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Deciphering migraine
Takahiro Takano and Maiken Nedergaard
Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, New York, USA.
Address correspondence to: Maiken Nedergaard, University of Rochester, 601 Elmwood Avenue, Box 605, MRB 1-9915B, Rochester, New York 14642, USA. Phone: (585) 273-2868; Fax: (585) 275-0550; E-mail: nedergaard@urmc.rochester.edu.
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Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, Department of Neurosurgery, University of Rochester, Rochester, New York, USA.
Address correspondence to: Maiken Nedergaard, University of Rochester, 601 Elmwood Avenue, Box 605, MRB 1-9915B, Rochester, New York 14642, USA. Phone: (585) 273-2868; Fax: (585) 275-0550; E-mail: nedergaard@urmc.rochester.edu.
Find articles by Nedergaard, M. in: JCI | PubMed | Google Scholar
Published December 22, 2008 - More info
J Clin Invest. 2009;119(1):16–19. https://doi.org/10.1172/JCI38051.
© 2008 The American Society for Clinical Investigation
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Abstract
Familial hemiplegic migraine type 1 (FHM1) is an autosomal dominant subtype of migraine with aura that is associated with hemiparesis. As with other types of migraine, it affects women more frequently than men. FHM1 is caused by mutations in the CACNA1A gene, which encodes the α1A subunit of Cav2.1 channels; the R192Q mutation in CACNA1A causes a mild form of FHM1, whereas the S218L mutation causes a severe, often lethal phenotype. Spreading depression (SD), a slowly propagating neuronal and glial cell depolarization that leads to depression of neuronal activity, is the most likely cause of migraine aura. Here, we have shown that transgenic mice expressing R192Q or S218L FHM1 mutations have increased SD frequency and propagation speed; enhanced corticostriatal propagation; and, similar to the human FHM1 phenotype, more severe and prolonged post-SD neurological deficits. The susceptibility to SD and neurological deficits is affected by allele dosage and is higher in S218L than R192Q mutants. Further, female S218L and R192Q mutant mice were more susceptible to SD and neurological deficits than males. This sex difference was abrogated by ovariectomy and senescence and was partially restored by estrogen replacement, implicating ovarian hormones in the observed sex differences in humans with FHM1. These findings demonstrate that genetic and hormonal factors modulate susceptibility to SD and neurological deficits in FHM1 mutant mice, providing a potential mechanism for the phenotypic diversity of human migraine and aura.
Authors
Katharina Eikermann-Haerter, Ergin Dileköz, Chiho Kudo, Sean I. Savitz, Christian Waeber, Michael J. Baum, Michel D. Ferrari, Arn M.J.M. van den Maagdenberg, Michael A. Moskowitz, Cenk Ayata
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Cortical spreading depression as a trigger of migraine pain
Written accounts of migraine are nearly as old as writing itself. Descriptions of headaches, dating to roughly 3000 BCE, have been found in the ruins of the ancient Sumerian civilization. When people lacked the understanding of the human body that modern medicine grants us, migraine pain was ascribed to the will of evil spirits or malevolent gods — doctors of the time recommended cranial trepanation as a way to release “unholy forces.” In the early seventeenth century, European clinicians first proposed the vascular hypothesis, which long dominated our views of migraine. Patients’ descriptions of the pulsating character of migraine pain led to the concept that the vasculature might play a central role in the severe headache typical of migraine (1).
