FINAL REPORT: Sex, Stress, and Migraine

Summary

Stress is the most commonly reported trigger of migraine, especially in women, who make up the majority of migraine sufferers. We do not know why this is the case, and there remains debate over whether stress really triggers migraine or is simply recalled more during a painful migraine episode. This project set out to clarify the effects of stress on migraine, examining females and males separately because the effects might be different. We used mice for our study, because this kind of mechanistic testing cannot be conducted in humans. Our subjects underwent 40 days of either stressful or normal conditions, after which we examined migraine-relevant pain responses and brain excitability. In addition to testing normal ‘wild-type’ mice, we tested mice carrying a gene mutation found in humans with familial migraine – the rationale for this was to see whether the effects of stress and sex were enhanced on a genetic background predisposed to migraine.

We found that stress induced migraine-relevant changes, specifically in females and in migraine transgenic animals. Injection of nitroglycerin (NTG), which induces migraine in humans, generated a larger response after stress in females (but not males) and in the transgenic mice. We also measured cortical spreading depression (CSD), which reflects migraine-related brain excitability. Here again we saw significant changes after stress in female and transgenic animals. What this shows is that stress is not just a bystander effect in migraine: it causes physiological changes in the nervous system that appear to facilitate an attack. Moreover these changes act disproportionately on females and those genetically disposed to migraine just as we see in the clinic.

Hypothesis vs. Findings

1. We initially proposed a 14 day chronic stress paradigm for evaluation of stress-induced migraine phenotype. However, neither 7 nor 14 days were sufficient in establishing a significant stress response, therefore we extended our paradigm to a 40 day chronic stress paradigm.

2. We found that males did not show a stress-related migraine phenotype like initially expected, however female wild-type mice showed a migraine relevant phenotype in both the NTG and CSD stress assays.

3. We initially did not propose the use of transgenic migraine models, however given the interesting results in wild-type animals, we elected to test the effects of stress on male and female mice carrying a mutation associated with familial migraine in humans. These mice showed a stress-induced migraine phenotype in both sexes.

4. We initially aimed to test the potential of an experimental anti-migraine compound, SPD, to mitigate stress and migraine-relevant phenotypes. However, as our paradigm was extended from 14 to 40 days, we had insufficient SPD to test its effects during the lengthened paradigm.

Unanswered Questions

Now that we have established these findings, the next step is to understand how stress affects sensory circuits in the brain, specifically in females and genetically-disposed individuals, in order to develop new treatment approaches.

What This Research Means To You

Stress is the most common reported trigger of migraine, especially in women. However it is unclear how stress and sex interact in the nervous system to generate migraine. Moreover, it is debated whether stress is even definitively associated with migraine, or whether it is a bystander effect that is noticed more around the attack.

Our study in mice showed that stress facilitates migraine-relevant pain responses and brain excitability, especially in females and in animals with a migraine genetic background. This shows that stress causes physiological changes in the nervous system that appear to facilitate migraine, arguing that stress indeed is a ‘real’ migraine trigger.

The next step is to understand how stress affects sensory circuits in the brain, specifically in females and genetically-disposed individuals, in order to develop new treatment approaches.