Improving peripheral vision through optical correction and stimulus motion

Linnaeus University Dissertations No 248/2016

I MPROVING PERIPHERAL VISION THROUGH OPTICAL CORRECTION AND STIMULUS MOTION

P ETER L EWIS

LINNAEUS UNIVERSITY PRESS

Improving peripheral vision through optical correction and stimulus motion Doctoral dissertation, Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden, 2016 Cover Image: Theoretical spatio-temporal contrast sensitivity (stCSF) surface for a peripheral retinal location. The coloured sections illustrate the changing shape of the contrast sensitivity function with varying temporal frequency. A foveal stCSF surface is superimposed for comparison. ISBN: 978-91-88357-14-4 Published by: Linnaeus University Press, 351 95 Växjö, Sweden Printed by: Elanders Sverige AB, 2016

Abstract

Lewis, Peter (2016). Improving peripheral vision through optical correction and stimulus motion. Linnaeus University Dissertation No 248/2016, ISBN: 978-9188357-14-4. Written in English.

The loss of central vision subsequent to macular disease is often extremely debilitating. People with central field loss (CFL) must use other peripheral areas of the retina in order to see; areas with inferior resolution capacity, which are also affected by off-axis optical errors. The overall aim of the work encompassed by this thesis was to identify and evaluate methods of improving vision for people with CFL; with focus on the effects of off-axis optical correction and stimulus motion on resolution acuity and contrast sensitivity. Off-axis optical errors were measured using a commercially-available COASHD VR open-view aberrometer. We used adaptive psychophysical methods to evaluate grating resolution acuity and contrast sensitivity in the peripheral visual field; drifting gratings were employed to measure the effect of motion on these two measures of visual performance. The effect of sphero-cylindrical correction and stimulus motion on visual performance in healthy eyes and in subjects with CFL was also studied; in addition, the effect of adaptive optics aberration correction was examined in one subject with CFL. The COAS-HD aberrometer provided rapid and reliable measurements of off-axis refractive errors. Correction of these errors gave improvements in lowcontrast resolution acuity in subjects with higher amounts of oblique astigmatism. Optical correction also improved high-contrast resolution acuity in most subjects with CFL, but not for healthy subjects. Adaptive optics correction improved both high and low contrast resolution acuity in the preferred retinal locus of a subject with CFL. The effect of stimulus motion depended on spatial frequency; motion of 7.5 Hz improved contrast sensitivity for stimuli of low spatial frequency in healthy and CFL subjects. Motion of 15 Hz had little effect on contrast sensitivity for low spatial frequency but resulted in reduced contrast sensitivity for higher spatial frequencies in healthy subjects. Finally, high-contrast resolution acuity was relatively insensitive to stimulus motion in the periphery. This thesis has served to broaden the knowledge regarding peripheral optical errors, stimulus motion and their effects on visual function, both in healthy subjects and in people with CFL. Overall it has shown that correction of offaxis refractive errors is important for optimizing peripheral vision in subjects with CFL; the use of an open-view aberrometer simplifies the determination of these errors. In addition, moderate stimulus motion can have a beneficial effect on contrast sensitivity for objects of predominantly low spatial frequency. Keywords: absolute central scotoma, central visual field loss, eccentric viewing, preferred retinal locus, open-view aberrometer, off-axis refractive errors, eccentric correction, dynamic visual acuity, spatial contrast sensitivity, temporal contrast sensitivity, spatio-temporal contrast sensitivity.

POPULÄRVETENSKAPLIG SAMMANFATTNING När ögat drabbas av sjukdomar i gula fläcken (makula) kan synen i de centrala områdena av synfältet försvinna helt. Detta innebär att man istället måste använda den perifera näthinnan, utanför makula, för att se med så kallad ”excentrisk fixation”. Tyvärr är upplösningsförmågan betydligt lägre ju längre ut man kommer i periferin vilket medför svårigheter att läsa, urskilja små detaljer och känna igen ansikten. När man använder excentrisk fixation kan det även uppstå fel i hur ögat bryter ljuset. Dessa optiska fel inkluderar till exempel astigmatism (brytningsfel) vilket kan korrigeras med glasögon, och mer komplexa fel (högre-ordningens aberrationer), som vanligtvis inte går att korrigera. Syftet med denna avhandling är att ge ökad förståelse för hur det perifera seendet fungerar och hur förutsättningarna för personer som drabbats av centralt synfältsbortfall kan förbättras. Vi har utvecklat metoder för att mäta perifer synfunktion, och först testat dessa på normalseende personer innan vi har gått över till forskningspersoner med centrala synfältsbortfall. Vi har använt ett kliniskt instrument med öppet synfält för att mäta de optiska felen som uppstår vid excentrisk fixation, och utvärderat synskärpa och kontrastseende med glasögonkorrektion. Andra mer specialiserade forskningsinstrument har också använts för att mäta och korrigera även de mer komplexa synfel. I stora drag visar de fem delarbetena att det är viktigt att mäta och korrigera perifera optiska fel – både för att den perifera synskärpan kan förbättras, och för att kontrastseende blir bättre. Dessutom förbättras synen när man ser rörliga objekt, framförallt kontrastseendet. Liknande resultat erhölls även för forskningspersoner med centralt synfältsbortfall, med undantag för att optisk korrektion även gav förbättrad synskärpa för hög kontrast objekt hos de med synfältsbortfall, vilket inte var fallet för friska ögon.

Det är viktigt att mäta och korrigera de optiska felen som uppstår i periferin och vara medveten om att rörliga objekt kan uppfattas lättare än stillastående. Mätinstrument med ett öppet synfält underlättar mätningen av perifera synfel. I framtiden borde det vara möjligt att både korrigera de mer komplexa optiska felen, samt utveckla nya elektroniska hjälpmedel som skapar en optimal rörelse för att ge en förbättrad synfunktion.

LIST OF PUBLICATIONS This thesis is based on the following papers, which will be referred to by their Roman numerals in the text: I. Lewis, P., Rosén, R., Unsbo, P., & Gustafsson, J. (2011). 'Resolution of static and dynamic stimuli in the peripheral visual field'. Vision Research. 51, 1829-34. II. Baskaran, K., Rosén, R., Lewis, P., Unsbo, P., & Gustafsson, J. (2012). 'Benefit of adaptive optics aberration correction at preferred retinal locus'. Optometry and Vision Science. 89, 1417-1423. III. Lewis, P., Baskaran, K., Rosén, R., Lundström, L., Unsbo, P., & Gustafsson, J. (2014). 'Objectively determined refraction improves peripheral vision'. Optometry and Vision Science. 91, 740-746. IV. Venkataraman, A., Lewis, P., Unsbo, P. & 'Peripheral contrast sensitivity for drifting stimuli'. Submitted for publication. V. Lewis, P., Venkataraman, A., & Lundström, L. 'Optical correction and stimulus motion improves peripheral vision in eyes with central scotoma'. Manuscript

Papers I, II, and III are reproduced with the permission from the respective publishers.

Till min familj

“The future belongs to the curious. The ones who are not afraid to try it, explore it, poke at it, question it and turn it inside out.” -Anonymous-

ABBREVIATIONS 2AFC 2IFC AMD anti-VEGF AO AREDS ATR CFL CFF cpd CNV CS CSF DVA HOA HS Hz LHON LOA logMAR MAR PRL qCSF RPE sCSF SLO stCSF SVA tCSF TRL WTR

Two-alternative forced choice Two-interval forced choice Age-related macular degeneration Anti-vascular endothelial growth factor Adaptive-optics Age-related Eye Disease Studies Against-the-rule (astigmatism) Central field loss Critical flicker frequency Cycles per degree Choroidal neovascularization Contrast sensitivity Contrast sensitivity function Dynamic visual acuity Higher-order aberration(s) Hartmann-Shack Hertz Lebers hereditary optic atrophy Lower-order aberration(s) Logarithm of Minimum angle of resolution Minimum angle of resolution Preferred retinal locus Quick CSF Retinal pigment epithelium Spatial contrast sensitivity function Scanning laser ophthalmoscope Spatio-temporal contrast sensitivity function Static visual acuity Temporal contrast sensitivity function Trained retinal locus With-the-rule (astigmatism)

TABLE OF CONTENTS 1.

INTRODUCTION ..................................................................................... 3 Statement of the problem ..................................................................... 3 Aims of this thesis ............................................................................... 4 2. ANATOMY & OPTICS OF THE EYE .................................................... 5 2.1 General anatomy – Optical components .............................................. 5 2.2 General anatomy – Neural components ............................................... 6 2.3 Optical errors ....................................................................................... 8 3. SPATIAL VISUAL FUNCTION ............................................................ 14 3.1 Visual acuity ...................................................................................... 14 3.2 Contrast sensitivity ............................................................................ 15 3.3 Peripheral visual acuity and contrast sensitivity ................................ 21 4. TEMPORAL VISUAL FUNCTION ....................................................... 24 4.1 Dynamic visual acuity (DVA) ........................................................... 24 4.2 Spatio-temporal contrast sensitivity................................................... 26 4.3 Peripheral DVA and spatio-temporal contrast sensitivity.................. 30 5. PSYCHOPHYSICS ................................................................................. 33 5.1 The psychometric function and its threshold ..................................... 33 5.2 Classical threshold determination ...................................................... 35 Method of adjustment................................................................. 35 Method of limits (staircase)........................................................ 36 Method of constant stimuli ......................................................... 36 5.3 Implemented psychophysical methodology....................................... 37 6. MEASUREMENT & CORRECTION OF OPTICAL ERRORS ............ 39 6.1 Peripheral refraction techniques ........................................................ 39 Subjective methods .................................................................... 39 Objective methods ...................................................................... 40 6.2 Correction of peripheral refractive errors .......................................... 44 7. CENTRAL VISUAL FIELD LOSS ........................................................ 46 7.1 Epidemiology..................................................................................... 46 7.2 Medical treatment options ................................................................. 52 8. VISUAL REHABILITATION OF PATIENTS WITH CFL ................... 54 8.1 The preferred retinal locus (PRL) ...................................................... 55 8.2 Optical correction and stimulus motion ............................................. 57 8.3 Magnification..................................................................................... 59 9. SUMMARY OF PAPERS ....................................................................... 62 10. CONCLUSIONS & OUTLOOK ............................................................. 65 11. ACKNOWLEDGEMENTS ..................................................................... 67 12. REFERENCES ........................................................................................ 70 1.1 1.2

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1. INTRODUCTION Of our five primary senses, hearing, sight, smell, touch, and taste, the sense of sight is often considered the most valuable; a disproportionate amount of the brain is allocated to vision and visual processing. For 10 percent of people older than 60, and 30 percent over the age of 75, the reality is that their vision will be adversely and irreversibly affected by age-related changes in the eye leading to the loss of central vision and blindness. Although not fully avoidable or curable, it is possible to ameliorate some of the effects of vision loss using magnifying devices and filter lenses in combination with compensatory techniques and non-optical devices. Until recently these were the only real alternatives, with limited focus on improving the optical quality of the peripheral eye or how image movement can be utilized to improve peripheral visual function.

