Selective amplification of ipRGC signals accounts for interictal photophobia in migraine

Second only to headache, photophobia is the most debilitating symptom reported by people with migraine. While the melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) are thought to play a role, how cone and melanopsin signals are integrated in this pathway to produce visual discomfort is poorly understood. We studied 60 people: 20 without headache and 20 each with interictal photophobia from migraine with or without aura. Participants viewed pulses of spectral change that selectively targeted melanopsin, the cones, or both, and rated the degree of visual discomfort produced by these stimuli while we also recorded pupil responses. We examined the data within a model that describes how cone and melanopsin signals are weighted and combined at the level of the retina, and how this combined signal is transformed into a rating of discomfort or pupil response. Our results indicate that people with migraine do not differ from headache-free controls in the manner in which melanopsin and cone signals are combined. Instead, people with migraine demonstrate an amplification of integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an amplification of pupil responses was not seen in the migraine group, nor were group differences found in surveys of other behaviors putatively linked to ipRGC function (chronotype, seasonal sensitivity, presence of a photic sneeze reflex). By revealing a dissociation in the amplification of discomfort versus pupil response, our findings suggest a post-retinal alteration in processing of ipRGC signals for photophobia in migraine. SignificanceThe melanopsin-containing, intrinsically photosensitive retinal ganglion cells (ipRGCs) may contribute to photophobia in migraine. We measured visual discomfort and pupil responses to cone and melanopsin stimulation--the photoreceptor inputs to the ipRGCs--in people with and without migraine. We find that people with migraine do not differ from those without headaches in how cone and melanopsin signals are weighted and combined to produce visual discomfort. Instead, migraine is associated with an amplification of ipRGC signals for discomfort. This effect of migraine upon ipRGC signals is limited to photophobia, as we did not find an enhancement of pupil responses or a change in other behaviors linked to ipRGC function. Our findings suggest a post-retinal amplification of ipRGC signals for photophobia in migraine.