Electrical Stimulation Of Retina Research Articles

The direct influence of retinal degeneration on electrical stimulation efficacy: Significant implications for retinal prostheses.

Photoreceptor loss and inner retinal network remodeling severely impacts the ability of retinal prosthetic devices to create artificial vision. We developed a computational model of a degenerating retina based on rodent data and tested its response to retinal electrical stimulation. This model includes detailed network connectivity and diverse neural intrinsic properties, capable of exploring how the degenerated retina influences the performance of electrical stimulation during the degeneration process. Our model suggests the possibility of quantitatively modulating retinal ON and OFF pathways between phase II and III of retinal degeneration without requiring any differences between ON and OFF RGC intrinsic cellular properties. The model also provided insights about how remodeling events influence stage-dependent differential electrical responses of ON and OFF pathways.Clinical Relevance-This data-driven model can guide future development of retinal prostheses and stimulation strategies that may benefit patients at different stages of retinal disease progression, particularly in the early and mid-stages, thus increasing their global acceptance.

Nature-inspired saccadic-like electrical stimulation paradigm promotes sustained retinal ganglion cell responses by spatiotemporally alternating activation of contiguous multi-electrode patterns

Objective. Retinal electrical stimulation using multi-electrode arrays (MEAs) aims to restore visual object perception in blind patients. However, the rate and duration of the artificial visual sensations are limited due to the rapid response decay of the stimulated neurons. Hence, we investigated a novel nature-inspired saccadic-like stimulation paradigm (biomimetic) to evoke sustained retinal responses. For implementation, the macroelectrode was replaced by several contiguous microelectrodes and activated non-simultaneously but alternating topologically. Approach. MEAs with hexagonally arranged electrodes were utilized to simulate and record mouse retinal ganglion cells (RGCs). Two shapes were presented electrically using MEAs: a 6e-hexagon (six hexagonally arranged 10 µm electrodes; 6e-hexagon diameter: 80 µm) and a double-bar (180 µm spaced, 320 µm in length). Electrodes of each shape were activated in three different modes (simultaneous, circular, and biomimetic (‘zig-zag’)), stimulating at different frequencies (1–20 Hz). Main results. The biomimetic stimulation generated enhanced RGC responses increasing the activity rate by 87.78%. In the spatiotemporal context, the electrical representation of the 6e-hexagon produced sustained and local RGC responses (∼130 µm corresponding to ∼2.5° of the human visual angle) for up to 90 s at 10 Hz stimulation and resolved the electrically presented double-bar. In contrast, during conventional simultaneous stimulation, the responses were poor and declined within seconds. Similarly, the applicability of the biomimetic mode for retinal implants (7 × 8 pixels) was successfully demonstrated. An object shape impersonating a smile was presented electrically, and the recorded data were used to emulate the implant’s performance. The spatiotemporal pixel mapping of the activity produced a complete retinal image of the smile. Significance. The application of electrical stimulation in the biomimetic mode produced locally enhanced RGC responses with significantly reduced fading effects and yielded advanced spatiotemporal performance reflecting the presented electrode shapes in the mapped activity imprint. Therefore, it is likely that the RGC responses persist long enough to evoke visual perception and generate a seamless image, taking advantage of the flicker fusion. Hence, replacing the implant’s macroelectrodes with microelectrodes and their activation in a topologically alternating biomimetic fashion may overcome the patient’s perceptual image fading, thereby enhancing the spatiotemporal characteristics of artificial vision.

Transcorneal Electrical Stimulation Induces Long-Lasting Enhancement of Brain Functional and Directional Connectivity in Retinal Degeneration Mice.

