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To characterize rod- and cone-pathway function in the 5xFAD mouse model of Alzheimer's disease (AD) using the full-field electroretinogram (ERG). Dark-adapted (DA; rod-pathway) and light-adapted (LA; cone-pathway) ERGs were recorded from three-month-old 5xFAD and wild type (WT) mice. ERGs were elicited by achromatic flashes (0.01-25 cd-s-m - 2 ). Amplitude and implicit time (IT) of the a-wave, b-wave, and oscillatory potentials (OPs) were calculated according to convention. In addition, the amplitude and IT of the photopic negative response (PhNR) were measured from the LA recordings. Amplitude and IT differences between the 5xFAD and WT groups were evaluated using quantile regression models. Under DA conditions, there were significant differences between the 5xFAD and WT groups in post-receptor function, whereas photoreceptor function did not differ significantly. Specifically, the DA a-wave amplitude did not differ between groups (p = 0.87), whereas the b-wave amplitude was reduced in the 5xFAD mice (p = 0.003). There were significant OP (p < 0.001) and a-wave (p = 0.04) delays, but the a-wave delay may be attributable to a post-receptor abnormality. Under LA conditions, the only 5xFAD abnormalities were in the PhNR, which was reduced (p = 0.009) and delayed (p = 0.04). The full-field ERG can be abnormal in the 5xFAD model of AD, with the greatest effects on post-receptor rod pathway function. These results indicate that retinal electrophysiology may be a useful tool for evaluating neural dysfunction in AD.

Purpose: To evaluate the nature and extent of functional abnormality in X-linked retinoschisis (XLRS) by comparing three dark-adapted, full-field measures: the electroretinogram (ERG), pupillary light reflex (PLR), and luminance threshold., Methods: ERGs, PLRs (pupil constriction due to light stimulation), and luminance thresholds were measured from seven XLRS subjects and from 10 normally sighted, age-similar controls. ERGs and PLRs were obtained for a range of flash strengths, and these data were fit with Naka-Rushton functions to derive the maximum saturated b-wave (Vmax) and PLR (Pmax) amplitudes. Additionally, semi-saturation constants were obtained for the b-wave (σ) and PLR (s). Values of 1/σ and 1/s provide sensitivity measures. Full-field, dark-adapted luminance thresholds were measured using 465-nm and 642-nm flash stimuli., Results: Vmax and 1/σ were significantly reduced in XLRS compared to the controls (both t ≥ 5.33, P < 0.001). In comparison, Pmax was normal in the XLRS subjects (t = 1.39, P = 0.19), but 1/s was reduced (t = 7.84, P < 0.001). Luminance thresholds for the control and XLRS groups did not differ significantly (F = 3.57, P = 0.08). Comparisons among measures indicated that pupil sensitivity was correlated with luminance threshold for the long- and short-wavelength stimuli (both, r ≥ 0.77, P ≤ 0.04). Correlations among all other measures were not statistically significant., Conclusions: The results indicate that the presumed bipolar cell dysfunction in XLRS, indicated by b-wave abnormalities, has complex downstream effects: Dark-adapted luminance threshold and maximum pupil responses are not significantly affected, but pupil sensitivity is reduced.

Purpose: To define the relationship between abnormalities in the activation phase of cone phototransduction and the oscillatory potentials (OPs) of the light-adapted electroretinogram in diabetics who have mild or no retinopathy., Methods: Subjects included 20 non-diabetic controls and 40 type-2 diabetics (20 had no clinically apparent diabetic retinopathy [NDR] and 20 had mild nonproliferative DR). Single flash responses for a series of stimulus retinal illuminances were measured under light-adapted conditions using conventional techniques. The a-waves of the responses were fit with a delayed Gaussian model to derive R mp3 (maximum amplitude of the massed photoreceptor response) and S (phototransduction sensitivity). OPs were extracted from the responses by conventional band-pass filtering., Results: Analysis of variance (ANVOA) indicated that both diabetic groups had significant OP amplitude and S reductions compared to the controls, whereas R mp3 did not differ significantly among the groups. Although log OP amplitude and log R mp3 were significantly correlated for the control subjects for each flash retinal illuminance (all r > 0.49, p < 0.03), log OP amplitude and log R mp3 were not correlated for either diabetic group for any flash retinal illuminance (all r ≤ 0.36, p ≥ 0.13). Log OP amplitude and log S were generally not correlated significantly for the control or diabetic groups., Conclusion: OP amplitude losses do not appear to be related to reduced cone sensitivity in early-stage diabetic retinopathy. This suggests that diabetes may separately affect cone function, as evidenced by cone phototransduction sensitivity losses, and inner-retina function, as evidenced by OP amplitude losses.

