Secondary Logo

The migraine eye

distinct rod-driven retinal pathways' response to dim light challenges the visual cortex hyperexcitability theory

Bernstein, Carolyn A.a,b; Nir, Rony-Reuvena,c; Noseda, Rodrigoa,c; Fulton, Anne B.a,d; Huntington, Shaelahe; Lee, Alice J.e; Bertisch, Suzanne M.a,f; Hovaguimian, Alexandraa,g; Buettner, Catherinea,h; Borsook, Davida,i; Burstein, Ramia,c,*

doi: 10.1097/j.pain.0000000000001434
Research Paper
Free
Editor's Choice

Migraine-type photophobia, most commonly described as exacerbation of headache by light, affects nearly 90% of the patients. It is the most bothersome symptom accompanying an attack. Using subjective psychophysical assessments, we showed that migraine patients are more sensitive to all colors of light during ictal than during interictal phase and that control subjects do not experience pain when exposed to different colors of light. Based on these findings, we suggested that color preference is unique to migraineurs (as it was not found in control subjects) rather than migraine phase (as it was found in both phases). To identify the origin of this photophobia in migraineurs, we compared the electrical waveforms that were generated in the retina and visual cortex of 46 interictal migraineurs to those generated in 42 healthy controls using color-based electroretinography and visual-evoked potential paradigms. Unexpectedly, it was the amplitude of the retinal rod-driven b wave, which was consistently larger (by 14%-19% in the light-adapted and 18%-34% in the dark-adapted flash ERG) in the migraineurs than in the controls, rather than the retinal cone-driven a wave or the visual-evoked potentials that differs most strikingly between the 2 groups. Mechanistically, these findings suggest that the inherent hypersensitivity to light among migraine patients may originate in the retinal rods rather than retinal cones or the visual cortex. Clinically, the findings may explain why migraineurs complain that the light is too bright even when it is dim to the extent that nonmigraineurs feel as if they are in a cave.

Affected by the disease, the eyes of migraine patients are more sensitive to light than the eyes of nonmigraine subjects.

aHarvard Medical School, Boston, MA, United States

bDepartment of Neurology, Brigham and Women's Faulkner Hospital, Boston, MA, United States

cDepartment of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

dDepartment of Ophthalmology, Children's Hospital Boston, Boston, MA, United States

eHarvard Catalyst Clinical Research Center, Beth Israel Deaconess Medical Center, Boston, MA, United States

fDepartment of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

gDepartment of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States

hDepartment of Medicine, Mount Auburn Hospital, Cambridge, MA, United States

iDepartment of Anesthesia, Critical Care and Pain Medicine, Center for Pain and the Brain, Boston Children's Hospital, Boston, MA, United States

Corresponding author. Address: Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, CLS-649, 3 Blackfan Circle, Boston, MA 02215, United States. Tel.: 617 735-2832; fax: 617 735-2833. E-mail address: rburstei@bidmc.harvard.edu (R. Burstein).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received July 30, 2018

Accepted September 20, 2018

Back to Top | Article Outline

1. Introduction

In ophthalmology, photophobia is commonly defined as an abnormal sensitivity, or intolerance, to light, especially discerned by the eyes (Dorland Medical). This definition, also termed photo-oculodynia, attempts to capture the pathological ocular perception of an otherwise innocuous visual stimulus as noxious or uncomfortable among patients suffering from a variety of ocular diseases.18 To capture the experience of migraine patients, the definition of photophobia was initially expanded to include discomfort in the eye or head,18 and later modified to reflect more accurately what patients experience as exacerbation of headache by light33,34 or a more general aversion to light during an attack,35 referred to here as “migraine-type photophobia.” Second only to the headache itself, photophobia is commonly identified by patients as the most disabling symptom of migraine29,44,53 because it repeatedly forces them to stop their work or home responsibilities, to be in dark environments. Accordingly, reducing photophobia is now considered by the Food and Drug Administration as a coprimary endpoint.24

