Model-based comparison of current flow in rod bipolar cells of healthy and early-stage degenerated retina.

Retinal degenerative diseases, such as retinitis pigmentosa, are generally thought to initiate with the loss of photoreceptors, though recent work suggests that plasticity and remodeling occurs prior to photoreceptor cell loss. This degeneration subsequently leads to death of other retinal neurons, creating functional alterations and extensive remodeling of retinal networks. Retinal prosthetic devices stimulate the surviving retinal cells by applying external current using implanted electrodes. Although these devices restore partial vision, the quality of restored vision is limited. Further knowledge about the precise changes in degenerated retina as the disease progresses is essential to understand how current flows in retinas undergoing degenerative disease and to improve the performance of retinal prostheses. We developed computational models that describe current flow from rod photoreceptors to rod bipolar cells (RodBCs) in the healthy and early-stage degenerated retina. Morphologically accurate models of retinal cells with their synapses are constructed based on retinal connectome datasets, created using serial section transmission electron microscopy (TEM) images of 70 nm-thick slices of either healthy (RC1) or early-stage degenerated (RPC1) rabbit retina. The passive membrane and active ion currents of each cell are implemented using conductance-based models in the Neuron simulation environment. In response to photocurrent input at rod photoreceptors, the simulated membrane potential at RodBCs in early degenerate tissue is approximately 10-20 mV lower than that of RodBCs of that observed in wild type retina. Results presented here suggest that although RodBCs in RPC1 show early, altered morphology compared to RC1, the lower membrane potential is primarily a consequence of reduced rod photoreceptor input to RodBCs in the degenerated retina. Frequency response and step input analyses suggest that individual cell responses of RodBCs in either healthy or early-degenerated retina, prior to substantial photoreceptor cell loss, do not differ significantly.

An extraocular electrical stimulation approach to slow down the progression of retinal degeneration in an animal model.

Retinal diseases such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are characterized by unrelenting neuronal death. However, electrical stimulation has been shown to induce neuroprotective changes in the retina capable of slowing down the progression of retinal blindness. In this work, a multi-scale computational model and modeling platform were used to design electrical stimulation strategies to better target the bipolar cells (BCs), that along with photoreceptors are affected at the early stage of retinal degenerative diseases. Our computational findings revealed that biphasic stimulus pulses of long pulse duration could decrease the activation threshold of BCs, and the differential stimulus threshold between ganglion cells (RGCs) and BCs, offering the potential of targeting the BCs during the early phase of degeneration. In vivo experiments were performed to evaluate the electrode placement and parameters found to target bipolar cells and evaluate the safety and efficacy of the treatment. Results indicate that the proposed transcorneal Electrical Stimulation (TES) strategy can attenuate retinal degeneration in a Royal College of Surgeon (RCS) rodent model, offering the potential to translate this work to clinical practice.

Selective Activation of Retinal Ganglion Cell Subtypes Through Targeted Electrical Stimulation Parameters.

To restore vision to the low vision, epiretinal implants have been developed to electrically stimulate the healthy retinal ganglion cells (RGCs) in the degenerate retina. Given the diversity of retinal ganglion cells as well as the difference in their visual function, selective activation of RGCs subtypes can significantly improve the quality of the restored vision. Our recent results demonstrated that with the proper modulation of the current amplitude, small D1-bistratified cells with the contribution to blue/yellow color opponent pathway can be selectively activated at high frequency (200 Hz). The computational results correlated with the clinical findings revealing the blue sensation of 5/7 subjects with epiretinal implants at high frequency. Here we further explored the impacts of alterations in pulse duration and interphase gap on the response of RGCs at high frequency. We used the developed RGCs, A2-monostratified and D1-bistratified, and examined their response to a range of pulse durations (0.1-1.2 ms) and interphase gaps (0-1 ms). We found that the use of short pulse durations with no interphase gap at high frequency increases the differential response of RGCs, offering better opportunities for selective activation of D1 cells. The presence of the interphase gap has shown to reduce the overall differential response of RGCs. We also explored how the low density of calcium channels enhances the responsiveness of RGCs at high frequency.