1.1

Statement of the problem

Macular degeneration is undisputedly one of the top two leading causes of irreversible vision loss in industrialized countries and it is predicted that the prevalence will increase dramatically over the coming decades due to an ageing population. It is predicted that approximately 196 million will be affected with macular degeneration within the next five years; this number increasing to 288 million by 2040 despite advances in medical treatment [1]. The global burden of AMD is estimated at a staggering 343 billion $USD yearly [2], but this sum does not take into account the reduction in “quality of life” associated with vision loss and subsequent socio-economic costs. Patients lose not only their ability to see, they also risk losing their independence, confidence and self-worth. Macular degeneration results in central visual field loss (CFL) and patients are forced to use peripheral areas of the retina when performing visual tasks. Unfortunately vision in the periphery is markedly reduced, due to both anatomical limitations and optical errors; the latter can be partially corrected,

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leaving the anatomical limitations. These can obviously not be altered, but proper choice of stimulus modulation can also be used to reduce its effect on vision.

1.2

Aims of this thesis

The main aim of the work encompassed by this thesis was to determine and evaluate methods of improving vision for people with central visual field loss. In particular we concentrated on measuring and correcting peripheral (offaxis) refractive errors, and controlling stimulus motion as means of enhancing peripheral visual function. The specific aims encompassed by the five papers in this thesis were to: 1) Evaluate a clinically-feasible method for measuring peripheral refractive errors [Paper III]. 2) Evaluate the effect of optical correction on resolution acuity and contrast sensitivity on a patient with central field loss [Paper II]. 3) Examine the impact of stimulus motion and optical correction on resolution acuity [Paper I, III] and contrast sensitivity in healthy subjects [Paper IV] and CFL subjects [Paper V].

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2. ANATOMY & OPTICS OF THE EYE The human eye is a highly specialized optical neuro-sensor, focusing visual information on the light-sensitive retina and doing the initial processing before conveying it to the visual cortex and other areas of the brain via the optic nerve. This chapter will cover the basic anatomy of the eye with emphasis on the components and structures relevant to this thesis. The last section provides an introduction to optical errors which affect visual performance.

2.1

General anatomy – Optical components

The eye, a slightly irregular sphere with an average diameter of 24.4 mm [3], contains the optical and neural elements which make the process of sight possible. Generally speaking, the anterior segment of the eye contains the optical elements needed for focusing images, and the posterior inner lining of the eye, the neural elements which convert light into electrical signals (see figure 2.1). Together, the cornea and sclera, the tough outer fibrous coat of the eye, form a protective envelope containing all these elements [4 (pp.16-20)]. The cornea and the tear-film covering it contribute approximately two thirds of the total 60 dioptre refractive (focusing) power of the eye. Normally transparent and devoid of blood vessels, the cornea is the first surface that light must pass through on its journey into the eye. Disruption in the regularity of the fibres making up the cornea by scarring or oedema cause a reduction in transparency which leads to increased light scatter and reduced image quality. Directly behind the cornea are the anterior and posterior chambers. The anterior chamber (the space bounded by the posterior cornea and anterior surface of iris) and the shallower posterior chamber (the space bounded by the posterior surface of the iris and anterior surface of the crystalline lens) are filled with a transparent fluid called the aqueous humour. Between the two lies the iris, a thin, circular contractile disk which serves to regulate the amount of light entering the eye via the pupil at its centre [4 (p.26), 5 (pp.3-6)].

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Directly posterior to the iris is the crystalline lens; this contributing the remaining 20 dioptres of refractive power of the eye. Its refractive power can be increased through the process of accommodation, in which the annular ring of ciliary muscle contracts leading to an increased curvature (shorter radius) of the lens [6]. Changes in the regular structure of the lens, as occurs with cataract formation, also leads to increased light scatter and reduced visual performance. Having passed the lens, light must traverse the vitreous humour containing a transparent gelatinous mass. This provides nutrition and structural support for the retina [5], which contains the neural elements necessary for vision.

Figure 2.1. Gross anatomy of the eye showing major landmarks.

2.2

General anatomy – Neural components

The retina is a thin, fragile tissue lining the inside two thirds of the eyeball. It receives nourishment from both the vitreous and the underlying choroid, a vascular layer sandwiched between the sclera and the retina. A thin membrane, Bruch’s membrane, serves as a barrier between the choroidal blood supply and the retinal pigment epithelium (RPE). The RPE is a single layer of darkly pigmented cells surrounding the outer segments (ends) of the rod and cone photoreceptors. It serves a number of functions: acting as a blood-retinal barrier (preventing fluid from leaking into the sub-retinal space),

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to reduce light scatter within the eye by absorbing stray light, and more crucially, is involved in phagocytosing the expended discs of the photoreceptor outer segments [5 (p.9)] thus acting as the “retinal janitor”. Disruption of the integrity of Bruch’s membrane or function of the RPE can have severe consequences as further discussed in Chapter 7, Anterior to the RPE lies the neural retina, consisting of five types of neurons: photoreceptors (rods and cones), horizontal cells, bipolar cells, amacrine cells, and ganglion cells (with associated axons projecting to the visual cortex), all orderly arranged in five alternating layers. The photoreceptors lie beneath the blood vessels and other four, generally transparent, cell layers which entails that light entering the eye must first pass through the entire thickness of the neural retina before reaching the outer segments of the photoreceptors [7 (p.627)]. The optic disc, approximately 1.7 mm in diameter, is the region of the retina where the optic nerve, comprised of the ganglion cell axons, exits the eye. Being devoid of light-sensitive photoreceptors, the optic disc is physiologically “blind” [5 (p.13)]. The macula, situated approximately 5° from the posterior pole of the eye and 15° temporal to the optic disc, comprises an area of 5.5 mm in diameter (~21° of visual angle) [7 (p.627)]. It contains the yellow xanthophyll pigments, lutein and zeaxanthin which are said to have a protective effect against short-wavelength blue light [8]; low dietary levels of these two have also been implicated in the development of cataract and age-related macular degeneration (AMD) [9]. The central 1.5 mm diameter (~5° of visual angle) of the macula is called the fovea and is slightly depressed in relation to the surrounding retina. This is seen as an oval light reflex on ophthalmoscopy or fundus photographs due to the increased thickness of the retina and internal limiting membrane at its perimeter [7 (p.627)]. The central floor of the fovea has a diameter of approximately 0.35 mm (~1.2° of visual angle) and is called the foveola. It is the thinnest portion of the macular region as it consists solely of cones and their nuclei; the ganglion cells are laterally displaced allowing for excellent resolution. The central portion of the fovea (an area extending to beyond the foveola) is also avascular, which permits light to reach the photoreceptors unimpeded [7 (p.627)]. As indicated above, the approximately 115 million rods, and 6.5 million cones are not homogenously distributed throughout the retina; the density varying between central and peripheral areas of the eye. Anatomical studies [10] estimate the density of cones to be 150000-200000 per mm2 in the foveola and rapidly decreasing with increasing retinal eccentricity to 2500 cells/mm2 near the extreme periphery [10, 11]. Rods are absent in the very centre of the fovea, reach a peak of 150000 cells per mm2 approximately 3-5 mm from the foveola, and fall to 30-40000 cells/mm2 towards the retinal periphery [11, 12].

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Rods are the predominant photoreceptor in the macula area, outnumbering cones by 9:1 compared to 20:1 for the eye as a whole [12]. In addition, the one million retinal ganglion cells are also unevenly distributed, paralleling the reduction in cones out to approximately 10-15°, and thereafter declining in numbers more rapidly. Within the central 150-300 μm of the fovea ganglion cells are absent (they are laterally displaced as mentioned earlier), but increase to peak levels at approximately 35000 [10] to 51000 per mm2 [13]; with two or more ganglion cells connecting to each individual cone [14, 15]. With increasing distance from the fovea, the ratio of cones to ganglion cells also increases, reaching 1000:1 in the far periphery. Cone photoreceptors are responsible for chromatic, high-resolution, photopic vision and are divided into three discrete types based on their maximal sensitivity to light of different wavelengths: short- (S, 426nm), medium- (M, 530nm) and long- (L, 557nm) wavelengths. Rods are specialized for low light levels or night vision and lack colour discrimination [5]. The two most common types of retinal ganglion cells are midget ganglion cells (P-cells, which synapse on parvocellular layers in the lateral geniculate nucleus), and the parasol ganglion cells (M-cells, which instead synapse on magnocellular layers). Midget (P) ganglion cells generally have small dendritic trees and are connected to a limited number of cones. They are involved in processing spatially detailed, sustained information, including contrast, form and red-green colour perception. The parasol (M) ganglion cells on the other hand, have relatively larger dendritic trees and are involved in processing transient information about changes in the stimulus, for example, motion. It is ultimately the “convergence” of cones onto ganglion cells that reduces the retinal sampling density in the peripheral visual field [15] as will be discussed further in Chapter 3.

2.3

Optical errors

For a sharp image to be formed on the retina the various optical components of the eye must work in synergy; light must be refracted sufficiently in accordance with the axial length of the eye. When light is not optimally focused on the retina the eye is said to suffer from optical errors or aberrations which will inevitably lead to a blurred retinal image and reduced vision. Aberrations are usually classified into chromatic or monochromatic aberrations; the distinction being that chromatic aberrations are manifest only with light consisting of more than one wavelength (as refractive index is wavelength-dependent), whereas monochromatic aberrations are present even with a single wavelength (monochromatic light). Aberrations are further divided into lower-order aberrations (LOA) and higher-order aberrations

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(HOA). Included under LOA are the common refractive errors, myopia, hyperopia and astigmatism; these are readily correctable with spectacle- or contact lenses. Refractive errors (LOA) Ideally, when parallel, distant rays of light are correctly focused on the retina in a healthy eye, which is fully relaxed (ie. not accommodating), the eye is said to be emmetropic (See figure 2.2 a); as such the far point (a point in space conjugate with the retina under relaxed accommodation) of the emmetropic eye will be at infinity. Myopia and hyperopia are also called spherical refractive errors as their magnitude is the same in all meridians; light rays come to a focus at a point that does not coincide with the retina as is clearly seen in figure 2.2 (b and c). The far point of a myopic eye will lie somewhere anterior to the eye, and behind the eye in the case of hyperopia.

Figure 2.2. Schematic representations of a) perfectly focused emmetropic eye, and eyes with b) myopic and b) hyperopic refractive errors.