To investigate neuromodulation of functional and directional connectivity features in both visual and non-visual brain cortices after short-term and long-term retinal electrical stimulation in retinal degeneration mice. We performed spontaneous electrocorticography (ECoG) in retinal degeneration (rd) mice following prolonged transcorneal electrical stimulation (pTES) at varying currents (400, 500 and 600 μA) and different time points (transient or day 1 post-stimulation, 1-week post-stimulation and 2-weeks post-stimulation). We also set up a sham control group of rd mice which did not receive any electrical stimulation. Subsequently we analyzed alterations in cross-frequency coupling (CFC), coherence and directional connectivity of the primary visual cortex and the prefrontal cortex. It was observed that the sham control group did not display any significant changes in brain connectivity across all stages of electrical stimulation. For the stimulated groups, we observed that transient electrical stimulation of the retina did not significantly alter brain coherence and connectivity. However, for 1-week post-stimulation, we identified enhanced increase in theta-gamma CFC. Meanwhile, enhanced coherence and directional connectivity appeared predominantly in theta, alpha and beta oscillations. These alterations occurred in both visual and non-visual brain regions and were dependent on the current amplitude of stimulation. Interestingly, 2-weeks post-stimulation demonstrated long-lasting enhancement in network coherence and connectivity patterns at the level of cross-oscillatory interaction, functional connectivity and directional inter-regional communication between the primary visual cortex and prefrontal cortex. Application of electrical stimulation to the retina evidently neuromodulates brain coherence and connectivity of visual and non-visual cortices in retinal degeneration mice and the observed alterations are largely maintained. pTES holds strong possibility of modulating higher cortical functions including pathways of cognition, awareness, emotion and memory.

Modulation of narrowband and broadband gamma connectivity in retinal degeneration mice according to electrical stimulation pulse width

Brain connectivity involves the structural, functional and effective communication between neurons across brain regions and is expressed in neuronal oscillations. Previous research has reported the evidence of two types of gamma oscillations namely the broadband gamma (30 Hz - 90 Hz) and narrowband gamma (55 Hz - 70 Hz) oscillations which have been implicated in excitatory and inhibitory network transmission. There is presently no systematic investigation of the relationship between electrical stimulation pulse width and narrow or broadband gamma oscillations in visual-deficient mice. In the current study, we set out to bridge this gap in knowledge by exploring the modulation of brain connectivity indices in broadband gamma and narrowband gamma oscillations in response to varying electrical stimulation pulse width in retinal degeneration (rd) mice. The results revealed that a low pulse width (0.5 ms/phase) strongly enhances coherence and directional connectivity of broadband and narrowband gamma oscillations in contra visual cortex and contra prefrontal cortex of rd mice. This study serves a crucial role in the design and utilisation of visual prostheses by contributing to the understanding of information transmission between different brain regions under retinal electrical stimulation in visual-deficit population.

Modulation of narrowband and broadband gamma connectivity in retinal degeneration mice according to electrical stimulation pulse width

Brain connectivity involves the structural, functional and effective communication between neurons across brain regions and is expressed in neuronal oscillations. Previous research has reported the evidence of two types of gamma oscillations namely the broadband gamma (30 Hz - 90 Hz) and narrowband gamma (55 Hz - 70 Hz) oscillations which have been implicated in excitatory and inhibitory network transmission. There is presently no systematic investigation of the relationship between electrical stimulation pulse width and narrow or broadband gamma oscillations in visual-deficient mice. In the current study, we set out to bridge this gap in knowledge by exploring the modulation of brain connectivity indices in broadband gamma and narrowband gamma oscillations in response to varying electrical stimulation pulse width in retinal degeneration (rd) mice. The results revealed that a low pulse width (0.5 ms/phase) strongly enhances coherence and directional connectivity of broadband and narrowband gamma oscillations in contra visual cortex and contra prefrontal cortex of rd mice. This study serves a crucial role in the design and utilisation of visual prostheses by contributing to the understanding of information transmission between different brain regions under retinal electrical stimulation in visual-deficit population.

Computational Modeling of Spatially Selective Retinal Stimulation With Temporally Interfering Electric Fields.

Retinal electrical stimulation is a widely utilized method to restore visual function for patients with retinal degenerative diseases. Transcorneal electrical stimulation (TES) represents an effective way to improve the visual function due to its potential neuroprotective effect. However, TES with single electrode fails to spatially and selectively stimulate retinal neurons. Herein, a computational modeling method was proposed to explore the feasibility of spatially selective retinal stimulation via temporally interfering electric fields. An eyeball model with multiple electrodes was constructed to simulate the interferential electric fields with various electrode montages and current ratios. The results demonstrated that the temporal interference (TI) stimulation would gradually generate an increasingly localized high-intensity region on retina as the return electrodes moved towards the posterior of the eyeball and got closer. Additionally, the position of the convergent region could be modulated by regulating the current ratio of different electrode channels. The TI strategy with multisite and steerable stimulation can stimulate local retinal region with certain convergence and a relatively large stimulation range, which would be a feasible approach for the spatially selective retinal neuromodulation.

