Minimum Conditions for the Induction of Cortical Spreading Depression: Implications for Migraine with Aura (S16.002)

Abstract

Objective: Determine whether cortical spreading depression can be induced under conditions physiologically compatible with migraine. Background Cortical spreading depression (CSD) is thought to be the mechanism of the migraine aura. If so, it must occur in awake humans, be focally inducible, and not be overtly injurious. In contrast, laboratory models of CSD use conditions that are associated with brain injury in humans. It is important to define the parameters under which CSD can be triggered, and determine whether any of these are plausible in migraine aura. Design/Methods: We used a novel microfluidic device to precisely vary extracellular potassium concentration (Ke) as well as the area exposed to this increased Ke, in a mouse brain slice model. Ke was varied over a range from 15 to 140 mM above normal baseline of 3 mM. Microfluidic port radius was varied from 75 to 250 µm. Whole slice perfusion was also performed. Results: We found that CSD was inducible with small areas exposed to high Ke, and large areas exposed to lower Ke levels, in an approximately hyperbolic relationship. For elevations in Ke unlikely to be associated with tissue damage ( 300 µm (on the order of magnitude of a cortical column or penetrating artery territory). Smaller areas supported CSD when Ke was raised to levels that can only be achieved by cell lysis. Perfusion of the whole brain slice yielded the lowest CSD threshold (15 mM Ke). Conclusions: Our results show that relatively large focal regions must be depolarized to generate CSD in a manner compatible with migraine aura. However they also suggest that the induction of CSD in migraine is physiologically plausible. Supported by: NIH NS 059072, NS 070084 (KCB). Disclosure: Dr. Brennan has nothing to disclose. Dr. Tang has nothing to disclose. Dr. Lopez-Valdes has nothing to disclose. Dr. Charles has received personal compensation for activites with MAP Pharmaceuticals and Merck & Co., Inc. Dr. Charles has received research support from MAP Pharmaceuticals. Dr. Ju has nothing to disclose.