Dynamic Stimulation of Visual Cortex Produces Form Vision in Sighted and Blind Humans.

A visual cortical prosthesis (VCP) has long been proposed as a strategy for restoring useful vision to the blind, under the assumption that visual percepts of small spots of light produced with electrical stimulation of visual cortex (phosphenes) will combine into coherent percepts of visual forms, like pixels on a video screen. We tested an alternative strategy in which shapes were traced on the surface of visual cortex by stimulating electrodes in dynamic sequence. In both sighted and blind participants, dynamic stimulation enabled accurate recognition of letter shapes predicted by the brain's spatial map of the visual world. Forms were presented and recognized rapidly by blind participants, up to 86 forms per minute. These findings demonstrate that a brain prosthetic can produce coherent percepts of visual forms.

Emerging Approaches for Restoration of Hearing and Vision.

Impairments of vision and hearing are highly prevalent conditions limiting the quality of life and presenting a major socioeconomic burden. For a long time, retinal and cochlear disorders have remained intractable for causal therapies, with sensory rehabilitation limited to glasses, hearing aids, and electrical cochlear or retinal implants. Recently, the application of gene therapy and optogenetics to eye and ear has generated hope for a fundamental improvement of vision and hearing restoration. To date, one gene therapy for the restoration of vision has been approved, and ongoing clinical trials will broaden its application including gene replacement, genome editing, and regenerative approaches. Moreover, optogenetics, i.e., controlling the activity of cells by light, offers a more general alternative strategy. Over little more than a decade, optogenetic approaches have been developed and applied to better understand the function of biological systems, while protein engineers have identified and designed new opsin variants with desired physiological features. Considering potential clinical applications of optogenetics, the spotlight is on the sensory systems, particularly the eye and ear. Multiple efforts have been undertaken to restore lost or hampered function in the eye and ear. Optogenetic stimulation promises to overcome fundamental shortcomings of electrical stimulation, namely, poor spatial resolution and cellular specificity, and accordingly to deliver more detailed sensory information. This review aims to provide a comprehensive reference on current gene therapeutic and optogenetic research relevant to the restoration of hearing and vision. We will introduce gene-therapeutic approaches and discuss the biotechnological and optoelectronic aspects of optogenetic hearing and vision restoration.

Cellular migration into a subretinal honeycomb-shaped prosthesis for high-resolution prosthetic vision.

In patients blinded by geographic atrophy, a subretinal photovoltaic implant with 100 µm pixels provided visual acuity closely matching the pixel pitch. However, such flat bipolar pixels cannot be scaled below 75 µm, limiting the attainable visual acuity. This limitation can be overcome by shaping the electric field with 3-dimensional (3-D) electrodes. In particular, elevating the return electrode on top of the honeycomb-shaped vertical walls surrounding each pixel extends the electric field vertically and decouples its penetration into tissue from the pixel width. This approach relies on migration of the retinal cells into the honeycomb wells. Here, we demonstrate that majority of the inner retinal neurons migrate into the 25 µm deep wells, leaving the third-order neurons, such as amacrine and ganglion cells, outside. This enables selective stimulation of the second-order neurons inside the wells, thus preserving the intraretinal signal processing in prosthetic vision. Comparable glial response to that with flat implants suggests that migration and separation of the retinal cells by the walls does not cause additional stress. Furthermore, retinal migration into the honeycombs does not negatively affect its electrical excitability, while grating acuity matches the pixel pitch down to 40 µm and reaches the 27 µm limit of natural resolution in rats with 20 µm pixels. These findings pave the way for 3-D subretinal prostheses with pixel sizes of cellular dimensions.

High-Fidelity Reproduction of Visual Signals by Electrical Stimulation in the Central Primate Retina.

