Research headed by teams at the University of Rochester Center for Translational Medicine and the University of Copenhagen describes for the first time how a spreading wave of disruption and the flow of fluid in the brain triggers headaches, detailing the connection between the neurological symptoms associated with aura and the migraine that follows. Findings from the mouse studies identify a novel non-synaptic signaling mechanism between the brain and peripheral sensory system important for migraine. The results also identify proteins that could be responsible for headaches and may serve as targets for new migraine drugs.

“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. “These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies.” Nedergaard is lead author of the team’s published paper in Science, titled, “Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model.’

It is estimated that one out of 10 people experience migraines, and in many of these cases the headache is preceded by an aura, a sensory disturbance that can include light flashes, blind spots, double vision, and tingling sensations or limb numbness. These symptoms typically appear five to 60 minutes prior to the headache.

The cause of aura, cortical spreading depression (CSD), is associated with a temporary depolarization of neurons and other cells caused by diffusion of glutamate and potassium that radiates like a wave across the brain, reducing oxygen levels and impairing blood flow. “… for a third of migraine patients, headache is preceded by aura, which is transient neurological deficits associated with CSD, a pathological depolarization of cortical tissue,” the authors wrote.  Most frequently, the depolarization event is located in the visual processing center of the brain cortex, hence the visual symptoms that first herald a coming headache.

While migraines auras arise in the brain, the organ itself cannot sense pain. During the aura phase, it is believed that waves of CSD are spontaneously triggered in the cerebral cortex or cerebellum, which, in turn, leads to the activation of pain receptors (nociceptors) in the peripheral nervous system (PNS). Previous research has suggested that CSD events release small molecules through the CSF that activate sensory nerve endings in the external tissues of the CNS (central nervous system), “outside” of the blood-brain barrier. These nerve endings are not exposed to cerebrospinal fluid (CSF).

However, the process of communication between the brain and peripheral sensory nerves in migraines has largely remained a mystery. As the team continued, “It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons.”

Nedergaard and her colleagues at the University of Rochester and the University of Copenhagen are pioneers in understanding the flow of fluids in the brain. In 2012, the Nedergaard lab was the first to describe the glymphatic system, which uses CSF to wash away toxic proteins in the brain. In partnership with experts in fluid dynamics, the team has built detailed models of how the CSF moves in the brain and its role in transporting 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 an aura. “Current evidence suggests that migraine headache is driven by activation of sensory nerve endings in the dura mata,” the investigators noted. The new study, which was conducted in mice, describes a different route and identifies proteins, many of which are potential new drug targets, that may be responsible for activating the nerves and causing pain.

As the depolarization wave spreads, neurons release a host of inflammatory and other proteins into CSF. In their 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. To do this, the team explained, “We developed a preparation for trigeminal ganglion imaging in vivo.”

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, using a combination of proteomic, histological, imaging, and functional approaches in a mouse model of classical migraine, the authors have identified a signaling pathway between the CNS and PNS at the trigeminal ganglion. The researchers’ studies in mice identified a previously unknown gap in the barrier that allowed CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to proteins released by the brain. The results found that “… CSF transports solutes directly into the trigeminal ganglion and activates receptors on trigeminal cells … CSF transport comprises a humoral signaling pathway between the brain and the trigeminal ganglion,” they further stated. “… as such, this flow route effectively permits fluid-borne communication between the CNS and PNS.”

After inducing CSD in experimental animals the team analyzed molecules in the CSF reaching the trigeminal ganglion, and their potential role in triggering headache. They first confirmed that CSD led to changes in gene expression and CSF protein content. “Bottom-up mass spectrometry on CSF obtained from adult mice with and without exposure to CSD detected proteins from 1,425 different genes. The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression. “After CSD, the expression of 155 of these proteins (11%) changed, and of these 155 proteins, 67 changed by more than twofold (21 up-regulated and 46 down-regulated) … We next sought to evaluate whether humoral agents within the CSD proteome could potentially drive headache by activating receptive cells.”

Their analyses identified within the up-regulated CSD proteome 12 protein ligands pairing with 28 distinct receptors in the ganglion. One of the proteins, calcitonin gene-related peptide (CGRP), is already the target of a new class of CGRP inhibitor drugs in development to treat migraine. “CGRP is encoded by the gene Calca, and the CSF transport of CGRP to the trigeminal ganglion could be directly involved in the development of migraine headache,” they wrote. “CGRP has also been found elevated in the CSF of migraine patients without aura, suggesting that in these patients as well, the trigeminal CSF pathway could drive headache.” 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. “Several of the ligands and receptors had previously been shown to be involved in processes such as hyperalgesia and inflammation,” the scientists further pointed out.

“We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system,” said first author Martin Kaag Rasmussen, PhD, a postdoctoral fellow at the University of Copenhagen. “Among the identified molecules are those already associated with migraines, but we didn’t know exactly how and where the migraine-inducing action occurred. 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. “This signaling route may therefore account for the unilaterality of migraine headache, as well as the typical delay between aura and headache onset.”

“Our data indicate that CSF transports solutes from the cortex to the trigeminal ganglion and, by so doing, establishes a nonsynaptic route of communication between the CNS and PNS that underlies the pathogenesis of classical migraine,” they concluded in their paper. “… defining the role of the ligand-receptor pairs identified in the CSD proteome may enable the discovery of new pharmacological targets, to the benefit of the large portion of patients not responding well to currently available therapies.”

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