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Interphotoreceptor retinoid-binding protein (IRBP) is an abundant glycoprotein in the subretinal space bound by the photoreceptor (PR) outer segments and the processes of the retinal pigmented epithelium (RPE). IRBP binds retinoids, including 11-cis-retinal and all-trans-retinol. In this study, visual function for demanding visual tasks was assessed in IRBP knock-out (KO) mice. Surprisingly, IRBP KO mice showed no differences in scotopic critical flicker frequency (CFF) compared to wildtype (WT). However, they did have lower photopic CFF than WT. IRBP KO mice had reduced scotopic and photopic acuity and contrast sensitivity compared to WT. IRBP KO mice had a significant reduction in outer nuclear layer (ONL) thickness, PR outer and inner segment, and full retinal thickness (FRT) compared to WT. There were fewer cones in IRBP KO mice. Overall, these results confirm substantial loss of rods and significant loss of cones within 30 days. Absence of IRBP resulted in cone circuit damage, reducing photopic flicker, contrast sensitivity, and spatial frequency sensitivity. The c-wave was reduced and accelerated in response to bright steps of light. This result also suggests altered retinal pigment epithelium activity. There appears to be a compensatory mechanism such as higher synaptic gain between PRs and bipolar cells since the loss of the b-wave did not linearly follow the loss of rods, or the a-wave. Scotopic CFF is normal despite thinning of ONL and reduced scotopic electroretinogram (ERG) in IRBP KO mice, suggesting either a redundancy or plasticity in circuits detecting (encoding) scotopic flicker at threshold even with substantial rod loss.

Elevated levels of the excitatory amino acid homocysteine (Hcy) have been implicated in retinal diseases in humans including glaucoma and macular degeneration. It is not clear whether elevated Hcy levels are pathogenic. Models of hyperhomocysteinemia (Hhcy) have proven useful in addressing this including mice with deficiency in the enzyme cystathionine β-synthase (CBS). Cbs +/- mice have a ∼two-fold increase in plasma and retinal Hcy levels. Previous studies of visual function and structure in Cbs +/- mice during the first 10 months of life revealed mild ganglion cell loss, but minimal electrophysiological alterations. It is not clear whether extended, chronic exposure to moderate Hhcy elevation will lead to visual function loss and retinal pathology. The present study addressed this by performing comprehensive analyses of retinal function/structure in 20 month Cbs +/- and Cbs +/+ (WT) mice including IOP, SD-OCT, scotopic and photopic ERG, pattern ERG (pERG), and visual acuity. Eyes were harvested for histology and immunohistochemical analysis of Brn3a (ganglion cells), dihydroethidium (oxidative stress) and GFAP (gliosis). The analyses revealed no difference in IOP between groups for age/strain. Visual acuity measured ∼0.36c/d for mice at 20 months in Cbs +/- and WT mice; contrast sensitivity did not differ between groups at either age. Similarly SD-OCT, scotopic/photopic ERG and pERG revealed no differences between 20 month Cbs +/- and WT mice. There was minimal disruption in retinal structure when eyes were examined histologically. Morphometric analysis revealed no significant differences in retinal layers. Immunohistochemistry revealed ∼5 RGCs/100 μm retinal length in both Cbs +/- and WT mice at 20 months. While there was greater oxidative stress and gliosis in older (20 month) mice versus young (4 month) mice, there was no difference in these parameters between the 20 month Cbs +/- and WT mice. We conclude that chronic, moderate Hhcy (at least due to deficiency of Cbs) is not accompanied by retinal structural/functional changes that differ significantly from age-matched WT littermates. Despite considerable evidence that severe Hhcy is toxic to retina, moderate Hhcy appears tolerated by retina suggesting compensatory cellular survival mechanisms., (Copyright © 2021. Published by Elsevier Ltd.)

Purpose: The purpose of this study was to present our hypothesis that aging alters metabolic function in ocular tissues. We tested the hypothesis by measuring metabolism in aged murine tissues alongside retinal responses to light., Methods: Scotopic and photopic electroretinogram (ERG) responses in young (3-6 months) and aged (23-26 months) C57Bl/6J mice were recorded. Metabolic flux in retina and eyecup explants was quantified using U-13C-glucose or U-13C-glutamine with gas chromatography-mass spectrometry (GC-MS), O2 consumption rate (OCR) in a perifusion apparatus, and quantifying adenosine triphosphatase (ATP) with a bioluminescence assay., Results: Scotopic and photopic ERG responses were reduced in aged mice. Glucose metabolism, glutamine metabolism, OCR, and ATP pools in retinal explants were mostly unaffected in aged mice. In eyecups, glutamine usage in the Krebs Cycle decreased while glucose metabolism, OCR, and ATP pools remained stable., Conclusions: Our examination of metabolism showed negligible impact of age on retina and an impairment of glutamine anaplerosis in eyecups. The metabolic stability of these tissues ex vivo suggests age-related metabolic alterations may not be intrinsic. Future experiments should focus on determining whether external factors including nutrient supply, oxygen availability, or structural changes influence ocular metabolism in vivo.

Purpose: Retinal ischemia/reperfusion (I/R) injury is a common cause of visual impairment and blindness for which there remain limited treatment options. Nucleoside reverse transcriptase inhibitors (NRTIs), such as zidovudine (AZT), have been shown to block the NLRP3 inflammasome and prevent retinal degeneration in a mouse model of age-related macular degeneration. The NLRP3 inflammasome has also been shown to be triggered in I/R injury. Therefore, we studied the neuroprotective effects of AZT using a pressure-induced retinal ischemia mouse model. Methods: C57BL/6J mice were randomly assigned to 1 of 2 treatment groups: vehicle-treated retinal I/R injury ( n  = 6) or AZT-treated retinal I/R injury ( n  = 6). Vehicle (1% dimethyl sulfoxide [DMSO] in phosphate-buffered saline [PBS]) or AZT 50 mg/kg in 1% DMSO in PBS were injected intraperitoneally twice daily for 5 days. On day 2 of treatment, retinal ischemia was induced by transient elevation of intraocular pressure for 45 min. Scotopic electroretinography (ERG) was used to quantify retinal function before and 1 week after retinal ischemic insult. Retinal morphology was examined 1 week after ischemic insult. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and caspase 1 immunostaining was performed 24 h after retinal I/R injury. Results: Following I/R injury, ERG a- and b-wave amplitudes were significantly reduced in the vehicle-treated mice. AZT treatment significantly attenuated I/R-induced loss of retinal function as compared with vehicle-treated mice. Additionally, AZT-treated mice experienced significantly less inner retinal thinning as compared with vehicle-treated mice. TUNEL-positive cells were prevalent in the vehicle-treated I/R injury mouse retinas compared with the AZT-treated I/R injury mouse retinas. More caspase-1 immunoreactivity was detected in ganglion cell layer and inner nuclear layer (INL) in vehicle-treated I/R injury group than in AZT-treated I/R injury group. Conclusion: AZT treatment resulted in relative preservation of retinal structure and function following ischemic insult as compared with controls. This suggests AZT may have therapeutic value in the management of retinal ischemic diseases.

Purpose: The measurement of standard visual acuity (VA) is the most well-known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions., Recent Findings: Sixty-five peer-reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age-related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod-cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined., Summary: Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient's level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment., (© 2021 The Authors Ophthalmic and Physiological Optics © 2021 The College of Optometrists.)

Purpose: Exposure to high-intensity or outdoor lighting has been shown to decrease the severity of myopia in both human epidemiological studies and animal models. Currently, it is not fully understood how light interacts with visual signaling to impact myopia. Previous work performed in the mouse retina has demonstrated that functional rod photoreceptors are needed to develop experimentally-induced myopia, alluding to an essential role for rod signaling in refractive development., Methods: To determine whether dim rod-dominated illuminance levels influence myopia susceptibility, we housed male C57BL/6J mice under 12:12 light/dark cycles with scotopic (1.6 × 10-3 candela/m2), mesopic (1.6 × 101 cd/m2), or photopic (4.7 × 103 cd/m2) lighting from post-natal day 23 (P23) to P38. Half the mice received monocular exposure to -10 diopter (D) lens defocus from P28-38. Molecular assays to measure expression and content of DA-related genes and protein were conducted to determine how illuminance and lens defocus alter dopamine (DA) synthesis, storage, uptake, and degradation and affect myopia susceptibility in mice., Results: We found that mice exposed to either scotopic or photopic lighting developed significantly less severe myopic refractive shifts (lens treated eye minus contralateral eye; -1.62 ± 0.37D and -1.74 ± 0.44D, respectively) than mice exposed to mesopic lighting (-3.61 ± 0.50D; P < 0.005). The 3,4-dihydroxyphenylacetic acid /DA ratio, indicating DA activity, was highest under photopic light regardless of lens defocus treatment (controls: 0.09 ± 0.011 pg/mg, lens defocus: 0.08 ± 0.008 pg/mg)., Conclusions: Lens defocus interacted with ambient conditions to differentially alter myopia susceptibility and DA-related genes and proteins. Collectively, these results show that scotopic and photopic lighting protect against lens-induced myopia, potentially indicating that a broad range of light levels are important in refractive development.