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In contrast, astigmatic (cylindrical) refractive errors arise where there is a difference in refractive power between two principal meridians. Astigmatism usually arises when the refracting surfaces of the eye, often the anterior cornea, have a toroidal shape (similar to that of a rugby ball or the convex side of a dessert spoon) in which the radii of curvature between the two principal meridians differ. Astigmatism can also occur if one or more of the refractive surfaces are tilted or transversely displaced with respect to one another [16 (p.60)]. Due to the differences in refractive power between the steepest and flattest meridians, astigmatism results in the formation of two line foci (see figure 2.3), each perpendicular to the corresponding principal meridians. Three possible scenarios can arise when astigmatism is associated with spherical refractive errors [16 (p.60)]: 1. Myopic astigmatism – occurring when the refractive power of the eye is too strong in relation to its length in one or both of the principal meridians. 2. Hypermetropic astigmatism – occurs when the refractive power of the eye is too weak in relation to its length in one or both of the principal meridians. 3. Mixed astigmatism – where the power of the eye is too strong in one principal meridian, and too weak in the other in relation to the length of the eye.

Figure 2.3. An astigmatic eye seen from the side, illustrating with-the-rule myopic astigmatism. In this case it is only the vertical meridian that is too powerful in relation to the length of the eye, giving rise to a horizontal line focus (green) anterior to the retina. This is corrected with a negative cylinder with an axis orientation of 180 degrees. In order to correct astigmatic refractive errors, sphero-cylindrical ophthalmic lenses are used; these generally have one surface that is spherical, and the other toroidal or cylindrical. The cylindrical component can, in simplest terms,

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be thought of as having power in only one meridian; the other meridian having zero curvature. The meridian parallel to that which is curved is known as the power meridian, and the other without curvature, the axis meridian or cylinder axis [17 (p.276)]. The net effect of a sphero-cylindrical lens is to selectively move one of the line images so that it coincides with the other, and concurrently ensure that this image is correctly focused on the retina. Astigmatism can also be classified in terms of the axis of the correcting cylinder. With-the-rule (WTR) astigmatism (often associated with a flatter cornea along the horizontal meridian than the vertical meridian) is corrected with a negative cylinder whose cylinder axis is parallel (±30°) to the horizontal meridian. In comparison, against-the-rule (ATR) astigmatism is corrected with a negative cylinder whose cylinder axis is parallel (±30°) to the vertical meridian. Astigmatism in which cylinder axes differ more than ±30° from the horizontal or vertical is called oblique astigmatism [16 (p.60)]. It is however important to note that the term ‘oblique’ is also used when referring to astigmatism arising when light enters an optical system “off-axis” as will be discussed below. To distinguish between the two during the remainder of this thesis, oblique astigmatism in which cylinder axes fall between 30-60° or 120150°, will be referred to as “axial oblique astigmatism”, and when discussing astigmatism occurring when light enters the eye off-axis, “off-axis astigmatism” or “oblique astigmatism”. To simplify statistical analysis of sphero-cylindrical refractive errors, it is possible to convert the sphere (S), cylinder (C) and axis (θ) into their vector components as described by Thibos et al [18]. The M-component corresponds to the mean spherical equivalent power; the J180 and J45 components represent the power of crossed cylinders with axes of 180 and 45 degrees respectively. A power scalar (P) combining these three components, can also be calculated by taking the square root sum of M2, J1802 and J452; this giving the equivalent amount of blur produced by an sphero-cylindrical correction [18]. This was the convention used during statistical analyses in Paper III. Higher order aberrations (HOA) HOAs are more complex optical imperfections which are generally not correctable with standard spectacles or contact lenses as rays of light never focus to a distinct point due to variations in refractive power over the area of the pupil [19, 20]. The higher-order monochromatic aberrations include coma, trefoil, spherical aberration, etc. Of these, spherical aberration is the only one compensated for clinically, occasionally being incorporated in the optical design of soft contact lenses. The other higher order aberrations are on average comparatively much smaller in magnitude in the fovea than the LOA’s [21] but their presence can lead to reduced contrast and halos around lights [22].

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Aberrations in the periphery Although an eye may be emmetropic foveally, it is still common to observe significant optical errors away from the optical axis. These off-axis errors also lead to degradation of the retinal image quality, reducing image contrast just as in the fovea. Thomas Young [23] was first to discover the presence of oblique astigmatism in the eye; the first attempt to objectively ascertain the peripheral refraction out to ±60° in the horizontal visual field was performed over 100 years later by Ferree et al [24, 25]. Some forty years later, Rempt et al [26] confirmed the presence of oblique astigmatism using off-axis retinoscopy. Since publication of studies by these research groups, a fervent interest in peripheral optical errors has ensued; much of this as a result of the interest in myopia development and its hypothesized association with peripheral image quality. Of the off-axis optical errors, coma and oblique astigmatism predominate in the periphery. Coma increases in a linear fashion with increasing eccentricity [27-29]. The image of a point source subject to coma will have a comet-like appearance (somewhat like a smudged teardrop), and may also give symptoms of monocular diplopia [30 (pp.113-117)]. Oblique astigmatism is seen to increase in a quadratic fashion with increasing eccentricity [28, 29] and occurs because the cornea and lens does not refract peripherally-incident light in a symmetric fashion. This results in the formation of two perpendicular line foci as for axial astigmatism. One usually makes a distinction between these two line foci - the tangential line focus and the sagittal line focus. For light entering the eye off-axis along the horizontal meridian the tangential line focus will be vertical and the sagittal line focus will be horizontal (See Figure 2.4). This has implications concerning the cylinder axis for different off-axis angles in the peripheral field as the axis of a negative correcting cylinder will be parallel with the tangential line focus. Along the horizontal meridian the cylinder axis will tend towards 90° (ATR), and along the vertical meridian the axis will be close to 180° (WTR). Intermediate to these two meridians the axis will be perpendicular (or tangential) to the actual off-axis field position [28, 31-34]. The presence of any axial astigmatism will naturally affect the resultant off-axis cylindrical correction, such that a person with axial WTRastigmatism may exhibit no astigmatism at a certain location along the horizontal meridian. In short, by simply adding 90° to the actual field position in degrees it is possible to ascertain the cylinder axis, remembering to consider the central refractive state of the eye. The methods used for measuring and correcting off-axis errors (in particular oblique astigmatism) will be discussed in more detail in chapter 6.

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The amount of astigmatism can differ markedly between iso-eccentric locations in the horizontal and vertical field, for example, with higher amounts reported in the nasal visual field than in the temporal visual field [27, 28, 31, 33, 35-38]. It has been speculated that this asymmetry could be due to a tilt of the crystalline lens [39] or the fact that the visual and optical axes of the eye are not coincident, on average differing by 5° (angle alpha) [16 (p.35)].

Figure 2.4. An illustration of off-axis (oblique) astigmatism, showing the relative positions of the sagittal and tangential line foci when incident light from a point source does not coincide with the optical axis of the eye. The tangential plane contains both the chief ray and optical axis, whereas the sagittal plane, which is perpendicular to the tangential plane, contains only the chief ray. (Adapted from figure 2 in Williams [40]).

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3. SPATIAL VISUAL FUNCTION Spatial visual function refers to the ability of the eye to discern or resolve the spatial features of objects within the visual field. Generally speaking, there are two primary measures of spatial visual function: visual acuity and contrast sensitivity. This chapter presents the basis of visual acuity and contrast sensitivity measurement, including factors limiting these two measures of visual function. The first two sections introduce the concepts of acuity and contrast sensitivity with focus on foveal function. The final section expands the discussion to include peripheral vision.

3.1

Visual acuity

Visual acuity is most commonly measured using static, high-contrast optotypes (letters, numbers or other symbols) and is specified in terms of the smallest spatial detail distinguishable by the subject. As the perceived size of an object depends not only on its size but also on viewing distance, it is appropriate to define visual acuity in terms of the visual angle of the detail subtended from the eye. Visual acuity is commonly divided into four general categories, described in Table 3.1, depending on the relative complexity of the visual task. The simplest form of acuity measurement is detection acuity, which relates to the ability to distinguish the presence or absence of an object or pattern from a uniform background (minimum angle of detection). Localisation or Vernier acuity concerns the ability to discern offsets or lateral displacement between, for example, parallel lines or dots. Vernier acuity is a form of hyperacuity as the minimum angle of displacement that can be resolved is 5-10 times smaller than for other acuity tasks (see Table 3.1) [41]. Resolution acuity refers to the minimum detail in a pattern that can be resolved by the visual system. Recognition acuity (or identification) adds a further degree of difficulty to the resolution task, in that the subject must in addition identify the optotypes (letters, numbers or symbols). Both resolution- and recognition acuity are often recorded in terms of the inverse of the Minimum Angle of Resolution

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(MAR); the smaller the resolvable/identifiable detail, the greater the acuity, such that:

V =

1

(3.1)

MAR

where V is visual acuity, and MAR, the minimum angle of resolution expressed in minutes of arc (1/60 of a degree). Visual acuity is often expressed as Snellen fractions (ie. 6/18, 4/12 or 20/60), which are useful as information regarding testing distance is retained. The numerator denotes the testing distance (in meters or feet), and the, denominator the distance at which the optotype subtends 1 arcmin. A larger denominator indicates worse acuity. In Europe it is also common to express acuity in decimal notation (Monoyer’s scale) [42]. Within vision research the use a logarithmic scale is recommended as this gives a more sensitive representation of the true performance of the visual system, especially when visual acuity is limited [4346]. The relationship between the different notations is shown in equation 3.2.

( )

logMAR = log10 (MAR ) = log10 1 V

(3.2)

For the sake of comparison, high decimal acuity or good vision indicates that the subject is able to discern small angular details. When acuity is expressed in logMAR, smaller values indicate better vision. A logMAR score of 0 corresponds to a decimal acuity of 1.0 (Snellen 6/6) and is considered normal for foveal vision although many people can actually see better than 1.5 (logMAR -0.18). Table 3.1 Typical foveal limits for various acuity tasks Acuity task Detection Localisation (Vernier acuity) Resolution Recognition

3.2

Typical limit (MAR) 15 seconds of arc 2-6 seconds of arc 0.5 minutes of arc 0.5 minutes of arc

(logMAR) -0.6 -1.4 to -1.0 -0.3 -0.3

Contrast sensitivity

High-contrast resolution or recognition acuity is the most widely used measure of visual function. It fails however in providing information regarding the sensitivity of the visual system to objects of varying sizes and contrasts. The visual environment is by no means exclusively composed of high contrast

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objects; contrast levels in natural scenes have been estimated at approximately 9.5% (SD ±8.5%) and 100 % contrast is extremely rare [47]. It is not uncommon for people to have normal high-contrast visual acuity, yet reduced sensitivity to larger objects of lower contrast. Contrast sensitivity has been suggested as a better indicator of problems in performing daily activities, mobility and orientation than high-contrast visual acuity [48-50]. The contrast sensitivity curve (fig. 3.1) describes the sensitivity of the visual system to sinusoidal luminance gratings of varying spatial frequencies and contrast levels; each point on the curve represents the inverse of the contrast detection threshold for individual spatial frequencies. “Spatial frequency” refers to the number of pairs of light and dark bars, or cycles, contained within one degree of visual angle and corresponds to the ‘detail size’ of the grating object. A high spatial frequency indicates many cycles per degree; a low spatial frequency, few cycles per degree. Contrast sensitivity (CS) is defined as: 1 CS = (3.3) Threshold Contrast

Figure. 3.1. Contrast sensitivity function (CSF) showing the relative sensitivity of the eye to varying spatial frequencies and contrast levels. Contrast decreases upwards along the Y-axis and spatial frequency increases along the X-axis. Viewed at arm’s length, it is possible to just discern the stripes below the black dotted curve.