Our understanding of migraine-type photophobia continues to evolve. In a recent series of studies, we reported that (1) none of the blind migraine patients who lacked light perception experienced photophobia, whereas those who could detect light tended to complain about worsening of their headache once light conditions were dominated by short wavelengths; (2) during migraine, patients with normal eyesight found white, blue, amber, and red lights to be more painful than green light, and that larger electrical amplitudes were generated by both the retina (a waves) and visual cortex (N2/P2 complexes) in response to white, blue, amber, and red lights as compared to green33; (3) regardless of headache intensity, all colors of light triggered unpleasant autonomic and affective symptoms, which we categorized as aversive; and (4) this nonspecific aversion to colors occurred more frequently in the ictal than the interictal phase, and more frequently in the interictal phase than in healthy controls.35 Incorporating these psychophysical and electrophysiological findings in migraine patients with our preclinical anatomical and physiological identification of novel retinothalamocortical, retinohypothalamic–sympathetic, and retinohypothalamic–parasympathetic pathways, we initially proposed that (1) in the absence of the optic nerve, migraine-type photophobia could not occur; (2) the exacerbation of headache by light was mediated by retinal projections to thalamic neurons that terminated in several sensory cortices; and (3) the retinal projections to the thalamus originated in melanopsinergic and nonmelanopsinergic retinal ganglion cells (RGCs) in migraine patients with normal eyesight, but mainly in melanopsinergic RGCs in blind migraine patients.34 We then concluded that initial activation of retinal cones and cone-driven postreceptor cells and subsequent activation of color-sensitive neurons in the visual cortex were required to mediate the aforementioned distinct color effects.33 This conclusion is heavily supported by the notion that color perception is generated by the visual cortex in response to signals that originate in retinal cones.13 Along this line, we also suggested that because the generation of color perception and its processing depend on color-sensitive, cone-opponent neurons in the visual cortex,13 the most reasonable way to explain why control subjects like colored light whereas migraineurs find colored light aversive is by abnormal functioning of the visual cortex.32

Continuing to probe the mechanisms of migraine-type photophobia, in the current study, we have attempted to determine whether it was the cortex, the retina, or both, that were more sensitive to light in migraine patients than in healthy controls and, if it were the retina, which type of photoreceptors were affected. To the best of our knowledge, this is the first study to compare the amplitudes of a waves and b waves of light-, flickering-, and dark-adapted electroretinograms (ERGs), as well as the N2/P2 amplitudes of visual-evoked potentials (VEPs) in response to different colors of light in both migraine patients and healthy controls.

Back to Top | Article Outline

2. Materials and methods

All study visits took place at Beth Israel Deaconess Medical Center (BIDMC), Boston, MA (September 2010-June 2017). The BIDMC Committee on Clinical Investigations approved the study, and all participants provided written informed consent. Patients were recruited from the BIDMC Comprehensive Headache Center, Neurology Clinic, the primary care clinic at Healthcare Associates, and from advertisements at BIDMC and Harvard Medical School. Women and men who were 15 to 85 years old were potentially eligible for the study if they met the International Classification of Headache Disorders Committee49 criteria for migraine with or without aura, were able to communicate in English, and were willing to attend a visit during an untreated migraine attack. Exclusion criteria included fewer than 5 headache-free days per month, chronic head or neck pain not attributed to migraine, chronic use of opioids (≥15 days/month for 3 previous consecutive months or longer), or having an ocular disease as defined in the study by Noseda et al.33 Participants were permitted to stop participating in the study at any time.

Back to Top | Article Outline

2.1. Electroretinography

Electroretinography responses were recorded in 46 migraine patients and 42 healthy controls. As recommended by the International Society for Clinical Electrophysiology of Vision,31 we used the full-field (ganzfeld) stimulation method because it favors recording stability, reproducibility, and reliability by delivering the photic stimuli to all photoreceptors in a relatively homogenous manner. To minimize discomfort, the pupils were not dilated and the ERG recordings were not done through a contact lens electrode. Rather, all ERG recordings were done using one disposable, low-impedance silver/nylon corneal recording electrode (DTL Plus) that is comfortable and easy to use, one reference gold cup electrode placed on the forehead, and a ground silver ear clip electrode placed on the ipsilateral ear. Amplification of signals, fixation point, and other technical aspects of our ERG recording were described previously.33

