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Introduction: Myopia is a refractive error associated with an increased risk of sight threatening ocular pathology. Its aetiology is heterogenous in nature, with a combination of genetic and environmental factors, such as less time spent outdoors, intensive education and increased near work (Rudnicka et al., 2016; Xiong, Sankaridurg, et al., 2017), shown to play a role in its development and progression (Morgan and Rose, 2019). Animal studies and some clinical observations suggest that relative peripheral hyperopia also promotes the development and progression of myopia (Nathan, 1985; Smith and Hung, 1998; Mutti et al., 2007; Sankaridurg et al., 2011; Santodomingo-Rubido et al., 2016; Chamberlain et al., 2019; Lam et al., 2019). The Northern Ireland Childhood Errors of Refraction 1.0 (NICER 1.0) Study, an epidemiological study of the prevalence of refractive error in white UK school children (Lisa O'Donoghue et al., 2010), commenced in 2006/2008. Since 2008 electronic devices have dramatically risen in popularity among UK children (Ofcom, 2011, 2020), which some researchers have implicated in the global surge in childhood myopia prevalence (Holden et al., 2016; Lanca and Saw, 2020). Aims: The overall aim of this thesis was to re-evaluate the prevalence of refractive error among white UK school children to determine trends in the prevalence and age of onset of myopia over the last decade. The present work also evaluated the relationship between relative peripheral refraction and changes in central refraction and axial length over one year in children. Methods: The present study employed identical sampling methodology and cycloplegic examination procedures to The NICER 1.0 Study (Lisa O'Donoghue et al., 2010). Comparisons were drawn between contemporary refractive data and data from age- and ethnicity-matched children in 2006/2008. Baseline measures of spherical equivalent refraction (SER) in the central and peripheral horizontal retina and axial length were recorded, and measurements were repeated after 12-months on a sub-group of children. Results and conclusions: This thesis established that the prevalence of childhood myopia has remained relatively unchanged in the UK over the last 12 years. There is no evidence that the age of onset of myopia has decreased in this time. The present work found that a hyperopic relative peripheral refraction in the nasal retina is a statistically significant predictor for accelerated eye growth in teenage myopes. Eye care clinicians should consider myopia control options that reduce relative peripheral hyperopia in cases of established myopes to slow further axial elongation.

Background: Myopia prevalence is rising around the world at a rate that cannot be explained by genetics alone therefore, environmental risk factors must have an influence. Accurate measurements of refractive error and potential risk factors are required to better understand the relationship between environment and refractive development such that evidence-based advice can be provided to patients and parents by eye care professionals. This thesis was designed to investigate some potentially modifiable risk factors for myopia in young UK children. Methods: One hundred children (aged 6-9) participated in cross-sectional evaluation of previously proposed environmental risk factors for myopia. Spherical equivalent refraction (SER) and axial length (AL) were determined by cycloplegic autorefraction and ocular biometry. Potential risk factors for myopia were measured using Actiwatch 2 and Clouclip devices. Screen time, sleep, physical activity, and parental myopia data were collected using questionnaires. 42 children were followed up 12-months after baseline and change in SER and AL measures examined. Correlations were explored between change in SER and AL and baseline environmental exposure profiles. Results and Conclusions: The data demonstrated that: • Compared with children classed as non-myopic (≥+0.75 D), pre-myopes/myopes (< +0.75) go to bed later and fall asleep faster (increasing their sleep efficiency), are exposed to higher illumination during sleep, and have poorer subjective sleep quality. Over 12-months, higher sleep efficiency and less wake after sleep onset were associated with faster axial elongation, whereas less time spent in mesopic light was associated with faster myopic progression. • Compared with children classed as non-myopic, pre-myopes/myopes spent significantly more time undertaking moderate-vigorous physical activity later in the day, potentially disrupting circadian rhythms. • More myopic SER's were significantly associated with increased time spent viewing at near on weekday mornings and increased time spent on intermediate viewing was significantly related to greater myopic shift over 12-months.• Using a phone/tablet for 1-2 hours/day, watching TV/video games 1-3 hours/day and a higher duration of near work all increased the likelihood of children demonstrating accelerated eye growth over a 12-month period. • Parents wishing to mitigate against myopia-promoting eye growth should encourage; less near work, less time on phones/tablets or watching TV/video games, less bright light and less physical activity in the evenings, earlier bedtimes and sleeping in darkness.

Hypothesis: It is possible to safely increase the conventional limits of corneal laser refractive surgery for high ametropia and irregular astigmatism using ablation profile modifications, pre and postoperative safety screening and monitoring, surgical technique improvements such as centration, introduction of the small incision lenticule extraction (SMILE) surgical procedure as an alternative to laser in-situ keratomileusis (LASIK), and the use of therapeutic options including topography-guided custom ablation and trans-epithelial phototherapeutic keratectomy. Results: A method for the safe treatment of high myopia up to -14.00 D by corneal laser refractive surgery was described through the use of aspherically optimized ablation profiles, residual stromal thickness mapping by VHF digital ultrasound for safe retreatment planning, a two-stage treatment protocol for high corrections and thin corneas, and flap creation by a femtosecond laser enabling the use of thinner flaps. Results were found to be comparable to those achieved by intraocular surgery, while avoiding the catastrophic risks of intraocular surgery. A method for the safe treatment of high hyperopia up to +7.00 D by corneal laser refractive surgery was described through the use of large optical zones and transition zones to maximize refractive stability, residual stromal thickness mapping by VHF digital ultrasound for safe retreatment planning, and a two-stage treatment protocol for high corrections. The safety of retreatments was also assessed by monitoring the epithelial thickness by VHF digital ultrasound as a more reliable parameter to avoid apical syndrome than using corneal curvature. This enabled retreatment to be safely performed in eyes with relatively thick epithelium but steep corneal curvature, and no retreatment performed in eyes with thin epithelium but otherwise flat corneal curvature. Results were found to be comparable to those achieved by intraocular surgery, while avoiding the catastrophic risks of intraocular surgery. The influence of ocular residual astigmatism on refractive predictability was evaluated and compared to prior publications to investigate potential methodological flaws. The method of grouping by a ratio was found to bias the results towards lower predictability in the high ocular residual astigmatism group due to the treated cylinder not being matched between groups. However, a small difference was still found after matching for treated cylinder with a slightly lower predictability in the group of eyes with high corneal astigmatism, high refractive cylinder, and high ocular residual astigmatism. But this result must take into account the potential for bias in this group due to potential errors in the manifest refraction, poor scan quality of the topography measurement, or the presence of non-orthogonal corneal astigmatism or other higher order aberrations. This study highlighted the importance of comparing the manifest refraction with the corneal astigmatism before surgery and to re-refract the patient if the ocular residual astigmatism is abnormally high. The ability to repair the complications of corneal laser refractive surgery is a critical component of achieving optimal outcomes. Quality of vision can be compromised by optical zone decentration or a small topographic optical zone. Topography-guided custom ablation was shown to be effective at improving the optical zone centration relative to the corneal vertex and enlarging the topographic optical zone. These topographic changes were associated with a significant reduction in corneal higher order aberrations. The last chapter introduced small incision lenticule extraction (SMILE) as a potential procedure that might be suited for the correction of high ametropia due to the preservation of the anterior stromal lamellae and Bowman's layer by not requiring a LASIK flap. A number of aspects of SMILE were evaluated. Firstly, cylinder predictability was found to vary according to the cylinder axis indicating the need for an angular dependent nomogram. Secondly, spherical aberration induction was shown to decrease for larger optical zones, with SMILE achieving greater spherical aberration control compared to aspherically-optimized LASIK. Thirdly, it was demonstrated that there was clinically negligible astigmatism effect due to the small incisions. Conclusion: Corneal laser refractive surgery can offer safe and effective treatment for a wide range of myopia, hyperopia, and astigmatism by using optimized ablation profile design, residual stromal thickness mapping, and a two-stage treatment protocol. Consideration of the epithelial thickness as the risk factor for apical syndrome in hyperopia also offers greater safety than that provided by corneal curvature. The methods described in this thesis may facilitate corneal laser refractive treatment in a cohort of patients in which intraocular surgical techniques have traditionally been preferred.

The relationship between accommodation and myopia has been under investigation for many years, and the effort to understand it is ongoing. In this thesis, an introduction to the state of myopia research is given first, with particular reference to studies of accommodation and higher-order ocular aberrations, which feature in the subsequent chapters. Following a brief introduction to the general technique of aberrometry and visual stimulus control using adaptive optics, the development of a monocular adaptive optics instrument for this purpose is described. The instrument is used to vary a dioptric stimulus and record the accommodation response in pilot studies and a detailed experiment, which has also been published elsewhere. It is found, among other things, that accommodation can respond to more than one different input level during its latency period, and that such inputs can be stored until components of the accommodation control system are free to process them. Indications of a minimum halting time for accommodation, of around 0.6 s, are presented. In later chapters, the development and testing of a new, binocular adaptive optics apparatus will be found. As well as binocular aberrometry and adaptive optics control of stimulus aberrations, this instrument displaces images to allow for and stimulate ocular convergence in binocular accommodation experiments. It is the first instrument in the world with its combined functionalities. Finally, the contribution of this thesis is summarised, and further instrumentation development and experiments are put forward for the continuation of this branch of accommodation and myopia research.

Retinal blur experienced by myopes during near work has been linked to myopia development and progression. Whether poor responses to blur signals are due to poor perceptual blur sensitivity (subjective depth of focus), poor neural accommodation responses (objective depth of focus) to blur or optical differences such as higher order aberrations making blur detection difficult is yet unclear. This study investigates whether myopes respond to blur differently compared to emmetropes and whether filtering spatial frequencies in reading text influence accommodation responses. Accommodative functions were investigated using spatial frequency filtered text targets of two different sizes (N10 and N20). Monocular objective depth of focus (DOF), accommodative microfluctuations, and dynamic accommodation were measured. Subjective DOF after cycloplegia was also recorded with the same targets. Higher order aberration measurements explored optical contributions to blur. Peripheral refraction and accommodative lag were also measured to consider how in combination they might increase peripheral retinal blur for near tasks. Results showed that myopes demonstrated larger subjective DOF. Subjective DOF was larger when viewing the peak text spatial frequency in both refractive error groups. The optimum focus was more myopic for text peak spatial frequencies. Levels of spherical aberration were correlated with the point of optimum focus. Objective DOF and accommodative microfluctuations were larger in myopes when viewing the peak text spatial frequencies. Dynamic accommodation showed that while myopes were not poorer at initiating accommodation responses they had longer positive response times. Accommodative lag, although not different in myopes, increases the peripheral hyperopic blur experienced for near tasks. Conclusion: Myopes were poorer at using retinal blur cues to refine accommodation responses especially when viewing peak text spatial frequencies. Larger positive response times, DOF and accommodative microfluctuations in myopes resulted in accommodative error and hyperopic blur for near tasks. Spherical aberration, previously thought to provide a myopigenic stimulus, was not different between refractive groups and is unlikely to be large enough to enhance DOF during naturalistic viewing. Blur adaptation studies might consider using peak text spatial frequencies as adaptation targets to reduce accommodation differences in myopes and emmetropes. Optical treatment strategies aimed at correcting peripheral refraction to control myopia should consider the combined effect of accommodative lag which increases levels of hyperopic peripheral blur experienced by myopes.

The aim of the present project was to analyse the link between peripheral posture, optics, optics and refractive error progression. Preliminary studies were conducted to ensure that peripheral aberrometry is valid for further analysis. The repeatability of the IRX-3 for peripheral aberrometry was asgood as for central measurements and the recalculation of elliptical pupils did not seem to be necessary for measurements up to 20 degrees eccentricity. Higher order aberration measurements werecomparable to other studies. Eye and head movements as well as working distance did not differ significantly between myopes and non-myopes. However, there was some evidence, that forward bending of the head during reading increases in association with higher refractive error progression rates. The link between central higher order aberrations and refractive error development was analysed by comparing higher order aberrations between isometropes and anisometropes. This analysisdid not show any significant association of higher order aberrations on the development, as no major differences were found between the two groups. For central vision, changes in biometric parameters during accommodation were analysed. It was found that biometric parameters change similarly in myopes and non-myopes. Peripheral accommodation was found to differ between myopes and emmetropes indicating that there might be an influence of peripheral refraction on myopisation. However, associationbetween peripheral refraction or peripheral aberrations and refractive error progression were not significant. The reason for this observation might be the low refractive error progression (0.04± 0.29 D in myopes and -0.12 ± 0.38 D in emmetropes) during one year in the study population.

