Towards Controlling Functionally-Distinct Retinal Ganglion Cells In Degenerate Retina

Muralidharan, Madhuvanthi; Guo, Tianruo; Shivdasani, Mohit N.; Tsai, David; Fried, Shelley I.; Cameron, Morven A.; Morley, John W.; Dokos, Socrates; Lovell, Nigel H.

doi:10.1109/embc44109.2020.9176595

Cited by 4 publications

(4 citation statements)

References 17 publications

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“…Specifically, OFF α‐S cells were activated at 20–100 µA across all frequencies, whereas OFF α‐T's exhibited activation between 150 and 240 µA at 1 kHz and ON α‐T's between 180 and 240 µA between 4 and 6 kHz. The ability to preferentially target ON versus OFF RGCs using amplitude‐modulated high‐frequency stimuli also persisted within rd1 mice in the presence of synaptic blockers, [ 81 ] suggesting the potential efficacy of this strategy for use in models of retinal degeneration. As these studies did not take into account the specific location of these cells along the nasal–temporal/dorsal–ventral axis of the mouse visual field, it remains an open question whether preferential stimulation parameters vary across regions of the retina where the morphology of RGCs within a single type has been shown to vary.…”

Section: Physiological Studies Exploring the Direct Activation Of Rgc...mentioning

confidence: 99%

Morphological Factors that Underlie Neural Sensitivity to Stimulation in the Retina

Raghuram

Werginz

Fried

et al. 2021

Advanced NanoBiomed Research

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Retinal prostheses are a promising therapeutic intervention for patients afflicted by outer retinal degenerative diseases such as retinitis pigmentosa and age‐related macular degeneration. Although significant advances in the development of retinal implants have been made, the quality of vision elicited by these devices remains largely suboptimal. The variability in the responses produced by retinal devices is most likely due to the differences between the natural cell‐type‐specific signaling that occur in the healthy retina versus the nonspecific activation of multiple cell types arising from artificial stimulation. To replicate these natural signaling patterns, stimulation strategies must be capable of preferentially activating specific retinal ganglion cell (RGC) types. To design more selective stimulation strategies, a better understanding of the morphological factors that underlie the sensitivity to prosthetic stimulation must be developed. Herein, the role that different anatomical components play in driving the direct activation of RGCs by extracellular stimulation is focused on. Briefly, 1) the variability in morphological properties of α‐RGCs is characterized, 2) the influence of morphology on the direct activation of RGCs by electric stimulation is detailed, and 3) some of the potential biophysical mechanisms that could explain differences in activation thresholds and electrically evoked responses between RGC types are described.

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Section: Physiological Studies Exploring the Direct Activation Of Rgc...mentioning

confidence: 99%

Morphological Factors that Underlie Neural Sensitivity to Stimulation in the Retina

Raghuram

Werginz

Fried

et al. 2021

Advanced NanoBiomed Research

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“…Retinal networks undergo significant remodelling during degenerative disease [50,[66][67][68][69]. These retinal network changes may influence the RGC responses to electrical stimulation, and biophysical mechanisms underlying the RGC responses in degenerative retina are still an open question [70][71][72][73][74][75]. In particular, an immunohistochemical study in human RP [69] discovered the extensive neuronal class switching between functionallydistinct bipolar cells in degenerated retina.…”

Section: Limitations and Future Workmentioning

confidence: 99%

“…Another potential limitation of our model is the lack of biological diversity in RGC intrinsic and morphological properties. RGCs can respond differentially to electrical stimulation purely due to their intrinsic and physical differences [43,49,71,[80][81][82][83][84][85][86][87]. More accurate model predictions can be achieved by including biological diversity in RGC intrinsic properties in the future work.…”

Section: Limitations and Future Workmentioning

confidence: 99%

Creation of virtual channels in the retina using synchronous and asynchronous stimulation—a modelling study

