Posterior retinal contour in adult human anisomyopia

PURPOSE. It is well documented that myopia is associated with an increase in axial length or, more specifically, in vitreous chamber depth. Whether the transverse dimensions of the eye also increase in myopia is relevant to further understanding of its development. METHODS. The posterior retinal surface was localized in two-dimensional space in both eyes of young adult white and Taiwanese-Chinese iso- and anisomyopes (N = 56), from measured keratometry, A-scan ultrasonography, and central and peripheral refraction (±35°) data, with the aid of a computer modeling program designed for this purpose. Anisomyopes had 2 D or more interocular difference in their refractive errors, with mean values in their more myopic eyes of -5.57 D and in their less myopic eyes of -3.25 D, similar to the means of the two isomyopic groups. The derived retinal contours for the more and less myopic eyes were compared by way of investigating ocular shape changes that accompany myopia, in the posterior region of the vitreous chamber. The presence and size of optic disc crescents were also investigated as an index of retinal stretching in myopia. RESULTS. Relative to the less myopic eyes of anisometropic subjects, the more myopic eyes were more elongated and also distorted into a more prolate shape in both the white and Chinese groups. However, the Chinese eyes showed a greater and more uniform relative expansion of the posterior retinal surface in their more myopic eyes, and this was associated with larger optic disc crescents. The changes in the eyes of whites displayed a nasal-temporal axial asymmetry, reflecting greater enlargement of the nasal retinal sector. CONCLUSIONS. Myopia is associated with increased axial length and a prolate shape. This prolate shape is consistent with the proposed idea that axial and transverse dimensions of the eye are regulated differently. The observations that ocular shape changes are larger but more symmetrical in Chinese eyes than in eyes of whites warrant further investigation.

Can partial coherence interferometry be used to determine retinal shape?

Purpose: To determine likely errors in estimating retinal shape using partial coherence interferometric instruments when no allowance is made for optical distortion. Method: Errors were estimated using Gullstrand’s No. 1 schematic eye and variants which included a 10 D axial myopic eye, an emmetropic eye with a gradient-index lens, and a 10.9 D accommodating eye with a gradient-index lens. Performance was simulated for two commercial instruments, the IOLMaster (Carl Zeiss Meditec) and the Lenstar LS 900 (Haag-Streit AG). The incident beam was directed towards either the centre of curvature of the anterior cornea (corneal-direction method) or the centre of the entrance pupil (pupil-direction method). Simple trigonometry was used with the corneal intercept and the incident beam angle to estimate retinal contour. Conics were fitted to the estimated contours. Results: The pupil-direction method gave estimates of retinal contour that were much too flat. The cornea-direction method gave similar results for IOLMaster and Lenstar approaches. The steepness of the retinal contour was slightly overestimated, the exact effects varying with the refractive error, gradient index and accommodation. Conclusion: These theoretical results suggest that, for field angles ≤30º, partial coherence interferometric instruments are of use in estimating retinal shape by the corneal-direction method with the assumptions of a regular retinal shape and no optical distortion. It may be possible to improve on these estimates out to larger field angles by using optical modeling to correct for distortion.

Myopia: structural and functional correlates

Ocular dimensions are widely recognised as key variants of refractive error. Previously, accurate depiction of eye shape in vivo was largely restricted by limitations in the imaging techniques available. This thesis describes unique applications of the recently introduced 3-dimensional magnetic resonance imaging (MRI) approach to evaluate human eye shape in a group of young adult subjects (n=76) with a range of ametropia (MSE= -19.76 to +4.38D). Specific MRI derived parameters of ocular shape are then correlated with measures of visual function. Key findings include the significant homogeneity of ocular volume in the anterior eye for a range of refractive errors, whilst significant volume changes occur in the posterior eye as a function of ametropia. Anterior vs. posterior eye differences have also been shown through evaluations of equivalent spherical radius; the posterior 25% cap of the eye was shown to be relatively steeper in myopes compared to emmetropes. Further analyses showed differences in retinal quadrant profiles; assessments of the maximum distance from the retinal surface to the presumed visual axes showed exaggerated growth of the temporal quadrant in myopic eyes. Comparisons of retinal contour values derived from transformation of peripheral refraction data were made with MRI; flatter retinal curvature values were noted when using the MRI technique. A distinctive feature of this work is the evaluation of the relationship between ocular structure and visual function. Multiple aspects of visual function were evaluated through several vehicles: multifocal electroretinogram testing, visual field sensitivity testing, and the use of psychophysical methods to determine ganglion cell density. The results show that many quadrantic structural and functional variations exist. In general, the data could not demonstrate a significant correlation between visual function and associated measures of ocular conformation either within or between myopic and emmetropic groups.

