Keratoconus is a primary cause of visual impairment in young people in the UK. Corneal cross-linking is a recently-introduced treatment for halting progression of keratoconus, which is more effective in early cases. It has long been observed that keratoconus is significantly more prevalent in those with Down’s syndrome (DS) when compared to the general population. Moreover, young people with Down’s syndrome are less able to report early symptoms of keratoconus, often presenting late to eye clinics when cross-linking is no longer possible. A cohort of children and young people with DS were examined with the aim of discovering optometric correlates of keratoconus and to establish the utility of these parameters as risk factors for identifying keratoconus in primary care. An abnormal retinoscopy reflex was found to be the earliest indicator of keratoconus, showing greater potential as a screening test than either refractive error or objective vision measurement. The cornea of individuals with DS is known to be thinner and steeper than usual. Despite this, the high prevalence of keratoconus in DS has long been attributed to eye-rubbing, despite the inherent difference in baseline shape. The current work revealed no relationship between eye rubbing and the development of keratoconus in DS eyes. In vivo biomechanical analysis demonstrated an increased deformation tendency in DS eyes vs. controls, largely accounted for by the decreased corneal thickness in the test group. These results suggest that the high prevalence of keratoconus in DS originates from biomechanical weakness, permitting the loss of regular corneal shape in the absence of eye rubbing. However, ultrastructural analysis of the cornea of the Tc1 mouse model of DS revealed an unaltered collagen and proteoglycan structure. Topographical examination of ‘cone’ morphology in individuals with and without DS demonstrated a similar phenotype at all stages of the disorder, indicating that people with DS and keratoconus may be a useful cohort for future genetic studies into keratoconus as a whole.

Cochlear implants have been shown to successfully restore hearing to the profoundly deaf. Despite this achievement, issues remain concerning the power consumption and the accuracy of stimulation. This thesis is mainly concerned with investigating the spread of stimulation voltage within the cochlea. The power required to generate the stimulus is also investigated, as is the feasibility of powering a fully implanted cochlear implant by harvesting energy from head motion. Several different models have been used to study the voltage distribution within the cochlea due to electrical stimulation from individual electrodes of a cochlear implant. A resistive cable model is first used to illustrate the fall-off of the voltage with distance at the electrode positions along the cochlea. A three-dimensional finite element model of the cochlea is then developed to obtain the voltage distribution at positions closer to the site of neural stimulation. This model is used to demonstrate the way that the voltage distribution varies with the geometry of the cochlea and the electrode array. It was found that placing the return electrode of the implant within the modiolus, as opposed to outside the cochlea, resulted in higher stimulation for the same current input, which reduces the power requirements. The model has also been used to investigate the consequences of a current-steering, or stimulation focussing, strategy that has previously been proposed. A generalisation of this strategy is suggested, whereby impedance information at the neural level, along the path of the spiral ganglion, was used to optimise the focussed voltage distribution at the target neurons. The power consumption of various stimulation strategies is then estimated in order to assess their energy efficiency. Strategies are defined by parameters such as stimulation rate and number of active channels. The feasibility has also been investigated of harvesting electrical energy from head motion, to power a fully-implanted cochlear implant. It was demonstrated that more power could be harvested from higher harmonics but that this would be sensitive to walking speed. The practical approach is to have a heavily damped device that is insensitive.

The cochlea plays an important role in human hearing. Its basic function is to map sounds of different frequencies onto corresponding characteristic positions on the basilar membrane, BM. When sounds enter the fluid-filled cochlea, deflections of the BM occur due to pressure differences between the cochlear fluid chambers. These deflections propagate along the cochlea to a frequency-dependent characteristic position and then decay away rapidly. The mechanics of the cochlea are modelled using both analytic and numerical models. In this thesis, the passive response of the cochlea is analysed, corresponding to its behaviour at high sound levels, to study the fluid coupling and waves in the cochlea. The fluid coupling is studied in 1D and 3D, uniform and non-uniform, uncoiled and coiled geometries, all with a passive basilar membrane. A ‘uniaxial model’, which is dependent on only a single dimension, is developed to represent the three-dimensional cochlea. The finite element method is also used to provide an independent check of the results from the analytic model. Analytic methods are used to predict waves due to different mechanisms in the passive cochlea, such as 1D and 3D fluid coupling and longitudinal BM dynamics. The wave finite element, WFE, method is then used to decompose the results of a full finite element model of the coupled cochlea into wave components. Results show that apart from the conventional slow wave, other additional types of wave in the passive cochlea do not appear to play a dominant role in normal passive cochlear function.