The Influence of Electrode Properties on Induced Voltage Gradient Along the Rat Optic Nerve.

Significant interest exists in the potential of electric field (EF) application to be developed into a technology to direct neuronal regeneration. In vitro, EFs were shown to direct the growth of retinal ganglion cell (RGC) axons, the neurons that make up the optic nerve. As larger EF gradients were shown to direct more efficient growth, investigations into the most effective stimulation strategies that can generate the greatest voltage gradient are needed before EF application can be developed into a technology to direct optic nerve regeneration in vivo. We performed ex-vivo experiments to compare the ability of different electrode materials, platinum vs. tungsten, to generate an EF gradient along the rat optic nerve. Platinum electrodes at both source and ground positions were found to generate the greatest voltage gradient along the optic nerve. Experimental results were used to inform an equivalent computational model of the optic nerve, which was subsequently employed to predict more effective electrode pair combinations. Our results confirmed that the platinum-platinum electrode pair generates the maximum voltage gradient which are highly dependent on electrode size and electrode-electrolyte interfaces. This computational platform can serve as a foundation for the development of electrical stimulation therapies for nerve regeneration.

Color and cellular selectivity of retinal ganglion cell subtypes through frequency modulation of electrical stimulation.

Epiretinal prostheses aim at electrically stimulating the inner most surviving retinal cells-retinal ganglion cells (RGCs)-to restore partial sight to the blind. Recent tests in patients with epiretinal implants have revealed that electrical stimulation of the retina results in the percept of color of the elicited phosphenes, which depends on the frequency of stimulation. This paper presents computational results that are predictive of this finding and further support our understanding of the mechanisms of color encoding in electrical stimulation of retina, which could prove pivotal for the design of advanced retinal prosthetics that elicit both percept and color. This provides, for the first time, a directly applicable "amplitude-frequency" stimulation strategy to "encode color" in future retinal prosthetics through a predictive computational tool to selectively target small bistratified cells, which have been shown to contribute to "blue-yellow" color opponency in the retinal circuitry. The presented results are validated with experimental data reported in the literature and correlated with findings in blind patients with a retinal prosthetic implant collected by our group.

On the Design of an Efficient Inductive Wireless Power Transfer for Passive Neurostimulation Systems.

In this paper, a minimally invasive wireless powered electronic lens (e-lens) with passive electrodes is presented for an ocular electrical stimulation. Previous research has focused on the differentiation property of the induction phenomenon and half wave rectifiers. However, these approaches are generally application specific, non efficient, suitable for low current, and deliver monophasic current stimulation. Existing rectifier-based techniques can lead to safety concerns as the offset voltage could change unpredictably. A new wireless power transfer circuit is presented for the design of an efficient system to wirelessly deliver charge-balanced biphasic waveforms through passive electrodes for transcorneal electrical stimulation. The absence of active components allows the development of a flexible e-lens system for therapeutic electrical stimulation of the eye.

A Computational Model Simulates Light-Evoked Responses in the Retinal Cone Pathway.

Partial vision restoration on degenerated retina can be achieved by electrically stimulating the surviving retinal ganglion cells via implanted electrodes to elicit a signal corresponding to the natural response of the cells. Realistic computational models of electrical stimulation of the retina can prove useful to test different stimulation strategies and improve the performance of retinal implants. Simulation of healthy retinal networks and their dynamical response to natural light stimulation may also help us understand how retinal processing takes place via a series of electrical signals flowing through different stages of retinal processing, ultimately giving rise to visual percepts. Such models may provide further insights on retinal network processing and thus guide the design of retinal prostheses and their stimulation protocols to generate more natural percepts. This work aims to characterize the photocurrent generated by healthy cone photoreceptors in response to a light flash stimulation and the resulting membrane potential for the photoreceptors and its postsynaptic cone bipolar cells. A simple network of ten cone photoreceptors synapsing with a cone bipolar cell is simulated using the NEURON environment and validated against patch-clamp recordings of cone photoreceptors and ON-type bipolar cells (ON-BC). The results presented will be valuable in modeling light-evoked or electrically stimulated retinal networks that comprise cone pathways. The computational models and methods developed in this work will serve as an integral building block in the development of large and realistic retinal networks.Clinical Relevance- Accurate computational model of a retinal neural network can help in predicting cell responses to electrical stimulation in vision restoration therapies using prostheses. It can be leveraged to optimize the stimulation parameters to match the natural light response of the network as closely as possible.