Ocular biometric investigation of anisometropia

The thesis aims to define further the biometric correlates in anisometropic eyes in order to provide a structural foundation for propositions concerning the development of ametropia.Biometric data are presented for 40 anisometropes and 40 isometropic controls drawn from Caucasian and Chinese populations.The principal finding was that the main structural correlate of myopia is an increase in axial rather than equatorial dimensions of the posterior globe. This finding has not been previously reported for in vivo work on humans. The computational method described in the thesis is a more accessible method for determination of eye shape than current imaging techniques such as magnetic resonance imaging or laser Doppler interferometry (LDI). Retinal contours derived from LDI and computation were shown to be closely matched. Corneal topography revealed no differences in corneal characteristics in anisometropic eyes, which supports the finding that anisometropia arises from differences in vitreous chamber depth.The corollary to axial expansion in myopia, that is retinal stretch in central regions of the posterior pole, was investigated by measurement of disc-to-fovea distances (DFD) using a scanning laser ophthalmoscope. DFD was found to increase with increased myopia, which demonstrates the primary contribution made by posterior central regions of the globe to axial expansion.The ocular pulse volume and choroidal blood flow, measured with the Ocular Blood Flow Tonograph, were found to be reduced in myopia; the reductions were found to be significantly correlated with vitreous chamber depth. The thesis includes preliminary data on whether the relationship arises from the influx of a blood bolus into eyes of different posterior volumes or represents actual differences in choroidal blood flow.The results presented in this thesis show the utility of computed retinal contour and demonstrate that the structural correlate of myopia is axial rather than equatorial expansion of the vitreous chamber. The technique is suitable for large population studies and its relative simplicity makes it feasible for longitudinal studies on the development of ametropia in, for example, children.

Contour house

Set atop a magnificent site on the Bellarine Peninsula, Contour House anchors itself into the landscape with a 5.5 meter-high folding concrete wall. This gesture is both protective and revealing, simultaneously creating an internal courtyard, while extending the spectacular 270- degree views into the living areas. This residence extends our interest in 'the journey' and ideas of place-making, particularly the manner in which it might challenge preconceived ways of living.

Discovery and characterization of IGFBP-mediated endocytosis in the human retinal pigment epithelial cell line ARPE-19

