36 research outputs found

    Simulation of epiretinal prostheses - Evaluation of geometrical factors affecting stimulation thresholds

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    <p>Abstract</p> <p>Background</p> <p>An accurate understanding of the electrical interaction between retinal prostheses and retinal tissue is important to design effective devices. Previous studies have used modelling approaches to simulate electric fields generated by epiretinal prostheses in saline and to simulate retinal ganglion cell (RGC) activation using passive or/and active biophysical models of the retina. These models have limited scope for studying an implanted human retinal prosthesis as they often do not account for real geometry and composition of the prosthesis-retina interface. This interface consists of real dimensions and location of stimulation and ground electrodes that are separated by the retinal tissue and surrounded by physiological fluids.</p> <p>Methods</p> <p>In this study, we combined the prosthesis-retina interface elements into a framework to evaluate the geometrical factors affecting stimulation thresholds for epiretinal prostheses used in clinical human trials, as described by Balthasar <it>et al</it>. in their Investigative Ophthalmology and Visual Science (IOVS) paper published in 2008 using the Argus I epiretinal implants. Finite element method (FEM) based computations were used to estimate threshold currents based on a threshold criterion employing a passive electric model of the retina.</p> <p>Results</p> <p>Threshold currents and impedances were estimated for different electrode-retina distances. The profiles and the values for thresholds and impedances obtained from our simulation framework are within the range of measured values in the only elaborate published clinical trial until now using Argus I epiretinal implants. An estimation of resolution for the electrodes used in these trials was provided. Our results reiterate the importance of close proximity between electrodes and retina for safe and efficient retinal stimulation.</p> <p>Conclusions</p> <p>The validation of our simulation framework being relevant for epiretinal prosthesis research is derived from the good agreement of the computed trends and values of the current study with measurements demonstrated in existing clinical trials on humans (Argus I). The proposed simulation framework could be used to generate the relationship between threshold and impedance for any electrode geometry and consequently be an effective tool for design engineers, surgeons and electrophysiologists.</p

    Retinal ganglion cells : physiology and prosthesis

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    The retina is responsible for encoding different aspects of the visual world. Light enters the eyes and is converted by the photoreceptors into electrochemical signals. These signals are processed by the retinal network and proceed afferently to the brain via the axons of the retinal ganglion cells (RGCs). The RGCs outputs are in the form of action potentials (spikes), which encrypt the visual information in terms of spike shape, firing frequencies, and the firing patterns. When the photoreceptors are gone due to disease, vision is lost. The idea of a retinal prosthesis is to activate the surviving RGCs by electrical stimulation in order to recreate vision. In this thesis, I have studied the physiological properties of the RGCs, and reconstructed natural RGC spike trains by electrical stimulation. Chapter 1 introduces the anatomy of the retina and the retinal neurons. How the RGCs respond to light. Electrical stimulation is also discussed. A brief historical summary of the receptive field properties and cell physiology is also presented. Chapter 2 characterizes the intrinsic properties of 16 morphologically defined types of rat RGCs. The intrinsic properties include the biophysical properties due to morphology and dendritic stratification, in addition to physiological properties such as firing behaviours. These properties are also compared with the cat RGC intrinsic properties in order to investigate the variations between the morphologically similar RGCs of the two species. The results suggest that the RGCs among species, even with similar morphologies, do not have conservative intrinsic properties. Chapter 3 examines the details of the spiking properties of the different rat RGC types. Spikes are initiated at the axonal initial segment. A 'single' spike recorded at the soma consists of an axonal spike and a somatic spike. The existence of the two spikes can be recognized by two humps in the phase plot, and further revealed in the higher derivatives of the membrane potential. A principal component analysis shows that the parameters extracted from the phase plots are very useful for a model-independent rat RGC classification. Chapter 4 establishes the foundations for electrical stimulation of the retina. The question is to what extent optimum placement of the stimulating and reference electrodes might be affected by anatomical location. Here we placed the stimulating electrode above or below the retinal inner limiting membrane and found no statistical difference between the thresholds. In addition, reflective axonal spikes from the cut end are discussed. Chapter 5 combines the knowledge obtained in the previous chapters for the sole purpose of reproducing natural RGC outputs when using electrical stimulation. The light responses of the eye under saccadic movements were recorded and used to form the stimulus patterns. The reconstructions were performed on the brisk-transient (BT) and the brisk-sustained (BS) RGCs. Our results suggested that BT RGCs are more capable of following the stimulated stimulus patterns over a wide range of frequencies than the BS RGCs. Chapter 6 concludes the whole thesis