Back to Top | Article Outline

2.1.1. Light-adapted, single-flash cone/rod ERG, light-adapted 30-Hz flicker cone ERG, and dark-adapted rod ERG

Before recording light-adapted ERG, participants were given 10 minutes to adapt to the background light. Before recording dark-adapted ERG, patients were kept in total darkness for 20 minutes. Stimulus intensity, frequency, duration, interval, number of stimuli, order of color presentation, background luminance, characterization of a waves and b waves, and calibration and quantification of photic stimulation were described in detail in the study by Noseda et al.33

Back to Top | Article Outline

2.2. Visual-evoked potential recording

Visual-evoked potentials were recorded in all 46 migraine patients and 42 healthy controls. Of these, only 29 migraine patients and 31 healthy controls yielded waveforms with clearly identifiable N1, P1, N2, and P2 deflections. As recommended by the International Society for Clinical Electrophysiology of Vision guideline for VEP standard,36 we elicited full-field light flashes using the ColorDome system. Recordings, electrode placements (Oz, Fz, Cz), room conditions, as well as intensity, frequency, duration, intervals, number, and order of stimuli (by color) were identical to those used in our recent study.33

Back to Top | Article Outline

3. Statistical analysis

All analyses were performed using SPSS version 25 (Statistical Package for the Social Sciences, IBM) and SAS version 9.4 (SAS Institute Inc., 2008). Statistical significance was set at P < 0.05. The primary outcome measures were defined as physiological markers attesting to the magnitude of individual responsiveness to the applied visual stimuli, namely the amplitudes of ERG-derived retinal a waves and b waves and VEP-derived cortical N2P2 complexes. Nonparametric Mann–Whitney tests compared the amplitudes of these markers between migraine patients and healthy controls as induced by white, blue, green, amber, and red lights.

Back to Top | Article Outline

4. Results

Forty-six patients diagnosed with migraine,49 photophobia, and no known ocular diseases were studied. Their demographics and headache characteristics are described in Table 1.

Table 1

Table 1

Back to Top | Article Outline

4.1. Electroretinography studies in migraineurs

To identify possible retinal contribution to migraine-type photophobia, we sought to determine whether the electrical signals that are generated by the retina in response to light differ in migraine patients as compared to healthy controls. To answer this question, we recorded ERG signals from the retina of 46 migraineurs and 42 healthy controls.

Back to Top | Article Outline

4.1.1. Light-adapted single-flash ERG

In these cone/rod ERGs, the b-wave amplitudes generated by all lights were larger in migraine patients as compared to healthy controls; these differences were statistically significant in response to white (106.21 [88.17-140.29] in migraine patients vs 84.21 [67.15-113.94] in healthy controls; P = 0.028), green (99.93 [78.75-121.88] vs 80.67 [59.79-119.24]; P = 0.03), amber (94.28 [79.54-119.39] vs 80.89 [56.65-111.57]; P = 0.032), and red (98.40 [87.92-119.47] vs 84.73 [63.04-109.92]; P = 0.019), but not blue (119.96 [95.94-150.89] vs 111.39 [81.12-141.81]; P = 0.120) (Fig. 1). By contrast, the a-wave amplitudes were comparable in migraine patients and healthy controls; this was true for all but the blue light (−43.08 [−50.38 to −35.56] vs −38.17 [−44.79 to −30.94]; P = 0.020).

Figure 1

Figure 1

Back to Top | Article Outline

4.1.2. Light-adapted flicker ERG

In these cone-mediated responses, no significant differences in b-wave or a-wave amplitudes were found between the migraine patients and healthy controls in any of the examined colors (Ps > 0.114) (Fig. 2).

Figure 2

Figure 2

Back to Top | Article Outline

4.1.3. Dark-adapted rod ERG

In these rod ERGs, the b-wave amplitudes generated by all lights were larger in migraine patients as compared to healthy controls; these differences were statistically significant in response to white (272.22 [192.87-336.81] in migraine patients vs 190.81 [151.04-246.52] in healthy controls; P = 0.028), green (229.98 [186.79-285.81] vs 151.82 [118.10-210.38]; P < 0.0001), amber (68.70 [45.70-101.43] vs 49.61 [28.64-73.35]; P = 0.009), and blue (281.27 [236.11-342.83] vs 222.46 [177.43-267.00]; P = 0.002), but not red (16.77 [5.64-42.41] vs 12.64 [0.78-19.00]; P = 0.289) (Fig. 3).

