Rochester (New York): For the first time, new research explains the relationship between the neurological symptoms of aura and the ensuing migraine, elucidating how a brain fluid flow disruption and a spreading wave of disruption cause headaches. New proteins uncovered in the study may also be the basis for future migraine medications since they may be the cause of headaches.
The findings of the study appeared in the journal Science.
New research has clarified how neurological aura symptoms are linked to subsequent migraines, revealing that disruptions in brain fluid flow and spreading waves of disruption contribute to headaches. The study identifies proteins that could potentially lead to new migraine treatments, as they seem to be central to causing headaches. These findings were published in the journal ‘Science’.
"In this study, we describe the interaction between the central and peripheral nervous system brought about 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 University of Rochester Center for Translational Neuromedicine and lead author of the new study.
"These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies."
About one in 10 people experience migraines, with approximately a quarter of these cases preceded by an aura—a sensory disturbance featuring light flashes, blind spots, double vision, and tingling or numbness in limbs. These symptoms typically manifest five to 60 minutes before the headache begins.
The aura is caused by cortical spreading depression, a phenomenon where neurons and other cells experience temporary depolarization due to the diffusion of glutamate and potassium. This depolarization spreads like a wave across the brain, leading to decreased oxygen levels and impaired blood flow. Most commonly, this event occurs in the visual processing center of the brain cortex, hence the visual symptoms that signal an impending headache.
While migraine auras arise in the brain, the organ itself cannot sense 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 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 process of communication between the brain and peripheral sensory nerves in migraines has largely remained a mystery.
The prevailing theory suggests that nerve endings situated on the outer surface of the brain's enclosing membranes trigger the headaches following an aura. However, a recent study conducted in mice proposes an alternative pathway. It identifies specific proteins, many of which could serve as promising targets for new medications, that potentially activate these nerves and induce pain.
As the depolarization wave spreads, neurons release a host of inflammatory and other proteins into 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.
It was assumed that the trigeminal ganglion, like the rest of the peripheral nervous system, rested outside the blood-brain-barrier, which tightly controls what molecules enter and leave the brain. However, the researchers identified a previously unknown gap in the barrier that allows CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to the cocktail of proteins released by the brain.
Analyzing the molecules, the researchers identified twelve proteins called ligands that bind with receptors on sensory nerves found in the trigeminal ganglion, potentially causing these cells to activate. The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading 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 important in migraine headaches as well.
"We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. Among the identified molecules 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, a postdoctoral fellow at the University of Copenhagen and first author of the study. "Defining the role of these newly identified ligand-receptor pairs may enable the discovery of new pharmacological targets, which could benefit the large portion of patients not responding to available therapies."
The researchers also observed that the transport of proteins released in one side of the brain reaches mostly the nerves in the trigeminal ganglion on the same side, potentially explaining why pain occurs on one side of the head during most migraines. (ANI)