Aura and the Mechanism of Migraine: The Next Treatment Target?

NeurologyLive, June 2019, Volume 2, Issue 3

The neurological symptoms of migraine aura are generally attributed to cortical spreading depression/depolarization, although that hypothesis does have its detractors. The question of whether CSD triggers migraine headache remains controversial.

The successful targeting of calcitonin gene-related peptide (CGRP) in agents that prevent or reduce migraine headaches1 demonstrates that treatments can emerge from uncovering mechanisms that underlie migraine. Migraine aura, which can precede or accompany attacks in approximately 1 in 3 migraineurs, has both prodromal and trigger elements that pose intriguing areas for research into migraine pathophysiology and potential interventions.

Symptoms of migraine aura can manifest as visual, sensory, and language disturbance and, in the rare hemiplegic migraine subtype, as disruption of motor function. Symptoms commonly persist for 5 to 60 minutes before the headache but can last longer and can coincide with or follow the headache attack. Visual phenomena, which are the most common symptoms of aura, typically occur in a hemifield as flashing light (spark photopsia), partial vision loss (scotoma), or fortification phenomena (teichopsia). Additional complex visual disturbances include metamorphopsia, micropsia, macropsia, zoom vision, and mosaic vision.

David Dodick, MD, of the department of neurology at Mayo Clinic in Phoenix, Arizona, noted a variety of other visual symptoms described by patients but not considered diagnostic of aura, including shimmering, undulations, and so-called heat waves.2

“A substantial proportion of our patients complain of very nondescript, vague visual blurring—their vision is just not right,” Dodick told NeurologyLive. “It may not be the classic sort of visual aura symptoms in the textbook, but nevertheless their vision is impaired. We don’t fully understand what these symptoms are, and they’re typically not described as having aura, so the question really is: Is aura much more common than we previously thought?"

“If you include all those patients who complain of some sort of visual distortion or visual impairment during migraine, then it’s much larger than the 20% or 30% figure that’s often used or quoted for the prevalence of migraine aura,” Dodick added.

Paresthesias are the next most common symptoms of aura and are likely to accompany visual symptoms. These usually involve the hand and the perioral region, as well as the arm, tongue, and lips. These can be bilateral but can also jump from one body part to another. Dodick suggested that patterns of paresthesias can be similar to patterns of visual symptoms, which “often transition from a positive sensation [scintillations] to a negative sensation [numbness].”2

Cortical Spreading Depression Under the Aura

The neurological symptoms of migraine aura are generally attributed to cortical spreading depression/depolarization (CSD), although that hypothesis does have its detractors,3 and the question of whether CSD triggers migraine headache also remains controversial.

The varied presentations of migraine aura have contributed to the difficulty in characterizing underlying neurologic processes and their links to migraine headache, according to Dodick.

“The variable timing of aura and headache symptoms has challenged not only clinical beliefs but also the biological bases and sequence of physiological events underlying a migraine attack,” he observed.2 “Classically, migraine has been described as a sequential phenomenon, where you might have sort of vague prodromal symptoms followed by an aura, followed by a headache, followed by a postdromal phase,” Dodick explained. “Migraine is really composed of multiple phases, but those phases aren’t neat and tidy and don’t always follow in a nice sequence.”

Dodick described CSD as a self-propagating wave of transient neuronal depolarization, a form of intense neuronal excitation associated with reversible breakdown of ion homeostasis and transient depression of neuronal activity.4 Neurons are depolarized by local elevations in extracellular potassium, and the disrupted cell membrane ionic gradients are marked by the influx of sodium and calcium and the release of glutamate.

These ionic shifts result in neuronal swelling, reciprocal decrease in extracellular space, and dendritic beading, which in turn lead to the release of amino acids and neurotransmitters that further the spread of depolarization. Glutamate is released as an excitatory neurotransmitter, with activation of N-methyl-D-aspartate (NMDA) receptors contributing to sustained depolarization accompanied by increased production of nitric oxide (NO) and arachidonic acid metabolites.5

Dodick suggested that initial accumulations of extracellular potassium occur as a result of repeated depolarization and repolarization of hyperexcitable neurons in the cortex, and the accumulation then further depolarizes the cells from which the potassium is released. He also pointed to evidence from animal studies that supports the proposition that CSD can activate trigeminal nociception and thereby trigger migraine headache.

