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View all 12 Articles. Electrical stimulation using implantable devices with arrays of stimulating electrodes is an emerging therapy for neurological diseases. The performance of these devices depends greatly on their ability to activate populations of neurons with high spatiotemporal resolution.

To study electrical stimulation of populations of neurons, retina serves as a useful model because the neural network is arranged in a planar array that is easy to access. Moreover, retinal prostheses are under development to restore vision by replacing the function of damaged light sensitive photoreceptors, which makes retinal research directly relevant for curing blindness.

Here we provide a progress review on stimulation strategies developed in recent years to improve the resolution of electrical stimulation in retinal prostheses. We focus on studies performed with explanted retinas, in which electrophysiological techniques are the most advanced. We summarize achievements in improving the spatial and temporal resolution of electrical stimulation of the retina and methods to selectively stimulate neurons with different visual functions.

Future directions for retinal prostheses development are also discussed, which could provide insights for other types of neuromodulatory devices in which high-resolution electrical stimulation is required. Vision is amongst the most vital tools for functioning in daily activities. In healthy eyes, light enters through the cornea and is focused by the cornea and lens, onto the retina, the light sensitive tissue lining the back of the eye Figure 1A.

The retina Figure 1B contains light sensitive photoreceptors, including rods and cones, which can then transduce the light into chemical and electrical als. The als are sent to other neurons in the retina, including bipolar cells and retinal ganglion cells RGCs.

RGCs have axons that collectively form the optic nerve and deliver neural als to the central brain. The brain processes the als in a series of complex ways to ultimately generate the sensation of vision. Figure 1. Retinal prostheses. A Schematic representation of the eye. Light enters the eye through cornea and is focused by the lens onto the retina.

B The retina is mainly composed of three layers of neurons, photoreceptors, bipolar cells and retinal ganglion cells RGCswith horizontal and amacrine cells in between.

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Three different placements of retinal prostheses are under development. Epi-retinal implants are in contact with the RGC layer; sub-retinal devices are between the pigment epithelium and the remaining retina, and suprachoroidal devices are implanted between the choroid and sclera.

Retinal degenerative diseases, including age-related macular degeneration AMD and retinitis pigmentosa RPare leading causes of major vision loss and blindness worldwide Bourne et al. Approximately one in every 3,—7, people is affected by RP Ferrari et al. Both diseases lead to the loss of photoreceptor cells, thus depleting the ability of retinas to transduce light into useful visual als.

For both AMD and RP, currently available therapies normally only aim to slow down the death of photoreceptors, by providing nutritional supplements Krishnadev et al. More recent treatments showing encouraging include gene therapy and cell transplantation Scholl et al. For both these therapies, several issues remain unresolved.

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Gene therapy currently suffers from limited recognized mutations for treatment Hartong et al. Over the last two decades, retinal prostheses that electrically stimulate surviving retinal neurons have emerged as a promising treatment for returning sight to the blind Goetz and Palanker, ; Weiland et al. These devices can be categorized into three types depending on the location of the electrode arrays Figure 1B. Epi-retinal devices have electrode arrays on top of the retina, in contact with the RGC layer. Sub-retinal implants are placed under the retina, closest to diseased photoreceptor layer.

Suprachoroidal implants are between the sclera and choroid. Most of the clinical released by these consortiums have been positive: patients have reported the ability to detect light, categorize large objects from a list and even identify large letters Zrenner et al.

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Nevertheless, the visual resolution obtained from existing devices is very limited, meaning that even recognizing simple objects is challenging. Crucial abilities, such as facial recognition, are not yet possible. Snellen acuity is commonly used for describing visual acuity. The clinical from retinal prostheses have been reviewed recently by Ayton et al. Animal testing can evaluate and predict the performance of devices prior to clinical trials.

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Compared with in vivo testing, ex vivo experiments using explanted retinas are normally easier to perform, with more advanced electrophysiological approaches and have provided a large amount of important information to understand the performance of retinal prostheses. The knowledge gained from ex vivo experiments ranges from a better understanding of electrical stimulation, potential explanations of clinical observations, to the development of novel stimulation strategies.

In this review, we first describe the current challenges in electrical stimulation of retinal neurons, which limit the performance of retinal prostheses. We then introduce the animal models commonly used, and recent advances in electrophysiological tools for retinal experiments.

After this, progress in the last 5 years in improving the resolution of electrical stimulation of retinal neurons is summarized. Finally, we discuss the trends for the next generation of retinal prostheses, which could provide insights to future development and guide the de of other neuromodulation devices. The key challenges that inhibit visual function of retinal prostheses can be summarized as follows: 1 limited spatial resolution; 2 limited temporal precision; and 3 unselective activation of different visual pathways.

Single electrode stimulation generates the perception of spots of light, referred to as phosphenes. However, patients often report phosphenes that are larger than the electrodes and distorted in shape. Ideally, stimulation of individual retinal neurons is desired to restore natural vision.

There are over 1.

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All of them are similar or far larger than the size of individual somas. There are several technical limitations to using higher density electrode arrays.

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For example, the impedance of electrodes increases when their size is reduced. High impedance electrodes require higher voltage stimulation drivers which consume more power. Many materials do not have suitable electrochemical properties to elicit neural activity within the safe charge injection limit.