The increasing prevalence of myopia over the past few decades and its association with potential ocular complications make myopia an important research topic. The present work is concerned with the structural and functional characteristics of a group of myopic and emmetropic individuals. The technical experiments in this work investigated firstly the effect of instrument alignment on peripheral refraction measurements and revealed that the corneal vertex was an acceptable alignment position of the Shin-Nippon NVision-K 5001 autorefractor, allowing consistent alignment with other instruments used in this research. Secondly, spectacles could be used to provide comparable vision to contact lenses in the visual performance studies. In the main experimental parts of this work, visual performance and multiple aspects of ocular structure were assessed across a wide range of eccentricities along the horizontal and vertical meridians within the same eyes. The structural properties of the myopic eye were measured through central and peripheral autorefraction, and through cornea to retina dimensions using non-contact biometry. In addition, the central and peripheral resolution acuities of myopic and emmetropic eyes for high and low contrast levels were investigated. Our structural and functional measurements revealed relatively prolate myopic eyes with reduced high contrast resolution acuity, compared to emmetropic eyes. Moreover, multiple regression analyses were performed at the fovea and outermost retinal eccentricities common to all core experiments but revealed no strong relationship between the structure and function of the myopic eye. Finally, regarding asymmetry, the nasal and superior retinae were found to be longer and to perform better in comparison to the temporal and superior retinae respectively.

The main experimental work of this thesis has been a cross-sectional study of the prevalence of refractive error and its biometric correlates in Middle Eastern adults. In addition dynamic accommodative responses and twenty-four hour axial length fluctuations were investigated in young myopic adults. The prevalence of myopia in 3000 Middle Eastern adults (age range 17-40 years) was similar to previously reported levels of myopia in the West. Myopia was associated with a higher level of education, occupations with a high nearwork demand and positive family history of myopia; all of which have been identified as risk factors for myopia development and progression Diurnal variations in axial length (AL) of similar magnitude to those previously reported in emmetropes were observed in myopes recruited in the current thesis. However, the pattern of the diurnal variation in AL was significantly different between early-onset myopes (EOMs) and late-onset myopes (LOMs). There were no significant differences between EOMs and LOMs in the dynamic accommodative response to a sinusoidally oscillating target. The accommodative phase lag was increased following 30 minute adaptation to myopic defocus using +2.00 D lens. However, intense prolonged (30 minute) nearwork was found to have no effect on accommodative gain or phase lag. A number of recommendations for further work on the prevalence of refractive error in the Middle East are suggested along with further research on diurnal AL variations and dynamic accommodative responses in EOMs and LOMs.

This thesis has investigated nearwork-induced transient myopia and accommodation responses in relation to refractive stability, multichromatic stimuli and orthokeratology. Five individual studies have been carried out. Initially an investigation into the temporal and dioptric aspects of nearwork-induced transient myopia was undertaken, suggesting that increased task duration does not increase the level, or slow the regression of post-task NITM, however an increase in the dioptric demand of the task does. In the second study, a longitudinal myopia progression study, these findings were related to short term myopia progression. The third investigation demonstrates the feasibility of measuring the biometric correlates of nearwork-induced transient myopia using a low coherence reflectometry device (LenStar, Haag Streit Koeniz, Switzerland). Fourthly, a comparison of the differences between static and dynamic accommodative responses, microfluctuations and nearwork-induced transient myopia produced when viewing a black/white target as oppose to a red/blue target has suggested the possibility of four accommodative responses to this multichromatic stimulus. Further investigation will be necessary to investigate if any of these response types are related to myopia progression. 2 The final study investigates the effect of two different designs of orthokeratology contact lenses (C5 and polynomial) on visual function. It appears to be the case that although the polynomial lens design has a larger refractive effect than the C5 lens it reduces both high and low contrast corrected visual acuity to a greater extent. The higher the baseline mean spherical equivalent refractive error the larger the detrimental effect.

The objective of the present studies was to assess whether there were predictable differences in the thickness of the human cornea in relation to stable manifest refractive error using a scanning slit optical topography method (Orbscan II).

Myopia is a refractive condition and develops because either the optical power of the eye is abnormally great or the eye is abnormally long, the optical consequences being that the focal length of the eye is too short for the physical length of the eye. The increase in axial length has been shown to match closely the dioptric error of the eye, in that a lmm increase in axial length usually generates 2 to 3D of myopia. The most common form of myopia is early-onset myopia (EO M) which occurs between 6 to 14 years of age. The second most common form of myopia is late-onset myopia (LOM) which emerges in late teens or early twenties, at a time when the eye should have ceased growing. The prevalence of LOM is increasing and research has indicated a link with excessive and sustained nearwork. The aim of this thesis was to examine the ocular biometric correlates associated with LOM and EOM development and progression. Biometric data was recorded on SO subjects, aged 16 to 26 years. The group was divided into 26 emmetropic subjects and 24 myopic subjects. Keratometry, corneal topography, ultrasonography, lens shape, central and peripheral refractive error, ocular blood flow and assessment of accommodation were measured on three occasions during an ISmonth to 2-year longitudinal study. Retinal contours were derived using a specially derived computer program. The thesis shows that myopia progression is related to an increase in vitreous chamber depth, a finding which supports previous work. The myopes exhibited hyperopic relative peripheral refractive error (PRE) and the emmetropes exhibited myopic relative PRE. Myopes demonstrated a prolate retinal shape and the retina became more prolate with myopia progression. The results show that a longitudinal, rather than equatorial, increase in the posterior segment is the principal structural correlate of myopia. Retinal shape, relative PRE and the ratio of axial length to corneal curvature have been indicated, in this thesis, as predictive factors for myopia onset and development. Data from this thesis demonstrates that myopia progression in the LOM group is the result of an increase in anterior segment power, owing to an increase in lens thickness, in conjunction with posterior segment elongation. Myopia progression in the EOM group is the product of a long posterior segment, which over-compensates for a weak anterior segment power. The weak anterior segment power in the EOM group is related to a combination of crystalline lens thinning and surface flattening. The results presented in this thesis confirm that posterior segment elongation is the main structural correlate in both EOM and LOM progression. The techniques and computer programs employed in the thesis are reproducible and robust providing a valuable framework for further myopia research and assessment of predictive factors.

Myopia, or nearsightedness, is the most common form of refractive error and is increasing in prevalence. As a result, there has been renewed interest in studying myopia from the context of light perception, beginning with the opsin family of G-Protein Coupled Receptors (GPCRs). Refractive phenotypes have been characterized in every opsin signaling pathway studied. This leaves only OPN3, which we hypothesized is involved in refractive development through Gi coupling (as shown in fish and mosquito). We have assessed Opn3 mutants and shown that the OPN3 germline, but not retina or lens conditional Opn3 knockout, shows a myopic refractive development phenotype. Despite this, Opn3 null eyes demonstrate an unchanged susceptibility to lens induced myopia, albeit with an altered expression signature for the GO/GROW genes that reflect refractive mismatch. Lens conditional Drd4 and Gnai2, but not Gnai3, knockouts manifested a hyperopia; although, Gi coupling to Opn3 cannot explain this phenotype. Light exposed ex-vivo lenses exhibited an Opn3-dependent, light-induced optical change which is potentiated by dopamine via the Drd4 receptor; however, this function does not play a role in refractive development. These data suggest that an OPN3 expression domain outside the retina and lens can control anterior eye development and thus the refractive performance of the eye. The work to exclude lens and retinal OPN3 as the contributing domain in this refractive phenotype is unique and suggests a distinct mechanism when compared to other opsins. Although our results would suggest the light-induced optical change in the lens does not have functional consequences for refractive development, studies of inhibitory G-proteins, as indicated by the hyperopia phenotype of both the Drd4 and Gnai2 lens conditional knockouts, provide an interesting avenue for examining refractive error originating from the lens.

White-to-white (WTW) distance is one of the anterior segment metrics of the eye that has significant clinical implications and utility. Traditionally used as a diagnostic tool for congenital glaucoma, microcornea, and megalocornea, WTW distance has also been found to play an important role in planning and predicting successful outcomes for refractive cataract and implantable collamer lens (ICL) surgeries. For example, it has become a standard measurement utilized for calculating both the refractive power of intraocular lenses (IOL) for cataract surgeries, and ICL size. The goal of this thesis is to review 1) the various ways in which WTW distance is used in the clinical setting and 2) whether it has any correlation to the degree of myopia. The current literature on WTW distance, including the various methods of measurement and its utility in clinical procedures is reviewed. Comparative evaluations of the various devices that can measure WTW distance show a generally good repeatability, with no gold standard for accurate measurement. Some argue that a manual measurement using a caliper at the slit lamp is the gold standard, but this method has been found to have high variability. Additionally, there is ongoing debate on whether WTW distance is sufficient for accurate ICL sizing and successful surgical outcomes. More recent data show alternative metrics such as sulcus-to-sulcus (STS) or angle-to-angle (ATA) diameter to be better predictors of accurate ICL sizes. Despite recent findings of better clinical outcomes using these internal ocular metrics for ICL surgery, whether they are cost effective and clinically significant enough to replace existing methods remains inconclusive. WTW distance and degree of myopia from the patient database at Boston Vision was also analyzed. A pairwise p-test with Bonferroni correction of WTW distance in 107 eyes with no myopia, low myopia, or high myopia revealed that there was no strong correlation between WTW and degree of myopia (p > 0.05). However, the WTW distance was smaller in females than in males (mean difference -0.3245; p < 0.001), which confirmed findings from a previous study. Based on these preliminary findings, it doesn’t seem clear that a correlation between WTW distance and degree of myopia exists. While the practical implications of WTW have been widely assessed, additional studies and research using a large dataset should be performed to accurately evaluate the utility of WTW in predicting myopia.

Myopia development has been attributed to eyeball elongation, but its driving force is not fully understood. Previous research suggests lack of time spent outdoors with exposure to high light levels or time spent on near-work as potential environmental risk factors. Although light levels are quantifiable with wearables, near-work relies solely on questionnaires for data collection and there remains a risk of subjective bias. Studies spanning decades identified that eye growth is optically guided. This proposal received further support from recent findings of larger changes in the thickness of the eye’s choroidal layer after short-term optical interventions compared with daily eye-length changes attributed to myopia. Most of these studies used a monocular optical appliance to manipulate potential myogenic factors, which may introduce confounders by disrupting the natural functionality of the visual system. This thesis reports on improvements in systems for characterising the visual dioptric space and its application to myopia studies. Understanding the driving forces of myopia will prevent related vision loss. Study I: An eye-tracker was developed and validated that incorporated time-of-flight (ToF) technology to obtain spatial information of the wearer’s field of view. By matching gaze data with point cloud data, the distance to the point of regard (DtPoR) is determined. Result: DtPoR can be measured continuously with clinically relevant accuracy to estimate near-work objectively. Study II: Near-work was measured with diary entries and compared with DtPoR estimations. Diversity of the dioptric landscape presented to the retina was assessed during near-work. Results: Objective and subjective measures of near-work were not found to highly correlate. Ecologically valid dioptric landscape during near-work decreases by up to -1.5 D towards the periphery of a 50˚ visual field. Study III: Choroid thickness changes were evaluated after exposure (approximately 30min) to a controlled, dioptrically diverse landscape with a global, sensitivity enhanced model. Result: No choroid thickness changes were found within the measuring field of approximately 45˚. Discussion The developed device could support future research to resolve disagreement between objective and subjective data of near-work and contribute to a better understanding of the ecological valid dioptric landscape. Proposed choroid layer thickness model might support short-term myopia-control research.