Electrical stimulation of retinal ganglion cells (RGCs) with electronic implants provides rudimentary artificial vision to people blinded by retinal degeneration. However, current devices stimulate indiscriminately and therefore cannot reproduce the intricate neural code of the retina. Recent work has demonstrated more precise activation of RGCs using focal electrical stimulation with multielectrode arrays in the peripheral macaque retina, but it is unclear how effective this can be in the central retina, which is required for high-resolution vision. This work probes the neural code and effectiveness of focal epiretinal stimulation in the central macaque retina, using large-scale electrical recording and stimulation ex vivo The functional organization, light response properties, and electrical properties of the major RGC types in the central retina were mostly similar to the peripheral retina, with some notable differences in density, kinetics, linearity, spiking statistics, and correlations. The major RGC types could be distinguished by their intrinsic electrical properties. Electrical stimulation targeting parasol cells revealed similar activation thresholds and reduced axon bundle activation in the central retina, but lower stimulation selectivity. Quantitative evaluation of the potential for image reconstruction from electrically evoked parasol cell signals revealed higher overall expected image quality in the central retina. An exploration of inadvertent midget cell activation suggested that it could contribute high spatial frequency noise to the visual signal carried by parasol cells. These results support the possibility of reproducing high-acuity visual signals in the central retina with an epiretinal implant.SIGNIFICANCE STATEMENT Artificial restoration of vision with retinal implants is a major treatment for blindness. However, present-day implants do not provide high-resolution visual perception, in part because they do not reproduce the natural neural code of the retina. Here, we demonstrate the level of visual signal reproduction that is possible with a future implant by examining how accurately responses to electrical stimulation of parasol retinal ganglion cells can convey visual signals. Although the precision of electrical stimulation in the central retina was diminished relative to the peripheral retina, the quality of expected visual signal reconstruction in parasol cells was greater. These findings suggest that visual signals could be restored with high fidelity in the central retina using a future retinal implant.

Optimizing Image Enhancement: Feature Engineering for Improved Classification in AI-Assisted Artificial Retinas.

Artificial retinas have revolutionized the lives of many blind people by enabling their ability to perceive vision via an implanted chip. Despite significant advancements, there are some limitations that cannot be ignored. Presenting all objects captured in a scene makes their identification difficult. Addressing this limitation is necessary because the artificial retina can utilize a very limited number of pixels to represent vision information. This problem in a multi-object scenario can be mitigated by enhancing images such that only the major objects are considered to be shown in vision. Although simple techniques like edge detection are used, they fall short in representing identifiable objects in complex scenarios, suggesting the idea of integrating primary object edges. To support this idea, the proposed classification model aims at identifying the primary objects based on a suggested set of selective features. The proposed classification model can then be equipped into the artificial retina system for filtering multiple primary objects to enhance vision. The suitability of handling multi-objects enables the system to cope with real-world complex scenarios. The proposed classification model is based on a multi-label deep neural network, specifically designed to leverage from the selective feature set. Initially, the enhanced images proposed in this research are compared with the ones that utilize an edge detection technique for single, dual, and multi-object images. These enhancements are also verified through an intensity profile analysis. Subsequently, the proposed classification model's performance is evaluated to show the significance of utilizing the suggested features. This includes evaluating the model's ability to correctly classify the top five, four, three, two, and one object(s), with respective accuracies of up to 84.8%, 85.2%, 86.8%, 91.8%, and 96.4%. Several comparisons such as training/validation loss and accuracies, precision, recall, specificity, and area under a curve indicate reliable results. Based on the overall evaluation of this study, it is concluded that using the suggested set of selective features not only improves the classification model's performance, but aligns with the specific problem to address the challenge of correctly identifying objects in multi-object scenarios. Therefore, the proposed classification model designed on the basis of selective features is considered to be a very useful tool in supporting the idea of optimizing image enhancement.

Implantable metaverse with retinal prostheses and bionic vision processing.

We present an implantable metaverse featuring retinal prostheses in association with bionic vision processing. Unlike conventional retinal prostheses, whose electrodes are spaced equidistantly, our solution is to rearrange the electrodes to match the distribution of ganglion cells. To naturally imitate the human vision, a scheme of bionic vision processing is developed. On top of a three-dimensional eye model, our bionic vision processing is able to visualize the monocular image, binocular image fusion, and parallax-induced depth map.

Long term positional stability of the Argus II retinal prosthesis epiretinal implant.

