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.

The study by Eikermann-Haerter and coworkers in this issue of the JCI sheds light on several key aspects of the basic biology of migraine headaches (17). The authors describe what is believed to be a novel phenotype in transgenic mice expressing the R192Q or S218L mutations in Cacna1a, both of which are associated with human FHM. Patients with the R192Q mutation suffer from FHM only, whereas the S218L mutation is associated with not only severe migraine but also risk of developing excessive edema in the setting of minor head injury (18). Eikermann-Haerter et al. show that both mutations decreased the threshold for eliciting CSD in mice, while increasing its rate of propagation, and this susceptibility was modulated by allele dosage (i.e., homozygotes > heterozygotes > wild-type). Both mutations lowered the threshold for the Ca_v2.1 channel opening and prolonged channel inactivation, but the S218L mutation was associated with more severe alterations in both channel activity and neurological deficits, compared with changes associated with the R192Q mutation. Interestingly, corticostriatal propagation of CSD was observed in the majority of mutant mice, and more serious and prolonged post-CSD neurological deficits followed, compared with those observed in wild-type mice. Moreover, the higher prevalence of migraine in females was replicated in the mutant mice. Female mutant mice were more susceptible to CSD, and their neurological deficits manifested more severely than those in their male equivalents. The sex difference was eliminated by ovariectomy and partially restored by estrogen replacement, suggesting that differences in CSD susceptibility between males and females involve the effect of ovarian hormones. Like any important study, this new work raises a number of questions: Only experimentally induced CSD was studied, and it is tempting to ask whether the mutant mice experience spontaneous waves of CSD. Moreover, FHM is a rare disease, and the current study does not directly address the pathogenesis of migraine with or without aura. Common migraine is a multifactorial polygenetic disease, and a genetic component can only been identified in about 50% of individuals with migraine. In these patients, recent genome-wide screens have pointed to several susceptibility loci, but no causative genes have been identified (7).

A recent study suggested that women with a lifetime history of migraine performed better on cognitive tests than did subjects without migraines (24). One possible explanation is that the migraine pain, similar to other types of pain, warned the patients and reinforced a healthier lifestyle that not only reduced migraine attack but also protected memory. Another possible explanation is that although the hypoxia-associated CSD represents an immediate danger, the long-term effect might be a strengthening of cortical circuits. A large body of literature documents that CSD is a preconditioning stimulus, similar to short-lasting episodes of ischemia (25). Thus, exposure to a wave of CSD might confer tolerance, allowing cortical neurons to survive an otherwise lethal subsequent episode of ischemia. The mechanism by which CSD increases ischemic tolerance is multifactorial and includes release of well-known trophic factors, including brain-derived neurotrophic factor (26). Thus, it is plausible that the beneficial effect of increased neuronal tolerance may, over the long term, outweigh the hypoxic stress associated with CSD.