Purpose Time outdoors has been shown to be protective against myopia development in school-age children, possibly due to bright, ambient light resulting in increased retinal dopamine and an inhibitory effect on axial elongation. Recently, Aleman et al. (2018) demonstrated that reading reversed text polarity (light text on a dark background vs. conventional dark text on a light background) increased choroidal thickness, which may be influenced by retinal dopamine release. Dopamine may also enhance melanopsin-driven pupillary responses (Sodhi and Hartwick, 2014). The current study seeks to evaluate whether reversed text polarity also enhances these pupillary responses to multiple pulses of blue and red light.MethodsTwenty subjects (11 females, 9 males) age 21-29 years with refractive errors ranging from -4.50 D to +1.03 D were recruited from The Ohio State University College of Optometry. Subjects pre-adapted in a darkened room by viewing a 32 cd/m2 uniform gray screen displayed on an iPad at 40 cm (36.1° by 27.6°) for 5 minutes before baseline pupil measures were taken on the RAPDx (Konan Medical, USA) pupilometer. Subjects then silently read an isoluminant text excerpt (angular text size: 12.8 minutes of arc) for 15 minutes, randomly chosen to be either traditional dark text on a light background (DonL) polarity, or light text on a dark background (LonD), all with an average luminance of 32 cd/m2. Pupil testing was repeated at the conclusion of the reading period. A second visit repeated the same procedure, using the opposite polarity from the first visit for the reading period. Normalized pupillary responses were measured in response to square-wave light pulses interwoven with darkness at 0.1 Hz in three color patterns: 12 pulses alternating between red and blue (6 of each color),, followed by 6 pulses of red, then 6 pulses of blue. There was no dark adaptation between the three color patterns.ResultsThe pupil became increasingly more constricted in response to the alternating presentation of blue stimuli after subjects read LonD compared to DonL text (p = 0.047). This difference appeared by the third pulse. The constriction in response to the initial two pulses of Alt. Blue was not significantly different between the two text polarities (p = 0.98) but became significantly more constricted by 2.4 ± 3.7% during pulses 3-6 after subjects read LonD compared to DonL text (p = 0.008). Greater pupillary constriction was not correlated with refractive error (p = 0.51). The pupillary responses showed no effect of text polarity during re-dilation in response to alternating blue (p = 0.93) or during constriction or re-dilation in response to alternating red or to the single color stimuli of either color (p-values between 0.21 – 0.96). When considering the effect of reading isoluminant text compared to viewing uniform gray, the pupillary constriction was significantly less during the alternating presentations by 2.3% - 4.1% during Pulses 2 and 1, respectively, independent of color and polarity. The pupil was less dilated by 1.8 ± 0.6% during the re-dilation phase in response to Single Color Blue independent of text polarity (p = 0.01) but there were no effects of isoluminant text on pupillary responses to Single Color Red (p

Background: Myopia is a highly prevalent disorder, and one of the first causes of blindness. In turn, alcohol consumption has been shown to be a risk factor for many diseases and a main contributor to the global burden of disease. However, no studies have investigated the relationship between alcohol intake and myopia. Our aim was to prospectively assess the association between alcohol intake and the development or progression of myopia. Methods: In a Spanish dynamic prospective cohort (the SUN Project) we assessed 15,642 university graduates, recruited between 1999 and 2018 and followed up biennially through mailed questionnaires. Alcohol intake was assessed with a validated 136-item food frequency questionnaire. Development or progression of myopia was collected in subsequent questionnaires during follow-up every two years. Results: Alcohol intake was linearly and significantly associated with a higher risk of myopia development or progression: the OR for 10-year incidence/progression of myopia was 1.05, 95% CI 1.01–1.09 per each 10-grams increase in alcohol intake. Conclusions: Alcohol consumption might lead to the development or progression of myopia, although confir- mation is needed for the mechanisms through which this association may occur, thus further research is needed to verify these findings

Purpose: Time spent outdoors has been consistently associated with delaying the onset of myopia. This association may be due to the involvement of intrinsically photosensitive retinal ganglion cells (ipRGCs), considering their role in long-term ambient illumination detection and connection with dopaminergic amacrine cells. Pupil responses driven by ipRGC input have typically been measured clinically in response to flashes of red and blue light following dark adaptation. However, this is not a feasible method for testing children, as dark adaptation adds a significant amount of time to each trial. The purpose of this study was to evaluate the effect of dark adaptation on the pupil responses to red and blue light stimulation. Methods: Subjects were 20 adults age 24.0 ± 2.37 years (average ± SD), 55% female, with an average spherical equivalent (SEQ) refractive error of -3.22 ± 2.78 diopters (Grand Seiko WR-5100K cycloplegic autorefraction), ranging from -10.61 to +0.77 diopters. The RAPDx pupilometer measured pupil sizes in response to blue and/or red light oscillating at a low temporal frequency of 0.1Hz. The standard testing protocol included 5 minutes of dark adaptation prior to each of three stimulus conditions: alternating red and blue, red-only, then blue-only. Subjects repeated this standard protocol without dark adaptation. This study also evaluated whether pupil responses might be enhanced by two minutes of red-only stimulation (instead of the standard one minute), once with and once without dark adaptation. These 4 test conditions were conducted in random order on separate days. The primary outcome measure was the difference in normalized pupil size in response to blue-only light compared to blue during the alternating condition. Results: Consistent with previous research, pupils tended to become more constricted with repeated exposure to blue light. The average difference (±SD) in normalized pupil size between blue-only and alternating blue conditions with dark adaptation was 10 ± 2.4%. Without dark adaptation, the pupil did not become as constricted with repeated exposure to blue light, with the difference reduced by 2.8% (repeated measures ANOVA; p

Many factors are involved in the development of myopia, including time spent outdoors during childhood and teenage years. However, aspects such as the precise amount of time outdoors required to prevent myopia and variations in light intensity on this process are not well understood.Surveys were distributed electronically to coaches of youth baseball and soccer teams across the United States and included questions about the number of hours their athletes practice per week during each season, the total number of athletes on their team, and the number of athletes who wear glasses or contact lenses to see far away. The survey responses were sorted by the location of team (northern or southern United States) as well as type of sport (baseball or soccer). Z scores were used to compare the overall proportion of myopia to population estimates: Kleinstein et al. (2012) = 16%, Holden et al. (2016) (ages 15-19) “2000” = 20% and “2050” = 33%. A two-way analysis of variance (ANOVA) tested for differences across sport and location.The proportion (± SD) of athletes with myopia were as follows: all teams (n = 1610, 19% ± 1%), northern teams (n = 598, 21% ± 2%), southern teams (n = 1012, 18% ± 1%), baseball teams (n = 859, 20% ± 1%), and soccer teams (n = 751, 19% ± 1%). The proportion of athletes with myopia in this sample was higher than Kleinstein et al. (2012) (Z=3.2, p=0.0005), not different from Holden et al (2016) “2000” (Z=-1.0, p=0.16), and less than Holden et al. (2016) “2050” (Z = -11.9, p0.05).Although these youth spend a great deal of time practicing outdoors, the proportion of athletes with myopia was still 20% overall. This proportion was not less than recent population estimates but did appear to be less than one group’s estimate of what the proportion of myopia might be for this age group in the year 2050. In this sample size, there was no effect of geographic location or type of sport played on the proportion of myopia. Future studies should continue to investigate the minimum amount of time outdoors or other factors that are needed to prevent myopia onset and reduce the rate of progression.

The objective of this thesis was to determine if a model to evaluate ocular response to short term exposure with optical defocus could be developed using the parameters of central and peripheral eye length and choroidal thickness. To achieve the objective, the following experiments were conducted: a) identify and improve methods to measure central and peripheral eye length and choroidal thickness and to determine repeatability of methods; b) conduct a provocative test to determine the limits of change of choroidal thickness; c) impose short term optical defocus on human eyes and measure central and peripheral eye length and choroidal thickness as well as accommodative response, and d) study the influence of time of day on eye length and choroidal thickness response to short term optical defocus. Eye length and choroidal thickness measurements were conducted with Lenstar (Haag‐Streit Koeniz, Switzerland) and SS OCT (Topcon, Tokyo, Japan) and a custom attachment for Lenstar was developed to enable peripheral eye length measurements. A 3D volume scan was conducted with OCT and choroidal thickness values extracted. Both central and peripheral retina (nasal, temporal, superior and inferior to 20º periphery, in 10º steps) were measured and repeatability assessed. The study involved 20 human adult participants who were measured twice. At the central retina, repeatability for eye length and choroidal thickness was ±13 μm and ±15μm, respectively. At the peripheral retinal locations, repeatability ranged from ±24 to ±93 μm for eye length and ±9 to ±35 μm for choroidal thickness. To estimate the extent to which the choroidal layer changes in thickness, a provocative test involving a change in body posture from sitting to recumbent position was conducted (n=15, adult participants). Choroidal thickness and intraocular pressure (IOP) were measured with the participant in the sitting position and after a change to a recumbent position. IOP increased by 1.02 ± 1.35 mmHg and choroid thickened by 10.39 ± 50.60 μm. The thickening of choroid was not significant. These data were to serve as benchmark to assess the response to optical defocus. In an experiment involving 22 adult human participants, the effects of 30 minutes exposure to optical defocus (myopic (+3.00 D), hyperopic (-3.00 D) and multifocal (Centre-distance, Plano/+2.50 D)) on central and peripheral eye length and choroidal thickness along both horizontal and vertical field meridians (up to 20º, in 10º steps) were investigated. The accommodative response of the eye was also measured. Each participant attended 3 visits (3 separate days, 07:00 a.m. to 11:00 a.m.) where the right eye was measured before and after 30 minutes of exposure to optical defocus. Immediately post exposure to myopic, hyperopic and multifocal defocus, central and peripheral eye length was mostly shorter (-5±12 μm centrally), longer (+4±14 μm centrally) and shorter (-8±14 μm centrally, p=0.02) respectively. In contrast, central and peripheral choroid mostly thinned (-5±20 μm centrally), thickened (+4±17 μm centrally) and thinned (centrally -1±27 μm) in response to myopic, hyperopic and multifocal defocus respectively (all non-significant). Overall choroidal thickness was 7 μm thinner, 5 μm thicker and 7 μm thinner in response to myopic, hyperopic and multifocal defocus, respectively. Post exposure, there were no significant changes in the accommodative response. The results suggested that variations in eye length and choroidal thickness changes were insignificant, except for central eye length change to multifocal defocus. To determine if there was a diurnal variation in the ocular response to imposed defocus, the effects of 30 minutes exposure to myopic, hyperopic and multifocal defocus in morning and evening on central and peripheral eye length and choroidal thickness was evaluated. Each participant (n=10 adults) attended 3 visits on 3 separate days, each between 5:00 p.m. and 8:00 p.m., where the right eye of the participant was exposed to defocus. Measurements were taken before and immediately after 30 minutes of exposure and compared with the results from the morning visits. Immediately post exposure, both central and peripheral eye length was shorter in response to myopic defocus, (morningevening; centrally, +5±11 μm versus -4±12 μm) and shorter in response to multifocal defocus (morningevening; centrally -19±22 μm versus -9±35 μm), thickened in response to hyperopic defocus (morning>evening; centrally +5±21 μm versus +6±18 μm) and thickened in response to multifocal defocus (morning >evening; centrally 9±28μm versus 4±34μm). Significant of these changes were the eye length changes, only at centre, in response to myopic and multifocal defocus in the evening compared to morning. Therefore, a final experiment was conducted to validate these findings (n=7 adults) and similarly found that central eye length was shorter following exposure to optical defocus in the evening, irrespective of the type of defocus (-11±13μm, -6±16 μm, and -16±19 μm for myopic, hyperopic and multifocal defocus respectively). The data indicates that the central and peripheral eye length reduces(shorter) in response to short term exposure to myopic and multifocal defocus and thus, may be useful to evaluate the ocular responses to defocus. Contrary to predictions that the choroidal response will be in anti-phase to eye length changes, surprisingly, the choroidal changes were small in magnitude (mostly

Aim: To explore the association of optic disc and retinal parameters with myopia, and to determine if models incorporating these parameters can discriminate between myopic versus non-myopic eyes as well as aid in predicting future onset/incidence and increased progression. Methods: Optic nerve head and retinal parameters were systematically analysed using retinal images, spherical equivalent refraction, and axial length data obtained from two pilot studies (n=58 adults; n=56 myopic children, respectively). Thereafter, an association of optic disc and retinal parameters with myopic versus non-myopic eyes were analysed using data from a large population study of Asian children (n= 2995; 6 to 9 years). Multiple logistic regression analysis was performed and receiver operating characteristic (ROC) curves used to determine the ability of optic disc/retinal features to a) differentiate myopes and non-myopes at baseline; b) predict 12-month myopia incidence c) predict 12-month spherical equivalent and axial length change of ≥-1.00D and ≥0.50 mm respectively. The models were validated in a small, independent sample of 380 Asian children aged 5 to 14 years. Results: Optic disc and retinal parameters such as disc rotation, tilt from Vertical, ovality, reduced short axis of the disc, temporal crescent, tessellations, temporal > nasal pRNFL thickness, reduced fovea to disc distance as well a thinner macular thickness were associated with myopia and/or incidence and/or progression. Models incorporating one or more of these parameters had sensitivity/specificity of 77%/83% to discriminate between myopic versus non-myopic eye; 69%/68% to predict the incidence of myopia, and 58%/ 82% and 66%/79% to predict spherical equivalent and axial length change of ≥ 1D and ≥ 0.50 mm respectively. In an independent sample, the sensitivity/specificity of the models to discriminate between myopic versus non-myopic eyes was 90%/79%; to predict the incidence of myopia was 83%/ 50%; whereas models to predict progression had low sensitivity but high specificity. Conclusion: This body of work adds to the knowledge on the optic disc and retinal features associated with myopia and demonstrates that models incorporating such parameters can successfully discriminate between myopic versus non-myopic eyes. These features are also associated with future incidence and/or progression; however, further work is needed to improve the accuracy of models to predict incidence and/or progression.