BACKGROUND: The Argus II Retinal Prosthesis System (Second Sight Medical Products, Sylmar, California) is an epiretinal prosthesis that serves to provide useful vision to people who are affected by retinal degenerative diseases such as retinitis pigmentosa (RP). The purpose of this study was to analyze postoperative movement of the electrode array. METHODS: Five patients diagnosed with profound retinal dystrophy who have undergone implantation of retinal prosthesis at Stony Brook University Hospital. Fundoscopy was performed at postoperative month 1 (M1), month 3 (M3), month 6 (M6), month 12 (M12), and month 24 (M24) visits. Fundoscopy was extracted and analyzed via NIH ImageJ. Data analysis was completed using IBM SPSS. Various lengths and angles were measured each postoperative month using ImageJ. RESULTS: There was no significant change in distance between the optic disc and the surgical handle (length AB) over the two-year span (F = 0.196, p = 0.705). There was a significant change in distance of length AB over time between patients between M3 and M6 (p = 0.025). A repeated measures ANOVA revealed that there was statistically significant change of the optic disc-tack-surgical handle angle (𝛾) (M1 to M24) (F = 3.527, p = 0.030). There was no significant change in angle 𝜟 (the angle to the horizontal of the image), angle 𝜶 (tack-optic disc-surgical handle), and angle 𝜷 (optic-disc-surgical handle-tack). CONCLUSION: Our results demonstrate that there may be postoperative movement of the retinal prosthesis over time, as a statistically significant downward rotation is reported over the 2 years span. It is important, moving forward, to further study this movement and to take into consideration such movement when designing retinal implants. It is important to note that this study is limited by the small sample size, and therefore, the conclusions drawn are limited.

Integrated Low-Voltage Compliance and Wide-Dynamic Stimulator Design for Neural Implantable Devices.

In this study, a pulse frequency modulation (PFM)-based stimulator is proposed for use in biomedical implantable devices. Conventionally, functional electrical stimulation (FES) techniques have been used to reinforce damaged nerves, such as retina tissue and brain tissue, by injecting a certain amount of charge into tissues. Although several design methods are present for implementing FES devices, an FES stimulator for retinal implants is difficult to realize because of the chip area, which needs to be inserted in a fovea, sized 5 mm x 5 mm, and power limitations to prevent the heat generation that causes tissue damage. In this work, we propose a novel stimulation structure to reduce the compliance voltage during stimulation, which can result in high-speed and low-voltage operation. A new stimulator that is composed of a modified high-speed PFM, a 4-bit counter, a serializer, a digital controller, and a current driver is designed and verified using a DB HiTek standard 0.18 µm process. This proposed stimulator can generate a charge up to 130 nC, consumes an average power of 375 µW during a stimulation period, and occupies a total area of 700 µm × 68 µm.

Retinal Prostheses: Engineering and Clinical Perspectives for Vision Restoration.

A retinal prosthesis, also known as a bionic eye, is a device that can be implanted to partially restore vision in patients with retinal diseases that have resulted in the loss of photoreceptors (e.g., age-related macular degeneration and retinitis pigmentosa). Recently, there have been major breakthroughs in retinal prosthesis technology, with the creation of numerous types of implants, including epiretinal, subretinal, and suprachoroidal sensors. These devices can stimulate the remaining cells in the retina with electric signals to create a visual sensation. A literature review of the pre-clinical and clinical studies published between 2017 and 2023 is conducted. This narrative review delves into the retinal anatomy, physiology, pathology, and principles underlying electronic retinal prostheses. Engineering aspects are explored, including electrode-retina alignment, electrode size and material, charge density, resolution limits, spatial selectivity, and bidirectional closed-loop systems. This article also discusses clinical aspects, focusing on safety, adverse events, visual function, outcomes, and the importance of rehabilitation programs. Moreover, there is ongoing debate over whether implantable retinal devices still offer a promising approach for the treatment of retinal diseases, considering the recent emergence of cell-based and gene-based therapies as well as optogenetics. This review compares retinal prostheses with these alternative therapies, providing a balanced perspective on their advantages and limitations. The recent advancements in retinal prosthesis technology are also outlined, emphasizing progress in engineering and the outlook of retinal prostheses. While acknowledging the challenges and complexities of the technology, this article highlights the significant potential of retinal prostheses for vision restoration in individuals with retinal diseases and calls for continued research and development to refine and enhance their performance, ultimately improving patient outcomes and quality of life.

Object recognition and localization enhancement in visual prostheses: a real-time mixed reality simulation.