The flicker electroretinogram (ERG) is typically analyzed in terms of peak-to-trough amplitude and implicit time. However, additional important information may be captured by spectral-domain analysis of the ERG harmonics (responses that occur at multiples of the stimulus frequency). This study describes an approach to analyze the harmonic components of the flicker ERG and its application to patients who have early-stage non-proliferative diabetic retinopathy (NPDR). Of particular interest were the sub-harmonic components occurring at 1.5x and 2.5x the stimulus frequency that produce cycle-to-cycle variation in amplitude termed "period doubling." Twenty visually-normal subjects, 20 diabetic subjects who have no clinically-apparent retinopathy (NDR), and 20 diabetic subjects who have mild NPDR participated. ERGs were recorded in response to sinusoidal flicker (27-63 Hz) and Fourier analysis was performed to extract fundamental and harmonic response amplitudes. Linear quantile mixed models (LQMMs) were used to compare the amplitude of the response components among the three subject groups. Results indicated that the maximum sub-harmonic amplitude occurred in the stimulus frequency range of 33-38 Hz for all subjects. The LQMMs showed a significant sub-harmonic amplitude reduction for the mild NPDR subjects compared to the controls; sub-harmonic amplitude for the NDR subjects did not differ significantly from the controls. In contrast, the fundamental response did not differ among the groups for stimulus frequencies between 33 and 38 Hz. Modeling these results indicated that subharmonic amplitude loss in mild NPDR subjects may be attributed to attenuated feedback occurring early in the retina, possibly at the synapse of cone photoreceptors and OFF bipolar cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Purpose: To define the nature and extent of cone photoreceptor abnormalities in diabetic individuals who have mild or no retinopathy by assessing the activation phase of cone phototransduction and the flicker ERG in these individuals., Methods: Light-adapted single-flash and flicker ERGs were recorded from 20 diabetic individuals who have no clinically apparent retinopathy (NDR), 20 diabetic individuals who have mild nonproliferative diabetic retinopathy (NPDR), and 20 nondiabetic, age-equivalent controls. A-waves elicited by flashes of different retinal illuminance were fit with a delayed Gaussian model to derive Rmp3 (maximum amplitude of the massed photoreceptor response) and S (phototransduction sensitivity). Fundamental amplitude and phase of ERGs elicited by full-field sinusoidal flicker were obtained across a frequency range of 6 to 100 Hz., Results: ANVOA indicated that both diabetic groups had significant S losses compared with the controls, whereas mean Rmp3 did not differ significantly among the groups. ANOVA also indicated significantly reduced flicker ERG amplitude for frequencies ≥56 Hz for both diabetic groups compared with the controls. Flicker ERG timing (phase) did not differ significantly among the groups. Log Rmp3 + log S was significantly correlated with the patients' high-frequency (62.5 Hz) flicker ERG amplitude loss (r = 0.69, P < 0.001)., Conclusions: The delayed Gaussian a-wave model is useful for characterizing abnormalities in the activation phase of cone phototransduction and can help explain flicker ERG abnormalities in early-stage diabetic retinopathy. Reduced cone sensitivity and attenuated high-frequency flicker ERGs provide evidence for impaired cone function in these individuals.

