Measuring Melanopsin Function in Humans to Understand Photophobia in Migraine

Bright light can be uncomfortable, and sometimes even painful, to look at. Bright light, however, hurts more in numerous clinical contexts, including in people who suffer from migraine headache. This pathology is referred to as photophobia or light sensitivity. Migraineurs tend to not only be light sensitive during headaches, but between headaches as well. Prior work has tentatively linked photophobia to the melanopsin and intrinsically photosensitive retinal ganglion cell (ipRGC) system. In the first chapter, this work describes how we can effectively probe the ipRGC system in healthy human subjects. We highlight the utility of silent substitution to selectively stimulate melanopsin to thereby isolate the ipRGCs from the rest of the retina. We then demonstrate that pupillometry is a stable measure of the response to this selective stimulation, and shows temporal properties consistent with the prolonged signal transduction associated with melanopsin. In the second chapter, we then extend these insights to the study of photophobia in migraine, comparing light-related responses in people with migraine to headache free controls. Through this project, we show that migraineurs find melanopsin-isolating stimuli more uncomfortable than headache free controls, providing some of the strongest evidence to date that variation in ipRGC function relates to clinical pathology in humans. We also show that migraineurs find cone-isolating stimuli more uncomfortable, suggesting that both melanopsin and cone signals contribute to photophobia. Finally, we show that pupil constriction is not similarly enhanced in migraine. By demonstrating this dissociation in light-mediated responses, we reveal a selective amplification of ipRGC signals, in a manner consistent with a post-retinal localization of photophobia