“The propagation of CSD is still not fully understood, and several hypotheses exist,” Dodick indicated. “Originally the interstitial diffusion of either potassium or glutamate was thought to lead to the propagation of CSD, but later hypotheses suggest that the propagation is mediated via gap junctions between glial cells or neurons.”4

In addition to inhibition of cortical activity that follows the slowly propagating wave (2-6 mm/min) of CSD in neuronal and glial cell membranes, CSD is associated with a wave of hyperemia followed by a prolonged phase of cortical oligemia.6 The increase in blood flow lasts approximately 1 to 2 minutes longer than the initial CSD event, and the following prolonged period of oligemia can last for 1 to 2 hours.

Andrew Russo, PhD, of the department of molecular physiology and biophysics at the University of Iowa in Iowa City, and colleagues have considered how, or whether, these changes in cerebral blood flow associated with CSD could contribute to migraine aura and/or headache physiology.

“These changes in cerebral blood flow and oxygenation, as well as the increased metabolic needs associated with CSD, lead to a mismatch of supply and demand, and normal mechanisms of cerebrovascular homeostasis are overwhelmed,” Russo and colleagues observed.7

Although models of brain injury have linked these changes in blood flow to progression of ischemia and worsening secondary injury and patient outcomes, Russo and colleagues acknowledged that in migraine, “it is unclear how the changes in cerebral blood flow associated with CSD contribute to migraine aura and/ or headache physiology.”7

Lyudmila Vinogradova, PhD, of the Institute of Higher Nervous Activity and Neurophysiology at the Russian Academy of Sciences in Moscow, suggested that CSD could also occur in migraine without aura by localizing in “clinically silent” areas of the brain.8 “There is experimental evidence that CSD may cause headache by activation and sensitization of nociceptive trigemino-vascular pathways,” Vinogradova observed. “On the other hand, some data indicate that aura and pain may be triggered by parallel mechanisms."8

“Clinical data on the variable relationship between aura and headache occurrence during migraine attacks have challenged the causative link of the 2 phenomena,” Vinogradova added. “An alternative view considers aura/CSD and headache as independent parallel events, both resulting from global brain dysfunction during the prodromal phase of the migraine attack.”8

In an interview with NeurologyLive, Vinogradova explained, “Imaging studies have shown activation of brainstem and hypo-thalamic networks during the premonitory phase, long before the onset of aura and headache. The early brainstem/diencephalon activation likely mediates premonitory symptomatology, including abnormal sensory processing and vulnerability to various risk factors, and can lead to both activation of trigemino-vascular nociception and triggering [of ] aura/CSD."

“As our recent experiments have shown, unilateral CSD is reliably triggered during acoustically induced hyperactivity of brainstem sensory networks in genetically predisposed animals. The findings highlight the potential role of the brainstem as a driver of CSD susceptibility and involvement of ascending pathways from the brainstem to the cortex in the initiation of CSD/aura,” Vinogradova indicated. “Thus, the prodromal dysfunction of brainstem networks may be the primary cause of both headache and CSD/aura. Which scenario works during the migraine attack needs further investigation,” Vinogradova said.

Marking Mechanisms of CSD

As CGRP has proved to be a viable target for therapeutic interventions in migraine, investigators have increasingly considered its possible role in CSD and migraine aura. Experimental observations have shown that cortical CGRP release is increased during elevated concentrations of potassium, and CGRP antagonism appears to modulate CSD.

Russo and colleagues noted that although there is little evidence that unambiguously connects CGRP and CSD, there are several lines of evidence that are indeed compelling. Most prominent of these is that both CGRP and CSD are associated with changes in cerebral blood flow. The initial hyperemia in CSD, for example, has been shown to be mediated in part by release of CGRP from ipsilateral trigeminal nerve fibers.

“This (and other cited evidence) reinforces the role that these nerve fibers play in vascular changes and thus supports the role that CSD plays in activation of the trigeminal nociceptive system in migraine,” Russo and colleagues suggested.7

They described neurovascular coupling as an important intersection between vascular and neural roles, in which neuronal interactions with vasculature mediate regional cerebral blood flow and maintain adequate perfusion. Russo and colleagues cited in vitro evidence of a bidirectional relation in neurovascular coupling in which changes in vascular tone can modulate neuronal activity, and they provided examples of pathologic inverse coupling in traumatic brain injury with increased CSD and exacerbation of ischemic conditions.

