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Purpose: Light transmitted by retinal photoreceptors provides the input for circadian photoentrainment. In diabetes, there is a high prevalence of circadian and sleep disruption but the underlying causes are not well understood. Patients with diabetes can exhibit dysfunctional photoreceptors but their role in circadian health is not known. Here we quantify photoreceptor function and contributions to circadian health and sleep in patients with diabetes without diabetic retinopathy and healthy controls., Methods: Rod, cone, and melanopsin function was derived using chromatic pupillometry in 47 participants including 23 patients with type 2 diabetes and 24 age-matched healthy controls after an ophthalmic examination including retinal thickness assessment using optical coherence tomography. Circadian health was determined using dim light melatonin onset (DLMO) and sleep questionnaires; light exposure was measured using actigraphy., Results: Compared with the control group, the patients with diabetes had a significantly earlier DLMO (1 hour) (P = 0.008), higher subjective sleep scores (P < 0.05), a reduction in pupil constriction amplitude for red stimuli (P = 0.039) and for the early postillumination pupil response (PIPR) for blue (P = 0.024) stimuli. There were no between-group differences in the light exposure pattern, activity levels, and intrinsic melanopsin-mediated PIPR amplitude (P > 0.05). A significant correlation was evident between outer retinal thickness and DLMO (r = -0.65, P = 0.03) and the pupil constriction amplitude (r = 0.63, P = 0.03); patients with thinner retina had earlier DLMO and lower pupil amplitudes., Conclusions: We infer that the observed changes in circadian function in patients with no diabetic retinopathy are due to structural and functional outer retinal rod photoreceptor deficits at early stage of diabetic eye disease.

Purpose: Melanopsin expressing intrinsically photosensitive retinal ganglion cells (ipRGC) input to multiple brain regions including those for pupil control, circadian rhythms, sleep and mood regulation. Here we measured ipRGC function and its relationship to sleep quality and depression in patients with advanced AMD., Methods: The melanopsin-mediated post-illumination pupil response (PIPR) was measured in 53 patients with advanced AMD (age 78.8 ± 8.8 years) and in 20 healthy controls (age 72.5 ± 3.3 years). Sleep quality and efficiency was assessed using the Pittsburgh Sleep Quality Index (PSQI). Risk of depression was determined using the Center for Epidemiologic Studies Depression questionnaire., Results: The group with AMD showed significantly reduced pupil constrictions (P = 0.039); PIPR amplitudes (P = 0.003); global sleep scores (P = 0.01); and higher levels of depression (P < 0.001) than the control group. There was a significant correlation between the PIPR amplitude and global sleep score in the AMD group (P = 0.01). The amplitude of PIPR significantly correlated with sleep efficiency (P = 0.008; regression, P = 0.01, R2 = 0.13), but not sleep quality (P = 0.23) in the AMD group. There was no correlation between PIPR and depression scores., Conclusions: Intrinsically photosensitive RGC dysfunction in advanced AMD contributes to the observed reduction in sleep efficiency. The correlation between the melanopsin-mediated PIPR and sleep may indicate reduced photic input to the suprachiasmatic nucleus and ventrolateral preoptic area due to ipRGC dysfunction in AMD.

Purpose: We determine the effect of short-term light adaptation on the pupil light reflex and the melanopsin mediated post-illumination pupil response (PIPR). Inner and outer retinal photoreceptor contributions to the dark-adapted pupil response were estimated., Methods: In Experiment A, light adaptation was studied using short wavelength lights ranging from subthreshold to suprathreshold irradiances for melanopsin signaling that were presented before (5-60 seconds) and after (30 seconds) a melanopsin-exciting stimulus pulse. We quantified the pupil constriction and the poststimulus response amplitudes during dark (PIPR) and light (poststimulus pupil response, PSPR) adaptation. In Experiment B, colored prestimulus adapting lights were univariant for melanopsin or rod excitation., Results: Increasing the prestimulus duration and irradiance of adapting lights increased the pupil constriction amplitude when normalized to the dark-adapted baseline but reduced its amplitude when normalized to the light-adapted baseline. Light adaptation at irradiances suprathreshold for melanopsin activation increased the PIPR amplitude, with larger changes at longer adaptation durations, whereas the PSPR amplitude became more attenuated with increasing irradiances, independent of duration. Rod versus melanospin univariant adaptation did not alter the constriction amplitude but increased the PIPR amplitude in the rod condition. Correlations between millimeter pupil constriction and PIPR amplitudes were eliminated when normalized to the baseline diameter., Conclusions: The findings have implications for standardizing light adaptation paradigms and the choice of pupil metrics in both laboratory and clinical settings. Light and dark adaptation have opposite effects on the pupil metrics, which should be normalized to baseline to minimize significant correlations between constriction and PIPR amplitudes.