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For simple periodic patterns such as those used in the experiments encompassed by this thesis, contrast is typically measured with the Michelson formula (equation 3.4) as opposed to the Weber formula (equation 3.5) which is better suited to non-repetitive stimuli such as letters presented on a homogenous background. CMichelson =

CWeber =

LMAX − LMIN (LMAX − LMIN ) ≡ LMAX + LMIN 2( LMEAN )

LMAX − LMIN LMAX

(3.4)

(3.5)

Where LMAX and LMIN denote the maximum and minimum luminance of the stimulus respectively and LMEAN, the mean luminance of the stimulus. From figure 3.1 it is possible to see that the visual system is least sensitive to high spatial frequencies, and most sensitive to moderate spatial frequencies. High contrast is required for high spatial frequency detail to be discerned whereas moderate spatial frequencies can be seen at lower levels of contrast. This results in a CSF curve with a peak at approximately 4 cycles per degree (cpd) and a reduction for both lower and higher spatial frequencies. The high spatial frequency cut-off represents the resolving capacity of the eye when contrast is maximal; this limit in the order of 60 cpd (or MAR of 0.5’ arcmin). The low spatial frequency drop-off and peak in the CSF can be explained in terms of the centre-surround arrangement of ganglion cells and associated lateral inhibition. If a periodic pattern is imaged onto an ON-centre ganglion cell, the response will depend on the distribution of light across the photoreceptors coupled to the cell. Maximal response occurs when light falls on the centre of the receptive field (described below) but not on the surround [51]. Three possible scenarios are presented in Fig. 3.2 below. In the first instance, the periodic pattern stimulates both the centre (+) and inhibitory surround (–) of the cell thus leading to a reduced response. In the second panel, the pattern optimally stimulates the central zone with minimal inhibition from the surround, leading to a maximized response. In the third panel, the pattern stimulates both the centre and surround to a similar amount which also results in a reduced response. For OFF-centre ganglion cells, the neural response will be the opposite. Studies during the late 60’s and early 70’s by Campbell & Robson [52], Blakemore & Campbell [53] and Graham & Nachmias [54] suggest that the

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visual system consists of a number of “channels”, each sensitive to a range of specific spatial frequencies. The overall shape of the CSF can be thought to consist of overlapping spatial frequency channels – a notion supported by the adaptation studies performed by Campbell & Robson [52], whereby prior adaptation to an individual spatial frequency led to a depression of the CSF within the region of that spatial frequency. As such, the visual system can then be thought to disassemble images into separate spatial frequency components for subsequent processing in the visual cortex.

Figure. 3.2. The ON-centre receptive field superimposed on sinewave gratings of increasing spatial frequency (from left to right). The strongest response is elicited when a bright bar falls on the receptive field’s centre (+), and dark bars on the surround (–), as seen in the middle panel. A weaker response is generated if light falls on the inhibitory surround as seen in the first and last panels. Adapted from [51]. Sinewave gratings are often used as stimuli when studying spatial vision as they are selective for individual spatial frequencies and they match the centresurround organization of ganglion receptive fields [51, 55, 56] (see Fig 3.3). In addition, optical errors do not alter the appearance of the gratings other than by reducing contrast [57 (p.94)]. The stimuli used for resolution measurements in all papers (I-V) were Gabor patches; the product of a Gaussian (or “normal”) distribution and sine wave pattern in two dimensions. Figure 3.4 shows the luminance profile of Gabor patch (A), the product of sine wave (B), and Gaussian distribution (C).

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–

+

–

Figure. 3.3. Comparison between the luminance profile of a Gabor (above) to that of a schematic ON-centre receptive field (below), illustrating how the central portion of the Gabor patch matches the excitatory (+) and inhibitory (–) zones of the receptive field. Gabor patches lend the added benefit that the edges of the grating fade out gradually (Fig 3.4A) eliminating abrupt luminance changes at the edge of a circular or square patch as is evident in Fig 3.4B. The use of gratings also makes it possible to present dynamic stimuli at well-defined locations in the visual field through phase modulation, as will be discussed in more depth in chapter 4.

Figure. 3.4. A Gabor grating (A), the product of a sinewave (B) and Gaussian curve (C). The three panels above represent the luminance profiles of the Gabor, sinewave and Gaussian.

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As can be envisaged, the accurate determination of the CSF with numerous different spatial frequencies is laborious. For example, in order to measure CS at five spatial frequencies (as recommended in the ANSI Z80.29 guidelines [58]), the typical number of trials needed is 100 per spatial frequency, requiring approximately 30 minutes of testing time [59, 60]. This is obviously not feasible in a clinical setting. Many of the clinical tests of contrast sensitivity therefore adopt a sampling approach whereby a more limited number of spatial frequencies or contrast levels are evaluated. Of the numerous tests available for evaluating contrast sensitivity; the first designed specifically for clinical use was the Arden plate test [61, 62], consisting of a series of printed sinewave gratings. These vary in contrast from top to bottom and the examiner unmasks the grating, in the direction of increasing contrast, until the subject is able to discern the grating. The contrast level at which the patient can first see the grating is recorded and the procedure repeated for each of the five remaining plates. Over the subsequent three and a half decades many new tests have been developed, for example The Vistech Chart, Melbourne Edge Test, Cambridge Low-Contrast Gratings Test, Pelli-Robson Letter Chart, Bailey-Lovie Chart, Mars letter contrast sensitivity test, FACT, SZB LCS Test, and Hiding Heidi. There are also a myriad of computer-based testing devices, e.g. Test Chart (Thomson Software Solutions, Hatfield, Hertfordshire, U.K.) and Freiburg Visual Acuity and Contrast Test (FrACT). However these computer-based tests show lower repeatability than for example, Pelli-Robson or Mars charts. Additionally, the results are questionable when CS is good; possibly due to issues with monitor calibration at low contrast levels, an important fact that must be considered also when using other computer-based tests [63, 64]. A deeper discussion of the aforementioned tests is beyond the scope of this thesis. However one noteworthy test is the recently-developed quick CSF method (qCSF), which is able to estimate the whole contrast sensitivity function within 2-5 minutes using a Bayesian adaptive procedure and gratings as stimuli [60]. The original qCSF has been further developed to include a spatially-filtered, letter-based test [65], and adapted for measuring CS in the peripheral visual field [66].

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3.3

Peripheral visual acuity and contrast sensitivity

This chapter has to this point focused on foveal visual function. Visual acuity and contrast sensitivity in the peripheral visual field are much worse than in the fovea; static visual acuity declines rapidly with increasing eccentricity, falling by half at 2.5 degrees and to 20% of foveal levels at 10 degrees [6771]. This rapid reduction in acuity is similar in all directions in the visual field out to approximately 10-15 degrees; at greater eccentricities there is an increasing asymmetry between nasal and temporal, as well as between superior and inferior locations in the visual field [72-77]. It is now generally accepted that three factors limit resolution thresholds of the eye: spacing of the photoreceptors, spacing of ganglion cells and the optics of the eye [40, 75, 78-90]. The contribution of each of these three factors depends on eccentricity. Foveal high contrast resolution acuity is predominantly limited by optical errors as well as by the spacing of the cones, whereas peripheral resolution is primarily limited by the spacing of the ganglion cell receptive fields, [13, 75, 84, 85, 90-94]. Anatomical studies by Østerberg [95], Curcio [10] and combined anatomical and functional tests [13, 15, 90] support these claims. Contrast sensitivity is also reduced in the peripheral visual field which is not surprising. There are numerous studies that have measured contrast sensitivity at peripheral locations in the visual field [56, 66, 96-106]; all have arrived at the same conclusion, that CS is depressed compared with foveal levels, and that the CSF curve shifts towards lower spatial frequencies. Figure 3.5 depicts the typical change in contrast sensitivity in the periphery (with the foveal curve for comparison). The dashed black line shows the resolution limit and the grey triangular section to the right shows the zone of spatial frequencies in which aliasing can occur; that is to say, where it is possible to detect the grating but not to correctly determine the true orientation of the grating.

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Figure. 3.5. Contrast sensitivity function (CSF) for the peripheral visual field (black) showing an overall depression compared to the foveal CSF (orange) and shift in peak CS towards lower spatial frequencies. The dashed black line indicates the limit of resolution and the shaded section to the right, the area in which aliasing can occur (see Fig. 3.6). Aliasing occurs when the details in a retinal image are too fine to be resolved by the neural sampling, yet coarse enough to be detected; the resulting percept being one of lower, distorted spatial frequencies [86, 94, 107-111] as simulated in Figure 3.6. It is important to be aware of the possibility of aliasing when measuring resolution thresholds in the periphery as subjects will be able to detect gratings with a spatial frequency above the resolution limit, yet not resolve them correctly; it is therefore essential to utilize forced-choice procedures rather than yes-no paradigms (this aspect is discussed more in chapter 5).

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Figure. 3.6. A schematic representation of aliasing. Two sinewave gratings imaged on the retina (a) are sampled by the receptive field (b) giving rise to the perceived image (c). The upper grating of low spatial frequency is correctly sampled whereas the lower grating of high spatial frequency is under-sampled leading to a distorted percept.(Adapted from [19])

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4. TEMPORAL VISUAL FUNCTION The previous chapter discussed visual function in terms of the minimum resolvable detail under high contrast and the sensitivity to spatial details when contrast is reduced. In both instances the assumption has been that the visual stimuli are stationary. This condition is however the exception rather than the rule, as there is generally some degree of relative motion between the eye and objects in space; either objects move in relation to the eye or vice versa. This chapter deals with temporal aspects of visual function whereby retinal images are in motion, resulting in local changes in luminance over time.

4.1

Dynamic visual acuity (DVA)

The interest in visual acuity in the presence of movement began during the late 1930’s when Blackburn [112] conducted elementary experiments regarding the detectability of objects in motion. During the following two decades, Ludvigh and Miller performed a methodical study into the effect of relative motion on visual acuity. Much of their work was performed at the Naval School of Aviation Medicine (Pensacola, Florida), as the use of high-speed fighter jets and associated problems of “excessive relative motion” demanded a better understanding of how well pilots could see under such conditions [113]. In 1953, these two pioneers coined the term “Dynamic Visual Acuity” (DVA)§ to differentiate visual acuity during the ocular pursuit of moving targets from standard “Static Visual Acuity” (SVA) where optotypes are static [114]. DVA is generally measured as a function of the angular velocity of the target expressed in degrees per second; DVA is then defined as the minimum angle of resolution under conditions of target movement.

