Reflexive Eye Closure in Response to Cone and Melanopsin Stimulation: A Study of Implicit Measures of Light Sensitivity in Migraine.

Objective: To quantify interictal photophobia in migraine with and without aura using reflexive eye closure as an implicit measure of light sensitivity, and to assess the contribution of melanopsin and cone signals to these responses. Methods: Participants were screened to meet criteria for one of three groups: headache-free (HAf) controls, migraine without aura (MwoA), and migraine with visual aura (MwA). MwoA and MwA participants were included if they endorsed ictal and interictal photophobia. Exclusion criteria included impaired vision, inability to collect usable pupillometry, and history of either head trauma or seizure. Participants viewed light pulses that selectively targeted melanopsin, the cones, or their combination during recording of orbicularis oculi electromyography (OO-EMG) and blinking activity. Results: We studied twenty participants in each group. MwA and MwoA groups reported increased visual discomfort to light stimuli (Discomfort rating, 400% contrast, MwA: 4.84 [95% CI: 0.33, 9.35]; MwoA: 5.23 [0.96, 9.50]) as compared to HAf controls (2.71 [0, 6.47]). Time course analysis of OO-EMG and blinking activity demonstrated that reflexive eye closure was tightly coupled to the light pulses. The MwA group had greater OO-EMG and blinking activity in response to these stimuli (EMG activity, 400% contrast: 42.9%Δ [28.4, 57.4]; Blink activity, 400% contrast: 11.2% [8.8, 13.6]) as compared to the MwoA (EMG activity, 400% contrast: 9.9%Δ [5.8, 14.0]; Blink activity, 400% contrast: 4.7% [3.5, 5.9]) and HAf control (EMG activity, 400% contrast: 13.2%Δ [7.1, 19.3]; Blink activity, 400% contrast: 4.5% [3.1, 5.9]) groups. Conclusions: Our findings suggest that the intrinsically-photosensitive retinal ganglion cells (ipRGCs), which integrate melanopsin and cone signals, provide the afferent input for light-induced reflexive eye closure in a photophobic state. Moreover, we find a dissociation between implicit and explicit measures of interictal photophobia depending on a history of visual aura in migraine. This implies distinct pathophysiology in forms of migraine, interacting with separate neural pathways by which the amplification of ipRGC signals elicit implicit and explicit signs of visual discomfort.