Characterising Functionally-Distinct Retinal Ganglion Cell Responses to High Frequency Electrical Stimulation

Retinal implants aim to provide artificial vision to those profoundly blind by stimulating the residual network to elicit visual percepts. While human clinical trials have demonstrated encouraging results including the presence of visual percepts as well as partial visual restoration, the vision quality provided remains limited. One potential cause of this poor performance has been attributed to the indiscriminate activation of functionally-different retinal ganglion cell (RGC) types. To combat this problem, a promising strategy has been to design stimulation strategies that are capable of selectively, or preferentially, activating different cell types. One such approach to realise this goal has been through the use of high frequency stimulation (HFS) which was shown to be effective in preferentially activating two major retinal ganglion cell types– ON and OFF. While encouraging, the utility of the technique to target a broader range of cell types, and under different stimulation conditions and environments was still unclear. The studies presented in this thesis were designed to improve the understanding of HFS based preferential activation. Using in vitro whole-cell patch clamp of RGCs in mice (C57BL/6J and rd1), an investigation into whether HFS could be used to preferentially activate four major RGC types namely, ON-sustained (ONS), ON-transient (ONT), OFF-sustained (OFFS), and OFF-transient (OFFT), was undertaken. Results suggested that three of the four targeted cell types could be preferentially activated against the remaining population. A subsequent study documented the responses and the preferential activation capabilities of the aforementioned cell types when the high frequencies were modulated with short stimulation bursts, varying sequence orders and in a continuous waveform. It was shown that the ON (sustained and transient) RGCs typically exhibited more consistent responses and preferential activation regions irrespective of the frequency order, or when presented as a continuous waveform. A final study examined the responses of rd1 ON and OFF RGCs to HFS both with and without the presynaptic degenerate network. The network did appear to have an effect on the HFS evoked responses, and particularly increased the variability of the responses which in turn affected the preferential activation of the cell types. Additionally, a comparison into the specific intrinsic properties between the rd1 and healthy RGCs found that these properties may differ between the cell groups. Overall, this thesis investigated the usefulness of HFS to preferentially activate different cell types and across various stimulation conditions and environments and found that HFS remains a viable stimulation technique to reduce indiscriminate activation of functionally-distinct cell types

Elicitation of retinal neural circuitry with vision prosthetic devices

Vision prostheses currently under development by several research groups aim to restore functional sight to the profoundly blind suffering from retinal neural degenerative diseases. Human clinical trials in the last decade have demonstrated the ability of these devices to elicit simple percepts, such as bright spots of light. However, further improvements in implant perceptual efficacy will critically depend on improved understanding of the retinal neural mechanisms underlying the electrically evoked responses, and on how these mechanisms could be controlled artificially. In the first part of this thesis I quantitatively study, using a new statistical analysis technique, the temporal response properties of the retinal ganglion cells (RGCs) following electrical stimulation of the retina. I also demonstrate conclusively, for the first time, that small electrodes placed in the subretinal space could reliably elicit direct RGC spiking responses. In the second part of the thesis I investigate the mechanisms underlying the previously observed RGC response depression during repeated electrical stimulation of these cells. The experimental findings lead me to the development of a new stimulation method for preventing the response depression. The image processor is a crucial component of a vision prosthesis. It replaces some of the neural computations that occur in a healthy retina by converting visual stimuli into electrical stimuli. In the final part of the thesis I implement an image processor for a vision prosthesis. I show that such devices could be built with appropriate embedded hardware. Benchmark testing suggests that, depending on the complexity of the image processing strategies, care should be exercised in generalising the performance of algorithms developed on standard computers to these embedded devices

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

Optical Methods in Sensing and Imaging for Medical and Biological Applications

The recent advances in optical sources and detectors have opened up new opportunities for sensing and imaging techniques which can be successfully used in biomedical and healthcare applications. This book, entitled ‘Optical Methods in Sensing and Imaging for Medical and Biological Applications’, focuses on various aspects of the research and development related to these areas. The book will be a valuable source of information presenting the recent advances in optical methods and novel techniques, as well as their applications in the fields of biomedicine and healthcare, to anyone interested in this subject