§

One should also note that the term ‘dynamic visual acuity’ is also used within the field of otolaryngology when diagnosing vestibular dysfunction. The difference with this measure of DVA is that the subject’s head is oscillated from side to side, thereby evoking the vestibulo-ocular reflex and compensatory eye movements. Defects in the vestibulo-ocular reflex will lead to reduced DVA.

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There are at least seven review-articles or theses in which the substantial volume of research concerning dynamic visual acuity is summarized; the first by Miller & Ludvigh [115], then Morrison [116], Hoffman, Rouse, and Ryan [117], Prestrude [118], Holland [119], Zavod [120] and a mini-review by Banks et al [121]. Most studies, with the exception of Low in 1947 [122], have concentrated on foveal DVA, and as such the remainder of this section will summarize the findings of these foveal DVA studies; peripheral DVA will be discussed in section 4.3. The 1962 review by Miller and Ludvigh [115] of the early research conducted from 1937 to 1959, in which many of their articles feature, gives a thorough yet concise overview of the various parameters influencing DVA. The general consensus to this point was that: 1) DVA diminishes with increasing target velocity [114] 2) DVA depends on the type of movement [114, 123, 124]: a. DVA is better for vertical, rather than horizontal movement b. There is no difference between left/right or up/down movement, or if the subject is in motion relative to the target. c. Circular motion leads to a more rapid decrease in DVA with increasing velocity than linear motion. 3) DVA at higher velocities (90°/sec) continues to improve with illumination in excess of 5000 lux, as opposed to SVA which reaches a plateau at 1000 lux [123, 124]. 4) DVA performance improves with training especially for higher velocities [125-127]. 5) DVA shows large variation between subjects; some subjects are more “velocity resistant” than others and show less deterioration in DVA with increasing velocity [125, 128]. 6) The reduction in DVA for increasing velocity is due to inaccuracies in tracking eye-movements, resulting in “image-smearing” on the retina [115]. These findings have been independently confirmed in subsequent studies [119, 120, 129-157]. The other noteworthy findings since the initial studies by Ludvigh and Miller are that males have slightly better DVA than females [132], and in addition, that DVA decreases with age [129-131]. The studies of Westheimer & McKee [136], Murphy [137], and Demer [142], Haarmeier & Their [151], Aznar-Casanova [153] gave weight to the notion that the deterioration in foveal DVA was indeed due to “retinal slip” as suggested by Ludvigh & Miller [114]; a mismatch between target velocity and pursuit movement of approximately 2-4°/sec is tolerated by the visual system, whereas greater amounts leads to reduced acuity. Aznar-Casanova [153] also compared DVA with drift-motion (where image movement is confined to, and

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is within a specific retinal area) as opposed to displacement movement (where the image as a whole moves over adjacent retinal areas) and found that displacement motion was better tolerated than drift motion; deterioration in acuity was already perceptible with drift-motion of 0.5°/sec.

4.2

Spatio-temporal contrast sensitivity

The overwhelming majority of DVA studies have adopted the use of high contrast stimuli. The noteworthy exceptions being Mayyasi [133], Miller [158] and Brown [159] who examined DVA, in low contrast, and de Lange [160, 161], Kelly [162-165] and Robson [166] who measured contrast sensitivity when stimuli were temporally modulated. Robson was the first to measure the combined spatio-temporal contrast sensitivity function; measuring contrast sensitivity at different temporal and spatial frequencies. Whereas normal spatial contrast sensitivity (sCS) concerns the sensitivity to contrast for stimuli of varying spatial frequency, temporal contrast sensitivity (tCS) describes the ability of the visual system to detect temporally-modulated or spatially uniform flickering stimuli. The periodic change (or modulation) in luminance over time is defined in terms of cycles per second (cps) or Hertz (Hz). This is equivalent to the number of periods striking a certain retinal area during the course of one second. Figure 4.1 shows the change in luminance for three temporally modulated sinusoids (A-C) with temporal frequencies of 0.5, 1.0 and 2.0 Hz respectively. The greater the number of periods passing a given point per second, the higher the temporal frequency. Spatially modulated sinusoidal gratings moving across the retina give rise to local luminance changes in time; the temporal frequency (w in cps) is dependent upon two factors: the spatial frequency of the grating (cpd) and the velocity of movement (°/sec) such that: w=

cycles degrees • = degree second

cycles second

(4.1)

It becomes evident (see Eq. 4.1) that the stimulus temporal frequency will be higher if either stimulus velocity or spatial frequency increases. It also highlights the relationship between spatial vision, temporal vision and motion perception.

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Figure. 4.1. Temporally modulated sinusoids. The temporal frequency in cycles per second (Hz) for each of the three panels are: A) 0.5 Hz, B) 1 Hz and C) 2 Hz. It is also possible to measure the resolution tCSF by having subjects determine the orientation of a grating as opposed to merely detecting the presence or absence of flicker [105, 167-169]. This is the method we employed in papers IV and V; we measured the peripheral resolution tCSF by having subjects determine the orientation of drifting Gabor gratings as opposed to solely detecting their presence. The temporal contrast sensitivity function (see Figure 4.2) resembles the bandpass form of the spatial contrast sensitivity function (see Figure 3.1), with a peak at moderate temporal frequencies, a high temporal frequency cut-off and a low temporal frequency fall-off. The peak and high temporal frequency cutoff are dependent on the stimulus spatial frequency and retinal illuminance [160-162, 166, 170]. The non-shaded region above a classic detection tCSF curve indicates that the stimulus (if still visible) is perceived as non-flickering. In the work of this thesis, the resolution tCSF has been evaluated by estimating the resolution CS (see section 3.2) for grating stimuli with varying drift speeds. The resolution tCSF will produce different values from the detection tCSF and the region above the curve will instead indicate that the orientation of the grating is no longer resolvable, independent of whether the actual movement is perceived or not.

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Figure. 4.2. A schematic temporal CSF (tCSF) with typical band-pass shape where contrast sensitivity is maximal at moderate temporal frequencies, minimum at high temporal frequencies and tapers off at low temporal frequencies. The classical method of determining the tCSF is by presenting a counterphase flickering grating and increasing the contrast level until the grating is seen to flicker. This procedure is repeated for a range of temporal frequencies and the contrast sensitivity (the reciprocal of threshold contrast) is plotted as a function of temporal frequency; the temporal frequency at which flicker is perceived only when contrast is 100% is in essence equivalent to the critical flicker frequency (CFF) which has been studied in depth [160, 161]. By repeating this procedure for numerous spatial frequencies it is possible to create a spatio-temporal CSF (stCSF) surface encompassing both the sCSF and tCSF [164, 166, 169, 171]. Cross sections through the stCSF surface elicit the shape of either the sCSF (for a temporal frequency of 0 Hz) or tCSF for a fixed spatial frequency as seen in Figure 4.3. For foveal vision the apex of this surface coincides with a spatial frequency of 3-4 cpd at a temporal frequency of 8-10Hz. The relationship between spatial and temporal frequency and associated effects on contrast sensitivity has previously been described by Kelly, Virsu et al, Krauskopf, and van Nes [164-166, 169, 171-173].

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Figure. 4.3. The foveal spatio-temporal CSF surface (stCSF) with crosssections through the surface at fixed temporal frequencies (blue, black and orange dashed sections). Contrast sensitivity increases upwards. (Adapted from Burbeck & Kelly [174] and Robson [166]) Examining the individual sCSF curves that comprise the stCSF in figure 4.3 one can see that contrast sensitivity for low spatial frequencies improves from low to medium temporal frequencies (compare orange and black dashed curves) but deteriorates when temporal frequency is high (blue dashed curve). High temporal frequency modulation results in the attenuation of contrast sensitivity at higher spatial frequencies. One can then postulate that the visibility of objects in which low spatial frequencies dominate may be enhanced if they are moved [164, 165, 173, 175]. As previously mentioned, a sinusoidal grating drifting across the retina results in local sinusoidal changes in luminance over time; the drift-velocity can be expressed either as degrees per second or in cycles per second (Hz). The rationale behind our choice of Gabors as stimuli for papers I – V was that these stimuli permit both static and dynamic presentation of individual spatial frequencies at well-defined locations within the visual field. Van Nes et al [175] and Kelly [165] also emphasize that drifting gratings (travelling waves) are more effective stimuli than counterphase (or standing waves) as they provide equal modulation for all points within the grating envelope, whereas counterphase gratings elicit full modulation only at their antinodes and none whatsoever at the nodes. Kelly takes this one step further by suggesting that “perhaps the stabilized travelling wave is, in some sense, the optimum spatiotemporal stimulus, reflecting certain fundamental properties of the visual pathways” [165].

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4.3

Peripheral DVA and spatio-temporal contrast sensitivity

Despite the great interest in motion perception and temporal contrast sensitivity during the fifties and sixties, very little research into peripheral DVA or tCSF was conducted. There are few references to peripheral DVA prior to 1970, the first a study by Low in 1947 [122], another by Hoogerheide in 1964 [176]. Both had methodological issues relating to the retinal area actually tested, or varying exposure times associated with increasing velocity. Despite this, it was possible to conclude that DVA deteriorated with increasing eccentricity, and that acuity for slowly moving targets in the far periphery was superior than for static targets. These findings were corroborated by Brown in 1972 in a series of experiments in which he measured peripheral DVA from 0 to 10 degrees (in 2.5° steps) using Landolt rings moving at 0 to 50 °/sec [155]. The major finding is that acuity improved for targets moving at 5-10 °/sec at eccentricities of 5 degrees or more. Beyond the 1970s, equally little has been published relating to peripheral DVA. Gordon Legge [177] investigated the effect on reading speed by scrolling text; subjects with normal vision experienced reduced reading speeds, whereas subjects with central visual field loss who used peripheral vision to see read 15% faster with scrolled text. The benefit of scrolled text presentation on reading speed has also been reported by Gustafsson & Inde [178]. Macedo, Crossland and Rubin [179] investigated the effect of retinal image slip on peripheral visual acuity and found that for non-crowded conditions, small amounts of image slip led to improved peripheral acuity; under crowded conditions retinal image slip degraded peripheral acuity. In Paper I (Lewis et al) [180] we examined the effect of relatively slow drift movement of 1-2°/sec on peripheral high-contrast acuity in the horizontal visual field, and anticipated similar results to those of Brown [155]. However no difference was observed between static and dynamic acuity other than in the fovea, where SVA was better than DVA. By first converting the measured acuities from logMAR to cpd, then expressing velocity in terms of temporal frequency (Hz) it is possible to suggest an alternative explanation regarding these results. From Table 4.1 it is evident that the stimulus temporal frequency varied depending on the spatial frequency of the grating at the limit of resolution. At 10° eccentricity (nasal and temporal) the stimulus temporal frequency varied between 7.5 and 19 Hz; at greater eccentricities the temporal frequency decreased as stimulus spatial frequencies were lower.