Night-vision handheld scopes are of wide use in military operations at dark conditions. In some cases in the battlefield, as in our case report, if there is no light coming from any source (neither from Moon nor from Stars), infrared light-emitting diode illumination can be coupled with night-vision goggles. Reflected illumination from the target is mostly blue filtered through the night-vision goggles objective lens. Retinal damage induced by unfiltered blue light and visible light has been previously reported. We described a phototoxic maculopathy induced by night-vision handheld scope assembled with infrared light-emitting diode illuminator in two soldiers who are on duty at nights for nearly two-thirds of the last year. The phototoxic maculopathy can represent with typical optical coherence tomography findings such as intraretinal hyperreflective accumulation particularly located on the surface of outer retinal segments defect or presumably in the vicinity of the light passageway. Here, we presented a unique factor causing phototoxic maculopathy.

Neuronal plasticity of the inner retina has been observed in response to photoreceptor degeneration. Typically, this phenomenon has been considered maladaptive and may preclude vision restoration in the blind. However, several recent studies utilizing triggered photoreceptor ablation have shown adaptive responses in bipolar cells expected to support normal vision. Whether such homeostatic plasticity occurs during progressive photoreceptor degenerative disease to help maintain normal visual behavior is unknown. We addressed this issue in an established mouse model of Retinitis Pigmentosa caused by the P23H mutation in rhodopsin. We show robust modulation of the retinal transcriptomic network, reminiscent of the neurodevelopmental state, and potentiation of rod - rod bipolar cell signaling following rod photoreceptor degeneration. Additionally, we found highly sensitive night vision in P23H mice even when more than half of the rod photoreceptors were lost. These results suggest retinal adaptation leading to persistent visual function during photoreceptor degenerative disease., Competing Interests: HL, NP, TB, JS, KP, FV No competing interests declared, (© 2020, Leinonen et al.)

From starlight to sunlight, adaptation alters retinal output, changing both the signal and noise among populations of retinal ganglion cells (RGCs). Here we determine how these light level-dependent changes impact decoding of retinal output, testing the importance of accounting for RGC noise correlations to optimally read out retinal activity. We find that at moonlight conditions, correlated noise is greater and assuming independent noise severely diminishes decoding performance. In fact, assuming independence among a local population of RGCs produces worse decoding than using a single RGC, demonstrating a failure of population codes when correlated noise is substantial and ignored. We generalize these results with a simple model to determine what conditions dictate this failure of population processing. This work elucidates the circumstances in which accounting for noise correlations is necessary to take advantage of population-level codes and shows that sensory adaptation can strongly impact decoding requirements on downstream brain areas.

Purpose: To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD)., Methods: At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models., Results: At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 µm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was -0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, -0.40 SD (P < 0.001) for regions with new occurring RPD, and -0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (-3.51 and -7.76 dB) and new occurring RPD (-2.06 and -5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing., Conclusions: This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.

Purpose: Retinitis pigmentosa (RP) is a blinding neurodegenerative disease of the retina that can be affected by many factors. The present study aimed to analyze the effect of different environmental light intensities in rd10 mice retina., Methods: C57BL/6J and rd10 mice were bred and housed under three different environmental light intensities: scotopic (5 lux), mesopic (50 lux), and photopic (300 lux). Visual function was studied using electroretinography and optomotor testing. The structural and morphological integrity of the retinas was evaluated by optical coherence tomography imaging and immunohistochemistry. Additionally, inflammatory processes and oxidative stress markers were analyzed by flow cytometry and western blotting., Results: When the environmental light intensity was higher, retinal function decreased in rd10 mice and was accompanied by light-dependent photoreceptor loss, followed by morphological alterations, and synaptic connectivity loss. Moreover, light-dependent retinal degeneration was accompanied by an increased number of inflammatory cells, which became more activated and phagocytic, and by an exacerbated reactive gliosis. Furthermore, light-dependent increment in oxidative stress markers in rd10 mice retina pointed to a possible mechanism for light-induced photoreceptor degeneration., Conclusions: An increase in rd10 mice housing light intensity accelerates retinal degeneration, activating cell death, oxidative stress pathways, and inflammatory cells. Lighting intensity is a key factor in the progression of retinal degeneration, and standardized lighting conditions are advisable for proper analysis and interpretation of experimental results from RP animal models, and specifically from rd10 mice. Also, it can be hypothesized that light protection could be an option to slow down retinal degeneration in some cases of RP.

Purpose: To determine the characteristics of the full-field electroretinograms (ERGs) of eyes with Stickler syndrome., Methods: Twenty-two eyes of 14 Japanese patients from nine families with Stickler syndrome were studied. All of the patients were found to have mutations in the COL2A1 gene and had undergone ERG recordings. The ERGs from one of the two eyes were compared to 11 eyes of 11 normal control subjects who were matched by age, sex, and refractive error., Results: One patient had non-recordable ERGs under both scotopic and photopic conditions. For the remaining 13 patients, the amplitudes of the b-waves of the scotopic combined, rod, and cone responses were significantly smaller than those of the control subjects (P = 0.0001, P = 0.015, P = 0.0006, respectively). The implicit times of the b-wave of the scotopic combined and photopic responses were significantly prolonged (P = 0.0037 and P = 0.0126). The age was inversely and significantly correlated with the amplitudes of the scotopic combined a-wave (P = 0.0184) and b-wave (P = 0.0076) in 13 eyes. The amplitudes of the scotopic combined b-wave amplitudes were not significantly correlated with the refractive error., Conclusions: The reduced or absent full-field ERGs in eyes with Stickler syndrome indicate that the physiology of the entire retina was negatively altered. The greater reduction in the ERGs with increasing age suggests that the physiological alterations of the retina are progressive.

Purpose: To determine the electroretinographical and psychophysical parameters that can help to verify patients' complaints of reduced night vision., Methods: We tested 275 consecutive patients with normal appearing fundi, complaining of visual difficulties at night, using flash electroretinography (ERG) and dark adaptation (DA) test. Two ERG parameters were used to assess a scotopic retinal function: the amplitude of the response to dim blue flash (the rod response) and the b-wave ratio (measured/expected). Dark adaptation was measured with green- and red-light stimuli after exposure to a bright, bleaching light. The psychophysical parameter of night vision was defined as the threshold for detection of the blue-green stimulus that was measured after 40-45 min in complete darkness., Results: Fifty-five patients were excluded from the analysis because of a discrepancy between the two ERG parameters in assessment of scotopic retinal function. The remaining 220 patients were divided into 4 groups: (1) normal ERG and normal DA, (2) subnormal ERG and subnormal DA, (3) normal ERG and subnormal DA and (4) subnormal ERG and normal DA. The ERG and DA tests supported the complaint of visual difficulties at night in 67 patients (group 2), while 34 patients were characterized as having normal scotopic visual function (group 1). The other 119 patients (groups 3 and 4) presented a diagnostic dilemma because one test (ERG or dark adaptation) showed normal scotopic function, while the other indicated subnormal scotopic function., Conclusion: Our findings indicate that ERG is an essential, but not sufficient test for verifying patient's complaint on visual difficulties in the dark. We suggest using both electroretinography and psychophysical dark adaptation to test patients complaining of reduced night vision.

Purpose: To report the clinical and genetic characteristics of 6 cases with late-onset night blindness with peripheral flecks accompanied by progressive trickle-like macular degeneration., Methods: Clinical and genetic data were collected from 6 independent patients who complained of night blindness in their fifth to eighth decade of life. The ophthalmological examinations included ophthalmoscopy, fundus autofluorescence (FAF), and full-field electroretinography (ERG). Whole exome sequencing with target gene analysis was performed to determine the causative genes and variants., Results: All of the patients first complained of night blindness at the ages of 40-71 years. Funduscopic examinations demonstrated white or atrophic flecks scattered in the posterior pole and peripheral retina bilaterally. FAF showed patchy hypo-autofluorescence spots in the posterior pole similar to that of the trickling type of age-related macular degeneration (AMD). The region of abnormal FAF rapidly expanded with age, and one eye developed a choroidal neovascularization. The full-field scotopic ERGs with 20 min of dark adaptation were severely reduced or extinguished in all cases. There was partial recovery of the ERGs after 180 min of dark adaptation. The cone ERGs were reduced in all cases. Whole exome sequencing revealed no pathogenic variants of 301 retinal disease-associated genes., Conclusions: The six cases had some common features with the flecked retina syndrome, familial drusen, and late-onset retinal degeneration although none had pathogenic variants causative for these disorders. These cases may represent a subset of severe trickling AMD or a new clinical entity of acquired pan-retinal visual cycle deficiency of unknown etiology.