Purpose: To determine whether melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) inputs to the pupil light reflex (PLR) are affected in early age-related macular degeneration (AMD)., Methods: The PLR was measured in 40 participants (20 early AMD and 20 age-matched controls) using a custom-built Maxwellian view pupillometer. Sinusoidal stimuli (0.5 Hz, 11.9 seconds duration, 35.6° diameter) were presented to the study eye and the consensual pupil response was measured to lights with high melanopsin excitation (464 nm [blue]) and with low melanopsin excitation (638 nm [red]) that biased activation to the outer retina. Two melanopsin PLR metrics were quantified: the phase amplitude percentage (PAP) during the sinusoidal stimulus presentation and the post-illumination pupil response (PIPR). The PLR during stimulus presentation was analyzed using latency to constriction, the transient pupil response and maximum pupil constriction metrics. Diagnostic accuracy was evaluated using receiver operating characteristic (ROC) curves., Results: The blue PIPR was significantly less sustained in the early AMD group (P < 0.001). The red PIPR was not significantly different between groups (P > 0.05). The PAP and blue stimulus constriction amplitude were significantly lower in the early AMD group (P < 0.05). There was no significant difference between groups in the latency or transient amplitude for both stimuli (P > 0.05). ROC analysis showed excellent diagnostic accuracy for the blue PIPR metrics (area under the curve > 0.9)., Conclusions: This is the initial report that the melanopsin-controlled PIPR is dysfunctional in early AMD. The noninvasive, objective measurement of the ipRGC controlled PIPR has excellent diagnostic accuracy for early AMD.

Purpose: The post-illumination pupil response (PIPR) has been quantified using four metrics, but the spectral sensitivity of only one is known; here we determine the other three. To optimize the human PIPR measurement, we determine the protocol producing the largest PIPR, the duration of the PIPR, and the metric(s) with the lowest coefficient of variation., Methods: The consensual pupil light reflex (PLR) was measured with a Maxwellian view pupillometer. Experiment 1: Spectral sensitivity of four PIPR metrics (plateau, 6 seconds, area under curve early and late recovery) was determined from a criterion PIPR to a 1-second pulse and fitted with vitamin A1 nomogram (λ(max) = 482 nm). Experiment 2: The PLR was measured as a function of three stimulus durations (1 second, 10 seconds, 30 seconds), five irradiances spanning low to high melanopsin excitation levels (retinal irradiance: 9.8-14.8 log quanta.cm(-2).s(-1)), and two wavelengths, one with high (465 nm) and one with low (637 nm) melanopsin excitation. Intra- and interindividual coefficients of variation (CV) were calculated., Results: The melanopsin (opn4) photopigment nomogram adequately describes the spectral sensitivity of all four PIPR metrics. The PIPR amplitude was largest with 1-second short-wavelength pulses (≥ 12.8 log quanta.cm(-2).s(-1)). The plateau and 6-second PIPR showed the least intra- and interindividual CV (≤ 0.2). The maximum duration of the sustained PIPR was 83.0 ± 48.0 seconds (mean ± SD) for 1-second pulses and 180.1 ± 106.2 seconds for 30-second pulses (465 nm; 14.8 log quanta.cm(-2).s(-1))., Conclusions: All current PIPR metrics provide a direct measure of the intrinsic melanopsin photoresponse. To measure progressive changes in melanopsin function in disease, we recommend that the PIPR be measured using short-duration pulses (e.g., ≤ 1 second) with high melanopsin excitation and analyzed with plateau and/or 6-second metrics. Our PIPR duration data provide a baseline for the selection of interstimulus intervals between consecutive pupil testing sequences.

Purpose: To determine whether glaucoma alters intrinsically photosensitive retinal ganglion cell (ipRGC) function., Methods: Forty-one patients (25 with glaucoma and 16 healthy age-matched control participants) were tested. Intrinsically photosensitive retinal ganglion cell function was directly measured by the sustained, postillumination pupil response (PIPR). Forty-one eyes of 41 participants were tested with 7°, 10-second, short-wavelength (488 nm; bluish) and long-wavelength (610 nm; reddish) stimuli (14.2 log photons · cm(-2) · s(-1)) presented to the right eye in Maxwellian view, and the consensual pupil response of the left eye was measured by infrared pupillometry. The difference between PIPR amplitude (percentage baseline pupil diameter), net PIPR (percentage change) and kinetics (time in mm · s(-1) to the PIPR plateau) for the blue and red stimuli in patients with early and advanced (moderate/severe) glaucoma was compared to that in age-matched control participants., Results: The blue PIPR was significantly smaller between normal participants and patients with advanced glaucoma, as well as between those with early and those with advanced glaucoma (P < 0.05). The kinetics of the red and blue PIPRs were not significantly different between any groups. Normal age-matched participants and patients with early-stage glaucoma were not significantly different on any parameter, and neither was the normal and glaucoma group (advanced and early combined)., Conclusions: Persons with moderate and severe glaucoma have a dysfunctional ipRGC-mediated PIPR. Intrinsically photosensitive retinal ganglion cell function measured directly with the PIPR may become a clinical indicator of progressive changes in glaucoma.

