Focal stimulation of retinal ganglion cells using subretinal 3D microelectrodes with peripheral electrodes of opposite current.

Unlabelled: Subretinal prostheses have been developed to stimulate survived retinal ganglion cells (RGCs), indirectly following the physiological visual pathways. However, current spreading from the prosthesis electrode causes the activation of unintended RGCs, thereby limiting the spatial resolution of artificial vision. This study proposes a strategy for focal stimulation of RGCs using a subretinal electrode array, in which six hexagonally arranged peripheral electrodes surround a stimulating electrode.

Multiple consecutive-biphasic pulse stimulation improves spatially localized firing of retinal ganglion cells in the degenerate retina.

Retinal prostheses have shown some clinical success in restoring vision in patients with retinitis pigmentosa. However, the post-implantation visual acuity does not exceed that of legal blindness. The reason for the poor visual acuity might be that (1) degenerate retinal ganglion cells (RGCs) are less responsive to electrical stimulation than normal RGCs, and (2) electrically-evoked RGC spikes show a more widespread not focal response.

High amplitude pulses on the same charge condition efficiently elicit bipolar cell-mediated retinal ganglion cell responses in the degenerate retina.

Retinal pigmentosa (RP) patients lose vision due to the loss of photoreceptors. Retinal prostheses bypass the dead photoreceptors by electrically stimulating surviving retinal neurons, such as bipolar cells or retinal ganglion cells (RGCs). In previous studies, stimulus charge has been mainly optimized to maximize the RGC response to electrical stimulation.

Outer retinal degeneration in a non-human primate model using temporary intravitreal tamponade with N-methyl-N-nitrosourea in cynomolgus monkeys.

The main objective of this study was to induce and evaluate drug-dose-dependent outer retinal degeneration in cynomolgus monkeys by application of N-methyl-N-nitrosourea (MNU).Intravitreal temporary tamponade induced outer retinal degeneration with MNU solutions (2-3 mg ml) after vitrectomy in five cynomolgus monkeys. Optical coherence tomography (OCT), fundus autofluorescence (FAF), full-field electroretinography (ffERG), and visual evoked potentials (VEP) were performed at baseline and weeks 2, 6, and 12 postoperatively.

Stage-Dependent Changes of Visual Function and Electrical Response of the Retina in the Mouse Model.

One of the critical prerequisites for the successful development of retinal prostheses is understanding the physiological features of retinal ganglion cells (RGCs) in the different stages of retinal degeneration (RD). This study used our custom-made mice, C57BL/6- /Korl mutated on the Pde6b gene in C57BL/6J mouse with the CRISPR/Cas9-based gene-editing method. We selected the postnatal day (P) 45, P70, P140, and P238 as representative ages for RD stages.

Correlated Activity in the Degenerate Retina Inhibits Focal Response to Electrical Stimulation.

Retinal prostheses have shown some clinical success in patients with retinitis pigmentosa and age-related macular degeneration. However, even after the implantation of a retinal prosthesis, the patient's visual acuity is at best less than 20/420. Reduced visual acuity may be explained by a decrease in the signal-to-noise ratio due to the spontaneous hyperactivity of retinal ganglion cells (RGCs) found in degenerate retinas.

An experimental pig model with outer retinal degeneration induced by temporary intravitreal loading of N-methyl-N-nitrosourea during vitrectomy.

We aimed to develop an outer retinal degeneration pig model induced by temporary intravitreal loading of N-methyl-N-nitrosourea (MNU) during vitrectomy. In a preliminary experiment involving 5 mini-pig cases to determine the appropriate concentration of MNU, the vitreous cavity of each eye was filled with 4, 8, 10, 12, or 16 mg/mL MNU for 10 min, which was then replaced with a balanced salt solution. Multimodal examinations including spectral-domain optical coherence tomography (OCT) images and full-field electroretinography (ffERG) were obtained at baseline and week 2, week 6, and week 12.

Spike-triggered Clustering for Retinal Ganglion Cell Classification.