Figure 3

Figure 3

Back to Top | Article Outline

4.2. Visual-evoked potential studies in migraineurs

As the leading theory about migraine photophobia suggests that it is a reflection of genetically determined hyperexcitable cortex, we also sought to determine whether the electrical signals that are generated by the cortex in response to light differ in migraine patients as compared to healthy controls. To answer this question, we also recorded standard-flash VEP from the same group of participants. Surprisingly, analyses of the N2-P2 amplitude revealed no statistically significant differences between migraine patients and healthy controls (Fig. 4). This was true for all colors of light: white (12.57 [9.94-16.40] in migraine patients vs 12.24 [9.42-16.46] in healthy controls; P = 0.830), green (11.37 [8.10-15.84] vs 11.81 [7.58-15.61]; P = 0.947), amber (15.64 [9.61-20.00] vs 12.80 [8.10-16.40]; P = 0.222), blue (14.28 [10.89-17.37] vs 13.59 [11.01-16.92]; P = 0.520), and red (13.65 [9.23-19.54] vs 13.14 [9.58-17.52]; P = 0.652).

Figure 4

Figure 4

Back to Top | Article Outline

5. Discussion

This is the first study in which the same experimental setup was used to evaluate the sensitivity of the visual system in migraine patients and control subjects. Using standard ERG and VEP stimulation paradigms, we show that the physiological marker that differentiates most strikingly the visual system of the 2 populations is the amplitude of the retinal rod-driven b wave. Notably, the 2 populations did not differ in the amplitudes of the retinal cone-driven a wave or the cortical N2-P2 VEP. These findings suggest that the inherent hypersensitivity to light among migraine patients, as compared to healthy subjects, may originate in the retinal rods rather than in the retinal cones or the visual cortex. By contrast, it is cone-driven retinal pathways and the visual cortex rather than retinal rods that seem to mediate the distinct pattern of exacerbation or alleviation of headache by the different colors of light among migraineurs.

In our recent studies on migraine-type photophobia, we showed that the exacerbation of headache by light depends on a novel retinothalamocortical pathway that originates in melanopsinergic RGCs in migraine patients who are blind and in both nonmelanopsinergic and melanopsinergic RGC in migraine patients with normal eyesight.34 Subsequently, we showed that among migraine patients with normal eyesight, the perception that blue and red exacerbate the headache more than amber and white and that amber and white exacerbate the headache more than green, which at low intensities can actually alleviate the headache, originates in retinal cones and is finalized in the visual cortex.33 Comparing migraine patients during ictal vs interictal phases vs healthy controls, we recently reported that the selective color effects we documented in migraineurs during the ictal phase are also observed in the interictal phase but not in healthy controls.32 Accordingly, we proposed that this subject-dependent rather than attack-dependent phenomenon is mediated by visual cortex neurons that “generate” color perception, namely V1 double-opponent cells, and color-encoding cells in V2 and the inferior and posterior inferior temporal cortex (V4). As discussed below, this conclusion is somewhat challenged by the current study.

Unexpectedly, it was the b-wave amplitude—rather than the a-wave amplitude—that most strikingly differentiated migraine patients from the healthy controls. As shown in Figures 1 and 3, the greater b-wave amplitude we recorded in the migraineurs, compared to controls, was apparent in both the light- and dark-adapted single-flash ERGs, whereas similar a-wave amplitudes were apparent in the light-adapted single-flash and flickering ERGs (Figs. 1 and 2). Current understanding attributes the origin of the ERG b wave, the corneal positive deflection, to the activation of Muller, bipolar, and potentially amacrine cells in the inner retina.1,27,38,39,45 This activation is actuated by rods under light intensities that are too low to trigger cone activation (scotopic conditions), and by both rods and cones under light intensities sufficient for triggering both (photopic conditions).39 By contrast, the origin of the a wave, the corneal negative deflection, is attributed mainly to activation of cones and postcone retinal pathways.9–11,37 Based on the above, we propose that the larger b-wave responses originated in rods rather than cones. This interpretation is further supported by the following: (1) the b-wave amplitude recorded under the dark-adapted condition could not have been generated by cones as the light intensity was below their activation threshold46,47; and (2) when the stimulus paradigm was such that only cones were activated (30-Hz flickering ERG),19 a-wave amplitudes were comparable in both groups.