No description available.

In this thesis the laser ray tracing (LRT) technique for measurement of ocular aberrations has been implemented, validated and applied, in conjunction with complementary techniques, to the study of ocular aberrations in human eyes. In particular, we studied optical aberrations in myopic and hyperopic eyes and the optical changes induced by refractive surgery for myopia and hyperopia. We have studied the impact of the optimisation of some experimental parameters on the estimation of the wave aberration. We demonstrated that although the polarisation state and wavelength of the illumination light affected the intensity patterns of the images obtained using reflectometric aberrometry (LRT and Hartmann Shack sensor), these changes did not affect the estimation of aberrations. We also showed that the difference in the defocus term (focus shift) due to the use of different wavelengths is in agreement with the Longitudinal Chromatic Aberration of the Indiana Chromatic Eye Model for average normal eyes, although intersubject variability is not negligible. In addition, we studied experimentally the influence of the geometrical distribution and density of the pupil sampling on the estimation of aberrations using artificial and normal human eyes, and performed numerical simulations to extend our results to "abnormal"eyes. We found that the spatial distribution of the samples can be more important than the number of samples, for both our measured as well as our simulated "abnormal" eyes. Experimentally, we did not find large differences across patterns except, as expected, for undersampled patterns. We found that hyperopic eyes tended to have more positive asphericity and greater total and corneal spherical aberrati on than myopic eyes, as well as greater 3rd and higher order aberrations. Although we found no significant differences between groups in terms of internal aberrations, internal spherical aberration showed a significant age-related shift toward less negative values in the hyperopic group. We also assessed the impact of the LASIK corneal surgery, a popular surgical technique for correction of refractive errors, on the optical quality for both myopic and hyperopic standard techniques. Third and higher order ocular and an terior corneal aberrations increased with the surgery. Ocular and corneal spherical aberration changed towards more positive values with myopic LASIK, and towards more negative values with hyperopic LASIK. Changes in internal spherical aberration were of opposite sign than those induced in corneal spherical aberration. Changes induced by hyperopic LASIK were larger than those induced by myopic LASIK for a similar attempted correction.

The presence of a bright light source in the visual field, particularly when viewed against a dark background, can generate a form of discomfort, which is often described as ‘discomfort glare’. The mechanisms for discomfort glare remain poorly understood, even after 50 years of multidisciplinary research in this field. The aim of this investigation was to investigate a number of relevant parameters that can affect discomfort glare in order to gain insights into the corresponding mechanisms. We measured retinal illuminance levels for discomfort glare at threshold as a function of source size, eccentricity and surrounding background luminance. In addition, the pupil size was measured throughout and related to the measured thresholds for discomfort glare. A group of 50 subjects with normal visual acuity and no clinical signs of eye disease took part in the primary study that measured discomfort glare thresholds as a function of source size. A light ‘homogenizer’ was used to integrate the concentrated light output from a quad LED light source. Pulse frequency modulation was used to control the intensity of the source and continuous pupil size measurements made it possible to calculate retinal illuminance. Discomfort glare thresholds were estimated by measuring the retinal illuminance of the glare source at threshold using a staircase procedure. Discomfort glare thresholds were measured as a function of glare source area, eccentricity and background luminance. The amplitude of pupil constriction was also measured both below and above the discomfort glare threshold. A model of contrast vision with the filtering of a photoreceptor signal through centre-surround ganglion cells was developed to account for the small size dependence of discomfort glare thresholds that was observed experimentally. Another model for scattered light was applied to compute the corresponding pupil constriction amplitude caused by the integrated photoreceptor signals generated by the glare source both within and outside the stimulus area. The threshold for discomfort glare decreased gradually with glare source size and increased with background luminance and showed little dependence on glare source eccentricity. The effect of forward light scatter in the eye was also investigated and a model was developed to account for the continued increase in pupil response amplitude well above the discomfort glare threshold. The effect of glare source size on discomfort glare thresholds could be predicted by a model involving photoreceptor saturation and edge response. When the scattered light outside the stimulus area was also taken into account, the pupil constriction amplitude increased log-linearly with stimulus retinal illuminance both below and above discomfort glare thresholds. These findings suggest that discomfort glare depended largely on the localised retinal illuminance and could be accounted for by the saturation of photoreceptor signals in the retina. The results and the pupil modeling work also suggest that the pupil response to light flux increments continued well above the discomfort glare threshold, largely as a result of light scattered outside the area of the glare source.

