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

Photophobia in migraine: a symptom cluster?

Photophobia is one of the most common symptoms in migraine, and the underlying mechanism is uncertain. The discovery of the intrinsically-photosensitive retinal ganglion cells (ipRGCs) which signal the intensity of light on the retina has led to discussion of their role in the pathogenesis of photophobia. In the current review, we discuss the relationship between pain and discomfort leading to light aversion (traditional photophobia) and discomfort from flicker, patterns, and colour that are also common in migraine and cannot be explained solely by ipRGC activity. We argue that, at least in migraine, a cortical mechanism provides a parsimonious explanation for discomfort from all forms of visual stimulation, and that the traditional definition of photophobia as pain in response to light may be too restrictive. Future investigation that directly compares the retinal and cortical contributions to photophobia in migraine with that in other conditions may offer better specificity in identifying biomarkers and possible mechanisms to target for treatment

Assessing migraine patients with multifocal pupillographic objective perimetry

Background: To establish the effects of stimulating intrinsically-photosensitive retinal ganglion cells (ipRGCs) on migraine severity, and to determine if migraine produces objectively-measured visual field defects. Methods: A randomized, open labelled, crossover study tested migraineurs and normal controls using multifocal pupillographic objective perimetry (mfPOP) with 44 test-regions/eye. A slow blue protocol (BP) stimulated ipRGCs, and a fast yellow protocol (YP) stimulated luminance channels. Migraine diaries assessed migraine severity. Per-region responses were analyzed according to response amplitude and time-to-peak. Results: Thirty-eight migraineurs (42.0 ± 16.5 years, 23 females) and 24 normal controls (39.2 ± 15.2 years, 14 females) were tested. The proportion of subjects developing a migraine did not differ after either protocol, either during the 1st day (odds ratio 1.0; 95% confidence interval 0.2–4.4, p = 0.48) or during the first 3 days after testing (odds ratio 0.8; 95% confidence interval 0.3–2.1, p = 0.68). Migraine days/week did not increase following testing with either protocol in comparison to the baseline week (1.4 ± 1.6 pre-testing (mean ± SD), 1.3 ± 1.4 post-BP, and 1.3 ± 1.2 post-YP; p = 0.96), neither did other measures of severity. Migraine occurring up to 2 weeks before testing significantly lowered amplitudes, − 0.64 ± 0.14 dB (mean ± SE), while triptan use increased amplitudes by 0.45 ± 0.10 dB, both at p < 0.001. Conclusions: Stimulating ipRGCs did not affect migraine occurrence or severity. Pupillary response characteristics were influenced by the occurrence of a recent migraine attack and a history of triptan use

Melanopic stimulation does not alter psychophysical threshold sensitivity for luminance flicker

In addition to the rod and cone photoreceptors the retina contains intrinsically photosensitive retinal ganglion cells (ipRGCs). These cells express the photopigment melanopsin and are known to be involved in reflexive visual functions such as pupil response and photo-entrainment of the circadian rhythm. It is possible that the ipRGCs contribute to conscious visual perception, either by providing an independent signal to the geniculo-striate pathway, or by interacting with and thus modifying signals arising from “classical” retinal ganglion cells that combine and contrast cone input. Here, we tested for the existence of an interaction by asking if a 350% change in melanopsin stimulation alters psychophysical sensitivity for the detection of luminance flicker. In Experiment 1, we tested for a change in the threshold for detecting luminance flicker in three participants after they adapted to backgrounds with different degrees of tonic melanopsin stimulation. In Experiments 2 and 3, this test was repeated, but now for luminance flicker presented on a transient pedestal of melanopsin stimulation. Across the three experiments, no effect of melanopsin stimulation upon threshold flicker sensitivity was found. Our results suggest that even large changes in melanopsin stimulation do not affect near-threshold, cone-mediated visual perception.TU Berlin, Open-Access-Mittel – 202