Melanopsin-containing Retinal Ganglion Cells Research Articles

The effect of reducing blue light from smartphone screen on subjective quality of sleep among students

ABSTRACT The exposure of humans to artificial light at night (ALAN) with predominant blue part of the visible spectrum is strongly influencing circadian rhythm and sleep through melanopsin-containing retinal ganglion cells (RGC). We hypothesized that reducing the amount of emitted blue light from screens of mobile phones during the night will increase sleep quality in our student population. The aim of the work was to investigate the effect of reducing blue light from smartphone screen during the night on subjective quality of sleep among students of medicine. The target population was students of medicine aged 20 to 22 years old of both sexes. The primary outcome of the study was subjective sleep quality, assessed by the Serbian version of the Pittsburgh Sleep Quality Index (PSQI). The mean total PSQI score before intervention was 6.83 ± 2.73 (bad), while after the intervention the same score was statistically significant reduced to 3.93 ± 1.68 (good) with large effect size. The study has shown that a reduction of blue light emission from LED backlight screens of mobile phones during the night leads to improved subjective quality of sleep in students, as well as improvement in daytime functioning and going to sleep.

0199 Iris color predicts melanopsin-driven retinal responses in older but not younger individuals

Abstract Introduction The retina contains melanopsin-containing retinal ganglion cells, which underlie non-image forming responses to light. The Post-Illumination Pupil Response (PIPR) can assess melanopsin cell responsivity, with applications for sleep disorders, mood disorders, and circadian entrainment. Lighter pigmented irises allow more light to pass through the retina. The present study tested an association between the PIPR and iris pigmentation. Methods Participants (N=49) included seasonal depression (n=26) and never-depressed controls (n=23). Photos of participants’ irises were rated using both the Franssen (2008) scale, a set of 24 standardized iris photos, and the Mackey (2011) scale, a 9-category rating system. Red and blue stimuli 13.5 log photons/cm2/s were presented, and infrared pupillometry measured pupil diameter for 40 seconds. We used multilevel regression with a random intercept of participant to predict the PIPR from each iris rating system separately, controlling for age, gender, and circadian time of testing determined from Dim Light Melatonin Onset. Results Agreement between raters, calculated using Cohen's κ, was moderate for both scales (Franssen, κ=0.57, 95% CI: 0.42 to 0.71, p<0.001; Mackey, κ=0.67, 95% CI: 0.53 to 0.81, p<0.001). Bivariate correlations showed age was inversely associated with iris color: older individuals had lighter iris pigmentation. Analyses were therefore stratified by age (older >=31 years: n=24; younger <31 years, n=25). Greater retinal responsivity was associated with lighter iris pigmentation in the older sample (Mackey: unstandardized b=-0.016; SE=0.005; p=0.002; Franssen: unstandardized b=-0.006; SE=0.002, p=0.002), but not the younger sample (Mackey: unstandardized b=-0.0008; SE=0.003; p=0.770; Franssen: unstandardized b=-0.0009; SE=0.002, p=0.619). There was no effect of iris color on PIPR in the whole sample (p’s >0.13). Conclusion Iris color explained ~8% of variance in the PIPR, indicating that PIPR studies should recruit samples with similar distributions of iris pigmentation across conditions and ages, as this finding was only seen in the older sample with more individuals with lighter iris pigmentation. Future studies will test iris pigmentation by light exposure interactions on the PIPR. Light stimuli focused to a point on the pupil (i.e., Maxwellian) would eliminate variation in the amount of light incident on the retina due to iris pigmentation. Support (If Any) NIMH K.A.R. MH103303

