Study reveals brain fluid dynamics that may explain migraine headaches and unlock new treatments

The new study explains for the first time how waves of chaos and fluid flow in the brain can cause headaches, and details the connection between aura-related neurological symptoms and subsequent migraines. The study also identifies a new protein that may be responsible for headaches, which could form the basis for new migraine medications.

“In this study, we describe an interaction between the central and peripheral nervous systems triggered by increased concentrations of proteins released in the brain during episodes of spreading depolarization, a phenomenon responsible for the aura associated with migraine,” the researchers said. Maiken Nedergaard, MD, DMScCo-Director, University of Rochester Center for Translational Neuroscience He is lead author of a new study published in the journal Science“These findings provide a number of new targets for inhibiting sensory neuron activation to prevent and treat migraine and to enhance existing therapies.”

It is estimated that one in 10 people experience a migraine, and in about a quarter of those cases, the headache is preceded by an aura – sensory disturbances such as flashing lights, blind spots, double vision, tingling sensations, numbness in the hands and feet, etc. These symptoms usually appear five to 60 minutes before the headache.

This aura is caused by a phenomenon called cortical spreading depression, where a wave of glutamate and potassium diffusion throughout the brain reduces oxygen levels and restricts blood flow, temporarily depolarizing neurons and other cells. This depolarization most often occurs in the visual processing centers of the brain's cortex, which is why visual symptoms are the first precursor to a headache.

Although migraine auras originate in the brain, the brain itself cannot sense pain. These signals are instead transmitted from the central nervous system (brain and spinal cord) to the peripheral nervous system. The peripheral nervous system is a communication network that transmits information between the brain and the rest of the body, and it also contains sensory nerves that carry information such as touch and pain. The communication process between the brain and peripheral sensory nerves in a migraine remains largely mysterious.

Fluid dynamics model reveals cause of migraine pain

Nedergaard and his colleagues from the University of Rochester and the University of Copenhagen are pioneers in uncovering how fluids flow in the brain. In 2012, his lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to flush toxic proteins from the brain. Working with experts in fluid mechanics, the team built a detailed model of how CSF moves through the brain and its role in transporting proteins, neurotransmitters, and other chemicals.

The most widely accepted theory is that nerve endings on the outer surface of the membrane that surrounds the brain are responsible for the headache that follows the aura. This new study in mice describes an alternative pathway and identifies proteins that may be responsible for activating nerves and causing pain, many of which could serve as new drug targets.

As the depolarization wave spreads, neurons release inflammatory and other proteins into the cerebrospinal fluid. In a series of experiments in mice, the researchers showed how the cerebrospinal fluid transports these proteins to the trigeminal ganglion, a large bundle of nerves at the base of the skull that supplies sensory information to the head and face.

The trigeminal ganglion, like other parts of the peripheral nervous system, was assumed to lie 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 allows cerebrospinal fluid to flow directly into the trigeminal ganglion, exposing the sensory nerve to a cocktail of proteins released by the brain.

Migraine-related protein doubles during EEG activity

“We have identified a new signaling pathway and several molecules that activate sensory neurons in the peripheral nervous system. Some of the identified molecules have already been associated with migraine, but it was unclear exactly how and where their migraine-inducing action occurs,” said Martin Kaag Rasmussen, PhD, a postdoctoral researcher at the University of Copenhagen and lead author of the study. “Defining the role of these newly identified ligand-receptor pairs may lead to the discovery of new pharmacological targets, which could benefit many patients for whom existing treatments are refractory.”

The researchers also observed that trafficking of proteins released on one side of the brain primarily reaches nerves in the trigeminal ganglion on that side, which may explain why most migraines cause pain on one side of the head.

Additional co-authors are Kjeld Mollgard, Peter Bork, Pia Weikop, Tina Esmail, Lylia Drici, Nicolai Albrechtsen, Matthias Mann, Yuki Mori and Jonathan Carlsen at the University of Copenhagen, Nguyen Huynh and Steve Goldman at URMC, and Nima Ghitani and Alexander Chesler at the National Institute of Neurological Disorders and Stroke (NINDS). This research was funded by the Novo Nordisk Foundation, NINDS, the U.S. Army Research Office, the Lundbeck Foundation and the Miriam and Sheldon G. Adelson Foundation for Medical Research.