Optometry and Vision Sciences - Theses
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ItemThe effects of ageing on ocular surface integrity( 2019)Purpose: Ageing is recognised as a major risk factor for several ocular pathologies, including dry eye disease. The aim of this thesis was to characterise the specific effect of ageing on key ocular surface parameters, in humans and mice. We hypothesised that there would be common ageing effects in both species that paralleled the pathophysiological features observed in dry eye disease. Method: The animal study involved healthy C57BL/6 female mice, aged 2 months (young, n=10) and 22 months (aged, n=10). Clinical assessments included measurements of corneal sensitivity (Cochet-Bonnet aesthesiometry, which is a contact corneal aesthesiometer), tear secretion (Phenol red thread test), tear film osmolarity (TearLab osmometer) and corneal thickness (optical coherence tomography). The anatomical integrity of the corneal nerves was examined ex vivo (using immunohistochemistry) by quantifying nerve density in the superficial epithelium (superficial terminals) and sub-basal plexus. The density and tree area of resident epithelial dendritic cells (DCs) were assessed using immunofluorescence and confocal microscopy. For the clinical study, 37 healthy male and female participants (15 male participants and 22 female participants) were recruited, and divided into four age categories: 20-35 years, 36-50 years, 51-65 years, and >65 years. Participants underwent a comprehensive characterisation of ocular surface health, including quantification of tear osmolarity, blink rate, slit lamp biomicroscopy and corneal sensitivity (using non-contact corneal aesthesiometry). In vivo confocal microscopy (IVCM) was performed to quantify a range of corneal nerve parameters, microneuroma density and DC density, in the central and peripheral cornea. Results: In the animal study, aged mice had significantly higher tear secretion, lower corneal sensitivity and a thicker corneal stroma but thinner epithelium compared with young mice. There was no significant inter-group difference for tear osmolarity. Aged mice showed a significantly lower cornea nerve density, in both the superficial terminals and sub-basal plexus, relative to young mice. DC density and morphology were similar in both age groups. In the human study, older age was associated with a reduction in central corneal sensitivity to a room temperature air stimulus, but not to a cold temperature stimulus. Tear osmolarity remained within normative ranges (<308mOsmol/L) in all age groups, although it was relatively higher in this parameter amongst individuals aged 36 to 50 years, compared to the 20 to 35 year olds (p = 0.0047). A range of ocular surface parameters, including corneal sub-basal nerve plexus density, DC density and microneuroma density were not subject to ageing effects but showed eccentricity-dependent differences. Blink rate and most standard clinical biomicroscopic findings were not significantly different between age groups. Conclusion: Ageing has differential effects on ocular surface parameters. A reduction in corneal sensitivity, and a relative maintenance of corneal DC density, was evident in older eyes in both species. The apparently disparate findings in relation to corneal nerve density between mice and humans may relate to the established limitations of in vivo imaging techniques, particularly with respect to image resolution. These findings, relating to ocular surface changes with physiological ageing, are of value for understanding the potential contribution of the ageing process to ocular surface diseases.
