Simulating the impact of photoreceptor loss and inner retinal network changes on electrical activity of the retina

Abstract

Objective: A major reason for poor visual outcomes provided by existing retinal prostheses is the limited knowledge of the impact of photoreceptor loss on retinal remodelling and its subsequent impact on neural responses to electrical stimulation. Computational network models of the neural retina assist in the understanding of normal retinal function but can be also useful for investigating diseased retinal responses to electrical stimulation. Approach: We developed and validated a biophysically detailed discrete neuronal network model of the retina in the software package NEURON. The model includes rod and cone photoreceptors, ON and OFF bipolar cell pathways, amacrine and horizontal cells and finally, ON and OFF retinal ganglion cells with detailed network connectivity and neural intrinsic properties. By accurately controlling the network parameters, we simulated the impact of varying levels of degeneration on retinal electrical function. Main results: Our model was able to reproduce characteristic monophasic and biphasic oscillatory patterns seen in ON and OFF neurons during retinal degeneration. Oscillatory activity occurred at 3 Hz with partial photoreceptor loss and at 6 Hz when all photoreceptor input to the retina was removed. Oscillations were found to gradually weaken, then disappear when synapses and gap junctions were destroyed in the inner retina. Without requiring any changes to intrinsic cellular properties of individual inner retinal neurons, our results suggest that changes in connectivity alone were sufficient to give rise to neural oscillations during photoreceptor degeneration, and significant network connectivity destruction in the inner retina terminated the oscillations. Significance: Our results provide a platform for further understanding physiological retinal changes with progressive photoreceptor and inner retinal degeneration. Furthermore, our model can be used to guide future stimulation strategies for retinal prostheses to benefit patients at different stages of disease progression, particularly in the early and mid-stages of retinal degeneration.

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

“…The model's performance has been well validated by a wide range of biological recordings across different animal models of RD [7,8]. More details of model structure, equations and parameters can be found in Ly et al [9].…”

Neural activity of retinal ganglion cells under continuous, dynamically-modulated high frequency electrical stimulation

“…Surviving inner retinal networks and remodelling events in the degenerate retina can severely impact the performance of electrical stimulation [66,67]. In addition, in degenerate retina, the loss of synaptic connections tends to be age-dependent [65,68] and pathway-dependent [69]. Future work using degenerate retinae at various stages of degeneration to identify the possible effects of using HFS on RGC responses may further help in optimising HFS parameters under more clinically-relevant conditions.…”

Editorial: Advances in bioelectronics and stimulation strategies for next generation neuroprosthetics

“…These new findings indicate the possibility of using electrical modulation to treat degenerative neural diseases. Neurodegenerative progression can affect the neuroprosthetic performance (Rattay et al, 2001 ; Hilker et al, 2005 ; Loizos et al, 2018 ; Ly et al, 2022 ). Croner et al have investigated the differential performance of cochlear stimulation in a cochlea with intact and degenerating spiral ganglion neurons (SGNs) using a biophysically detailed computational model of the human cochlea (Bai et al, 2019b ).…”