Insulin-like growth factor binding proteins (IGFBPs) are prime regulators of IGF-action in numerous cell types including the retinal pigment epithelium (RPE). The RPE performs several functions essential for vision, including growth factor secretion and waste removal via a phagocytic process mediated in part by vitronectin (Vn). In the course of studying the effects of IGFBPs on IGF-mediated VEGF secretion and Vn-mediated phagocytosis in the RPE cell line ARPE-19, we have discovered that these cells avidly ingest synthetic microspheres (2.0 μm diameter) coated with IGFBPs. Given the novelty of this finding and the established role for endocytosis in mediating IGFBP actions in other cell types, we have explored the potential role of candidate cell surface receptors. Moreover, we have examined the role of key IGFBP structural motifs, by comparing responses to three members of the IGFBP family (IGFBP-3, IGFBP-4 and IGFBP-5) which display overlapping variations in primary structure and glycosylation status. Coating of microspheres (FluoSpheres®, sulfate modified polystyrene filled with a fluorophore) was conducted at 37 °C for 1 h using 20 μg/mL of test protein, followed by extensive washing. Binding of proteins was confirmed using a microBCA assay. The negative control consisted of microspheres treated with 0.1% bovine serum albumin (BSA), and all test samples were post-treated with BSA in an effort to coat any remaining free protein binding sites, which might otherwise encourage non-specific interactions with the cell surface. Serum-starved cultures of ARPE-19 cells were incubated with microspheres for 24 h, using a ratio of approximately 100 microspheres per cell. Uptake of microspheres was quantified using a fluorometer and was confirmed visually by confocal fluorescence microscopy. The ARPE-19 cells displayed little affinity for BSA-treated microspheres, but avidly ingested large quantities of those pre-treated with Vn (ANOVA; p < 0.001). Strong responses were also observed towards recombinant formulations of non-glycosylated IGFBP-3, glycosylated IGFBP-3 and glycosylated IGFBP-5 (all p < 0.001), while glycosylated IGFBP-4 induced a relatively minor response (p < 0.05). The response to IGFBP-3 was unaffected in the presence of excess soluble IGFBP-3, IGF-I or Vn. Likewise, soluble IGFBP-3 did not induce uptake of BSA-treated microspheres. Antibodies to either the transferrin receptor or type 1 IGF-receptor displayed slight inhibitory effects on responses to IGFBPs and Vn. Heparin abolished responses to Vn, IGFBP-5 and non-glycosylated IGFBP-3, but only partially inhibited the response to glycosylated IGFBP-3. Our results demonstrate for the first time IGFBP-mediated endocytosis in ARPE-19 cells and suggest roles for the IGFBP-heparin-binding domain and glycosylation status. These findings have important implications for understanding the mechanisms of IGFBP actions on the RPE, and in particular suggest a role for IGFBP-endocytosis.

Fusing shrinking and expanding active contour models for robust IRIS segmentation

The performance of iris recognition systems is significantly affected by the segmentation accuracy, especially in non- ideal iris images. This paper proposes an improved method to localise non-circular iris images quickly and accurately. Shrinking and expanding active contour methods are consolidated when localising inner and outer iris boundaries. First, the pupil region is roughly estimated based on histogram thresholding and morphological operations. There- after, a shrinking active contour model is used to precisely locate the inner iris boundary. Finally, the estimated inner iris boundary is used as an initial contour for an expanding active contour scheme to find the outer iris boundary. The proposed scheme is robust in finding exact the iris boundaries of non-circular and off-angle irises. In addition, occlusions of the iris images from eyelids and eyelashes are automatically excluded from the detected iris region. Experimental results on CASIA v3.0 iris databases indicate the accuracy of proposed technique.