Purpose: To evaluate rod-isolated, cone-isolated, and combined rod and cone flicker electroretinograms (ERGs) as a possible means to identify electrophysiological abnormalities in carriers of X-linked retinoschisis (XLRS)., Methods: Full-field ERGs were recorded from six carriers of XLRS (aged 34-66 years) and eight normally sighted subjects (aged 27-59 years) under rod-isolated (ERGR), cone-isolated (ERGC), and combined rod and cone (ERGR+C) conditions. ERGs were obtained using a four-primary LED-based ganzfeld photostimulator and standard recording techniques. The four primaries were modulated sinusoidally in phase to achieve combined rod and cone activation (ERGR+C) or in different phases to achieve ERGR and ERGC by means of triple silent substitution. After 30 min of dark adaptation, 8- and 15-Hz ERGR, ERGC, and ERGR+C responses were obtained at a mean luminance level of 24 scot. cd/m(2). Standard ISCEV ERGs were also obtained from each subject., Results: The ISCEV and 15-Hz flicker ERGs were generally within the normal range for the carriers. The 8-Hz ERGR, ERGC, and ERGR+C amplitudes were also generally normal. In contrast, the carriers had ERGR, ERGC, and ERGR+C timing abnormalities, with phase advances beyond the range of normal for the ERGR (four carriers), ERGC (four carriers), and ERGR+C (three carriers). Only one carrier had normal 8-Hz responses under all conditions., Conclusions: The 8-Hz ERG timing abnormalities in five of six carriers indicate that retinal function is not necessarily normal in carriers of XLRS. The 8-Hz flicker ERG may be useful for studying retinal function in these individuals.

Purpose: To evaluate rod and cone contributions to the dark-adapted 15-Hz flicker electroretinogram (ERG) across a broad range of stimulus luminances by comparing rod-isolating (ERGR), cone-isolating (ERGC), and non-receptor-specific (ERGR+C) responses., Methods: Dark-adapted, full-field 15-Hz ERGs were obtained from four normally sighted subjects (ages 29-36 years) using a four-primary LED-based stimulating system. The primaries were either modulated sinusoidally in phase (ERGR+C) or were modulated in counter-phase to achieve rod isolation (ERGR) or cone isolation (ERGC) by means of triple silent substitution. Measurements were made for a broad range of luminances (-2.5 to 1.8 log scot. cd/m(2) in 0.2 log unit steps). Fourier analysis was used to obtain the amplitude and phase of the fundamental response component at each stimulus luminance., Results: Stimulus luminance had different effects on response amplitudes and phases under the three paradigms. Specifically, ERGC amplitude and phase increased monotonically as luminance increased. The effects on ERGR+C and ERGR were complex: ERGR+C and ERGR amplitude was small and the phase decreased for low luminances, whereas amplitude and phase increased sharply at moderate luminances. For high luminances, ERGR+C amplitude and phase increased, whereas ERGR amplitude decreased and phase was approximately constant., Conclusions: At low luminances, the ERGR+C and ERGR functions can be attributed to interactions between two rod pathways. At high luminances, the functions can be accounted for by interactions between rod and cone pathways (ERGR+C) or rod insensitivity (ERGR). The ERGR paradigm minimizes cone intrusion, permitting assessment of rod function over a large range of luminance levels.

This study determined if the pupillary light reflex (PLR) driven by brief stimulus presentations can be accounted for by the product of stimulus luminance and area (i.e., corneal flux density, CFD) under conditions biased toward the rod, cone, and melanopsin pathways. Five visually normal subjects participated in the study. Stimuli consisted of 1-s short- and long-wavelength flashes that spanned a large range of luminance and angular subtense. The stimuli were presented in the central visual field in the dark (rod and melanopsin conditions) and against a rod-suppressing short-wavelength background (cone condition). Rod- and cone-mediated PLRs were measured at the maximum constriction after stimulus onset whereas the melanopsin-mediated PLR was measured 5-7 s after stimulus offset. The rod- and melanopsin-mediated PLRs were well accounted for by CFD, such that doubling the stimulus luminance had the same effect on the PLR as doubling the stimulus area. Melanopsin-mediated PLRs were elicited only by short-wavelength, large (>16°) stimuli with luminance greater than 10 cd/m(2), but when present, the melanopsin-mediated PLR was well accounted for by CFD. In contrast, CFD could not account for the cone-mediated PLR because the PLR was approximately independent of stimulus size but strongly dependent on stimulus luminance. These findings highlight important differences in how stimulus luminance and size combine to govern the PLR elicited by brief flashes under rod-, cone-, and melanopsin-mediated conditions., (© 2015 ARVO.)