Purpose: To evaluate the feasibility in the clinical practice of a fast and simple mesopic microperimetry examination comparing the retinal sensitivity in eyes with drusen and reticular pseudodrusen by scotopic and mesopic testing., Methods: In eyes with only drusen and only reticular pseudodrusen, retinal sensitivity was assessed by mesopic testing and after 35 minutes of dark adaptation by scotopic testing using 2 grids of 6 and 10 stimulus points., Results: Fifteen eyes with drusen and 14 eyes with reticular pseudodrusen were enrolled with mean best-corrected visual acuity of 20/20. In mesopic and scotopic examination, we found significant higher retinal sensitivity of eyes with drusen compared with reticular pseudodrusen (P < 0.001). The mean duration of the examination of mesopic testing was less than 2 minutes, significantly reduced compared with scotopic testing (P < 0.01)., Conclusion: Eyes with reticular pseudodrusen presented a significantly reduced retinal sensitivity than eyes with drusen with scotopic and mesopic testing. The different retinal sensitivity between patients was found despite both group presenting good visual acuity. The retinal sensitivity evaluated by mesopic testing may replace the use of scotopic testing and best-corrected visual acuity examination, saving time and providing useful information in the assessment of macular function to identify patients with risk of disease progression.

Purpose: To assess retinal function in young patients with X-linked juvenile retinoschisis (XLRS), a disorder that is known to alter ERG postreceptor retinal components and also possibly photoreceptor components., Methods: ERG responses to full-field stimuli were recorded under scotopic and photopic conditions in 12 XLRS patients aged 1 to 15 (median 8) years. A- and b-wave amplitudes and implicit times were examined over a range of stimulus intensities. Rod and cone photoreceptor (SROD, RROD, SCONE, RCONE) and rod-driven postreceptor (log σ, VMAX) response parameters were calculated from the a- and b-waves. Data from XLRS patients were evaluated for significant change with age., Results: A- and b-wave amplitudes were smaller in XLRS patients compared with controls under both scotopic and photopic conditions. Saturated photoresponse amplitude (RROD), postreceptor b-wave (log σ), and saturated b-wave amplitude (VMAX) were significantly lower in XLRS patients than in controls; SROD did not differ between the two groups. SCONE and RCONE values were normal. In XLRS patients, neither a- and b-wave amplitudes nor calculated parameters (SROD, RROD, log σ, VMAX,SCONE, and RCONE) changed with age., Conclusions: In these young XLRS patients, RROD and a-wave amplitudes were significantly smaller than in controls. Thus, in addition to XLRS causing postreceptor dysfunction, an effect of XLRS on rod photoreceptors cannot be ignored.

Non-damaging heating of the retina and RPE provides a promising treatment for retinal diseases. However, the lack of proper control over the temperature hinders the development of safe and repeatable procedures. Here, we demonstrate with mice a non-invasive method for estimating the temperature changes in the retina and the RPE during a heating procedure. The method is based on monitoring the temperature dependent properties of retinal photoresponses recorded by electroretinography (ERG). In this study, our aim was to investigate the feasibility of ERG signal for retinal temperature estimation, utilizing a-wave and b-wave kinetics as the source of temperature information. We quantified the temperature dependencies of photoresponse kinetics and developed two linear regression models between the temperature and the photoresponse features, enabling temperature estimation. With the first model, based on the a-wave of a single photoresponse, the RMS error obtained for retinal temperature estimation was <0.9 °C. The second model, applying the b-waves of five dim flash responses, an RMS error of <0.7 °C was achieved. In addition, we tested the sensitivity of the method to small changes in light stimulus strength and investigated suitable stimulus intervals for continuous retinal temperature monitoring. The proposed method provides a convenient technique for monitoring mouse retinal and RPE temperature with ERG recording when studying controlled retinal heating. Similar temperature dependencies exist in human ERG suggesting that this approach could also be applicable in clinical heating treatments., (Copyright © 2019. Published by Elsevier Ltd.)

Background and Objectives: To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD)., Patients and Methods: Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis., Results: Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = -0.06; P = .32) or drusen volume (r = -0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = -0.39; P = .24) and drusen volume (r = -0.36; P = .30)., Conclusions: In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e236-e241.]., (Copyright 2019, SLACK Incorporated.)

Purpose: The aim of this study was to examine the ophthalmological characteristics and genotypes of patients with congenital retinal pathologies, who display a bull's-eye maculopathy in the fundus, along with a negative scotopic electroretinogram., Methods: We analysed the results of five patients showing both a bull's-eye maculopathy, as well as a negative scotopic ERG evoked by a bright flash. Their median age was 39 years (range 11-63 years): three males and two females. All underwent a comprehensive examination with determination of distant visual acuity (ETDRS) and recording of the full-field ERG (scotopic and photopic). Fundus, OCT, and FAF images were obtained, the kinetic visual field was determined, and colour vision (D-15) was tested in most patients. Targeted gene panel sequencing was performed on peripheral blood., Results: One patient carried a homozygous ABCA4 mutation and an additional heterozygous variant in CRX. Two of the five patients were shown to have a heterozygous mutation in the CRX gene, one of whom had an additional heterozygous ABCA4 mutation. Two patients had the common heterozygous mutation c.2413G>A;p.Arg838His in GUCY2D. In all of the patients, there was a reduction in the amplitude of the b-wave with a regular a-wave amplitude in the scotopic bright-flash ERG., Conclusions: The five patients with bull's-eye maculopathy along with a negative ERG had differing genotypes. Mutations were found in the CRX gene (2 patients), the ABCA4 gene (1 patient), and the GUCY2D gene (2 patients).

Retinal lesions in the posterior pole of laboratory mice occur due to native, developmental abnormalities or as a consequence of environmental or experimental conditions. In this study, we investigated the rate and extent of retinal lesions as a result of prolonged ocular exposure following general anesthesia. Following experimental preparation induction procedures (EPIP) involving general anesthesia, mydriasis/cycloplegia, and topical anesthesia to the cornea, two ocular recovery conditions (protected and unprotected) were tested within two different animal recovery chambers (open or closed). The anterior and posterior poles were evaluated for the development of retinal lesions using digital color photography, scanning laser ophthalmoscopy, and spectral-domain optical coherence during anesthesia recovery and up to 2.5 months thereafter. In some mice, electroretinograms, histological and immunohistological evaluations were performed to assess functional and structural changes that accompanied the retinal lesions detected by in vivo imaging. Our data suggests that prolonged ocular surface exposure to circulating ambient room air leads to significant anterior and posterior segment ocular complications. The most abundant, semi-reversible complication observed was the development of lesions in the outer retina, which had a 90% probability of occurring after 45 min of exposure. The lesions mostly resolved short-term, but functional and imaging evidence suggest that some perturbations to the outer retina may persist one or more months following initial development., (Copyright © 2019. Published by Elsevier Ltd.)

Glaucoma is traditionally considered an asymptomatic disease until later stages. However, questionnaire studies revealed visual complaints related to various tasks, especially under extreme luminance conditions (such as outdoor at night on an unlit road or outside in the sun). We measured contrast sensitivity (CS) over a luminance range of 6 log units spanning the scotopic to photopic range and we aimed (1) to determine whether Weber's law also holds under extremely high luminance conditions and (2) to compare CS as a function of spatial frequency and luminance between glaucoma patients and healthy subjects. We included 22 glaucoma patients and 51 controls, all with normal visual acuity. For the second aim, we used a subgroup of 22 age-similar controls. Vertically oriented sine-wave gratings were generated with a projector-based setup (stimulus size 8x5 degrees). CS was measured monocularly at 1, 3, and 10 cycles per degree (cpd); mean luminance ranged from 0.0085 to 8500 cd/m 2 . ANOVA was used to analyze the effect of glaucoma, luminance, and spatial frequency on logCS. In controls, Weber's law held for 3 and 10 cpd; for 1 cpd, CS dropped above 1000 cd/m 2 (P = 0.003). The logCS versus log luminance curves did not differ grossly between patients and controls (P = 0.14; typically 0-0.2 log units); the difference became larger with decreasing luminance (P = 0.003) but did not depend clearly on spatial frequency (P = 0.27). We conclude that differences between glaucoma and healthy were relatively modest for the spatially redundant, static stimulus as used in the current study., (Copyright © 2019. Published by Elsevier Ltd.)

