Rochester [New York], For the first time, new research explains the relationship between the neurological symptoms of aura and the resulting migraine, clarifying how a disruption of brain fluid flow and a spreading wave of disruption cause headaches. The new proteins discovered in the study may also be the basis of future migraine drugs, as they may be the cause of headaches.
The study's findings appeared in the journal Science.
"In this study, we describe the interaction between the central and peripheral nervous system caused by increased concentrations of proteins released in the brain during an episode of generalized depolarization, a phenomenon responsible for the aura associated with migraines," said Maiken Nedergaard, M.D. , DMSc, co-director of the Center for Translational Neuromedicine at the University of Rochester and lead author of the new study. "These findings provide us with a number of new targets for suppressing sensory nerve activation to prevent and treat migraines and strengthen existing therapies." ".
An estimated one in 10 people experience migraines, and in about a quarter of these cases the headache is preceded by an aura, a sensory disturbance that can include flashes of light, blind spots, double vision, and sensations of tingling or numbness. of the extremities. 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 the diffusion of glutamate and potassium that radiates as a wave through the brain, reducing oxygen levels and altering blood flow. . Most often, the depolarization event is located in the visual processing center of the cerebral cortex, hence the visual symptoms that first announce an impending headache. While migraine auras arise in the brain, the organ itself can't feel the 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 sensory nerves responsible for sending information such as touch. and pain. The communication process between the brain and peripheral sensory nerves in migraines 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, her lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to remove toxic proteins from the brain. In collaboration with fluid dynamics experts, the team has built detailed models of how CSF moves in the brain and its role in the transport of proteins, neurotransmitters and other chemicals.
The most widely accepted theory is that nerve endings resting on the outer surface of the membranes that enclose the brain are responsible for the headaches that follow the aura. The new study, which was 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 depolarization wave propagates, Neurons release a large amount 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 supplies sensory information to the head and face.
The trigeminal ganglion, like the rest of the peripheral nervous system, was supposed to rest outside the blood-brain barrier, which strictly 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 the sensory nerves to the cocktail of proteins released by the brain.
By analyzing the molecules, the researchers identified twelve proteins called ligands that bind to receptors on sensory nerves found in the trigeminal ganglion, potentially causing these cells to activate. The concentrations of several of these proteins found in the CSF more than doubled after widespread cortical depression. 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 likely also important in migraines. "We have identified a new 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-inducing action occurred," said Martin Kaag Rasmussen, PhD, postdoctoral fellow at the University of Copenhagen and first author of the study. "Defining the role of these newly identified ligand-receptor pairs may allow the discovery of new drug targets, which could benefit a large portion of patients who do not respond to available therapies."
The researchers also observed that transport of proteins released on one side of the brain mainly reaches the trigeminal ganglion nerves on the same side, which could explain why pain occurs on one side of the head during most migraines.
The study's findings appeared in the journal Science.
"In this study, we describe the interaction between the central and peripheral nervous system caused by increased concentrations of proteins released in the brain during an episode of generalized depolarization, a phenomenon responsible for the aura associated with migraines," said Maiken Nedergaard, M.D. , DMSc, co-director of the Center for Translational Neuromedicine at the University of Rochester and lead author of the new study. "These findings provide us with a number of new targets for suppressing sensory nerve activation to prevent and treat migraines and strengthen existing therapies." ".
An estimated one in 10 people experience migraines, and in about a quarter of these cases the headache is preceded by an aura, a sensory disturbance that can include flashes of light, blind spots, double vision, and sensations of tingling or numbness. of the extremities. 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 the diffusion of glutamate and potassium that radiates as a wave through the brain, reducing oxygen levels and altering blood flow. . Most often, the depolarization event is located in the visual processing center of the cerebral cortex, hence the visual symptoms that first announce an impending headache. While migraine auras arise in the brain, the organ itself can't feel the 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 sensory nerves responsible for sending information such as touch. and pain. The communication process between the brain and peripheral sensory nerves in migraines 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, her lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to remove toxic proteins from the brain. In collaboration with fluid dynamics experts, the team has built detailed models of how CSF moves in the brain and its role in the transport of proteins, neurotransmitters and other chemicals.
The most widely accepted theory is that nerve endings resting on the outer surface of the membranes that enclose the brain are responsible for the headaches that follow the aura. The new study, which was 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 depolarization wave propagates, Neurons release a large amount 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 supplies sensory information to the head and face.
The trigeminal ganglion, like the rest of the peripheral nervous system, was supposed to rest outside the blood-brain barrier, which strictly 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 the sensory nerves to the cocktail of proteins released by the brain.
By analyzing the molecules, the researchers identified twelve proteins called ligands that bind to receptors on sensory nerves found in the trigeminal ganglion, potentially causing these cells to activate. The concentrations of several of these proteins found in the CSF more than doubled after widespread cortical depression. 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 likely also important in migraines. "We have identified a new 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-inducing action occurred," said Martin Kaag Rasmussen, PhD, postdoctoral fellow at the University of Copenhagen and first author of the study. "Defining the role of these newly identified ligand-receptor pairs may allow the discovery of new drug targets, which could benefit a large portion of patients who do not respond to available therapies."
The researchers also observed that transport of proteins released on one side of the brain mainly reaches the trigeminal ganglion nerves on the same side, which could explain why pain occurs on one side of the head during most migraines.