Purpose: To determine whether participants with normal visual acuity, no ophthalmoscopically signs of age-related maculopathy (ARM) in both eyes, and who are carriers of the CFH, LOC387715, and HRTA1 high-risk genotypes (gene-positive) have impaired rod- and cone-mediated mesopic visual function compared with persons who do not carry the risk genotypes (gene-negative)., Methods: Fifty-three Caucasian study participants (mean 55.8 ± 6.1) were genotyped for CFH, LOC387715/ARMS2, and HRTA1 polymorphisms. Single-nucleotide polymorphisms were genotyped in the CFH (rs380390), LOC387715/ARMS2 (rs10490924), and HTRA1 (rs11200638) genes using optimized gene-expression assays. The critical fusion frequency (CFF) mediated by cones alone (long-, middle-, and short-wavelength sensitive cones, LMS) and by the combined activities of cones and rods (LMSR) were determined. The stimuli were generated using a four-primary photostimulator that provides independent control of the photoreceptor excitation under mesopic light levels. Visual function was further assessed using standard clinical tests, flicker perimetry, and microperimetry., Results: The mesopic CFF mediated by rods and cones (LMSR) was significantly reduced in gene-positive compared to gene-negative participants after correction for age (P = 0.03). Cone-mediated CFF (LMS) was not significantly different between gene-positive and -negative participants. There were no significant associations between flicker perimetry and microperimetry and genotype., Conclusions: This is the first study to relate ARM risk genotypes with mesopic visual function in clinically normal persons. These preliminary results could become of clinical importance because mesopic vision may be used as a biomarker to document subclinical retinal changes in persons with risk genotypes and to determine whether those persons progress into manifest disease.

Purpose: To measure the effect of acute, mild, systemic hypoxia on neuroretinal function in two different age groups., Methods: The slow-flash paradigm of the multifocal electroretinogram (mfERG) was measured in two different oxygenation levels. Twelve participants of two age groups (28 +/- 4 and 55 +/- 5 years) breathed room air (normoxia) or 12% oxygen (hypoxia)., Results: During normoxia (SaO(2) = 98%) there was a significantly different effect between the younger and older participants on the mfERG positive waveform components (N1P1 amplitudes and P1 implicit times; P < 0.001). Hypoxia (SaO(2) = 90%) significantly decreased N1P1 response density amplitudes in the central retinal field in both groups, with a larger effect in the older group (P < 0.001). There was no significant change in function of the cellular generators of oscillatory potentials (OPs)., Conclusion: The results extend recent findings by showing a greater effect of hypoxia on ON- and OFF-bipolar cell function in healthy older persons than in younger persons, but no effect on OPs during moderate acute hypoxia in either age group.

Purpose: To investigate the global-flash multifocal electroretinogram (mfERG) in early age-related maculopathy (ARM)., Methods: Thirty-two eyes from 20 healthy control subjects and 12 age-matched subjects with early ARM were investigated with the conventional and the global-flash mfERG. Early ARM subjects were graded according to an international grading system. The conventional mfERG consisted of 103 hexagons flickering according to a pseudorandom m-sequence. The global-flash mfERG paradigm used four frames starting with the conventional m-sequence stimulation, followed by a dark frame, a global flash, and another dark frame. The responses include a direct response (DR) and a later induced component (IC). The first-order kernel peak-to-trough response densities of the conventional mfERG (N1P1), the global-flash DR and IC, and the implicit times of the conventional P1, global-flash DR, and IC peak were analyzed after averaging the results into five groups according to five field locations: a central area and four quadrants., Results: There was a significant reduction of the global-flash mfERG DR response density (P < or = 0.05) in the early ARM group compared with the control group. Neither the IC response density nor DR and IC implicit times were significantly impaired. However, the superior retina showed longer implicit times than did the inferior retina for the DR in the early ARM group. There was no significant correlation between funduscopic features and the central averaged responses of the global-flash mfERG (for the DR response density: r = -0.19, P = 0.3, or for the DR implicit time: r = -0.18, P = 0.3). None of the conventional mfERG parameters was significantly different between the two groups., Conclusions: The global-flash mfERG detects deficits in early ARM before the conventional mfERG. Retinal ischemia may play a role in producing function impairment in ARM.