Purpose: Dark-adapted visual fields were obtained from patients with inherited retinal degeneration (IRD) and controls to evaluate the effect that age, retinal region, and disease had on scotopic sensitivity. Intra- and intersession test-retest repeatabilities for patients and controls were measured to establish significant change for longitudinal studies., Methods: A total of 41 patients with IRD and 30 controls had one eye dilated and dark-adapted for 40 minutes. Scotopic sensitivity was measured with a Medmont dark-adapted chromatic (DAC) perimeter (size V stimulus, 200-ms duration, background luminance < 0.0001 cd/m2, dynamic range 0-75 decibel [dB]). Mixed effects analysis was performed to analyze age, retinal eccentricity, and sensitivity. The intra-/intersession coefficients of repeatability (CR) were calculated for controls and patients with IRD., Results: Each additional year was associated with lower sensitivity (-0.22 dB) per year in normal controls over age 50 compared to younger controls (12-49 years). The superior field had lower sensitivity than the inferior, but the nasal field was not different compared to the temporal field in normal controls. The CR for intra- and intersession testing on mean sensitivity (MS)/pointwise sensitivity (PWS) were ±1.5/±8.5 and ±3.3/±9.8 dB, respectively, for patients with IRD. Control MS/PWS CR were ±1.5/±6.1 dB for intrasession and ±1.7/±6.8 dB for intersession DAC perimetry., Conclusions: The DAC perimeter is an important asset because it tests a wide field of scotopic vision. The CR are comparable to those of other perimetry devices. Effects of age and retinal region should be considered when assessing scotopic sensitivity measured with the DAC perimeter.

Diabetic retinopathy is a major cause of reduced visual acuity and acquired blindness. The aim of this work was to analyze functional and vascular changes in diabetic Meriones shawi (M.sh) an animal model of metabolic syndrome and type 2 diabetes. The animals were divided into four groups. Two groups were fed a high fat diet (HFD) for 3 and 7 months, two other groups served as age-matched controls. Retinal function was assessed using full field electroretinogram (Ff-ERG). Retinal thickness and vasculature were examined by optical coherence tomography, eye fundus and fluorescein angiography. Immunohistochemistry was used to examine key proteins of glutamate metabolism and synaptic transmission. Diabetic animals exhibited significantly delayed scotopic and photopic ERG responses and decreases in scotopic and photopic a- and b-wave amplitudes at both time points. Furthermore, a decrease of the amplitude of the flicker response and variable changes in the scotopic and photopic oscillatory potentials was reported. A significant decrease in retinal thickness was observed. No evident change in the visual streak area and no sign of vascular abnormality was present; however, some exudates in the periphery were visible in 7 months diabetic animals. Imunohistochemistry detected a decrease in the expression of glutamate synthetase, vesicular glutamate transporter 1 and synaptophysin proteins. Results indicate that a significant retinal dysfunction was present in the HFD induced diabetes involving both rod and cone pathways and this dysfunction correlate well with the morphological abnormalities reported previously. Furthermore, neurodegeneration and abnormalities in retinal function occur before vascular alterations would be detectable in diabetic M.sh., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON., Methods: We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions., Results: The key results of validating this newly modified model, "controlled orbital impact (COI)," included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare., Conclusions: Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.

The aim of this study was to compare the quality of electroretinogram (ERG) recordings using a custom built active electrode with attached amplifier versus a standard (passive) ERG electrode. Scotopic and photopic ERG responses were recorded from five adult albino rabbits using a custom built active electrode on one eye and a passive electrode on the other. For the active electrode, the ERG-jet electrode (Universo S.A., La Chaux-De-Fonds, Switzerland) was used as the transducer with the cable cut short and soldered directly to the input of a customized amplifier. The passive electrode was a standard ERG jet electrode. The signal to noise ratio and reproducibility of ERGs were compared. The noise was significantly lower in the active electrode compared to the passive electrode (p = 0.009) resulting in signals being recorded at lower stimulation strengths with the active electrode. The scotopic a-wave was significantly larger in the active electrode at all supra-threshold stimulation intensities (p < 0.05) and the scotopic b-wave amplitudes were also higher in the active electrode at all supra-threshold stimulation intensities but was only statistically significant between -3.25 and -1 log cd.s.m -2 (p < 0.05). The photopic a- and b-wave amplitudes were also higher in the active electrode and statistically significant between -0.75 and 0.48 log cd.s.m -2 for the a-wave and -1.25 to -1 log cd.s.m -2 for the b-wave (p < 0.05). The intra-observer repeatability, inter-sessions reproducibility and reliability of the signals were better in the active electrode as evidenced by lower coefficient of variation (CV) and coefficient of repeatability (CR) with high intra-class correlation coefficient (ICC) of the a- and b-wave parameters of the active electrode. These findings suggest that the custom built active ERG electrode produces less noise than the passive electrode, allowing responses to be recorded at lower stimulation strengths. It produces greater signal amplitudes and improved reproducibility and is therefore a better device for investigating retinal function., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: We investigated the relationship between visual parameters that are commonly affected during glaucomatous disease progression with functional measures of retina physiology using electroretinography and behavioral measures of visual function in a mouse model of glaucoma. Electroretinogram components measuring retinal ganglion cell (RGC) responses were determined using the non-invasive Ganzfeld flash electroretinography (fERG) to assess RGC loss in a mouse model of glaucoma., Methods: Intraocular pressure (IOP), behaviorally assessed measures of visual function, namely visual acuity and contrast sensitivity as well as fERG responses were recorded in 4- and 11-month-old male DBA/2 mice. Scotopic threshold response (STR) and photopic negative response components as well as oscillatory potentials (OPs) were isolated from fERG responses and correlated with IOP, optomotor reflex measurements, and RGC counts., Results: The 11-month-old DBA/2 mice had significantly elevated IOP, reduced visual performance, as assessed behaviorally, significant RGC loss, deficits in standardized fERG responses, reduced STRs, and differences in OP amplitudes and latencies, when compared with 4-month-old mice of the same strain. STRs and OPs correlated with some visual and physiological parameters. In addition, elevated IOP and RGC loss correlated positively with measures of visual function, specifically with surrogate measures of RGC function derived from fERG., Conclusions: Our data suggest that RGC function as well as interactions of RGCs with other retinal cell types is impaired during glaucoma. In addition, a later OP wavelet denoted as OP4 in this study was identified as a very reproducible indicator of loss of visual function in the glaucoma mouse model.

In this study, we show the capability of Müller glial cells to transport light through the inverted retina of reptiles, specifically the retina of the spectacled caimans. Thus, confirming that Müller cells of lower vertebrates also improve retinal light transmission. Confocal imaging of freshly isolated retinal wholemounts, that preserved the refractive index landscape of the tissue, indicated that the retina of the spectacled caiman is adapted for vision under dim light conditions. For light transmission experiments, we used a setup with two axially aligned objectives imaging the retina from both sides to project the light onto the inner (vitreal) surface and to detect the transmitted light behind the retina at the receptor layer. Simultaneously, a confocal microscope obtained images of the Müller cells embedded within the vital tissue. Projections of light onto several representative Müller cell trunks within the inner plexiform layer, i.e. (i) trunks with a straight orientation, (ii) trunks which are formed by the inner processes and (iii) trunks which get split into inner processes, were associated with increases in the intensity of the transmitted light. Projections of light onto the periphery of the Müller cell endfeet resulted in a lower intensity of transmitted light. In this way, retinal glial (Müller) cells support dim light vision by improving the signal-to-noise ratio which increases the sensitivity to light. The field of illuminated photoreceptors mainly include rods reflecting the rod dominance of the of tissue. A subpopulation of Müller cells with downstreaming cone cells led to a high-intensity illumination of the cones, while the surrounding rods were illuminated by light of lower intensity. Therefore, Müller cells that lie in front of cones may adapt the intensity of the transmitted light to the different sensitivities of cones and rods, presumably allowing a simultaneous vision with both receptor types under dim light conditions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

