve?

The trigeminal nerve, known as nervus trigeminus in Latin, is the fifth cranial nerve. It has sensory fibers (for perception) and motor fibers (for movement control). Its name (trigeminus means “threefold” or “triplet” in Latin) refers to its three main branches. These three branches connect to the eyes, upper jaw, and lower jaw.

Cranial nerves are those with fibers emerging directly from the brain or radiating into the brain. Most cranial nerves connect directly to special groups of nerve cells in the brain stem, which are known as cranial nerve nuclei. Each cranial nerve has at least one entry or exit point within the skull. The trigeminal ganglion inside the skull serves as a branching point for the threefold nerve. Ganglia, which function as control hubs in the central nervous system, are collections of neural cell bodies forming small thickened structures, or “nerve nodes”. Ganglia are control centers in the nervous system.

The trigeminal nerve has a central role in migraines

For a long time, researchers suspected that the trigeminal nerve plays a major role in triggering migraine attacks. However, the exact processes involved remained unclear. Through extensive studies, Danish neurobiologist Maiken Nedergaard and her team have now made progress in understanding this link. (This team previously gained recognition in the early 2010s for discovering the glymphatic system, which clears waste from the brain during sleep; check out our article “Nighttime brain cleansing and headaches” in this blog).

Current research suggests that a particular sequence of events occurs in the run-up to a migraine attack. The process begins with a wave of electrical activity spreading across the cortex, the brain’s outer layer. This wave is known as "cortical spreading depression” (CSD).

The new explanation of what happens in a migraine attack is based on Nedergaard’s team’s observation that the CSD wave changes the composition of cerebrospinal fluid (CSF; the fluid responsible for clearing waste from the brain). After the CSD wave, the CSF contains different substances than before. This change in the CSF could indicate which substances contribute to triggering an attack, giving clues about how researchers might one day intervene in the migraine process.

The team’s research focused on specific protein components in the CSF. It is suggested that these protein components bind to special sites (receptors) on the trigeminal nerve (a nerve strongly linked to migraines) and trigger it into action.

CGRP: a powerful substance

A substance called calcitonin gene-related peptide (CGRP) is known to play a key role in migraines. CGRP is a powerful vasodilator, meaning it can widen blood vessels. It is also involved in controlling inflammation.

While many studies have linked CGRP to migraine attacks, how it is released and its precise function in the migraine process remained unclear. Missing from the research was a clear understanding of how this peptide integrates into the migraine process. With a series of sophisticated experiments, Nedergaard and her team brought us closer to solving this mystery. Using contrast dyes and scans, the researchers mapped out the pathway CGRP follows before triggering migraine attacks.

How CGRP leads to a migraine

Nedergaard’s study outlines the following sequence of events:
– Cortical spreading depression occurs in one side of the brain, producing substances that cause pain.
– These pain-inducing substances travel with the cerebrospinal fluid toward the trigeminal nerve.

A remarkable thing happens next. At the base of the trigeminal nerve, Nedergaard’s team discovered an opening where CSF can enter the central nervous system freely. Through this opening, migraine-triggering substances, including CGRP, enter the central nervous system. This discovery challenges the long-held belief among scientists that the CNS is completely sealed off for protection. Instead, the CNS lets certain substances through. The final step in the migraine-triggering sequence is set in motion:

– The trigeminal nerve is activated, causing the typical pain signals of a migraine.

Unique features of migraine pain

These new insights help explain two distinctive features of migraine pain:

1) The delay between aura and pain: It takes time for the substances to reach the trigeminal nerve, explaining why there is often a delay between the aura (when cortical spreading depression occurs) and the actual pain. This delay likely varies between individuals and even between attacks in the same person.

2) Migraine pain is felt on one side of the head. This is because the pain-causing substances are produced and build up only on the side where the pain later occurs. In other words, migraine pain is felt on the side of the head where the cortical spreading depression happened.

New findings, new hope?

As with any scientific breakthrough, the question is what it might lead to. For the first time in the long history of migraine research, we have a detailed understanding of the sequence of events in a migraine attack. This could open up new avenues for research that, ideally, would allow intervention in the critical chain of events, potentially preventing many migraine attacks.