From aura to attack: new insights into the trigeminal nerve

Up to ten percent of people with migraine experience the phenomenon known as “aura”. The ancient Greeks used this term to describe a cool breath of air. Today, it is used in medicine to mean the neurological disturbances that can precede a migraine attack.

A research team from Copenhagen has recently succeeded in unraveling the key mechanisms underlying the processes between aura and migraine attack. In doing so, they have also questioned a long-established principle in medical science.

What is an aura like?

People with migraines can experience auras differently. Common neurological disorders during an aura include

Visual disturbances. These are the most frequent aura symptom. Visual disturbances often occur in the form of a “fortification spectrum”, a star-like figure that appears in the visual field. This zigzag pattern gradually expands to one side of the visual field, leaving a blind spot (scotoma) at its center. Scotomas can occur on their own, without additional visual phenomena, presenting as a blind spot that grows over time.

Sensory disturbances. These are the second most common aura symptoms and can feel like prickling sensations on the skin. They typically start in a specific area of the body and gradually spread. A numb area often forms at the center of the sensory disturbance, affecting parts of the face or sometimes an entire side of the body. However, areas of numbness can also appear on their own.

Speech and motor impairments. Affects on speech are a rare aura symptom. Sufferers may have difficulty pronouncing words correctly (dysphasia). One-sided motor weakness is another rare occurrence.

With very few exceptions, aura symptoms completely subside with the onset of the migraine attack.

An exploration: the trigeminal nerve

The trigeminal nerve is the fifth of the cranial nerves, with sensory fibers for perception and motor fibers for control. Its name reflects its three main branches (from the Latin trigeminus, meaning “threefold” or “triplet”), which innervate 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 are connected to specialized clusters of nerve cells in the brainstem. These clusters 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 trigeminal nerve. Ganglia, which function as control hubs in the central nervous system, are collections of neural cell bodies forming small thickened structures, or “nerve knots”.

The trigeminal nerve has a central role in migraines

Medical research has long suggested that the trigeminal nerve might play a crucial role in triggering migraine attacks, although the exact mechanisms remained largely unknown. Danish neurobiologist Maiken Nedergaard and her team have recently clarified this connection in a series of groundbreaking experiments. (This team previously gained recognition in the early 2010s for discovering the glymphatic system, which plays a role in nighttime brain cleansing; read more in this article).

Current research suggests that migraine attacks begin with a wave-like excitation in the brain’s cortex, a phenomenon known as cortical spreading depression (CSD). This research led to new observations about cerebrospinal fluid (CSF), the brain’s waste-clearing liquid. After this wave of excitation, which signals the onset of a migraine attack, CSF has a different chemical composition. Researchers believe that this shift could reveal which substances might contribute to cortical spreading depression.

The study focused on specific protein components in the CSF that may activate receptors in the trigeminal nerve, which is so central to the migraine process.

CGRP: a potent peptide

A molecule known as calcitonin gene-related peptide (CGRP) has recently gained attention for its central role in migraine onset. Peptides are chains of amino acids in specific sequences. When chains exceed around 100 amino acids, they are known as proteins. So basically, peptides are short proteins.

CGRP, a neuropeptide consisting of 37 amino acids, is found primarily in the central nervous system. It is also found elsewhere, for example in nerve endings around the heart. CGRP is an exceptionally powerful vasodilator and also plays a role in regulating inflammation.

While many studies point to CGRP’s central role in migraine development, its exact release and effects have long been speculative. 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 agents and functional magnetic resonance imaging (fMRI), the researchers mapped out the pathway CGRP follows before triggering migraine attacks.

CGRP’s pathway

The sequence of events looks like this:

• Cortical spreading depression occurs in the visual cortex of the cerebrum.
• Substances that activate the trigeminal nerve, including CGRP, and other pain-mediating substances, are produced in large quantities and released into the CSF.
• The glymphatic system flushes these substances toward the trigeminal nerve, driven by the pulsing movements of blood vessel walls.
• CSF eventually reaches the trigeminal ganglion.

At this point, a remarkable process unfolds which – if it happens the way the Danish researchers suspect – challenges a long-held principle in neurology. For many years, conventional wisdom held that the central nervous system (CNS) is completely sealed off from peripheral (non-CNS) nervous tissue to protect it from toxins, infections, and other threats.

However, Nedergaard and her team have now revealed the existence of a small area at the root of the trigeminal nerve that defies this isolation: a tiny gap with a permeable membrane. CSF can pass through this “trigeminal gap” unchecked, smuggling in CGRP and other migraine-inducing substances and then transporting its cargo directly to the trigeminal root ganglion (that is, into the CNS). Here, 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

This new understanding explains two distinctive features of migraine pain:

1) The delay between aura and pain: Since it takes time for substances to reach the trigeminal nerve, there’s a temporal gap between the aura (cortical spreading depression) and the migraine pain itself. This delay likely varies between individuals and even between attacks in the same person.

2) One-sided head pain: Migraine pain is usually felt on one side of the head, which corresponds to the side where the substances accumulate and trigger pain. This is because the substances are produced on the side where cortical spreading depression occurred.

New findings, new hope?

As with any scientific breakthrough, it will be interesting to see what might follow. 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 aimed at intervening in these processes, potentially preventing many migraine attacks in the future.