Retinal neurovascular responses to transcorneal electrical stimulation measured with optical coherence tomography.

Noninvasive transcorneal electrical stimulation (TES) has emerged as a potential strategy to facilitate visual restoration and promote retinal cell survival for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the neurovascular responses of retinal neurons evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses under TES in vivo simultaneously. Significant increases of both positive and negative intrinsic optical signal (IOS) changes were recorded in all three segmented retinal layers, which mainly related to neural activities. However, the changes of TES-induced retinal vascular responses, including blood velocity, cross-sectional area of vessel, and blood flow, were not significant. It suggests that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling under TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal stimulation in clinical treatment and technology. Impact statement Noninvasive transcorneal electrical stimulation (TES) has emerged as an effective treatment for certain retinal and optic nerve diseases owing to its neuroprotective effects. However, the retinal neurovascular responses evoked by TES have not been completely determined. To investigate this issue, we utilized a custom-designed spectral-domain optical coherence tomography (SD-OCT) to record the retinal neural and vascular responses evoked by TES in vivo simultaneously. The present study suggested that TES mainly elicited neural responses in retina, while no significant vascular responses were evoked. Our results provide experimental evidence to the mechanism of retinal neurovascular coupling evoked by TES. Additionally, the present study also suggests that SD-OCT could be utilized as a promoting method to explore neurovascular responses under retinal electrical stimulation.

Biomedical Applications: Ultrasound‐Induced Wireless Energy Harvesting for Potential Retinal Electrical Stimulation Application (Adv. Funct. Mater. 33/2019)

Biomedical Applications: Ultrasound‐Induced Wireless Energy Harvesting for Potential Retinal Electrical Stimulation Application (Adv. Funct. Mater. 33/2019)

Optimizing Stimulation Strategies for Retinal Electrical Stimulation: a Modelling Study.

In this research, a continuum multi-compartmental model of retinal electrical stimulation was utilized to find the best strategy for activating retinal ganglion cells (RGCs). Two types of return electrodes configuration placed suprachoroidally were used: monopolar and hexapolar. The current was delivered either simultaneously or sequentially with two kinds of waveforms: biphasic symmetric charge-balanced cathodic and anodic first pulses. Our results revealed there is no significant difference in current threshold between single monopolar and hexapolar stimulation regardless of the applied current stimulus waveform. Moreover, sequential stimulation for both monopolar or hexapolar was more effective in reducing current threshold than simultaneous stimulation when biphasic cathodic first pulses were used. Concurrent monopolar stimulation was significant in reducing the current threshold compared to single monopolar whereas concurrent hexapolar did not alter the current threshold. Overall, concurrent monopolar stimulation was efficacious in reducing current threshold regardless of the stimulus waveforms and sequential stimulation was more useful only with biphasic cathodic first pulses.

Ultrasound‐Induced Wireless Energy Harvesting for Potential Retinal Electrical Stimulation Application

AbstractRetinal electrical stimulation for people with neurodegenerative diseases has shown to be feasible for direct excitation of neurons as a means of restoring vision. In this work, a new electrical stimulation strategy is proposed using ultrasound‐driven wireless energy harvesting technology to convert acoustic energy to electricity through the piezoelectric effect. The design, fabrication, and performance of a millimeter‐scale flexible ultrasound patch that utilizes an environment‐friendly lead‐free piezocomposite are described. A modified dice‐and‐fill technique is used to manufacture the microstructure of the piezocomposite and to generate improved electrical and acoustic properties. The as‐developed device can be attached on a complex surface and be driven by ultrasound to produce adjustable electrical outputs, reaching a maximum output power of 45 mW cm−2. Potential applications for charging energy storage devices and powering commercial electronics using the device are demonstrated. The considerable current signals (e.g., current >72 µA and current density >9.2 nA µm−2) that are higher than the average thresholds of retinal stimulation are also obtained in the ex vivo experiment of an implanted environment, showing great potential to be integrated on implanted biomedical devices for electrical stimulation application.

