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Background: Melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) signal the environmental light to mediate circadian photoentrainment and sleep-wake cycles. There is high prevalence of circadian and sleep disruption in people with Parkinson's disease, however the underlying mechanisms of these symptoms are not clear., Objective: Based on recent evidence of anatomical and functional loss of melanopsin ganglion cells in Parkinson's disease, we evaluate the link between melanopsin function, circadian, and sleep behavior., Methods: The pupil light reflex and melanopsin-mediated post-illumination pupil response were measured using chromatic pupillometry in 30 optimally medicated people with Parkinson's disease and 29 age-matched healthy controls. Circadian health was determined using dim light melatonin onset, sleep questionnaires, and actigraphy. Ophthalmic examination quantified eye health and optical coherence tomography measured retinal thickness., Results: The melanopsin-mediated post-illumination pupil response amplitudes were significantly reduced in Parkinson's disease (p < 0.0001) and correlated with poor sleep quality (r2 = 33; p < 0.001) and nerve fiber layer thinning (r2 = 0.40; p < 0.001). People with Parkinson's disease had significantly poorer sleep quality with higher subjective sleep scores (p < 0.05) and earlier melatonin onset (p = 0.01). Pupil light (outer retinal) response metrics, daily light exposure and outer retinal thickness were similar between the groups (p > 0.05)., Conclusion: Our evidence-based data identify a mechanism through which inner retinal ipRGC dysfunction contributes to sleep disruption in Parkinson's disease in the presence of normal outer retinal (rod-cone photoreceptor) function. Our findings provide a rationale for designing new treatment approaches in Parkinson's disease through melanopsin photoreceptor-targeted light therapies for improving sleep-wake cycles.

The precise control of visual sensitivity to variations in external lighting is critical for optimising human visual function in a changing environment. In photopic illumination, the cone photoreceptors and their post-receptoral pathways have a primary role in regulating these adjustments; it is not fully understood how a small population of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) can interact with the three cone photoreceptor classes to modulate human visual function. Here we investigated interactions between these inner and outer retinal photoreceptor classes in participants with trichromatic colour vision under conditions that independently controlled the excitations of ipRGCs, cones and rods in the retina. In the peripheral retina, we show that interaction between melanopsin- and cone-directed signals affect conscious, image-forming vision. The interaction patterns are inconsistent with any potential effects arising from artefacts due to open-field and penumbral-cone contrasts, or rod intrusion. For cone signals mediated via each of the three primary visual pathways, melanopsin activation enhances contrast sensitivity. The contrast response functions indicate this enhancement is a more generalised facilitation effect that onsets at ∼9% melanopsin contrast. The implication for human vision is that the contrast sensitivity of cone-mediated visual processes can be modulated by the level of melanopsin excitation in the stimulus light., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

This study investigated how invisible extrinsic temporal white noise that correlates with the activity of one of the three [magnocellular (MC), parvocellular (PC), or koniocellular (KC)] post-receptoral pathways alters mesopic rod signaling. A four-primary photostimulator provided independent control of the rod and three cone photoreceptor excitations. The rod contributions to the three post-receptoral pathways were estimated by perceptually matching a 20% contrast rod pulse by independently varying the LMS (MC pathway), +L-M (PC pathway), and S-cone (KC pathway) excitations. We show that extrinsic cone noise caused a predominant decrease in the overall magnitude and ratio of the rod contributions to each pathway. Thus, the relative cone activity in the post-receptoral pathways determines the relative mesopic rod inputs to each pathway.

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.