    Optimal electrical activation of retinal ganglion cells

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    Retinal prostheses are emerging as a viable therapy option for those blinded by degenerative eye conditions that destroy the photoreceptors of the retina but spare the retinal ganglion cells (RGCs). My research sought to address the issue of how a retinal prosthesis might best activate these cells by way of electrical stimulation. Whole-cell patch clamp recordings were made in explanted retinal wholemount preparations from normally-sighted rats. Stimulating electrodes were fabricated from nitrogen-doped ultra-nanocrystalline diamond (N-UNCD) and placed on the epiretinal surface, adjacent to the cell soma. Electrical stimuli were delivered against a distant monopolar return electrode. Using rectangular, biphasic constant current waveforms as employed by modern retinal prostheses, I examined which waveform parameters had the greatest effect on RGC activation thresholds. In a second set of experiments intracellular current injection was employed to assess the effectiveness of sinusoidal current waveforms in selectively activating different RGC subsets. These recordings were also used to validate a biophysical model of RGC activation. Where possible, recorded cells were identified and classified based on 3D confocal reconstruction of their morphology. Electrodes fabricated from N-UNCD were able to electrically activate RGCs while remaining well within the electrochemical limits of the material. They were found to exhibit high electrochemical stability and were resistant to morphological and electrochemical changes over one week of continuous pulsing at charge injection limits. Retinal ganglion cells invariably favoured cathodic-first biphasic current pulses of short first-phase duration, with a small interphase interval. The majority of cells (63\%) were most sensitive to a highly asymmetric waveform: a short-cathodic phase followed by a longer duration, lower amplitude anodic phase. Using the optimal interphase interval led to median charge savings of 14\% compared to the charge required in the absence of any inter-phase interval. Optimising phase duration resulted in median charge savings of 22\%. All RGCs became desensitised to repetitive electrical stimulation. The efficacy of a given stimulus delivered repeatedly decreased after the first stimulus, stabilising at a lower efficacy by the thirtieth pulse. This asymptotic efficacy decreased with increasing stimulus frequency. Cells with smaller somas and dendritic fields were better able to sustain repetitive activation at high frequency. Intracellular sinusoidal stimulation was used to demonstrate that certain RGC subsets, defined on the basis of morphological type, stratification, and size, were more responsive to high frequency stimulation. Simulated RGC responses were validated by experimental data, which confirmed that ON cell responses were heavily suppressed by stimulus frequencies of 20 Hz and higher. OFF cells, on the other hand, were able to sustain repetitive activation over all tested frequencies. Additional simulations suggest this difference may be plausibly attributed to the presence of low-voltage-activated calcium channels in OFF but not ON RGCs. The results of my work demonstrate that (a) N-UNCD is a suitable material for retinal prosthesis applications; (b) a careful choice of electrical waveform parameters can significantly improve prosthesis efficacy; and (c) it may be possible to bias neural activation for certain RGC populations by varying the frequency of stimulation

    Photogenetic Retinal Prosthesis

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    The last few decades have witnessed an immense effort to develop working retinal implants for patients suffering from retinal degeneration diseases such as retinitis pigmentosa. However, it is becoming apparent that this approach is unable to restore levels of vision that will be sufficient to offer significant improvement in the quality of life of patients. Herein, a new type of retinal prosthesis that is based on genetic expression of microbial light sensitive ion channel, Chanelrhodopsin-2 (ChR2), and a remote light stimulation is examined. First, the dynamics of the ChR2 stimulation is characterized and it is shown that (1) the temporal resolution of ChR2-evoked spiking is limited by a continuous drop in its depolarization efficiency that is due to (a) frequency-independent desensitization process and (b) slow photocurrent shutting, which leads to a frequency-dependent post-spike depolarization and (2) the ChR2 response to light can be accurately reproduced by a four-state model consisting of two interconnected branches of open and close states. Then, a stimulation prototype is developed and its functionality is demonstrated in-vitro. The prototype uses a new micro-emissive matrix which enables generating of two-dimensional stimulation patterns with enhanced resolution compared to the conventional retinal implants. Finally, based on the micro-emitters matrix, a new technique for sub-cellular and network-level neuroscience experimentations is shown. The capacity to excite sub-cellular compartments is demonstrated and an example utility to fast map variability in dendrites conductance is shown. The outcomes of this thesis present an outline and a first proof-of-concept for a future photogenetic retinal prosthesis. In addition, they provide the emerging optogenetic technology with a detailed analysis of its temporal resolution and a tool to expand its spatial resolution, which can have immediate high impact applications in modulating the activity of sub-cellular compartments, mapping neuronal networks and studying synchrony and plasticity effects

