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For the first time, new research has clarified the connection between the neurological symptoms of aura and the migraine that follows, explaining how a disruption in brain fluid flow and the spreading wave of disruption lead to the headache. The new proteins discovered in the study could also be the basis for future migraine drugs because they may be responsible for what triggers the headache.
The findings of the study were published in the journal Science.
“In this study, we describe the interaction between the central and peripheral nervous systems that results from increased concentrations of a protein released in the brain during propagation of depolarization, a phenomenon that is responsible for the aura associated with migraine,” said Maiken Nedergaard, MD, DMSc, co-director of the Translational Neuromedicine Center at the University of Rochester and lead author of the new study.
“These findings provide us with several new targets to suppress sensory nerve activation and strengthen existing treatments for the prevention and treatment of migraine.”
It is estimated that one in 10 people experience migraines and about a quarter of these cases are preceded by aura, a sensory disturbance that can include light flashes, blind spots, double vision and tingling sensations or limb numbness. These symptoms usually appear 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 a proliferation of glutamate and potassium that spreads like a wave across 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 precede the oncoming headache.
While migraine auras originate in the brain, the organ itself cannot feel pain. Instead these signals must be transmitted from the central nervous system — the brain and spinal cord — to the peripheral nervous system, the communication network that transmits information between the brain and the rest of the body and includes the sensory nerves responsible for sending information such as touch and pain. The process of communication between the brain and peripheral sensory nerves in migraine remains largely a mystery.
Nedergaard and his colleagues at the University of Rochester and the University of Copenhagen are pioneers in understanding fluid flow in the brain. In 2012, his lab first described the glymphatic system, which uses cerebrospinal fluid (CSF) to wash away toxic proteins in the brain. In partnership with experts in fluid dynamics, the team has built detailed models of the movement of CSF in the brain and its role in transporting proteins, neurotransmitters and other chemicals.
The most widely accepted theory is that nerve endings located on the outer surface of the membranes that surround the brain are responsible for the headaches that follow the aura. The new study, conducted in mice, describes a different pathway and identifies proteins, several of which are potential new drug targets, that may be responsible for activating nerves and causing pain.
As the depolarization wave propagates, neurons release a number of inflammatory and other proteins into the CSF. In a series of experiments on mice, the researchers showed how the CSF transports these proteins to the trigeminal ganglion, a large bundle of nerves that resides at the base of the skull and provides sensory information to the head and face.
It was assumed that the trigeminal ganglion, like the rest of the peripheral nervous system, resided outside the blood-brain barrier, which regulates molecules that enter and exit the brain. However, the researchers identified a previously unknown gap in the barrier that allows CSF to flow directly into the trigeminal ganglion, exposing the sensory nerves to a cocktail of proteins released by the brain.
Analyzing the molecules, the researchers identified twelve proteins called ligands that bind to receptors on sensory nerves found in the trigeminal ganglion, potentially activating these cells. The concentrations of several of these proteins found in the CSF more than doubled after cortical spreading depression. One of the proteins, calcitonin gene-related peptide (CGRP), is already the target of a new class of drugs for treating and preventing migraines called CGRP inhibitors. The other identified proteins are known to play a role in other pain conditions, such as neuropathic pain, and are likely also important in migraine headaches.
“We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. The identified molecules include molecules that have already been associated with migraine, but we did not know exactly how and where the migraine-inducing action occurred,” said Martin Kaag Rasmussen, postdoctoral fellow at the University of Copenhagen and first author of the study. “Defining the role of these newly identified ligand-receptor pairs may make it possible to discover new pharmacological targets, which could benefit the large proportion of patients who do not respond to available treatments.”
The researchers also observed that proteins released from one side of the brain mostly transported nerves to the trigeminal ganglion on that same side, which possibly explains why most migraines cause pain on one side of the head.
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