0196 Retinal responsivity is associated with circadian phase and circadian alignment but not sleep timing

Abstract Introduction Light entrains the central circadian clock, with projections from the retina to the SCN through melanopsin-containing retinal ganglion cells (ipRGCs). Altered responsivity to light reflects ipRGC functioning and may be a physiological vulnerability for disrupted photoentrainment. Understanding how retinal responsivity relates to sleep and circadian timing may inform who might most benefit from sleep and circadian interventions. Methods 64 participants (85 observations) ages 20-66 years old were recruited during winter (n=35) and summer months (n=50), and included individuals with seasonal depression (n=33) and nonseasonal, never depressed controls (n=31). The post-illumination pupil response (PIPR) to red and blue light was used to measure the responsivity of ipRGCs (average 1:30pm; 10am-7pm). Circadian phase was assessed using Dim Light Melatonin Onset (DLMO), collected every 30-minutes on Friday evenings. Midsleep timing was measured using actigraphy (average number nights=4), and circadian alignment was calculated as the DLMO-midsleep phase angle. We performed a multilevel regression to determine the relationship between PIPR and markers of sleep and circadian timing, accounting for repeated seasonal assessments with a random intercept of participant. Covariates included age, gender, diagnostic group, and circadian time of PIPR assessments. We ran sensitivity analyses including photoperiod length on the day of PIPR assessment to account for potential light exposure on the PIPR. Results Greater retinal responsivity was associated with later DLMO (b=4.45; partially standardized b=0.28; SE=1.84; p=0.03), and shorter DLMO-midsleep phase angle (b= -7.33; partially standardized b= -0.32; SE=2.51; p=0.004), but not midsleep (b= -3.44; partially standardized b= -0.14; SE=2.35; p>0.05). Individuals with later DLMO had PIPR assessments at earlier circadian times (b= -0.12; SE=0.04; p=0.01). Older participants (b= -0.04; SE=0.02; p=0.04) and controls (b= -0.95; SE=0.44; p=0.04) had earlier sleep midpoints, but covariates were not associated with circadian markers. The association between circadian timing and PIPR became nonsignificant (b=4.15; partially standardized b=0.26; SE=1.88; p=0.06) when including photoperiod. Conclusion Retinal responsivity was associated with circadian but not behavioral sleep timing, suggesting ipRGC functioning may have downstream effects on circadian entrainment. Assessing circadian variation of retinal responsivity remains a crucial next step prior to testing whether retinal responsivity impacts response to circadian-focused interventions. Support (If Any) NIMH K.A.R.MH103303

Melanopsin-driven pupil response in summer and winter in unipolar seasonal affective disorder

A retinal subsensitivity to environmental light may trigger Seasonal Affective Disorder (SAD) under low wintertime light conditions. The main aim of this study was to assess the responses of melanopsin-containing retinal ganglion cells in participants (N= 65) diagnosed with unipolar SAD compared to controls with no history of depression. Participants attended a summer visit, a winter visit, or both. Retinal responses to light were measured using the post-illumination pupil response (PIPR) to assess melanopsin-driven responses in the non-visual light input pathway. Linear mixed-effects modeling was used to test a group*season interaction on the Net PIPR (red minus blue light response, percent baseline). We observed a significant group*season interaction such that the PIPR decreased from summer to winter significantly in the SAD group while not in the control group. The SAD group PIPR was significantly lower in winter compared to controls but did not differ between groups in summer. Only 60% of the participants underwent an eye health exam, although all participants reported no history of retinal pathology, and eye exam status was neither associated with outcome nor different between groups. This seasonal variation in melanopsin driven non-visual responses to light may be a risk factor for SAD, and further highlights individual differences in responses to light for direct or indirect effects of light on mood.

A quantitative analysis of the retinofugal projections in congenital and late-onset blindness