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ItemRetinal neurovascular coupling in streptozotocin diabetic rats( 2019)Diabetic retinopathy (DR) is a significant cause of vision impairment worldwide, and it is projected to incur a rising global disease burden. Although the pathophysiology of diabetic retinopathy had been historically characterised as a vascular disease, there is a growing body of evidence to suggest that DR is also a process of retinal neurodegeneration. There is also evidence that functional changes occur to the retinal vasculature’s capacity to respond to physiological stimuli, before anatomical changes manifest. Additionally, there is evidence to suggest that neuronal dysfunction precedes anatomical evidence of neurodegeneration in both clinical and experimental studies of diabetes. These findings were examined in Chapter 2, and collectively suggest that functional deficits of both the vascular and neuronal retinal components may be key components of DR pathogenesis. Several research questions were proposed in this thesis in order to further understand vascular and neuronal interactions in the retina, at the earliest stages of diabetes. In order to model an early stage of diabetic disease, 4 weeks of hyperglycaemia was introduced to a cohort of dark Agouti laboratory rats using streptozotocin (STZ). Flickering light was used to stimulate neuronal driven vasodilation in the retina, and the autoregulatory capacity of retinal vasculature was challenged through inhalation of oxygen and carbon dioxide. Electroretinography was conducted to assess retinal function, and the scotopic threshold response (STR) was recorded during gas inhalation as a measure of inner retinal functional response to an autoregulatory challenge. A series of pilot studies were undertaken to optimise the parameters of flicker stimulation, gas delivery, retinal imaging and electroretinography. These materials and methods were described in Chapter 3. Flicker stimulation reliably produced vasodilation of inner retinal arteries and veins, although this response was not significantly affected by 4 weeks of STZ hyperglycaemia. Oxygen and carbon dioxide breathing introduced vasodilation and vasoconstriction of the inner retinal arteries and veins, respectively. The speed of venous vasoconstriction was reduced in STZ animals during oxygen breathing, and carbon dioxide breathing revealed a reduced arterial vasodilatory capacity in STZ animals. These findings were described and discussed in Chapter 4, and they indicate that, despite normal retinal neurovascular coupling, subtle autoregulatory deficits in the retinal vasculature are present at an early stage of diabetes. The oscillatory potentials and STR were found to be reduced after 4 weeks of hyperglycaemia, suggesting a manifest deficit of inner retinal function. Additionally, carbon dioxide breathing introduced an increase in the peak positive STR (pSTR) amplitude in both normal and STZ animals, whereas oxygen breathing resulted in a decrease of pSTR amplitude that was more significant in the STZ cohort. These findings were described and discussed in Chapter 5, and they seem to suggest that that relative inner retinal ischemia may be present early in the course of diabetes. Furthermore, this effect could be exacerbated by vasoconstrictive stimuli. The overall experimental findings suggest that neurovascular coupling is unaffected at an early stage of diabetes, despite findings of inner retinal dysfunction and subtle deficit of vascular autoregulation in the retina. This suggests, in addition to neuronal and vascular activity, that other physiological processes, likely mediated by glial cells, may be implicated in the modulation neurovascular interactions in the retina. These experimental findings and implications were discussed in Chapter 6, as well as study limitations and future directions of research.
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ItemIllusory motion perception in migraine( 2019)In between attacks, people with migraine report experiencing both visual discomfort and visual illusions induced by stationary high contrast striped patterns. Since both visual illusion and discomfort have been assessed through largely qualitative self-report, it is unclear how their mechanisms might be related with each other. This thesis aimed to investigate whether subjective reports of visual discomfort in people with migraine are associated with the strength of a motion illusion outside attacks. To determine the stimulus for motion illusion strength to be quantified, Experiment 1 measured the physical motion speeds that cancelled the illusory motion effect of five variants of the Fraser-Wilcox illusion in people who do not experience headache. The stimulus type that produced the most robust illusory motion was chosen for subsequent experiments. Experiment 2 compared the motion illusion strength between people with migraine with aura, people with migraine without aura, and non-headache control participants. The relationship between motion illusion strength and self-reported frequency of experiencing visual discomfort in daily life was also investigated. The results indicated that subjective visual discomfort was elevated in people with migraine with aura but that visual discomfort was not accompanied by greater motion illusion strength. These findings suggest that susceptibility to daily visual discomfort is not related to perceived speed of the motion illusion. Experiment 3 investigated whether motion illusion strength is associated with contrast discrimination threshold and motion sensitivity regardless of migraine status. The results revealed that people with better contrast discrimination, but not motion sensitivity, tended to perceive faster motion illusions. The findings of this thesis verify previous self-reports of increased visual discomfort in people with migraine. The experiments, however, do not support that this self-reported experience is derived from differences in contrast discrimination or motion sensitivity, for the types of stimuli used herein. The Fraser-Wilcox motion illusion does not seem to test the same mechanisms as involved in self-reported visual discomfort.