It has been shown that mammalian retinal glial (Müller) cells act as living optical fibers that guide the light through the retinal tissue to the photoreceptor cells (Agte et al., 2011; Franze et al., 2007). However, for nonmammalian species it is unclear whether Müller cells also improve the transretinal light transmission. Furthermore, for nonmammalian species there is a lack of ultrastructural data of the retinal cells, which, in general, delivers fundamental information of the retinal function, i.e. the vision of the species. A detailed study of the cellular ultrastructure provides a basic approach of the research. Thus, the aim of the present study was to investigate the retina of the spectacled caimans at electron and light microscopical levels to describe the structural features. For electron microscopy, we used a superfast microwave fixation procedure in order to achieve more precise ultrastructural information than common fixation techniques. As result, our detailed ultrastructural study of all retinal parts shows structural features which strongly indicate that the caiman retina is adapted to dim light and night vision. Various structural characteristics of Müller cells suppose that the Müller cell may increase the light intensity along the path of light through the neuroretina and, thus, increase the sensitivity of the scotopic vision of spectacled caimans. Müller cells traverse the whole thickness of the neuroretina and thus may guide the light from the inner retinal surface to the photoreceptor cell perikarya and the Müller cell microvilli between the photoreceptor segments. Thick Müller cell trunks/processes traverse the layers which contain light-scattering structures, i.e., nerve fibers and synapses. Large Müller cell somata run through the inner nuclear layer and contain flattened, elongated Müller cell nuclei which are arranged along the light path and, thus, may reduce the loss of the light intensity along the retinal light path. The oblique arrangement of many Müller cell trunks/processes in the inner plexiform layer and the large Müller cell somata in the inner nuclear layer may suggest that light guidance through Müller cells increases the visual sensitivity. Furthermore, an adaptation of the caiman retina to low light levels is strongly supported by detailed ultrastructural data of other retinal parts, e.g. by (i) the presence of a guanine-based retinal tapetum, (ii) the rod dominance of the retina, (iii) the presence of photoreceptor cell nuclei, which penetrate the outer limiting membrane, (iv) the relatively low densities of photoreceptor and neuronal cells which is compensated by (v) the presence of rods with long and thick outer segments, that may increase the probability of photon absorption. According to a cell number analysis, the central and temporal areas of the dorsal tapetal retina, which supports downward prey detection in darker water, are the sites of the highest diurnal contrast/color vision, i.e. cone vision and of the highest retinal light sensitivity, i.e. rod vision., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Pigmented and albino rabbits are commonly used in visual research; however, the lack of pigment in the eyes may affect retinal responses. Here, we compare and describe the differences of retinal function between pigmented (English Butterfly) and albino (New Zealand) rabbits., Methods: Electroretinograms were recorded in pigmented and albino rabbits in the dark-adapted eye, in the light-adapted eye and for four temporal frequencies in the light-adapted eye. The implicit time and amplitude of the a- and b-waves were analyzed, as well as the amplitude and phase of the first harmonic component of the photopic flicker response., Results: Albino rabbits presented significantly larger amplitudes for both a- and b-waves at all intensities and frequencies. The intensity-response function of the scotopic b-wave also showed that the albino retina is more sensitive than the pigmented retina and the larger flicker amplitudes found in the albino group also revealed post-receptoral changes specifically related to cone pathways., Conclusions: The larger amplitude of albino receptoral and post-receptoral activities might be attributed to greater availability of light due to scatter and reflection at the retinal layer, and as the differences in response amplitudes between the groups increase with flicker frequency, we suggest that ON bipolar cells recover faster in the albino group, suggesting that this might be a mechanism to explain the higher temporal resolution for albinos compared to the pigmented group.

Owl monkeys are the only one species possessing the nocturnal lifestyles among the simian monkeys. Their eyes and retinas have been interested associating with the nocturnal adaptation. We examined the cellular specificity and electroretinogram (ERG) reactivity in the retina of the owl monkeys by comparison with the squirrel monkeys, taxonomically close-species and expressing diurnal behavior. Owl monkeys did not have clear structure of the foveal pit by the funduscope, whereas the retinal wholemount specimens indicated a small-condensed spot of the ganglion cells. There were abundant numbers of the rod photoreceptor cells in owl monkeys than those of the squirrel monkeys. However, the owl monkeys' retina did not possess superiority for rod cell-reactivity in the scotopic ERG responses. Scanning electron microscopic observation revealed that the rod cells in owl monkeys' retina had very small-sized inner and outer segments as compared with squirrel monkeys. Owl monkeys showed typical nocturnal traits such as rod-cell dominance. However, the individual photoreceptor cells seemed to be functionally weak for visual capacity, caused from the morphological immaturity at the inner and outer segments.

Purpose: To examine the topographic correlation between retinal morphology and retinal sensitivity by mesopic and scotopic fundus-controlled perimetry (FCP) in eyes with intermediate AMD., Methods: Thirty-five eyes from 32 patients (mean age 70.9 years) and 29 age-matched controls prospectively underwent spectral-domain optical coherence tomography (SD-OCT) imaging. Mesopic (Goldman III, 200 ms, 4-2 strategy) and scotopic (Goldman V, 200 ms, 4-2 strategy) FCP with a 56-stimulus point grid was performed in AMD patients with the MP-1S. Thickness values of different retinal layers were measured at each stimulus point and compared, topographically corresponding to values in controls of similar age for pointwise structural-functional analysis., Results: The overall mean sensitivity in patients was 16.9 ± 3.0 dB for mesopic and 14.0 ± 3.7 dB for scotopic testing. Within the central 4° of the macula, reduced mesopic and scotopic sensitivity values were found (P < 0.0001). These findings correlated to central increasing retinal pigment epithelium-drusen complex (RPEDC) thickness and central decreasing outer nuclear layer (ONL) and photoreceptor (PR)-segments thickness (P < 0.0001, respectively). Structure-function correlations revealed that a reduction of mesopic and scotopic sensitivity was associated with increasing thickness of the total retina and the RPEDC and a decrease of the ONL and the PR-segments (P < 0.001, respectively)., Conclusions: Accumulation of sub-RPE material in patients with intermediate AMD is spatially associated to quantifiable structural alterations in various retinal layers and to corresponding retinal dysfunction. The topographic analysis of retinal thickness and retinal sensitivity will be helpful for a better understanding of the disease process and for the evaluation of new interventional approaches.

Purpose: The aim was to investigate the effect of axial length on full-field electroretinogram (ffERG) and multifocal electroretinogram (mfERG) in young Indian subjects., Methods: One hundred subjects (44 male) with refractive errors from +0.50 to -18.00 DS and no myopic retinopathy underwent axial length measurement. ffERG was measured, which included scotopic and photopic responses according to International Society for Clinical Electrophysiology of Vision (ISCEV) guidelines. The mfERG was recorded after correcting for refractive error according to ISCEV standards. The dark-adapted and light-adapted parameters of ffERG and N1, P1 parameters of six rings in mfERG were analysed with axial length, controlled for refractive error. The subjects were divided into seven groups based on axial length. The b/a ratio of dark-adapted and light-adapted 3.0 ffERG and P1/N1 ratio of mfERG amplitudes were analysed for seven groups of axial length., Results: The axial length ranged from 21.79 to 30.55 mm. Significant negative correlations were noted for ffERG and mfERG amplitudes, whereas implicit times showed minimal delay with increase in axial length. In ffERG, the scotopic responses were more decreased compared to photopic responses. In mfERG, P1 and N1 amplitudes were significantly decreased in all the rings in all groups and more reduction was noted in the central ring compared to peripheral rings. The P1 amplitudes were more affected as compared to N1 amplitudes. The light-adapted and dark-adapted 3.0 ERG b/a ratio and P1/N1 ratio for seven axial length groups did not show statistically significant difference. The ERG parameters were not significant with refractive error., Conclusion: This study quantifies the relationship of axial length with ffERG and mfERG parameters in a young Indian population. Although the amplitudes were reduced significantly, the implicit times were not significantly affected. The ERG parameters were more related to axial length than refractive error. Hence, interpretation of ffERG and mfERG parameters needs careful consideration in subjects with increasing axial length., (© 2017 Optometry Australia.)