    Mediating Retinal Ganglion Cell Spike Rates Using High-Frequency Electrical Stimulation

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    Recent retinal studies have directed more attention to sophisticated stimulation strategies based on high-frequency (&gt;1.0 kHz) electrical stimulation (HFS). In these studies, each retinal ganglion cell (RGC) type demonstrated a characteristic stimulus-strength-dependent response to HFS, offering the intriguing possibility of focally targeting retinal neurons to provide useful visual information by retinal prosthetics. Ionic mechanisms are known to affect the responses of electrogenic cells during electrical stimulation. However, how these mechanisms affect RGC responses is not well understood at present, particularly when applying HFS. Here, we investigate this issue via an in silico model of the RGC. We calibrate and validate the model using an in vitro retinal preparation. An RGC model based on accurate biophysics and realistic representation of cell morphology, was used to investigate how RGCs respond to HFS. The model was able to closely replicate the stimulus-strength-dependent suppression of RGC action potentials observed experimentally. Our results suggest that spike inhibition during HFS is due to local membrane hyperpolarization caused by outward membrane currents near the stimulus electrode. In addition, the extent of HFS-induced inhibition can be largely altered by the intrinsic properties of the inward sodium current. Finally, stimulus-strength-dependent suppression can be modulated by a wide range of stimulation frequencies, under generalized electrode placement conditions. In vitro experiments verified the computational modeling data. This modeling and experimental approach can be extended to further our understanding on the effects of novel stimulus strategies by simulating RGC stimulus-response profiles over a wider range of stimulation frequencies and electrode locations than have previously been explored

    Analysis of Factors Affecting the Performance of Retinal Prostheses Using Finite Element Modelling of Electric Field Distribution in the Retina

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    This dissertation proposes a computational framework targeted at improving the design of currently employed retinal prostheses. The framework was used for analysing factors impacting the performance of prostheses in terms of electrical stimulation for retinal neurons, which might lead to a perception of pixelated vision. Despite their demonstrated effectiveness, the chronic and safe usage of these retinal prostheses in human and animal trials is jeopardised due to high stimulation thresholds. This is related to the distance between the stimulating electrodes and the retinal neurons resulting from the implantation procedure. The major goal of this dissertation was to evaluate the stimulation efficacy in current implantable planar microelectrode-based retinal prostheses and consequently demonstrate their weakness, thereby providing scope for the development of future implants. The effect of geometrical factors i.e., electrode-retina distance and electrode size on stimulation applied to the retina by retinal prostheses was studied. To this end, a finite element method based simulation framework to compute electric field distribution in the retina was constructed. An electrical model of the retina was an integral part of the framework, essentially represented by a resistivity profile of the multi-layered retina. The elements of a retinal prosthesis were modelled by incorporating realistic electrode sizes, an anatomical and electrical model of the retina, a precise positioning of stimulation and return electrodes and the location of the implant with respect to the retina representing the epiretinal and subretinal stimulation schemes. The simulations were carried out both in quasi-static and direct current (DC) modes. It was observed that electrode-electrolyte interface and tissue capacitance could be safely neglected in our model based on the magnitude of the applied voltage stimulus and frequencies under consideration. Therefore, all simulations were conducted in DC mode. Thresholds and lateral extents of the stimulation were computed for electrode sizes corresponding to existing and self-fabricated implants. The values and trends obtained were in agreement with experiments from literature and our collaborators at the les Hôpitaux Universitaires de Genève (HUG). In the subretinal stimulation scheme, the computed variation of impedance with electrode-retina distance correlated well with time varying in vivo impedance measurements in rats conducted in collaboration with the Institut de la Vision, INSERM, Paris. Finally, it was also reiterated that the currently employed retinal prostheses are not very efficient due to a significant distance between the stimulation electrode and the retinal cells. In addition, I present a new experimental technique for measuring the absolute and local resistivity profile in high-resolution along the retinal depth, based on impedance spectroscopy using a bipolar microprobe. This experiment was devised to extract the resistivity profile of an embryonic chick retina to construct an electrical model for the simulation framework to simulate in vitro retinal stimulation experiments conducted by HUG collaborators. We validated the capability of the technique in rat and embryonic chick retinas. In conclusion, the computational framework presented in this dissertation is more realistic than those found in literature, but represents only a preliminary step towards an accurate model of a real implantation scenario in vivo. The simulation results are in agreement with results from clinical trials in humans for epiretinal configuration (literature) and with in vitro results for epiretinal and subretinal stimulation applied to chick retinas (HUG). The developed simulation framework computes quantities that can form a reference for quality control during surgery while inserting implants in the eye and functionality checks by electrophysiologists. Furthermore, this framework is useful in deciding the specifications of stimulation electrodes such as optimal size, shape, material, array density, and the position of the reference electrode to name a few. The work presented here offers to aid in optimising retinal prostheses and implantation procedures for patients and eventually contributes towards improving their quality of life