Retinal ganglion cells (RGCs), the retina's output neurons, encode visual information through spiking. The RGC receptive field (RF) represents the basic unit of visual information processing in the retina. RFs are commonly estimated using the spike-triggered average (STA), which is the average of the stimulus patterns to which a given RGC is sensitive.

Synchrony of Spontaneous Burst Firing between Retinal Ganglion Cells Across Species.

Neurons communicate with other neurons in response to environmental changes. Their goal is to transmit information to their targets reliably. A burst, which consists of multiple spikes within a short time interval, plays an essential role in enhancing the reliability of information transmission through synapses.

New Features of Receptive Fields in Mouse Retina through Spike-triggered Covariance.

Retinal ganglion cells (RGCs) encode various spatiotemporal features of visual information into spiking patterns. The receptive field (RF) of each RGC is usually calculated by spike-triggered average (STA), which is fast and easy to understand, but limited to simple and unimodal RFs. As an alternative, spike-triggered covariance (STC) has been proposed to characterize more complex patterns in RFs.

Morphologic and electrophysiologic findings of retinal degeneration after intravitreal sodium iodate injection following vitrectomy in canines.

We developed and characterized a canine model of outer retinal degeneration induced by sodium iodate (SI) intravitreal injection after vitrectomy. In the preliminary study, we repeatedly injected SI intravitreally into the eyes of three canines to develop outer retinal degeneration two weeks after vitrectomy. Based on the preliminary study, a single dose of either 1.

The effects of intravitreal sodium iodate injection on retinal degeneration following vitrectomy in rabbits.

We sought to develop and characterize outer retinal degeneration induced by intravitreal injection of sodium iodate (SI) after vitrectomy in rabbits. To determine the effective dose of SI, the right eyes of 19 male New Zealand white rabbits received an intravitreal injection of SI or sham. Based on the dose-dependence results, 0.

A 3D flexible microelectrode array for subretinal stimulation.

Objective: Various retinal prostheses have been developed to restore the vision for blind patients, and some of them are already in clinical use. In this paper, we present a three-dimensional (3D) microelectrode array for a subretinal device that can effectively stimulate retinal cells.

Approach: To investigate the effect of electrode designs on the electric field distribution, we simulated various electrode shapes and sizes using finite element analysis.

Development of a Post-vitrectomy Injection of N-methyl-N-nitrosourea as a Localized Retinal Degeneration Rabbit Model.

Since genetic models for retinal degeneration (RD) in animals larger than rodents have not been firmly established to date, we sought in the present study to develop a new rabbit model of drug-induced RD. First, intravitreal injection of N-methyl-N-nitrosourea (MNU) without vitrectomy in rabbits was performed with different doses. One month after injection, morphological changes in the retinas were identified with ultra-wide-field color fundus photography (FP) and fundus autofluorescence (AF) imaging as well as spectral-domain optical coherence tomography (OCT).

Formulation and Implementation of Nonlinear Integral Equations to Model Neural Dynamics Within the Vertebrate Retina.

Existing computational models of the retina often compromise between the biophysical accuracy and a hardware-adaptable methodology of implementation. When compared to the current modes of vision restoration, algorithmic models often contain a greater correlation between stimuli and the affected neural network, but lack physical hardware practicality. Thus, if the present processing methods are adapted to complement very-large-scale circuit design techniques, it is anticipated that it will engender a more feasible approach to the physical construction of the artificial retina.

Amplitude Modulation-based Electrical Stimulation for Encoding Multipixel Spatiotemporal Visual Information in Retinal Neural Activities.

Retinal implants have been developed as a promising way to restore partial vision for the blind. The observation and analysis of neural activities can offer valuable insights for successful prosthetic electrical stimulation. Retinal ganglion cell (RGC) activities have been investigated to provide knowledge on the requirements for electrical stimulation, such as threshold current and the effect of stimulation waveforms.

The LIM protein complex establishes a retinal circuitry of visual adaptation by regulating Pax6 α-enhancer activity.

