Migraines, characterized by debilitating symptoms such as throbbing head pain, nausea, blurred vision, and fatigue, affect a billion people worldwide. Despite their prevalence, the underlying mechanisms that trigger these severe headaches have long puzzled scientists. However, a recent study in mice, published in Science on July 4, 2023, offers new insights into the neurological events that may spark migraines.
The Study and Its Findings
The study suggests that a brief ‘brain blackout,’ where neuronal activity shuts down, temporarily alters the content of cerebrospinal fluid (CSF), the clear liquid surrounding the brain and spinal cord. This altered CSF then travels through a previously unknown anatomical gap to nerves in the skull, activating pain and inflammatory receptors and causing headaches.
“This work is a shift in how we think the headaches originate,” says Gregory Dussor, a neuroscientist at the University of Texas at Dallas. “A headache might just be a general warning sign for lots of things happening inside the brain that aren’t normal.”
“Migraine is actually protective in that way. The pain is protective because it’s telling the person to rest and recover and sleep,” adds study co-author Maiken Nedergaard, a neuroscientist at the University of Copenhagen.
Understanding Headache Pain
The brain itself has no pain receptors; the sensation of headaches comes from areas outside the brain in the peripheral nervous system. The challenge has been understanding how the brain, which is not directly linked to the peripheral nervous system, triggers nerves to cause headaches. This gap in understanding has made migraines difficult to treat effectively.
The Role of Cortical Spreading Depression
The researchers focused on a particular type of headache called aural migraine. One-third of migraine sufferers experience an aura phase before their headache, characterized by symptoms such as nausea, vomiting, sensitivity to light, and numbness. During this phase, the brain experiences a cortical spreading depression (CSD), a temporary shutdown of neuronal activity.
Previous studies suggested that migraines occur when molecules in the cerebrospinal fluid drain from the brain and activate nerves in the meninges, the protective layers of the brain and spinal cord. Nedergaard’s team explored whether similar leaks in the cerebrospinal fluid could activate the trigeminal nerve, which runs through the face and skull.
Discoveries in the Trigeminal Nerve
The researchers bred mice that experienced CSDs and analyzed their cerebrospinal fluid’s movement and content. They found significant changes in protein concentrations during a CSD. Some proteins dropped to less than half their usual levels, while others, including the pain-transmitting protein CGRP (a target of migraine medications), more than doubled.
They also discovered a previously unknown gap in the protective layers around the trigeminal ganglion, allowing cerebrospinal fluid to flood into these nerve cells. Testing spinal fluids with different protein concentrations on control mice revealed that fluid collected shortly after a CSD increased trigeminal nerve activity, suggesting headaches could be triggered by pain signals from these activated cells. However, fluid collected 2.5 hours after CSDs did not have the same effect.
“Whatever is released in the cerebrospinal fluid is degraded. So, it’s a short-lasting phenomenon,” explains Nedergaard.Implications and Future Research
The study highlights a potential interaction between changes in the brain and the peripheral nervous system, emphasizing the need for further exploration of this crosstalk. “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,” says Philip Holland, a neuroscientist at King’s College London.
Dussor suggests that future studies should investigate why the proteins in spinal fluid that reach the trigeminal ganglion result in headaches and not other types of pain. “This is going to raise a whole lot of interesting questions in the field, and it’s going to be probably the source of a lot of new research projects.”
This research marks a significant step toward understanding migraines, offering new avenues for developing more effective treatments and improving the quality of life for millions of sufferers worldwide.