Vision loss early in life has dramatic consequences on the organization of the visual system and hence on structural plasticity of its remnant components. Most of the studies on the anatomical changes in the brain following visual deprivation have focused on the re-organization of the visual cortex and its afferent and efferent projections. In this study, we performed a quantitative analysis of the volume and size of the optic chiasm, optic nerve, optic tract and the lateral geniculate nucleus (LGN), the retino recipient thalamic nucleus. Analysis was carried out on structural T1-weighted MRIs from 22 congenitally blind (CB), 14 late blind (LB) and 29 age -and sex-matched sighted control (SC) subjects. We manually segmented the optic nerve, optic chiasm and optic tract, while LGN volumes were extracted using in-house software. We also measured voxel intensity of optic nerve, optic chiasm and optic tract. Mean volumes of the optic nerve, optic tract and optic chiasm were reduced by 50 to 60% in both CB and LB participants. No significant differences were found between the congenitally and late-onset blind participants for any of the measures. Our data further revealed reduced white matter voxel intensities in optic nerve, optic chiasm and optic tract in blind compared to sighted participants, suggesting decreased myelin content in the atrophied white matter. The LGN was reduced by 50% and 44% in CB and LB, respectively. In LB, optic nerve volume correlated negatively with the blindness duration index; no such correlation was found for optic chiasm, optic tract and LGN. The observation that despite the absence of visual input about half of the subcortical retinofugal projections are structurally preserved raises the question of their functional role. One possibility is that the surviving fibers play a role in the maintenance of circadian rhythms in the blind through the intrinsically photosensitive melanopsin-containing retinal ganglion cells.

The Effect of Refractive Error on Melanopsin-Driven Pupillary Responses.

PurposeHuman and animal studies suggest that light-mediated dopamine release may underlie the protective effect of time outdoors on myopia development. Melanopsin-containing retinal ganglion cells may be involved in this process by integrating ambient light exposure and regulating retinal dopamine levels. The study evaluates this potential involvement by examining whether melanopsin-driven pupillary responses are associated with adult refractive error.MethodsSubjects were 45 young adults (73% female, 24.1 ± 1.8 years) with refractive errors ranging from –6.33 D to +1.70 D. The RAPDx (Konan Medical) pupillometer measured normalized pupillary responses to three forms of square-wave light pulses alternating with darkness at 0.1 Hz: alternating long wavelength (red, peak at 608 nm) and short wavelength (blue, peak at 448 nm), followed by red only and then blue only.ResultsNon-myopic subjects displayed greater pupillary constriction in the blue-only condition and slower redilation following blue light offset than subjects with myopia (P = 0.011). Pupillary responses were not significantly different between myopic and non-myopic subjects in the red-only condition (P = 0.15). More hyperopic/less myopic refractive error as a continuous variable was linearly related to larger increases in pupillary constriction in response to blue-only stimuli (r = 0.48, P = 0.001).ConclusionsRepeated light exposures to blue test stimuli resulted in an adaptation in the pupillary response (more constriction and slower redilation), presumably due to increased melanopsin-mediated input in more hyperopic/less myopic adults. This adaptive property supports a possible role for these ganglion cells in the protective effects of time outdoors on myopia development.

Dopaminergic Retinal Cell Loss and Visual Dysfunction in Parkinson Disease.

Considering the demonstrated implication of the retina in Parkinson disease (PD) pathology and the importance of dopaminergic cells in this tissue, we aimed to analyze the state of the dopaminergic amacrine cells and some of their main postsynaptic neurons in the retina of PD. Using immunohistochemistry and confocal microscopy, we evaluated morphology, number, and synaptic connections of dopaminergic cells and their postsynaptic cells, AII amacrine and melanopsin-containing retinal ganglion cells, in control and PD eyes from human donors. In PD, dopaminergic amacrine cell number was reduced between 58% and 26% in different retinal regions, involving a decline in the number of synaptic contacts with AII amacrine cells (by 60%) and melanopsin cells (by 35%). Despite losing their main synaptic input, AII cells were not reduced in number, but they showed cellular alterations compromising their adequate function: (1) a loss of mitochondria inside their lobular appendages, which may indicate an energetic failure; and (2) a loss of connexin 36, suggesting alterations in the AII coupling and in visual signal transmission from the rod pathway. The dopaminergic system impairment and the affection of the rod pathway through the AII cells may explain and be partially responsible for the reduced contrast sensitivity or electroretinographic response described in PD. Also, dopamine reduction and the loss of synaptic contacts with melanopsin cells may contribute to the melanopsin retinal ganglion cell loss previously described and to the disturbances in circadian rhythm and sleep reported in PD patients. These data support the idea that the retina reproduces brain neurodegeneration and is highly involved in PD pathology. ANN NEUROL 2020;88:893-906.