By far, the most surprising finding of this study is that the N2-P2 amplitude of the VEP, although different for the different colors of light, was similar in the migraineurs and healthy controls (Fig. 4). It is surprising because it challenges the notion that migraine-type photophobia originates in what is thought to be genetically predetermined hyperexcitable visual cortex.21 Although evidence for cortical hyperexcitability in migraineurs is overwhelming and we do not by any means dispute the data, little evidence exists to support the view that it is the hyperexcitable visual cortex that actually mediates the abnormal sensitivity to light. The origin of the theory that the visual cortex is hyperexcitable could be found in old VEP studies.42 The introduction of functional imaging techniques to the field of neuroscience gave rise to a large number of high-quality publications that showed even more convincingly that the visual cortex of the migraine brain responds more vigorously to lower intensity of stimulation than the visual cortex of the nonmigraine brain.6,8,15,22,25,26,30,41,51 Based on these studies, it was accepted that the migraine brain in general and the visual cortex in particular are hyperexcitable, hyperreactive, or hyperresponsive,4,14,16,51,55 either because of inherent defect in ionic channels that modulate excitability or because of inherent defect in cortical habituation.3,14,16,42,50 Although these studies are convincing, they lack a correlation with psychophysical assessments of the actual sensitivity of the participants to each of the photic stimuli that were used to measure the cortical responsiveness, without which one cannot conclude with certainty that the hyperexcitable visual cortex is the culprit of photophobia. The study by Boulloche et al.6 exemplifies this point most elegantly as it shows that although activation of the visual cortex by light is always stronger in migraineurs than in controls, the visual discomfort is not. Of relevance to the main finding of the current study is the study by Martin et al.,30 in which the authors showed that when simultaneous psychophysical assessment and functional magnetic resonance imaging were used to evaluate sensitivity to light and BOLD signals in the visual cortex of migraineurs and controls, it was only the low luminance conditions that differentiated the 2 groups most strikingly (see Fig. 1 in the study by Martin).

Anecdotally, one of the most common complaints of spouses of migraineurs is that they feel like they “live in a cave.” This complaint is attributed to the fact that even when all windows are covered, and the most intense light bulb in the room is 40 W—to the extent that it is depressing—it is still too bright and unbearable to their migraine spouse. This repeated complaint helps us place the clinical significance of this study in the right context. Because rod signals differentiated migraineurs from controls most significantly, and because rods are the class of retinal photoreceptors we use to detect and process the dimmest of light, we propose here that migraine-type photophobia originates in retinal rods and is transformed through RGCs to brain areas such as the hypothalamus, brainstem, and medial thalamus, each of which can contribute to what patients describe as aversion to light.

Further support to the proposal that migraine-type photophobia originates in the eye could be found in recent discoveries of the role played by calcitonin gene-related peptide (CGRP), a potent neuropeptide vasodilator,7,23 in migraine pathophysiology.20,40 Rich distribution of CGRP in Muller cells (major contributors to the ERG b wave), and calcitonin-like receptor and receptor activity-modifying protein 1 (RAMP1) in the nerve fiber layer of the retina5,54 raise the possibility that the enhanced rod responses to light in the migraine patients is partially mediated by retinal CGRP signaling. In support of this intriguing proposal, and of relevance to the current study, Cao et al.12 reported that intermediate doses of CGRP increase the b-wave amplitude in response to low intensities of photic stimuli. If CGRP plays a functional role in modulating retinal responses to light, the elimination or reduction of photophobia by drugs that are too large to cross the blood–brain barrier and enter the brain may be explained mechanistically by their ability to reduce CGRP signaling in the retina—a concept not tested so far. Along this line, it may be justified to take a closer look at the possibility that CGRP signaling may also alter olfactory, auditory, and balance perception at the level of the olfactory, auditory, and vestibular nerves or their corresponding sensing receptors and organs. Supporting such scenarios are studies showing evidence for presence of CGRP in efferent neurons innervating hair cells organs such as the cochlea, lateral line, semicircular canals, and otolithic end organs2,17,43,48,52 and for CGRP role in efferent modulation of the afferent output of these cells.28 We are unaware of studies showing modulation of olfactory stimuli by CGRP at the level of the nasal mucosa or the olfactory nerve.