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ItemIntegration of auditory and visual temporal rate in aging( 2017)This thesis investigated how aging affects the integration of visual flicker (the temporal modulation of luminance) with auditory flutter (the temporal modulation of sound amplitude) to produce a unified audiovisual percept of temporal modulation rate. A group of younger and older adults judged the temporal rate of an auditory and/or visual stimulus oscillating at 10 Hz. Whichever sensory modality discriminates temporal rate more precisely, contributes more to the audiovisual percept. Consequently, the first experiment explored how aging affected the precision of auditory temporal rate discrimination relative to vision. Auditory temporal rate discrimination in older adults was degraded by an age-related impairment in sensitivity to auditory amplitude modulation. In subsequent audiovisual experiments, auditory modulation depth was individually tailored to equate flutter and flicker temporal rate discrimination thresholds to normalise for this age-related sensory loss. When auditory and visual rates were conflicting, partial integration distorted perceived rate such that the auditory or visual rate subjectively equivalent to a reference was nonveridical. Distortions in perceived rate were unaffected by older age, indicating that the ability to integrate conflicting auditory and visual rates is preserved in aging. However, younger adults’ heightened sensitivity to auditory amplitude modulation was sufficient to increase the influence of audition on perceived rate when the modulation depth of auditory flutter was the same as the average older adult. Therefore, the age-related impairment in auditory rate discriminability is expected to increase visual influence on audiovisual rate perception in older adults. When auditory and visual rates are identical, temporal rate discrimination thresholds improved in line with statistically optimal integration in younger but not older adults. This indicates an age-related impairment in integration, which will be further compounded by the age-related decline in auditory temporal rate discriminability under natural conditions. These findings indicate that older adults will perceive audiovisual temporal rate differently to younger adults. These age-related changes in audiovisual rate perception will be the complex product of the age-related interaction between rate congruence and integration ability, and the age-related decline in auditory temporal rate discrimination.
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ItemThe role of oral long chain omega-3 supplements for treating dry eye disease( 2017)Dry eye disease (DED) is a highly prevalent multifactorial eye condition. While traditional therapies, such as ocular lubricants, provide symptomatic relief for dry eye sufferers, they do not treat the inflammatory overlay found in DED. Omega-3 (ω-3) essential fatty acid (EFA) supplements show promise as a potential treatment for DED. The major aim of this thesis was to compare the efficacy of two forms of long chain ω-3 EFAs, stored primarily as either triacylglycerides (fish oil) or as phospholipids (krill oil), for treating DED. In this regard, a randomised, placebo-controlled, double-masked, three-arm, parallel- group clinical trial was conducted. Sixty participants with clinically significant DED-related symptoms were enrolled for a three-month study. In addition this thesis aimed to determine the effects of elevated tear osmolarity on central corneal thickness (CCT) and corneal reflectivity. In a cross-sectional study involving 38 participants with hyperosmolar tears and 10 age-similar controls with normo-osmolar tears, anterior-segment optical coherence tomography (OCT) was used to detect subtle corneal microstructural changes that occur in association with tear hyperosmolarity. This study aimed to examine the effects of elevated tear osmolarity on central corneal thickness (CCT); and to measure the effects of elevated tear osmolarity and corneal reflectivity. Central corneal thickness (CCT) of participants with severely hyperosmolar tears (defined as eyes in the upper quartile for tear hyperosmolarity, 539.1 ± 7.4 µm) was found to be less than those with mildly hyperosmolar tears (defined as hyperosmolar eyes in the lower quartile for tear hyperosmolarity, 622.7±5.8 µm, p<0.0001) and control eyes (583.1 ± 15.0 µm, p = 0.02). Central corneal reflectivity (45.1 ± 0.3 versus 48.1 ± 0.6 greyscale units, p = 0.02) was relatively lower and peak tear film reflectivity higher (by 4.8% ± 3.5%, p = 0.04) in eyes with hyperosmolar tears than eyes having normo-osmolar tears. In order to test the relative efficacy of two forms of long-chain ω-3 EFA supplements over a three month intervention