This thesis describes the developm ent o f Dynamic Noise Perimetry (DNP), a novel method based on the equivalent noise input technique. The method, specifically targeted to an early stage o f OAG, used a 0.5 cycle per degree sine-wave grating presented at 8Hz in conjunction with an external noise m ask that was optimised for the stimulus. Equivalent noise and sampling efficiency w ere determ ined at various locations within the visual field to identify a stage o f the disease that was analogous to ganglion cell shrinkage, a stage which is believed to precede conventional methods o f detection. A pilot study initially determ ined w hether the spatial parameters o f the mask, in terms o f noise check size, were dependent on the spatial and temporal param eters o f the grating stimulus. The results show ed that the m axim al dimensions o f each check, i.e. the critical check size, were correlated w ith the drift frequency o f the stimulus. In a second and preliminary study, the variation in the critical check size with grating spatial and temporal frequency was investigated as a function o f eccentricity. Critical noise check size, in terms o f noise checks per cycle, decreased w ith increasing spatial frequency and drift frequency o f the stimulus, and with eccentric viewing. These results were used to optim ise the critical parameters for the noise mask. Temporal contrast sensitivity, equivalent noise and sampling efficiency were determined at various locations in the visual field, in 20 normal individuals and in 10 individuals with OAG. Temporal contrast sensitivity was reduced, and equivalent noise levels were elevated in early OAG, w hen com pared with normal individuals. Derivative measures o f sampling efficiency and equivalent noise declined with glaucomatous field loss. DNP was able to identify individuals w ith OAG, at locations which exhibited abnormal Pattern Deviation values and/ or abnorm al retinal nerve fibre layer thickness. DNP clearly warrants further development

The optical and biomechanical properties of the cornea are largely governed by the collagen-rich stroma, a layer that represents approximately 90% of the total thickness. It has been postulated that a novel corneal layer exists in the posterior stroma, immediately above Descemet’s membrane, termed ‘pre-Descemet’s layer’. The main aim of this thesis was to determine if this region has different structural properties to the overlying stroma. A second aim was to examine the elastic fibre distribution throughout the depth of the stroma in healthy and diseased corneas, with focus on pre-Descemet’s layer. Techniques used include serial block face scanning electron microscopy, transmission electron microscopy, and X-ray diffraction, amongst various other imaging techniques. Depth analysis revealed that centre-to-centre interfibrillar spacing was significantly lower in the first ~10µm of stroma distal to Descemet’s membrane compared to overlying regions in central cornea. Three-dimensional analysis revealed the presence of long elastic fibres running throughout the stroma, parallel to the surface of the cornea, which were concentrated in pre-Descemet’s layer. This elastic material seemed to originate from the limbus as fenestrated sheets before travelling radially into the cornea as small fibres. This data provides evidence for pre-Descemet’s layer containing altered biomechanical properties that may contribute to the formation of a variable cleavage plane observed during pneumodissection. Additionally, the elastic fibre network is likely to play an important role in the deformation and recovery of the cornea. Furthermore, the presence of elastic fibres in foetal cornea suggests a potential role in development. The distribution of elastic fibres was very different in keratoconic buttons. No fibres were located above Descemet’s membrane, whereas the elastic fibres appeared concentrated below the epithelium in thinned coned regions, potentially as a biomechanical response to prevent rupture. Attempts were made to elucidate a functional role for elastic fibres by studying the corneas from a mouse model for Marfan syndrome, where there was a ~50% reduction in elastic fibre quantity. These corneas were significantly thinner and flatter than wild types suggesting that elastic fibres play a role in maintaining the shape of the cornea. Overall, this thesis has characterised pre-Descemet’s layer, demonstrating that structural differences are present. It is likely that the network of elastic fibres described in this thesis play a multi-functional role in the cornea.

Age-related macular degeneration (AMD) is predicted to affect 196 million people by 2020 (Wong et al. 2014). To date there is no clear pathogenesis for the condition however, hypoxia has been implicated (Stefánsson et al. 2011). Currently, treatment is only available for neovascular AMD. To develop treatments targeted for early AMD a better understanding of the pathogenesis is required. There is also a need for sensitive functional biomarkers to improve diagnosis and monitoring and to expedite the evaluation of therauptics in clinical trials. The aim of this research was to investigate the hypothesis that hypoxia is involved in the pathogenesis of early AMD. Studies were carried out exploring the effect of transient systemic hypoxia (14% oxygen) and hyperoxia (60% oxygen) on scotopic thresholds and electroretinograms (ERGs) of participants with early AMD. It was hypothesised that the visual function of participants with AMD, but not age-matched controls, would improve during the hyperoxic episode and that hypoxia would have a greater detrimental effect on visual function in people with early AMD. There were no significant differences in scotopic thresholds within each group when breathing 60% or 14% oxygen compared to medical air (21% oxygen). There were also no significant differences in full-field ERG parameters between gas conditions or groups, apart from the amplitude of the b-wave which was significantly reduced under hypoxia in the control group. The amplitude of the focal flicker ERG was significantly higher in the control group than the AMD group when breathing both 14% and 21% oxygen. However, there were no significant differences in the parameters of the focal ERG within each group. These findings suggest that hypoxia is not responsible for the elevation of scotopic thresholds reported in AMD. There is also no evidence that ERG changes are attributable to hypoxia. This thesis provides no evidence to support the role of hypoxia in the pathogenesis of early AMD.

