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Migraines affect over a billion people globally, causing debilitating symptoms such as throbbing head pain, nausea, and fatigue lasting for days. Despite their prevalence, understanding how these severe headaches originate has been a longstanding challenge for scientists.

A study conducted on mice offers new insights into the neurological processes underlying migraines. Researchers propose that during cortical spreading depression (CSD), a momentary shutdown of neuronal activity, changes occur in the cerebrospinal fluid surrounding the brain and spinal cord. This altered fluid, they suggest, may flow through previously unknown anatomical pathways to activate pain and inflammatory receptors in the skull, thereby triggering migraines.

"This work is a shift in how we think the headaches originate. A headache might just be a general warning sign for lots of things happening inside the brain that aren't normal," said Gregory Dussor, a neuroscientist at the University of Texas at Dallas.

Study co-author Maiken Nedergaard from the University of Copenhagen added, "Migraine is actually protective in that way. The pain is protective because it's telling the person to rest and recover and sleep."

Unlike other types of pain, migraines originate from areas outside the brain, where pain receptors are absent. This disconnect between brain activity and peripheral nervous system response complicates treatment efforts.

Published on July 4 in Science, the study focused on a mouse model of aural migraine, often preceded by an aura phase with symptoms such as sensitivity to light and numbness. During this phase, CSD triggers changes in the cerebrospinal fluid that researchers believe activate nerves in the meninges, layers protecting the brain and spinal cord.

Nedergaard's team investigated whether similar leaks in cerebrospinal fluid activate the trigeminal nerve, which extends through the face and skull, concentrating at the trigeminal ganglia. These nerve clusters play a crucial role in transmitting sensory information and contain receptors for pain and inflammatory proteins.

Analyzing cerebrospinal fluid from mice experiencing CSDs, researchers observed significant fluctuations in protein concentrations, including an increase in CGRP, a protein targeted by migraine medications. They also identified a novel gap in protective layers around the trigeminal ganglion, allowing fluid to affect nerve cells, potentially triggering migraines, Nature reported.

Philip Holland, a neuroscientist at King's College London, commented, "It really shows this nice potential interaction between how something changing in the brain could impact the periphery. There can be a crosstalk between these two components of the nervous system, and we should be more aware of it."

Future studies, Dussor suggested, should delve into why proteins in cerebrospinal fluid affect the trigeminal ganglion specifically for migraines and not other types of pain, paving the way for expanded understanding and innovative therapies.