Selective amplification of ipRGC signals accounts for interictal photophobia in migraine

Abstract

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 visual 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 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 enhanced response to integrated ipRGC signals for discomfort. This effect of migraine is selective for ratings of visual discomfort, in that an enhancement 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 vs. pupil response, our findings suggest a postretinal alteration in processing of ipRGC signals for photophobia in migraine.

Keywords: ipRGCs; melanopsin; migraine; photophobia.

Fig. 1.

Experiment overview. (A) There are several classes of melanopsin-containing ipRGCs, which vary in their central projections, function, and extent to which they receive input from cones. The ipRGCs project to the somatosensory thalamus and the lateral geniculate nucleus, where their signals may contribute to light sensitivity. Other ipRGCs project to the pretectal nuclei to control the size of the pupil. Not shown are numerous, additional subcortical projection targets of the ipRGCs (e.g., the suprachiasmatic nucleus). RGC, retinal ganglion cell. (B) The spectral sensitivity functions of the relevant photoreceptors under daylight conditions. S, M, and L refer to the short-, medium-, and long-wavelength sensitive cones, respectively. (C) Shown are pairs of spectra (background: black; stimulus: red) that differ in excitation for the targeted photoreceptors. In Left, Center, and Right, the stimuli produce equal contrast on the cones and melanopsin (termed light flux), contrast only on melanopsin, and equal contrast across all three classes of cones but no contrast on melanopsin, respectively. (D) Each trial featured a 4-s period during which the stimulus transitioned from the background to the stimulation spectrum and back. Twelve seconds after stimulus offset, the subject provided a discomfort rating. There was an intertrial interval that varied between 1.5 and 2.5 s. (E) The light from a digital spectral integrator was presented to the pharmacologically dilated right eye of the subject through an artificial pupil. The consensual pupillary light response of left eye was recorded with an infrared camera. (F) The stimulus spectra were presented in an eyepiece with a 27.5°-diameter field, with the central 5° obscured to minimize macular stimulation.

Fig. 2.

Discomfort ratings by stimulus and group. Each row presents the discomfort ratings elicited by stimuli that targeted a particular combination of photoreceptors, and each column contains the data from each individual group (n = 20 participants per group). The stimuli were presented at three different contrast levels (100, 200, and 400%), and these (log-spaced) values define the x axis of each subplot. The median (across trial) discomfort rating for a given stimulus and contrast is shown for each participant (filled circles), as is the mean rating across participants (open circles). The best-fit line to the mean discomfort rating across participants as a function of log contrast is shown in each subplot.

Fig. 3.

A two-stage model of discomfort ratings. We developed a two-stage model that describes discomfort ratings as a function of melanopsin and cone stimulation. (A) In the first stage, (Left) melanopsin contrast (C_Mel) is weighted by a scaling factor (α) and then combined with cone contrast (C_Cone) under the control of the Minkowski exponent (β). The output of this stage is ipRGC contrast, which is log transformed and passed to the second stage (Right). Here, the signal undergoes an affine transform to produce a discomfort rating, under the control of a slope and offset parameter (the latter being expressed as the modeled discomfort rating at 200% ipRGC contrast). (B) The model was fit to the discomfort data from each group, yielding estimates of the model parameters (±2 SEM obtained via bootstrapping). The P value associated with a two-tailed t value, taken with respect to the pooled SEs, is presented for the comparison of each of the migraine groups with the control group for each parameter (n = 20 participants per group). (C) Stage 1 of the model transforms the stimuli used in the experiment to common units of ipRGC contrast. Each plot presents the discomfort ratings (individual participants in filled circles, group means in open circles) in terms of ipRGC contrast, with the parameters at stage 1 forced to be the same across groups. The nine open circles correspond to the nine stimuli used in the experiment (three contrast levels each of melanopsin, cone, and light flux stimulation). The fit of the second stage of the model (which can vary across groups) provides the fit line.

Fig. 4.

Pupil response by stimulus and group. (A) The average pupil response across participants within each group (n = 20 participants per group) is shown for each stimulus type (columns) at each contrast level (rows). The responses from the three groups for each stimulus type are superimposed. (B) We summarized the pupil responses by taking the mean of the percent change in amplitude of the pupil area across the recording period. These data were then fit with the two-stage model (Fig. 3). No significant differences between the groups in the parameter estimates were found (±2 SEM obtained via bootstrapping), although both the relative melanopsin scaling and Minkowski exponent values are smaller for pupil responses than was observed for discomfort ratings. (C) As no significant differences between groups were found for the parameters, we refit our model to the data forcing all parameters to be the same across groups. The plots report individual (filled circles) and mean (open circles) pupil response as a function of modeled ipRGC contrast.