Purpose: Outdoor activity is one of several factors identified as risk factors for myopia development. The retina’s exposure to bright light may be one of the features of being outside that contributes to this protective effect. Specialized cells in the retina, ipRGCs, are thought to control this process. Since pupillary responses to blue light have been a useful measurement of ipRGC activity related to refractive error in past studies, and ipRGC activity may also contribute to slowing eye growth and myopia through their connection with amacrine cells and release of retinal dopamine, we are investigating the effects of bright light exposure on pupillary responses in order to better understand the protective nature of outdoor time on myopia development.Methods: Ten non-myopic subjects were each assigned to spend a large amount of time outdoors (target = 12 hours total) for 5 days and a small amount of time outdoors (target = 2 hours total) for 5 days with at least 5 days of separation between the experimental time periods. Pupillary responses to alternating blue and red light, followed by red light, then blue light as single colors were measured at the initial visit and following each 5 day period. Data were compared to data from a similar previous study with 10 myopic subjects. Results: Subjects spent an average (±SD) of 0.74 ± 0.24 more log lux-minutes outdoors in the high light exposure compared to the low light exposure week (p

The multifocal electroretinogram (mfERG) provides an objective electrophysiological assessment of central retinal function. Using this technique, many focal retinal responses are recorded from the cone-driven retina in a matter of minutes. MfERG metrics can be used to identify focal areas of retinal dysfunction (a delay in the timing of the mfERG response, a decrease in its amplitude, or both indicate abnormal retinal function) even when there are no visible signs of retinopathy. The mfERG is an objective test of retinal function, but the timing and amplitude of the response are measured subjectively by manually marking the location of key points within the mfERG waveform. As a result, mfERG metrics may differ between graders, especially when the waveform is irregular (e.g., in cases of active eye disease or when the response is contaminated with electrical interference). Differences in mfERG measurements due to variability between graders may be a concern in longitudinal or multicenter research studies when more than one person is tasked with measuring the mfERG response. Mathematical modeling of the mfERG waveform might be an objective method to reliably and efficiently measure mfERG metrics and mitigate the effects of inter-rater variability. One aim of this research was to model the mfERG waveform using a custom Fourier curve fitting algorithm and automatically extract mfERG timing and amplitude measures. Data presented here show that custom curve fitting using a Fourier model accurately and objectively identified and measured the peak time and amplitude of key mfERG waveform parameters.The second aim of this research was to utilize the model to efficiently and reliably measure mfERG response parameters at different retinal eccentricities. These measurements were used to investigate the relationship between peripheral axial length and retinal function (i.e., mfERG peak time and amplitude). We found that axial length was not a significant predictor of mfERG peak time nor amplitude in our study population. This was an unexpected finding as other researchers have reported that mfERG peak times were delayed and amplitudes were decreased in eyes with myopia. Subjects tested in comparable studies had higher levels of myopia (and longer axial lengths) than those tested in our study population. It is probable that the subjects in other studies (with higher levels of myopia) had early, undetectable myopia-related pathology that caused retinal dysfunction whereas our subjects (with lower levels of myopia) did not.Lastly, changes in peripheral retinal function in response to systematic changes in peripheral myopic defocus were investigated. Multifocal contact lenses that induce peripheral defocus as a stimulus to slow eye growth are a popular treatment to control myopia progression. However, peripheral myopic defocus may have unforeseen consequences, especially in younger patients who are currently being prescribed multifocal contact lenses for myopia control. Here, we found that induced peripheral myopic defocus decreased the amplitude of the mfERG response. This finding suggests peripheral blur may potentially cause photoreceptor or bipolar cell (or both) dysfunction. The mfERG may offer an objective method to quantify the short-term and long-term effects of peripheral myopic defocus on retinal function.

Myopia (near-sightedness) has become a significant public health concern, as its prevalence continues to increase in the United States and around the world. Further, myopia is also linked to potentially blinding ocular disease. Growing evidence from a number of studies links myopia with an increased risk of glaucoma, a leading cause of irreversible blindness. Eyes with primary open angle glaucoma typically exhibit high intraocular pressure (IOP) and altered diurnal IOP rhythms. The structural organization of the lamina cribrosa (LC) of the optic nerve head may also render eyes more vulnerable to nerve fiber damage, the origin of vision loss in glaucoma. One or more of these factors may also contribute to the increased risk of glaucoma in myopic eyes. IOP could play a role in normal ocular “growth” (enlargement), by exerting a stretching influence on the scleral wall of the eye. During myopia development and progression, scleral remodelling is upregulated, rendering it more susceptible to the stretching influences of IOP, with eye enlargement accelerating as a consequence. The converse that ocular elongation can be slowed by decreasing IOP and so the tension experienced by the sclera was tested in a set of experiments using a topical ocular hypotensive drug, specifically latanoprost. Its effects on both normal and “myopic” ocular growth in guinea pigs undergoing monocular form deprivation were examined, and treatment-induced ultrastructural changes in the sclera were quantified. With advances in high-resolution imaging and electron microscopy, we were able to characterize the effects of the above ocular hypotensive drug on the microarchitectural changes in the sclera and optic nerve head, including the LC. Our results demonstrate that daily topical latanoprost is effective in both lowering IOP and slowing myopia progression in myopic guinea pig eyes. It also seems to protect the myopic scleral remodelling. These findings will open the opportunities to explore lowering IOP as a myopia control treatment option that may also reduce any future risk of glaucoma in myopic children.

Myopia, or nearsightedness, is a common vision disorder characterized by an abnormal increase in eye elongation, leading to a mismatch in the refractive power of the eye and the location of the retina. Myopia has dramatically increased in prevalence over the last 50 years, currently affecting half of college-aged individuals in the United States and almost all young adults in certain Asian populations. This trend is not a temporary aberration; myopia is projected to afflict nearly half of the global population by the year 2050.Traditionally, myopia is "corrected" using glasses, contact lenses, or refractive surgery. Although these solutions allow for clear vision, they do not rectify the underlying structural changes associated with myopia, including the lengthening of the eye and the thinning of its layers. As a result, there remains an increased risk of vision-threatening complications, such as glaucoma, retinal detachment, myopic maculopathy, and choroidal neovascularization. In the past, these complications were regarded as characteristic of "pathological" myopia. However, it is now known that no amount of myopia is considered safe; the more severe the myopia, the greater the risk, starting from even the smallest measurable amounts.In addition, not all myopes have access to refractive correction. Uncorrected refractive error accounts for over half of global vision impairment. It has also been estimated that uncorrected myopia is associated with an annual global potential productivity loss of $244 billion.With these startling figures, there have been renewed efforts to develop and prescribe treatments for myopia. Inspired by the influence of animal models on myopia research thus far, we sought to further one of the most popular mammalian models of myopia, the guinea pig, to allow for mechanistic exploration that is not possible in human clinical trials.Chapter 1 reviews the process of emmetropization and refractive error development as understood from observations in humans and experiments in animal models. Current clinical recommendations are also summarized.Chapter 2 presents a qualitative synthesis of the known relevant ocular characteristics of the guinea pig myopia model. Guinea pigs have emerged as a popular mammalian model because of the relative ease of housing and husbandry, larger eyes, and better visual acuity compared to other laboratory rodents. However, guinea pigs aren't perfect subjects for the human condition we are attempting to model. Knowledge of the optical quality of the guinea pig eye isn't firmly established, and experimental models of myopia depend on manipulating the visual experience.In Chapter 3, we detail the optical aberrations of the guinea pig eye. Using a custom-built Shack-Hartmann wavefront sensor, we fit a Zernike polynomial function to the images collected from adolescent guinea pigs. The optical quality of the eyes was assessed in terms of individual Zernike coefficients, and data were further analyzed to derive root-mean-square wavefront errors, modulation transfer functions, point spread functions, and depth of focus. These data are compared with visually normal young adult human eyes. While visual acuity is much poorer in the guinea pig eye compared to the human eye, high order aberrations do not appear to be major sources of image quality degradation. It is still unknown what optical information the eye is using to generate growth modulatory signals. However, the measurement of the optical aberrations of the guinea pig eye is an important step forward, allowing the nature of the defocus stimuli and their effects on retinal image quality to be better understood in this mammalian model.Chapter 4 presents the results of a novel method of inducing myopia in the guinea pig model. Historically, spectacle-mounted lenses and diffusers are used to induce myopia in guinea pigs. These lenses are typically mounted on Velcro ring supports, which are then glued to the fur surrounding the guinea pigs' eyes. While shown to be safe and effective, there are significant limitations with this process. The lenses (or diffusers) can be removed by the guinea pigs if they scratch at the velcro site, requiring very frequent monitoring and reapplication. As a result, experiments using spectacle-mounted lenses cannot be conducted over a long period of time. We designed and tested rigid gas permeable contact lenses as an alternative method for inducing myopia in guinea pigs, which will also allow for testing contact lens treatments in this animal model.Finally, the ability of atropine to prevent the development of myopia is a fairly consistent finding in animal studies. However, important exceptions have been noted. In Chapter 5, we establish that topically applied 1\% atropine is effective in reducing myopia progression in guinea pigs. After two weeks of treatment with either daily or weekly applied atropine, guinea pigs treated with our contact lens-induced myopia model developed significantly less myopia compared to those treated with a placebo drop.The overarching goal of this research is to further our basic understanding of the guinea pig eye so that we can continue to use this model to test translational clinical treatments.

The eye is an incredibly complex organ, composed of a wide spectrum of tissues. This ranges from the vascular (e.g. choroid) to the extracellular matrix (ECM) rich (e.g. cornea) to the neural (e.g. retina). Working together in concert, these tissues coordinate a wide variety of disparate activities, with exquisite temporal, spatial and functional precision, in order to facilitate vision. Given this high degree of complexity and variability across its components, the eye in many ways approximates the body in miniature. And just like the body at large, ocular tissues utilize the full complement of steroid hormones to facilitate these activities; both in the normal and under pathological conditions.The impact of steroid hormones has been particularly well studied in the context of (1) sexually dimorphic processes and structures and (2) tissue growth and remodeling of ECM rich tissues (e.g. solid tumors and skin), as they appear exquisitely sensitive to steroid hormone signaling to drive their growth. Interestingly, myopia, an ocular pathology that is one the leading drivers of blindness worldwide, is characterized by (1) excessive ECM tissue remodeling of the sclera, leading to scleral thinning and ocular elongation (often, with greatest effect, during childhood and/or adolescence), and (2) its sexually dimorphic character; on the average it presents both more commonly and with greater phenotypic severity in females. Despite these characteristics, the affect and regulation of steroid hormones and their receptors on myopia progression, and with particular emphasis on the sclera, has received sparingly little study. In this dissertation we work to remedy this. Here we explore the changes that occur in steroid hormones and their cognate receptors, both systemically and locally (i.e. at the level of the sclera), as myopia progresses, in a well validated form-deprivation, chicken based model of the pathology. Leveraging a host of biometric (i.e. high frequency a-scan ultrasonography and retinoscopy), biochemical (i.e. western blotting), analytical chemistry (tandem mass spectrometry) and molecular biology (i.e. quantitative real-time polymerase chain reaction) tools we discover a strong associations between glucocorticoid metabolism in the sclera and myopia progression. More explicitly we observe lower scleral levels of the major glucocorticoid species in chicken, corticosterone, concomitant with a drop in transcripts of its biosynthetic enzyme (HSD11β1) and myopia progression, irrespective of sex (chapter 3). We also find several sex-specific disparities including: higher degrees of myopia in female subjects (Chapter 2), differences in the transcriptional expression levels of several sex hormone receptors (Chapter 4) and elevated progesterone levels in female form deprived sclera (Chapter 3). In aggregate our findings argue for a possible role of steroid hormones regulating ocular growth and tissue remodeling during myopia progression, both in manners that are independent from and dependent upon subject’s sex.

