"It’s not an imagined headache, and it’s not a mild condition," says Michael Moskowitz, Brain Prize recipient for his dogma-defying research
He found that no scientist had yet mapped the nerves carrying sensation from the circle of Willis, a network of arteries in the innermost layer of the meninges that supply blood to the brain. The brain itself doesn’t register pain, but the meninges, the brain’s three-layered covering, do. It seemed a promising place to start.
So using a novel polymer-based technology developed in partnership with MIT chemical engineer Robert Langer, Moskowitz showed that nerve fibers that wrap around the circle of Willis travel back to the brain via the trigeminal nerve, which also carries sensation from the forehead, where headaches are often felt. His lab then found that these nerves contain and release neuropeptides, setting up a cascade that causes meningeal inflammation and other harmful effects.
It was a stark departure from the previous belief about migraine, which was that the condition was purely caused by the dilation of blood vessels.
In later research, Moskowitz demonstrated that classical migraine drugs called ergots and triptans acted in a completely different and unexpected way than had been assumed: Rather than constricting blood vessels, the drugs blocked those harmful neuropeptides from being released from nerve fibers in the first place.
“That changed 100 years of dogma about how the ergots worked,” Moskowitz said. It also led to a new class of drugs that blocked neuropeptide release without vessel constriction In addition, it led to the development of drugs and antibodies that block the action of CGRP, a major neuropeptide in this pathway; those drugs are still in use today. Other neuropeptides discovered through his research are providing promising leads for future migraine therapies, said Moskowitz, who in 2021 received the Brain Prize for his contributions to migraine research.
Building on the breakthrough, his lab began to look for the trigger that caused the release of peptides in the first place. They identified cortical spreading depression, a slow-moving tsunami of electrical and chemical changes in the brain. As the wave progresses, it can trigger migraine’s varied symptoms. For example, the migraine’s classic visual aura occurs as the chemical and electrical changes move through the brain’s visual cortex.
