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Optical coherence tomography and electroretinography studies have revealed structural and functional retinal alterations in individuals with schizophrenia spectrum disorders (SSDs). However, it remains unclear which specific retinal layers are affected; how the retina, brain, and clinical symptomatology are connected; and how alterations of the visual system are related to genetic disease risk. Optical coherence tomography, electroretinography, and brain magnetic resonance imaging were applied to comprehensively investigate the visual system in a cohort of 103 patients with SSDs and 130 healthy control individuals. The sparse partial least squares algorithm was used to identify multivariate associations between clinical disease phenotype and biological alterations of the visual system. The association of the revealed patterns with individual polygenic disease risk for schizophrenia was explored in a post hoc analysis. In addition, covariate-adjusted case-control comparisons were performed for each individual optical coherence tomography and electroretinography parameter. The sparse partial least squares analysis yielded a phenotype-eye-brain signature of SSDs in which greater disease severity, longer duration of illness, and impaired cognition were associated with electrophysiological alterations and microstructural thinning of most retinal layers. Higher individual loading onto this disease-relevant signature of the visual system was significantly associated with elevated polygenic risk for schizophrenia. In case-control comparisons, patients with SSDs had lower macular thickness, thinner retinal nerve fiber and inner plexiform layers, less negative a-wave amplitude, and lower b-wave amplitude. This study demonstrates multimodal microstructural and electrophysiological retinal alterations in individuals with SSDs that are associated with disease severity and individual polygenic burden. [ABSTRACT FROM AUTHOR]

Retinal ischemia–reperfusion (I/R) injury is a critical pathogenic mechanism in various eye diseases, and an effective therapeutic strategy remains unresolved. Natural derivatives have recently reemerged; therefore, in our present study, we examined the potential therapeutic effects of a stilbenoid that is chemically related to resveratrol. Pterostilbene, recognized for its anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective properties, counteracts oxidative stress during I/R injury through various mechanisms. This study explored pterostilbene as a retinoprotective agent. Male Sprague Dawley rats underwent retinal I/R injury and one-week reperfusion and were treated with either vehicle or pterostilbene. After this functional electroretinographical (ERG) measurement, Western blot and histological analyses were performed. Pterostilbene treatment significantly improved retinal function, as evidenced by increased b-wave amplitude on ERG. Histological studies showed reduced retinal thinning and preserved the retinal structure in the pterostilbene-treated groups. Moreover, Western blot analysis revealed a decreased expression of glial fibrillary acidic protein (GFAP) and heat shock protein 70 (HSP70), indicating reduced glial activation and cellular stress. Additionally, the expression of pro-apoptotic and inflammatory markers, poly(ADP-ribose) polymerase 1 (PARP1) and nuclear factor kappa B (NFκB) was significantly reduced in the pterostilbene-treated group. These findings suggest that pterostilbene offers protective effects on the retina by diminishing oxidative stress, inflammation, and apoptosis, thus preserving retinal function and structure following I/R injury. This study underscores pterostilbene's potential as a neuroprotective therapeutic agent for treating retinal ischemic injury and related disorders. [ABSTRACT FROM AUTHOR]

Purpose: To describe progression of best-corrected visual acuity (BCVA), full-field stimulus thresholds (FST), and electroretinography (ERG) over 4 years in the USH2A-related Retinal Degeneration study and to assess their suitability as clinical trial endpoints. Design: Prospective natural history study. Participants: Participants (n = 105) with biallelic disease-causing sequence variants in USH2A and BCVA letter scores of ≥54 were included. Methods: BCVA, FST, fundus-guided microperimetry, static perimetry, and spectral domain OCT were performed annually and ERG at baseline and 4 years only. Mixed effects models were used to estimate annual rates of change with 95% confidence intervals. Associations of change from baseline to 4 years between BCVA, FST, ERG, and other metrics were assessed with Spearman correlation coefficients (rs). Main Outcome Measures: Best-corrected visual acuity, FST, and ERG. Results: The annual rate of decline in BCVA was 0.83 (95% confidence interval: 0.65−1.02) letters/year. For FST, the change was 0.09 (0.07−0.11) log cd.s/m2/year for white threshold, 0.10 (0.08−0.12) log cd.s/m2/year for blue threshold, and 0.05 (0.04−0.06) log cd.s/m2/year for red threshold. Changes were 22.6 (17.4−28.2)%/year for white threshold, 26.0 (20.3−32.1)%/year for blue threshold, and 12.3 (8.7−16.0)%/year for red threshold. The high percentage of eyes with undetectable ERGs at baseline limited assessment of change. Conclusions: Best-corrected visual acuity was not a sensitive measure of progression over 4 years. Full-field stimulus threshold was a more sensitive measure; however, additional information on the clinical relevance of changes in FST is needed before this test can be adopted as an endpoint for clinical trials. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia–reperfusion. It was also observed to counteract retinal thinning after ischemia–reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia–reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops. [ABSTRACT FROM AUTHOR]

Retinal ischemia–reperfusion (I/R) injury is a critical pathogenic mechanism in various eye diseases, and an effective therapeutic strategy remains unresolved. Natural derivatives have recently reemerged; therefore, in our present study, we examined the potential therapeutic effects of a stilbenoid that is chemically related to resveratrol. Pterostilbene, recognized for its anti-inflammatory, anti-carcinogenic, anti-diabetic, and neuroprotective properties, counteracts oxidative stress during I/R injury through various mechanisms. This study explored pterostilbene as a retinoprotective agent. Male Sprague Dawley rats underwent retinal I/R injury and one-week reperfusion and were treated with either vehicle or pterostilbene. After this functional electroretinographical (ERG) measurement, Western blot and histological analyses were performed. Pterostilbene treatment significantly improved retinal function, as evidenced by increased b-wave amplitude on ERG. Histological studies showed reduced retinal thinning and preserved the retinal structure in the pterostilbene-treated groups. Moreover, Western blot analysis revealed a decreased expression of glial fibrillary acidic protein (GFAP) and heat shock protein 70 (HSP70), indicating reduced glial activation and cellular stress. Additionally, the expression of pro-apoptotic and inflammatory markers, poly(ADP-ribose) polymerase 1 (PARP1) and nuclear factor kappa B (NFκB) was significantly reduced in the pterostilbene-treated group. These findings suggest that pterostilbene offers protective effects on the retina by diminishing oxidative stress, inflammation, and apoptosis, thus preserving retinal function and structure following I/R injury. This study underscores pterostilbene’s potential as a neuroprotective therapeutic agent for treating retinal ischemic injury and related disorders.