Both animal and human studies have demonstrated that the peripheral retina influences central refractive error development. It is hypothesised that peripheral hyperopic defocus may act as a strong stimulus for axial eye elongation. However, conflicting reports have been published suggesting no influence of peripheral refraction on human central refractive error development. Therefore, the role of the peripheral retina on myopia development in human eyes is yet to be understood. Interestingly, optical treatments that have been developed to induce peripheral myopic defocus using peripheral add power have been found to show some myopia control effects, indicating peripheral refraction may play a role in myopia development. Currently, orthokeratology (OK) is considered as the most effective optical treatment for myopia control. It is hypothesised that mid-peripheral corneal steepening may induce peripheral myopic defocus changes in myopic eyes treated with conventional OK lenses. However, there is large variability in myopia control outcomes with OK treatment which may be due to differences in ocular shape and peripheral refraction among individuals. Attempts to individualise peripheral optical defocus changes through manipulation of anterior corneal shape using OK lens designs are tedious and time consuming. Instead of manipulating the anterior corneal shape, this thesis aims to use large diameter (LD) rigid lenses as a novel optical model to induce peripheral defocus changes by anterior contact lens surface manipulations to mimic the OK optical treatment effect. However, before manipulating the front surface profile of these LD contact lenses, there was a need to understand the fitting aspects of LD contact lenses. To investigate the fitting aspects of LD contact lenses, the CASIA swept source (SS) anterior segment optical coherence tomographer (OCT) was used extensively in the research studies reported in this thesis. It has been reported previously that OCT instruments have inbuilt distortions. Therefore, the accuracy and repeatability of this instrument was studied using verified contact lens parameters (front and back surface radii of curvature, rf and rb; centre and peripheral thickness). The current study found that the CASIA SS-OCT was incorporated with distortion correction and necessitated no further correction of scanned images, by providing accurate contact lens (rf and thickness) measurements when compared to verified parameters. Furthermore, good intra and intersession repeatability was found in measuring both contact lens and corneal thicknesses. LD rigid contact lenses rest on the bulbar conjunctiva, creating a tear reservoir between the cornea and lens. Due to the soft compressible nature of the conjunctiva, LD contact lenses sink into the tissue, reducing the amount of tear reservoir over time. Change in the amount of clearance or lens settling has been reported to have no effect on over-refraction measurements. It has been demonstrated that the sclera is asymmetric in shape and fitting LD lenses with back surface toric lens peripheries help to align the sclera for better stability. Therefore, the effects of back surface sphere and toric lens peripheries of two commercially available LD contact lenses (KATT, 16.5 mm diameter and EpiCon LC, 13.5 mm diameter) on lens settling, on-eye stability and refraction were investigated over 8 hours of lens wear in normal eyes. The maximum lens settling occurred at 4 hours for KATT lenses and 1 hour for EpiCon LC lenses. Sphere or toric back surface peripheries did not influence lens settling. Furthermore, KATT lenses with back surface toric lens periphery were found to rotate minimally on the eye during settling and had minimal or no effect on central and peripheral refraction profiles when compared to other lens types. With LD lens settling over time, the conjunctival tissue has been found to show significant compression. The short term (2 hours) effects of LD contact lens wear on conjunctival cell morphology as a result of tissue compression was investigated using the confocal microscope. LD lens wear induced increased mean cell diameter which indicated spreading of cells, and reduced superficial epithelial cell density. Based on the outcomes of initial studies on LD fitting aspects, KATT lenses with toric back surface periphery were found to give the most stable platform, and stable peripheral refraction can be achieved in short-term wearing lens trials. Therefore, KATT lenses with toric back surface periphery were selected as the model to modify the front surface profile to induce peripheral refraction changes. To explore the possibility of inducing specified changes in peripheral defocus, the front optic zone diameter (FOZD) of KATT lenses was altered to model the central treatment zone (TZ) induced by OK treatment. Three different FOZD lenses (6 mm, 4 mm and 3 mm) were fabricated to induce peripheral refraction changes. Both 4 mm and 3 mm lenses were found to induce significant peripheral myopic defocus changes along the horizontal meridian compared to 6 mm FOZD lenses. This suggests that a smaller TZ diameter in OK may induce greater peripheral refraction changes than a larger TZ diameter. This is the first study to demonstrate the use of front surface manipulations of LD contact lenses as a model to induce desired changes in peripheral refraction similar to the OK optical treatment effect. The effects of manipulating other parameters of the anterior surface of LD contact lenses such as front surface asphericity, zone to zone curvature changes and combinations of FOZD and asphericity changes are yet to be explored. This may potentially guide us in the development of novel OK lens designs to induce specific changes in peripheral defocus for more effective myopia control in children.

Time outdoors is protective against myopia onset, but does not have an effect on myopia progression. Stimulation of the retina by light causes release of dopamine by a retinal circuit including intrinsically photosensitive retinal ganglion cells (ipRGCs), dopaminergic amacrine cells, and photoreceptors. The aim of the current study is to investigate the relationship between ipRGC-mediated pupil dynamics, refractive error, and time outdoors. Twenty-five healthy adult subjects wore visible light and UV sensitive badges for one week to monitor their light exposure and time outdoors. Pupil testing included 3 test sequences of flickering light (0.1 Hz) in the following order: 1) alternating red and blue light flashes (2 min duration); 2) red-only flashes (1 min); 3) and blue-only flashes (1 min). Subjects completed an activity and dietary survey, and blood and saliva samples were collected. There was a significant correlation between refractive error (SEQ, D) and the difference in the mean pupil responses to blue light in the third (blue-only) versus the first (alt blue) test (r=0.42, p=0.037), but not for the difference in the responses to the red light in the second (red-only) versus the first (alt red) test. For this measure of the change in the pupil responses to blue light, an interaction existed between refractive error, and the amount of light exposure over the previous 3 and 5 days. In addition, the decay constants for the pupil re-dilation rates in the blue-only trial correlated to refractive error (r=0.44, p=0.028). Findings of the present study indicated that pupil responses to blue light changed more in non-myopes, relative to myopes, over the course of the three tests used in this protocol. A hypothesis for an underlying mechanism is that the light exposure during the first two tests stimulated retinal dopamine release that affected ipRGC light responses, and this neuromodulatory pathway may be deficient in myopes. Consistent with this hypothesis, prior light exposure over the preceding 3 to 5 days caused pupil re-dilation rates evoked by the blue-only stimulus to be slower, indicative of enhanced ipRGC contribution, in non-myopes but not myopes. More longitudinal research with children is necessary to further investigate the possible role of this dopaminergic retinal circuit in ocular growth and refractive development.

Introduction: Thicker ciliary muscles have been associated with more myopic refractive errors. The mechanism leading to thicker ciliary muscles in myopic subjects is currently unknown. Therefore, the purpose of this dissertation was to develop methods for understanding the ciliary muscle and to begin to dissect the mechanism(s) that could be leading thicker ciliary muscles in myopic subjects. Methods: Guinea pigs were the primary subjects utilized in this study. Retinoscopy, ultrasound, and photometric analysis were used to understand biometric outcomes (e.g., refractive error, axial length). Histology was used to analyze and track normal guinea pig ciliary muscle development and differences between form-deprived and control eyes. Uniaxial stretch was applied to guinea pig eyes, and control and treated eyes were compared with RNA-Seq. RNA-Seq was also used to determine differences between form-deprived and control eyes. Results: Normal ciliary muscle volume was significantly correlated with log age (p = 0.001), ocular length (p = 0.003), limbal circumference (p = 0.01), and equatorial diameter (p = 0.003), though it was not related to normal refractive error. Normal ciliary muscle growth occurs via a combination of hypotrophy and hyperplasia during the first 20 days of life, and it switches to pure hypertrophy thereafter. Stretch induced ocular genetic changes suggest that the integrin-signaling pathway and/or the PDGF signaling pathway (ligand independent) are present in the ciliary body, and these pathways could be responsible for the thicker ciliary bodies associated with myopia. Genetic and histological trends suggest that form deprivation-induced myopia inhibits ciliary muscle growth. Two guinea pig strains that were new to myopia research were found to have variable susceptibility to form deprivation myopia. Discussion: This dissertation produced a new animal model for studying the ciliary muscle, though its usefulness for studying the ciliary muscle’s relationship with myopia is yet to be determined. This dissertation also identified new pathways that may be leading to thicker ciliary muscles in myopic subjects. Additional work is needed to fully understand these pathways and to determine the full mechanism leading to thicker ciliary muscles in myopic subjects.

Myopia is a large public health concern both in the United States and worldwide. Previous research has shown that time spent outdoors is protective against the development of myopia. Intrinsically photosensitive retinal ganglion cells (ipRGCs) encode ambient light levels and help regulate a variety of functions including pupil constriction. The purpose of the study was to examine different methods of measuring time outdoors and to examine the association between exposure to outdoor light, spherical equivalent refractive error, and presumed ipRGC input to the pupil responses to red and blue light. Subjects were 20 young adults (mean age 24.9±1.8 years, 13 female) who wore a personal visible light monitor (Daysimeter) and an ultra-violet light monitor on an armband for an average of 7.1 ± 0.43 days. Time outdoors was measured by both the Daysimeter and UV badge, as well as a survey completed at a follow up visit. For the purposes of the study, time outdoors was defined as exposure to >1000 lux or any non-zero UV value. Light exposure over the previous 1, 3, 12, and 24 hours, 3 days, and 5 days was calculated as was total light exposure in log(lux-minutes). Using the RAPDx, pupilometer, pupil responses to 0.1Hz flashes were tested under 3 stimulus conditions: 1) alternating red and blue, 2) red-only, and 3) blue-only. The alternating trial lasted for 2 minutes and the single color trials lasted 1 minute with 5 minutes of dark adaptation prior to each trial. The study showed that the Daysimeter was a good method for the measurement of time outdoors because it agreed best with the activity survey (slope = 0.68, R2 = 0.46). Pupil constriction to red tended to increase during the trial when alternated with blue. There were significant associations between this increasing pupil constriction to red when alternated with blue for longer-term, greater light exposure (r = 0.46, p = 0.042 at 3 days; r = -0.51, p = 0.021 at 5 days) but not for the shorter time periods (1, 3, 12, and 24 hours). The difference in blue pulses during the alternating color protocol and blue pulses during the single color protocol were significantly related to spherical equivalent refractive error (r = 0.58, p = 0.008).The Daysimeter was validated in the study as a good objective measurement for time outdoors. The association between light exposure over several days and differences in the pupil response suggests that there is an ocular pathway that is modified by long-term light adaptation. The interaction between preceding blue light pulses and red light-driven pupil constriction is consistent with a role for blue-light-sensitive ipRGCs mediating this adaptive effect. Greater photopotentiation shown by larger differences in alternating and single color blue values were associated with less myopic refractive error. This is consistent with the theory that time outdoors is beneficial due to greater exposure to visible light and therefore an increase in ipRGC activity.

Myopia has become a public health problem, affecting nearly one-third of people in the United States. There have been many proposed mechanisms of myopia control,including atropine, undercorrection, corneal reshaping therapy, progressive additionlenses, and soft bifocal contact lenses. Soft bifocal contact lenses are thought to decrease the progression of myopia through peripheral defocus created by the contact lenses. There is currently only peer-reviewed literature on myopia control with center distance soft bifocal contact lenses, so it is unknown whether center near soft bifocal contact lenses slow the progression of myopia. The purpose of this study was to determine if center near multifocal contact lenses (Biofinity “N”) provide comparable vision to center distance multifocal contact lenses (Biofinity “D”), as well as to determine if they provide as much peripheral myopic defocus as the center distance lenses in children aged 8 to 14 years. Both subjective and objective vision was measured while the subject was wearing each type of lens. Peripheral defocus in 4 positions of gaze (central, 10° nasal, 20° nasal, 30° nasal) was measured post-dilation using an autorefractor. It was found that center distance contact lenses provide better overall subjective vision than center near (9.0 /10.0 vs. 6.5/10.0, Wilcoxon rank sum p

Aim: To investigate the relationship between peripheral retinal refractive errors and progression of refractive errors, especially myopia in terms of spherical equivalent and axial length in Chinese children. Methods: A pilot study investigated the impact of single-vision spectacle correction for their effect on peripheral refractive errors. Then, Eighty-six healthy Chinese children (mean age: 9.9± 0.58 yrs, 9-11 yrs) were enrolled in a longitudinal trial and screened at baseline and 6 monthly in tervals for 18 months. Statistical significance was set at p < 0.05. Results: The pilot study found absolute hyperopic peripheral defocus with eyes corrected with single vision spectacles. In the longitudinal study, age significantly influenced progression (younger children progressed faster than older children p=0.009). With respect to central and peripheral refractive error profile, from baseline to 18 months, the central myopic shift was most in myopic eyes and least in hyperopic eyes (-1.34±0.27 D vs -0.49±0.14 D respectively). In the hyperopic eyes, the myopic shift was mostly central and in the temporal visual field. This resulted in the difference between central and nasal field refractive errors increasing with time and resulting in re lative hyperopia in the nasal visual field. In the moderate myopes, the magnitude of myopic shift was similar for both central and peripheral retinal points whereas in low myopic eyes the magnitude of myopic shift was similar for central and nasal visual field. Conclusion: Absolute hyperopic peripheral defocus was found within myopic eyes corrected with single vision spectacles. It appeared that in eyes that emmetropic and hyperopic, whilst there was a myopic shift over time, this was mostly limited to the central 20 degrees of the retina and indicative of an axial stretch ing. This predominantly central shift also resulted in hyperopic defocus at the retinal periphery. In those eyes that were myopic eyes, over time, there was a myopic shift at both the central and peripheral retina and was suggested of a global stretching. It may be that the initiation of hyperopic retinal defocus at the retinal periphery possibly plays a role in the initiation of this global stretching, but the evidence is not clear.