Purpose: To estimate heritability of parameters of human retinal electrophysiology and to explore which parameters change with age., Design: Prospective, classic twin study., Participants: Adult monozygotic and dizygotic twin pairs recruited from the TwinsUK cohort., Methods: Electroretinogram responses were recorded using conductive fiber electrodes in response to stimuli incorporating standards set by the International Society for the Clinical Electrophysiology of Vision. These parameters were extracted; in addition, photopic negative-response (PhNR; originating from retinal ganglion cells) and i-wave components were extracted from responses to the photopic single flash. Parameter values were averaged from both eyes., Main Outcome Measures: Mean values were calculated for the cohort. Correlation coefficients with age were calculated (averaging parameters from both twins from each pair). Coefficients of intrapair correlation were calculated for monozygotic and dizygotic twins. Age-adjusted heritability estimates were derived using standard maximum likelihood structural equation twin modeling., Results: Responses were recorded from 210 participants in total (59 monozygotic and 46 dizygotic twin pairs). Ninety-three percent were women. Mean age for the cohort was 62.4 years (standard deviation, 11.4 years). In general, response amplitudes correlated negatively, and implicit times positively, with age. Correlations were statistically significant (P < 0.05) and moderate or strong (coefficient, >0.35) for the following parameters: scotopic standard and bright-flash a-wave implicit times, photopic 30-Hz flicker and single-flash b-wave implicit times, and PhNR and i-wave implicit times. Intrapair correlations were higher for monozygotic than dizygotic twins, suggesting important genetic influences. Age-adjusted estimates of heritability were significant for all parameters (except scotopic dim-flash b-wave implicit time), ranging from 0.34 to 0.85. Highest estimates were for photopic single-flash a-wave and b-wave amplitudes (0.84 and 0.85, respectively)., Conclusions: This study explored heritability of retinal electrophysiologic parameters and included measurements reflecting ganglion cell function. Most parameters showed significant heritability, indicating that genetic factors are important, determining up to 85% of the variance in some cone system response parameters. Scotopic responses tended to show lower heritability (possibly relating to greater rod system susceptibility to environmental factors). Future studies can explore the identity of these genetic factors, improving our understanding of how they shape retinal function., (Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the retinal function of a diurnal murid rodent, Psammomys obesus, with that of Wistar albino rat and human subjects., Materials and Methods: Adult Psammomys obesus were captured and transferred to the animal facilities where they were maintained at 25°C with standard light/dark cycles and natural halophilic plants, rich in water and mineral salts. Standard full-field photopic and scotopic electroretinograms were obtained., Results: The right eye of all animals displayed well detectable and reproducible scotopic and photopic electroretinogram (ERG) responses. Results were compared with those obtained from human subjects and Wistar rats. ERG measurement showed that the amplitudes of scotopic responses in Psammomys obesus are quite similar to those of human subjects. The amplitude of the photopic a-wave was comparable to that of humans and six times higher than that of the albino rat. The amplitudes of photopic b-wave, photopic oscillatory potentials (OPs), and 30 Hz flicker were all markedly larger in Psammomys obesus compared to those obtained from human subjects and Wistar rats. Furthermore, like the human photopic ERG, the photopic ERG of Psammomys obesus also includes prominent post b-wave components (i.e. i- and d-waves) while the ERG of Wistar rats does not., Conclusions: Our results suggest that the retinal function of Psammomys obesus, especially the cone-mediated function, shares several features with that of human subjects. We believe that Psammomys obesus represents an interesting alternative to study the structure and function of the normal and diseased retina in a human-like rodent model of retinal function.

Purpose: To correlate partial outer retinal thickness with scotopic and mesopic fundus-controlled perimetry in patients with reticular drusen (RDR)., Design: Observational case series with controls of similar age., Methods: Twenty eyes from 18 patients with RDR (mean age 75.8 years) and 20 eyes from 20 healthy controls (mean age 75.5 years) were included. Scotopic and mesopic fundus-controlled perimetry was performed in patients. The localized partial outer retinal thickness at the site of test stimuli was determined as the distance between the outer border of the outer plexiform layer and the inner border of the ellipsoid zone and topographically corrected according to measurements in controls., Results: The mean partial outer retinal thickness in patients was 65.8 μm over areas with RDR and 76.4 μm (P < .0001) over nonaffected retinal areas. Mesopic and scotopic sensitivity were reduced corresponding to areas with RDR (mean scotopic 12.8 dB and mean mesopic 17.2 dB) as compared to nonaffected retinal areas (18.2 dB and 18.4 dB) (P < .001, P = .001). On average, a reduction of partial outer retinal thickness by 1 μm was associated with a decrease of scotopic function of 0.96 dB., Conclusions: The extent of outer retinal thinning in the presence of RDR is spatially associated with the extent of impairment in scotopic retinal function, indicating a direct structural-functional correlation of structural changes to loss of rod function. High-resolution retinal imaging in combination with scotopic fundus-controlled perimetry allows for a more refined structure-function correlation in diseases with a presumed higher vulnerability of rod compared with cone function., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: To explore early findings that individuals with autism spectrum disorder (ASD) have reduced scotopic ERG b-wave amplitudes., Methods: Light-adapted (LA) and dark-adapted (DA) ERGs were produced by a range of flash strengths that included and extended the ISCEV standard from two subject groups: a high-functioning ASD group N = 11 and a Control group N = 15 for DA and N = 14 for LA ERGs who were matched for mean age and range. Flash strengths ranged from DA -4.0 to 2.3 log phot cd s m(-2) and LA -0.5 to 1.0 log phot cd s m(-2), and Naka-Rushton curves were fitted to DA b-wave amplitude over the first growth limb (-4.0 to -1.0 log phot cd s m(-2)). The derived parameters (V max, K m and n) were compared between groups. Scotopic 15-Hz flicker ERGs (14.93 Hz) were recorded to 10 flash strengths presented in ascending order from -3.0 to 0.5 log Td s to assess the slow and fast rod pathways, respectively. LA 30-Hz flicker ERGs, oscillatory potentials (OPs) and the responses to prolonged 120-ms ON-OFF stimuli were also recorded., Results: The ISCEV LA b-wave amplitude produced by 0.5 log phot cd s m(-2) was lower in the ASD group (p < 0.001). Repeated measures ANOVA for the LA b-wave amplitude series forming the photopic hill was significantly (p = 0.01) different between groups. No group differences were observed for the distributions of the time to peaks of LA a-wave, b-wave or the photopic negative responses (phNR) (p > 0.08) to the single flash stimuli, but there was a significant difference in the distribution for the LA b-wave amplitudes (corrected p = 0.006). The prolonged 120-ms ON responses were smaller in the ASD group (corrected p = 0.003), but the OFF response amplitude (p > 0.6) and ON and OFF times to peaks (p > 0.4) were similar between groups. The LA OPs showed an earlier bifurcation of OP2 in the younger ASD participants; however, no other differences were apparent in the OPs or 30-Hz flicker waveforms. DA b-wave amplitudes fell below the control 5th centile of the controls for some individuals including four ASD participants (36 %) at the 1.5 log phot cd s m(-2) flash strength and two (18%) ASD participants at the lower -2 log phot cd s m(-2) flash strength. However, across the 13 flash strengths, there were no significant group differences for b-wave amplitude's growth (repeated measures ANOVA p = 0.83). Nor were there any significant differences between the groups for the Naka-Rushton parameters (p > 0.09). No group differences were observed in the 15-Hz scotopic flicker phase or amplitude (p > 0.1), DA ERG a-wave amplitude or time to peak (p > 26). The DA b-wave time to peak at 0.5 log phot cd s m(-2) was longer in the ASD group (p = 0.04)., Conclusion: Under LA conditions, the b-wave is reduced across the ASD group, along with the ON response of the prolonged flash ERG. Some ASD individuals also show subnormal DA ERG b-wave amplitudes. These exploratory findings suggest there is altered cone-ON bipolar signalling in ASD.

Purpose: To determine bioelectrical function and structural changes of the retina in patients with early stages of Parkinson's disease (PD)., Materials and Methods: Thirty-eight eyes of 20 patients with early idiopathic PD and 38 eyes of 20 healthy age- and sex-matched controls were ophthalmologically examined, including assessment of distance best-corrected visual acuity (DBCVA), slit lamp examination of the anterior and posterior segment of the eye, evaluation of the eye structures: paramacular retinal thickness (RT) and retinal nerve fiber layer (RNFL) thickness with the aid of OCT, and the bioelectrical function by full-field electroretinogram (ERG). Additionally, PD patients were interviewed as to the presence of dopamine-dependent visual functions abnormalities., Results: In patients with early PD, statistically significant changes in comparison with the control group were observed in ERG. They contained a reduction in mean amplitudes of the scotopic a-wave (rod-cone response), the scotopic oscillatory potentials (OPs)--OP2 and OP3, the photopic b-wave, and a reduction in the overall index (OP1 + OP2 + OP3) and a prolongation of mean peak times of the scotopic OP1, OP2, OP3, OP4 (p < 0.05). A questionnaire concerning abnormalities of dopamine-dependent visual functions revealed that PD patients with abnormal peak times of OP1, OP2, and OP3 reported non-specific visual disturbances more frequently in comparison with PD patients with normal peak times of OPs. Other analyzed parameters of ERG, DBCVA, RT, and RNFL did not significantly differ between patients with PD and the control group., Conclusion: In patients with early PD, bioelectrical dysfunction of the retina was observed in the ERG test, probably as a result of dopamine deficiency in the retina. The results of our study indicate that ERG may also be a useful tool for understanding the reason for non-specific visual disturbances occurring in PD patients.

