Electrical and Electronic Engineering - Theses
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ItemA predictive model of retinal ganglion cell responses to electrical stimulation( 2016)Degenerative diseases such as retinitis pigmentosa and age-related macular degeneration result in the loss of photoreceptor cells, which function to transduce light into a neural signal. However, retinal ganglion cells (RGCs), the output cells of the retina, and other cells within the retina often survive in high numbers. Recent developments in visual prostheses have demonstrated that electrical stimulation of the retina is becoming a viable therapy for those blinded through degenerative diseases. While the developments of retinal prostheses are still in their infancy, clinical trials have shown that the vision produced by retinal prostheses can appear complex in both space and time. The development of improved stimulation strategies for the bionic eye requires an understanding of the effects of RGCs to electrical stimulation. This thesis investigates a model that can be used to predict responses of RGCs to arbitrary patterns of electrical stimulation. Intracellular whole cell patch clamp recordings were made in whole mount preparations from normal sighted rats to develop RGC response models to electrical stimulation. Recordings were made at room temperature (~24ºC). Stimulation was applied using a custom-made multi electrode array and consisted of random amplitude biphasic pulses applied at constant frequency. Short-latency responses were correlated with the stimulation applied and a spike triggered covariance technique was used to determine spatial features of the stimulation that resulted in a response. Generally, the spatial arrangements of electrodes that influenced the cell’s response were as expected: the electrodes closest to the recorded cell had largest influence on the cell’s response. An extracellular recording technique was applied to model the long-latency responses to electrical stimulation. Recordings were made close to physiological temperature (~34ºC). The mathematical model used during the intracellular recordings was adapted to also model temporal features of stimulation. Temporal features of stimulation for many cells were complex; the polarity and spatial organisation of stimulation changed over time. Additionally, both excitatory and suppressive features of electrical stimulation were revealed by the model. The effects of temperature were examined to investigate whether some differences observed in results for the two recording techniques could be explained by the temperature used during the two experiments. In vitro recordings at different temperatures were used to investigate how retinal responses changed at different temperatures. The sensitivity of RGCs to electrical stimulation was found to be higher at temperatures closer to physiological temperature. Additionally, a greater amount of long latency activity was observed, suggesting increased activation of the retinal network. Simulations were used to explore an algorithm for achieving spatial control of neural activation. The algorithm made use of the error between recorded and target responses to fine tune the stimulation applied. The simulations suggested that the model can be used to manipulate spatial interactions in a predictable manner, thereby improving spatial fidelity. Additionally, closed loop stimulation may be used to mitigate undesirable effects of stimulation that are observed clinically, such as fading; a phenomena that results in the visual percept produced by electrical stimulation disappearing over time despite constant stimulation. Electrical stimulation of the retina often results in indiscriminate activation of many RGC types. A major goal of electrical stimulation is the targeted activation of certain cell types, such as ON cells or OFF cells. Traditionally, light responses are used to classify cell types. In the degenerate retina, where light responses are not obtainable, other methods are required to identify cells. Analysis of recorded intracellular responses revealed that the action potential waveform may contain identifiable features that could be used to establish the cell type. A previously developed multi compartment model of a RGC was used to relate features in morphology and electrophysiology to features in the action potential waveform. Overall, the results of my investigations demonstrate that RGC responses to electrical stimulation can be accurately modelled and predicted. Complex spatiotemporal features of electrical stimulation can be extracted and explained in a computationally simple model. The work presented here can aid in future developments of improved stimulation strategies that achieve a tighter control of neural activation.
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ItemThe condition of the retina in retinitis pigmentosa during late stages of degeneration( 2012)Retinitis pigmentosa (RP) is a family of inherited retinal degenerations that are characterised by photoreceptor death resulting in blindness. It was once thought that following photoreceptor death, the inner retina remained unchanged. However, studies have begun to show that there are extensive changes at late stages in the disease process. This thesis further extends these studies by examining the inner retina at various time points after photoreceptor death so that the cellular changes that arise throughout the degenerative process can be characterised. A novel transgenic mouse model, the rd1-FTL, was used to document the condition of the retina. This animal model expresses a mutation which results in retinal degeneration as well as containing an axonal targeted transgenic marker gene that labels all neurons that have the c-fos gene activated. A combination of enzyme histochemistry and fluorescence immunohistochemistry was used to reveal an up-regulation of c-fos in the central retina following complete photoreceptor loss that remained throughout the later stages of degeneration. This was also coupled with a major glial dysfunction in this area. Neurochemical analysis prior to and during c-fos upregulation revealed significant changes in the inner retina. Amino acid immunocytochemistry was used to show that many amino acids in the degenerated retina were altered in patches across the retina. The most significant changes were documented in Müller cells and bipolar cells. Additionally, gross remodelling of neural and glial cells occurred in the retina which worsened as animals aged. A comprehensive morphological analysis of retinal ganglion cells in the degenerated retina showed that the cell types which covered the largest area in the retina were altered whilst the smaller cells types remained unchanged. However, these smaller cells did show altered morphology in regions that also expressed c-fos in late stages of degeneration. Furthermore, there were significant changes in the stratification of many ganglion cells in the degenerated retina that included the loss of certain cell types as well as different branching patterns of dendrites. Overall, this thesis shows that there are extensive changes in the inner retina following photoreceptor loss. It provides a thorough examination at different stages in the degenerative process to highlight the varying conditions that can occur in this disease. Approaches aimed at vision restoration rely on a strong understanding of this underlying cellular anatomy and this work will assist with the design of these approaches.