Purpose: Electroretinograms elicited by photopigment isolating white noise stimuli (wnERGs) in mice were measured. The dependency of rod- and coneopsin-driven wnERGs on mean luminance was studied. Methods: Temporal white noise stimuli (containing all frequencies up to 20 Hz, equal amplitudes, random phases) that modulated either rhodopsin, S-opsin or L*-opsin, using the double silent substitution technique, were used to record wnERGs in mice expressing a human L*-opsin instead of the native murine M-opsin. Responses were recorded at 4 mean luminances (MLs). Impulse response functions (IRFs) were obtained by cross-correlating the wnERG recordings with the corresponding modulation of the photopigment excitation elicited by the stimulus. So-called modulation transfer functions (MTFs) were obtained by performing a Fourier transform on the IRFs. Potentials of two repeated wnERG recordings at corresponding time points were plotted against each other. The correlation coefficient (r2 repr) of the linear regression through these data was used to quantify reproducibility. Another correlation coefficient (r2 ML) was used to quantify the correlations of the wnERGs obtained at different MLs with those at the highest (for cone isolating stimuli) or lowest (for rod isolating stimuli) ML. Results: IRFs showed an initial negative (a-wave like) trough N1 and a subsequent positive (b-wave like) peak P1. No oscillatory potential-like components were observed. At 0.4 and 1.0 log cd/m2 ML robust L*- and S-opsin-driven IRFs were obtained that displayed similar latencies and dependencies on ML. L*-opsindriven IRFs were 2.5-3 times larger than S-opsin-driven IRFs. Rhodopsin-driven IRFs were observed at -0.8 and - 0.2 log cd/m² and decreased in amplitude with increasing ML. They displayed an additional pronounced late negativity (N2), which may be a correlate of retinal ganglion cell activity. R² repr and r² ML values increased for cones with increasing ML whereas they decreased for rods. For rhodopsin-driven MTFs at low MLs and L*-opsin-driven MTFs at high MLs amplitudes decreased with increasing frequency, with much faster decreasing amplitudes for rhodopsin. A delay was calculated from MTF phases showing larger delays for rhodopsin- vs. low delays for L*-opsin-driven responses. Conclusion: Opsin-isolating wnERGs in mice show characteristics of different retinal cell types and their connected pathways. [ABSTRACT FROM AUTHOR]

Introduction: The retina, a window into the brain, allows for the investigation of many disease-associated inflammatory and neurodegenerative changes affecting the central nervous system (CNS). Multiple sclerosis (MS), an autoimmune disease targeting the CNS, typically impacts on the visual system including the retina. Hence, we aimed to establish innovative functional retinal measures of MS-related damage, e.g., spatially resolved non-invasive retinal electrophysiology, backed by established morphological retinal imaging markers, i.e., optical coherence tomography (OCT). Methods: 20 healthy controls (HC) and 37 people with MS [17 without history of optic neuritis (NON) and 20 with (HON) history of optic neuritis] were included. In this work, we differentially assessed photoreceptor/bipolar cells (distal retina) and retinal ganglion cell (RGC, proximal retina) function besides structural assessment (OCT). We compared two multifocal electroretinography-based approaches, i.e., the multifocal pattern electroretinogram (mfPERG) and the multifocal electroretinogram to record photopic negative response (mfERGPhNR). Structural assessment utilized peripapillary retinal nerve fiber layer thickness (pRNFL) and macular scans to calculate outer nuclear thickness (ONL) and macular ganglion cell inner plexiform layer thickness (GCIPL). One eye was randomly selected per subject. Results: In NON, photoreceptor/bipolar cell layer had dysfunctional responses evidenced by reduced mfERGPhNR-N1 peak time of the summed response, but preserved structural integrity. Further, both NON and HON demonstrated abnormal RGC responses as evidenced by the photopic negative response of mfERGPhNR (mfPhNR) and mfPERG indices (P < 0.05). Structurally, only HON had thinned retina at the level of RGCs in the macula (GCIPL, P < 0.01) and the peripapillary area (pRNFL, P < 0.01). All three modalities showed good performance to differentiate MS-related damage from HC, 71-81% area under curve. Conclusion: In conclusion, while structural damage was evident mainly for HON, functional measures were the only retinal read-outs of MS-related retinal damage that were independent of optic neuritis, observed for NON. These results indicate retinal MS-related inflammatory processes in the retina prior to optic neuritis. They highlight the importance of retinal electrophysiology in MS diagnostics and its potential as a sensitive biomarker for follow-up in innovative interventions. [ABSTRACT FROM AUTHOR]

Retinal vascular diseases and consequential metabolic disturbances in the eye are major concerns for healthcare systems all around the world. BGP-15, a drug candidate small-molecule [O-(3-piperidino-2-hydroxy-1-propyl) nicotinic amidoxime dihydrochloride], has been formerly demonstrated by our workgroup to be retinoprotective both in the short and long term. Based on these results, the present study was performed to investigate the efficacy of BGP in an eyedrop formulation containing sulfobutylether-β-cyclodextrin (SBECD), which is a solubility enhancer as well. Electroretinographical evaluations were carried out and BGP was demonstrated to improve both scotopic and photopic retinal a- and b-waves, shorten their implicit times and restore oscillatory potentials after ischemia–reperfusion. It was also observed to counteract retinal thinning after ischemia–reperfusion in the eyes of Sprague Dawley rats. This small-molecule drug candidate is able to compensate for experimental global eye ischemia–reperfusion injury elicited by ligation of blood vessels in rats. We successfully demonstrated that BGP is able to exert its protective effects on the retina even if administered in the form of eyedrops.

PurposeElectroretinograms elicited by photopigment isolating white noise stimuli (wnERGs) in mice were measured. The dependency of rod- and cone-opsin-driven wnERGs on mean luminance was studied.MethodsTemporal white noise stimuli (containing all frequencies up to 20 Hz, equal amplitudes, random phases) that modulated either rhodopsin, S-opsin or L*-opsin, using the double silent substitution technique, were used to record wnERGs in mice expressing a human L*-opsin instead of the native murine M-opsin. Responses were recorded at 4 mean luminances (MLs).Impulse response functions (IRFs) were obtained by cross-correlating the wnERG recordings with the corresponding modulation of the photopigment excitation elicited by the stimulus. So-called modulation transfer functions (MTFs) were obtained by performing a Fourier transform on the IRFs.Potentials of two repeated wnERG recordings at corresponding time points were plotted against each other. The correlation coefficient (r2repr) of the linear regression through these data was used to quantify reproducibility. Another correlation coefficient (r2ML) was used to quantify the correlations of the wnERGs obtained at different MLs with those at the highest (for cone isolating stimuli) or lowest (for rod isolating stimuli) ML.ResultsIRFs showed an initial negative (a-wave like) trough N1 and a subsequent positive (b-wave like) peak P1. No oscillatory potential-like components were observed. At 0.4 and 1.0 log cd/m2 ML robust L*- and S-opsin-driven IRFs were obtained that displayed similar latencies and dependencies on ML. L*-opsin-driven IRFs were 2.5–3 times larger than S-opsin-driven IRFs. Rhodopsin-driven IRFs were observed at −0.8 and − 0.2 log cd/m2 and decreased in amplitude with increasing ML. They displayed an additional pronounced late negativity (N2), which may be a correlate of retinal ganglion cell activity.R2repr and r2ML values increased for cones with increasing ML whereas they decreased for rods. For rhodopsin-driven MTFs at low MLs and L*-opsin-driven MTFs at high MLs amplitudes decreased with increasing frequency, with much faster decreasing amplitudes for rhodopsin. A delay was calculated from MTF phases showing larger delays for rhodopsin- vs. low delays for L*-opsin-driven responses.ConclusionOpsin-isolating wnERGs in mice show characteristics of different retinal cell types and their connected pathways.