period, a randomised, placebo-controlled, double-masked, three-arm, parallel-group clinical trial was conducted. Sixty participants with clinically significant DED-related symptoms (Ocular Surface Disease Index Score (OSDI) score of 18-64) and tear hyperosmolarity (≥ 316 mOsmol/L) were randomly allocated (1:1:1) to one of three groups: triacylglyceride ω-3 EFAs (1000 mg/day eicosapentaenoic acid, EPA + 500 mg/day docosahexaenoic acid, DHA), phospholipid ω-3 EFAs (945 mg/day EPA, + 510 mg/day DHA) or placebo (1500 mg/day of olive oil). Primary outcome measures were: mean change in tear osmolarity and OSDI score from baseline (Day 1) to Day 90. Secondary outcomes included: mean change in key clinical signs of DED (ocular surface staining, ocular redness, meibomian gland integrity, anterior blepharitis, tear stability, tear production and tear volume). Fifty-four participants completed the study. Tear osmolarity was significantly reduced from baseline in both the triacylglyceride (fish oil) [n = 19, -19.8 ± 4.5 mOsmol/L, p < 0.001] and phospholipid (krill oil) [n = 18, -18.6 ± 4 mOsmol/L, p < 0.001] groups at Day 90. Only the krill oil group showed a significant reduction in OSDI symptom score [-61.4% ± 5.2%, p = 0.009] relative to the placebo group [n = 17, -32.4% ± 9.6%] at Day 90. Secondary outcome measures of ocular redness, meibomian gland capping, tear stability and corneal staining, were all significantly improved with long-chain ω-3 EFA treatment at Day 90 compared to baseline. There were no significant inter-group difference in tear production, tear volume, corneal thickness, corneal transparency, peak tear film reflectivity or Symptom Assessment in Dry Eye (SANDE) questionnaire scores relative to baseline. These two studies give insight into both the corneal micro-structural changes that occur in association with tear hyperosmolarity and provide evidence that moderate daily doses of long-chain ω-3 EFA supplements, in either predominantly triacylglyceride or phospholipid form, significantly reduce key clinical signs and symptoms of DED, compared to placebo over a three-month treatment period.
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ItemThe effect of chronic hypertension on retinal susceptibility to chronic intraocular pressure elevation( 2016)Higher blood pressure and thus better blood flow should protect the eye against glaucoma, but epidemiological studies suggest the opposite. This thesis provides direct experimental evidence in a rodent model of glaucoma that chronic hypertension impairs the capacity of the ocular blood vessels to cope with changes in blood pressure. This negates any benefit gained from having higher blood perfusion into the eye. These data provide an explanation for why chronic hypertension is a risk factor for glaucoma.
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ItemVascular autoregulation: retina as a non-invasive biomarker for the brain( 2016)The retinal vasculature maybe a useful surrogate for the brain blood vascular network. There has yet to be a direct comparison of the capacity of vessels in the eye and brain to respond to changes in blood pressure or blood gas concentration. We showed that arteries in the rat’s eye and brain demonstrated qualitatively similar vascular autoregulatory capacity in response to a wide range of blood pressure and different blood gas concentrations.
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ItemInvesting the laser-induced model of choroidal neovascularisation in Long Evans rats( 2016)Laser-induced choroidal neovascularisation (LI CNV) involves delivering laser energy to the retina to produce a breach in Bruch’s membrane (BM). Elevation of pro-angiogenic and inflammatory cytokines in addition to extracellular matrix remodelling promotes the ingrowth of CNV following breach. A review of CNV, the effect of laser on the retina, and LI CNV is given in Chapter 2. Calibration of laser and all experimental methods are dealt with in Chapter 3. The dose-response of laser energy for BM breach is investigated in experimental Chapter 4 along with non-invasive measures of BM rupture. The minimum laser energy required for successful breach of BM on 95% of occasions was determined. The change in pro-angiogenic and inflammatory markers following laser rupture of BM was investigated in Chapter 5 using a laser energy flux of 5.10 J/mm2. The rate at which laser lesions converted to experimental CNV using this laser energy was investigated. We show that the presence of bubble at the time of laser application is an accurate predictor of BM breach at 28 days as established by IHC. SD-OCT is also an accurate predictor of breach that has advantages in allowing longitudinal (non-invasive) study of the animal. This could enhance the development of therapeutic interventions.