Russo and colleagues recently proposed a model for bidirectional communication by CGRP at this neurovascular intersection, in which CSD results in elevated CGRP with subsequent alterations in signaling that could contribute to the pathophysiology of migraine.7

“Despite the success [with CGRP-blocking antibodies], where and how CGRP is causing migraine remain mostly unknown,” Russo told NeurologyLive. “There is general agreement that 1 site of action is likely to be the trigeminovascular system of nerves innervating the meningeal blood vessels surrounding the brain,” Russo said. “However, it is an open question whether CGRP-based drugs may also affect CSD, which underlies the aura experience of about a third of [patients with] migraine."

“We have speculated that there could be a connection between CGRP and CSD, [and] I think it’s possible that the vascular actions of CGRP could contribute to CSD,” Russo added. “To be clear, I do not think that CGRP can trigger CSD, but rather, it may be able to modulate the CSD event. Likewise, our preclinical studies indicate that multiple CSD events can increase CGRP levels in the brain.”

The case for a primary role of glutamate in CSD was presented by Andrew Charles, MD, of the department of neurology at the David Geffen School of Medicine at the University of California, Los Angeles, and colleague Jan Hoffman, MD, PhD, of King’s College London.9

They described the release of glutamate in CSD as a “regenerative process,” with the subsequent activation of presynaptic NMDA receptors eliciting further release of glutamate. Charles and Hoffman offered evidence that inhibitors of glutamate receptors, particularly NMDA receptor antagonists, inhibit the initiation and propagation of CSD and that methods to “unblock” NMDA receptors, such as lowering extracellular magnesium, evoke CSD.

This experimental evidence “indicate[s] that activation of NMDA receptors play[s] a key role in generating CSD,” Hoffman and Charles noted.9

A possible role of NO in CSD and related vascular effects, and how its endogenous production by NO synthase (NOS) might offer a target for a synthase inhibitor in migraine pathogenesis, was recently assessed by Simon Akerman, PhD, of the department of neural and pain sciences at the University of Maryland in Baltimore, and colleagues.10

Akerman and colleagues noted that the cortical hyperemia and oligemia in CSD are accompanied with NO changes and that these are significantly attenuated with NOS inhibition. The experiments linking CSD and NO cited by Akerman and colleagues include studies with animals primed with administration of nitroglycerin—an NO donor known for causing migraine-like headache—that demonstrate that CSD induction significantly enhances NO release and increases expression of neuronal NOS mRNA and protein in the cerebral cortex.

Although Akerman and colleagues have found evidence that increased NO release can occur with induction of CSD, a route to reducing CSD by countering NO has not yet been identified. They concluded that methods of inhibiting CSD to prevent migraine aura are more likely to emerge from directions other than targeting NO and its production.

“Several studies demonstrate that [although] NOS inhibition might reduce NO release mediated by CSD, it has little [effect] on the overall cerebrovascular changes, suggesting NO release does not directly regulate the regional cerebral vascular changes during CSD,” Akerman and colleagues indicated.10

Other neurophysiologic targets being evaluated for potential intervention into CSD include 2 ion channel—gating sites, the acid-sensing ion channels (ASICs) and the transient receptor potential ankyrin type 1 (TRPA1) channels.

The ASICs, expressed throughout the central and peripheral nervous system, are sensitive to changes in pH. Their response to acidosis, brought on by a range of pathological processes such as tissue ischemia and inflammation, is thought to be the basis for a role in mediating cell death in such conditions as stroke and traumatic brain injury.11

Gregory Dussor, PhD, of the School of Behavioral and Brain Sciences at The University of Texas at Dallas, and colleagues noted studies that suggest that a reduced pH from CSD, from hypoxia or ischemia from vessel changes, could lead to the propagation of the CSD across a cortical area. “Understanding brain metabolism during migraine attacks using functional imaging, and further imaging of aura in migraineurs, may provide us with additional understanding of how changes in pH and subsequently ASIC activity may contribute to CSD,” they indicated.11

TRPA1 is a nonselective transmembrane cation channel in the central and peripheral nervous system that serves as a sensor of oxidative, nitrative, and electrophilic stress. Minyan Wang, PhD, of the Centre for Neuroscience at Xi’an Jiaotong-Liverpool University in Suzhou, China, and colleagues found that a TRPA1 agonist, umbellulone, could facilitate propagation of CSD and that administration of selective TRPA1 antagonists (A967079 and HC-030031) could reduce CSD magnitude.12