Introduction: Wistar Han rats are a preferred strain of rodents for general toxicology and safety pharmacology studies in drug development. In some of these studies, visual functional tests that assess for retinal toxicity are included as an additional endpoint. Although the influence of gender on human retinal function has been documented for more than 6 decades, preclinically it is still uncertain if there are differences in retinal function between naïve male and female Wistar Han rats.Methods: In this study, sex-related differences in the retinal function were quantified by analyzing electroretinography (ERG) in 7-9-week-old (n = 52 males and 51 females) and 21–23-week-old Wistar Han rats (n = 48 males and 51 females). Optokinetic tracking response, brainstem auditory evoked potential, ultrasonic vocalization and histology were tested and evaluated in a subset of animals to investigate the potential compensation mechanisms of spontaneous blindness.Results/Discussion: Absence of scotopic and photopic ERG responses was found in 13% of 7-9-week-old (7/52) and 19% of 21–23-week-old males (9/48), but none of female rats (0/51). The averaged amplitudes of rod- and cone-mediated ERG b-wave responses obtained from males were significantly smaller than the amplitudes of the same responses from age-matched females (−43% and −26%, respectively) at 7–9 weeks of age. There was no difference in the retinal and brain morphology, brainstem auditory responses, or ultrasonic vocalizations between the animals with normal and abnormal ERGs at 21–23 weeks of age. In summary, male Wistar Han rats had altered retinal responses, including a complete lack of responses to test flash stimuli (i.e., blindness), when compared with female rats at 7–9 and 21–23 weeks of age. Therefore, sex differences should be considered when using Wistar Han rats in toxicity and safety pharmacology studies with regards to data interpretation of retinal functional assessments.

IntroductionThe retina, a window into the brain, allows for the investigation of many disease-associated inflammatory and neurodegenerative changes affecting the central nervous system (CNS). Multiple sclerosis (MS), an autoimmune disease targeting the CNS, typically impacts on the visual system including the retina. Hence, we aimed to establish innovative functional retinal measures of MS-related damage, e.g., spatially resolved non-invasive retinal electrophysiology, backed by established morphological retinal imaging markers, i.e., optical coherence tomography (OCT).Methods20 healthy controls (HC) and 37 people with MS [17 without history of optic neuritis (NON) and 20 with (HON) history of optic neuritis] were included. In this work, we differentially assessed photoreceptor/bipolar cells (distal retina) and retinal ganglion cell (RGC, proximal retina) function besides structural assessment (OCT). We compared two multifocal electroretinography-based approaches, i.e., the multifocal pattern electroretinogram (mfPERG) and the multifocal electroretinogram to record photopic negative response (mfERGPhNR). Structural assessment utilized peripapillary retinal nerve fiber layer thickness (pRNFL) and macular scans to calculate outer nuclear thickness (ONL) and macular ganglion cell inner plexiform layer thickness (GCIPL). One eye was randomly selected per subject.ResultsIn NON, photoreceptor/bipolar cell layer had dysfunctional responses evidenced by reduced mfERGPhNR-N1 peak time of the summed response, but preserved structural integrity. Further, both NON and HON demonstrated abnormal RGC responses as evidenced by the photopic negative response of mfERGPhNR (mfPhNR) and mfPERG indices (P < 0.05). Structurally, only HON had thinned retina at the level of RGCs in the macula (GCIPL, P < 0.01) and the peripapillary area (pRNFL, P < 0.01). All three modalities showed good performance to differentiate MS-related damage from HC, 71–81% area under curve.ConclusionIn conclusion, while structural damage was evident mainly for HON, functional measures were the only retinal read-outs of MS-related retinal damage that were independent of optic neuritis, observed for NON. These results indicate retinal MS-related inflammatory processes in the retina prior to optic neuritis. They highlight the importance of retinal electrophysiology in MS diagnostics and its potential as a sensitive biomarker for follow-up in innovative interventions.

Purpose: To find a new approach of pan-retinal photocoagulation (PRP) with less damage to the retina in the treatment of severe non-proliferative diabetic retinopathy (NPDR), this study compared functional changes in the retina after subthreshold and threshold PRP treatment in severe NPDR eyes.Methods: Post hoc analysis of a randomized clinical trial was conducted in this study. Seventy eyes of 35 patients with bilateral, symmetric, severe NPDR were enrolled. Two eyes from the same patient were randomized into two groups, one eye received subthreshold PRP (S-PRP) and the other eye received threshold PRP (T-PRP). Comprehensive ophthalmological evaluations were performed on the baseline and every 3 months for 1 year. Visual field (VF) and full-field electroretinography (ERG) were performed on the baseline and repeated at month 12.Results: During the 12-month follow-up, 4 eyes (11.4%) in the S-PRP group and 3 eyes (8.6%) in the T-PRP group progressed to proliferative diabetic retinopathy (PDR) stage, and there was no statistical difference in PDR progression rate between the two groups (P = 0.69). In addition, the changes in best-corrected visual acuity (BCVA) from baseline to month 12 between the two groups had no statistical difference (P = 0.30). From baseline to month 12, changes in central VF between the two groups had no statistical difference (P = 0.25), but changes in total score points of peripheral VF in the S-PRP group (- 242.1 ± 210.8 dB) and the T-PRP group (- 308.9 ± 209.7 dB) were statistically significant (P = 0.03). At month 12, ERG records showed that the amplitude of dark-adapted 0.01 ERG, dark-adapted 3.0 ERG, oscillatory potentials, light-adapted 3.0 ERG, and 30 Hz flicker ERG of both groups were significantly decreased from the baseline (P < 0.05). In addition, the amplitude of each ERG record in the S-PRP group decreased significantly less than those in the T-PRP group (P < 0.05).Conclusions: Subthreshold PRP is as effective as threshold PRP for preventing severe NPDR progress to PDR within 1 year with less damage to periphery VF and retinal function.Trial Registration: Clinicaltrials: gov Identifier: NCT01759121. [ABSTRACT FROM AUTHOR]

