Maintaining close proximity between the electrode array and the retinal surface is critical in developing a successful retinal implant. With the development of chronic electrode arrays that are stable and flush on the retinal surface, it is likely that the influence of other factors such as electrode size, retinal degeneration, and subject age will become more apparent. (ClinicalTrials.gov number, NCT00279500.).

PURPOSE With the long-term goal of restoring functional vision in patients with retinal degenerative diseases, the eyes of blind human subjects were implanted chronically with epiretinal prostheses consisting of two-dimensional electrode arrays that directly stimulated cells of the neural retina. METHODS Psychophysical techniques were used to measure the brightness of electrically generated percepts on single electrodes using a variety of electrical stimulation patterns. RESULTS It was possible to predict the sensitivity of the human visual system to a wide variety of retinal electrical stimulation patterns using a simple and biologically plausible model. CONCLUSIONS This is the first study to demonstrate that, on the single-electrode level, retinal electrical stimulation in humans can produce visual qualia that are predictable using a quantitative model, a prerequisite for a successful retinal prosthesis.

When a planar object is rotated with respect to a directional light source, the reflected luminance changes. If surface lightness is to be a reliable guide to surface identity, observers must compensate for such changes. To the extent they do, observers are said to be lightness constant. We report data from a lightness matching task that assesses lightness constancy with respect to changes in object slant. On each trial, observers viewed an achromatic standard object and indicated the best match from a palette of 36 grayscale samples. The standard object and the palette were visible simultaneously within an experimental chamber. The chamber illumination was provided from above by a theater stage lamp. The standard objects were uniformly-painted flat cards. Different groups of naive observers made matches under two sets of instructions. In the Neutral Instructions, observers were asked to match the appearance of the standard and palette sample. In the Paint Instructions, observers were asked to choose the palette sample that was painted the same as the standard. Several broad conclusions may be drawn from the results. First, data for most observers were neither luminance matches nor lightness constant matches. Second, there were large and reliable individual differences. To characterize these, a constancy index was obtained for each observer by comparing how well the data were accounted for by both luminance matching and lightness constancy. The index could take on values between 0 (luminance matching) and 1 (lightness constancy). Individual observer indices ranged between 0.17 and 0.63 with mean 0.40 and median 0.40. An auxiliary slant-matching experiment rules out variation in perceived slant as the source of the individual variability. Third, the effect of instructions was small compared to the inter-observer variability. Implications of the data for models of lightness perception are discussed.

PURPOSE With the goal of eventually restoring functional vision in patients with retinal degenerative diseases, USC/Second Sight Medical Products, Inc. chronically implanted blind human subjects with a prototype epiretinal prosthesis consisting of a 4 × 4 array of 16 stimulating electrodes. To accurately represent a visual scene, a visual prosthesis must convey luminance information across a range of brightness levels. To achieve this, the brightness of phosphenes produced by an individual electrode should scale appropriately with luminance, and the same luminance should produce equivalently bright phosphenes across the entire electrode array. The goal was to examine how apparent brightness changes as a function of stimulation intensity across electrodes. METHODS As described in previous studies, electrical stimulation of intact cells of the neural retina using this prosthetic device reliably elicits visual percepts in human subjects blinded by retinitis pigmentosa. Here, apparent brightness for a range of electrical amplitudes was measured using both subjective magnitude rating and brightness-matching procedures in chronically implanted human subjects. RESULTS It was found that apparent brightness can be described as a power function of stimulation intensity. The same model can also predict brightness matching across electrodes. CONCLUSIONS These results suggest that a relatively simple model for scaling current across electrodes may be capable of producing equivalently bright phosphenes across an entire array.

PurposeHuman long (L) and middle (M) wavelength cone opsin genes are highly variable due to intermixing. Two L/M cone opsin interchange mutants, designated LIAVA and LVAVA, are associated with clinical diagnoses, including red-green color vision deficiency, blue cone monochromacy, cone degeneration, myopia, and Bornholm Eye Disease. Because the protein and splicing codes are carried by the same nucleotides, intermixing L and M genes can cause disease by affecting protein structure and splicing.MethodsGenetically engineered mice were created to allow investigation of the consequences of altered protein structure alone, and the effects on cone morphology were examined using immunohistochemistry. In humans and mice, cone function was evaluated using the electroretinogram (ERG) under L/M- or short (S) wavelength cone isolating conditions. Effects of LIAVA and LVAVA genes on splicing were evaluated using a minigene assay.ResultsERGs and histology in mice revealed protein toxicity for the LVAVA but not for the LIAVA opsin. Minigene assays showed that the dominant messenger RNA (mRNA) was aberrantly spliced for both variants; however, the LVAVA gene produced a small but significant amount of full-length mRNA and LVAVA subjects had correspondingly reduced ERG amplitudes. In contrast, the LIAVA subject had no L/M cone ERG.ConclusionsDramatic differences in phenotype can result from seemingly minor differences in genotype through divergent effects on the dual amino acid and splicing codes.Translational RelevanceThe mechanism by which individual mutations contribute to clinical phenotypes provides valuable information for diagnosis and prognosis of vision disorders associated with L/M interchange mutations, and it informs strategies for developing therapies.