et al. 2020

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Objective. The spatial resolution of an implantable neural stimulator can be improved by creation of virtual channels (VCs). VCs are commonly achieved through synchronized stimulation of multiple electrodes. It remains unknown whether asynchronous stimulation is able to generate comparable VC performance in retinal stimulation, and how VC can be optimized by re-designing stimulation settings. This study begins with exploring the feasibility of creating VCs using synchronous and asynchronous epiretinal stimulation, and ending with predicting the possible VC performance with a thorough exploration of stimulation parameter space. Approach. A computational model of epiretinal dual-electrode stimulation is developed to simulate the neural activity of a population of retinal ganglion cells (RGCs) under both synchronous and asynchronous stimulation conditions. The interaction between the electrode and RGCs under a range of stimulation parameters are simulated. Main results. Our simulation based on direct RGC activation suggests that VCs can be created using asynchronous stimulation. Two VC performance measures: 1) linearity in the change in centroid location of activated RGC populations, and 2) consistency in the size of activated RGC populations, have comparable performance under asynchronous and synchronous stimulation with appropriately selected stimulation parameters. Significance. Our findings support the possibility of creating VCs by directly activating RGCs under synchronous and asynchronous stimulation conditions. This study establishes the fundamental capability of VC creation based on temporal interactions within the RGC population alone and does not include the effects of potential indirect activation of any surviving inner retinal network neurons. Our results provide theoretical evidence for designing next-generation retinal prosthesis with higher spatial resolution.

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“…An alternative promising vision restoration strategy is the electrical stimulation of the remaining viable retinal circuitry using retinal prostheses composed of an electrode array implanted in the sub-, epi retinal, or suprachoroidal spaces (Palanker and Goetz, 2018;Palanker, 2023;Wu et al, 2023). The various stimulus parameters (Muralidharan et al;Guo et al, 2018;Twyford et al, 2014) and electrode configurations (Mathieson et al, 2012;Boinagrov et al, 2014;Seo et al, 2023) determine the extent of the spatial spread of activation and whether stimulation induces direct activation of the RGCs or network activation; both are critical in determining the obtained resolution and quality of the restored vision. Therefore, investigating the induced RGCs responses is a common practice when studying retinal prosthetic and other vision restoration approaches.…”

Section: Introductionmentioning

confidence: 99%

A novel GCaMP6f-RCS rat model for studying electrical stimulation in the degenerated retina

Azrad Leibovitch,

Farah,

Markus

et al. 2024

Front. Cell Dev. Biol.

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Background: Retinal prostheses aim to restore vision by electrically stimulating the remaining viable retinal cells in Retinal Degeneration (RD) cases. Research in this field necessitates a comprehensive analysis of retinal ganglion cells’ (RGCs) responses to assess the obtained visual acuity and quality. Here we present a novel animal model which facilitates the optical recording of RGCs activity in an RD rat. This model can significantly enhance the functional evaluation of vision restoration treatments.Methods: The development of the novel rat model is based on crossbreeding a retinal degenerated Royal College of Surgeons (RCS) rat with a transgenic line expressing the genetic calcium indicator GCaMP6f in the RGCs. Characterization of the model was achieved using Optical Coherence Tomography (OCT) imaging, histology, and electroretinography (ERG) at the ages of 4, 8, and 12 weeks. Additionally, optical recordings of RGCs function in response to ex-vivo subretinal electrical stimulations were performed.Results: Histological investigations confirmed the high expression of GCaMP6f in the RGCs and minimal expression in the inner nuclear layer (INL). OCT imaging and histological studies revealed the expected gradual retinal degeneration, as evident by the decrease in retinal thickness with age and the formation of subretinal debris. This degeneration was further confirmed by ERG recordings, which demonstrated a significant decrease in the b-wave amplitude throughout the degeneration process, culminating in its absence at 12 weeks in the GCaMP6f-RCS rat. Importantly, the feasibility of investigating subretinal stimulation was demonstrated, revealing a consistent increase in activation threshold throughout degeneration. Furthermore, an increase in the diameter of the activated area with increasing currents was observed. The spatial spread of the activation area in the GCaMP6f-RCS rat was found to be smaller and exhibited faster activation dynamics compared with the GCaMP6f-LE strain.Conclusion: This novel animal model offers an opportunity to deepen our understanding of prosthetically induced retinal responses, potentially leading to significant advancements in prosthetic interventions in visual impairments.

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Towards Controlling Functionally-Distinct Retinal Ganglion Cells In Degenerate Retina

Cited by 4 publications

References 17 publications

Morphological Factors that Underlie Neural Sensitivity to Stimulation in the Retina

Morphological Factors that Underlie Neural Sensitivity to Stimulation in the Retina

Creation of virtual channels in the retina using synchronous and asynchronous stimulation—a modelling study

A novel GCaMP6f-RCS rat model for studying electrical stimulation in the degenerated retina

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