Examination of Zinc in the Circadian System

Zinc is a trace element that is essential for a large number of biological and biochemical processes in the body. In the nervous system zinc is packaged into synaptic vesicles by the ZnT3 transporter, and synaptic release of zinc can influence the activity of postsynaptic cells, either directly through its own cognate receptors, or indirectly by modulating activation of receptors for other neurotransmitters. Here, we explore the anatomical and functional aspects of zinc in the circadian system. Melanopsin-containing retinal ganglion cells in the mouse retina were found to colocalize ZnT3, indicating that they can release zinc at their synaptic targets. While the master circadian clock in the hamster suprachiasmatic nucleus (SCN) was found to contain, at best, sparse zincergic input, the intergeniculate leaflet (IGL) of hamsters and mice were found to have prominent zincergic input. Levels of zinc in these areas were not affected by time of day. Additionally, IGL zinc staining persisted following enucleation, indicating other prominent sources of zinc instead of, or in addition to, the retina. Neither enhancement nor chelation of free zinc at either the SCN or IGL altered circadian responses to phase-shifting light in hamsters. Finally, entrainment, free-running, and circadian responses to light were explored in mice lacking the ZnT3 gene. In every aspect explored, the ZnT3 knockout mice were not significantly different from their wildtype counterparts. These findings highlight the presence of zinc in areas critical for circadian functioning but have yet to identify a role for zinc in these areas.

Photosensitive Melanopsin-Containing Retinal Ganglion Cells in Health and Disease: Implications for Circadian Rhythms.

Melanopsin-containing retinal ganglion cells (mRGCs) represent a third class of retinal photoreceptors involved in regulating the pupillary light reflex and circadian photoentrainment, among other things. The functional integrity of the circadian system and melanopsin cells is an essential component of well-being and health, being both impaired in aging and disease. Here we review evidence of melanopsin-expressing cell alterations in aging and neurodegenerative diseases and their correlation with the development of circadian rhythm disorders. In healthy humans, the average density of melanopsin-positive cells falls after age 70, accompanied by age-dependent atrophy of dendritic arborization. In addition to aging, inner and outer retinal diseases also involve progressive deterioration and loss of mRGCs that positively correlates with progressive alterations in circadian rhythms. Among others, mRGC number and plexus complexity are impaired in Parkinson’s disease patients; changes that may explain sleep and circadian rhythm disorders in this pathology. The key role of mRGCs in circadian photoentrainment and their loss in age and disease endorse the importance of eye care, even if vision is lost, to preserve melanopsin ganglion cells and their essential functions in the maintenance of an adequate quality of life.

Rod Photoreceptor Activation Alone Defines the Release of Dopamine in the Retina

Retinal dopamine is released by a specialized subset of amacrine cells in response to light and has a potent influence on how the retina responds to, and encodes, visual information. Here, we address the critical question of which retinal photoreceptor is responsible for coordinating the release of this neuromodulator. Although all three photoreceptor classes-rods, cones, and melanopsin-containing retinal ganglion cells (mRGCs)-have been shown to provide electrophysiological inputs to dopaminergic amacrine cells (DACs), we show here that the release of dopamine is defined only by rod photoreceptors. Remarkably, this rod signal coordinates both a suppressive signal at low intensities and drives dopamine release at very bright light intensities. These data further reveal that dopamine release does not necessarily correlate with electrophysiological activity of DACs and add to a growing body of evidence that rods define aspects of retinal function at very bright light levels.

Effect of Single and Combined Monochromatic Light on the Human Pupillary Light Response.