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Table 4.1 Dynamic visual acuity (in logMAR) for stimulus velocities of 1 and 2°/sec in the horizontal visual field (N= nasal field, T=temporal field). The stimulus velocity expressed in cycles per second (Hz) is shown in bold, below each corresponding acuity value. Velocity

N 30

N 20

N 10

FOV

T 10

T 20

T 30

1°/sec

1.12 2.3 1.13 4.4

0.86 4.1 0.91 7.4

0.60 7.5 0.50 19.0

0.06 26.1 0.12 45.5

0.50 9.5 0.57 16.1

0.68 6.3 0.72 11.4

0.80 4.8 0.81 9.3

(Hz)

2°/sec (Hz)

How does this then fit in with the previous section (4.2) concerning contrast sensitivity in the spatio-temporal realm? Examining the individual sCSF curves measured at various temporal frequencies of Allen & Hess [181], Koenderink et al [56], and Virsu & Rovamo [169], it is possible to create peripheral stCSF surfaces for various eccentricities by plotting each sCSF at its respective temporal frequency (see Figure 4.4). As can be seen in figure 4.4, the peripheral stCSF is generally depressed and has a lower high-contrast spatial frequency cut-off as would be expected from our knowledge regarding peripheral resolution.

Figure. 4.4. A schematic spatio-temporal CSF surface for a peripheral retinal location (dark blue), in relation to a foveal stCSF surface (dashed grey). Also shown are cross-sections through the peripheral stCSF surface at fixed temporal frequencies (blue, black and orange dashed sections).The three stars represent high-contrast acuity for static (green) and dynamic (red) stimuli of varying temporal frequency.

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It is also evident that, just as for the foveal stCSF, contrast sensitivity for the lowest spatial frequencies improves from low to medium temporal frequencies (orange and black dashed curves) but deteriorates when temporal frequency is high (blue dashed curve). The attenuation at higher temporal frequencies is not as pronounced as for foveal vision as shown by Allen & Hess [181]. In addition, due to the shift in sensitivity of the visual system towards lower spatial frequencies in the peripheral field [66] (as a result of sampling limitation) and due to better temporal resolution in the peripheral field there appears to be a greater tolerance to retinal motion. Changes in DVA should be minimal when measured solely at high contrast and relatively low velocities (see the three stars on the floor of the stCSF graph) as was the case in Paper I. Conversely, one would expect low contrast objects comprised predominantly of low spatial frequency components to be more visible when set in motion; the degree of improvement dependent upon the spatio-temporal characteristics at the specific area in the visual field. This was the basis for papers IV and V, in which we measured the peripheral stCSF in normally-sighted subjects and in subjects with central field loss (CFL). These measurements and how they pertain to patients with CFL will be described further in Chapter 8. In Paper IV, we evaluated peripheral (10°) contrast sensitivity for gratings moving at various temporal frequencies on three healthy subjects; effectively repeating the measurements of Daly [170] and Kelly [164, 165], but in the peripheral field. The results showed that contrast sensitivity for low spatial frequencies improved for stimulus motion of low temporal frequency, much in line with the previous foveal studies where optimal CS is obtained with stimulus modulation of 5-10 Hz. For higher spatial frequencies, stimulus modulation of 10 and 15 Hz caused a reduction in CS which is in line with the results of Wright and Johnston [182]. One other interesting result in paper IV is that the high-contrast cut off was not affected by stimulus motion, thus confirming the results seen in paper I, that stimulus motion does not affect high-contrast resolution acuity for lower temporal frequencies. This can be explained in terms of the speed of temporal processing which is higher in the peripheral retina than in the fovea [56, 169, 181, 183]; the perceived contrast of temporally modulated stimuli is less attenuated by stimulus motion, and resolution acuity will consequently be sampling-limited rather than contrastlimited. In comparison, the lower temporal resolution in the fovea will result in “motion smear” of the retinal image [179, 184, 185], thus reducing perceived contrast and limiting spatial resolution. This is more clearly seen in figure 4.4 where a theoretical spatio-temporal CSF is depicted. The higher temporal frequency cut-off extends the CS surface along the temporal frequency axis with little effect on high contrast spatial resolution until high temporal frequencies are reached.

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5. PSYCHOPHYSICS Psychophysics is the study of the relationship between the magnitude of the physical stimuli and the sensation or perception induced by these stimuli. Many of the procedures encountered in eye-care, such as visual acuity measurement, subjective refraction, colour vision and visual field testing involve psychophysical methodologies. For example, during the measurement of visual acuity the patient is presented with letters of varying sizes (physical stimuli) which he/she must identify and read (the perceptual response).

5.1

The psychometric function and its threshold

Psychophysically based clinical procedures often entail determination of a threshold, commonly the most difficult stimulus that can be perceived. For visual acuity measurements, the threshold is the minimum angle of resolution (MAR), and for contrast sensitivity measurements, the lowest amount of contrast that still permits the detection or resolution of a stimulus. Threshold determination in humans is confounded by the fact that humans are not “perfect observers” and as such the threshold varies for repeated measurements [5 (p.243)]. The degree to which repeated measures vary depends on numerous factors, such as task-complexity or the alertness of the subject. For a simple test involving a Yes/No response, the subject is asked to report whether a stimulus is seen or not. This type of yes/no testing is encountered when measuring visual fields, in which the threshold corresponds to the intensity of light that can just be detected; the subject presses a button each time she or he sees a faint point of light. The normal subject will not show a clear cut-off, below which the stimulus is never seen, and above, where it is always seen (see figure 5.1a). Instead, there will exist a range over which stimuli will be correctly seen a certain percentage of the time they are presented. As such, a frequency-of-seeing curve (or psychometric function) can be drawn (see figure 5.1b); the slope of the transition zone from 0%

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correct to 100% correct dependent on the amount of “neural noise” present. Disease or normal ageing processes can increase this noise thus making it more difficult to give correct, repeatable responses; the slope of the transition zone will become flatter as a result [5 (p.245)].

Figure 5.1. Psychometric curves for (a) a “perfect observer” and (b) normal observer. The threshold is the stimulus intensity or size that can just be discerned. In a Yes/No task for a normal observer the threshold equates to the stimulus intensity/size correctly seen 50% of presentations. The width of the grey transition zone and slope of the curve vary depending on the level of neural noise (Adapted from figure 11-1 in Schwartz p.244 [5 (p.244)])

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Forced choice task With a yes/no task, it is possible that the subjects’ decision making will suffer from response bias. Certain subjects have a tendency of answering “yes” when stimuli are near threshold, while others respond “no” more often; this bias towards a certain response will ultimately affect the measured threshold[186]. To overcome this problem a forced-choice approach may be used. In an experiment in which there exist two alternative answers it is common that the subject is required to give a response even when they are unsure or cannot see the stimulus; this is called a “forced-choice”. With two alternatives it is possible for the subject to guess the correct response 50% of the time. When there are four alternatives from which to choose, there is a 25% probability that the subject guesses correctly. For a two-alternative forced choice procedure (2AFC) it is therefore customary to determine the threshold based on the criterion that the subject must respond correctly 75% of the time, at a point mid-way between the 50% guessing rate and 100%. A procedure that involves a four alternative forced choice (4AFC) will have a guess rate of 25% and thus the threshold will coincide with 62.5% correct responses. A larger number of choices lead to a psychometric function with a greater slope, making threshold determination more reliable, but also more complicated for the subject [5 (p.252)]. The possibility also exists of presenting stimuli in different time-intervals, with one interval being blank, and have the subject determine in which of two presentations (or intervals) the stimulus is actually present. This is called a two interval forced choice procedure (2IFC) and is suitable when measuring detection thresholds.

5.2

Classical threshold determination

There are several methods available for determining thresholds. The three classical psychophysical techniques are: the method of adjustment, method of limits and the method of constant stimuli. Each has its own strengths and weaknesses as will be briefly discussed below. Method of adjustment The method of adjustment is the most elementary method for determining threshold and relies on the subject to adjust the stimulus intensity to the point that it is barely visible (or invisible). By repeating this procedure a number of times and averaging the results, thresholds can rapidly be determined making this method pleasant for the subject. Unfortunately as the subject is in control of the stimulus, his or her decisions on subsequent trials may be biased [5 (p.250), 187 (pp.15-18)].

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Method of limits (staircase) The method of limits encompasses three techniques: the method of ascending or descending limits and the staircase method. In the first two, the examiner systematically increases (or decreases) the stimulus intensity until the subject reports that it becomes visible (or disappears). The intensity at which the stimulus becomes visible is recorded and the procedure is repeated for several trials; the threshold is determined by averaging these results. The method of descending limits is commonly used when visual acuity is determined; large letters are initially shown and, as the subject reads them correctly their size is gradually reduced until they are too small to resolve. This method has the added benefit that the subject has time to grow accustomed to the procedure whilst the task is relatively simple. Both the methods of ascending and descending limits are prone to anticipation effects especially if the initial stimulus intensity is kept constant [5 (p.246)]. A combination of these two methods, the staircase method (or up-and-down method), overcomes some of the problems experienced with the individual methods by including both ascending and descending limits within a single trial. As the name suggests, the stimulus is increased or decreased in a stepwise manner; the stimulus is increased until it becomes visible then reduced again until it vanishes, before being increased again. The point at which one changes from an ascending staircase to a descending staircase, or vice versa, is called a reversal point. The threshold is determined by the stimulus intensity after a certain number of “reversals”. The staircase method is quick and reliable for threshold determination, and variations of it are used, for example, in visual field testing [5 (p.247)]. Method of constant stimuli In the method of constant stimuli, the stimulus intensity is randomly varied from one presentation to the next. A range of stimuli are presented, from very difficult to see, to very easy. As the stimuli are presented in a random order, the subject will not have any expectations regarding the upcoming presentations; their expectation levels remaining constant over the course of an experimental run. This method also allows the shape of the frequency-ofseeing curve to be found, and as such both threshold and slope can be determined. The disadvantage of this method is that many stimuli have to be included to sample the frequency-of-seeing curve sufficiently. This makes the procedure tedious for subjects and is also very time consuming [5 (p.248)].

