RESUMEN
Photovoltaic subretinal prosthesis is designed for restoration of central vision in patients with age-related macular degeneration (AMD). We investigated the utility of prosthetic central vision for complex visual tasks using augmented-reality (AR) glasses simulating reduced acuity, contrast, and visual field. AR glasses with blocked central 20° of visual field included an integrated video camera and software which adjusts the image quality according to three user-defined parameters: resolution, corresponding to the equivalent pixel size of an implant; field of view, corresponding to the implant size; and number of grayscale levels. The real-time processed video was streamed on a screen in front of the right eye. Nineteen healthy participants were recruited to complete visual tasks including vision charts, sentence reading, and face recognition. With vision charts, letter acuity exceeded the pixel-sampling limit by 0.2 logMAR. Reading speed decreased with increasing pixel size and with reduced field of view (7°-12°). In the face recognition task (four-way forced choice, 5° angular size) participants identified faces at >75% accuracy, even with 100 µm pixels and only two grayscale levels. With 60 µm pixels and eight grayscale levels, the accuracy exceeded 97%. Subjects with simulated prosthetic vision performed slightly better than the sampling limit on the letter acuity tasks, and were highly accurate at recognizing faces, even with 100 µm/pixel resolution. These results indicate feasibility of reading and face recognition using prosthetic central vision even with 100 µm pixels, and performance improves further with smaller pixels.
Asunto(s)
Realidad Aumentada , Desempeño Psicomotor/fisiología , Trastornos de la Visión/fisiopatología , Percepción Visual/fisiología , Prótesis Visuales , Adolescente , Adulto , Anciano , Simulación por Computador , Sensibilidad de Contraste/fisiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Agudeza Visual/fisiología , Campos Visuales/fisiología , Adulto JovenRESUMEN
Subretinal prostheses aim at restoring sight to patients blinded by photoreceptor degeneration using electrical activation of the surviving inner retinal neurons. Today, such implants deliver visual information with low-frequency stimulation, resulting in discontinuous visual percepts. We measured retinal responses to complex visual stimuli delivered at video rate via a photovoltaic subretinal implant and by visible light. Using a multielectrode array to record from retinal ganglion cells (RGCs) in the healthy and degenerated rat retina ex vivo, we estimated their spatiotemporal properties from the spike-triggered average responses to photovoltaic binary white noise stimulus with 70-µm pixel size at 20-Hz frame rate. The average photovoltaic receptive field size was 194 ± 3 µm (mean ± SE), similar to that of visual responses (221 ± 4 µm), but response latency was significantly shorter with photovoltaic stimulation. Both visual and photovoltaic receptive fields had an opposing center-surround structure. In the healthy retina, ON RGCs had photovoltaic OFF responses, and vice versa. This reversal is consistent with depolarization of photoreceptors by electrical pulses, as opposed to their hyperpolarization under increasing light, although alternative mechanisms cannot be excluded. In degenerate retina, both ON and OFF photovoltaic responses were observed, but in the absence of visual responses, it is not clear what functional RGC types they correspond to. Degenerate retina maintained the antagonistic center-surround organization of receptive fields. These fast and spatially localized network-mediated ON and OFF responses to subretinal stimulation via photovoltaic pixels with local return electrodes raise confidence in the possibility of providing more functional prosthetic vision. NEW & NOTEWORTHY Retinal prostheses currently in clinical use have struggled to deliver visual information at naturalistic frequencies, resulting in discontinuous percepts. We demonstrate modulation of the retinal ganglion cells (RGC) activity using complex spatiotemporal stimuli delivered via subretinal photovoltaic implant at 20 Hz in healthy and in degenerate retina. RGCs exhibit fast and localized ON and OFF network-mediated responses, with antagonistic center-surround organization of their receptive fields.
Asunto(s)
Células Ganglionares de la Retina/fisiología , Prótesis Visuales , Potenciales de Acción , Animales , Ratas , Ratas Long-EvansRESUMEN
Localized stimulation of the inner retinal neurons for high-acuity prosthetic vision requires small pixels and minimal crosstalk from the neighboring electrodes. Local return electrodes within each pixel limit the crosstalk, but they over-constrain the electric field, thus precluding the efficient stimulation with subretinal pixels smaller than 55 µm. Here we demonstrate a high-resolution prosthetic vision based on a novel design of a photovoltaic array, where field confinement is achieved dynamically, leveraging the adjustable conductivity of the diodes under forward bias to turn the designated pixels into transient returns. We validated the computational modeling of the field confinement in such an optically-controlled circuit by in-vitro and in-vivo measurements. Most importantly, using this strategy, we demonstrated that the grating acuity with 40 µm pixels matches the pixel pitch, while with 20 µm pixels, it reaches the 28 µm limit of the natural visual resolution in rats. This method enables customized field shaping based on individual retinal thickness and distance from the implant, paving the way to higher acuity of prosthetic vision in atrophic macular degeneration.