“Interestingly, the inhibitor action of A967079 on CSD was reversed by exogenous calcitonin gene-related peptide,” Wang and colleagues reported.12 “We conclude that cortical TRPA1 is critical in regulating cortical susceptibility to CSD, which involves CGRP,” they indicated. “The data strongly suggest that deactivation of TRPA1 channels and blockade of CGRP would have therapeutic benefits in preventing migraine with aura.”12

Seeking Means to Intervene in Aura

Evidence that CGRP might modulate CSD events has led to intriguing in vivo and animal studies with CGRP inhibitors and receptor antagonists. In one study, the CGRP receptor antagonist olcegepant inhibited repetitive CSD events and altered vascular responses to CSD.13 In a study with the anti-CGRP monoclonal antibody fremanezumab, administration in rats was reported to prevent activation of central trigeminovascular neurons induced by CSD.14

“However, to be clear, there is no evidence to date that CGRP can actually trigger CSD events, only that blockage of CGRP can modulate CSD,” Russo and colleagues cautioned.7

Charles and Hoffman noted that antagonists of glutamate found to inhibit the initiation and propagation of CSD include topiramate, memantine, and ketamine. However, they cautioned that “thus far...there is no definitive pharmacological evidence that specifically targets glutamate or its receptors as an effective strategy for acute or preventive migraine therapy.”9

Although directly targeting nitric oxide has not yet been shown to be an effective means of interrupting CSD, investigators have conducted several trials with tonabersat (SB-220453), which acts as a gap junction modulator. Preclinical experiments indicate that it inhibited NO release and CSD following induction with potassium.10

Akerman and colleagues found the data from clinical trials with acute use of tonabersat are inconsistent but generally negative for aborting headaches. They suggested, however, that daily administration of tonabersat, which is slowly absorbed, could have preventive benefits.10

“As a preventive, tonabersat did show some efficacy in reducing headache days, but studies had a high placebo rate, complicating conclusions derived from the study,” they noted.10

Investigators have conducted experiments with the ASIC1 channel to interfere with migraine aura with amiloride, which, in addition to blocking sodium channels in its antidiuretic actions, is also a nonspecific ASIC blocker. It was found to inhibit CSD in a needle-prick rat CSD model and reduced cerebral vasodilation in the rat model from electrical stimulation over the cranium.11

Dussor and colleagues related that a small clinical trial in 7 patients with treatment-refractory migraine with aura found that the drug reduced aura and headache symptoms in 4 of the patients.11

Nostrums and Nutraceuticals

In addition to potential interventions for migraine aura that have emerged from neurophysiology studies, agents touted for this condition have also been drawn from folk medicine rather than experimentation and generally without controlled trial assessment. Given the many nostrums and nutraceuticals that have been tried over the years to treat migraine attacks in the absence of consistently effective treatments, such products could be expected to also apply for migraine aura. One product, aptly branded Aurastop, was recently evaluated in a case-report patient series—without blinding, a control group, or placebo control— supported by the Italian Society for the Study of Headaches.15

The product is a mixture of tanacetum parthenium— commonly known as feverfew, which has a long history of use in migraine preparations—with Griffonia simplicifolia and magnesium. The product was provided to 200 subjects with a diagnosis of migraine with aura who had experienced at least 3 episodes a year. Patients took an Aurastop tablet at the onset of aura and could be repeat administration if pain ensued. Patients continued to use previously ordered analgesics and/or triptans.

The investigators reported that the product was associated with a reduction in mean (± SD) duration of aura from 43.2 ± 19.3 minutes to 18.2 ± 10.3 minutes. In addition, disability associated with the aura—defined by the patient and rated on a scale of 0

to 5—was reduced from a median interquartile range score of 5 (4-5) to 2 (1-2).

The investigators offered the apparent success in reducing the duration of aura and related disability as “indirect evidence” that the product could be interfering with “the peripheral-central sensitization and with the TRPA1 and NMDA-dependent synaptic transmission as well.”15 They further suggested that the product “may influence the early phases of migraine aura and cortical spreading depolarization resulting in pain and the accompanying symptoms.”15

Regardless of whether this study strengthens evidence from previous anecdotal reports on Aurastop, which the investigators described as “sparse,” their discussion in the report coincides with the general consensus on the importance of CSD and its component mechanisms to manifestations of migraine aura.


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