This study defined the amplitude and phase characteristics of rod- and cone-isolated flicker electroretinograms (ERGs) and determined how these responses summate to generate the nonreceptor-specific ERG. Full-field ERGs were obtained from six normally sighted subjects (age 26 to 44 years) using a four-primary LED-based photostimulator and standard recording techniques. The four primaries were either modulated sinusoidally in phase to achieve simultaneous rod and cone activation (ERGR+C; nonreceptor-specific) or in different phases to achieve rod-isolated (ERGR) and cone-isolated (ERGC) responses by means of triple silent substitution. ERGs were measured at two mean luminance levels (2.4 and 24 cd/m2), two contrasts (20 and 40%), and four temporal frequencies (2-15 Hz). Fundamental amplitude and phase for each condition were derived by Fourier analysis. Response amplitude and phase depended on the stimulus conditions (frequency, mean luminance, and contrast), however, for all conditions: 1) response phase decreased monotonically as stimulus frequency increased; 2) response amplitude tended to decrease monotonically as stimulus frequency increased, with the exception of the 24 cd/m2, 40% contrast ERGR+C that was sharply V-shaped; 3) ERGR phase was delayed (32 to 210 deg) relative to the ERGC phase; 4) ERGR amplitude was typically equal to or lower than the ERGC amplitude, with the exception of the 2.4 cd/m2, 40% contrast condition; and 5) the pattern of ERGR+C responses could be accounted for by a vector summation model of the rod and cone pathway signals. The results show that the ERGR+C amplitude and phase can be predicted from ERGR and ERGC amplitude and phase. For conditions that elicit ERGR and ERGC responses that have approximately equal amplitude and opposite phase, there is strong destructive interference between the rod and cone responses that attenuates the ERGR+C. Conditions that elicit equal amplitude and opposite phase rod and cone responses may be particularly useful for evaluating rod-cone interactions.

Purpose: We determined the relative contributions of rods, cones, and melanopsin to pupil responses in humans using temporal sinusoidal stimulation for light levels spanning the low mesopic to photopic range., Methods: A four-primary Ganzfeld photostimulator controlled flicker stimulations at seven light levels (-2.7 to 2 log cd/m(2)) and five frequencies (0.5-8 Hz). Pupil diameter was measured using a high-resolution eye tracker. Three kinds of sinusoidal photoreceptor modulations were generated using silent substitution: rod modulation, cone modulation, and combined rod and cone modulation in phase (experiment 1) or cone phase shifted (experiment 2) from a fixed rod phase. The melanopsin excitation was computed for each condition. A vector sum model was used to estimate the relative contribution of rods, cones, and melanopsin to the pupil response., Results: From experiment 1, the pupil frequency response peaked at 1 Hz at two mesopic light levels for the three modulation conditions. Analyzing the rod-cone phase difference for the combined modulations (experiment 2) identified a V-shaped response amplitude with a minimum between 135° and 180°. The pupil response phases increased as cone modulation phase increased. The pupil amplitude increased with increasing light level for cone, and combined (in-phase rod and cone) modulation, but not for the rod modulation., Conclusions: These results demonstrate that cone- and rod-pathway contributions are more predominant than melanopsin contribution to the phasic pupil response. The combined rod, cone, and melanopsin inputs to the phasic state of the pupil light reflex follow linear summation.

At certain temporal frequencies, the human cone flicker electroretinogram (ERG) contains multiple additional responses following the termination of a flicker train. The purpose of this study was to determine whether these poststimulus responses are a continuing response to the terminated flicker train or represent the oscillation of a resonant system. ERGs were recorded from 10 visually normal adults in response to full-field sinusoidally modulated flicker trains presented against a short-wavelength rod-saturating adapting field. The amplitude and timing properties of the poststimulus responses were evaluated within the context of a model of a second-order resonant system. At stimulus frequencies between 41.7 and 71.4 Hz, the majority of subjects showed at least three additional ERG responses following the termination of the flicker train. The interval between the poststimulus responses was approximately constant across stimulus frequency, with a mean of 14.4 ms, corresponding to a frequency of 69.4 Hz. The amplitude and timing characteristics of the poststimulus ERG responses were well described by an underdamped second-order system with a resonance frequency of 70.3 Hz. The observed poststimulus ERG responses may represent resonant oscillations of retinal ON bipolar cells, as has been proposed for electrophysiological recordings of poststimulus responses from retinal ganglion cells. However, further investigation is required to determine the types of retinal neurons involved in the generation of the poststimulus responses of the human flicker ERG.