Asunto(s)
Prótesis Visuales , Ratas , Animales , Agudeza Visual , Retina/fisiología , Visión Ocular , Electrónica , Estimulación EléctricaRESUMEN
Objective.To restore central vision in patients with atrophic age-related macular degeneration, we replace the lost photoreceptors with photovoltaic pixels, which convert light into current and stimulate the secondary retinal neurons. Clinical trials demonstrated prosthetic acuity closely matching the sampling limit of the 100µm pixels, and hence smaller pixels are required for improving visual acuity. However, with smaller flat bipolar pixels, the electric field penetration depth and the photodiode responsivity significantly decrease, making the device inefficient. Smaller pixels may be enabled by (a) increasing the diode responsivity using vertical p-n junctions and (b) directing the electric field in tissue vertically. Here, we demonstrate such novel photodiodes and test the retinal stimulation in a vertical electric field.Approach.Arrays of silicon photodiodes of 55, 40, 30, and 20µm in width, with vertical p-n junctions, were fabricated. The electric field in the retina was directed vertically using a common return electrode at the edge of the device. Optical and electronic performance of the diodes was characterizedin-vitro, and retinal stimulation threshold measured by recording the visually evoked potentials in rats with retinal degeneration.Main results.The photodiodes exhibited sufficiently low dark current (<10 pA) and responsivity at 880 nm wavelength as high as 0.51 A W-1, with 85% internal quantum efficiency, independent of pixel size. Field mapping in saline demonstrated uniformity of the pixel performance in the array. The full-field stimulation threshold was as low as 0.057±0.029mW mm-2with 10 ms pulses, independent of pixel size.Significance.Photodiodes with vertical p-n junctions demonstrated excellent charge collection efficiency independent of pixel size, down to 20µm. Vertically oriented electric field provides a stimulation threshold that is independent of pixel size. These results are the first steps in validation of scaling down the photovoltaic pixels for subretinal stimulation.
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Degeneración Retiniana , Neuronas Retinianas , Prótesis Visuales , Animales , Estimulación Eléctrica , Humanos , Ratas , Degeneración Retiniana/terapia , Neuronas Retinianas/fisiología , SilicioRESUMEN
Objective. Patients with photovoltaic subretinal implant PRIMA demonstrated letter acuity â¼0.1 logMAR worse than sampling limit for 100µm pixels (1.3 logMAR) and performed slower than healthy subjects tested with equivalently pixelated images. To explore the underlying differences between natural and prosthetic vision, we compare the fidelity of retinal response to visual and subretinal electrical stimulation through single-cell modeling and ensemble decoding.Approach. Responses of retinal ganglion cells (RGCs) to optical or electrical white noise stimulation in healthy and degenerate rat retinas were recorded via multi-electrode array. Each RGC was fit with linear-nonlinear and convolutional neural network models. To characterize RGC noise, we compared statistics of spike-triggered averages (STAs) in RGCs responding to electrical or visual stimulation of healthy and degenerate retinas. At the population level, we constructed a linear decoder to determine the accuracy of the ensemble of RGCs onN-way discrimination tasks.Main results. Although computational models can match natural visual responses well (correlation â¼0.6), they fit significantly worse to spike timings elicited by electrical stimulation of the healthy retina (correlation â¼0.15). In the degenerate retina, response to electrical stimulation is equally bad. The signal-to-noise ratio of electrical STAs in degenerate retinas matched that of the natural responses when 78 ± 6.5% of the spikes were replaced with random timing. However, the noise in RGC responses contributed minimally to errors in ensemble decoding. The determining factor in accuracy of decoding was the number of responding cells. To compensate for fewer responding cells under electrical stimulation than in natural vision, more presentations of the same stimulus are required to deliver sufficient information for image decoding.Significance. Slower-than-natural pattern identification by patients with the PRIMA implant may be explained by the lower number of electrically activated cells than in natural vision, which is compensated by a larger number of the stimulus presentations.