It was the Canadian psychologist Peter Milner who, in 1958, first noted the striking similarities between the progression of migraine aura and cortical spreading depression (CSD). CSD is a self-propagating wave of tissue depolarization that migrates without a loss in depolarization amplitude and is followed by a prolonged period of suppressed neural activity (2). Milner saw the connection between this and the migraine aura, because it was known that the scintillating scotomata (often manifesting as flashes of light in a geometric pattern that slowly move across the visual field) that precede and accompany migraine pain propagate at a rate of about 3 mm/min through the visual cortex (3). It is now generally accepted that CSD constitutes the biological basis of most, if not all, types of migraine. Approximately 30% of migraine patients experience this aura (4). The idea that CSD is the endogenous trigger of migraine was initially met with considerable skepticism; one article of the time called this theory “ingenious, if absurd” (quoted in ref. 5). One obvious issue noted was that the brain itself is not capable of sensing pain. Thus, how might a transient wave of cortical depolarization give rise to the prolonged state of pain that clearly involves the vasculature? Insight came from Moskowitz and coworkers, who showed that CSD induces long-lasting changes in extracranial blood flow, including dilatation of the middle meningeal artery and extravasation of plasma protein (6). In short, CSD disrupted the blood-brain barrier, resulting in MMP9-dependent pathway–mediated extravasation of blood-borne factors, which in turn activated the nociceptive nerve afferent fibers around meningeal vessels (6) (Figure 1). Additional pathways, including those involving gap junctions, cytokines, and NO release, may contribute to the activation of trigeminal ganglion nerve afferents and to the prolonged pain associated with migraine headaches (7, 8). Migraine without aura may result from advancement of CSD waves in regions (such as cerebellum) where the tissue depolarization is not perceived by the patient.
Figure 1The link between CSD and migraine pain. CSD is most often initiated in the occipital cortex of patients with visual migraine aura. It is believed that CSD is ignited by local elevation of extracellular K+ levels in pockets of intense excitatory transmission. When K+ levels reach a critical threshold of 10–12 mM, a self-propagating CSD wave is initiated and advances across the cortex with a slow velocity of 3 mm/min. The threshold for CSD initiation is reduced in FHM patients with mutations in the Cav2.1 Ca2+ channel because the higher Ca2+ level in dendrites facilitates glutamate release and thereby increases the likelihood that K+ levels will reach the CSD threshold. A combination of stress and food intake may be sufficient to ignite CSD in patients with FHM, whereas stronger stimulation is required in the rest of the population. The lower diagram depicts the cortical events linking CSD to migraine pain. The high extracellular K+ level at the edge of the CSD wavefront is key for wave propagation. K+ is normalized within minutes, but the restoration of normal membrane potential of neurons and glial cells is a high energy–demanding process. The cortical tissue experiences a minutes-lasting period of severe reduction of tissue O2 tension (hypoxia) during CSD because O2 consumption transiently exceeds the vascular supply of O2. This hypoxia has several consequences: (a) Neurons exhibit severe morphological distortions, swelling, and transient loss of dendritic spines. Normal dendritic structures are reestablished 15–20 minutes later, coinciding with the reappearance of a normal EEG pattern. This hypoxic phase is followed by prolonged vasoconstriction and reduction of local blood flow. (b) The CSD wave activates MMP9, resulting in opening of the blood-brain barrier (BBB) and extravasation of plasma protein. The leakage of blood-borne factors activates nociceptive afferent neurons from trigeminal ganglion innervating meningeal arteries, connecting to trigeminal nucleus caudalis, triggering the migraine pain. (c) CSD triggers preconditioning — an endogenous mechanism of neuroprotection that raises ischemic tolerance.
The initial skepticism surrounding CSD as an endogenous trigger of migraine pain has vanished in recent years, because functional MRI imaging of changes in blood oxygen level–dependent (BOLD) signal have shown that the visual aura of migraine is temporally linked to a slowly advancing wave of BOLD signal, which propagates across the visual cortex. The pattern of changes of BOLD signals a patient experienced during visual aura proved identical to those that were observed in experimentally elicited CSD (9). Additional evidence was obtained by magnetoencephalography, which documented that visual scotomata were accompanied by slow changes in the cortical magnetic field, and these were indistinguishable from those recorded during CSD (10). An important question thereby arose: What is the nature of the trigger for spontaneous waves of CSD, antecedent to or accompanying a migraine episode? Experimentally, strong focal stimulation is needed to evoke CSD. Various approaches have been used, including inserting a needle into the exposed cortex, electrical stimulation, or topical application of high K+ concentrations or glutamate agonists (e.g., NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]) (11). It is also known that multiple waves of CSD often are spontaneously elicited in the setting of acute neurological injury, including stroke or head trauma (12). Interestingly, the CSD waves last longer in the ischemic brain, and the frequency with which they are generated correlates with the degree of ischemic damage (13). However, stroke or head trauma is not responsible for the CSD waves in patients with migraine, making it difficult to explain how and why CSD is initiated in the absence of focal stimulation.
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