New Brain Pathway Could Help Stop Migraine Pain

A newly identified communication route connecting distant nerve centres in the brain and skull with the rest of the body may offer a fresh way to halt migraine pain before it takes hold.

Scientists have spent years seeking to establish where migraines originate in the brain and how these one-sided, nausea-inducing headaches cause pain and symptoms including vomiting. A clearer understanding could reveal methods to prevent migraines or, at minimum, relieve the intense pain after it begins.

How migraine aura may reach pain nerves

Around one-third of people with migraines experience an aura beforehand, often as shimmering lights or blurred vision. This is preceded by a wave of unusual brain activity moving across the cortex, the brain’s outermost layer.

Exactly how activity within the brain influences receptors on pain-detecting neurons beyond it has, however, remained unclear.

The brain is enclosed by the blood-brain barrier, a protective layer that prevents potentially dangerous substances and pathogens from entering the central nervous system (CNS). The spinal cord is similarly protected by a barrier that also prevents large molecules from crossing.

A major nerve junction between the CNS and the peripheral nervous system, which includes nerves elsewhere in the body, is the trigeminal ganglion. This bean-shaped collection of nerves, already associated with migraines and headaches, sits at the base of the skull and relays sensory signals from the face and jaws to the brain.

Researchers had believed that the trigeminal ganglion lay outside the blood-brain barrier. This would make it a relatively accessible target for medicines such as CGRP inhibitors, a promising newer form of migraine treatment.

That location would also mean, however, that the trigeminal ganglion was not exposed to the cerebrospinal fluid (CSF) surrounding the brain and spinal cord.

CSF pathway to the trigeminal ganglion

A new mouse study has found the reverse to be true. It showed that CSF delivers signalling molecules directly to cells in the trigeminal ganglion, avoiding the slower established pathway through the meninges, the three-layered membranes that surround the brain and spinal cord.

"We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache," University of Copenhagen biologist Martin Kaag Rasmussen and colleagues explain in their published paper.

Using a sequence of real-time imaging experiments, the team followed CSF as it travelled from the brain’s visual cortex - the most frequent location of migraine aura - to the trigeminal ganglion in mice.

The fluid swiftly moved into the trigeminal ganglion’s root. Further dissections revealed that this area does not have the tightly enclosing sheath that prevents dissolved molecules from entering the trigeminal nerves farther along their thin extensions.

In addition, molecules dissolved in CSF from one cortical hemisphere mainly travelled to the trigeminal ganglion on the same side of the head. This may help account for the fact that migraines are commonly one-sided.

Rasmussen and his colleagues also discovered that the animals’ CSF changed after an aura. It contained CGRP (calcitonin gene-related peptide), along with other molecules released by the cortex after a wave of abnormal brain activity had passed through; these molecules activated nerves in the trigeminal ganglion.

Implications for migraine treatment

"Our observations indicate that the trigeminal CSF uptake drives the immediate migraine headache," Rasmussen and colleagues write. However, "we also found that CSF composition quickly normalizes, suggesting that other processes might drive headache at later phases."

There are, of course, clear differences between mice and humans, as well as between their brains and their migraines. Even so, the researchers hope that identifying this signalling route "may enable the discovery of new [drug] targets, to the benefit of the large portion of patients not responding well to currently available therapies."

Their results already indicate that CSF is not merely a fluid responsible for flushing the body’s ‘waste clearance system’, but an important carrier of signals. Yet much remains to be learned about how fluids move through the brain.

"Together, these findings provide a new mechanism that links the central and peripheral nervous systems," neuroscientists Andrew Russo, of the University of Iowa, and Jeffrey Iliff, at the University of Washington, write in a perspective accompanying the study.

"Similarly, this mechanism may explain the intermingled clinical associations between traumatic brain injury, sleep disruption, and posttraumatic headache."

The study was published in Science.