People with schizophrenia exhibit increased intra-individual variability in both behavioral and neural signatures of cognition. Examination of intra-individual variability may uncover a unique functionally relevant aspect of impairment that is not captured by typical between-group comparisons of mean or median values. We and others have observed that retinal activity measured using electroretinography (ERG) is significantly reduced in people with schizophrenia; however, it is currently unclear whether greater intra-individual variability in the retinal response can also be observed. To investigate this, we examined intra-individual variability from 25 individuals with schizophrenia and 24 healthy controls under two fERG conditions: (1) a light-adapted condition in which schizophrenia patients demonstrated reduced amplitudes; and (2) a dark-adapted condition in which the groups did not differ in amplitudes. Intraclass correlation coefficients (ICC) were generated to measure intra-individual variability for each subject, reflecting the consistency of activation values (in μv) across all sampling points (at a 2 kHz sampling rate) within all trials within a condition. Contrary to our predictions, results indicated that the schizophrenia and healthy control groups did not differ in intra-individual variability in fERG responses in either the light- or dark-adapted conditions. This finding remained consistent when variability was calculated as the standard deviation (SD) and coefficient of variation (CV) of maximum positive and negative microvolt values within the a- and b-wave time windows. This suggests that although elevated variability in schizophrenia may be observed at perceptual and cognitive levels of processing, it is not present in the earliest stages of sensory processing in vision.

A four-parameter model of spectral sensitivity curves was developed. Empirical equations were designed for A1- and A2-based visual pigments with the main α-band maximum absorptions (λmax) from 350 nm, near the ultraviolet, up to 635 nm in the far-red part of the spectrum. Subtraction of the α-band from the full absorbance spectrum left a “β-band” described by a λmax-dependent Gaussian equation. Compatibility of our templates with A1- and A2-based spectra was tested on the electroretinographic (ERG-derived) scotopic action spectra recorded in dogfish shark, eel, Prussian carp and perch. To more precisely estimate the accuracy of our model, we compared it with widely used templates for visual pigments. There was almost no difference between the tested models in fitting the above-mentioned spectral data. One of the advantages of our model is that in the fitting of spectral sensitivity data it uses non-transformed wavelengths and the shape of the curve remains the same for a broad range of λmax values. Compared to multiparameter templates of other authors, our model was designed with fewer (four) parameters, which we believe can bring us closer to understanding the true nature of the absorption curve. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 173045]

People with schizophrenia exhibit increased intra-individual variability in both behavioral and neural signatures of cognition. Examination of intra-individual variability may uncover a unique functionally relevant aspect of impairment that is not captured by typical between-group comparisons of mean or median values. We and others have observed that retinal activity measured using electroretinography (ERG) is significantly reduced in people with schizophrenia; however, it is currently unclear whether greater intra-individual variability in the retinal response can also be observed. To investigate this, we examined intra-individual variability from 25 individuals with schizophrenia and 24 healthy controls under two fERG conditions: (1) a light-adapted condition in which schizophrenia patients demonstrated reduced amplitudes; and (2) a dark-adapted condition in which the groups did not differ in amplitudes. Intraclass correlation coefficients (ICC) were generated to measure intra-individual variability for each subject, reflecting the consistency of activation values (in μv) across all sampling points (at a 2 kHz sampling rate) within all trials within a condition. Contrary to our predictions, results indicated that the schizophrenia and healthy control groups did not differ in intra-individual variability in fERG responses in either the light- or dark-adapted conditions. This finding remained consistent when variability was calculated as the standard deviation (SD) and coefficient of variation (CV) of maximum positive and negative microvolt values within the a- and b-wave time windows. This suggests that although elevated variability in schizophrenia may be observed at perceptual and cognitive levels of processing, it is not present in the earliest stages of sensory processing in vision. [ABSTRACT FROM AUTHOR]

Background: Differences between people with schizophrenia and psychiatrically healthy controls have been consistently demonstrated on measures of retinal function such as electroretinography (ERG), and measures of retinal structure such as optical coherence tomography (OCT). Since our 2015 review of this literature, multiple new studies have been published using these techniques. At the same time, the accumulation of data has highlighted the "fault lines" in these fields, suggesting methodological considerations that need greater attention in future studies.Methods: We reviewed studies of ERG and OCT in schizophrenia, as well as data from studies whose findings are relevant to interpreting these papers, such as those on effects of the following on ERG and OCT data: comorbid medical conditions that are over-represented in schizophrenia, smoking, antipsychotic medication, substance abuse, sex and gender, obesity, attention, motivation, and influences of brain activity on retinal function.Results: Recent ERG and OCT studies continue to support the hypothesis of retinal structural and functional abnormalities in schizophrenia, and suggest that these are relevant to understanding broader aspects of pathophysiology, neurodevelopment, and neurodegeneration in this disorder. However, there are differences in findings which suggest that the effects of multiple variables on ERG and OCT data need further clarification.Conclusions: The retina, as the only component of the CNS that can be imaged directly in live humans, has potential to clarify important aspects of schizophrenia. With greater attention to specific methodological issues, the true potential of ERG and OCT as biomarkers for important clinical phenomena in schizophrenia should become apparent. [ABSTRACT FROM AUTHOR]

Abstract Background Retinitis pigmentosa (RP) is the most common inherited retinal degenerative disease yet with no effective treatment available. The sigma-1 receptor (S1R), a ligand-regulated chaperone, emerges as a potential retina-protective therapeutic target. In particular, pharmacological activation of S1R was recently shown to rescue cones in the rd10 mouse, a rod Pde6b mutant that recapitulates the RP pathology of autonomous rod degeneration followed by secondary death of cones. The mechanisms underlying the S1R protection for cones are not understood in detail. Methods By rearing rd10/S1R−/− and rd10/S1R+/+ mice in dim light to decelerate rapid rod/cone degeneration, we were able to compare their retinal biochemistry, histology and functions throughout postnatal 3–6 weeks (3 W–6 W). Results The receptor-interacting protein kinases (RIP1/RIP3) and their interaction (proximity ligation) dramatically up-regulated after 5 W in rd10/S1R−/− (versus rd10/S1R+/+) retinas, indicative of intensified necroptosis activation, which was accompanied by exacerbated loss of cones. Greater rod loss in rd10/S1R−/− versus rd10/S1R+/+ retinas was evidenced by more cleaved Caspase3 (4 W) and lower rod electro-retinographic a-waves (4 W–6 W), concomitant with reduced LC3-II and CHOP (4 W–6 W), markers of autophagy and endoplasmic reticulum stress response, respectively. However, the opposite occurred at 3 W. Conclusion This study reveals previously uncharacterized S1R-associated mechanisms during rd10 photoreceptor degeneration, including S1R’s influences on necroptosis and autophagy as well as its biphasic role in rod degeneration upstream of cone death.