Mechanisms underlying activation of retinal bipolar cells through targeted electrical stimulation: a computational study.

Objective. Retinal implants have been developed to electrically stimulate healthy retinal neurons in the progressively degenerated retina. Several stimulation approaches have been proposed to improve the visual percept induced in patients with retinal prostheses. We introduce a computational model capable of simulating the effects of electrical stimulation on retinal neurons. Leveraging this computational platform, we delve into the underlying mechanisms influencing the sensitivity of retinal neurons' response to various stimulus waveforms.Approach. We implemented a model of spiking bipolar cells (BCs) in the magnocellular pathway of the primate retina, diffuse BC subtypes (DB4), and utilized our multiscale admittance method (AM)-NEURON computational platform to characterize the response of BCs to epiretinal electrical stimulation with monophasic, symmetric, and asymmetric biphasic pulses.Main results. Our investigations yielded four notable results: (a) the latency of BCs increases as stimulation pulse duration lengthens; conversely, this latency decreases as the current amplitude increases. (b) Stimulation with a long anodic-first symmetric biphasic pulse (duration > 8 ms) results in a significant decrease in spiking threshold compared to stimulation with similar cathodic-first pulses (from 98.2 to 57.5µA). (c) The hyperpolarization-activated cyclic nucleotide-gated channel was a prominent contributor to the reduced threshold of BCs in response to long anodic-first stimulus pulses. (d) Finally, extending the study to asymmetric waveforms, our results predict a lower BCs threshold using asymmetric long anodic-first pulses compared to that of asymmetric short cathodic-first stimulation.Significance. This study predicts the effects of several stimulation parameters on spiking BCs response to electrical stimulation. Of importance, our findings shed light on mechanisms underlying the experimental observations from the literature, thus highlighting the capability of the methodology to predict and guide the development of electrical stimulation protocols to generate a desired biological response, thereby constituting an ideal testbed for the development of electroceutical devices.

Electrode Spacing and Current Distribution in Electrical Stimulation of Peripheral Nerve: A Computational Modeling Study using Realistic Nerve Models.

Electrical stimulation of peripheral nerves has long been used and proven effective in restoring function caused by disease or injury. Accurate placement of electrodes is often critical to properly excite the nerve and yield the desired outcome. Computational modeling is becoming an important tool that can guide the rapid development and optimization of such implantable neural stimulation devices. Here, we developed a heterogeneous very high-resolution computational model of a realistic peripheral nerve stimulated by a current source through cuff electrodes. We then calculated the current distribution inside the nerve and investigated the effect of electrodes spacing on current penetration. In the present study, we first describe model implementation and calibration; we then detail the methodology we use to calculate current distribution and apply it to characterize the effect of electrodes distance on current penetration. Our computational results indicate that when the source and return cuff electrodes are placed close to each other, the penetration depth in the nerve is shallower than the cases in which the electrode distance is larger. This study outlines the utility of the proposed computational methods and anatomically correct high-resolution models in guiding and optimizing experimental nerve stimulation protocols.

Modeling ON Cone Bipolar Cells for Electrical Stimulation.

Retinal prosthetic systems have been developed to help blind patients suffering from retinal degenerative diseases gain some useful form of vision. Various experimental and computational studies have been performed to test electrical stimulation strategies that can improve the performance of these devices. Detailed computational models of retinal neurons, such as retinal ganglion cells (RGCs) and bipolar cells (BCs), allow us to explore the mechanisms underlying the response of cells to electrical stimulation. While electrophysiological studies have shown the presence of voltage-gated ionic channels in different regions of BCs, many of the existing cone BCs models are assumed to be passive or only contain calcium channels at the synaptic terminals. We have utilized our Admittance Method (AM)-NEURON computational platform to implement a more realistic model of ON-BCs. Our model closely replicates the recent patch-clamp experiments directly measuring the response of ON-BCs to epiretinal electrical stimulation and thereby predicts the regional distributions of the ionic channels. Our computational results further indicate that outward potassium current strongly contributes to the depolarizing voltage transient of ON-BCs in response to electrical stimulation.