Comparison of temporal processing and motion perception in emmetropes and myopes

While spatial determinants of emmetropization have been examined extensively in animal models and spatial processing of human myopes has also been studied, there have been few studies investigating temporal aspects of emmetropization and temporal processing in human myopia. The influence of temporal light modulation on eye growth and refractive compensation has been observed in animal models and there is evidence of temporal visual processing deficits in individuals with high myopia or other pathologies. Given this, the aims of this work were to examine the relationships between myopia (i.e. degree of myopia and progression status) and temporal visual performance and to consider any temporal processing deficits in terms of the parallel retinocortical pathways. Three psychophysical studies investigating temporal processing performance were conducted in young adult myopes and non-myopes: (1) backward visual masking, (2) dot motion perception and (3) phantom contour. For each experiment there were approximately 30 young emmetropes, 30 low myopes (myopia less than 5 D) and 30 high myopes (5 to 12 D). In the backward visual masking experiment, myopes were also classified according to their progression status (30 stable myopes and 30 progressing myopes). The first study was based on the observation that the visibility of a target is reduced by a second target, termed the mask, presented quickly after the first target. Myopes were more affected by the mask when the task was biased towards the magnocellular pathway; myopes had a 25% mean reduction in performance compared with emmetropes. However, there was no difference in the effect of the mask when the task was biased towards the parvocellular system. For all test conditions, there was no significant correlation between backward visual masking task performance and either the degree of myopia or myopia progression status. The dot motion perception study measured detection thresholds for the minimum displacement of moving dots, the maximum displacement of moving dots and degree of motion coherence required to correctly determine the direction of motion. The visual processing of these tasks is dominated by the magnocellular pathway. Compared with emmetropes, high myopes had reduced ability to detect the minimum displacement of moving dots for stimuli presented at the fovea (20% higher mean threshold) and possibly at the inferior nasal retina. The minimum displacement threshold was significantly and positively correlated to myopia magnitude and axial length, and significantly and negatively correlated with retinal thickness for the inferior nasal retina. The performance of emmetropes and myopes for all the other dot motion perception tasks were similar. In the phantom contour study, the highest temporal frequency of the flickering phantom pattern at which the contour was visible was determined. Myopes had significantly lower flicker detection limits (21.8 ± 7.1 Hz) than emmetropes (25.6 ± 8.8 Hz) for tasks biased towards the magnocellular pathway for both high (99%) and low (5%) contrast stimuli. There was no difference in flicker limits for a phantom contour task biased towards the parvocellular pathway. For all phantom contour tasks, there was no significant correlation between flicker detection thresholds and magnitude of myopia. Of the psychophysical temporal tasks studied here those primarily involving processing by the magnocellular pathway revealed differences in performance of the refractive error groups. While there are a number of interpretations for this data, this suggests that there may be a temporal processing deficit in some myopes that is selective for the magnocellular system. The minimum displacement dot motion perception task appears the most sensitive test, of those studied, for investigating changes in visual temporal processing in myopia. Data from the visual masking and phantom contour tasks suggest that the alterations to temporal processing occur at an early stage of myopia development. In addition, the link between increased minimum displacement threshold and decreasing retinal thickness suggests that there is a retinal component to the observed modifications in temporal processing.

Exploring retinal and functional markers of diabetic neuropathy

Diabetic peripheral neuropathy (DPN) is one of the most debilitating complications of diabetes. DPN is a major cause of foot ulceration and lower limb amputation. Early diagnosis and management is a key factor in reducing morbidity and mortality. Current techniques for clinical assessment of DPN are relatively insensitive for detecting early disease or involve invasive procedures such as skin biopsies. There is a need for less painful, non-invasive and safe evaluation methods. Eye care professionals already play an important role in the management of diabetic retinopathy; however recent studies have indicated that the eye may also be an important site for the diagnosis and monitoring of neuropathy. Corneal nerve morphology has been shown to be a promising marker of diabetic neuropathy occurring elsewhere in the body, and emerging evidence tentatively suggests that retinal anatomical markers and a range of functional visual indicators could similarly provide useful information regarding neural damage in diabetes – although this line of research is, as yet, less well established. This review outlines the growing body of evidence supporting a potential diagnostic role for retinal structure and visual functional markers in the diagnosis and monitoring of peripheral neuropathy in diabetes.

Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the pupillary light reflex and circadian rhythm

Recently discovered intrinsically photosensitive melanopsin retinal ganglion cells contribute to the maintenance of pupil diameter, recovery and post-illumination components of the pupillary light reflex and provide the primary environmental light input to the suprachiasmatic nucleus for photoentrainment of the circadian rhythm. This review summarises recent progress in understanding intrinsically photosensitive ganglion cell histology and physiological properties in the context of their contribution to the pupillary and circadian functions and introduces a clinical framework for using the pupillary light reflex to evaluate inner retinal (intrinsically photosensitive melanopsin ganglion cell) and outer retinal (rod and cone photoreceptor) function in the detection of retinal eye disease.