The aim of this study was to explore the role of autophagy in response to blue light damage in aged mice and in human retinal pigmented epithelium (hRPE) cells. Blue light damage to the retina was induced in 10-month-old (10 mo) C57 mice and hRPE cells. Flash electroretinography was used to assess retinal function. Retinal structure changes were observed by electron microscopy. Western blot was conducted to determine the expression levels of the following proteins: cleaved caspase-3, p38 mitogen-activated protein kinases, protein kinase R-like endoplasmic reticulum kinase (PERK), autophagy marker light chain 3 (LC3), P62, and Beclin-1. On day 1 after light damage to the 10 mo mice, retinal function was changed. The latent periods of a-wave and b-wave were delayed, and amplitude was reduced. The electron microscopy results revealed mitochondria damage in the retinal pigmented epithelium and a disorganized photoreceptor outer segment (OS). PERK, LC3, and Beclin-1 were upregulated, whereas P62 was not. On day 5 after the blue light damage, restoration of electroretinography and OS was observed. PERK, LC3, and Beclin-1 were downregulated, whereas P62 was not. Protein changes in vitro were consistent with in vivo. The present study provided structural and functional evidence that autophagy plays an important role in the response to blue lightinduced retinal damage. [ABSTRACT FROM AUTHOR]

GABA A receptor subunit gene (GABR) mutations are significant causes of epilepsy, including syndromic epilepsy. This report for the first time, describes intractable epilepsy and blindness due to optic atrophy in our patient, who has a microdeletion of the GABRA1 and GABRG2 genes. We then characterized the molecular phenotypes and determined patho-mechanisms underlying the genotype-phenotype correlations in a mouse model who is haploinsufficient for both genes (Gabra1 +/− /Gabrg2 +/− mouse). Electroencephalography was conducted in both human and mice with the same gene loss. GABA A receptor expression was evaluated by biochemical and imaging approaches. Optic nerve atrophy was evaluated with fundus photography in human while electronic microscopy, visual evoked potential and electroretinography recordings were conducted in mice. The patient has bilateral optical nerve atrophy. Mice displayed spontaneous seizures, reduced electroretinography oscillatory potential and reduced GABA A receptor α1, β2 and γ2 subunit expression in various brain regions. Electronic microscopy showed that mice also had optic nerve degeneration, as indicated by increased G-ratio, the ratio of the inner axonal diameter to the total outer diameter, suggesting impaired myelination of axons. More importantly, we identified that phenobarbital was the most effective anticonvulsant in mice and the patient's seizures were also controlled with phenobarbital after failing multiple anti-seizure drugs. This study is the first report of haploinsufficiency of two GABR epilepsy genes and visual impairment due to altered axonal myelination and resultant optic nerve atrophy. The study suggests the far-reaching impact of GABR mutations and the translational significance of animal models with the same etiology. • A microdeletion of GABRA1 and GABRG2 caused epilepsy in both mouse and human. • A microdeletion of GABRA1 and GABRG2 caused blindness optical nerve degeneration. • The expression of GABA A receptors was reduced in various brain regions in the mouse model of GABRA1 and GABRG2 deletion. • The seizures in both the mouse model of disease and patient were mitigated with phenobarbital. • Haploinsufficiency of GABRA1 and GABRG2 can cause disease phenotype more than just epilepsy. [ABSTRACT FROM AUTHOR]

Electroretinography (ERG) is a functional test of the outer retina. During an examination, the retina is selectively stimulated. The stimulation of the retina produces a response of the individual retinal cells and reveals information about its function. The ERG examination requires very specific conditions in order to avoid undesirable factors which may adversely affect the recordings. The electroretinography examination may be performed for a short period (“rapid protocol”), commonly used to access retinal activity. The “long protocol” is used for the differential diagnosis of retinal disorders. It is mainly used in diagnosing and evaluating retinal dysfunction when there are no ophthalmic lesions present. The main indications for electroretinography are the pre-operative examination of cataract patient and the early diagnosis of inherited retinal diseases. In veterinary ophthalmology, ERG is performed under general anesthesia. The ERG results have wave forms with characteristic components depending upon several factors. Its interpretation requires knowledge of retinal pathology and electrophysiology

Purpose: Our aim was to compare the electroretinographic (ERG) responses of two eyes obtained by consecutive unilateral recordings to those obtained by a simultaneous bilateral recording in sheep.Methods: Eight sheep underwent two full-field ERG recordings, using two recording strategies of the standard ISCEV protocol: consecutive unilateral recordings of one eye after the other, and simultaneous bilateral recording of both eyes. The order of recording strategy within an animal (unilateral/bilateral), eye recording sequence in the unilateral session (OD/OS), and amplifier channel assignment for each eye were all randomized. To test whether duration of dark adaptation and/or anesthesia affect the results, the ISCEV protocol was recorded bilaterally in six additional eyes following 38 min of patched dark adaptation, as was done for the second eye recorded in the consecutive unilateral recordings.Results: The second recorded eye in the unilateral session had significantly higher scotopic b-wave amplitudes compared to the first recorded eye and to the bilaterally recorded eyes. A-wave amplitudes of the dark-adapted mixed rod-cone responses to a high-intensity flash were also significantly higher in the second eye compared to the first eye recorded unilaterally and to the bilaterally recorded eyes. Light-adapted responses were unaffected by the recording strategy. When the ISCEV protocol was recorded after 38 min of dark adaptation, the scotopic responses were higher than in the first eyes, and similar to those of the second eyes recorded unilaterally, suggesting that indeed the longer duration of anesthesia and dark adaptation are responsible for the increased scotopic responses of the second eye.Conclusions: Consecutive unilateral ERG recordings of two eyes result in higher amplitudes of the dark-adapted responses of the eye recorded second, compared to the eye recorded first and to bilaterally recorded eyes. The differences in scotopic responses can be attributed to different duration of dark adaptation and/or anesthesia of the two consecutively recorded eyes. Photopic responses are not affected. Therefore, simultaneous bilateral ERG responses should be recorded when possible, especially for evaluation of scotopic responses. [ABSTRACT FROM AUTHOR]