The purpose of this study was to evaluate the efficacy of topical dorzolamide 2% eye drops on macular function and thickness in a case of enhanced S-cone syndrome (ESCS). A 24-year-old Asian man with enhanced S-cone syndrome treated with topical dorzolamide in the left eye participated in the study. Examinations performed before and during treatment were included visual acuity (VA), contrast sensitivity measured with briefly presented grating targets (grating CS) and the Pelli-Robson chart (P-R CS), microperimetry (MP), and spectral-domain optical coherence tomography (SD-OCT). Following 4 months of treatment, the mean thickness of the central 1-mm foveal subfield of the left eye, as measured by SD-OCT, decreased from 551 to 242 μm. Mean MP sensitivity within the central 12 degrees (28 points) increased from 9.4 dB at baseline to 11.2 dB. Although Pelli-Robson contrast sensitivity improved only minimally in the left eye, grating contrast sensitivity improved by more than a factor of two. Mean log MAR VA was 0.22 OD and 1.00 OS (at baseline), which improved to 0.10 OD and 0.66 OS after 4 months of treatment. The results indicate that in our patient with enhanced S-cone syndrome, treatment with topical dorzolamide was effective in improving macular thickness, VA, microperimetry sensitivity, and grating contrast sensitivity. These measures of retinal structure and function are sensitive tools for evaluating the effects of treatment in enhanced S-cone syndrome patients with cystoid macular edema. Further investigation is warranted to assess the relationships among visual performance for daily activities, visual sensitivity, and macular thickness.

Omitting a stimulus from a train of repetitive stimuli, by either interrupting or terminating the train, can elicit an electrophysiological response that occurs at the time appropriate for the omitted stimulus. This study investigated whether such an omitted stimulus response (OSR) is present in the flicker electroretinogram (ERG) of the human cone system. ERGs were recorded from 11 visually normal subjects in response to full-field sinusoidal flicker trains presented against a rod-desensitizing adapting field at frequencies ranging from 12.5 to 100 Hz. Recordings were synchronized with the onset of the stimulus trains, and the amplitude and relative delay of any additional ERG responses following the offset of the flicker train were analyzed. At stimulus frequencies below 35 Hz, the number of ERG responses always equaled the number of stimulus cycles. However, over the frequency range of 38.5 to 100 Hz, the ERG contained an extra response following flicker train offset. At stimulus frequencies from 38.5 to 62.5 Hz, there was a constant delay between the peak of the extra ERG response and the time at which the next stimulus would have occurred had the flicker train continued. This constant delay is characteristic of an OSR. In addition, an extra ERG response was apparent at these same stimulus frequencies if the flicker train was interrupted by omitting stimulus cycles from the middle of the train. The pattern of ERG findings is consistent with a recently proposed model of the OSR that attributes the phenomenon to a resonant oscillation in retinal bipolar cells.

Purpose: Under certain conditions, the full-field flicker electroretinogram (ERG) of the cone system can show period doubling, such that the shape of the ERG waveform alternates from cycle to cycle. The purpose of this study was to determine the relationship between stimulus temporal frequency and the amplitudes of the spectral components of the ERG that correspond to period doubling., Method: ERGs were recorded from 10 visually normal subjects in response to full-field sinusoidal flicker presented at frequencies ranging from 12.5 to 100 Hz. Period doubling was apparent over the stimulus frequency range from 25 to 100 Hz and was quantified in terms of the amplitudes of spectral components of the ERG waveform that corresponded to half the stimulus frequency (f/2) and three and five times that frequency (3f/2 and 5f/2)., Results: At stimulus frequencies between 30 and 40 Hz, the amplitude of f/2 was significantly lower than either 3f/2 or 5f/2, which themselves did not differ significantly. At stimulus frequencies between 40 and 60 Hz, all three response components were equivalent in amplitude. At stimulus frequencies above 60 Hz, however, the amplitudes of 3f/2 and 5f/2 were reduced significantly compared to f/2., Conclusion: There is a frequency-dependent relationship among the spectral components of the flicker ERG that correspond to period doubling. The amplitude of f/2 underestimates the magnitude of period doubling at stimulus frequencies between 30 and 40 Hz, whereas the amplitudes of 3f/2 and 5f/2 underestimate the degree of period doubling at stimulus frequencies above 60 Hz. The explanation for the frequency dependence of these spectral components remains to be resolved.