Large Phase Differences between L-Cone-and M-Cone- Driven Electroretinograms in Retinitis Pigmentosa

PURPOSE. To study the dynamics and interactions of the signals originating in the long-(L-) and middle (M)-wavelength-sensitive cone pathways in patients with retinitis pigmentosa (RP). METHODS. Twenty-six patients with RP and 29 normal subjects participated in the study. Electroretinographic (ERG) responses were measured to stimuli that modulated exclusively the L-or the M-cones or the two simultaneously (both in-phase and in counter-phase) with varying ratios of Lto M-cone contrasts. S-cones were not modulated. RESULTS. The data of the normal subjects and of the patients can be described by a model in which the amplitudes and the phases of the signals originating in the L-and M-cones are vector summed. In the RP patients, there was a general reduction in ERG sensitivity. The L-cone-driven ERG response was significantly delayed, whereas the M-cone-driven ERG response was phase advanced. CONCLUSIONS. Large dynamic differences between L-and M-cone-driven ERGs can be detected in RP. As a result, the interaction between the L-and M-cone systems, when modulated simultaneously at 30 Hz, is subtractive in RP patients and additive in normal subjects. Our data show that the use of only a standard white flicker ERG might lead to a misinterpretation of the mechanisms involved in retinal disorders, because the phases of different cone-driven responses are not considered. (Invest Ophthalmol Vis Sci. 2000;41:3225-3233) T he term retinitis pigmentosa (RP) is used for a group of progressive retinal diseases representing the most frequent retinal dystrophy with a prevalence of approximately 1:4000 and a frequency of heterozygotes of approximately 1:15. 1-3 Approximately 1.5 million people are affected around the world. 5-7 It has been shown that in early cases of RP the scotopic (rod) electroretinogram (ERG) is markedly reduced, whereas the photopic (cone) flash ERG is relatively normal. 8 The conedriven responses to 30-Hz white flicker have normal or reduced amplitudes, and they are usually delayed. 4,9 -12 To date, it is unresolved how changes in the different cones or their postreceptoral pathways contribute to these delays. There have been attempts to differentiate between the involvement of the three different cone systems in RP. RP patients exhibited reduced short (S-) wavelength-sensitive cone-driven ERGs; a subset of those patients showed significantly greater loss in the S-cone-driven ERG than in the mixed long (L)-and middle (M)-cone-driven ERG, We measured ERG responses to stimuli that either selectively modulated the L-or the M-cones or modulated the two simultaneously. Extensive data on normal subjects have been published recently. 14 RP patients showed generally larger ERG thresholds for nearly all combinations of L-and M-cone modulation. Surprisingly, the L-cone-driven ERG was very much delayed, whereas the M-cone-driven ERG was phase-advanced compared with normal observers. RP patients showed smaller ERG thresholds to counter-phase modulation than to in-phase modulation of the L-and M-cones, indicative of a subtractive interaction between the L-and M-cone-driven ERGs. This is probably caused by the increase in phase difference between the L-and M-cone-driven responses. (The term "L-and Mcone-driven ERGs" is used to refer to the responses originating in the L-and the M-cones, including the subsequent postreceptoral stages. The uncertainty about the exact cellular origins of the ERG does not influence the data interpretation.) METHODS Subjects Twenty-six patients (age range, 11-59 years) with different forms of RP (7 autosomal dominant RP, 1 autosomal recessive RP, 3 Usher II syndrome, 10 simplex RP, 1 X-linked RP [X-RP], and 4 carriers of X-RP) participated in the study. The diagnosis was based on history, symmetrical bilateral involvement, the typical alterations of the pigment epithelium layer, by visual field, and Ganzfeld electroretinography according to the ISCEV standard

Reinforcement learning in local energy markets

Local energy markets (LEMs) are well suited to address the challenges of the European energy transition movement. They incite investments in renewable energy sources (RES), can improve the integration of RES into the energy system, and empower local communities. However, as electricity is a low involvement good, residential households have neither the expertise nor do they want to put in the time and effort to trade themselves on their own on short-term LEMs. Thus, machine learning algorithms are proposed to take over the bidding for households under realistic market information. We simulate a LEM on a 15 min merit-order market mechanism and deploy reinforcement learning as strategic learning for the agents. In a multi-agent simulation of 100 households including PV, micro-cogeneration, and demand shifting appliances, we show how participants in a LEM can achieve a self-sufficiency of up to 30% with trading and 41,4% with trading and demand response (DR) through an installation of only 5kWp PV panels in 45% of the households under affordable energy prices. A sensitivity analysis shows how the results differ according to the share of renewable generation and degree of demand flexibility

Multifocal electroretinographical changes in monkeys with experimental ocular hypertension: a longitudinal study