Blindness is a main threat that affects the daily life activities of any human. Visual prostheses have been introduced to provide artificial vision to the blind with the aim of allowing them to restore confidence and independence. In this article, we propose an approach that involves four image enhancement techniques to facilitate object recognition and localization for visual prostheses users. These techniques are clip art representation of the objects, edge sharpening, corner enhancement and electrode dropout handling. The proposed techniques are tested in a real-time mixed reality simulation environment that mimics vision perceived by visual prostheses users. Twelve experiments were conducted to measure the performance of the participants in object recognition and localization. The experiments involved single objects, multiple objects and navigation. To evaluate the performance of the participants in objects recognition, we measure their recognition time, recognition accuracy and confidence level. For object localization, two metrics were used to measure the performance of the participants which are the grasping attempt time and the grasping accuracy. The results demonstrate that using all enhancement techniques simultaneously gives higher accuracy, higher confidence level and less time for recognizing and grasping objects in comparison to not applying the enhancement techniques or applying pair-wise combinations of them. Visual prostheses could benefit from the proposed approach to provide users with an enhanced perception.

Novel vision restoration techniques: 3D bioprinting, gene and stem cell therapy, optogenetics, and the bionic eye.

BACKGROUND: Vision restoration has been one of the most sought-after goals of ophthalmology because of its inception. Despite these problems being tackled from numerous different perspectives, a concrete solution has not yet been achieved. An optimal solution will have significant implications on the patient's quality of life, socioeconomic status, and mental health. METHODS: This article will explore new and innovative approaches with one common aim-to restore functional vision for the visually impaired. These novel techniques include 3D bioprinting, stem cell therapy, gene therapy, implantable devices, and optogenetics. RESULTS: While the techniques mentioned above show significant promise, they are currently in various stages of development ranging from clinical trials to commercial availability. Restoration of minimal vision in specific cases has already been achieved by the different methods but optimization of different parameters like biocompatibility, spatiotemporal resolution, and minimizing the costs are essential for widespread use. CONCLUSION: The developments over the past decade have resulted in multiple milestones in each of the techniques with many solutions getting approved by the FDA. This article will compare these novel techniques and highlight the major advantages and drawbacks of each of them.

An infrared image-enhancement algorithm in simulated prosthetic vision: Enlarging working environment of future retinal prostheses.

BACKGROUND: Most existing retinal prostheses contain a built-in visible-light camera module that captures images of the surrounding environment. Thus, in case of insufficient or lack of visible light, the camera fails to work, and the retinal prostheses enter a dormant or "OFF" state. A simple and effective solution is replacing the visible-light camera with a dual-mode camera. The present research aimed to achieve two main purposes: (1) to explore whether the dual-mode camera in prosthesis recipients works under no visible-light conditions and (2) to assess its performance. METHODS: To accomplish these aims, we enrolled subjects in a psychophysical experiment under simulated prosthetic vision conditions. We found that the subjects could complete some simple visual tasks, but the recognition performance under the infrared mode was significantly inferior to that under the visible-light mode. These results inspired us to develop and propose a feasible infrared image-enhancement processing algorithm. Another psychophysical experiment was performed to verify the feasibility of the algorithm. RESULTS: The obtained results showed that the average efficiency of the subjects completing visual tasks using our enhancement algorithm (0.014 ± 0.001) was significantly higher (p < 0.001) than that of subjects using direct pixelization (0.007 ± 0.001). CONCLUSIONS: We concluded that a dual-mode camera could be a feasible solution to improving the performance of retinal prostheses as the camera adapted better to the specific existing ambient light conditions. Dual-mode cameras combined with this infrared image-enhancement algorithm could provide a promising direction for the design of future retinal prostheses.

Visual-tactile shape perception in the visually restored with artificial vision.

Retinal prostheses partially restore vision to late blind patients with retinitis pigmentosa through electrical stimulation of still-viable retinal ganglion cells. We investigated whether the late blind can perform visual-tactile shape matching following the partial restoration of vision via retinal prostheses after decades of blindness. We tested for visual-visual, tactile-tactile, and visual-tactile two-dimensional shape matching with six Argus II retinal prosthesis patients, ten sighted controls, and eight sighted controls with simulated ultra-low vision. In the Argus II patients, the visual-visual shape matching performance was significantly greater than chance. Although the visual-tactile shape matching performance of the Argus II patients was not significantly greater than chance, it was significantly higher with longer duration of prosthesis use. The sighted controls using natural vision and the sighted controls with simulated ultra-low vision both performed the visual-visual and visual-tactile shape matching tasks significantly more accurately than the Argus II patients. The tactile-tactile matching was not significantly different between the Argus II patients and sighted controls with or without simulated ultra-low vision. These results show that experienced retinal prosthesis patients can match shapes across the senses and integrate artificial vision with somatosensation. The correlation of retinal prosthesis patients' crossmodal shape matching performance with the duration of device use supports the value of experience to crossmodal shape learning. These crossmodal shape matching results in Argus II patients are the first step toward understanding crossmodal perception after artificial visual restoration.