Melanopsin expressing intrinsically photosensitive Retinal Ganglion Cells (ipRGCs) entirely control the post-illumination pupil response (PIPR) from 6 s post-stimulus to the plateau during redilation after light offset. However, the photoreceptor contributions to the early redilation phase of the PIPR (< 6 s post-stimulus) have not been reported. Here, we evaluated the photoreceptor contributions to the early phase PIPR (0.6 s to 5.0 s) by measuring the spectral sensitivity of the criterion PIPR amplitude in response to 1 s light pulses at five narrowband stimulus wavelengths (409, 464, 508, 531 and 592 nm). The retinal irradiance producing a criterion PIPR was normalised to the peak and fitted by either a single photopigment nomogram or the combined melanopsin and rhodopsin spectral nomograms with the +L+M cone photopic luminous efficiency (Vλ) function. We show that the PIPR spectral sensitivity at times ≥ 1.7 s after light offset is best described by the melanopsin nomogram. At times < 1.7 s, the peak PIPR sensitivity shifts to longer wavelengths (range: 482 to 498 nm) and is best described by the combined photoreceptor nomogram, with major contributions from melanopsin and rhodopsin. This first report of melanopsin and rhodopsin contributions to the early phase PIPR is in line with the electrophysiological findings of ipRGC and rod signalling after the cessation of light stimuli and provides a cut-off time for isolating photoreceptor specific function in healthy and diseased eyes., Competing Interests: The authors have declared that no competing interests exist.

Intrinsically photosensitive retinal ganglion cells (ipRGCs) regulate pupil size by integrating extrinsic rod and cone signals with intrinsic melanopsin-mediated phototransduction. Light adapted pupil diameter is determined by the corneal flux density (CFD), and for central visual field stimulation the melanopsin-mediated post-illumination pupil response (PIPR) follows this same CFD relationship. Rods, cones, and ipRGCs vary in size, density, and distribution across the retina, but how these differences affect the amplitude and timing of the extrinsic and intrinsic pupil light reflex in the central and peripheral retina is unknown. We determined the relationship between stimulus area and photon flux with stimuli constant for CFD, irradiance, or area at central (0°) and peripheral (20°) eccentricities with high and low melanopsin excitation. We show that the pupil constriction amplitude was similar at both eccentricities and the time to minimum diameter increased as melanopsin excitation increased. In contrast, the peripheral PIPR follows a CFD relationship but with lower amplitude compared with that at the fovea. This indicates differences in the spatial and temporal characteristics of extrinsic and intrinsic ipRGC inputs to the pupil control pathway for the central and peripheral retina. The eccentricity-dependent change in PIPR amplitude may be analogous to the hill of vision observed in visual perimetry; such knowledge is an important precursor to the development of pupil perimetry paradigms to measure the PIPR in select regions of the visual field.

Melanopsin containing intrinsically photosensitive Retinal Ganglion cells (ipRGCs) mediate the pupil light reflex (PLR) during light onset and at light offset (the post-illumination pupil response, PIPR). Recent evidence shows that the PLR and PIPR can provide non-invasive, objective markers of age-related retinal and optic nerve disease; however there is no consensus on the effects of healthy ageing or refractive error on the ipRGC mediated pupil function. Here we isolated melanopsin contributions to the pupil control pathway in 59 human participants with no ocular pathology across a range of ages and refractive errors. We show that there is no effect of age or refractive error on ipRGC inputs to the human pupil control pathway. The stability of the ipRGC mediated pupil response across the human lifespan provides a functional correlate of their robustness observed during ageing in rodent models.