Another common cause of low spatial confinement of activation is a gap between the electrode array and the surface of the retina. The electric field above a stimulating electrode rapidly spre in a lateral direction with distance above the electrode resulting in a loss of spatial confinement.

Epi-retinal devices are intended to stimulate RGCs, however large electrode-retina gaps after surgery have been reported Gregori et al. Sub-retinal devices stimulate nearby inner retinal neurons and thereby take advantage of the natural al processing by sending als in the direction that a healthy retina would normally employ. For these devices, there is also potential separation between the inner retinal cells and the surface of the electrode array as degenerative retina often have a layer of debris as photoreceptors are replaced during degeneration.

Even when the placement of the electrodes is close and the size of the electrodes is comparable to the targeting neurons, there are other biological issues to be resolved. One critical problem is the activation of RGCs axon bundles Fried et al. This phenomenon occurs when electrodes not only stimulate the nearby neurons, but also errantly stimulate neurons from remote locations connected to the activated axons passing near the electrode.

In addition to localized activation, electrical stimulation with high temporal precision is required to replicate visual responses in retina. RGCs can be stimulated either directly by the electrode or indirectly through the retinal network. Network mediated stimulation may take advantages of the natural al processing in the retina. In a subset of RGCs, their responses through network mediated stimulation were found to be similar to a natural light response, although delays of tens of ms were observed Im and Fried, However, retinal remodeling can happen during degeneration Jones and Marc,making it unclear if the natural al processing function in retina is preserved or not.

Compared with network mediated responses, the responses of RGCs to direct stimulation normally happen within a short delay below 5 ms.

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However, the encoding of images based on the direct RGC responses requires sophisticated image processing techniques in order to for the natural visual processing in retinal circuits. Another problem limiting temporal performance is the loss of responses to high frequency repetitive stimulation which has been found in all types of retinal cells.

In a healthy retina, photoreceptors can resolve repetitive frequencies of 20—50 Hz Zrenner,leading to the RGCs firing at frequencies over Hz Koch et al. Therefore, the loss of responses to high frequency repetitive stimulation may be one of the reasons for image fading.

The third limitation for existing devices originates from the non-selective stimulation of the many visual pathways within retina. In natural vision, ON and OFF cells in any patch of visual space are not activated simultaneously as light and dark patches are segregated. To date, more than 30 types of mammalian RGCs have been identified Baden et al. Current retinal prostheses stimulate all types of retinal neurons in a similar manner without any preference, which is very different from the way that a healthy retina processes images.

Approaches for selective activation of different RGC types are expected to ificantly improve the vision restored. The animal models that have been used for visual processing research range from salamander to primates including humans. The most popular models for studying the responses of retinal cells to electrical stimulation are mice, rats, rabbits and monkeys. Mammalian species share similar types of neurons in retina, e. However, there are also some differences between species.

For example, in humans and some other mammals such as monkeys and cats, the location of the highest acuity in the retina is a small region at the center of the visual field that has the highest density of RGCs area centralis. In rabbits, the area of highest acuity in their retina is not a single, restricted region but an elongated zone running across the retina, referred to as the visual streak. In contrast, rodents have RGCs distributed more uniformly without an obvious area centralis or visual streak. The terminology commonly used for referring to different types of RGCs in each species differs Table 1.

For example, RGCs with large somas, large dendritic sizes and large receptive fields are referred to as Alpha or A cells in rodents and cats, but can also be known as Y cells in cats. These cells are similar to so called brisk transient cells in rabbits and parasol cells in primates.

RGCs with very small somas, small dendritic sizes and also small receptive fields are known as Beta or B cells in cats and rodents, but can also be known as X cells in cats. These cells are similar to so-called brisk sustained cells in rabbits and midget cells in monkeys.

In primate, the midget cells are known to be the main vehicle for generating high-resolution vision, but the function of beta cells in rodents is less clear Sanes and Masland, Despite the differences between retinas in rodents and primates, rodents are now the most popular species for research, in part due to their low costs and shorter breeding periods. Rodent animal models of retinal degeneration are also available, which are more relevant for studying retinal responses in terms of retinal prostheses. There are at least 15 mouse models of retinal degeneration with varying rates of photoreceptor loss, from a few days rd1to several months rd10 Chang et al.

Photoreceptor degeneration is faster in RCS rats with complete death of photoreceptors and loss of light responses by the age of 90 days P90 Ryals et al. In the other two types of rats, the degeneration is slower, with light responses being found even at P in P23h rats Sekirnjak et al. Depending on the stage of retinal degeneration of interest, different animal models In need of over the top stimulation w been used for different reasons.

Abnormal spontaneous behaviors have been reported in degenerated retinas, e. During electrical stimulation, such abnormal spontaneous activities lead to low al-to-noise ratios Choi et al. Several studies have also reported elevated thresholds for RGC stimulation in degenerated retinas Jensen and Rizzo, ; Chan et al. The differences observed between degenerated and healthy retinas further indicate the importance of using animal models with retinal degeneration for developing stimulation strategies for retinal prostheses. Several electrophysiological tools have been applied for recording the responses of retinal neurons to electrical stimulation Figure 2.

Figure 2.

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