A new mouse study has unveiled a previously unknown pathway between the brain and peripheral nerves, potentially explaining the connection between aura symptoms and migraine headaches. For years, researchers have puzzled over how migraines trigger auras—brief neurological symptoms that occur before or during migraines. This newly identified brain-to-nerve communication route might hold the key, according to the study.
Each year, over 1 billion people experience migraines, with around one-quarter of these including an aura. These sensory symptoms may involve seeing non-existent lights, hearing sounds, or feeling tingling or numbness. Scientists have linked these auras to “cortical spreading depression,” waves of abnormal activity that move across the brain and temporarily disable certain neurons. These waves are believed to activate pain-detecting nerves outside the brain by releasing chemicals into the cerebrospinal fluid (CSF), which surrounds and cushions the brain.
The exact mechanism by which these chemicals reach the nerves was unclear until now. The study, published in the journal *Science* on July 4, explored how CSF exits the brain by focusing on a neuron cluster called the trigeminal ganglion. This bundle transmits signals from facial and jaw nerves to the brain, connecting near the brainstem. Researchers found that this nerve bundle also provides a pathway for CSF and its molecules to leave the brain.
Using genetically engineered mice with neurons that glow in the presence of calcium, a key element for sending electrical signals, researchers tracked CSF flow by injecting tracers into the mice’s brains. They observed that CSF appeared in the trigeminal ganglion about four minutes after injection, followed by a significant increase in calcium activity, showing that CSF can carry molecules outside the brain through this route.
The study suggests that waves of abnormal brain activity push pain-triggering molecules from the brain to the trigeminal ganglion, where these molecules activate sensory nerves. This discovery links the aura phase to the migraine headache. The research also identified 12 proteins that activate pain-sensing nerves, only one of which—calcitonin gene-related peptide (CGRP)—is currently targeted by migraine therapies. This finding opens the door to new treatment options for patients who don’t respond well to existing therapies.
However, the study’s findings are based on mouse models. Human brains, with more folds, may differ in how efficiently abnormal waves travel and how quickly CSF flows out, which could impact pain-triggering processes. Future research will need to investigate these mechanisms in humans or more human-like models and explore the new pain-triggering proteins identified.
This groundbreaking research could lead to new diagnostic tests and treatments for migraines and other headache disorders, offering hope to millions of sufferers.