Myopia, or nearsightedness, is a common refractive error characterized by an abnormally large increase in eye elongation that leads to a mismatch between the eye's refracting power and the location of the retina. Besides causing blurry vision when left uncorrected, myopia carries a significant risk of vision-threatening complications such as glaucoma, retinal detachment, myopicmaculopathy, and choroidal neovascularization. Billions of dollars are spent worldwide on the correction of myopia and treatment of its associated complications. In addition to the threat it posesto the ocular health of working-age populations, the steady climb in myopia prevalence reported in most countries adds urgency to the need for innovative and reliable myopia-control therapies.Taking inspiration from the concept behind scleral buckling surgery - in which a strip of cadaver sclera is used to brace the weakened posterior pole of the eye - we sought to develop a hydrogel-basedtherapy with the intended action of slowing or preventing subsequent excessive elongation, by way of rehabilitating the myopic sclera in the early stages of the disease.Chapter 2 describes the development of a guinea pig myopia model, for use in testing our experimental myopia-control therapy. Guinea pigs have emerged as a popular mammalian myopia model because of their ease of housing and husbandry, relatively large eyes, and better visual acuity than other laboratory rodents (mice and rats). After establishing a breeding colony using breeders donated from a myopia lab at the University of Auckland, we successfully induced myopia in guinea pigs using a form deprivation model. In the course of our studies, we also tried to induce myopia using defocusing lens and form deprivation in guinea pigs from a commercial research supplier. To our surprise, those animals proved resistant to any kind of myopia-inducing stimuli. The researchimplications of such potential strain-related variability in responses are discussed, including the need to exercise due caution in comparing results from different myopia research laboratories.In Chapter 3, we detail the optimization and in vitro characterization of a hyaluronic acid (HyA) hydrogel investigated as a myopia-control therapy. Using parallel plate rheology we determined the modulus of hydrogels of two different monomer contents, 2.0 and 3.3 weight percent by volume. Both were much softer than the native sclera, i.e. 200 and 800 Pa compared to ~2 MPa. Throughcytotoxicity and proliferation assays we found that both softer and stiffer hydrogels were biocompatible with guinea pig scleral fibroblasts, although proliferation rates were higher for cellscultured on the tissue culture polystyrene control surface. Interestingly, cell proliferation proved to be independent of the concentration of the bsp-RGD(15) cell-binding peptide included in the hydrogel. This suggests that scleral fibroblasts were able to engage with other binding sites on the scaffold, perhaps hyaluronan receptor CD44. Likewise, cells were observed to migrate through hydrogels with no bsp-RGD(15) peptide in a novel migration assay in which cells were allowed to first form a stable monolayer before being exposed to the hydrogels.Chapter 4 presents the results of in vivo testing of 200 Pa HyA hydrogel containing 380 μM of cell bindingpeptide in our established guinea pig myopia model. After a 7-day period of myopia induction through form deprivation, guinea pigs received a posterior sub-Tenon's capsule injection of either HyA hydrogels or the triethanolamine buffer used to prepare the hydrogel (sham treatment). After an additional three weeks of form deprivation, both groups of treated guinea pigs (hydrogel and sham) exhibited a significant amount of myopia control, as indicated by normalization of the axial lengths of treated eyes relative to their contralateral (fellow) eyes. In fact, the treatment effects were not significantly different from each other. The myopia control effect is tentatively attributed to thickening of Tenon's capsule at the surgical site, with the secondary effect of enhancing the mechanical stability of the posterior sclera. The changes in Tenon's capsule could bethe product of a wound healing response triggered by the surgical manipulation. Functional measurements (flash electroretinograms and visual acuity) revealed no evidence of adverse effects ofthe treatments. Intraocular pressure was also unaffected by them. In discussing the findings of this study, two possible novel myopia-control therapies are proposed for further investigation: an HyAhydrogel-based implant customized to also deliver an anti-myopia drug for additional control, and a sub-Tenon's capsule surgical manipulation, of the type used for sham injections of buffer.

This dissertation combines research on three topics in applied energy economics. The first two papers investigate whether consumers are informed about and pay attention to energy costs in residential housing. The first paper explores this issue in the rental housing market, while the second paper focuses on housing purchases. The third paper, based on joint work with AJ Bostian and Harrison Fell, uses a laboratory experiment to test the effects of positive versus negative cost shocks on mulit-unit procurement auction performance. The first paper explores whether there are energy cost information asymmetries between landlords and tenants. If tenants are uninformed about energy costs, landlords cannot capitalize energy efficiency investments into higher rents, leading to under-investment. I exploit variation in energy costs in the form of relative heating fuel price changes inthe northeastern United States where some apartment units heat with oil and some units heat with natural gas. I develop a search model to describe the matching of landlords and tenants, and derive predictions about the incidence of relative fuel price changes, tenant turnover, and efficiency investments under both symmetric and asymmetric information. My model predicts that, under symmetric full information, these outcomes will not differ depending on whether landlords or tenants pay for energy. In contrast, under asymmetric information, the demand of uninformed tenants for units that heat with oil rather than gas will not shift when oil prices rise relative to gas prices. In a search model, this leads to different market outcomes when landlords, rather than tenants, pay for energy. I find that the capitalization of energy prices into rents, turnover rates, and energy efficiency investments differ between the two payment regimes in ways that are consistent with asymmetric information.The second paper explores whether home buyers are myopic about future energy costs. I exploit variation in energy costs in the form of fuel price changes in Massachusetts where there is an even distribution of homes that heat with oil and homes that heat with natural gas. I find that relative fuel price shifts cause relative changes in housing transaction prices that are consistent with full capitalization of the present value of future energy cost differences under low discount rates. These findings are consistent with home buyers being attentive to energy costs at point of sale and are not consistent with myopia.The third paper uses a laboratory experiment to test the effects of positive versus negative costs shocks on multi-unit procurement auction performance. Output prices tend to respond more quickly to increases in input prices than to decreases in input prices. While standard economic theory would not predict this pattern, it is found in many market settings. We compare outcomes in uniform price and discriminatory (pay-as-bid) auctions for two different kinds of costs shocks. First we look at ``industry wide'' cost shocks where the cost of a common input changes uniformly for all bidders. We also look at idiosyncratic cost shocks, where bidders' individual costs are changing, but the expected Walrasian price remains fixed. We find evidence for a new explanation of asymmetric passthrough in multi-unit procurement auctions related to the bidding incentives in discriminatory auctions. Discriminatory auctions may be worse than uniform at ``tracking'' shifts in underlying costs, leading to price adjustment asymmetries and production inefficiencies.

Myopia (near-sightedness) is one of the most common ocular disorders in humans. Due to the dramatic increases in prevalence of myopia worldwide, especially in children and young adults, myopia has also become a significant public health problem, both socially and economically. While the prevalence and severity of myopia continue to increase, effective therapeutic interventions for myopia remain limited. Currently, management of myopia is largely limited to traditional optical corrections - spectacles, contact lenses, and refractive surgery - which correct distance vision but have no effect on myopia progression. While slowed myopia progression has been reported in clinical studies using the contact lens-based, corneal reshaping therapy and atropine, a pharmaceutical agent, these approaches come with limitations and in the latter case, significant ocular side-effects. Uncontrolled progression may lead to high "degenerative" myopia, for which posterior scleral reinforcement surgery remains the only treatment option and a last resort directed at preserving vision. Thus there is a clear need for new myopia control treatments. Understanding more about the molecular and cellular mechanisms underlying myopic eye growth has the potential to uncover novel treatment options. This dissertation presents results from three investigations into the role of the retinal pigment epithelium (RPE) in eye growth regulation, focusing on molecular and cellular mechanisms, and using both in vivo animal models and in vitro cell culture models. In the first in vivo study (Chapter 2), we investigated expression of candidate genes in chick RPE of imposing short-term optical defocus. Specifically, gene expression levels of the three bone morphogenetic proteins (BMP-2, 4 & 7) were examined after 2 and 48 h of treatment, with negative and positive lenses used to impose defocus of opposite sign. These growth factors were observed to be differentially and bidirectionally expressed in RPE, expression generally increasing with imposed myopia, which is associated with ocular growth inhibition. Because eyes had little chance to change their dimensions with such short-term lens treatments, these genes are assumed to play important roles in the onset and early phase of defocus-induced ocular growth changes. For this reason, these genes represent potential targets for molecular-based myopia treatments. In the second study (Chapter 3), high-through gene expression profiling was employed to examine changes in gene expression in chick RPE with long-term imposed hyperopic defocus, which resulted in eyes being longer than normal and highly myopic. This DNA microarray screening revealed changes in the expression of many genes, including BMPs, noggin (NOG), dopamine receptor D4 (DRD4), retinoic acid receptor, beta (RARB), and retinal pigment epithelium-derived rhodopsin homolog (RRH). Some of these genes showed increased expression while others showed decreased expression. It is plausible that some may be linked the ocular pathological complications seen in myopia, while others may be linked to ocular growth regulation, the imposed visual conditions resulting in sustained, increased ocular growth. The third and final study (Chapter 4), addressed the possibility of an RPE site for the anti-myopia action of apomorphine (APO), a dopamine receptor agonist, observed in animal studies. We further investigated the possibility that TGF-â secretion from RPE mediates this inhibitory growth effect. APO applied to cultured human fetal RPE cells was found to alter the secretion of both TGFâ1 and TGFâ2, which was biased towards the basal (choroidal) side. These growth factors also exhibited constitutive polarized secretion, albeit biased in the opposite direction to APO-induced paracrine secretion. The results for APO are consistent with its observed inhibitory (anti-myopia) effects in vivo and offer the RPE as a possible site of action. In summary, the research reported in this dissertation provides evidence that RPE plays an important role in postnatal eye growth regulation, (including myopic growth), as a conduit for relaying growth modulatory retinal signals to choroid/sclera. Genes and molecules identified in these studies offer potential directions for novel anti-myopia treatments, with the RPE being a potential target for the same.

Optical signals of the peripheral retina control eye growth and associated myopia more than previously believed. Traditional thought held that the fovea must play the largest role in progression of refractive error because of its integral role in vision. However, recent research shows that the peripheral retina may be involved. In Rhesus monkeys, peripheral form deprivation and optically induced hyperopia lead to increased axial elongation and myopia. Furthermore, emmetropization occurs when the peripheral cue is removed, even after ablation of the central retina. Human myopes have relative hyperopic blur in the periphery, whereas emmetropes and hyperopes exhibit emmetropia or myopia in the retinal periphery. In fact, relative peripheral hyperopia precedes myopia onset by two years in children. This peripheral hyperopic blur may be a signal for myopic eye growth. Tracking the 3-dimensional shape of the eye through peripheral measurements could provide clues about how peripheral blur increases axial elongation. Understanding these optical signals and pathways could be valuable in ultimately determining how to manage or prevent myopia.Research has focused on methods to stymie eye growth by inducing peripheral myopic defocus. It is therefore important to determine whether any change in peripheral eye length is greater than that which can be expected by measurement error alone. This study aims to determine the inter-occasion repeatability of peripheral axial length measurements using the IOLMaster in order to learn more about the growth of peripheral eye.To assess the repeatability of the IOLMaster in measuring peripheral eye length, we performed five measurements of both non-cycloplegic and cycloplegic (two drops of 1% tropicamide) axial length in primary gaze and at gazes 20 degrees nasal, temporal, superior, and inferior. The same examiner repeated the measurements one week (± 2 days) later to assess how similar the measurements were from one week to the next, assuming that no significant eye growth would happen in that span of time.A total of 30 subjects completed the study. The 95% limits of agreement (LoA) for the cycloplegic repeatability at each location were: central (-0.05, +0.07), nasal (-0.24, +0.23), temporal (-0.14, +0.12), superior (-0.11, +0.11), and inferior (-0.11, +0.11). The 95% LoA for the non-cycloplegic repeatability at each location were: central (-0.07, +0.06), nasal (-0.17, +0.17), temporal (-0.11, +0.09), superior (-0.27, +0.23), and inferior (-0.15, +0.13). In general, nasal measurements were the least repeatable of the peripheral locations. Neither cycloplegic nor non-cycloplegic measurements consistently provided better repeatability at all locations. However, cycloplegic measurements provide shorter eye lengths than non-cycloplegic measurements (p < 0.001). If peripheral eye length is to be measured over time, operators of the IOLMaster must be consistent in whether or not they use cycloplegic drops. Users of the IOLMaster can be confident that any change of 0.25 mm in peripheral eye length is due to a real change in the eye and not due to measurement error. Repeatability of the IOLMaster is quite good for tracking peripheral eye growth.

Complex diseases such as cardiovascular disease, pterygia, glaucoma, and myopia are caused by polygenic, environmental and lifestyle factors. Studying genetics of complex diseases within population isolates has multiple benefits over studies conducted in single families and unrelated populations. Generally, there is increased power to detect heritable effects. Also, the presence of multiple households within an extended pedigree disentangles confounding environmental variables from true genetic effects. Isolated populations also contain greater potential for identifying underlying causal quantitative trait loci. This thesis work focuses on heritability and genome-wide linkage analyses of cardiovascular disease and three eye diseases: pterygia, glaucoma, and myopia in the Norfolk Island population isolate. This study investigates gene-environment interactions of four complex diseases: cardiovascular disease, pterygia, glaucoma, and myopia.