The pupillary light reflex (PLR) is a neurological reflex driven by rods, cones, and melanopsin-containing retinal ganglion cells. Our aim was to achieve a more precise picture of the effects of 5-min duration monochromatic light stimuli, alone or in combination, on the human PLR, to determine its spectral sensitivity and to assess the importance of photon flux. Using pupillometry, the PLR was assessed in 13 participants (6 women) aged 27.2 ± 5.41 years (mean ± SD) during 5-min light stimuli of purple (437 nm), blue (479 nm), red (627 nm), and combinations of red+purple or red+blue light. In addition, nine 5-min, photon-matched light stimuli, ranging in 10 nm increments peaking between 420 and 500 nm were tested in 15 participants (8 women) aged 25.7 ± 8.90 years. Maximum pupil constriction, time to achieve this, constriction velocity, area under the curve (AUC) at short (0–60 s), and longer duration (240–300 s) light exposures, and 6-s post-illumination pupillary response (6-s PIPR) were assessed. Photoreceptor activation was estimated by mathematical modeling. The velocity of constriction was significantly faster with blue monochromatic light than with red or purple light. Within the blue light spectrum (between 420 and 500 nm), the velocity of constriction was significantly faster with the 480 nm light stimulus, while the slowest pupil constriction was observed with 430 nm light. Maximum pupil constriction was achieved with 470 nm light, and the greatest AUC0−60 and AUC240−300 was observed with 490 and 460 nm light, respectively. The 6-s PIPR was maximum after 490 nm light stimulus. Both the transient (AUC0−60) and sustained (AUC240−300) response was significantly correlated with melanopic activation. Higher photon fluxes for both purple and blue light produced greater amplitude sustained pupillary constriction. The findings confirm human PLR dependence on wavelength, monochromatic or bichromatic light and photon flux under 5-min duration light stimuli. Since the most rapid and high amplitude PLR occurred within the 460–490 nm light range (alone or combined), our results suggest that color discrimination should be studied under total or partial substitution of this blue light range (460–490 nm) by shorter wavelengths (~440 nm). Thus for nocturnal lighting, replacement of blue light with purple light might be a plausible solution to preserve color discrimination while minimizing melanopic activation.

Rod Photoreceptor Activation Alone Defines the Release of Dopamine in the Retina

Retinal dopamine is released by a specialised subset of amacrine cells in response to light and has a potent influence on how the retina responds to, and encodes, visual information. Here we address the critical question of which retinal photoreceptor is responsible for coordinating the release of this neuromodulator. While all three photoreceptor classes: rods, cones and melanopsin-containing retinal ganglion cells (mRGCs) have been shown to provide electrophysiological inputs to dopaminergic amacrine cells (DACs), we show here that the release of dopamine is defined only by rod photoreceptors. Remarkably, this rod signal coordinates both a suppressive signal at low intensities, and drives dopamine release at very bright light intensities. These data further reveal that dopamine release does not necessarily correlate with electrophysiological activity of dopaminergic amacrine cells and add to a growing body of evidence that rods define aspects of retinal function at very bright light levels.

Binocular Summation in Postillumination Pupil Response Driven by Melanopsin-Containing Retinal Ganglion Cells.

To investigate how melanopsin-mediated intrinsically photosensitive retinal ganglion cell (ipRGC) signals are integrated binocularly using chromatic pupillometry. We hypothesized that if the melanopsin system is summative, there will be a greater postillumination pupillary response (PIPR) under binocular conditions after viewing bright blue light. Pupillary responses in 10 visually normal participants were recorded with an eye tracker following full-field stimulation of red (long wavelength) and blue (short wavelength) light of equal intensity (dim: 0.1 cd [candela]/m2, bright: 60 cd/m2) and duration (400 ms). Individual monocular (left eye) pupil responses were measured first, followed by binocular responses. Each participant repeated the same protocol on 3 separate days, at similar times of day. PIPR was recorded for bright red and blue conditions only, whereas maximum pupillary constriction (MPC) was measured under both bright and dim conditions during red and blue light stimulation. Bright blue light stimulation induced greater PIPR under binocular than monocular viewing conditions (F(1,9) = 79.52, P < 0.001). Bright red light stimulation induced minimal PIPR and showed no significant difference between viewing conditions post Bonferroni correction (F(1,9) = 5.49, P = 0.04). MPC was greater during binocular than monocular viewing conditions for all light stimuli, but was greatest following blue compared to red light stimulation. A larger PIPR was induced using a binocular than a monocular full-field stimulus of equal intensity and duration, demonstrating that melanopsin-mediated ipRGC signals are summated binocularly. This study expands our current understanding of the melanopsin system and may be used as an additional marker to stratify diseases according to their etiologies.

Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson\u2019s disease

Parkinson’s disease (PD) patients often suffer from non-motor symptoms like sleep dysregulation, mood disturbances or circadian rhythms dysfunction. The melanopsin-containing retinal ganglion cells are involved in the control and regulation of these processes and may be affected in PD, as other retinal and visual implications have been described in the disease. Number and morphology of human melanopsin-containing retinal ganglion cells were evaluated by immunohistochemistry in eyes from donors with PD or control. The Sholl number of intersections, the number of branches, and the number of terminals from the Sholl analysis were significantly reduced in PD melanopsin ganglion cells. Also, the density of these cells significantly decreased in PD compared to controls. Degeneration and impairment of the retinal melanopsin system may affect to sleep and circadian dysfunction reported in PD pathology, and its protection or stimulation may lead to better disease prospect and global quality of life of patients.

Vision: Melanopsin as a Raumgeber

Two new studies show that neural systems receiving inputs from the melanopsin-containing retinal ganglion cells encode spatial information and therefore see the world in more detail than previously thought.

Retinal Ganglion Cells and Circadian Rhythms in Alzheimer's Disease, Parkinson's Disease, and Beyond.

There is increasing awareness on the role played by circadian rhythm abnormalities in neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The characterization of the circadian dysfunction parallels the mounting evidence that the hallmarks of neurodegeneration also affect the retina and frequently lead to loss of retinal ganglion cells (RGCs) and to different degrees of optic neuropathy. In the RGC population, there is the subgroup of cells intrinsically photosensitive and expressing the photopigment melanopsin [melanopsin-containing retinal ganglion cells (mRGCs)], which are now well known to drive the entrainment of circadian rhythms to the light–dark cycles. Thus, the correlation between the pathological changes affecting the retina and mRGCs with the circadian imbalance in these neurodegenerative diseases is now clearly emerging, pointing to the possibility that these patients might be amenable to and benefit from light therapy. Currently, this connection is better established for AD and PD, but the same scenario may apply to other neurodegenerative disorders, such as Huntington’s disease. This review highlights similarities and differences in the retinal/circadian rhythm axis in these neurodegenerative diseases posing a working frame for future studies.

Pupillary responses to short-wavelength light are preserved in aging

With aging, less blue light reaches the retina due to gradual yellowing of the lens. This could result in reduced activation of blue light-sensitive melanopsin-containing retinal ganglion cells, which mediate non-visual light responses (e.g., the pupillary light reflex, melatonin suppression, and circadian resetting). Herein, we tested the hypothesis that older individuals show greater impairment of pupillary responses to blue light relative to red light. Dose-response curves for pupillary constriction to 469-nm blue light and 631-nm red light were compared between young normal adults aged 21–30 years (n = 60) and older adults aged ≥50 years (normal, n = 54; mild cataract, n = 107; severe cataract, n = 18). Irrespective of wavelength, pupillary responses were reduced in older individuals and further attenuated by severe, but not mild, cataract. The reduction in pupillary responses was comparable in response to blue light and red light, suggesting that lens yellowing did not selectively reduce melanopsin-dependent light responses. Compensatory mechanisms likely occur in aging that ensure relative constancy of pupillary responses to blue light despite changes in lens transmission.

Regulation of Reentrainment Function Is Dependent on a Certain Minimal Number of Intact Functional ipRGCs in rd Mice.