Clinical Progress and Optimization of Information Processing in Artificial Visual Prostheses.

Visual prostheses, used to assist in restoring functional vision to the visually impaired, convert captured external images into corresponding electrical stimulation patterns that are stimulated by implanted microelectrodes to induce phosphenes and eventually visual perception. Detecting and providing useful visual information to the prosthesis wearer under limited artificial vision has been an important concern in the field of visual prosthesis. Along with the development of prosthetic device design and stimulus encoding methods, researchers have explored the possibility of the application of computer vision by simulating visual perception under prosthetic vision. Effective image processing in computer vision is performed to optimize artificial visual information and improve the ability to restore various important visual functions in implant recipients, allowing them to better achieve their daily demands. This paper first reviews the recent clinical implantation of different types of visual prostheses, summarizes the artificial visual perception of implant recipients, and especially focuses on its irregularities, such as dropout and distorted phosphenes. Then, the important aspects of computer vision in the optimization of visual information processing are reviewed, and the possibilities and shortcomings of these solutions are discussed. Ultimately, the development direction and emphasis issues for improving the performance of visual prosthesis devices are summarized.

Two-Way Communication Digital Power Controllers for Wireless Retinal Prosthesis Systems.

Power-efficient digital controllers are proposed for wireless retinal prosthetic systems. Power management plays an important role in reducing the power consumption and avoiding malfunctions in implantable medical devices. In the case of implantable devices with only one-way communication, the received power level is uncertain because there is no feedback on the power status. Accordingly, system breakdown due to inefficient power management should be avoided to prevent harm to patients. In this study, digital power controllers were developed for achieving two-way communication. Three controllers-a forward and back telemetry control unit, a power control unit, and a preamble control unit-operated simultaneously to control the class-E amplifier input power, provided command data to stimulators, monitored the power levels of the implanted devices, and generated back telemetry data. For performance verification, we implemented a digital power control system using a field-programmable gate array and then demonstrated it by employing a wireless telemetry system.

Retinal Organoids and Retinal Prostheses: An Overview.

Despite the progress of modern medicine in the last decades, millions of people diagnosed with retinal dystrophies (RDs), such as retinitis pigmentosa, or age-related diseases, such as age-related macular degeneration, are suffering from severe visual impairment or even legal blindness. On the one hand, the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) and the progress of three-dimensional (3D) retinal organoids (ROs) technology provide a great opportunity to study, understand, and even treat retinal diseases. On the other hand, research advances in the field of electronic retinal prosthesis using inorganic photovoltaic polymers and the emergence of organic semiconductors represent an encouraging therapeutical strategy to restore vision to patients at the late onset of the disease. This review will provide an overview of the latest advancement in both fields. We first describe the retina and the photoreceptors, briefly mention the most used RD animal models, then focus on the latest RO differentiation protocols, carry out an overview of the current technology on inorganic and organic retinal prostheses to restore vision, and finally summarize the potential utility and applications of ROs.

In Vitro Cytotoxicity of D18 and Y6 as Potential Organic Photovoltaic Materials for Retinal Prostheses.

Millions of people worldwide are diagnosed with retinal dystrophies such as retinitis pigmentosa and age-related macular degeneration. A retinal prosthesis using organic photovoltaic (OPV) semiconductors is a promising therapeutic device to restore vision to patients at the late onset of the disease. However, an appropriate cytotoxicity approach has to be employed on the OPV materials before using them as retinal implants. In this study, we followed ISO standards to assess the cytotoxicity of D18, Y6, PFN-Br and PDIN individually, and as mixtures of D18/Y6, D18/Y6/PFN-Br and D18/Y6/PDIN. These materials were proven for their high performance as organic solar cells. Human RPE cells were put in direct and indirect contact with these materials to analyze their cytotoxicity by the MTT assay, apoptosis by flow cytometry, and measurements of cell morphology and proliferation by immunofluorescence. We also assessed electrophysiological recordings on mouse retinal explants via microelectrode arrays (MEAs) coated with D18/Y6. In contrast to PFN-Br and PDIN, all in vitro experiments show no cytotoxicity of D18 and Y6 alone or as a D18/Y6 mixture. We conclude that D18/Y6 is safe to be subsequently investigated as a retinal prosthesis.

