New pathway in brain may help end migraines: ScienceAlert

A newly discovered communication pathway that connects widely separated nerve centers in the brain and skull with the body outside could provide a new target for nipping migraine pain in the bud.

Researchers have long tried to figure out where migraines start in the brain and how these one-sided, nauseating headaches cause pain and other symptoms, such as vomiting. Understanding this could help us find new ways to prevent migraines, or at least ease the searing pain once they start.

In a third of people who suffer from migraines, the attack is preceded by an aura, a shimmering light or blurred vision that is itself preceded by a wave of abnormal brain activity that spreads through the cortex, the outer layer of the brain.

But how this activity in the brain affects receptors on pain-sensitive neurons outside it is not yet fully understood.

The brain is surrounded by a protective layer, the blood-brain barrier, which keeps potentially harmful substances and pathogens out of the central nervous system (CNS). The spinal cord also has its own cocoon, which prevents large molecules from passing through.

A major nerve hub that connects the CNS to all the nerves outside it—the peripheral nervous system—is the trigeminal ganglion. This bean-shaped nerve cluster, already involved in migraines and headaches, is located at the base of the skull and transmits sensory information from the face and jaws to the brain.

Researchers thought the trigeminal ganglion lay outside the blood-brain barrier, which is helpful to know because it could be an easier target for drugs such as CGRP inhibitors, a promising new type of migraine therapy.

However, this positioning meant that the trigeminal ganglion was not in contact with the cerebrospinal fluid surrounding the brain and spinal cord.

A new study in mice shows just the opposite: CSF transports signaling molecules directly to cells in the trigeminal ganglion, bypassing the slower, more familiar route through the meninges, a three-layered membrane that surrounds the brain and spinal cord.

“We have identified a communication pathway between the central and peripheral nervous systems that could explain the relationship between migraine aura and headache,” biologist Martin Kaag Rasmussen of the University of Copenhagen and colleagues explain in their published paper.

In a series of real-time imaging experiments, the researchers tracked brain currents from the brain’s visual cortex, the most common site of migraine aura, to the trigeminal ganglion in mice.

The fluid quickly penetrated into the root of the trigeminal ganglion. Further dissection revealed that the ganglion lacked a tight sheath to prevent dissolved molecules from penetrating further into the thin bodies of the trigeminal nerve.

Furthermore, the molecules dissolved in the cerebrospinal fluid flowed from one hemisphere mainly to the trigeminal ganglion on the same side of the head. This could explain why migraines often occur on one side.

Rasmussen and colleagues also found that the contents of the animals’ cerebrospinal fluid changed after an aura. It contained CGRP (calcitonin gene-related peptide) and other molecules that were released from the cortex after a wave of abnormal brain activity had passed through it. These molecules activated the trigeminal nerves.

“Our observations indicate that trigeminal CSF uptake drives the immediate migraine headache,” Rasmussen and colleagues write. “However, we also found that CSF composition rapidly normalizes, suggesting that other processes may drive headaches in later phases.”

There are also clear differences between mice, humans, their brains, and migraines. Still, the researchers hope that identifying this new signaling pathway will “enable the discovery of new [drug] goals, for the benefit of the large proportion of patients who do not respond well to currently available therapies.”

Their findings already suggest that CSF is much more than a simple fluid that flushes the body’s ‘waste disposal system’, and is instead an important signal carrier. However, there is still much to discover about fluid flow in the brain.

“Together, these findings provide a novel mechanism that links the central and peripheral nervous systems,” neuroscientists Andrew Russo of the University of Iowa and Jeffrey Iliff of the University of Washington wrote in an accompanying commentary to the study.

“Similarly, this mechanism may explain the divergent clinical associations between traumatic brain injury, sleep disturbance, and post-traumatic headache.”

The research was published in Science.

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