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Retina , Células Ganglionares de la Retina , Animales , Estimulación Eléctrica , Humanos , Estimulación Luminosa , Ratas , Células Ganglionares de la Retina/fisiología , Visión OcularRESUMEN
High-resolution visual prostheses require small, densely packed pixels, but limited penetration depth of the electric field formed by a planar electrode array constrains such miniaturization. We present a novel honeycomb configuration of an electrode array with vertically separated active and return electrodes designed to leverage migration of retinal cells into voids in the subretinal space. Insulating walls surrounding each pixel decouple the field penetration depth from the pixel width by aligning the electric field vertically, enabling a decrease of the pixel size down to cellular dimensions. We demonstrate that inner retinal cells migrate into the 25 µm deep honeycomb wells as narrow as 18 µm, resulting in more than half of these cells residing within the electrode cavities. Immune response to honeycombs is comparable to that with planar arrays. Modeled stimulation threshold current density with honeycombs does not increase substantially with reduced pixel size, unlike quadratic increase with planar arrays. This 3-D electrode configuration may enable functional restoration of central vision with acuity better than 20/100 for millions of patients suffering from age-related macular degeneration.
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Neuronas/fisiología , Diseño de Prótesis , Retina/cirugía , Degeneración Retiniana/cirugía , Prótesis Visuales , Animales , Modelos Animales de Enfermedad , Electrodos Implantados , Implantación de Prótesis , Ratas , Retina/fisiopatología , Degeneración Retiniana/fisiopatologíaRESUMEN
OBJECTIVE: Retinal prostheses aim to restore sight by electrically stimulating the surviving retinal neurons. In clinical trials of the current retinal implants, prosthetic visual acuity does not exceed 20/550. However, to provide meaningful restoration of central vision in patients blinded by age-related macular degeneration (AMD), prosthetic acuity should be at least 20/200, necessitating a pixel pitch of about 50 µm or lower. With such small pixels, stimulation thresholds are high due to limited penetration of electric field into tissue. Here, we address this challenge with our latest photovoltaic arrays and evaluate their performance in vivo. APPROACH: We fabricated photovoltaic arrays with 55 and 40 µm pixels (a) in flat geometry, and (b) with active electrodes on 10 µm tall pillars. The arrays were implanted subretinally into rats with degenerate retina. Stimulation thresholds and grating acuity were evaluated using measurements of the visually evoked potentials (VEP). MAIN RESULTS: With 55 µm pixels, we measured grating acuity of 48 ± 11 µm, which matches the linear pixel pitch of the hexagonal array. This geometrically corresponds to a visual acuity of 20/192 in a human eye, matching the threshold of legal blindness in the US (20/200). With pillar electrodes, the irradiance threshold was nearly halved, and duration threshold reduced by more than three-fold, compared to flat pixels. With 40 µm pixels, VEP was too low for reliable measurements of the grating acuity, even with pillar electrodes. SIGNIFICANCE: While being helpful for treating a complete loss of sight, current prosthetic technologies are insufficient for addressing the leading cause of untreatable visual impairment-AMD. Subretinal photovoltaic arrays may provide sufficient visual acuity for restoration of central vision in patients blinded by AMD.
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Electrodos Implantados , Potenciales Evocados Visuales/fisiología , Implantación de Prótesis/métodos , Retina/fisiología , Prótesis Visuales , Animales , Implantación de Prótesis/instrumentación , Ratas , Ratas Long-Evans , Retina/cirugía , Degeneración Retiniana/genética , Degeneración Retiniana/fisiopatología , Degeneración Retiniana/cirugíaRESUMEN
Subretinal prostheses are designed to restore sight in patients blinded by retinal degeneration using electrical stimulation of the inner retinal neurons. To relate retinal output to perception, we studied behavioral thresholds in blind rats with photovoltaic subretinal prostheses stimulated by full-field pulsed illumination at 20 Hz, and measured retinal ganglion cell (RGC) responses to similar stimuli ex-vivo. Behaviorally, rats exhibited startling response to changes in brightness, with an average contrast threshold of 12%, which could not be explained by changes in the average RGC spiking rate. However, RGCs exhibited millisecond-scale variations in spike timing, even when the average rate did not change significantly. At 12% temporal contrast, changes in firing patterns of prosthetic response were as significant as with 2.3% contrast steps in visible light stimulation of healthy retinas. This suggests that millisecond-scale changes in spiking patterns define perceptual thresholds of prosthetic vision. Response to the last pulse in the stimulation burst lasted longer than the steady-state response during the burst. This may be interpreted as an excitatory OFF response to prosthetic stimulation, and can explain behavioral response to decrease in illumination. Contrast enhancement of images prior to delivery to subretinal prosthesis can partially compensate for reduced contrast sensitivity of prosthetic vision.