Innovative Technologies for Optimized Artificial Vision. / Innovative Technologien für optimiertes künstliches Sehen.

Despite significant advances in the treatment of severe eye diseases, certain forms of blindness cannot be cured or improved to this day. These include, for example, retinitis pigmentosa, a hereditary degeneration of photoreceptors. Technology approaches with implantable visual prostheses based on electrical stimulation of remaining neurons in the retina or cortex, have already been tested in a number of patients with limited results. New findings in the biology of these diseases as well as new technological developments give hope for better results in the future.

[Modern concepts of bionic vision]. / Sovremennye kontseptsii bionicheskogo zreniya.

Loss of vision is a pressing medical and social problem leading to profound disability, loss of ability to work, serious alterations in the psycho-emotional state, and a decline of the quality of life. When conservative or surgical treatment can not help restore vision, the use of visual prosthesis - bionic eye - can be an effective solution. This review covers the main modern approaches to the development of visual prosthetic systems. Analysis of publications revealed that there are several main approaches to visual prosthesis differing primarily by the anatomical structure targeted for stimulation in order to activate visual sensations. The most significant among them are retinal prostheses, optic nerve stimulation, and cortical visual prostheses. Currently, retinal prostheses such as ARGUS II demonstrate the most successful results, since the stimulation of the surviving neural structures of the retina is a relatively easy task, but their field of application is limited to diseases associated with pathological changes in photoreceptors. The development of cortical visual prostheses is more difficult, but in the future they may allow using more stimulation channels to obtain a more detailed visual perception. In addition, cortical visual prostheses are universal, as they do not require preservation of any structures of the visual organ, only the primary visual cortex.

Restoring Color Perception to the Blind: An Electrical Stimulation Strategy of Retina in Patients with End-stage Retinitis Pigmentosa.

PURPOSE: Bioelectronic retinal prostheses that stimulate the remaining inner retinal neurons, bypassing degenerated photoreceptors, have been demonstrated to restore some vision in patients blinded by retinitis pigmentosa (RP). These implants encode luminance of the visual scene into electrical stimulation, however, leaving out chromatic information. Yet color plays an important role in visual processing when it comes to recognizing objects and orienting to the environment, especially at low spatial resolution as generated by current retinal prostheses. In this study, we tested the feasibility of partially restoring color perception in blind RP patients, with the aim to provide chromatic information as an extra visual cue. DESIGN: Case series. PARTICIPANTS: Seven subjects blinded by advanced RP and monocularly fitted with an epiretinal prosthesis. METHODS: Frequency-modulated electrical stimulation of retina was tested. Phosphene brightness was controlled by amplitude tuning, and color perception was acquired using the Red, Yellow, Green, and Blue (RYGB) hue and saturation scaling model. MAIN OUTCOME MEASURES: Brightness and color of the electrically elicited visual perception reported by the subjects. RESULTS: Within the tested parameter space, 5 of 7 subjects perceived chromatic colors along or nearby the blue-yellow axis in color space. Aggregate data obtained from 20 electrodes of the 5 subjects show that an increase of the stimulation frequency from 6 to 120 Hz shifted color perception toward blue/purple despite a significant inter-subject variation in the transition frequency. The correlation between frequency and blue-yellow perception exhibited a good level of consistency over time and spatially matched multi-color perception was possible with simultaneous stimulation of paired electrodes. No obvious correlation was found between blue sensations and array placement or status of visual impairment. CONCLUSIONS: These findings present a strategy for the generation and control of color perception along the blue-yellow axis in blind patients with RP by electrically stimulating the retina. It could transform the current prosthetic vision landscape by leading in a new direction beyond the efforts to improve the visual acuity. This study also offers new insights into the response of our visual system to electrical stimuli in the photoreceptor-less retina that warrant further mechanistic investigation.