The circadian response of intrinsically photosensitive retinal ganglion cells

Intrinsically photosensitive retinal ganglion cells (ipRGC) signal environmental light level to the central circadian clock and contribute to the pupil light reflex. It is unknown if ipRGC activity is subject to extrinsic (central) or intrinsic (retinal) network-mediated circadian modulation during light entrainment and phase shifting. Eleven younger persons (18–30 years) with no ophthalmological, medical or sleep disorders participated. The activity of the inner (ipRGC) and outer retina (cone photoreceptors) was assessed hourly using the pupil light reflex during a 24 h period of constant environmental illumination (10 lux). Exogenous circadian cues of activity, sleep, posture, caffeine, ambient temperature, caloric intake and ambient illumination were controlled. Dim-light melatonin onset (DLMO) was determined from salivary melatonin assay at hourly intervals, and participant melatonin onset values were set to 14 h to adjust clock time to circadian time. Here we demonstrate in humans that the ipRGC controlled post-illumination pupil response has a circadian rhythm independent of external light cues. This circadian variation precedes melatonin onset and the minimum ipRGC driven pupil response occurs post melatonin onset. Outer retinal photoreceptor contributions to the inner retinal ipRGC driven post-illumination pupil response also show circadian variation whereas direct outer retinal cone inputs to the pupil light reflex do not, indicating that intrinsically photosensitive (melanopsin) retinal ganglion cells mediate this circadian variation.

Intrinsically photosensitive melanopsin retinal ganglion cell contributions to the post-illumination pupil response and circadian rhythm

Intrinsically photosensitive retinal ganglion cells (ipRGCs) in the eye transmit the environmental light level, projecting to the suprachiasmatic nucleus (SCN) (Berson, Dunn & Takao, 2002; Hattar, Liao, Takao, Berson & Yau, 2002), the location of the circadian biological clock, and the olivary pretectal nucleus (OPN) of the pretectum, the start of the pupil reflex pathway (Hattar, Liao, Takao, Berson & Yau, 2002; Dacey, Liao, Peterson, Robinson, Smith, Pokorny, Yau & Gamlin, 2005). The SCN synchronizes the circadian rhythm, a cycle of biological processes coordinated to the solar day, and drives the sleep/wake cycle by controlling the release of melatonin from the pineal gland (Claustrat, Brun & Chazot, 2005). Encoded photic input from ipRGCs to the OPN also contributes to the pupil light reflex (PLR), the constriction and recovery of the pupil in response to light. IpRGCs control the post-illumination component of the PLR, the partial pupil constriction maintained for > 30 sec after a stimulus offset (Gamlin, McDougal, Pokorny, Smith, Yau & Dacey, 2007; Kankipati, Girkin & Gamlin, 2010; Markwell, Feigl & Zele, 2010). It is unknown if intrinsic ipRGC and cone-mediated inputs to ipRGCs show circadian variation in their photon-counting activity under constant illumination. If ipRGCs demonstrate circadian variation of the pupil response under constant illumination in vivo, when in vitro ipRGC activity does not (Weng, Wong & Berson, 2009), this would support central control of the ipRGC circadian activity. A preliminary experiment was conducted to determine the spectral sensitivity of the ipRGC post-illumination pupil response under the experimental conditions, confirming the successful isolation of the ipRGC response (Gamlin, et al., 2007) for the circadian experiment. In this main experiment, we demonstrate that ipRGC photon-counting activity has a circadian rhythm under constant experimental conditions, while direct rod and cone contributions to the PLR do not. Intrinsic ipRGC contributions to the post-illumination pupil response decreased 2:46 h prior to melatonin onset for our group model, with the peak ipRGC attenuation occurring 1:25 h after melatonin onset. Our results suggest a centrally controlled evening decrease in ipRGC activity, independent of environmental light, which is temporally synchronized (demonstrates a temporal phase-advanced relationship) to the SCN mediated release of melatonin. In the future the ipRGC post-illumination pupil response could be developed as a fast, non-invasive measure of circadian rhythm. This study establishes a basis for future investigation of cortical feedback mechanisms that modulate ipRGC activity.