Purpose To investigate the effect of partial ablation of melanopsin-containing retinal ganglion cells (mcRGCs) on nonimage-forming (NIF) visual functions in rd mice lacking rods. Methods The rd mice were intravitreally injected with different doses (100 ng/μl, 200 ng/μl, and 400 ng/μl) of immunotoxin melanopsin-SAP. And then, the density of ipRGCs was examined. After establishing the animal models with different degrees of ipRGC damage, a wheel-running system was used to evaluate their reentrainment response. Results Intravitreal injection of melanopsin-SAP led to partial ablation of ipRGCs in a dose-dependent manner. The survival rates of ipRGCs in the 100 ng/μl, 200 ng/μl, and 400 ng/μl groups were 74.14% ± 4.15%, 39.25% ± 2.29%, and 38.38% ± 3.74%, respectively. The wheel-running experiments showed that more severe ipRGC loss was associated with a longer time needed for reentrainment. When the light/dark cycle was delayed by 8 h, the rd mice in the PBS control group took 4.67 ± 0.79 days to complete the synchronization with the shifted cycle, while those in the 100 ng/μl and 200 ng/μl groups required 7.90 ± 0.55 days and 11.00 ± 0.79 days to complete the synchronization with the new light/dark cycle, respectively. Conclusion Our study indicates that the regulation of some NIF visual functions is dependent on a certain minimal number of intact functional ipRGCs.

A neurodegenerative perspective on mitochondrial optic neuropathies.

Mitochondrial optic neuropathies constitute an important cause of chronic visual morbidity and registrable blindness in both the paediatric and adult population. It is a genetically heterogeneous group of disorders caused by both mitochondrial DNA (mtDNA) mutations and a growing list of nuclear genetic defects that invariably affect a critical component of the mitochondrial machinery. The two classical paradigms are Leber hereditary optic neuropathy (LHON), which is a primary mtDNA disorder, and autosomal dominant optic atrophy (DOA) secondary to pathogenic mutations within the nuclear gene OPA1 that encodes for a mitochondrial inner membrane protein. The defining neuropathological feature is the preferential loss of retinal ganglion cells (RGCs) within the inner retina but, rather strikingly, the smaller calibre RGCs that constitute the papillomacular bundle are particularly vulnerable, whereas melanopsin-containing RGCs are relatively spared. Although the majority of patients with LHON and DOA will present with isolated optic nerve involvement, some individuals will also develop additional neurological complications pointing towards a greater vulnerability of the central nervous system (CNS) in susceptible mutation carriers. These so-called “plus” phenotypes are mechanistically important as they put the loss of RGCs within the broader perspective of neuronal loss and mitochondrial dysfunction, highlighting common pathways that could be modulated to halt progressive neurodegeneration in other related CNS disorders. The management of patients with mitochondrial optic neuropathies still remains largely supportive, but the development of effective disease-modifying treatments is now within tantalising reach helped by major advances in drug discovery and delivery, and targeted genetic manipulation.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1625-2) contains supplementary material, which is available to authorized users.

Cerebral neural correlates of differential melanopic photic stimulation in humans

Photic stimulation of rods, cones and intrinsically photosensitive melanopsin-containing retinal ganglion cells (ipRGCs) mediates non-visual light responses, including entrainment of circadian rhythms and pupillary light reflex. Unlike visual responses to photic stimulation, the cerebral correlates of non-visual light responses in humans remains elusive. In this study, we used functional magnetic resonance imaging (fMRI) in 14 healthy young participants, to localize cerebral regions which are differentially activated by metameric light that gave rise to different levels of melanopic excitation. Mean blood oxygen-level dependent (BOLD) responses disclosed bilateral activation of the frontal eye fields during exposure to light geared towards melanopsin. Furthermore, multivariate pattern analyses showed distinct bilateral pattern activity in the inferior temporal gyri and the caudate nuclei. Taken together, our findings suggest that melanopsin-based photoreception activates a cerebral network including frontal regions, classically involved in attention and ocular motor responses.