Background: Sub-Saharan Africa faces an epidemic of diabetes. The prevalence and incidence of sight threatening diabetic retinopathy in developed countries and associations between systemic factors, including glycaemic control, blood pressure and blood lipid levels, are well documented. In contrast the epidemiological literature from sub-Saharan Africa is sparse. In this resource-poor setting, population-specific variables such as a high burden of infectious disease and anaemia are likely to affect the spectrum of pathology encountered. I aimed to investigate the prevalence, incidence and progression of diabetic retinopathy in Southern Malawi, to investigate the risk factors for diabetic retinopathy severity and progression in this population and to characterise endothelial function in Southern Malawian subjects with diabetes. Methods: I established the Malawi Diabetic Retinopathy Study, a 24 month prospective cohort study. Subjects were systematically sampled from two hospital-based, primary care diabetes clinics. Visual acuity, glycaemic control, systolic blood pressure, HIV status, urine albumin–creatinine ratio, and haemoglobin and serum lipid levels were assessed. Retinopathy was graded at an accredited reading centre using modified Wisconsin grading of four-field mydriatic photographs. Additionally, in order to investigate DR progression at five years, a cohort of subjects recruited to a cross-sectional study of diabetes complications in 2007 were traced and assessed. In a nested case-control study, serum markers of endothelial dysfunction and pulse amplitude tonometry were measured in a subset of subjects from the main cohort plus subjects without diabetes. Results: 357 subjects were recruited to the 24 month cohort study. At baseline 13.4% subjects were HIV-positive and 15.1% were anaemic. Baseline prevalence rates of any retinopathy, sight threatening diabetic retinopathy and proliferative retinopathy were 50.1% (95% CI 44.9–55.3), 29.4% (95% CI 24.7–34.1) and 7.3% (95% CI 4.6–10.0), respectively. Cumulative incidence at 2 years of sight threatening diabetic retinopathy for subjects with level 10 (no retinopathy), level 20 (background) and level 30 at baseline was 2.7% (95% CI 0.1-5.3), 27.3% (16.4-38.2) and 25.0% (0-67.4), respectively. In a multivariate logistic analysis, 2 step progression of diabetic retinopathy at 2 years was associated with HbA1c (odds ratio 1.27, 95%CI 1.12-1.45), baseline grade of DR (1.39, 1.02-1.91) and HIV infection (OR 0.16, 0.03-0.78). At 2 years, rates of progression to visual loss were: ≥15 letters lost in 17 subjects (5.8%), moderate visual impairment (<60 letters) in 3 subjects (1.0%), severe visual impairment ( < 50 letters) in 5 subjects (1.7%). The five year incidence of sight threatening diabetic retinopathy in subjects recruited to the 2007 cross sectional study, for those with level 10 and level 20 retinopathy at baseline, was 19.4% (11.3-27.4) and 81.3% (62.1-100), respectively. In the case control study of endothelial function higher serum VEGF and E-selectin were associated with having diabetes in multivariate regression. Serum VCAM-1 was associated with death in multivariate regression. Conclusions: I report the first cohort study of diabetic retinopathy from sub-Saharan Africa. I found a prevalence of sight threatening diabetic retinopathy, in subjects attending diabetes clinics, approximately 3 times that reported in recent European studies and a prevalence of proliferative retinopathy approximately 10 times higher. Progression to sight threatening diabetic retinopathy occurred approximately 3 times more frequently than reported in Europe. The negative association of HIV infection with retinopathy progression is a new finding. I report the first evidence from sub-Saharan Africa of endothelial dysfunction in subjects with diabetes and of an association between levels of endothelial biomarkers and mortality in these subjects. Results presented in this thesis highlight the urgent need for provision of services for retinopathy detection and management to avoid a large burden of vision loss.

