For a billion people worldwide, the symptoms can be devastating: throbbing headaches, nausea, blurred vision and fatigue that can last for days. But how brain activity triggers this most severe of headaches – migraines – has long puzzled scientists.

A study 1on mice, published inScienceon July 4th, now provides clues to the neurological events that trigger migraines. It suggests that a brief brain loss - when neuronal activity stops - temporarily changes the contents of the cerebrospinal fluid, the clear fluid that surrounds the brain and spinal cord. This altered fluid is thought to be transported through a previously unknown gap in the anatomy to nerves in the skull, where it activates pain and inflammatory receptors and causes headaches.

“This work is a rethinking of how we view the origins of headaches,” says Gregory Dussor, a neurologist at the University of Texas at Dallas in Richardson. “A headache could simply be a general warning sign that there are a lot of things going on in the brain that are not normal.”

"Migraine is actually protective in this respect. The pain is protective because it tells the person to rest and recover and sleep," says co-author Maiken Nedergaard, a neurologist at the University of Copenhagen.

Painless brain

The brain itself has no pain receptors; The sensation of a headache comes from areas outside the brain, located in the peripheral nervous system. But how the brain, which is not directly connected to the peripheral nervous system, activates nerves to cause headaches is poorly understood, making them difficult to treat.

Scientists working with a mouse model of a specific type of headache called auricular migraine set out to research this. A third of migraine sufferers experience a phase before their headache, known as an aura, which has symptoms such as nausea, vomiting, sensitivity to light and numbness. It can last from five minutes to an hour. During the aura, the brain experiences a depression called cortical spread (CSD) when neuronal activity stops for a short period of time.

Studies of migraines suggested that headaches occur when molecules in the cerebrospinal fluid drain from the brain and activate nerves in the meninges, the layers that protect the brain and spinal cord.

Nedergaard's team wanted to explore whether there were similar leaks in the cerebrospinal fluid that activate the trigeminal nerve, which runs through the face and skull. The nerve branches connect in the trigeminal ganglion at the base of the skull. This is a hub for relaying sensory information between the face and jaw to the brain and contains receptors for pain and inflammatory proteins.

bundle of nerves

The authors bred mice that experienced CSDs and analyzed the movement and contents of their cerebrospinal fluid. During a CSD, they found that the concentrations of some proteins in the fluid fell to less than half their usual levels. Levels of other proteins doubled, including the pain-transmitting protein CGRP, which is a target of migraine drugs.

The researchers also discovered a previously unknown gap in the protective layers around the trigeminal ganglion that allows cerebrospinal fluid to flow into these nerve cells. They therefore tested whether spinal fluids with different protein concentrations affected the trigeminal nerves in control mice.

The fluid collected shortly after a CSD increased the activity of trigeminal nerve cells - suggesting that headaches could be triggered by pain signals from these activated cells. Fluid collected 2.5 hours after CSDs did not have the same effect.

"Whatever is released in the cerebrospinal fluid is broken down. So it's a short-term phenomenon," says Nedergaard.

"It really shows this beautiful potential interaction in how a change in the brain can affect the periphery. There may be an exchange between these two components of the nervous system, and we should be more aware of that," says Philip Holland, a neurologist at King's College London.

Dussor suggests that future studies should examine why the proteins in the spinal fluid that hit the trigeminal ganglion cause headaches and not another type of pain. “This will raise a lot of interesting questions in the industry and will probably be the starting point for many new research projects.”