The visual responses of vertebrates are sensitive to the overall composition of retinal interneurons including amacrine cells, which tune the activity of the retinal circuitry. The expression of is regulated by multiple cis-DNA elements including the intronic α-enhancer, which is active in GABAergic amacrine cell subsets. Here, we report that the transforming growth factor ß1-induced transcript 1 protein (Tgfb1i1) interacts with the LIM domain transcription factors Lhx3 and Isl1 to inhibit the α-enhancer in the post-natal mouse retina.

Topographic prominence discriminator for the detection of short-latency spikes of retinal ganglion cells.

Objective: Direct stimulation of retinal ganglion cells in degenerate retinas by implanting epi-retinal prostheses is a recognized strategy for restoration of visual perception in patients with retinitis pigmentosa or age-related macular degeneration. Elucidating the best stimulus-response paradigms in the laboratory using multielectrode arrays (MEA) is complicated by the fact that the short-latency spikes (within 10 ms) elicited by direct retinal ganglion cell (RGC) stimulation are obscured by the stimulus artifact which is generated by the electrical stimulator.

Approach: We developed an artifact subtraction algorithm based on topographic prominence discrimination, wherein the duration of prominences within the stimulus artifact is used as a strategy for identifying the artifact for subtraction and clarifying the obfuscated spikes which are then quantified using standard thresholding.

Neuron Stimulation Device Integrated with Silicon Nanowire-Based Photodetection Circuit on a Flexible Substrate.

This paper proposes a neural stimulation device integrated with a silicon nanowire (SiNW)-based photodetection circuit for the activation of neurons with light. The proposed device is comprised of a voltage divider and a current driver in which SiNWs are used as photodetector and field-effect transistors; it has the functions of detecting light, generating a stimulation signal in proportion to the light intensity, and transmitting the signal to a micro electrode. To show the applicability of the proposed neural stimulation device as a high-resolution retinal prosthesis system, a high-density neural stimulation device with a unit cell size of 110 × 110 μ m and a resolution of 32 × 32 was fabricated on a flexible film with a thickness of approximately 50 μm.

Spontaneous Oscillatory Rhythms in the Degenerating Mouse Retina Modulate Retinal Ganglion Cell Responses to Electrical Stimulation.

Characterization of the electrical activity of the retina in the animal models of retinal degeneration has been carried out in part to understand the progression of retinal degenerative diseases like age-related macular degeneration (AMD) and retinitis pigmentosa (RP), but also to determine optimum stimulus paradigms for use with retinal prosthetic devices. The models most studied in this regard have been the two lines of mice deficient in the β-subunit of phosphodiesterase (rd1 and rd10 mice), where the degenerating retinas exhibit characteristic spontaneous hyperactivity and oscillatory local field potentials (LFPs). Additionally, there is a robust ~10 Hz rhythmic burst of retinal ganglion cell (RGC) spikes on the trough of the oscillatory LFP.

Visual Acuity Testing Using a Random Method Visual Acuity Application.

Background: A visual acuity (VA) testing application for the iPad® (Apple, Cupertino, CA) tablet computer using the mirroring technique was developed that randomly presented letters categorized by cognoscibility. The aim of this study was to assess whether measurements of distance VA using this application were in agreement with existing standard clinical tests of VA in adults with normal vision.

Materials And Methods: Forty-three normally sighted subjects were tested using the Early Treatment of Diabetic Retinopathy Study (ETDRS) chart.

Effect of Stimulus Waveform of Biphasic Current Pulse on Retinal Ganglion Cell Responses in Retinal Degeneration (rd1) mice.

A retinal prosthesis is being developed for the restoration of vision in patients with retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Determining optimal electrical stimulation parameters for the prosthesis is one of the most important elements for the development of a viable retinal prosthesis. Here, we investigated the effects of different charge-balanced biphasic pulses with regard to their effectiveness in evoking retinal ganglion cell (RGC) responses.