Rods, cones and melanopsin containing intrinsically photosensitive retinal ganglion cells (ipRGCs) operate in concert to regulate pupil diameter. The temporal properties of intrinsic ipRGC signalling are distinct to those of rods and cones, including longer latencies and sustained signalling after light offset. We examined whether the melanopsin mediated post-illumination pupil response (PIPR) and pupil constriction were dependent upon the inter-stimulus interval (ISI) between successive light pulses and the temporal frequency of sinusoidal light stimuli. Melanopsin excitation was altered by variation of stimulus wavelength (464 nm and 638 nm lights) and irradiance (11.4 and 15.2 log photons cm(-2) s(-1)). We found that 6s PIPR amplitude was independent of ISI and temporal frequency for all melanopsin excitation levels, indicating complete summation. In contrast to the PIPR, the maximum pupil constriction increased with increasing ISI with high and low melanopsin excitation, but time to minimum diameter was slower with high melanopsin excitation only. This melanopsin response to briefly presented pulses (16 and 100 ms) slows the temporal response of the maximum pupil constriction. We also demonstrate that high melanopsin excitation attenuates the phasic peak-trough pupil amplitude compared to conditions with low melanopsin excitation, indicating an interaction between inner and outer retinal inputs to the pupil light reflex. We infer that outer retina summation is important for rapidly controlling pupil diameter in response to short timescale fluctuations in illumination and may occur at two potential sites, one that is presynaptic to extrinsic photoreceptor input to ipRGCs, or another within the pupil control pathway if ipRGCs have differential temporal tuning to extrinsic and intrinsic signalling., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are a class of photoreceptors with established roles in non-image-forming processes. Their contributions to image-forming vision may include the estimation of brightness. Animal models have been central for understanding the physiological mechanisms of ipRGC function and there is evidence of conservation of function across species. Intrinsically photosensitive retinal ganglion cells can be divided into five ganglion cell subtypes that show morphological and functional diversity. Research in humans has established that ipRGCs signal environmental irradiance to entrain the central body clock to the solar day for regulating circadian processes and sleep. In addition, ipRGCs mediate the pupil light reflex (PLR), making the PLR a readily accessible behavioral marker of ipRGC activity. Less is known about ipRGC function in retinal and optic nerve disease, with emerging research providing insight into their function in diabetes, retinitis pigmentosa, glaucoma, and hereditary optic neuropathy. We briefly review the anatomical distributions, projections, and basic physiological mechanisms of ipRGCs and their proposed and known functions in animals and humans with and without eye disease. We introduce a paradigm for differentiating inner and outer retinal inputs to the pupillary control pathway in retinal disease and apply this paradigm to patients with age-related macular degeneration (AMD). In these cases of patients with AMD, we provide the initial evidence that ipRGC function is altered and that the dysfunction is more pronounced in advanced disease. Our perspective is that with refined pupillometry paradigms, the PLR can be extended to AMD assessment as a tool for the measurement of inner and outer retinal dysfunction.

Purpose: This study investigates the clinical utility of the melanopsin-expressing intrinsically photosensitive retinal ganglion cell (ipRGC) controlled post-illumination pupil response (PIPR) as a novel technique for documenting inner retinal function in patients with Type II diabetes without diabetic retinopathy., Methods: The PIPR was measured in seven patients with Type II diabetes, normal retinal nerve fibre thickness and no diabetic retinopathy compared to healthy age-similar controls. A 488- and 610-nm, 7.15-diameter stimulus was presented in Maxwellian view to the right eye and the left consensual pupil light reflex was recorded., Results: The group data for the blue PIPR (488 nm) identified a trend of reduced ipRGC function in patients with diabetes with no retinopathy. The transient pupil constriction was lower on average in the diabetic group. The relationship between duration of diabetes and the blue PIPR amplitude was linear, suggesting that ipRGC function decreases with increasing diabetes duration., Conclusion: This is the first report to show that the ipRGC-controlled PIPR may have clinical applications as a non-invasive technique for determining the progression of inner neuroretinal changes in patients with diabetes before they are ophthalmoscopically or anatomically evident. The lower transient pupil constriction amplitude indicates that outer retinal photoreceptor inputs to the pupil light reflex may also be affected in diabetes., (© 2011 The Authors. Acta Ophthalmologica © 2011 Acta Ophthalmologica Scandinavica Foundation.)

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.

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18-30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation.

Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter, recovery and post-illumination components of the pupillary light reflex and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm. This review summarises recent progress in understanding intrinsically photosensitive ganglion cell histology and physiological properties in the context of their contribution to the pupillary and circadian functions and introduces a clinical framework for using the pupillary light reflex to evaluate inner retinal (intrinsically photosensitive melanopsin ganglion cell) and outer retinal (rod and cone photoreceptor) function in the detection of retinal eye disease.