Retinotopic Responses in the Visual Cortex Elicited by Epiretinal Electrical Stimulation in Normal and Retinal Degenerate Rats.

PurposeElectronic retinal prostheses restore vision in people with outer retinal degeneration by electrically stimulating the inner retina. We characterized visual cortex electrophysiologic response elicited by electrical stimulation of retina in normally sighted and retinal degenerate rats.MethodsNine normally sighted Long Evans and 11 S334ter line 3 retinal degenerate (rd) rats were used to map cortical responses elicited by epiretinal electrical stimulation in four quadrants of the retina. Six normal and six rd rats were used to compare the dendritic spine density of neurons in the visual cortex.ResultsThe rd rats required higher stimulus amplitudes to elicit responses in the visual cortex. The cortical electrically evoked responses (EERs) for both healthy and rd rats show a dose-response characteristic with respect to the stimulus amplitude. The EER maps in healthy rats show retinotopic organization. For rd rats, cortical retinotopy is not well preserved. The neurons in the visual cortex of rd rats show a 10% higher dendritic spine density than in the healthy rats.ConclusionsCortical activity maps, produced when epiretinal stimulation is applied to quadrants of the retina, exhibit retinotopy in normal but not rd rats. This is likely due to a combination of degeneration of the retina and increased stimulus thresholds in rd, which broadens the activated area of the retina.Translational RelevanceLoss of retinotopy is evident in rd rats. If a similar loss of retinotopy is present in humans, retinal prostheses design must include flexibility to account for patient specific variability.

Retinal Prostheses

Artificial vision is restoring sight by electrical stimulation of the visual system at the level of retina, optic nerve, lateral geniculate body, or occipital cortex. The development of artificial vision began with occipital cortex prosthesis; however, retinal prosthesis has advanced faster in recent years. Currently, multiple efforts are focused on finding the optimal approach for restoring vision through an implantable retinal microelectrode array system. Retinal prostheses function by stimulating the inner retinal neurons that survive retinal degeneration. In these devices, the visual information, gathered by a light detector, is transformed into controlled patterns of electrical pulses, which are in turn delivered to the surviving retinal neurons by an electrode array. Retinal prostheses are classified based on where the stimulating array is implanted (ie, epiretinal, subretinal, suprachoroidal, or episcleral). Recent regulatory approval of 2 retinal prostheses has greatly escalated interest in the potential of these devices to treat blindness secondary to outer retinal degeneration. This review will focus on the technical and operational features and functional outcomes of clinically tested retinal prostheses. We will discuss the major barriers and some of the more promising solutions to improve the outcomes of restoring vision with electrical retinal stimulation.

The Spatial Extent of Epiretinal Electrical Stimulation in the Healthy Mouse Retina

Background/Aims: Retinal prostheses use electrical stimulation to restore functional vision to patients blinded by retinitis pigmentosa. A key detail is the spatial pattern of ganglion cells activated by stimulation. Therefore, we characterized the spatial extent of network-mediated electrical activation of retinal ganglion cells (RGCs) in the epiretinal monopolar electrode configuration. Methods: Healthy mouse RGC activities were recorded with a micro-electrode array (MEA). The stimuli consisted of monophasic rectangular cathodic voltage pulses and cycling full-field light flashes. Results: Voltage tuning curves exhibited significant hysteresis, reflecting adaptation to electrical stimulation on the time scale of seconds. Responses decreased from 0 to 300 µm, and were also dependent on the strength of stimulation. Applying the Rayleigh criterion to the half-width at half-maximum of the electrical point spread function suggests a visual acuity limit of no better than 20/946. Threshold voltage showed only a modest increase across these distances. Conclusion: The existence of significant hysteresis requires that future investigations of electrical retinal stimulation control for such long-memory adaptation. The spread of electrical activation beyond 200 µm suggests that neighbouring electrodes in epiretinal implants based on indirect stimulation of RGCs may be indiscriminable at interelectrode spacings as large as 400 µm.