Purpose: The zebrafish is an established animal model commonly used in biological, neuroscience, and genetic research. We have developed a new light stimulating system using white light-emitting diodes (LEDs) to elicit ERGs from zebrafish larvae. The purpose of this study was to record full-field ERGs and to evaluate the inter-trial reliability of the ERGs recorded with our system from zebrafish larvae. Methods: The stimulating device used white LEDs that were attached to a stereomicroscope, and the location of the recording electrode on the cornea could be monitored while the eye was being stimulated. Full-field scotopic and photopic ERGs were recorded from larvae at the age of 5-7 days post-fertilization (dpf). Intensity-response curves were constructed from the ERGs. Inter-trial reliability of the ERGs recorded by our system was evaluated. Results: This stimulating system could be used for efficient and reliable ERG recordings from 5-7 dpf larvae. The amplitudes, implicit times, and the waveforms of the scotopic and photopic ERGs were similar to those reported in earlier studies. Inter-trial reliability of the amplitudes of the photopic ERG b-waves was excellent with an intra-class correlation coefficient of 0.98. Conclusion: We conclude that this new light stimulation system using white LEDs attached to a stereomicroscope will be helpful in recording reliable ERGs from zebrafish larvae. [ABSTRACT FROM AUTHOR]

Introduction: Wistar Han rats are a preferred strain of rodents for general toxicology and safety pharmacology studies in drug development. In some of these studies, visual functional tests that assess for retinal toxicity are included as an additional endpoint. Although the influence of gender on human retinal function has been documented for more than 6 decades, preclinically it is still uncertain if there are differences in retinal function between naïve male and female Wistar Han rats. Methods: In this study, sex-related differences in the retinal function were quantified by analyzing electroretinography (ERG) in 7-9-week-old ( n = 52 males and 51 females) and 21-23-week-old Wistar Han rats ( n = 48 males and 51 females). Optokinetic tracking response, brainstem auditory evoked potential, ultrasonic vocalization and histology were tested and evaluated in a subset of animals to investigate the potential compensation mechanisms of spontaneous blindness. Results/Discussion: Absence of scotopic and photopic ERG responses was found in 13% of 7-9-week-old (7/52) and 19% of 21-23-week-old males (9/48), but none of female rats (0/51). The averaged amplitudes of rod- and cone-mediated ERG b -wave responses obtained from males were significantly smaller than the amplitudes of the same responses from age-matched females (-43% and -26%, respectively) at 7-9 weeks of age. There was no difference in the retinal and brain morphology, brainstem auditory responses, or ultrasonic vocalizations between the animals with normal and abnormal ERGs at 21-23 weeks of age. In summary, male Wistar Han rats had altered retinal responses, including a complete lack of responses to test flash stimuli (i.e., blindness), when compared with female rats at 7-9 and 21-23 weeks of age. Therefore, sex differences should be considered when using Wistar Han rats in toxicity and safety pharmacology studies with regards to data interpretation of retinal functional assessments., Competing Interests: All authors were employed by Pfizer at the time of the study., (Copyright © 2023 Tyszkiewicz, Hwang, Manickam, Jakubczak, Walters, Bolt, Santos and Liu.)

We have presented our recent efforts on genotoxicity and intraocular biocompatibility of hydroxylated graphene (G-OH) prepared by ball milling. We have previously demonstrated that the as-synthesized G-OH could be considered as an excellent alternative for graphene oxide which had been applied widely. Following our last report on G-OH, we carried out detailed studies on genotoxicity and in vivo biocompatibility of G-OH in this work. Less than 5% enhanced caspase-3 level was observed for cells exposed to more than 50 μg/mL G-OH over 72 h, suggesting G-OH caused cell apoptosis was slight. The G-OH induced DNA damage was also found to be mild since expression of p53 and ROS regeneration level was quite low even at high concentration of G-OH over a long time. Cell viability was found to be higher than 90% with 50 μg/mL G-OH and 80% with 100 μg/mL G-OH using flow cytometry. Comet results suggested that less than 5% tail could be found with 100 μg/mL G-OH. TEM results confirmed that G-OH could penetrate into and out of the cytoplasm by means of endocytosis and exocytosis without causing damage on cell membranes. In vivo biocompatibility of G-OH was studied by intravitreal injection of G-OH into rabbits. The ocular fundus photography results showed that G-OH could be diffused in the vitreous body gradually without any damage caused. Injection of G-OH had caused few damages on eyesight related functions such as intraocular pressure, electroretinogram and histological structures of the retina. [ABSTRACT FROM AUTHOR]

Purpose: Recently we reported on day blindness in sheep caused by a mutation in the CNGA3 gene, thus making affected sheep a naturally occurring large animal model for therapeutic intervention in CNGA3 achromatopsia patients. The purpose of this study was to characterize flicker cone function in normal and day blind sheep, with the aim of generating a normative data base for ongoing gene therapy studies. Methods: Electoretinographic (ERG) cone responses were evoked with full-field conditions in 10 normal, 6 heterozygous carriers and 36 day blind sheep. Following light adaptation (10 min, 30 cd/m), responses were recorded at four increasing light intensities (1, 2.5, 5 and 10 cd s/m). At each of these intensities, a single photopic flash response followed by 8 cone flicker responses (10-80 Hz) was recorded. Results were used to generate a normative data base for the three groups. Differences between day blind and normal control animals were tested in two age-matched groups ( n = 10 per group). Results: The normal sheep cone ERG wave is bipartite in nature, with critical flicker fusion frequency (CFF) >80 Hz. In all four flash intensities, the single photopic flash a-wave and b-wave amplitudes were significantly lower ( p < 0.005), and implicit times significantly delayed ( p < 0.0001), in day blind animals. In all four flash intensities, CFF values were significantly lower ( p < 0.0001) in day blind sheep. Conclusions: Cone function is severely depressed in day blind sheep. Our results will provide a normative data base for ongoing gene therapy studies. [ABSTRACT FROM AUTHOR]

Purpose: In murine disease models, particularly in cases when retinal electrical activity is reduced, an event-related component becomes apparent that does not change with the stimulus intensity in electroretinogram (ERG) recordings. In this work, we show that this electric component is evoked by the sound of the flash discharge rather than the light flash itself. Methods: Wild-type mice (C57BL/6), mice with rod function only ( Cnga3), mice lacking any photoreceptor function ( Cnga3 rho), and mice with no auditory function ( Cdh23) were examined with Xenon flash ERG systems. An acoustic noise generator was used to mask discharge sounds. Results: ERG recording modalities were identified where usually no discernible response can be elicited. These include photopic conditions in Cnga3 mice, photopic conditions together with very low stimulus intensities in C57BL/6 mice, and both scotopic and photopic conditions in Cnga3 rho mice. However, in all of these cases, small signals, featuring an initial a-wave like deflection at about 20 ms and a subsequent b-wave like deflection peaking at about 40 ms after the flash, were detected. In contrast, such signals could not be detected in deaf Cdh23 mice. Furthermore, masking the Xenon discharge sound by continuous acoustic noise led to a loss of the event-related signals in a reversible manner. Conclusions: We could identify an auditory event-related component, presumably resembling auditory evoked potentials, as a major source of ERG signals of non-visual origin in mice. This finding may be of particular importance for the analysis and interpretation of ERG data in mice with reduced visual responses. [ABSTRACT FROM AUTHOR]