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5.3

Implemented psychophysical methodology

Fortunately, adaptive psychophysical procedures have been developed which make the process of threshold determination much more effective than the classical methods. Adaptive algorithms are in essence staircase methods, but achieve greater efficiency by considering the previous responses before increasing or decreasing stimulus intensity. Based on the previous responses the adaptive algorithm determine the “most probable” threshold estimate and present the next stimulus at this level. There are many adaptive methods, including PEST, “best PEST”, Quest [186] and the Psi (ψ) method [188]. The Psi method introduced by Kontsevich & Tyler [188] is an advanced method based on Bayesian probability theory. Similar to the method of constant stimuli, it allows both threshold and slope of the psychometric function to be determined simultaneously. The Psi method is reported to determine thresholds more rapidly and with less variation than other adaptive methods [188, 189]. A more detailed description of the mathematics behind the Psi method is beyond the scope of this thesis, and as such the reader is referred to the paper by Kontsevich & Tyler [188]. Measurements of peripheral visual function are often difficult and time consuming [190], even more so in the presence of a disease [5 (p.245)]. Owing to the reported benefits and reduced number of trials required to determine threshold we chose the Psi method and forced choice tasks exclusively for measurement of visual thresholds (acuity and contrast) in all papers (I-V). The 2AFC procedure was used in all papers when measuring resolution acuity or contrast sensitivity; the subject had to determine the orientation of Gabor stimuli. In Paper I the second control experiment used a 2IFC procedure to ascertain whether a subject could appreciate stimulus motion or not. As such, the guessing rate for both procedures was 50%. The implemented Psi (ψ) method also incorporates the possibility of allowing a certain percentage of erroneous responses or “lapses” during a measurement. This lapse rate was set at 2% in Paper I and III and 5% in Papers IV and V. A lapse rate of 5% will result in the threshold coinciding with 72.5% correct responses, or half way between the guess rate of 50% and 95% (100% less the lapse rate). The lapse rate means that the procedure is relatively insensitive to occasional mistakes during the beginning of an experiment, and lapses do not

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significantly affect the number of trials required before the procedure converges on the threshold [188]. In Papers I and II, we presented 30 trials and this was sufficient for the Psi method to converge on threshold. In Paper III 40 trials were used, and in the two remaining papers, 50 trials. The decision to have larger number of trials was grounded on the complexity of the psychophysical task; measurements at low contrast and those performed on eyes with macular disease are inherently more difficult.

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6. MEASUREMENT & CORRECTION OF OPTICAL ERRORS As mentioned in chapter 2, the first systematic measurements of peripheral refractive errors were conducted by Ferree in the early 1930’s. Naturally attempts had been made to quantify peripheral refraction prior to this, but the methods employed were impractical in a clinical setting, both due to their complexity and because the results were not expressed in dioptres [191]. This chapter will briefly summarize the more common methods of determining offaxis optical errors that are currently in use, as well as the correction of these errors and their effect on visual function.

6.1

Peripheral refraction techniques

Subjective methods It is generally accepted that subjective refraction is the “gold-standard” for determining foveal refractive errors, whereby the patient must choose between different combinations of lenses to achieve clearest vision, generally using high-contrast optotypes. The clinical end-point of a refraction can be defined as the optimal combination of spherical and cylindrical trial lenses that give maximal visual acuity; such that the addition of +0.25 D sphere produces a “just-noticeable” reduction in acuity and additional -0.25 D spherical power does not lead to improved visual acuity. This procedure is inherently more difficult in the periphery due to the poorer resolution and the presence of larger optical aberrations in the peripheral visual field which makes the eye less sensitive to refractive errors for high contrast stimuli [85, 189, 192]. This necessitates the use of “bracketing” techniques whereby much larger steps (for example, ±2.00  ±10.00 D) are initially chosen so that the patient is able to observe a distinct difference in clarity between the two lens alternatives. By adjusting the power of the trial lenses so that the patient deems the two alternatives to be “identical” then

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subsequently reducing the step size to ±1.00 and finally ±0.50 (depending on the patients’ acuity) it is possible to fine-tune and establish the appropriate spherical correcting lens. Cylindrical refractive errors can also be determined in a similar manner, by using Jackson cross-cylinders of higher power (±1.00 or ±0.50 D) than the standard ±0.25 D. If one suspects the presence of large cylindrical powers it is also possible to rotate a high-powered cylindrical lens (-5.00 DC) through 180° to ascertain the preferred cylinder axis, after which the bracketing technique is used to optimize both power and axis of the cylindrical correction [193 (pp.764-766)]. It is obvious that this procedure can be arduous, especially when a patient is unable to discern differences between lenses of high powers. As such it is typical to first obtain a starting-point with the aid of an objective technique as will be described below. Variations of the subjective routine using contrastdetection have also been utilized [79, 88, 190, 194], though these methods require high levels of concentration from the patient and are also timeconsuming [195]. Therefore this method can hardly be considered practical in a clinical setting.

Objective methods There are a number of objective refraction methods available for measuring off-axis refractive errors. Some require a high degree of skill on the part of the examiner to obtain accurate and reliable results, while others necessitate instrument-modification in order to measure refractive errors at larger eccentricities. Retinoscopy From the late 1800’s, prior to the advent of auto-refraction, retinoscopy was widely practised. Within minutes, it can provide the clinician with an excellent starting point from which to commence the subjective refraction. Retinoscopy is the technique in which a streak (or sometimes, a spot) of light is directed into the patient’s eye and the relative movement seen in the pupil, of the reflex from the retina, is observed. With the aid of sphero-cylindrical lenses this relative movement is “neutralized” and the refractive error of the eye can be established. Although deemed an objective technique as no feedback is required from the patient, retinoscopy still requires a subjective decision on the part of the examiner and is therefore exposed to human error [196 (pp.345-366)]. A large number of studies have used retinoscopy to determine peripheral refractive errors [26, 190, 197-199], with Rempt et al [26] being the first to

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provide data out to 60° along the horizontal meridian. They observed a “double sliding-door reflex” which made interpretation of the retinoscopic reflex difficult, more so with increasing eccentricity; beyond 60° they found retinoscopy to be “practically impossible”. The difficulties in obtaining reliable results with off-axis retinoscopy have also been reported by other researchers [85, 190, 200, 201]. In particular, discrepancies may occur in cylinder power and axis at large angles due to increased aberrations in the periphery and the narrow elliptical shape of the pupil [85, 178, 190, 199-201]. These factors limit the use of off-axis retinoscopy for all but the most experienced practitioner. Auto-refraction Automatic objective refractors (autorefractors) contain electronic photosensors which analyse light (often infrared wavelengths invisible to the patient) reflected from the retina. The refractive error of the eye can thus be rapidly measured without the need for subjective decisions from the patient or examiner. Various measurement principles are used in the different instruments and include: the Scheiner disc principle, retinoscopy, “best focus”, knife-edge and image-size analysis principles [196 (pp.367-381)]. Further details regarding each of these methods are beyond the scope of this thesis. Since their advent in the early 1970’s autorefractors have become firmly established in ophthalmologic and optometric practice. One inherent problem with autorefractors is that they can result in measurement-inaccuracies due to pseudomyopia, which occurs when the subject accommodates during measurement due to the close proximity of the instrument to the eye. Although the fixation target within the instrument is placed at optical infinity fogging mechanisms are required to minimise this instrument-induced myopia. One alternative to counteract this problem is to use cycloplegic drops to paralyze accommodation; however this is not always a viable option in countries that restrict their use. Another alternative is to use an “open-view” system which allows the subject to fixate on real-world targets in the distance. The added advantage of having an unrestricted view is that patients who use an eccentric viewing strategy can continue to do so during measurements off-axis, which would otherwise cause problems. Two companies, Canon and Shin-Nippon, have produced open-view autorefractors in order to overcome the problems of instrument myopia. The first such instrument, the Canon Autoref R-1 was released in 1981, followed some 20 years later by the Shin-Nippon SRW5000 (Shin-Nippon, Rexxam Industrial Co. Ltd, Japan). The latter has since been superseded by the ShinNippon NVision K5001 open-view autorefractor which permits measurements

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with pupil diameters of a minimum of 2.3mm (as opposed to 2.9mm for its predecessor and 3.5mm for the Canon Autoref R-1). Of these three instruments, the Shin-Nippon NVision K5001 (also marketed as the Grand Seiko WR-5100K) is the only one still available for purchase. All three of these open-view autorefractors have been extensively used for measuring off-axis refractive errors [31, 39, 88, 202-208]. The Shin-Nippon NVision K5001 has been shown to provide reliable and accurate measurement of refractive error compared with subjective refraction both on-axis (spherical equivalent difference ± SD of within 0.14 ± 0.35 D) [204] and off-axis [206]. The repeatability (1.96 x SD of repeated measures) for larger off-axis angles decreases but is still within ±0.57 D for eccentricities of up to 30°. Moore & Berntsen [206] suggested that increasing astigmatism probably accounts (in part) to the decreasing repeatability, but also due to the presence of higherorder aberrations. HS-Aberrometers (Wavefront sensors) The problems associated with higher-order aberrations when measuring offaxis refractive errors can be reduced by using wavefront sensors or aberrometers. HOAs can have significant effects on peripheral visual function and it is therefore advantageous if these can also be measured along with the lower-order aberrations, defocus (sphere) and astigmatism. Many aberrometers nowadays are based on the Hartmann-Shack (HS) technique in which light from a point-source imaged on the retina is traced out of the eye, through an array of micro-lenses in a pupil-conjugate plane, and subsequently recorded by a light-detector [196]. Due to the large number of lenses it is possible to follow the path of light from many different locations in the pupil and see to what extent these rays deviate from those of a “perfect” plane wavefront. Individual points of light are imaged on the light-detector and their position recorded, relative to a non-deviated point. This information is then used to calculate the total aberrations of the eye [196 (pp.287-312), 209-211]. Lundström et al [83, 190] showed the HS-technique to be more useful than retinoscopy and subjective refraction when evaluating peripheral refractive errors. Atchison [202] also found the HS-technique to compare favorably with data obtained using an open-view autorefractor (the Shin-Nippon SRW5000). Most studies in which peripheral aberrations have been measured have used laboratory-built HS-aberrometers. Commercial aberrometers are available, and the Complete Ophthalmic Analysis System (COAS) HS-aberrometer (AMO Wavefront Sciences, Albuquerque, NM) was the first to give clinicians the possibility to measure HOAs with an open-view. The COAS exists in two formats, the “standard” with 1452 micro-lenses (44x33 array) and the “high-

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definition” COAS-HD with 5146 micro-lenses (83x62 array) giving approximately twice as many sampling points over a similar pupil area; the COAS-HD gives approximately 766 sample points for a 5 mm pupil, or roughly 40 samples/mm2 as opposed to 20 samples/mm2 for the standard COAS. The COAS-HD has also been produced with a “Vision Research” (VR) optical relay system incorporating a beam-splitter, which permits off-axis, open-view measurements; other commercial aberrometers are not suited for off-axis measurements without prior modification. Baskaran et al [212] examined the repeatability of the COAD-HD VR on a group of young emmetropic subjects and found the instrument to give rapid and repeatable on-axis and off-axis results, with better intra-class correlation coefficients (ICC) for coma, oblique astigmatism and spherical aberration (all ≥ 0.90) than the other HOAs, (all 0.35 to 0.89). Because COAS not only measures higher-order aberrations, but also the lower-order aberrations of sphere and cylinder, it is possible to use it as an autorefractor. It is capable of measuring refractive errors between -15 D of myopia and +7 D of hyperopia, and astigmatism of up to 6 D for a minimum pupil diameter of 3.5mm. It outperformed the Nidek ARK-2000 autorefractor with respect to repeatability with and without cycloplegia [213]. COAS did not induce any significant instrument myopia when used for foveal measurements on myopes [213], though in a larger heterogeneous group containing more young hyperopes, instrument myopia was approximately 0.25 D [20]. The conclusion based on these foveal repeatability studies was that COAS can be used as a “fast and reliable autorefractor” with the added benefit of access to HOA data [20, 213]. A number of other studies in which HS-aberrometers, autorefractors, retinoscopy and subjective refraction have been compared for off-axis measurements have been summarized in the excellent review by Fedtke [195]. The general conclusion that can be drawn is that open-view autorefractors and HS-sensors elicit comparable results with respect to subjective refraction, however may underestimate the magnitude of the oblique astigmatism slightly. Notwithstanding, Atchison [214] found the difference between COAS and subjective refraction to be within 0.50D for off-axis measurements.