Targeted Stimulation of Retinal Ganglion Cells in Epiretinal Prostheses: A Multiscale Computational Study.

Retinal prostheses aim at restoring partial sight to patients that are blind due to retinal degenerative diseases by electrically stimulating the surviving healthy retinal neurons. Ideally, the electrical stimulation of the retina is intended to induce localized, focused, percepts only; however, some epiretinal implant subjects have reported seeing elongated phosphenes in a single electrode stimulation due to the axonal activation of retinal ganglion cells (RGCs). This issue can be addressed by properly devising stimulation waveforms so that the possibility of inducing axonal activation of RGCs is minimized. While strategies to devise electrical stimulation waveforms to achieve a focal RGCs response have been reported in literature, the underlying mechanisms are not well understood. This article intends to address this gap; we developed morphologically and biophysically realistic computational models of two classified RGCs: D1-bistratified and A2-monostratified. Computational results suggest that the sodium channel band (SOCB) is less sensitive to modulations in stimulation parameters than the distal axon (DA), and DA stimulus threshold is less sensitive to physiological differences among RGCs. Therefore, over a range of RGCs distal axon diameters, short-pulse symmetric biphasic waveforms can enhance the stimulation threshold difference between the SOCB and the DA. Appropriately designed waveforms can avoid axonal activation of RGCs, implying a consequential reduction of undesired strikes in the visual field.

Responsiveness of Retinal Ganglion Cells Through Frequency Modulation of Electrical Stimulation: A Computational Modeling Study.

Electrical stimulation of surviving retinal neurons has proven effective in restoring sight to totally blind patients affected by retinal degenerative diseases. Morphological and biophysical differences among retinal ganglion cells (RGCs) are important factors affecting their response to epiretinal electrical stimulation. Although detailed models of ON and OFF RGCs have already been investigated, here we developed morphologically and biophysically realistic computational models of two classified RGCs, D1-bistratified and A2-monostratified, and analyzed their response to alternations in stimulation frequency (up to 200 Hz). Results show that the D1-bistratified cell is more responsive to high frequency stimulation compared to the A2-monostratified cell. This differential RGCs response suggests a potential avenue for selective activation, and in turn different encoded percept of RGCs.

Admittance Method for Estimating Local Field Potentials Generated in a Multi-Scale Neuron Model of the Hippocampus.

Significant progress has been made toward model-based prediction of neral tissue activation in response to extracellular electrical stimulation, but challenges remain in the accurate and efficient estimation of distributed local field potentials (LFP). Analytical methods of estimating electric fields are a first-order approximation that may be suitable for model validation, but they are computationally expensive and cannot accurately capture boundary conditions in heterogeneous tissue. While there are many appropriate numerical methods of solving electric fields in neural tissue models, there isn't an established standard for mesh geometry nor a well-known rule for handling any mismatch in spatial resolution. Moreover, the challenge of misalignment between current sources and mesh nodes in a finite-element or resistor-network method volume conduction model needs to be further investigated. Therefore, using a previously published and validated multi-scale model of the hippocampus, the authors have formulated an algorithm for LFP estimation, and by extension, bidirectional communication between discretized and numerically solved volume conduction models and biologically detailed neural circuit models constructed in NEURON. Development of this algorithm required that we assess meshes of (i) unstructured tetrahedral and grid-based hexahedral geometries as well as (ii) differing approaches for managing the spatial misalignment of current sources and mesh nodes. The resulting algorithm is validated through the comparison of Admittance Method predicted evoked potentials with analytically estimated LFPs. Establishing this method is a critical step toward closed-loop integration of volume conductor and NEURON models that could lead to substantial improvement of the predictive power of multi-scale stimulation models of cortical tissue. These models may be used to deepen our understanding of hippocampal pathologies and the identification of efficacious electroceutical treatments.