Back to Top | Article Outline

Conflict of interest statement

The authors have no conflict of interest to declare.

Back to Top | Article Outline

Acknowledgements

This research was supported by NIH grants R37 NS079678, RO1 NS069847 (RB). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, National Institutes of Health Award UL1 TR001102) and financial contributions from Harvard University and its affiliated academic health care centers. The funding sources were not involved in the study design; collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, or the National Institutes of Health.

Back to Top | Article Outline

References

[1]. Abd-El-Barr MM, Pennesi ME, Saszik SM, Barrow AJ, Lem J, Bramblett DE, Paul DL, Frishman LJ, Wu SM. Genetic dissection of rod and cone pathways in the dark-adapted mouse retina. J Neurophysiol 2009;102:1945–55.
[2]. Adams JC, Mroz EA, Sewell WF. A possible neurotransmitter role for CGRP in a hair-cell sensory organ. Brain Res 1987;419:347–51.
[3]. Afra J, Cecchini AP, De Pasqua V, Albert A, Schoenen J. Visual evoked potentials during long periods of pattern-reversal stimulation in migraine. Brain 1998;121:233–41.
[4]. Aurora SK, Wilkinson F. The brain is hyperexcitable in migraine. Cephalalgia 2007;27:1442–53.
[5]. Blixt FW, Radziwon-Balicka A, Edvinsson L, Warfvinge K. Distribution of CGRP and its receptor components CLR and RAMP1 in the rat retina. Exp Eye Res 2017;161:124–31.
[6]. Boulloche N, Denuelle M, Payoux P, Fabre N, Trotter Y, Geraud G. Photophobia in migraine: an interictal PET study of cortical hyperexcitability and its modulation by pain. J Neurol Neurosurg Psychiatry 2010;81:978–84.
[7]. Brain SD, Grant AD. Vascular actions of calcitonin gene-related peptide and adrenomedullin. Physiol Rev 2004;84:903–34.
[8]. Bramanti P, Grugno R, Vitetta A, Di Bella P, Muscara N, Nappi G. Migraine with and without aura: electrophysiological and functional neuroimaging evidence. Funct Neurol 2005;20:29–32.
[9]. Brown KT, Murakami M. Biphasic form of the early receptor potential of the monkey retina. Nature 1964;204:739–40.
[10]. Brown KT, Wiesel TN. Analysis of the intraretinal electroretinogram in the intact cat eye. J Physiol 1961;158:229–56.
[11]. Brown KT, Wiesel TN. Localization of origins of electroretinogram components by intraretinal recording in the intact cat eye. J Physiol 1961;158:257–80.
[12]. Cao W, Drumheller A, Zaharia M, Lafond G, Brunette JR, Jolicoeur FB. Effects of calcitonin gene-related peptide on the rabbit electroretinogram. Neuropeptides 1993;24:151–7.
[13]. Conway BR. Color vision, cones, and color-coding in the cortex. Neuroscientist 2009;15:274–90.
[14]. Coppola G, Pierelli F, Schoenen J. Is the cerebral cortex hyperexcitable or hyperresponsive in migraine? Cephalalgia 2007;27:1427–39.
[15]. Coppola G, Pierelli F, Schoenen J. Habituation and migraine. Neurobiol Learn Mem 2009;92:249–59.
[16]. Demarquay G, Mauguiere F. Central nervous system underpinnings of sensory hypersensitivity in migraine: insights from neuroimaging and electrophysiological studies. Headache 2016;56:1418–38.
[17]. Dickerson IM, Bussey-Gaborski R, Holt JC, Jordan PM, Luebke AE. Maturation of suprathreshold auditory nerve activity involves cochlear CGRP-receptor complex formation. Physiol Rep 2016;4:e12869.
[18]. Digre KB, Brennan KC. Shedding light on photophobia. J Neuroophthalmol 2012;32:68–81.
[19]. Dodt E. Cone electroretinography by flicker. Nature 1951;168:738.