The aims of this thesis were to investigate peripheral refraction in different refractive groups and verify the use of peripheral refraction as a measure of ocular shape. Furthermore, manipulation of peripheral refraction with orthokeratology (OK) and soft contact lenses (SCLs) for potential myopia control were explored. Characteristic peripheral refraction profiles were measured using the Shin-Nippon NVision-K 5001 autorefractor in emmetropes (relative peripheral myopia) and myopes (relative peripheral hyperopia). East Asian moderate myopes had greater amounts of relative peripheral hyperopia compared to Caucasians with a similar central refractive error. This was interpreted to reflect a more prolate ocular shape in the myopic Asian eye. Calculated axial length from peripheral refraction was found to comparable to direct axial length measurements with the IOLMaster in the nasal retina and to underestimate axial length in the temporal retina. Although not entirely comparable, peripheral refraction is still able to give information on the shape of eyes with different refractive errors. Conventional corrections of central myopia induce hyperopia onto the peripheral retina. However, OK lenses were found to cause a hyperopic shift in the central visual field (VF) in both myopic children and adults. This caused peripheral refraction which was initially relatively hyperopic to become relatively myopic compared to the central refraction. Furthermore, changing the optic zone diameter or steepening the periphery of the OK lens was found to cause no significant effect. Relative hyperopic peripheral refraction was measured along the horizontal VF with under (+0.75DS), full, over (-0.75DS) SCL correction and multifocal SCLs with a distance centre and plus power (+2.00) periphery were found to induce less peripheral hyperopia compared to single vision (SV) SCL correction. OK allows the peripheral retina to experience myopic defocus while central myopia is corrected, and multifocal SCLs are able to reduce the amount of relative peripheral hyperopia compared to SV SCLs. This may explain the reduced myopia progression reported with OK and multifocal SCLs. The effects of manipulating other OK lens parameters for potential customised myopia control are yet to be explored, and the impact of myopic peripheral defocus on myopia progression in children is yet to be ascertained.

Aim: To determine an association if any, between ‘on’ and ‘off-axis’ ocular aberrations and a myopic change in refractive error using the data obtained longitudinally. Methods: On and off-axis aberrations of cyclopleged eyes (5 mm pupil diameter) of 646 children were measured during 2004-2005 (age, 12.7 ± 0.4 years) and 5 years later in 2009-2010 (age, 17.1 ± 0.5 years). Change in spherical equivalent (M) from baseline to follow-up visit was determined and eyes characterised as ‘myopic change’ (≥ 0.50D), ‘no change’ (from 0.49D to +0.49D) and ‘hyperopic change’ (≥ +0.50D). Baseline data of eyes with ‘myopic change’ and ‘no change’ were compared to determine if any baseline characteristics predicted a future myopic change. Also, the change in ‘on’ and ‘off-axis’ aberrations with time were correlated with change in M, using general linear model. Significance level was set at p

Myopia, or nearsightedness, is a form of visual impairment in which distant objects appear blurry due to excessive axial eye growth that is mismatched to the eye's refractive power. This condition, though treatable with spectacles, contact lenses, or refractive surgery, continues to increase in prevalence, particularly in some Asian countries, where up to 80-90% of young people and students are myopic. High myopia (< -6.00 D) is associated with greater risk of glaucoma, retinal detachment, and other blinding complications.Myopia is a complex disease with both genetic and environmental components. Rising myopia prevalence rates have mirrored lifestyle shifts that include reduced outdoor and light exposure. The directionality and impact of environmental risk factors, particularly light exposure, on myopia, continue to be poorly understood, partly due to the lack of in vivo and realtime instruments for measuring these effects. This dissertation examines the role of environmental risk factors in myopia, and introduces two new methods for quantitatively studying light and nearwork in humans. Evidence from animal studies suggests short bursts of bright light may be sufficient to retard myopic eye growth. Recent questionnaire-based studies have found increased exposure to sunlight or outdoor environments to be correlated with reduced myopia in children. We supplemented the questionnaire approach with objectively gathered data from light sensors, and compared the accuracy of the two approaches. Maximum intensity, cumulative light exposure, frequency of intensity change, or time spent in bright light were not correlated with refractive error. Subjects overestimated time spent outdoors, and these estimates were in poor agreement with time reported by the sensor data. This is the first multi-season study to use both the questionnaire and light sensor methods coupled with local weather data to investigate light and outdoor effects in myopia.The duration and degree of another myopia risk factor, nearwork, are typically estimated retrospectively through questionnaires that assess reading, computer use, and other visual behaviors. There are, however, no comprehensive methods of measuring working or fixation distance in realtime during natural tasks. Here we present a new approach for studying the dioptric environment in humans. A head-mounted eye tracking device was adapted to be fully mobile for the realtime measurement of eye movements, including convergence. This device was validated in a small sample of young adults. We conducted exploratory analyses of possible task-related trends in fixational behavior, fixation distance, horizontal eye movements, blinks, and saccades. We found large differences in some of these metrics between reading and walking tasks; these task-dependent changes in visual behavior may underlie the nearwork effect in myopia progression.Light sensing and eye tracking are new techniques for quantifying behaviors that are thought to be involved in myopia development. Unlike questionnaires, these methods provide realtime, unbiased data at the temporal resolution that is relevant to refractive error development. Environmental pressures may be a tipping point toward pathological eye growth for genetically susceptible individuals, and further work in this vein could lead to simple behavioral interventions to curb myopia progression.

Purpose: To develop a measurement protocol using the Zeiss Visante™ AS-OCT to asses changes in the shape and size of the ciliary muscle with accommodation and to determine the test-retest repeatability of these measurements.Methods: Twenty-five adults (17 females) ages 22-27 years (mean ± SD = 23.8 ± 1.1 years) were recruited. The ciliary muscle was imaged at two separate visits two weeks apart with the Zeiss Visante Anterior Segment OCT. While subjects viewed targets at two different stimulus levels (1 D and 4 D), the ciliary muscle was imaged six times and accommodation was monitored with the PowerRefractor. Ciliary muscle thickness (CMT) measurements were obtained at four muscle locations; 1 mm (CMT1), 2 mm (CMT2), and 3mm (CMT3) posterior to the scleral spur as well as (CMTMAX) at the point of maximal muscle thickness. The action of the ciliary muscle during accommodation was described by our data in two ways. The „raw change‟ was calculated as the change in ciliary muscle thickness calculated based on the accommodative target (the change in accommodation from distance to the 4D target). The „standardized change‟ was calculated as the ratio as (change in CMT/accommodative response) represented the amount of thickening or thinning that occurred in the ciliary muscle per diopter of accommodation. Finally, the repeatability measurements between visit 1 and visit 2 were analyzed using a Bland-Altman analysis.Results: The mean accommodative response measured with the PowerRefractor at visit 1 was 3.97±0.87D with a range of -1.87 to -4.95D and -3.92±0.82 with a range of -2.79 to -5.39D at visit 2. The change in ciliary muscle thickness per diopter of accommodation was calculated based on both the accommodative stimulus and the measured accommodative response (PowerRefractor) at the four thickness locations. Ciliary muscle thinning from 1D to 4D of accommodation was statistically significant at CMT3. Thickening of the ciliary muscle with accommodation was observed at both CMT1 and CMTMAX while no statistical thickening or thinning was present at CMT2. Bland-Altman repeatability analysis between the two visits was non-significant for every muscle location. The 2D stimulus was not considered in these calculations because the majority of subjects failed to produce any accommodative effort to the 2D target.Conclusion: The combination of the Visante Anterior Segment OCT and the PowerRefractor is a feasible tool for measuring the change in ciliary muscle thickness with accommodation. There was a wide range of accommodative responses during the time of image capture in this study. This indicates is it essential to know the accommodative response at the exact time of image capture for the most accurate calculations of change in ciliary muscle thickness with accommodation.

According to the Centers for Disease Control, the most frequent ocular condition afflicting the United States population is refractive error. In most instances, refractive error occurs due to an improper match between the axial length of the eye and objects at optical infinity (i.e., myopia, hyperopia or astigmatism) or due to the loss of ability to focus on near objects with age (presbyopia). The ability of the eye to coordinate growth of the organ while the organism physically matures is of particular interest to vision scientists. In humans, this relationship appears to be changing as the prevalence of refractive errors, particularly myopia, increases. This alteration in the regulation on ocular growth can be detrimental, as myopia is associated with potentially blinding diseases such as glaucoma, retinal detachment, retinoschesis and myopic retinal degeneration. A number of potential mechanisms have been proposed for why the prevalence of myopia is on the rise; however, our knowledge of ocular growth regulation is incomplete. Further insight into how ocular growth is regulated may help scientists and clinicians develop effective therapeutic interventions to slow, or possibly prevent, myopia development.Chapter 1 of the dissertation addresses the significant literature regarding the development of myopia in experimental animals, with an emphasis on the role of unobstructed vision in normal refractive development and potential mechanisms involved in regulating ocular growth. Chapter 2 of the dissertation examines the role of Insulin-like Growth Factor 1 (IGF1) and Fibroblast Growth Factor 2 (FGF2) in the regulation of ocular growth. Recent research implicates insulin as a potent stimulator of ocular growth. In chickens, a combination of IGF1 & FGF2 radically alters ocular growth, leading to increased intraocular pressure, axial length and anterior chamber changes leading to the development of extreme myopia. Chapter 3 examines the expression of guanine-nucleotide binding protein β3 (GNB3), also known as cone β-transducin, in multiple species. We demonstrate that a mutant chicken model with congenital reduction in vision, the Retinopathy, Globe Enlarged (RGE), lacks GNB3 in retinal neurons critical for normal visual signal transduction. Chapter 4 of the dissertation examines whether the RGE chicken can respond to experimental visual manipulations known to cause ocular growth and myopia in multiple animal species. The dissertation concludes with Chapter 5, a discussion of the pertinence of the finding of this research and proposed future avenues of investigation to further our understanding of regulation of ocular growth.

Peripheral refractive error has assumed considerable importance with the discovery that it can influence eye growth. The link between the peripheral state of the eye and myopia development demands rapid and accurate measurements at individual and population levels. Currently, the use of conventional refraction techniques requires time-consuming sequential re-alignments. The aims of this thesis were to identify and assess methodological limitations of current techniques, test new concepts and develop a method of obtaining more rapid and accurate peripheral refraction measurements. At first, the impact of pupil misalignment was investigated using a conventional autorefractor. As visual field angle increased, tolerance to pupil misalignment decreased significantly, making peripheral measurements particularly susceptible to this measurement error. It was also shown that the peripheral entrance pupil shape is not elliptical as currently assumed, adding further potential for pupil misalignment. Based on these findings, means to rectify pupil alignment-related errors when using conventional instruments were established and validated. Having ascertained limitations of current peripheral refractometry, a novel instrument concept was proposed, the EyeMapper. The EyeMapper was designed to perform a rapid peripheral (and central) refraction scan, from -50° to +50°, using 10 stationary deflecting prisms and a scanning mirror. Like most autorefractors, the operation was based on the ring-autorefraction principle. The optical design, consisting of 5 intertwined optical sub-systems was developed. Safety aspects and criteria for instrument components were assessed and the operation principle was verified experimentally. Experimental testing identified an obstacle relating to the ring-image analysis and it revealed that peripheral higher order aberrations have the potential to interfere with the sphero-cylindrical refraction readings obtained when applying this ring-autorefraction principle. A technique that segregates higher and lower order aberrations was thus deemed more suitable for measuring peripheral refraction. Hence, the EyeMapper design was updated to include wavefront measurements. The prototype instrument was then built and experimentally tested over a range of refractive errors. The EyeMapper uses an array of beam steering mirrors and a scanning mirror to perform a rapid peripheral refraction scan in one meridian. Three-dimensional power maps of the eye can be obtained by pivoting the instrument around its optical axis.

