Temporal structure in spiking patterns of ganglion cells defines perceptual thresholds in rodents with subretinal prosthesis.

Subretinal prostheses are designed to restore sight in patients blinded by retinal degeneration using electrical stimulation of the inner retinal neurons. To relate retinal output to perception, we studied behavioral thresholds in blind rats with photovoltaic subretinal prostheses stimulated by full-field pulsed illumination at 20 Hz, and measured retinal ganglion cell (RGC) responses to similar stimuli ex-vivo. Behaviorally, rats exhibited startling response to changes in brightness, with an average contrast threshold of 12%, which could not be explained by changes in the average RGC spiking rate. However, RGCs exhibited millisecond-scale variations in spike timing, even when the average rate did not change significantly. At 12% temporal contrast, changes in firing patterns of prosthetic response were as significant as with 2.3% contrast steps in visible light stimulation of healthy retinas. This suggests that millisecond-scale changes in spiking patterns define perceptual thresholds of prosthetic vision. Response to the last pulse in the stimulation burst lasted longer than the steady-state response during the burst. This may be interpreted as an excitatory OFF response to prosthetic stimulation, and can explain behavioral response to decrease in illumination. Contrast enhancement of images prior to delivery to subretinal prosthesis can partially compensate for reduced contrast sensitivity of prosthetic vision

Photovoltaic restoration of sight with high visual acuity

Patients with retinal degeneration lose sight due to the gradual demise of photoreceptors. Electrical stimulation of surviving retinal neurons provides an alternative route for the delivery of visual information. We demonstrate that subretinal implants with 70-μm-wide photovoltaic pixels provide highly localized stimulation of retinal neurons in rats. The electrical receptive fields recorded in retinal ganglion cells were similar in size to the natural visual receptive fields. Similarly to normal vision, the retinal response to prosthetic stimulation exhibited flicker fusion at high frequencies, adaptation to static images and nonlinear spatial summation. In rats with retinal degeneration, these photovoltaic arrays elicited retinal responses with a spatial resolution of 64 ± 11 μm, corresponding to half of the normal visual acuity in healthy rats. The ease of implantation of these wireless and modular arrays, combined with their high resolution, opens the door to the functional restoration of sight in patients blinded by retinal degeneration

A model of ganglion axon pathways accounts for percepts elicited by retinal implants.

Degenerative retinal diseases such as retinitis pigmentosa and macular degeneration cause irreversible vision loss in more than 10 million people worldwide. Retinal prostheses, now implanted in over 250 patients worldwide, electrically stimulate surviving cells in order to evoke neuronal responses that are interpreted by the brain as visual percepts ('phosphenes'). However, instead of seeing focal spots of light, current implant users perceive highly distorted phosphenes that vary in shape both across subjects and electrodes. We characterized these distortions by asking users of the Argus retinal prosthesis system (Second Sight Medical Products Inc.) to draw electrically elicited percepts on a touchscreen. Using ophthalmic fundus imaging and computational modeling, we show that elicited percepts can be accurately predicted by the topographic organization of optic nerve fiber bundles in each subject's retina, successfully replicating visual percepts ranging from 'blobs' to oriented 'streaks' and 'wedges' depending on the retinal location of the stimulating electrode. This provides the first evidence that activation of passing axon fibers accounts for the rich repertoire of phosphene shape commonly reported in psychophysical experiments, which can severely distort the quality of the generated visual experience. Overall our findings argue for more detailed modeling of biological detail across neural engineering applications

Retinal drug delivery: rethinking outcomes for the efficient replication of retinal behavior

The retina is a highly organized structure that is considered to be "an approachable part of the brain." It is attracting the interest of development scientists, as it provides a model neurovascular system. Over the last few years, we have been witnessing significant development in the knowledge of the mechanisms that induce the shape of the retinal vascular system, as well as knowledge of disease processes that lead to retina degeneration. Knowledge and understanding of how our vision works are crucial to creating a hardware-adaptive computational model that can replicate retinal behavior. The neuronal system is nonlinear and very intricate. It is thus instrumental to have a clear view of the neurophysiological and neuroanatomic processes and to take into account the underlying principles that govern the process of hardware transformation to produce an appropriate model that can be mapped to a physical device. The mechanistic and integrated computational models have enormous potential toward helping to understand disease mechanisms and to explain the associations identified in large model-free data sets. The approach used is modulated and based on different models of drug administration, including the geometry of the eye. This work aimed to review the recently used mathematical models to map a directed retinal network.The authors acknowledge the financial support received from the Portuguese Science and Technology Foundation (FCT/MCT) and the European Funds (PRODER/COMPETE) for the project UIDB/04469/2020 (strategic fund), co-financed by FEDER, under the Partnership Agreement PT2020. The authors also acknowledge FAPESP – São Paulo Research Foundation, for the financial support for the publication of the article.info:eu-repo/semantics/publishedVersio