Retinal and Cortical Activation by Electrical Stimulation with Retina Implants

In Germany, about 30,000 to 40,000 people suffer from retinitis pigmentosa (RP), which ultimately results in blindness. The only aid to blind RP patients are retinal implants: These have been under development for several years and have now been approved as a medical product. Retinal implants produce visual perceptions in response to electrical stimulation of the degenerated retina and are useful in the everyday life of blind people. However, the currently achievable quality of vision is such that people with a retinal implant are still legally blind. The visual quality that can be achieved with epi- and subretinal implants depends not only on patient-specific factors such as individual history and status of retinal degeneration, but especially on the interface between implant and retina and the quality of the achievable neuronal activation. Biophysical approaches to functional improvements of the implants are founded on the physiology of the retina (cell density, intraretinal interconnections), are based on technical optimisation of the interface (electrode materials, size and density), and exploit the stimulation protocols with which visual information is fed into the degenerated retina (time courses of electrical stimuli, spatiotemporal stimulation pattern). Optimisation of stimulation parameters can be supported by a detailed analysis of cortical responses, with appropriate electrophysiological and optical methods. This article looks at both the physiological and biophysical fundamentals of electrical retinal stimulation, as well as the resulting retinal and cortical activation.

Effects of different three-dimensional electrodes on epiretinal electrical stimulation by modeling analysis.

BackgroundEpiretinal prostheses have been greatly successful in helping restore the vision of patients blinded by retinal degenerative diseases. The design of stimulating electrodes plays a crucial role in the performance of epiretinal prostheses. The objective of this study was to investigate, through computational modeling analysis, the effects on the excitation of retinal ganglion cells (RGCs) when different three-dimensional (3-D) electrodes were placed in the epiretinal space.Methods3-D finite element models of retinal electrical stimulation were created in COMSOL using a platinum microelectrode, a vitreous body, multi-layered retinal tissue, and retinal pigment epithelium (RPE). Disk and non-planar electrodes with different 3-D structures were used in the epiretinal electrical stimulation. In addition, a multi-RGC model including ionic mechanisms was constructed in NEURON to study the excitability of RGCs in response to epiretinal electrical stimulation by different types of electrodes. Threshold current, threshold charge density, and the activated RGC area were the three key factors used to evaluate the stimulating electrode’s performance.ResultsAs the electrode-retina distance increased, both threshold current and threshold charge density showed an approximately linear relationship. Increasing the disk electrode’s diameter resulted in an increase in threshold current and a decrease in threshold charge density. Non-planar electrodes evoked different activation responses in RGCs than the disk electrode. Concave electrodes produced superior stimulation localization and electrode safety while convex electrodes performed relatively poorly.ConclusionsInvestigation of epiretinal electrical stimulation using different 3-D electrodes would further the optimization of electrode design and help improve the performance of epiretinal prostheses. The combination of finite element analysis in COMSOL and NEURON software provides an efficient way to evaluate the influences of various 3-D electrodes on epiretinal electrical stimulation. Non-planar electrodes had larger threshold currents than disk electrodes. Of the five types of electrodes, concave hemispherical electrodes may be the ideal option, considering their superior stimulation localization and electrode safety.

A 3D-continuum bidomain model of retinal electrical stimulation using an anatomically detailed mesh.

A continuum bidomain model of sub-retinal electrical stimulation on an anatomically detailed mesh of retina is presented. The underlying geometry is made up of 256 B-scans of optical coherence tomography (OCT) images of a healthy human retina, covering approximately 6×2 mm(2) centered on the macula. The OCT images are initially segmented and digitized into five major retinal layers comprising passive and active retinal cell types. This computational mesh is then used to model a subretinal hexapolar biphasic electrical stimulation. Our results indicate that the ultra-structure of the retina results in an asymmetric spatial extracellular potential distribution, leading to an irregular pattern of retinal ganglion cell activation. This finding is in contrast to focal circular activation previously reported in retinal electrical stimulation modeling with a uniform mesh.

Safety and efficacy of explanting or replacing suprachoroidal electrode arrays in a feline model.

