Degenerative retinal diseases such as retinitis pigmentosa and macular degeneration cause irreversible vision loss in more than 10 million people worldwide. Retinal prostheses, now implanted in over 250 patients worldwide, electrically stimulate surviving cells in order to evoke neuronal responses that are interpreted by the brain as visual percepts (‘phosphenes’). However, instead of seeing focal spots of light, current implant users perceive highly distorted phosphenes that vary in shape both across subjects and electrodes. We characterized these distortions by asking users of the Argus retinal prosthesis system (Second Sight Medical Products Inc.) to draw electrically elicited percepts on a touchscreen. Using ophthalmic fundus imaging and computational modeling, we show that elicited percepts can be accurately predicted by the topographic organization of optic nerve fiber bundles in each subject’s retina, successfully replicating visual percepts ranging from ‘blobs’ to oriented ‘streaks’ and ‘wedges’ depending on the retinal location of the stimulating electrode. This provides the first evidence that activation of passing axon fibers accounts for the rich repertoire of phosphene shape commonly reported in psychophysical experiments, which can severely distort the quality of the generated visual experience. Overall our findings argue for more detailed modeling of biological detail across neural engineering applications.

Retinal prosthetic implants are the only approved treatment for retinitis pigmentosa, a disease of the eye that causes blindness through gradual degeneration of photoreceptors. An array of microelectrodes triggered by input from a camera stimulates surviving retinal neurons, each electrode acting as a pixel. Unintended stimulation of retinal ganglion cell axons causes patients to see large, oblong shapes of light, rather than focal spots, making it difficult for them to perceive forms. To address this problem, we performed calcium imaging in isolated retinas and mapped the patterns of cells activated by different electrical stimulation protocols. We found that pulse durations two orders of magnitude longer than those typically used in existing implants stimulate inner retinal neurons while avoiding activation of ganglion cell axons, thus confining retinal responses to the site of the electrode. We show that multielectrode stimulation with 25-ms pulses can pattern letters on the retina corresponding to a Snellen acuity of 20/312. We validated our findings in a patient with an implanted epiretinal prosthesis by demonstrating that 25-ms pulses evoke focal spots of light.

Given that amplitude and frequency have separable effects on percept size, these findings suggest that frequency modulation improves the encoding of a wide range of brightness levels without a loss of spatial resolution. Future retinal prosthesis designs could benefit from having the flexibility to manipulate pulse train amplitude and frequency independently (clinicaltrials.gov number, NCT00279500).

A retinal prosthesis system to restore sight for the blind is under development. The system is analogous to cochlear implants, in which photoreceptor input is bypassed and replaced by direct electrical stimulation of the retinal ganglion cells. Currently, six test subjects have been implanted with a 4x4 electrode array and stimulator. We report here psychophysical clinical data examining how stimulation amplitude affects phosphene shape and repeatability on a single electrode. Phosphene shape data was quantified by a set of numerical descriptors calculated from image moments. Comparison of phosphene descriptors for a single electrode across repeated trials and amplitude levels measured the repeatability within an amplitude group. Our experimental findings show that stimulation of the retina creates repeatable percept shapes and that an increase in stimulation amplitude causes a significant change in size and shape of phosphenes.

12Degenerative retinal diseases such as retinitis pigmentosa and macular degeneration cause 13 irreversible vision loss in more than 10 million people worldwide. Retinal prostheses, now 14 implanted in more than 250 patients worldwide, electrically stimulate surviving cells in order to 15 evoke neuronal responses that are interpreted by the brain as visual percepts ('phosphenes'). 16However, instead of seeing focal spots of light, users of current epiretinal devices perceive highly 17 distorted phosphenes, which vary in shape not just across subjects but also across electrodes, 18 resulting in distorted percepts. We characterized these distortions by asking users of the Argus 19retinal prosthesis system (Second Sight Medical Products, Inc.) to draw percepts elicited by single-20 electrode stimulation on a touchscreen. Based on ophthalmic fundus photographs, we then 21 developed a computational model of the topographic organization of optic nerve fiber bundles in 22 each subject's retina, and used this model to successfully simulate predicted patient percepts. Our 23 model shows that activation of passing axon fibers contributes to the rich repertoire of phosphene 24shapes reported by patients in our psychophysical measurements, successfully replicating visual 25 percepts ranging from 'blobs' to oriented 'streaks' and 'wedges' depending on the retinal location 26 of the stimulating electrode. This model provides a first step towards future devices that 27 incorporate stimulation strategies tailored to each individual patient's retinal neurophysiology. 28 Impact 29 Current retinal implant users report seeing distorted and often elongated shapes rather than small 30 focal spots of light that match the shape of the implant electrodes. Here we show that the perceptual 31 experience of retinal implant users can be accurately predicted using a computational model that 32simulates each individual patient's retinal ganglion axon pathways. This opens up the possibility 33 for future devices that incorporate stimulation strategies tailored to each individual patient's retina. 34Wuyyuru, V., Sahel, J., Stanga, P., et al. (2013). The Argus II epiretinal prosthesis system allows 595 letter and word reading and long-term function in patients with profound vision loss. Br J 596Ophthalmol 97, 632-636. 597

Purpose.Retinal implants use electrical stimulation to elicit flashes of light (“phosphenes”). Single-electrode phosphene shape has been shown to vary systematically with stimulus amplitude and frequency as well as the retinal location of the stimulating electrode, due to incidental activation of passing nerve fiber bundles. However, this knowledge has yet to be extended to paired-electrode stimulation.Methods.We retrospectively analyzed 4402 phosphene drawings made by three blind subjects implanted with an Argus II Retinal Prosthesis. Phosphene shape (characterized by area, perimeter, major and minor axis length; normalized per subject) and number of perceived phosphenes were averaged across trials and correlated with the corresponding single-electrode parameters. In addition, the number of phosphenes was correlated with stimulus amplitude and neuroanatomical parameters: electrode-retina (“height”) and electrode-fovea distance (“eccentricity”) as well as the electrode-electrode distance to (“between-axon”) and along axon bundles (“along- axon”). Statistical analyses were conducted using linear regression and partial correlation analysis.Results.Simple regression revealed that each paired-electrode shape descriptor could be predicted by the sum of the two corresponding single- electrode shape descriptors (p < .001). Multiple regression revealed that paired- electrode phosphene shape was primarily predicted by stimulus amplitude, electrode- retina distance, and electrode-fovea distance (p < .05). Interestingly, the number of elicited phosphenes increased with between-axon distance (β= .162, p < .05), but not with along-axon distance (p > .05).Conclusions.The shape of phosphenes elicited by paired-electrode stimulation was well predicted by the shape of their corresponding single-electrode phosphenes, suggesting that two-point perception can be expressed as the linear summation of single-point perception. We also found that the number of perceived phosphenes increased with the between-axon distance of the two electrodes, providing further evidence in support of the axon map model for epiretinal stimulation. These findings contribute to the growing literature on phosphene perception and have important implications for the design of future retinal prostheses.

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