    Information transmission in normal vision and optogenetically resensitised dystrophic retinas

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    Phd ThesisThe retina is a sophisticated image processing machine, transforming the visual scene as detected by the photoreceptors into a pattern of action potentials that is sent to the brain by the retinal ganglion cells (RGCs), where it is further processed to help us understand and navigate the world. Understanding this encoding process is important on a number of levels. First, it informs the study of upstream visual processing by elucidating the signals higher visual areas receive as input and how they relate to the outside world. Second, it is important for the development of treatments for retinal blindness, such as retinal prosthetics. In this thesis, I present work using multielectrode array (MEA) recordings of RGC populations from ex-vivo retinal wholemounts to study various aspects of retinal information processing. My results fall into two main themes. In the rst part, in collaboration with Dr Geo rey Portelli and Dr Pierre Kornprobst of INRIA, I use ashed gratings of varying spatial frequency and phase to compare di erent coding strategies that the retina might use. These results show that information is encoded synergistically by pairs of neurons and that, of the codes tested, a Rank Order Code based on the relative order of ring of the rst spikes of a population of neurons following a stimulus provides information about the stimulus faster and more e ciently than other codes. In the later parts, I use optogenetic stimulation of RGCs in congenitally blind retinas to study how visual information is corrupted by the spontaneous hyperactivity that arises as a result of photoreceptor degeneration. I show that by dampening this activity with the gap junction blocker meclofenamic acid, I can improve the signal-to-noise ratio, spatial acuity and contrast sensitivity of prosthetically evoked responses. Taken together, this work provides important insights for the future development of retinal prostheses

    Characterization of Retinal Ganglion Cell Responses to Electrical Stimulation Using White Noise

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    Retinitis pigmentosa and age-related macular degeneration are two leading causes of degenerative blindness. While there is still not a definitive course of treatment for either of these diseases, there is currently the world over, many different treatment strategies being explored. Of these various strategies, one of the most successful has been retinal implants. Retinal implants are microelectrode or photodiode arrays, that are implanted in the eye of a patient, to electrically stimulate the degenerating retina. Clinical trials have shown that many patients implanted with such a device, are able to regain a certain degree of functional vision. However, while the results of these ongoing clinical trials have been promising, there are still many technical challenges that need to be overcome. One of the biggest challenges facing present implants is the inability to preferentially stimulate different retinal pathways. This is because retinal implants use large-amplitude current or voltage pulses. This in turn leads to the indiscriminate activation of multiple classes of retinal ganglion cells (RGCs), and therefore, an overall reduction in the restored visual acuity. To tackle this issue, we decided to explore a novel stimulus paradigm, in which we present to the retina, a stream of smaller-amplitude subthreshold voltage pulses. By then correlating the retinal spikes to the stimuli preceding them, we calculate temporal input filters for various classes of RGCs, using a technique called spike-triggered averaging (STA). In doing this, we found that ON and OFF RGCs have electrical filters, which are very distinct from each other. This finding creates the possibility for the selective activation of the retina through the use of STA-based waveforms. Finally, using statistical models, we verify how well these temporal filters can predict RGC responses to novel electrical stimuli. In a broad sense, our work represents the successful application of systems engineering tools to retinal prosthetics, in an attempt to answer one of the field’s most difficult questions, namely selective stimulation of the retina
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