Purpose To study the time course of changes in the multifocal electroretinograms (mfERG) in monkeys with experimental ocular hypertension (OHT). Methods The mfERGs were recorded in 12 eyes out of 6 monkeys. Two baseline measurements were used to quantify the reproducibility, the inter-ocular and the inter-individual variability of the ERG signals. Thereafter, the trabeculum of one eye of each animal was laser-coagulated in one to three sessions to induce OHT. ERG measurements were repeated regularly in a period of 18months and the changes in ERG waveforms were quantified. Results All animals displayed OHT (between 20 and 50mmHg) in the laser-coagulated eyes. An ERG change was defined as the sum of differences during the first 90ms between the laser-coagulated eye and the same eye before laser coagulation and between the laser-coagulated eye and the non-treated fellow eye. Three animals displayed significant changes for nearly all retinal areas and all stimulus conditions. The three remaining animals displayed significant changes only in one comparison, indicating very mild changes. The data indicate that a high stimulus contrast is more sensitive to detect changes, probably because of a better signal-to-noise ratio. Moreover, the comparisons with the fellow eye are more sensitive to detect changes than comparisons with the measurements before laser-coagulation. Conclusions OHT does not always lead to ERG changes. Comparisons with fellow eyes using high contrast stimuli are more sensitive to detect changes related to OH

Frequency dependency of temporal contrast adaptation in normal subjects

AbstractThe aim of this study was to determine the influence of temporal frequency of temporal contrast adaptation on contrast sensitivity in healthy subjects. Temporal contrast sensitivities (TCS) were measured monocularly in seven healthy subjects with a modified ERG full-field bowl stimulator at eight different test temporal frequencies (9, 15, 20, 25, 31, 37, 44, 51Hz) using a two-alternative-forced-choice strategy. Before each presentation of the test stimulus, a 100% contrast adapting flicker stimulus was presented (frequencies: 9, 15, 20, 25, 31, 37, 44, 51, 100Hz). At each adapting frequency, a complete set of TCSs was measured. All temporal contrast sensitivities decreased with increasing temporal frequencies. Adaptation led to a general temporal contrast sensitivity decrease. Largest adaptation effects were seen at an adaptation frequency of 25Hz. Reduction of contrast sensitivity was significantly larger at 25Hz adaptation than at 9Hz adaptation (t-test of paired samples, Bonferroni corrected). The results of this study showed a general TCS decrease with the largest effect at an adaptation frequency of 25Hz. This finding indicates that the contrast adaptation probably occurred in the magnocellular-pathway. In future clinical studies adaptation effects could be investigated in patients with reduced temporal contrast sensitivity

Rod Electroretinograms Elicited by Silent Substitution Stimuli from the Light-Adapted Human Eye

YesPurpose: To demonstrate that silent substitution stimuli can be used to generate electroretinograms (ERGs) that effectively isolate rod photoreceptor function in humans without the need for dark adaptation, and that this approach constitutes a viable alternative to current clinical standard testing protocols. Methods: Rod-isolating and non-isolating sinusoidal flicker stimuli were generated on a 4 primary light-emitting diode (LED) Ganzfeld stimulator to elicit ERGs from participants with normal and compromised rod function who had not undergone dark-adaptation. Responses were subjected to Fourier analysis, and the amplitude and phase of the fundamental were used to examine temporal frequency and retinal illuminance response characteristics. Results: Electroretinograms elicited by rod-isolating silent substitution stimuli exhibit low-pass temporal frequency response characteristics with an upper response limit of 30 Hz. Responses are optimal between 5 and 8 Hz and between 10 and 100 photopic trolands (Td). There is a significant correlation between the response amplitudes obtained with the silent substitution method and current standard clinical protocols. Analysis of signal-to-noise ratios reveals significant differences between subjects with normal and compromised rod function. Conclusions: Silent substitution provides an effective method for the isolation of human rod photoreceptor function in subjects with normal as well as compromised rod function when stimuli are used within appropriate parameter ranges. Translational Relevance: This method of generating rod-mediated ERGs can be achieved without time-consuming periods of dark adaptation, provides improved isolation of rod- from cone-based activity, and will lead to the development of faster clinical electrophysiologic testing protocols with improved selectivity

