Groundbreaking research sheds light on migraine mechanisms and potential treatments

New research describes for the first time how an expanding disturbance wave and the flow of fluid in the brain cause headaches, detailing the link between the neurological symptoms associated with the aura and the migraine that follows. The study also identifies new proteins that could be responsible for the headaches and may serve as a basis for new anti-migraine drugs.

“In this study, we describe the interaction between the central and peripheral nervous systems caused by increased concentrations of proteins released in the brain during an episode of spreading depolarization, a phenomenon responsible for the aura associated with migraines” , said Maiken Nedergaard, MD. , DMSc, co-director of the Center for Translational Neuromedicine at the University of Rochester and lead author of the new study, which is published in the journal Science. “These findings provide us with a number of new targets for suppressing sensory nerve activation for the prevention and treatment of migraine and enhancing existing therapies.”

It is estimated that one in 10 people experience migraines, and about a quarter of these headaches are preceded by an aura, a sensory disturbance that can include flashes of light, blind spots, double vision, and tingling or numbness in the extremities. These symptoms usually occur five to 60 minutes before the headache.

The cause of the aura is a phenomenon called cortical spreading depression, a temporary depolarization of neurons and other cells caused by glutamate and potassium spillover that radiates like a wave through the brain, reducing oxygen levels and impairing blood flow. Most often, the depolarization event is located in the visual processing center of the cerebral cortex, hence the visual symptoms that first herald an impending headache.

While migraine auras occur in the brain, the organ itself cannot sense the pain. These signals must instead be transmitted from the central nervous system—the brain and spinal cord—to the peripheral nervous system, the communication network that relays information between the brain and the rest of the body and includes sensory nerves responsible for sending information such as touch and pain. The communication process between the brain and peripheral sensory nerves in migraines has remained largely a mystery.

Fluid dynamics models shed light on the origin of migraine pain

Nedergaard and her colleagues at the University of Rochester and the University of Copenhagen are pioneering the understanding of fluid flow in the brain. In 2012, her lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to remove toxic proteins in the brain. Working with experts in fluid dynamics, the team has created detailed models of how CSF moves in the brain and its role in transporting proteins, neurotransmitters and other chemicals.

The most widely accepted theory is that the nerve endings resting on the outer surface of the membranes that enclose the brain are responsible for the headaches that follow an aura. The new study, conducted in mice, describes a different pathway and identifies proteins, many of which are potential new drug targets, that may be responsible for activating nerves and causing pain.

As the depolarizing wave propagates, neurons release a host of inflammatory and other proteins into the CSF. In a series of experiments in mice, the researchers showed how CSF transports these proteins to the trigeminal ganglion, a large bundle of nerves that rests at the base of the skull and provides sensory information to the head and face.

It was thought that the trigeminal ganglion, like the rest of the peripheral nervous system, was located outside the blood-brain barrier, which tightly controls which molecules enter and leave the brain. However, the researchers identified a previously unknown gap in the barrier that allowed CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to the cocktail of proteins released by the brain.

Migraine-related proteins double during brain wave activity

By analyzing the molecules, the researchers identified twelve proteins called ligands that bind to receptors on sensory nerves located in the trigeminal ganglion, possibly causing these cells to activate. The concentrations of several of these proteins found in the CSF were more than doubled after inhibition of cortical proliferation. 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 probably important in migraine headaches as well.

We have identified a novel signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. Among the molecules identified are those already associated with migraines, but we didn’t know exactly how and where the migraine-causing action occurred. Determining the role of these newly identified ligand-receptor pairs may allow the discovery of new pharmacological targets, which could benefit the large proportion of patients who do not respond to available therapies.”

Martin Kaag Rasmussen, PhD, postdoctoral fellow, University of Copenhagen and first author of the study

The researchers also noticed that the transport of proteins released on one side of the brain mainly reaches the nerves in the trigeminal ganglion on the same side, possibly explaining why the pain occurs on one side of the head in most migraines.

Additional co-authors Kjeld Mollgard, Peter Bork, Pia Weikop, Tina Esmail, Lylia Drici, Nicolai Albrechtsen, Matthias Mann, Yuki Mori, and Jonathan Carlsen with the University of Copenhagen, Nguyen Huynh and Steve Goldman with URMC, and Nima Ghitani Chesler with the National Institute of Neurological Disorders and Stroke (NINDS). The research was supported by funding from the Novo Nordisk Foundation, NINDS, the US Army Research Office, the Lundbeck Foundation, and the Drs. Miriam and Sheldon G. Adelson.