FINAL REPORT: Neurosteroid Regulation of Cortical Spreading Depression

Summary

Migraine in women has long been known to be affected by changes in hormone levels that accompany puberty, the menstrual cycle, pregnancy and menopause. To date, most studies have focused on hormones that are produced outside of the brain in the periphery. However, recently it has been shown that individual neurons in the brain can produce similar hormones known as neurosteroids. Neurosteroids act on a unique part of the inhibitory system in the brain that may be important to the development of migraine.

For 20-30% of patients their migraine is preceded by an aura that is most often perceived as flashing lights or blind spots in their visual field. This migraine aura is a neurological phenomenon thought to be an underlying cause of migraine and develops from a process known as spreading depression. Initiation of spreading depression can activate the pathways leading to migraine pain and its prevention is a common target of migraine therapies. Previous studies have shown that during periods of high neurosteroid levels, such as prior to menstruation or in pregnancy, women are at an increased risk for migraine with aura. We therefore hypothesized that neurosteroids may act to alter cortical excitability and exacerbate migraine by promoting spreading depression.

To investigate this, we utilized an advanced imaging approach combined with electrophysiological recordings in a rat model of spreading depression. We determined that neurosteroids selectively and rapidly alter inhibitory GABAergic neurotransmission in the cerebral cortex. Neurosteroids alter network excitability and increase the amplitude and propagation speed of cortical spreading depression. Taken together, these data suggest that the actions of neurosteroids may play an important role in the pathophysiology of hormonal-related migraine.

Hypothesis vs. Findings

The aim of this project was to determine whether neurosteroids acting in the brain alter the susceptibility and severity of spreading depression. That goal was met. We showed that neurosteroids primarily act on select neurons in the brain and as a result increase the susceptibility to spreading depression.

Unanswered Questions

The funding by the Migraine Research Foundation has been instrumental in establishing a role of neurosteroids in the development of migraine with aura. Additional studies will be needed to answer important questions including: What controls the release of neurosteroids? What impact do neurosteroids and enhanced cortical spreading depression have on the activation of migraine pain pathways? Do migraine patients exhibit altered neurosteroid production? Most importantly, how might we therapeutically target neurosteroids to treat migraine?

What This Research Means To You

Our research suggests that neurosteroids may play an important role in predisposing the brain to develop migraine aura. Neurosteroids may represent a new target for the development of novel migraine treatments.