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Seasonal Affective Disorder (SAD) patients crave and eat more carbohydrates (CHO) in fall-winter when depressed, especially in the evenings, and feel energetic thereafter. Evening CHO-rich meals can phase delay circadian rhythms, and glucose increases retinal response to light. We studied timed CHO- or protein-rich (PROT) diet as a putative therapy for SAD. Unmedicated, DSM-IV-diagnosed depressed women with SAD (n=22, 19-63 yrs) in the follicular phase of the menstrual cycle (present in 19) were randomized to nine days of eating ∼1600 kcal of either CHO before 12:00 h (n=9), CHO after 18:00 h (n=6), or PROT after 18:00 h (n=7); only water was allowed for the rest of the day. Measurements included the depression questionnaire SIGH-SAD (with 21-item Hamilton depression subscale), Eating Behavior Questionnaire (DEBQ), percentage fat (by bioimpedancemetry), clinical biochemistry (glucose, cholesterol, triglycerides, TSH, T4, cortisol), and electroretinogram (ERG). No differential effects of diet were found on any of the studied parameters (except DEBQ). Clinically, participants improved slightly; the 21-HDRS score (mean±SD) decreased from 19.6±6.4 to 14.4±7.4 (p=.004). Percent change correlated significantly with menstrual day at diet onset (mood improved the first week after menstruation onset), change in available sunshine (more sunlight, better mood), and initial percentage fat (fatter patients improved more). Scotopic ERG amplitude was diminished after treatment (p=.025, three groups combined), probably due to greater exposure to sunshine in 14/22 subjects (partial correlation analysis significant). Keeping in mind the limitations of this ambulatory study (i.e., inability to control outdoor light exposure, small number of participants, and briefness of intervention), it is suggested that the 25% clinical improvement (of the order of magnitude of placebo) is not related to nutrient diet or its timing, but rather to natural changes during the menstrual cycle, available sunshine, and ease of dieting for fatter patients. [ABSTRACT FROM AUTHOR]

To obtain a driver's licence certain requirements for visual acuity and visual field have to be fulfilled. Mesopic contrast and glare sensitivity are not regularly tested and are not crucial to passing the driving test. We report a case of a 39-year-old professional bus driver whose only complaint was increased glare sensitivity. After he had been involved in four traffic accidents, ophthalmological investigations revealed binocular annular scotomata and night blindness, leading to the diagnosis of rod-cone dystrophy. Enhanced glare sensitivity is a common complaint in elderly people or people with the beginnings of cataract but may also represent an initial symptom of a retinal disorder. It is therefore advisable for traffic safety if drivers with such complaints undergo a complete ophthalmological investigation including visual field testing. [ABSTRACT FROM AUTHOR]

Purpose: To report the clinical, electrophysiological, and immunological features of a patient with X-linked hyper-IgM immunodeficiency syndrome type 1 (HIGM1) accompanied by a novel type of autoimmune retinopathy, including retinal pigment epithelium (RPE) hypersensitivity. Methods: Comprehensive ophthalmological examinations, electrophysiological function testing, and inquiries into the immunological status of a 13-year-old presenting with subacute loss of vision in association with a molecularly confirmed diagnosis of HIGM1 were performed. The patient was genotyped by a PCR-based sequence tag content mapping strategy to define the genetic defect within the causative X-HIM gene TNFSF5 . Since conventional allogenic bone marrow transplantation has been reported to cure HIGM1, a peripheral blood stem-cell transplantation was performed. Results: (1) The patient's reduced visual acuity included prolonged dark adaptation and visual field constriction. Electrophysiology revealed a ‘negative ERG’ indicating post-receptoral dysfunction. (2) Initial immunological examination of the patient's serum identified abnormal antibody activity with components of the photoreceptors and the inner nuclear layer. The patient later developed indications of RPE hypersensitivity. A massively reduced light-peak to dark-trough ratio of the EOG slow oscillations (L/D ratio) corresponded to impaired RPE-photoreceptor complex function. (3) Molecular genetic analyses revealed the patient to be nullizygous for the tumor necrosis factor ligand member 5 gene (TNFSF5; CD40LG). A large chromosomal deletion of ~27.6–32.3 kb in size was identified in Xq26. (4) The transplant with its associated immunomodulation appeared to worsen rather than improve the patient's condition. Conclusions: The fundus appearance and electrophysiological function testing revealed indications of atypical retinal degeneration. However, the clinical course and the serological findings were consistent with those of ocular autoimmunity involving both antiretinal activity and RPE hypersensitivity. In this case, peripheral stem-cell transfusion with its associated chemotherapy failed to benefit the patient's vision; indications of autoimmunity appeared to increase following this treatment. [ABSTRACT FROM AUTHOR]

We wanted to determine the characteristics associated with electrophysiological and neurochemical changes secondary to ischemic insult as well as correlate these electrophysiological and neurochemical changes. A Ganzfeld source was used to elicit electroretinograms in anesthetized adult Sprague-Dawley rats. Following baseline recordings, one eye was removed for control quantitative amino acid immunocytochemistry, and ischemic insult was induced by cervical dislocation. Following the induction of ischemia, a single electroretinogram signal was collected at 1, 2, 4, 6, 8, 16, 32 or 64 min, after which the eye was removed for immunocytochemistry. The post-receptoral b-wave was undetectable after 1 min post-ischemia, whereas phototransduction declined more gradually and persisted for up to 16 min post-mortem. Both phototransduction saturated amplitude and sensitivity decayed with a similar time course (tc=3.06 (2.73, 3.48) versus 3.29 (2.61, 4.62) min). Significant elevation of amino acid neurotransmitter levels was not observed until 6 min post-mortem. Between 8 and 16 min post-ischemia, glutamate and GABA were significantly accumulated in neurons and Mu¨ller cells (p<0.05). Beyond 16 min, the neurotransmitter elevation in neurons and Mu¨ller cells was relatively attenuated. Aspartate immunoreactivity was significantly elevated at 4 and 6 min post-ischemia in neurons, prior to a change in any other amino acid. Moreover, of the amino acids assessed the post-ischemic change in aspartate immunoreactivity showed the best correlation with phototransduction decay (r2=0.68). Our findings show that complete impairment of phototransduction coincides with the accumulation of amino acid neurotransmitter. The correlation of aspartate immunoreactivity and phototransduction provides evidence of heightened glutamate oxidation during ischemic insult. [Copyright &y& Elsevier]