Aim: I aimed to investigate methods of delivering neuroprotection to the retina: a) using magnetofection (a non-viral transfection technique) in ocular tissue, b) using stem cells as a vector of neuroprotection delivery and c) harnessing galvanotaxis to direct migration of stem cells into the retina. Methods: For the recipient test bed of the experiments in my thesis, I used retinal explants from mice. The viability of retinal explants was determined using retinal ganglion cell health as a read-out in the form of Sholl plots. I also explored magnetofection with oscillation as a non-viral technique for neuroprotection delivery in ocular tissue using cornea and retinal explants. Using the galvanotaxis technique, I explored its use in directing neural stem cells in-vitro with an electrotactic chamber and ex-vivo on a retinal explant in a modified Boyden chamber. Finally, I magnetofected neural stem cells to over-express BDNF and directed their migration into the retina using galvanotaxis. Results: The retinal explants had a viability of up to 3 days based on the Sholl plots of retinal ganglion cells. Magnetofection with oscillation transfected cornea endothelium and the retinal ganglion cell layer with GFP in the explant models. It also transfected neural stem cells with BDNF-myc. Directed migration with neural stem cells occurred in the electrotactic chamber as well as in the retinal explant model. In the absence of electric field, no migration into the retina occurred. Neurospheres transfected with BDNF-myc also migrated into the retina when exposed to an electric field. Conclusion: Within the period of up to 3 days, retinal explants can be used to investigate neuroprotective therapeutic agents using Sholl plots of retinal ganglion cells. Magnetofection with oscillation is a novel non-viral technique for potentially transfecting the eye in the anterior and posterior segments. Neurospheres can be directed to migrate into the retina using an electric field in the ex-vivo model.

The purpose of this thesis was to develop further the concept of Dynamic Noise Perimetry (DNP). The influence of 4 different strengths of Gaussian filter on the DNP stimulus edge, without and with a noise mask, was separately investigated in 15 normal individuals at three eccentricities. The DNP threshold was not affected by the filtering. The critical check size of the noise mask was investigated in 11 normal individuals at three eccentricities for 8 different checks per cycle. The critical check size at the fovea was 4 checks per cycle and in the periphery between 2 and 4 checks per cycle. The influence of optical defocus was investigated in 11 normal individuals at three eccentricities. For a defocus of +4.00DS, sensitivity without the noise mask declined by approximately 1dB; with the noise mask sensitivity increased by 1dB. The original ‘Proof of Concept’ threshold algorithm, which enabled the estimation of threshold at one location in approximately 3 minutes, underwent numerous modifications. The final iteration permitted threshold estimation at 45 locations in approximately 7 minutes. Five of the ten individuals with open angle glaucoma who had undergone DNP and standard automated perimetry (SAP) in 2007 were re-examined, using an identical protocol, after a follow-up of four years. The abnormality with DNP at baseline was present at the follow-up in all five individuals and was more severe in 3 individuals. Only 2 individuals exhibited abnormality by SAP. The influence of the learning effect on the outcome of DNP was evaluated, in one designated eye at each of the five weekly visits, for 10 ‘young’ and 8 ‘elderly’ normal individuals naïve to perimetry. Optimum performance was essentially achieved at the third visit without and with the noise mask.

Despite the association of neuronal cell loss with a wide range of neurodegenerative disorders, the mechanisms leading to this cell death remain poorly understood. In this thesis I have investigated these mechanisms and tested whether they represent viable targets for therapeutic intervention. The adult mouse retinal explant is a popular model of axotomy-induced neuronal degeneration but has been limited by the lack of morphometric data. Since dendritic pruning is well-evidenced to precede cell loss in neurodegenerative diseases, including glaucoma and Alzheimer’s disease, I investigated whether the quantification of dendritic morphology of retinal ganglion cells in the retinal explant could be used as a more sensitive measure of neuronal health after axotomy. I report here that retinal ganglion cell dendrite loss precedes cell loss by at least 7 days and that this retraction is substantially retarded following treatment with brain-derived neurotrophic factor applied at the time of explantation. Perhaps most importantly, I demonstrate for the first time in this model that delayed application of brain-derived neurotrophic factor significantly protects against dendritic retraction of retinal ganglion cells. The work outlined in this thesis thus supports the targeting of dendritic outgrowth and/or synaptic connectivity for the treatment of neurodegenerative disorders.