Purpose: To determine the characteristics of patients with cone (CD) and cone-rod dystrophies (CRD) and to evaluate the changes in flash electroretinograms in both groups., Methods: The retrospective study involved 48 patients-34 with CRD and 14 with CD. The patients underwent full ophthalmological examination, including Goldmann perimetry and full-field flash electroretinogram (FERG) within the initial examination. These examinations were then repeated seven, or more, years later. The longest follow-up period was 10 years, with the mean at 8.2 years. During both examinations, we assessed the amplitudes of the b wave in the scotopic ERG test 0.01 (which reflects rod response), the maximal scotopic ERG test 3.0 (which reflects cone and rod response) and the photopic 3.0 ERG test (which reflects cone response). The results were then compared against normal values., Results: The progression over time of ERG b wave amplitudes in the scotopic ERG 0.01, maximal scotopic ERG 3.0 and photopic ERG tests was assessed. There were significant differences in rod, maximal and cone responses, between CD and CRD patients. While rod responses were markedly decreased in CRD patients during their initial examination, the decrease in the rod function in both CD and CRD patients was similar in their follow-up examination (p = 0.2398). Moreover, during initial examination, maximal responses were less common amongst CRD patients, over those with CD. Following the observation period, patients suffering from CRD exhibited a significant decrease in both maximal (p = 0.0125) and cone (p = 0.0046) responses., Conclusion: The clinical course of CRD and CD may vary; however, the latter appears to have a more favourable course than former. Although, at initial examination, the cone function was more diminished in CD patients, the final examinations reveal a more significant drop for CRD patients. Consequently, a differential diagnosis is essential for treating patients and forecasting their disease progression.

Purpose: The global or gross response index of visual performance measured from the eye does not necessarily translate to global responses measured from the brain. A better understanding of this relationship would facilitate the monitoring of disease models that affect the visual pathway. We consider whether rod- and cone-retino-cortical-pathways are equally affected by acute IOP elevation., Methods: Acute, stepwise IOP elevation (10, 30, 40, 50, 60, 70 mm Hg) was induced in anesthetized dark- (N = 8) and light-adapted pigmented rats (N = 6). Electroretinogram (ERG) and visual evoked potentials (VEP) were simultaneously measured after 10 minutes at each step. Relative amplitudes (treated/baseline, %) as a function of IOP level were described with a cumulative normal function., Results: Our results showed decline in scotopic and photopic ERGs with IOP elevation. Photopic ERG responses were less sensitive to IOP challenge than scotopic ERG responses. Despite significant reductions of ganglion cell-mediated waveforms at 70 mm Hg, the VEP showed only subtle decreases in amplitude. Intraocular pressure elevation produced similar effects on rod- and cone-mediated VEP waveforms., Conclusions: We show that cone signals are less sensitive than rod ERGs to acute IOP challenge. Also, retinal signals are more sensitive than are cortical signals to IOP stress, suggesting that cortical processing may act to salvage reductions expected from attenuated retinal output.

Purpose: We have monitored retinal function in patients treated for retinoblastoma (primarily, but not exclusively by intra-arterial chemotherapy infusion) by electroretinography (ERG) recordings for the past 7 years. We here present data from 599 ERG studies of 108 patients, in which a complete ERG protocol including both photopic and scotopic recordings was performed, in justification of our frequent practice of reporting primarily 30-Hz photopic flicker amplitude data., Methods: Patients referred for treatment of retinoblastoma underwent ERG recordings during examination under anesthesia whenever possible: at baseline and following most treatment sessions. Correlations were calculated for the complete datasets between the four primary amplitude response parameters: photopic single flash b-wave, photopic 30-Hz flicker peak-to-trough, scotopic rod-isolating b-wave, and scotopic maximal flash b-wave., Results: Using our adaptation of the International Society for Clinical Electrophysiology of Vision-recommended standard ERG protocol, ERG responses of eyes of patients with untreated retinoblastoma or following traditional or intra-arterial treatment for retinoblastoma show very high correlations between 30-Hz flicker amplitude responses and three other standard photopic and scotopic ERG response amplitudes. Reductions in ERG amplitudes seen in these eyes following treatment show no significant difference between retinal dysfunction estimated using rod- or cone-dominated responses., Conclusion: These observations support the use of photopic response amplitudes (especially in response to 30-Hz flicker) as the primary ERG outcome measure in studies of treated and untreated eyes with retinoblastoma when more complete ERG protocols may be impractical.

Neuronal ceroid lipofuscinoses (NCL) are characterized by lysosomal accumulation of autofluorescent material and lead to degeneration of the central nervous system. Patients affected by the juvenile form of NCL (JNCL), the most common form of the disease, develop visual failure prior to mental and motor deficits. It is currently unclear if the corresponding mouse model, Cln3 (Δex7/8) knock-in, develops the same retinal phenotype and electroretinogram (ERG) measurements as affected patients. The aim of our study was to investigate the visual disease progression in the Cln3 (Δex7/8) mice using scotopic and photopic ERGs as well as optokinetic tracking (OKT) at different ages. The results were then compared with age-matched controls.The amplitudes of the a-wave and b-wave (scotopic ERG) decrease significantly in Cln3 (Δex7/8) mice starting at the age of 12 months. A reduction in the b/a-amplitude ratio indicates a degeneration preferentially of the inner retina. An amplitude reduction observed in the Cln3 (+/+) control mice may be attributed to an additional Crb1 (rd8) mutation. Using optokinetic tracking (OKT) the Cln3 (Δex7/8) mice show a progressive decline in visual acuity after 12 months of age.

Retinal microcircuits for night vision at the absolute threshold are required to relay a single-photon rod signal reliably to ganglion cells via rod bipolar (RB) cells and AII amacrine cells. To assess the noise reduction of intercellular signal transmission in this rod-specific pathway, we quantified its synaptic connectivity by 3D reconstruction of a series of electron micrographs. In most cases (94%), each rod made ribbon synaptic contacts onto two adjacent RB cells. Conversely, each RB cell was contacted by 25 rods. Each RB axon terminal contacted four or five AII amacrine cells via 53 ribbon synapses. Thus, the signal from one rod may be represented as 106 replicates at two RB axons. Moreover, the two adjacent RB cells contacted two to four AII amacrine cells in common, where the signals relayed by two RB cells were reunited. In more detail, over 50% of each RB output was directed predominantly to a single, preferred AII amacrine cell, although each RB cell also separately contacted another one to three AII amacrine cells. Most of the replicate signals at two RB axons were collected on a few AII amacrine cells via reunions, dominant connections, and electrical coupling by AII-AII gap junctions. Thus the original signal may be reliably represented by signal amplification with focal accumulation without gathering unnecessary noise from a wide surrounding area. This allocation of RB-AII synaptic contacts may serve as the structural basis for the physiological properties of the AII single-photon response that include high amplification, local adaptation, and regenerative acceleration., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Retinal ganglion cell death underlies the pathophysiology of neurodegenerative disorders such as glaucoma or optic nerve trauma. To assess the potential influence of photoreceptor degeneration on retinal ganglion cell survival, and to evaluate functionality, we took advantage of the optic nerve section mouse model., Methods: Surviving retinal ganglion cells were double-stained by exposing both superior colliculi to fluorogold, and by applying dextran-tetramethylrhodamine to the injured optic nerve stump. To assess retinal function in wild-type animals, electroretinograms were recorded on the injured eyes and compared with the contralateral. Similar labelling experiments were carried out on retinal degeneration 1 mice. Surviving retinal ganglion cells were counted 21 days after axotomy and compared with wild-type mice. No functional experiments were performed on retinal degeneration 1 animals because they do not develop normal electroretinographical responses., Results: A significant decrease in retinal ganglion cell density was observed 6 days after axotomy in the wild type. Functional studies revealed that, in scotopic conditions, axotomy induced a significant amplitude decrease in the positive scotopic threshold response component of the electroretinogram. Such decrease paralleled cell loss, suggesting it may be an appropriate technique to evaluate functionality. When comparing retinal ganglion cell densities in wild-type and retinal degeneration 1 mice, a significant greater survival was observed on the latter., Conclusions: After optic nerve section, electroretinographical recordings exhibited a progressive decrease in the amplitude of the positive scotopic threshold response wave, reflecting ganglion cell loss. Interestingly, rod degeneration seemed, at least initially, to protect from axotomy-driven damage., (© 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To assess the significance and evolution of parafoveal rings of high-density fundus autofluorescence (AF) in 12 patients with retinitis pigmentosa (RP)., Methods: Twelve patients with autosomal recessive RP or Usher syndrome type 2 were ascertained who had a parafoveal ring of high-density AF and a visual acuity of 20/30 or better at baseline. Photopic and scotopic fine matrix mapping (FMM) were performed to test sensitivity across the macula. AF imaging and FMM were repeated after 4 to 8 years and optical coherence tomography (OCT) performed., Results: The size of the AF ring reduced over time and disappeared in one subject. Photopic thresholds were normal over the fovea; thresholds were elevated by 0.6 log units over the ring and by 1.2 log units external to the ring at baseline and differed by less than 0.1 log unit at follow-up. Mild photopic losses close to the internal edge of the ring were detected at baseline or follow-up in all. Mean scotopic thresholds over parafoveal areas within the ring were markedly elevated in 8 of 10 at baseline and were severely elevated in 9 of 11 at follow-up. The eccentricity of the inner edge of the AF ring corresponded closely with the lateral extent of the inner segment ellipsoid band in the OCT image., Conclusions: Ring constriction was largely coincident with progressive centripetal photopic threshold elevation led by worsening of rod photoreceptor function. The rate of constriction differed across patients, and a ring may reach a critical minimum before disappearing, at which stage central visual loss occurs. The structural and functional changes associated with rings of increased autofluorescence confirm that they provide an objective index of macular involvement and may aid the management of RP patients and the monitoring of future treatment efficacy.