Purpose: To study the histology and the physiological function of the retina in the neurological myelin mutant, taiep rats during the postnatal developmental period (P20–P360). Methods: Electroretinography (ERG) was applied to evaluate intensity dependence and spectral sensitivity of the responses to light. Retinal histology, morphometry, and immunocytochemistry were used to characterize the structure of the retina, with particular emphasis on the Mu¨ller (glial) cells. Results: In the taiep rats of all ages studied, the scotopic ERG showed normal a- and b-wave amplitudes and latencies; likewise, the scotopic spectral sensitivity function was the same for control and taiep animals, with a maximal sensitivity (λmax) at 500 nm. However, in adult taiep rats (P90 to P360) a secondary cornea-positive wave (‘b2’) was observed in response to high stimulus intensities, which never occurred in controls. This correlated with the observation that in the photopic ERG responses of the taiep rats, the b-wave was reduced in amplitude, and was followed by a rapid cornea-negative after-potential. After 1 year of life, in taiep rats the outer plexiform layer (OPL) became slightly thinner and the inner plexiform/ganglion cell layers (IPL/GCL) appeared to be swollen, and increased in thickness; in addition, the number of retinal neurons (particularly, of photoreceptor cells) slightly decreased. Increased GFAP immunoreactivity revealed a hypertrophy and reactivity of the Mu¨ller cells in 1-year-old taiep rats. Conclusions: The present results suggest the occurrence of a relatively mild and slowly progressing neural retinal alteration in taiep rats, which becomes histologically and functionally evident at the end of the first year of life, and mainly affects the circuit(s) of the photopic ON-response. It is speculated that this alteration is due to missing/altered signals from demyelinated optic nerve. [Copyright &y& Elsevier]

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19–40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers. (Chronobiology International, 18(6), 957–971, 2001) [ABSTRACT FROM AUTHOR]

Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to evaluate baseline best corrected visual acuity (BCVA), full-field electroretinography (ERG), full-field stimulus thresholds (FST), and their relationship with baseline demographic and clinical characteristics in the Rate of Progression in Usher syndrome type 2 ( USH2A )-related Retinal Degeneration (RUSH2A) multicenter study., Methods: Participants had Usher syndrome type 2 (USH2, N = 80) or autosomal recessive nonsyndromic retinitis pigmentosa (ARRP, N  = 47) associated with biallelic variants in the USH2A gene. Associations of demographic and clinical characteristics with BCVA, ERG, and FST were assessed with regression models., Results: In comparison to ARRP, USH2 had worse BCVA (median 79 vs. 82 letters; P < 0.001 adjusted for age), lower rod-mediated ERG b-wave amplitudes (median 0.0 vs. 6.6 µV; P < 0.001) and 30 Hz flicker cone-mediated ERG amplitudes (median 1.5 vs. 3.1 µV; P  = 0.001), and higher (white, blue, and red) FST thresholds (means [-26, -31, -23 dB] vs. [-39, -45, -28 dB]; P < 0.001 for all stimuli). After adjusting for age, gender, and duration of vision loss, the difference in BCVA between diagnosis groups was attenuated ( P  = 0.09). Only diagnosis was associated with rod- and cone-mediated ERG parameters, whereas both genders ( P  = 0.04) and duration of visual loss ( P < 0.001) also were associated with FST white stimulus., Conclusions: USH2 participants had worse BCVA, ERG, and FST than ARRP participants. FST was strongly associated with duration of disease; it remains to be determined whether it will be a sensitive measure of progression., Translational Relevance: Using standardized research protocols in RUSH2A, measures have been identified to monitor disease progression and treatment response and differentiate features of prognostic relevance between USH2 and ARRP participants with USH2A mutations., Competing Interests: Disclosure: D.G. Birch, Biogen/Nightstarx (F), Acucela (C), ProQR (F, C), Nacuity (C), AGTC (F, C), Editas (C), 4D Therapeutics (F, C); P. Cheng None; J.L. Duncan, 4D Therapeutics (C), Acucela (F), AGTC (C), DTx Pharma, Inc. (C), Editas (C), Eloxx (C), Gyroscope (C), Biogen/Nightstarx (F, C), ProQR (C), Spark (C), SparingVision (S), Vedere Bio (S), Horama (C); A.R. Ayala None; M.G. Maguire Genentech/Roche (C), Regenera (C); I. Audo Novartis (C), SparingVision (C); J.K. Cheetham, AbbVie (I); T.A. Durham None; A.T. Fahim None; F.L. Ferris III, Bausch and Lomb (P, R), Janssen Research & Development, LLC (C) Viewpoint Therapeutics, Inc (C), Genetech (C), Norvo Nordisk (C), Apellis (C), Roche (C), SemaThera PTC Therapeutics (C), Regenera (C), Novartis (C), Eyevensys (C), Kodiak (C), 4D Molecular (C), Clear Side Biomedical (C); E. Heon None; R.M. Huckfeldt, AGTC (F), Spark (F), Biogen (F), ProQR (F), MeiraGTx (F); A. Iannaccone, Alia Therapeutics (S), ClearView Healthcare Partners (C), Teladoc Health (C), GLG Group (C), Guidepoint (C), Astellas Institute for Regenerative Medicine (C), Roivant Pharma (C), Editas (C), Rhythm Pharmaceuticals (C), IQVIA (C), Gyroscope (C), Ocugen (C), AGTC (F), AbbVie (F), Acucela (F), ProQR (F), Retinagenix (F), 4D Molecular Therapeutics (F), BridgeBio Pharma/Retinagenix (F); N.W. Khan None; E.M. Lad, Biogen/Nightstarx (C) and Novartis (C); M. Michaelides, MeiraGTx (F), Stargazer Pharma (F), Acucela (F), Astellas (F), ProQR (F), 2CTech (F); M.E. Pennesi, AbbVie/Editas (C), Spark Therapeutics (C), Wave Biosciences (C), Astellas Pharmaceuticals (C), RegenexBio (C), Iveric (C), Biogen (C), Novartis (C), Adverum (C), Gensight (F), ProQR (F), Horama (F), Eyevensys (F), Nayan (F) (I), Nacuity (F, I), Ocugen (F, I), Vedere Bio (F, I), SparingVision (F, I), AGTC (C), Sanofi (C); K. Stingl, ProQR (F); A. Vincent, ADVERUM Biotechnologies INC (C); C.Y. Weng, Allergan/AbbVie, Inc. (C), Alcon (C), Alimera Sciences (C), Regeneron (C), Novartis (C), Dutch Ophthalmic Research Center (C), (Copyright 2020 The Authors.)