Relief Following Chronic Stress Augments Spreading Depolarization Susceptibility in Familial Hemiplegic Migraine Mice

Abstract

Cortical spreading depolarization (CSD) is the electrophysiological substrate of migraine aura, and a putative trigger of trigeminovascular activation and migraine headache. Many migraineurs report stress or relief after a stress triggers an attack. We tested whether various stress conditions might modulate CSD susceptibility and whether this is dependent on genetic factors. Male and female wild type and familial hemiplegic migraine type1 (FHM1) knock-in mice heterozygous for the S218L missense mutation were subjected to acute or chronic stress, or chronic stress followed by relief (36 h). Acute stress was induced by restraint and exposure to bright light and white noise (3 h). Chronic stress was induced for 28 days by two cycles of repeated exposure of mice to a rat (7 days), physical restraint (3 days), and forced swimming (3 days). Electrical CSD threshold and KCl-induced (300 mM) CSD frequency were determined in occipital cortex in vivo at the end of each protocol. Relief after chronic stress reduced the electrical CSD threshold and increased the frequency of KCl-induced CSDs in FHM1 mutants only. Acute or chronic stress without relief did not affect CSD susceptibility in either strain. Stress status did not affect CSD propagation speed, duration or amplitude. In summary, relief after chronic stress, but not acute or chronic stress alone, augments CSD in genetically susceptible mice. Therefore, enhanced CSD susceptibility may explain why, in certain patients, migraine attacks typically occur during a period of stress relief such as weekends or holidays.

Keywords: FHM1; acute stress; chronic stress; cortical spreading depolarization; stress relief; weekend migraine.

Figure 1.. Experimental protocols and timeline

(A) The timeline of acute and chronic stress, and stress withdrawal paradigms. Each cohort had a naive control group maintained in a stress-free environment for the same duration. (B) Experimental setup to measure the electrical CSD threshold (bipolar stimulation electrode on left occipital cortex) and the frequency of KCl-induced CSDs (topical KCl application via a cotton ball on right occipital cortex) over approximately two hours of CSD susceptibility testing. Microelectrode positions for electrophysiological confirmation of CSDs are also shown.

Figure 2.. Chronic stress

Upper panel shows representative intracortical DC potential tracings of electrical CSD threshold (left) and KCl-induced CSD frequency (right) determination in FHM1 mice. Cathodal stimulation was stepwise doubled until a CSD developed. Lower panel shows the CSD threshold (left) and frequency (right) data from wild-type (WT) and FHM1 mutant mice (whiskers, full range; box, interquartile range; line, median, +, mean). Two-way ANOVA (stress status and sex as independent variables) p values, and individual data points are also shown (gray circles male, white circles female). *p<0.05 vs. other groups.

Figure 3.. Acute stress

CSD threshold (left) and frequency (right) are shown from wild-type (WT) and FHM1 mutant mice (whiskers, full range; box, interquartile range; line, median, +, mean). Individual data points are also shown. All animals were female. There was no statistically significant difference (two-way ANOVA, stress status and genotype as independent variables.