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Scientists finally discover what causes migraines

New research has unveiled how a spreading wave of disruption and fluid flow in the brain triggers headaches, linking the neurological symptoms of aura to the subsequent migraine. The study has also identified new proteins that could serve as foundations for new migraine drugs.

“In this study, we describe the interaction between the central and peripheral nervous system brought about by increased concentrations of proteins released in the brain during an episode of spreading depolarization, a phenomenon responsible for the aura associated with migraines,” said senior author Maiken Nedergaard, the co-director of the University of Rochester Center for Translational Neuromedicine

“These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies.”

Many migraines are preceded by an aura

Approximately one out of ten people experience migraines, and in one-fourth of these cases, the headache is preceded by an aura. This sensory disturbance can include light flashes, blind spots, double vision, and tingling sensations or limb numbness, usually appearing five to 60 minutes before the headache.

The cause of the aura is a phenomenon called cortical spreading depression. This temporary depolarization of neurons and other cells is caused by the diffusion of glutamate and potassium, radiating like a wave across the brain, reducing oxygen levels and impairing blood flow. 

Most frequently, the depolarization event is located in the brain’s visual processing center, hence the visual symptoms that often precede a migraine.

Brain communication during migraines

Although auras arise in the brain, the brain itself cannot sense pain. Instead, pain signals are transmitted from the central nervous system (consisting of the brain and spinal cord) to the peripheral nervous system, which includes sensory nerves responsible for sending information such as touch and pain. 

Until recently, the process of communication between the brain and these peripheral nerves in migraines has largely remained a mystery.

Fluids circulating the brain

Nedergaard and her colleagues at the University of Rochester and the University of Copenhagen are well-known pioneers in understanding how fluids circulate in the brain. 

In 2012, Nedergard’s lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to eliminate toxic proteins in the brain. 

Together with experts in fluid dynamics, the team has built detailed models of how CSF moves in the brain, along with its role in transporting proteins, neurotransmitters, and other types of chemicals.

An unexpected source of migraines 

Previously, scientists argued that nerve endings on the outer surface of the membranes enclosing the brain are responsible for the headaches following an aura. 

However, the new study, conducted in mice, describes a different route and identifies proteins – many of which are currently potential new drug targets – which may be responsible for activating the nerves and causing pain.

As the depolarization wave spreads, neurons release a variety of inflammatory proteins (as well as other types of proteins) into the CSF. 

The investigation revealed how CSF transports these proteins to the trigeminal ganglion, a massive bundle of nerves located at the base of the skull that supplies sensory information to the head and face.

Scientists have previously assumed that the trigeminal ganglion, like the rest of the peripheral nervous system, resided outside the blood-brain barrier, which tightly controls what molecules enter and leave the brain. 

However, Nedergaard and her team identified a previously unknown gap in the barrier, allowing CSF to flow directly into the trigeminal ganglion and expose sensory nerves to the proteins released by the brain.

Identifying the proteins involved 

The experts identified twelve proteins called ligands that bind with receptors on sensory nerves found in the trigeminal ganglion, potentially causing these cells to activate. The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression. 

One of these proteins, the calcitonin gene-related peptide (CGRP), is already the target of a new class of drugs called CGRP inhibitors, which aim to treat and prevent migraines. 

Other identified proteins are known to play a role in other pain conditions, such as neuropathic pain, and are likely important in migraine headaches as well.

Targets for new migraine drugs 

“We’ve identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. Among the identified molecules are those already associated with migraines, but we didn’t know exactly how and where the migraine-inducing action occurred,” said lead author Martin Kaag Rasmussen, a postdoctoral fellow at the University of Copenhagen. 

“Defining the role of these newly identified ligand-receptor pairs may enable the discovery of new pharmacological targets, which could benefit the large portion of patients not responding to available therapies.”

Finally, the researchers found that the transport of proteins released in one side of the brain reaches mostly the nerves in the trigeminal ganglion on the same side, potentially explaining why pain occurs on one side of the head during most migraines.

The study is published in the journal Science.


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