Migraine Auras Explained: Breakthrough Discovery Reveals Link Between Brain Fluid Flow and Headaches

For the first time, scientists have uncovered the mysterious connection between the neurological symptoms of aura and the subsequent migraine headache. A groundbreaking study published in the journal Science has shed light on how a disruption in brain fluid flow and a spreading wave of disruption cause headaches. The research has also identified new proteins that could be the basis for future migraine medications.

According to Dr. Maiken Nedergaard, co-director of the University of Rochester Center for Translational Neuromedicine and lead author of the study, the findings provide a wealth of new targets to suppress sensory nerve activation and prevent and treat migraines. “These findings give us a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies,” she said.

Migraines affect one in 10 people, with about a quarter of these cases preceded by an aura, a sensory disturbance that can include light flashes, blind spots, double vision, and tingling sensations or limb numbness. These symptoms typically appear five to 60 minutes before the headache. The aura is caused by a phenomenon called cortical spreading depression, a temporary depolarization of neurons and other cells that radiates like a wave across the brain, reducing oxygen levels and impairing blood flow.

The brain itself cannot sense pain, so the signals must be transmitted from the central nervous system to the peripheral nervous system, which includes sensory nerves responsible for sending information such as touch and pain. The process of communication between the brain and peripheral sensory nerves in migraines has remained a mystery until now.

Dr. Nedergaard and her team, along with experts in fluid dynamics, have built detailed models of how cerebrospinal fluid (CSF) moves in the brain and its role in transporting proteins, neurotransmitters, and other chemicals. They discovered that as the depolarization wave spreads, neurons release a host of inflammatory and other proteins into CSF, which then transport these proteins to the trigeminal ganglion, a large bundle of nerves at the base of the skull.

The researchers found a previously unknown gap in the blood-brain barrier that allows CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to the cocktail of proteins released by the brain. They identified 12 proteins called ligands that bind with receptors on sensory nerves, 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 the proteins, calcitonin gene-related peptide (CGRP), is already the target of a new class of drugs to treat and prevent migraines called CGRP inhibitors. 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.

The study’s first author, Martin Kaag Rasmussen, a postdoctoral fellow at the University of Copenhagen, said, “We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. 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.”

The researchers also observed 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. This breakthrough discovery could lead to the development of new treatments for migraines and improve the lives of millions of people worldwide.

Historical Context:

Migraines have been a known condition for centuries, with ancient civilizations describing symptoms similar to those experienced today. However, the understanding of the underlying mechanisms and causes of migraines has evolved significantly over time. In the 19th century, the term “migraine” was coined by French physician Pierre Briquet, who described the condition as a “hemicrania” or “half-headache.” Since then, research has focused on identifying the triggers and symptoms of migraines, with various theories and treatments emerging. Despite this, the exact mechanisms behind migraines, particularly the connection between aura and headache, remained unclear until the recent breakthrough discovery.

Breakthrough Discovery:

• Scientists have uncovered the link between brain fluid flow and migraines, revealing that a disruption in brain fluid flow and a spreading wave of disruption cause headaches.
• The study found that a previously unknown gap in the blood-brain barrier allows cerebrospinal fluid (CSF) to flow directly into the trigeminal ganglion, exposing sensory nerves to a cocktail of proteins released by the brain.
• The researchers identified 12 proteins called ligands that bind with receptors on sensory nerves, potentially causing these cells to activate.
• The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression.
• The study’s findings provide new targets to suppress sensory nerve activation and prevent and treat migraines.

Summary in Bullet Points:

• Migraines affect one in 10 people, with about a quarter of cases preceded by an aura, a sensory disturbance that can include light flashes, blind spots, double vision, and tingling sensations or limb numbness. • The aura is caused by cortical spreading depression, a temporary depolarization of neurons and other cells that radiates like a wave across the brain, reducing oxygen levels and impairing blood flow. • The brain itself cannot sense pain, so signals must be transmitted from the central nervous system to the peripheral nervous system, which includes sensory nerves responsible for sending information such as touch and pain. • The study found that as the depolarization wave spreads, neurons release a host of inflammatory and other proteins into CSF, which then transport these proteins to the trigeminal ganglion. • The researchers identified 12 proteins called ligands that bind with receptors on sensory nerves, potentially causing these cells to activate. • The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression. • The study’s findings provide new targets to suppress sensory nerve activation and prevent and treat migraines. • The discovery could lead to the development of new treatments for migraines and improve the lives of millions of people worldwide.