[20]. Edvinsson L, Haanes KA, Warfvinge K, Krause DN. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat Rev Neurol 2018;14:338–50.
[21]. Ferrari MD, Klever RR, Terwindt GM, Ayata C, van den Maagdenberg AM. Migraine pathophysiology: lessons from mouse models and human genetics. Lancet Neurol 2015;14:65–80.
[22]. Fumal A, Laureys S, Di Clemente L, Boly M, Bohotin V, Vandenheede M, Coppola G, Salmon E, Kupers R, Schoenen J. Orbitofrontal cortex involvement in chronic analgesic-overuse headache evolving from episodic migraine. Brain 2006;129:543–50.
[23]. Grant AD, Tam CW, Lazar Z, Shih MK, Brain SD. The calcitonin gene-related peptide (CGRP) receptor antagonist BIBN4096BS blocks CGRP and adrenomedullin vasoactive responses in the microvasculature. Br J Pharmacol 2004;142:1091–8.
[24]. Guidance for industry migraine: developing drugs for acute treatment. In: USdohah services, editor. Division of Neurology Products, Center for Drug Evaluation and Research. Silver Spring, MD: Food and Drug Administration, 2014.
[25]. Huang J, Cooper TG, Satana B, Kaufman DI, Cao Y. Visual distortion provoked by a stimulus in migraine associated with hyperneuronal activity. Headache 2003;43:664–71.
[26]. Huang J, Delano M, Cao Y. Visual cortical inhibitory function in migraine is not generally impaired: evidence from a combined psychophysical test with an fMRI study. Cephalalgia 2006;26:554–60.
[27]. Jurklies B, Kaelin-Lang A, Niemeyer G. Cholinergic effects on cat retina in vitro: changes in rod- and cone-driven b-wave and optic nerve response. Vision Res 1996;36:797–816.
[28]. Koppl C. Evolution of the octavolateral efferent system. In: Ryugo DK, Fay RR, AN Popper, editors. Aditory and vestibular efferents. London: Springer, 2011. p. 2017–60.
[29]. Lipton RB, Serrano D, Buse DC, Pavlovic JM, Blumenfeld AM, Dodick DW, Aurora SK, Becker WJ, Diener HC, Wang SJ, Vincent MB, Hindiyeh NA, Starling AJ, Gillard PJ, Varon SF, Reed ML. Improving the detection of chronic migraine: development and validation of identify chronic migraine (ID-CM). Cephalalgia 2016;36:203–15.
[30]. Martin H, Sanchez del Rio M, de Silanes CL, Alvarez-Linera J, Hernandez JA, Pareja JA. Photoreactivity of the occipital cortex measured by functional magnetic resonance imaging-blood oxygenation level dependent in migraine patients and healthy volunteers: pathophysiological implications. Headache 2011;51:1520–8.
[31]. McCulloch DL, Marmor MF, Brigell MG, Hamilton R, Holder GE, Tzekov R, Bach M. ISCEV Standard for full-field clinical electroretinography (2015 update). Doc Ophthalmol 2015;130:1–12.
[32]. Nir RR, Lee AJ, Huntington S, Noseda R, Bernstein CA, Fulton AB, Bertisch SM, Hovaguimian A, Buettner C, Borsook D, Burstein R. Color-selective photophobia in ictal vs interictal migraineurs and in healthy controls. PAIN 2018;159:2030–34.
[33]. Noseda R, Bernstein CA, Nir RR, Lee AJ, Fulton AB, Bertisch SM, Hovaguimian A, Cestari DM, Saavedra-Walker R, Borsook D, Doran BL, Buettner C, Burstein R. Migraine photophobia originating in cone-driven retinal pathways. Brain 2016;139:1971–86.
[34]. Noseda R, Kainz V, Jakubowski M, Gooley JJ, Saper CB, Digre K, Burstein R. A neural mechanism for exacerbation of headache by light. Nat Neurosci 2010;13:239–45.
[35]. Noseda R, Lee AJ, Nir RR, Bernstein CA, Kainz VM, Bertisch SM, Buettner C, Borsook D, Burstein R. Neural mechanism for hypothalamic-mediated autonomic responses to light during migraine. Proc Natl Acad Sci U S A 2017;114:E5689–E5692.