Objective: To describe novel electroretinographic (ERG) findings associated with congenital disorder of glycosylation due to phosphomannomutase deficiency (PMM2-CDG) (previously known as congenital disorder of glycosylation type 1a)., Methods: Two male siblings with genetically confirmed PMM2-CDG underwent full-field ERG to a range of scotopic and photopic flash luminances that extended the International Society for Clinical Electrophysiology of Vision standard protocol and included scotopic 15-Hz flicker and photopic prolonged on-off stimulation., Results: Photopic prolonged ERGs were profoundly electronegative with absent b-waves but preserved oscillatory potentials. Prolonged off-responses and off-oscillatory potentials were preserved. Transient full-field photopic ERGs revealed a broad a-wave and narrow b-wave, and the photopic 30-Hz flicker ERG had a sawtooth waveform. The scotopic b-waves of both cases were attenuated to the fifth percentile, whereas scotopic a-wave amplitudes were at the 50th to 75th percentile, giving a reduced a:b ratio. The scotopic a-wave waveform was well defined to bright flash luminance. The number of scotopic oscillatory potentials was preserved, although amplitudes were smaller than average. Scotopic 15-Hz flicker ERGs were evident to a range of flash luminances and showed an expected phase cancellation between -1.5 and -1.0 log scotopic td (troland) • s, but phase increased only for the fast rod pathway., Conclusions: We find, for the first time to our knowledge, an association of PMM2-CDG with a selective on-pathway dysfunction in the retina. This ERG phenotype localizes the site of retinal dysfunction to the on-bipolar synapse with photoreceptors. Modeling the unusual combination of ERG findings helps our understanding of the role of N -glycosylation at this synapse and provides a focus for future studies of potential intervention.

Purpose: To investigate the effect of old age (3 vs. 18 months) on the retinal function of albino (Sprague-Dawley [SD]) and pigmented (Long-Evans [LE]) rats., Methods: Electroretinograms (ERG) were recorded in both albino (SD; 3 months old n = 16, 18 months old n = 16) and pigmented (LE; 3 months n = 16, 18 months n = 5) rats. Data are analyzed for photoreceptor, ON-bipolar, and retinal ganglion cell (RCG) amplitudes as well as photoreceptor and ON-bipolar cell sensitivities., Results: In the pigmented strain, senescence results in decreased photoreceptor output, but ON-bipolar and retinal ganglion cell amplitudes were preserved, due to a relative increase in ON-bipolar cell sensitivity. In the albino rats, although ageing decreased both photoreceptor and ON-bipolar cell amplitudes, increased photoreceptor sensitivity produced a relative sparing of retinal ganglion cell amplitude., Conclusions: Both strains show evidence of retinal plasticity with senescence, albeit at different retinal levels. The exact mechanisms underlying sensitivity changes require further investigation. Nevertheless, given the findings of previous human studies, pigmented rats appear to be a more appropriate model for human ageing. Future work using animals to study the effect of ageing need careful consideration in strain selection.

The flash electroretinogram (ERG) was used to characterize the scotopic retinal function in a marsupial. Key parameter values of the a- and b-waves of adult male sugar gliders, Petaurus breviceps breviceps, elicited with ganzfeld flashes were determined under dark- and light-adapted conditions. Using standard histological methods, the thicknesses of the major layers of the retina were assessed to provide insight into the nature of the ERG responses. The ERG and histological results were compared to corresponding data for placental C57Bl/6 mice to establish whether the functional retinal specialization that underlies scotopic visual function in a marsupial parallels that of a placental mouse. The sensitivity of the a-wave assessed with the Lamb and Pugh (Invest Ophthalmol Vis Sci 47:5138-5152, 2006) "model" and that of the b-wave assessed with standard methods were lower in the sugar glider compared to the mouse. The thickness of the sugar glider retina was two-third of that of the mouse. The high-intensity flash ERG of the sugar glider substantially differed in shape from that of the mouse reflecting perhaps structural and functional differences between the two species at the level of the inner retina.

Purpose: To describe in detail the clinical phenotype and electrophysiological features of three patients with Leber congenital amaurosis caused by mutations of AIPL1., Methods: Ophthalmologic examination, color fundus photography, detailed electrophysiological assessment, and screening of AIPL1 were undertaken in three subjects. One patient also underwent visual field testing and spectral domain-optical coherence tomography., Results: All three patients, two of whom were siblings, had histories consistent with Leber congenital amaurosis (severely reduced vision, poorly responsive pupils, and nystagmus presenting within the first year of life). However, each patient had recordable and similar electroretinograms (ERGs), which demonstrated absent cone-driven responses and slow insensitive scotopic responses. The first patient was found to have a homozygous Trp278 stop mutation in AIPL1, whereas the siblings were each found to have novel heterozygous mutations in AIPL1 (Leu17Pro and Lys214Asn)., Conclusions: Patients with mutations in AIPL1 may present with Leber congenital amaurosis and residual ERGs characterized by slow insensitive scotopic responses. Such responses are likely seen only in very young patients and may not be seen with the typical filter settings recommended by the ISCEV standards because of low-pass filtering. Progressive loss of residual ERG activity in young LCA patients with AIPL1 mutations suggests that gene replacement therapy will likely have to be performed early.

High-resolution magnetic resonance imaging (MRI) provides non-invasive images of retinal anatomy, physiology, and function with depth-resolved laminar resolution. Eye movement and drift, however, could limit high spatial resolution imaging, and anesthetics that minimize eye movement could significantly attenuate retinal function. The aim of this study was to determine the optimal anesthetic preparations to minimize eye movement and maximize visual-evoked retinal response in rats. Eye movements were examined by imaging of the cornea with a charge-coupled device (CCD) camera under isoflurane, urethane, ketamine/xylazine, and propofol anesthesia at typical dosages in rats. Combination of the paralytic pancuronium bromide with isoflurane or ketamine/xylazine anesthesia was also examined for the eye movement studies. Visual-evoked retinal responses were evaluated using full-field electroretinography (ERG) under isoflurane, ketamine/xylazine, urethane, and ketamine/xylazine + pancuronium anesthesia in rats. The degree of eye movement, measured as displacement per unit time, was the smallest under 1% isoflurane + pancuronium anesthesia. The ketamine/xylazine groups showed larger dark-adapted ERG a- and b-waves than other anesthetics tested. The isoflurane group showed the shortest b-wave implicit times. Photopic ERGs in the ketamine/xylazine groups showed the largest b-waves with the isoflurane group showing slightly shorter implicit times at the higher flash intensities. Oscillatory potentials revealed an early peak in the isoflurane group compared with ketamine/xylazine and urethane groups. Pancuronium did not affect the a- and b-wave, but did increase oscillatory potential amplitudes. Compared with the other anesthetics tested here, ketamine/xylazine + pancuronium was the best combination to minimize eye movement and maximize retinal function. These findings should set the stage for further development and application of high-resolution functional imaging techniques, such as MRI, to study retinal anatomy, physiology, and function in anesthetized rats.