Glaucoma is a leading cause of blindness. As a progressive condition, it is important to monitor how the visual field (VF) changes over time with perimetry in preventing vision from deteriorating to a stage where quality of life is affected. However, there is little evidence of how clinical measurements correlate with meaningful quality of life landmarks for the patient or, by extension, the proportion of patients in danger of progressing to these landmarks. Further, measurement variability associated with visual fields make it difficult to monitor true change over time. The purpose of this thesis was to use large-scale clinical data (almost 500,000 VFs) to address some of these issues. The first study attempted to relate clinical measurements of glaucoma severity to UK legal fitness to drive status. Legal fitness to drive (LFTD) was estimated using the integrated visual field as a surrogate of the Esterman test, which is the approved method by the UK DVLA of defining LFTD, while the mean deviation (MD) was used to represent defect severity. An MD of -14dB or worse in the better eye was found to be associated with a 92% (95% Confidence Interval [CI]: 87-95%) probability of being legally unfit to drive. The second study used a statistical model to estimate the number of patients progressing at rates that could lead to this landmark of significant visual impairment or blindness in their predicted remaining lifetime. A significant minority of patients were progressing at rates that could lead to statutory blindness, as defined by the US Social Security Administration, in their predicted remaining lifetime (5.2% [CI: 4.5-6.0%]) with a further 10% in danger of becoming legally unfit to drive (10.4% [CI: 9.4-11.4%]). More than 90% (CI: 85.7-94.3%) of patients predicted to progress to statutory blindness had an MD worse than -6dB in at least one eye at presentation, suggesting an association between baseline VF damage and risk of future impairment. The next section investigated whether choice of testing algorithm, SITA Standard or SITA Fast, affected the time taken to detect progression in VF follow-up. The precision of the tests was measured using linear modelling techniques and the impact of these differences was analysed using simulations. Though SITA Fast was found to be slightly less precise, no evidence was found to suggest that this resulted in progression being detected later. The final study evaluated a validated and published risk calculator, which utilised baseline risk factors to profile risk of fast progression. A simpler model using baseline VF data was developed to have similar statistical properties for comparison(including equivalent R2 statistics). The results suggested that risk calculators with low R2 statistics had little utility for predicting future progression rate in clinical practice. Together these results contribute a variety of novel findings and demonstrate the benefit of using large quantities of data collected from the everyday clinical milieu to extend clinical knowledge.

Injury to optic nerve (ON) axons plays a major role in glaucoma progression. ON crush is an established model of axonal injury which results in retrograde degeneration and death of retinal ganglion cells (RGCs). However, it is unknown how signal transmission to higher visual structures such as primary visual cortex (V1) is affected after ON crush. In human glaucoma, visual function is assessed using visual field (VF) tests, but it is also not clear how the test results relate to the disease progression in the retina. Unilateral ON crush was performed on the left eyes of adult C57BL/6 mice. V1 function of the right hemisphere was assessed longitudinally by optical imaging (OI) and in vivo calcium two-photon imaging under anaesthesia before and at 7 days, 14 days and 30 days after ON crush. Human retinas from glaucoma patients were investigated for changes in RGC density and compared to the score from the VF data obtained prior to the patients’ death. ISI and 2P experiments demonstrate a significant shift in OD towards the ipsilateral eye and significant reduction of signal magnitude in V1 in response to contralateral eye stimulation in all ON crush animals. Additionally, response magnitude to ipsilateral eye stimulation was significantly increased after ON crush. While there was significant RGC loss in human glaucoma compared to age matched controls that was correlated to mean VF loss, the scores from the individual VF test points were uncorrelated to RGC density in anatomically equivalent areas. This work demonstrates that unilateral ON crush results in immediate loss of signal transmission from the retina to V1 via a crushed ON. A significant increase of responsiveness in V1 to non-crushed eye stimulation was observed, which indicates that injury of the ON in adulthood may evoke compensatory plasticity in V1.

Autosomal dominant optic atrophy (ADOA) is an inherited optic neuropathy due to mutation in the OPA1 gene. Patients present with bilateral optic nerve head pallor and loss of visual function. Patients also show a reduction in the P50:N95 ratio of the pattern electroretinogram (PERG) and thinning of the retinal nerve fibre layer (RNFL) and macula. In a mouse model of ADOA, previously generated in this laboratory, the defect first manifested as a dendritic pruning of RGCs, which appeared to be ON-centre specific. Electrophysiological evidence in both humans and the mutant mice showed a reduction in the photopic negative component (PhNR) of the brief flash electroretinogram (ERG). The separation of the photopic ERG into ON- and OFF-pathway components using long-duration monochromatic (red) flash on a rod suppressing blue background, provided an opportunity to assess ON- and OFF-RGC function in ADOA, which had not been previously investigated in humans. This study therefore aimed to assess the effect of ADOA on the red-on blue PhNR-ON and PhNR-OFF components to determine whether the PhNR-ON was a selective marker for ADOA. In this thesis, a protocol was developed for recording long duration red-on-blue PhNRs from the macula (focal) and entire retina (full-field). A comparison of the retinotopic characteristics of the PhNRs (brief and long-duration) with the N95 of the PERG and the distribution of RGCs in the retina showed that the PhNR was capable of assessing RGC function. Retinal function was then probed in twelve participants with ADOA and sixteen controls using focal and full-field long duration ERG, full-field brief flash ERG and PERG. Retinal structure was also assessed using optical coherence tomography. In conclusion, this thesis found that the PhNR-ON and PhNR-OFF amplitudes were equally affected with no evidence of a preferential ON-pathway loss.

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.