Myopia or nearsightedness is a condition in which the axial length of the eye is too long relative to its optical focal length. This condition is reaching epidemic levels worldwide, and has become a tremendous public health burden. Myopia is one of the leading causes of vision loss and high myopia significantly increases the risk of permanent blindness. Consequently, myopia cannot be considered as a benign condition and early interventions aimed at slowing down or even stopping the progression of myopia rather than merely correcting the associated optical focusing error is of great importance. The consistent evidence from animal model studies showing that imposed hyperopic defocus, if sustained, comprises an effective myopogenic stimulus, accelerating eye growth, while imposed myopic defocus slows ocular elongation, has motivated clinical studies using bifocal and progressive addition spectacles for myopia control. While these studies, reviewed in Chapter 2 of this dissertation, failed to provide convincing evidence for a clinically significant treatment effect, i.e., slowed myopia progression; smaller scale, non-randomized studies using multifocal soft contact lenses and orthokeratology lenses have shown much more promising effects in terms of slowing myopia progression. However, the mechanism(s) underlying the latter anti-myopia treatment effects are poorly understood, thereby limiting their further refinement. In addition to the aforementioned systematic review of relevant clinical evidence for optical interventions for myopia control, this dissertation described 3 other studies using chick model, representing efforts to further understand how multifocal optical environments affect normal ocular development, specifically the process of emmetropization. These manipulations have also been used as a tool to investigate the mechanism underlying the myopia controlling effect of the novel contact lens applications referred above. Chapter 2 describes a systematic review and meta-analysis performed on randomized controlled trials investigating the effects of three traditional optical interventions, bifocal and progressive addition spectacles, and rigid contact lenses, all believed to control myopia progression, based on anecdotal evidence. The overall treatment effect was estimated to be only small and clinically insignificant. A number of reasons were proposed to explain the discrepancy between the results of related animal studies and these clinical trials - strong support for optical control of myopia from the former studies and inconclusive results from the latter studies. Poor compliance to the spectacle corrections in clinical studies, inaccurate measurement of adherence to the treatments, inadequate and potentially, ambiguous classification systems for clinical myopia, and potential flaws in the optical designs are likely to have contributed to the discouraging results from the clinical trials. Chapter 3 describes the first of three studies in which the chick model was used to test the effects on ocular growth of a series of custom-designed 2-zone multifocal "spectacle" lenses. This and the two follow-up studies using this model have the following merits; they made use of standardized experimental paradigms and objective methods of measurement to track ocular changes. The first study applied the lenses in a simple experimental paradigm, in which monocular lenses were attached to the normal eyes of young chickens. The 2-zone lenses included a plano zone, either in the center or peripheral surround, with either positive or negative power (+5 or -5 D) incorporated into the other zone. The size of the central zone was also allowed to vary, to control the size of the unifocal central and peripheral retinal areas, and intermediate multifocal zone, as was the placement of the powered zone, i.e. in the center or periphery of the lenses. Single vision lenses were included as a control treatment. Two important observations from this study were that 1) peripheral optical defocus can influence both peripheral (off-axis) and central (on-axis) refractive error development and 2) the inhibitory effect on axial ocular growth of myopic defocus imposed using 2-zone lenses (positive zones) could exceed that induced by single vision lenses of the same power. These results suggested complex interactions between adjacent retinal regions, with the peripheral retina apparently able to decode optical defocus, as well as complex interactions between the eyes own optical aberrations and those of the 2-zone lenses, which introduced large amounts of spherical aberration. Chapter 4 described a closely related study in which subsets of the same 2-zone lenses were tested on eyes that had undergone surgical manipulations (sectioning of the ciliary nerve, CNX or iridectomy, ID) to investigate the influence of the pupil size of the eye as well as accommodation on the effects of the 2-zone lenses. Both were uncontrolled in the first study; yet create a dynamic optical system on which the multifocal optical environment was imposed. The ID surgery produced a fixed dilated pupil without any effect on accommodation (confirmed in another study, reported in Appendix I), while the CNX surgery produced a similarly enlarged pupil while also eliminating accommodation. This study revealed pupil size to be a critical factor in the treatment effects of 2-zone lenses, likely to reflect at least in part, its influence on the optical experience of various retinal zones (center to periphery), and also suggested a significant role of accommodation in the decoding of imposed optical defocus stimuli, in this case, complex multifocal optical stimuli. Chapter 5 described a third study which attempted to develop a clinically more relevant scenario; specifically, 2-zone lenses that incorporated two different negative powers (-5 & -10 D) in two optical zones (center & periphery or vice versa), were tested on both normal eyes and eyes made myopic before being fitted with one of the 2-zone lenses. The latter combination was intended to simulate the ocular conditions created when concentric multifocal contact lenses, i.e. with a near addition, are prescribed to human myopes, one of the novel, myopia control treatments currently being explored. When the 2-zone lenses were fitted to normal eyes, they induced myopia, of a magnitude falling between the values expected, had single vision lenses of the same powers been used. However, on myopic eyes, the lenses had a strong myopia inhibiting effect with the already induced myopia undergoing substantial regression. This result supports the further investigation of appropriately designed concentric multifocal contact lenses for the control of myopia progression. In summary, the studies reported in this dissertation indicate complex interactions between central and peripheral retinal regions in decoding and responding to complex defocus signals as well as critical influences of pupil size and accommodation on these processes. The strong and consistent inhibitory effects on ocular growth of concentric 2-zone lenses incorporating a zone of either positive power or a near addition, 2-zone designs lend plausibility to the notion of using custom-designed novel optical treatments for the control of myopia progression.

Purpose: Several factors have been found to be candidate risk factors in myopic development and progression. Outdoor activity, in particular, has been found to be protective in the development of myopia. A possible component of outdooractivity could be vitamin D. We are investigating the effects of activity as well as dietary and circulating levels of vitamin D on myopes and non-myopes.Methods: Thirty-two subjects provided information regarding diet and activity by means of surveys. A smaller number of subjects that met refractive error criteria (n=22) provided 200 μl of blood to analyze circulating vitamin D as well as a 2 ml sample of saliva for SNP analysis of the vitamin D receptor gene.Results: Activity, both indoors and outdoors, were not significantly different for myopes versus non-myopes. Unadjusted levels of circulating vitamin D were notsignificant as well. Linear regression adjusted for four dietary variables (calcium, food folate, theobromine, and total sugar) and age showed myopes had 3.41 ng/ml less circulating blood vitamin D than non-myopes (p=0.005, R-squared=0.76). Odds ratios from SNP analysis of VDR gene were not significant in increasing the risk of being myopic.Conclusions: Outdoor and indoor activities were not significantly associated with circulating levels of vitamin D. Calcium and theobromine were positively associated while food folate and total sugar were negatively associated with blood vitamin D levels. Blood vitamin D levels were lower in myopes once adjusted for age, and dietary variables. Other intrinsic factors including single nucleotide polymorphisms in the vitamin D receptors were not significant for increasing the risk of being myopic.

Refractive error is identified as the deviation from emmetropia that progresses either towards myopia or hyperopia. This phenotypic occurrence has been documented as being jointly due to genetics and the environment. This study looks to assess the contribution of heredity while considering the environment in refractive error development. Using data from the Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) study, there were 912 sibling pairs identified, ranging in age from 6 to 14 years, from various ethnic backgrounds. Linear regression analyses of the spherical equivalent and the ocular axial length were performed, controlling for age, while factoring in the environmental variables and ethnicity to determine their relevance. Heritability was calculated using the slope determined from the analyses of the spherical equivalent and axial length data of all available refractive errors. The heritability (h2) found from the spherical equivalent data for this total sample produced a genetic variance of 0.784 with a 95% confidence interval of 0.648 - 0.920 (78.4% with a 95% CI 64.8% – 92.0%). The heritability (h2) found from the axial length data for this total sample produced a genetic variance of 0.834 with a 95% confidence interval of 0.708 - 0.958 (83.4% with a 95% CI 70.8% – 95.8%). The best overall model determined from the greatest adjusted R square value for spherical equivalent was 0.146, and the best overall model for axial length resulted in an adjusted R square value of 0.175. Because of the shared genetics between siblings, a realistic R square value in this study’s would be 0.25, indicating that this model explains a reasonable portion of the variance of refractive error between siblings. The heritability values and ranges found confirm that genetics are significant in the development of a subject’s spherical equivalent and axial length. Controlling for the environment had little impact on the heritability values that were determined.

The purpose of this study was to determine the relationships among ciliary body thickness, anterior scleral thickness, accommodative lag, and refractive error in adults as well as the difference between nasal and temporal ciliary body thickness.Subjects with varying refractive error (range: -11.03 to +3.13 D) were recruited. Cycloplegic refractive error, axial length, accommodative lag (4.00-D stimulus), and ciliary body thickness (CBT2, CBT3) and anterior scleral thickness (AST2) at 2 and 3 mm posterior to the scleral spur were measured. Repeated measures regression models were used to define the relationship between CBT2, CBT3 and refractive error, axial length, or accommodative lag, and also AST2 and refractive error or axial length. A Bland-Altman analysis was utilized to determine the difference between nasal and temporal ciliary body thickness.The relationships between CBT2 and CBT3 and refractive error were statistically significant (p = 0.04 and 0.02 respectively). The relationships between CBT2 and CBT3 and axial length were statistically significant (p = 0.01 and 0.002 respectively). No relationship was found between AST2 and refractive error or between AST2 and axial length (all p > 0.05). The relationship between ciliary body thickness and accommodative lag was not significant at any measurement point.The ciliary body was thicker in patients with increasing myopia and increasing axial lengths. Further studies are needed to determine if thicker ciliary bodies are related to the etiology of myopia and to determine if differences in the etiology exist for low-to-moderate myopia as opposed to high myopia.

Introduction: This thesis is divided into three sections: I) Literature review; II) Manuscript (in the format specified for submission to the International Journal of Osteopathic Medicine); and III) Appendices. Objective: To investigate the short term effect of a novel osteopathic technique on the axial length of the eye. Methods: A single-blinded pre-test post-test experimental design was adopted. Two experiments were conducted to investigate two types of intervention: i) muscle energy technique (MET) targeted at the medial and lateral recti; and ii) MET targeted at all six extraocular muscles. The axial length of the eye was objectively measured using partial coherence interferometry (IOLMaster, Carl Zeiss Meditec, Germany) operated by qualified optometrists. Phoria was measured with a Maddox wing to determine whether there was any change in extraocular muscle tension. Tests for stereo acuity and the near point of convergence were conducted to give indications of subjects‟ state of binocular vision. Two tailed paired t tests were undertaken to compare both mean axial length, and mean phoria, pre and post-intervention. The pre and post-intervention data for axial length were also compared for individual subjects. Subjects: Two groups of 10 adults (n=20) between the age of 18 and 35 with refractive error between -1 and -6 D were recruited from the general community. Volunteers with strabismus, active ocular disease, heart disease, or diabetes were excluded. Results: Analysis of group data showed insufficient statistical evidence to support either method of intervention in effecting a clinically important change in axial length. Analysis of data from individual subjects revealed two eyes (in two different subjects) out of 40 eyes that underwent a change of ≥ 0.093 mm (equivalent to 0.25 D). Statistical analysis of phoria failed to find sufficient evidence to validate the efficacy of the intervention in effecting changes in relative muscle tension in the extraocular muscles. Conclusion: MET targeted at the extraocular muscles was ineffective in altering the axial length of the eye. Further development work in application of the intervention techniques is necessary if further work is to be conducted in this area.

In orthokeratology (OK), flat centre, steeper mid-periphery rigid contact lenses are used to reshape the cornea to temporarily eliminate the myopia of the wearer, and vice versa for the hyperope. There is evidence also that OK retards the progression of myopia by reducing relative peripheral hyperopia. However, currently OK is regarded as a ‘niche’ procedure mainly due to discomfort and the perceived complicated fitting procedure associated with rigid OK lenses. This thesis explores the potential for soft contact lenses (SCLs) to be used for OK. An understanding of the lens design parameters influencing on-eye pressure distribution of SCLs was developed by employing a finite element (FE) model. When worn inverted, some SCLs have been reported to produce orthokeratology-like changes in corneal shape. The FE model developed was used to examine the effects of inversion on the internal stresses and shape of SCLs. Inverted SCLs were found to have drastically altered on-eye pressure profiles compared to lenses worn correctly. This was found to be due primarily to the changes in lens shape rather than internal stress, thus SCL inversion was not found to be instrumental in achieving OK effects. Novel SCLs not requiring inversion to exhibit pressure differentials when worn were designed. These lenses produced OK-type corneal shape changes. However, they also produced a small persistent, localised steep central zone in both the lens and the cornea. Analysis of stress within the lenses demonstrated that buckling of the lens was the likely reason for this lack of central conformity. Increasing central lens thickness mitigated buckling and the associated central corneal steepening, but only the most extreme lens design worn in the closed eye flattened the cornea centrally. The FE model developed offers valuable insights into the principal factors producing pressure differentials beneath SCLs. If SCL OK is to become a viable alternative for the correction of myopia, central corneal steepening associated with buckling of the central portion of the lens needs to be overcome and some suggestions were made as to how this could be achieved.

At present, guinea pigs have been increasingly used for the study of human myopia. However, little is known about involvement of genetics, protein profiles and key molecules in axial growth of the guinea pig eyes in normal and manipulated visual conditions. This study evaluated the suitability of guinea pigs as an animal model for the study of human refractive errors based on comparison with other currently available species. Various aspects of guinea pigs as an animal model have been researched in this study including the development of refraction and axial components of the guinea pig eye under a normal visual environment, genetic profiles of the guinea pig eye compared with human and mouse eyes, changes in protein profiles, refraction and axial components of the eye during myopic development and recovery (after termination of form deprivation or hyperopic defocus) in response to manipulated visual environments and pharmacological intervention using subconjunctival injection of apomorphine, a non-selective dopamine receptor agonist. Guinea pigs had baseline ocular biometry comparable to humans under a normal visual environment and had similar process of emmetropization compared to humans. Moreover, guinea pigs appeared to be closer to humans than mice based on the ocular gene profiles. Axial myopia induced in guinea pigs was effective. The myopia and recovery were mainly due to changes in vitreous length and choroidal thickness. In respect of pharmacological intervention, a subconjunctival injection of apomorphine could inhibit form-deprivation myopia by slowing axial elongation of the eye in guinea pigs. This study evaluated this myopic animal model comprehensively at the phenotypic genetic and proteomic levels. Guinea pigs are now only the second small animal with detailed gene and protein changes compared to humans. This study the first to use a pharmacological model with detailed dose response curves. Based on the evidence obtained guinea pigs an alternative to other currently available species for the study of the development of human refractive errors.