[36]. Odom JV, Bach M, Brigell M, Holder GE, McCulloch DL, Tormene AP, Vaegan. ISCEV standard for clinical visual evoked potentials (2009 update). Doc Ophthalmol 2010;120:111–19.
[37]. Penn RD, Hagins WA. Signal transmission along retinal rods and the origin of the electroretinographic a-wave. Nature 1969;223:201–4.
[38]. Pinilla I, Lund RD, Sauve Y. Contribution of rod and cone pathways to the dark-adapted electroretinogram (ERG) b-wave following retinal degeneration in RCS rats. Vision Res 2004;44:2467–74.
[39]. Robson JG, Frishman LJ. Dissecting the dark-adapted electroretinogram. Doc Ophthalmol 1998;95:187–215.
[40]. Russo AF. Calcitonin gene-related peptide (CGRP): a new target for migraine. Annu Rev Pharmacol Toxicol 2015;55:533–52.
[41]. Sandor PS, Dydak U, Schoenen J, Kollias SS, Hess K, Boesiger P, Agosti RM. MR-spectroscopic imaging during visual stimulation in subgroups of migraine with aura. Cephalalgia 2005;25:507–18.
[42]. Schoenen J, Ambrosini A, Sandor PS, Maertens de Noordhout A. Evoked potentials and transcranial magnetic stimulation in migraine: published data and viewpoint on their pathophysiologic significance. Clin Neurophysiol 2003;114:955–72.
[43]. Sliwinska-Kowalska M, Parakkal M, Schneider ME, Fex J. CGRP-like immunoreactivity in the Guinea pig organ of corti: a light and electron microscopy study. Hear Res 1989;42:83–95.
[44]. Smetana GW. The diagnostic value of historical features in primary headache syndromes: a comprehensive review. Arch Intern Med 2000;160:2729–37.
[45]. Stockton RA, Slaughter MM. B-wave of the electroretinogram. A reflection of ON bipolar cell activity. J Gen Physiol 1989;93:101–22.
[46]. Sugita Y, Suzuki H, Tasaki K. Human rods are acting in the light and cones are inhibited in the dark. Tohoku J Exp Med 1989;157:365–72.
[47]. Sugita Y, Tasaki K. The activation of cones in scotopic and rods in photopic vision. Tohoku J Exp Med 1988;156:311–17.
[48]. Takeda N, Doi K, Mori N, Yamazaki H, Tohyama M, Matsunaga T. Localization and fine structure of calcitonin gene-related peptide (CGRP)-like immunoreactive nerve fibres in the organ of Corti of Guinea pigs by immunohistochemistry. Acta Otolaryngol 1987;103:567–71.
[49]. The International Classification of Headache Disorders re. The international classification of headache Disorders, 3rd edition (beta version). Cephalalgia 2013;33:629–808.
[50]. Valeriani M, Fierro B, Brighina F. Brain excitability in migraine: hyperexcitability or inhibited inhibition? PAIN 2007;132:219–20; author reply 220–212.
[51]. Vincent M, Pedra E, Mourao-Miranda J, Bramati IE, Henrique AR, Moll J. Enhanced interictal responsiveness of the migraineous visual cortex to incongruent bar stimulation: a functional MRI visual activation study. Cephalalgia 2003;23:860–8.
[52]. Wackym PA, Micevych PE, Ward PH. Immunoelectron microscopy of the human inner ear. Laryngoscope 1990;100:447–54.
[53]. Walters AB, Smitherman TA. Development and validation of a four-item migraine screening algorithm among a nonclinical sample: the migraine-4. Headache 2016;56:86–94.
[54]. Wang Y, Li Y, Wang M. Involvement of CGRP receptors in retinal spreading depression. Pharmacol Rep 2016;68:935–8.
[55]. Welch KM. Contemporary concepts of migraine pathogenesis. Neurology 2003;61(8 suppl 4):S2–8.
Keywords:

Headache; Electroretinography; Visual-evoked potential; Night vision; Photophobia; CGRP; Retina; CSD

© 2019 International Association for the Study of Pain