25 Hz adaptation: Influence on recovery time in glaucoma

INTRODUCTION. Normal temporal contrast sensitivity is maximally influenced by pre-adaptation with 25-Hz temporal contrast flicker. The aim of this study was to investigate the effects of 25-Hz contrast adaptation on recovery of contrast sensitivity in normals, patients with ocular hypertension, preperimetric, perimetric and advanced perimetric open-angle glaucoma. MATERIALS AND METHODS. Temporal contrast sensitivity was examined after pre-adaptation with 25 Hz in the following: 43 normals, 14 ocular hypertension, 10 preperimetric primary open-angle glaucoma, and 33 perimetric open-an­gle glaucoma patients. After pre-adaptation (the time after which a test stimulus could be detected again), recovery time (RT) was measured at 3% and 5% test contrast. Additionally, 25 patients with advanced perimetric open-angle glaucoma were measured at 12%, 25%, and 35% contrast and compared to a normal group consisting of 15 subjects. RESULTS. 1. Measurements of RT are reliable (Cronbach’s a > 0.8). 2. RT was age-dependent requiring an age-correction in further analyses. 3. RT3% and RT5% were significantly prolonged in perimetric primary open-angle glau­coma compared to normals (3% test contrast: p = 0.007; 5% test contrast: p = 0.035). 4. Within each group, RT3% and RT5% were significantly different at both test contrasts (normals, perimetric open-angle glaucoma: p < 0.001; ocular hypertension: p = 0.007; preperimetric open-angle glaucoma: p = 0.035). 5. RT3% and RT5% were significantly correlated with mean defect (p < 0.001) and retinal nerve fibre layer thickness (p = 0.018). RT5% was correlated with loss variance (p = 0.048). 6. RT12%, RT25% and RT35% were significantly prolonged in advanced perimetric glaucoma (p < 0.001), and correlated with mean defect (p < 0.001, p = 0.002, p = 0.013) and retinal nerve fibre layer thickness (p < 0.001, p = 0.003, p = 0.013). RT12% was also correlated with loss variance (p = 0.016). CONCLUSIONS. Measurements of RT after 25-Hz pre-adaptation can be used in glaucoma diagnosis and follow-up examination, especially in monitoring glaucoma progress in advanced perimetric primary open-angle glaucoma

Temporal contrast sensitivity: A potential parameter for glaucoma progression, especially in advanced stages

INTRODUCTION. Previously it could be shown that temporal contrast sensitivity is affected by glaucoma and maximally influenced after 25-Hz adaptation in normals. This study investigated different kinds of 25-Hz temporal contrast adaptation on TCS in patients with ocular hypertension, preperimetric primary open-angle glaucoma, and perimetric open-angle glaucoma. Additionally, correlations of measured data with parameters of glaucoma diagnostic were done and assessed for the potential use of TCS as a parameter for glaucoma progression. MATERIALS AND METHODS. One hundred and four subjects were included: 44 normals, 14 ocular hypertensions, 11 preperimetric primary open-angle glaucomas, and 35 perimetric open-angle glaucomas. Using the Erlangen Flicker Test, temporal contrast sensitivity was measured without adaptation, after pre-adaptation and after pre- and re-adaptations at 25 Hz. Reliability analyses were done. RESULTS. All test strategies showed high reliability (a-Cronbach’s > 0.86). In normals, age-dependency of temporal contrast sensitivity without adaptation (p = 0.052) and after pre- and re-adaptation (p = 0.008) was observed. Temporal contrast sensitivity is significantly reduced after pre-adaptation for all subjects (p < 0.001). Reduction of temporal contrast sensitivity after pre- and re-adaptations was significant in all groups (p < 0.001), but it was smaller than after single pre-adaptation (p < 0.001). Temporal contrast sensitivity without adaptation was significantly reduced in patients with perimetric glaucoma (p = 0.040) but not in patients with ocular hypertension and preperimetric glaucoma. Correlation analyses yielded a significant correlation between temporal contrast sensitivity without adaptation and mean defect (p = 0.003, r = –0.329), loss variance (p = 0.027, r = –0.256), and retinal nerve fibre layer thickness (p < 0.001, r = 0.413) for all subjects and between temporal contrast sensitivity after pre-adaptation and mean defect (p = 0.045, r = –0.239). CONCLUSIONS. Temporal contrast sensitivity seems to be affected in perimetric glaucoma with an overall reduction after adaptation. Significant correlations of temporal contrast sensitivity with perimetric and morphologic parameters offer new aspects of its potential use as a glaucoma progressions marker, especially in advanced stages when perimetric diagnosis is limited

Xist and Tsix Transcription Dynamics Is Regulated by the X-to-Autosome Ratio and Semistable Transcriptional States

In female mammals, X chromosome inactivation (XCI) is a key process in the control of gene dosage compensation between X-linked genes and autosomes. Xist and Tsix, two overlapping antisense-transcribed noncoding genes, are central elements of the X inactivation center (Xic) regulating XCI. Xist upregulation results in the coating of the entire X chromosome by Xist RNA in cis, whereas Tsix transcription acts as a negative regulator of Xist. Here, we generated Xist and Tsix reporter mouse embryonic stem (ES) cell lines to study the genetic and dynamic regulation of these genes upon differentiation. Our results revealed mutually antagonistic roles for Tsix on Xist and vice versa and indicate the presence of semistable transcriptional states of the Xic locus predicting the outcome of XCI. These transcriptional states are instructed by the X-to-autosome ratio, directed by regulators of XCI, and can be modulated by tissue culture conditions