A key requirement for retinal prostheses is the ability for safe removal or replacement. We examined whether suprachoroidal electrode arrays can be removed or replaced after implantation. Suprachoroidal electrode arrays were unilaterally implanted into 13 adult felines. After 1 month, arrays were surgically explanted (n = 6), replaced (n = 5) or undisturbed (n = 2). The retina was assessed periodically using fundus photography and optical coherence tomography. Three months after the initial implantation, the function of replaced or undisturbed arrays was assessed by measuring the responses of the visual cortex to retinal electrical stimulation. The histopathology of tissues surrounding the implant was examined. Array explantation or replacement was successful in all cases. Fundus photography showed localized disruption to the tapetum lucidum near the implant's tip in seven subjects following implantation. Although optical coherence tomography showed localized retinal changes, there were no widespread statistically significant differences in the thickness of the retinal layers or choroid. The distance between the electrodes and retina increased after device replacement but returned to control values within eight weeks (P < 0.03). Staphylomas developed near the scleral wound in five animals after device explantation. Device replacement did not alter the cortical evoked potential threshold. Histopathology showed localized outer nuclear layer thinning, tapetal disruption and pseudo-rosette formation, but the overall retinal morphology was preserved. It is feasible to remove or replace conformable medical grade silicone electrode arrays implanted suprachoroidally. The scleral wound requires careful closure to minimize the risk of staphylomas.

Preservation of retinotopic map in retinal degeneration

Retinal degenerations trigger the loss of photoreceptors and cause the remaining de-afferented neural retina to undergo remodeling. Concerns over this potential retinal synaptic reorganization following visual loss have raised questions regarding the usefulness of visual restoration via retinal electrical stimulation. We have used quantitative positron emission tomography (PET) and 2-deoxy-2-[18F]fluoro-d-glucose (FDG) to objectively evaluate the connection between the retina and the primary visual cortex under both light and transcorneal electrical stimulation (TcES) in five subjects with retinal degeneration (RD) who have had more than ten years of light-perception-only best visual acuity and five age-matched normal-sighted controls. All subjects underwent quantitative PET with FDG as the metabolic tracer during stimulation of the right eye under both light stimulation condition and transcorneal electrical stimulation (TcES) using ERG-Jet contact lens electrode. Cortical activation maps from each stimulation condition were obtained using statistical parametric mapping. TcES phosphene threshold current and qualitative visual cortex activation from both stimulation conditions were compared between the two subject groups. Average phosphene threshold current was 0.72 ± 0.18 mA for the five normal-sighted controls and 3.08 ± 2.01 mA for the retinal degenerative subjects. Phosphene threshold current was significantly higher in retinal degenerative subjects compared to normal-sighted controls (p < 0.05). We found both light stimulation and TcES resulted in retinotopically mapped primary visual cortex activation in both groups. In addition, the patterns of early visual area activation between the two subject groups are more similar during TcES than light stimulation. Our findings suggest primary visual cortex continues to maintain its retinotopy in RD subjects despite prolonged visual loss.

Vision Rehabilitation by Electrical Retinal Stimulation: Review of Microelectrode Approaches

Vision Rehabilitation by Electrical Retinal Stimulation: Review of Microelectrode Approaches

A continuum model of retinal electrical stimulation**This paper was originally submitted for the special issue containing contributions from the Sixth Biennial Research Congress of The Eye and the Chip.

A continuum mathematical model of retinal electrical stimulation is described. The model is represented by a passive vitreous domain, a thin layer of active retinal ganglion cell (RGC) tissue adjacent to deeper passive neural layers of the retina, the retinal pigmented epithelium (RPE) and choroid thus ending at the sclera. To validate the model, in vitro epiretinal responses to stimuli from 50 µm disk electrodes, arranged in a hexagonal mosaic, were recorded from rabbit retinas. 100 µs/phase anodic-first biphasic current pulses were delivered to the retinal surface in both the mathematical model and experiments. RGC responses were simulated and recorded using extracellular microelectrodes. The model's epiretinal thresholds compared favorably with the in vitro data. In addition, simulations showed that single-return bipolar electrodes recruited a larger area of the retina than twin-return or six-return electrodes arranged in a hexagonal layout in which a central stimulating electrode is surrounded by six, eqi-spaced returns. Simulations were also undertaken to investigate the patterns of RGC activation in an anatomically-accurate model of the retina, as well as RGC activation patterns for subretinal and suprachoroidal bipolar stimulation.