Zapping the Retina - Understanding electrical responsiveness and electrical desensitization in mouse retinal ganglion cells

The field of science and technology has come a long way since the famous 70’s science fiction series “The Six Million Dollar Man,” where a disabled pilot was transformed into a bionic superhero after receiving artificial implants. What was indeed once a science fiction has now turned into a science fact with the development of various electronic devices interfacing the human neurons in the brain, retina, and limbs. One such advancement was the development of retinal implants. Over the past two decades, the field of retinal prosthetics has made significant advancement in restoring functional vision in patients blinded by diseases such as Retinitis pigmentosa (RP) and Age-related macular degeneration (AMD). RP and AMD are the two leading cause of degenerative blindness. While there is still no definitive cure for either of these diseases, various treatment strategies are currently being explored. Of the various options, the most successful one has been the retinal implants. Retinal implants are small microelectrode or photodiode arrays, which are implanted in the eye of a patient, to stimulate the degenerating retina electrically. They are broadly classified into three types depending on the placement ̶ epiretinal (close proximity to retinal ganglion cells, RGCs) , subretinal (close proximity to bipolar cells, BP) and suprachoroidal (close proximity to choroid). While the ongoing human trials have shown promising results, there remains a considerable variability among patients concerning the quality of visual percepts which limits the working potential of these implants. One such limitation often reported by the implanted patients is “ fading” of visual percepts. Fading refers to the limited ability to elicit temporally stable visual percepts. While, this is not a primary concern for epiretinal implants , it is often observed in subretinal and suprachoroidal implants which use the remaining retinal network to control the temporal spiking pattern of the ganglion cells. The neural correlate of fading is often referred to as “electrical desensitization”, which is the reduction of ganglion cell responses to repetitive electrical stimulation . While much is known about the temporal component of desensitization ( time constant, τ), the spatial aspects (space constant, λ) has not been well characterized. Further, how both these aspects interact to generate spiking responses, remains poorly understood. These crucial questions formed the critical components of my thesis. To address these questions, we stimulated the retinal network electrically, with voltage and current pulses and recorded the corresponding spiking activity using the microelectrode arrays (MEAs). While addressing the primary question of my thesis, we were able to address few idiosyncrasies which has currently stymied the field of retinal prosthetics. At a conceptual level, we have developed an experimental and analysis framework by which one can identify the single stimulus that will activate the most ganglion cells (Chapter 2, Part 1). This stimulus is optimal for ‘blind’ experiments where the specific response properties of each cell are unknown. Furthermore, we attempted to understand the correspondence between the electrical response patterns and visual response types (Chapter 2, Part2). In Chapter 3, we sought to understand better how the visual responses parameters change during ongoing electrical stimulation. We demonstrated that apart from the adaptation occurring due to visual stimulation and invitro experimental conditions, the electrical stimulation alters the RGC visual responses, suggesting the requirement for stimulation-induced changes to be incorporated in the designing of stimulation paradigms for the implant. Finally addressing the primary question (Chapter 4) of my thesis with which we started, we were able to demonstrate, that the electrical desensitization requires the interaction of both time and distance and is not a global phenomenon of the retina. In the final chapter (Chapter 5) we summarize the results of the thesis, discuss the key outcomes and its relevance to the prosthetic field and other vision restoration strategies and the potential future directions of this research. Therefore, in future, to improve the efficacy of retinal prostheses and patient outcomes, it is crucial to have an in-depth understanding of the responsiveness of the retinal circuitry to electrical stimulation

Simulating and optimizing electrical current flow and neuronal activation in retinal implants

© 2018 Dr Timothy Bede Esler[Abstract Withheld

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

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

Information processing in a midbrain visual pathway

Visual information is processed in brain via the intricate interactions between neurons. We investigated a midbrain visual pathway: optic tectum and its isthmic nucleus) that is motion sensitive and is thought as part of attentional system. We determined the physiological properties of individual neurons as well as their synaptic connections with intracellular recordings. We reproduced the center-surround receptive field structure of tectal neurons in a dynamical recurrent feedback loop. We reveal in a computational model that the anti-topographic inhibitory feedback could mediate competitive stimulus selection in a complex visual scene. We also investigated the dynamics of the competitive selection in a rate model. The isthmotectal feedback loop gates the information transfer from tectum to thalamic rotundus. We discussed the role of a localized feedback projection in contributing to the gating mechanisms with both experimental and numerical approaches. We further discussed the dynamics of the isthmotectal system by considering the propagation delays between different components. We conclude that the isthmotectal system is involved in attention-like competitive stimulus selection and control the information coding in the motion sensitive SGC-I neurons by modulating the retino-tectal synaptic transmission

Neutral coding - A report based on an NRP work session

Neural coding by impulses and trains on single and multiple channels, and representation of information in nonimpulse carrier