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ItemDeveloping eye care and an analysis of eye conditions in Papua New Guinea( 2007)Accessible and affordable eye care is only a dream for much of the population of developing countries. Strategies for improving the visual welfare of these people need to be appropriate to the local situation. In 1992 a proposal was devised to address the lack of eye care in Papua New Guinea. This thesis examines the outcome of this proposal and reports on the ophthalmic data collected by these trained eye nurses.Method: In 1994, 11 National nurses were trained in a 3 month intensive course to become ‘eye nurses’. A basic set of equipment was provided to each eye nurse. Appropriate follow-up and annual conferences supported this initial training. A second group of 14 eye nurses were trained in 1997. Monthly eye clinic reports from the eye nurses provide significant data on eye conditions and visual welfare in PNGResults: After 6 years 80% of the eye nurses were still actively working in eye care. An analysis was made of the eye conditions of the 30,000 patients examined by the eye nurses over this 6 year period. The data is generally consistent with previous ophthalmic data from Papua New Guinea. The eye nurses were able to provide appropriate eye care for 80% of the presenting patients without Optometric or Ophthalmic assistance.Conclusions: Training nurses to become ‘eye nurses’ functioning as basic optometrists is an effective strategy in improving eye care in developing countries. The eye nurses were able to deliver sustainable, accessible, affordable and appropriate eye care, independently treating and managing the most common eye conditions in Papua New Guinea.
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ItemThe relationship between ocular blood flow, oxygen saturation and visual function during IOP elevation( 2013)PURPOSE: This thesis explores the intra- and inter-session repeatability of retinal vessel oxygen saturation measured using the Oxymap retinal oximeter (Chapter 3). Moreover, it considers the effect of moderate intraocular pressure (IOP) perturbation on retinal oxygen saturation, blood flow and the pattern electroretinogram (PERG) in young, healthy participants (Chapter 4). METHODS: Ten fundus oximetry images were acquired from 18 healthy participants (age 22 -38) using the Oxymap retinal oximeter T1, with a further ten images obtained one to two weeks later. All pixels returned from the vessel detection algorithm were analysed by plotting frequency histograms of oxygen saturation, which were then modelled using Gaussian functions to return peak oxygen saturation for arteries and veins of various diameters. Intra- and inter-session variability was quantified by evaluating the coefficient of variation and establishing the 95% confidence limits on this coefficient using Bland and Altman analysis. In a further study, 23 young (22-38 years), healthy participants had PERG, retinal oximetry and flowmetry images recorded before, during and after IOP elevation. Using a probe placed on the lower eyelid, IOP was increased by ~30 mmHg to lower ocular perfusion pressure (OPP) by ~30%. Steady-state PERG waveforms (8.3 Hz) were recorded bilaterally (200 sweeps) to return the second harmonic amplitude (16.7 reversals/sec). Peak oxygen saturation for arteries and veins of various diameters on oximetry (Oxymap retinal oximeter) was assessed by fitting Gaussian functions to frequency histograms of all pixels. Blood flow, volume and velocity (Heidelberg retinal flowmeter) were averaged within a 10x10 pixel window at the temporal retina. RESULTS: Bland and Altman analysis showed that there was no bias within and between recording sessions, with variable intra- and inter-session confidence limits depending on the analysis technique and number of images analysed (Chapter 3). In Chapter 4, PERG amplitude was significantly reduced (F(2,44) = 24.24, p < 0.01) and phase significantly delayed (F(2,44) = 17.00, p < 0.01) during IOP perturbation. Contralateral eyes were unchanged. Arterial oxygen saturation remained the same (F(1.43,30.08) = 3.69, p = 0.05), whereas venous saturations reduced (F(1.39,29.15) = 38.64, p < 0.01). Blood flow was shown to change across the 3 conditions (F(2,36) = 5.37, p < 0.01). Poor correlation was found between OPP reduction and either PERG amplitude, PERG phase or venous oxygen saturation. CONCLUSIONS: Oxymap retinal oxygen saturation measurements of arteries and veins are variable, both within and between clinical sessions. Like PERG amplitude, retinal oxygen saturation is sensitive to an acute, moderate IOP perturbation in young participants. The implications of the above outcomes and future directions are discussed in Chapter 5.