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6.2

Correction of peripheral refractive errors

In Paper III [215] we used the COAS-HD VR to determine off-axis refractive errors on young emmetropic subjects and subsequently measured the effect of refractive correction on peripheral low-contrast resolution acuity. For subjects with measured off-axis astigmatism greater than -1.25 D the average improvement in visual acuity was 0.1 logMAR (equivalent to an improvement of one line). The correction of off-axis refractive errors, (which generally predominate over the HOAs) improves the contrast of the retinal image, and low-contrast acuity approaches the limits dictated by the neural sampling of the eye. By evaluating the effect of additional defocus (±1.00D) over the measured refractive errors we were also able show that the off-axis COAS measurements were accurate to within ±1.00D at 20°. This further confirms that COAS is clinically useful even when it comes to determining off-axis refractive errors. Although the measurement of off-axis refractive errors gives important information about how optical errors vary at different locations in the visual field (which may be important in terms of myopia-development), it is still somewhat surprising that very few studies have followed up with measurements of visual acuity or contrast sensitivity with these corrections in place. Millodot & Lamont [192] performed both off-axis retinoscopy and subjective refraction on three subjects; their results showed reasonable agreement out to 30° but they failed to report visual acuity. Wang et al [1996] were the first to present details of corrected off-axis acuity and were able to show that off-axis errors had a detrimental effect on detection acuity. In 2005, Lundström et al [190] evaluated four methods of determining the eccentric correction on a large group of healthy subjects: a subjective eccentric refraction using a contrast detection task (as opposed to high-contrast resolution discrimination), streak-retinoscopy, photorefraction, and with a Hartman-Shack sensor. The contrast detection task took 30-45 minutes and proved tiring for most patients, though was not impossible. Retinoscopy and photrefraction were both difficult at larger eccentricities due to instrument limitations and large peripheral aberrations. The HS-sensor proved most useful, also providing information about the total wavefront aberrations of the eye. In a subsequent study, Lundström et al [84] used an HS-sensor to determine off-axis correction and subsequently measured high-contrast resolution acuity under a variety of refractive corrections: on-axis sph/cyl correction, off-axis best sphere correction, off-axis sph/cyl correction and full off-axis aberration correction. There were no significant differences in acuity between any of the four corrective conditions, which confirmed the results of earlier studies in

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which peripheral high-contrast acuity was unaffected by refractive errors [85, 87, 216]. That high-contrast acuity remained unaffected was attributed to neural limitations in the periphery but did not exclude the possibility that other visual functions (such as contrast sensitivity, detection acuity or motion perception) could benefit from off-axis correction. This was later affirmed in a study by Rosén et al [189] in which high-contrast grating acuity remained relatively unaffected by optical defocus, whereas detection acuity and lowcontrast resolution was impaired even by small errors. In Paper II [217] we measured and corrected off-axis errors in the PRL of a subject with central field loss subsequent to Stargardt disease. The optical correction was determined and corrected for in real-time using a lab-built, adaptive optics (AO) HS-aberrometer. The AO system makes use of a deformable mirror to correct for the HOA’s measured by the HS-sensor. The mirror can address multiple points in the pupil individually and the compensation can thereby be tailored so that otherwise deviated rays are focused to a single (close to diffraction limited) point on the retina. As mentioned in chapter 2, sphero-cylindrical lenses do not permit the correction of HOA’s in general. However, the AO system permitted us to selectively correct for both LOA and HOA and compare visual function with habitual spectacle correction. The results of this study are discussed in section 8.2. Paper V also provides evidence that the correction of off-axis refractive errors is important, serving to improve peripheral resolution acuity and contrast sensitivity in subjects with CFL. The correction of off-axis refractive errors measured with the COAS-HD VR aberrometer gave improvements in visual acuity under different levels of contrast. These results will also be discussed in further detail in section 8.2. In conclusion, open-view autorefractors and HS-aberrometers have been shown to provide accurate and repeatable measurements of off-axis refractive errors, these often within 0.50 to 1.00D of subjective results. The correction of these off-axis refractive errors does improve certain aspects of visual function, such as low-contrast visual acuity and contrast sensitivity. The determination of the optimal correction for CFL patients by means of subjective refraction can be a challenging prospect, especially for clinicians with limited experience in examining patients with reduced visual acuity. As such, objective measurement techniques can simplify the process, by providing a reliable starting-point from which the subjective “fine-tuning” of the refraction can be performed.

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7. CENTRAL VISUAL FIELD LOSS Although the central ten degrees of the visual field constitute a mere 2% of the entire visual field, the loss of function within this area is debilitating; ordinary tasks such as reading, writing or recognising faces, become much more challenging. In this chapter the major causes of central visual field loss, as well as current treatment options will be discussed.

7.1

Epidemiology

In 2010 the number of visually impaired people in the world was estimated at 285 million [218], over 39 million of those were blind (according to the International Classification of Diseases (ICD) update 2016 [219] – See Table 7.1). These numbers have since been revised by Wong et al (in 2014), suggesting a worldwide prevalence of 191 million and 32.4 million visually impaired and blind, respectively [1]. Of the 740 million living in Europe [220], approximately 1.75% are visually impaired or blind; for the sake of comparison, the number of visually impaired or blind in Sweden (with a population of 9,7 million - 2015) is in the order of 100,000 to 120,000 of whom 3000 are children [221]. Macular diseases are not the major cause of visual impairment globally; uncorrected refractive errors and cataracts account for almost 80% of visual impairment cases, but these two conditions are generally considered reversible. Of the non-reversible causes of visual impairment, macular degeneration lies currently in second place behind glaucoma, and just ahead of diabetes. However due to demographical changes with an ageing population, its prevalence is predicted to increase dramatically [1, 222-224]. It is however perceivable that the prevalence of severe visual impairment and blindness due to macular degeneration will increase somewhat more slowly as new treatment options become available – these will be described in section 7.2.

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Table 7.1 WHO categories of visual impairment according to ICD-10 Version: 2016. Visual function is divided into four levels: normal vision or mild visual impairment, moderate visual impairment, severe visual impairment, and blindness [219].

Presenting visual acuity Category

0

Mild or no visual impairment

1

Moderate visual impairment

2

Severe visual impairment

3

Blindness †

4

Blindness

5

Blindness

9

Worse than: Snellen Decimal (logMAR)

6/18 0.3 (0.52) 6/60 0.1 (1.0) 3/60 0.05 (1.3) 1/60* 0.02 (1.7)

Equal to or better than: Snellen Decimal (logMAR) 6/18 0.3 (0.52) 6/60 0.1 (1.0) 3/60 0.05 (1.3) 1/60 0.02 (1.7) Light perception

No light perception Undetermined or unspecified

† Taking visual field into account: If the visual field of the better eye is no greater than 10° in radius around central fixation, impairment falls under category 3

* Or counts fingers (CF) at 1 metre.

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Although age-related macular degeneration (AMD) is the chief cause of central field loss (CFL) in industrialized countries, macular function can also be compromised by other conditions, such as diabetic- or hypertensive retinopathy, Stargardt macular dystrophy, Cone dystrophy and Lebers hereditary optic neuropathy; all of which primarily affect visual function at the retinal level, either by causing photoreceptor damage or initiating degeneration of ganglion cells and their axons. CFL can also arise when intracranial tumours compress the optic nerve or other regions of the visual pathway, though this is less common. In addition to age-related macular degeneration, a brief summary of the more common causes of CFL with relevance to Paper V is presented here. Macular degeneration. Macular dystrophies and macular degeneration lead to the disruption of the central region of the retina, and subsequently to absolute central scotoma or loss of macular visual function. In many industrialized countries, age-related macular degeneration is the principal cause of permanent central visual field loss in people over the age of 60; accounting for approximately 8.7% of visual impairment globally [1]. It is a progressive, chronic condition which accounts for the rise in prevalence with age; the prevalence of early AMD for those less than 55 years is between 3-6%, increasing to 13-25% for those 75 years of age and older, depending on ethnicity [1]. Caucasians run an increased risk of developing AMD compared with those of Asiatic origin, who in turn have a higher risk than people of African origin [1, 225 (p.4)]. Other factors related to AMD have been identified of which smoking is seen as the most consistently reported risk factor; smoking increases the likelihood of developing AMD by up to 2-3 times [226]. Genetics have also been implicated [225 (p.33)], with certain genes also reported to compound the effects of smoking [227]. In addition, AMD is more prevalent among women [228]. AMD is generally classified into two subgroups: “dry”, atrophic AMD and “wet”, neovascular AMD. The latter, causing more rapid and devastating visual impairment is fortunately the least common form, affecting approximately 10-15% of patients [229]. Dry AMD is characterized by the presence of focal yellowish drusen and pigmentary changes of the retinal pigment epithelium [230] (See Figure 7.1).

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Figure 7.1 Fundus photograph showing medium and large drusen (yellowish deposits) in, and surrounding the fovea of the right eye of a person with dry AMD. The black arrow indicates the approximate position of the fovea. Initially these manifestations do not give rise to any pronounced visual symptoms and are considered to be normal ageing changes if the drusen are small (“drupelets” ≤63 μm) and there are no associated pigmentary abnormalities. Larger drusen (>63 μm to ≤ 125 μm), in the absence of pigmentary changes, are the sign of “early AMD” (see Table 7.2). As AMD progresses waste products continue to collect within the retina as the ability of the RPE to digest these molecules decreases, which in turn results in inflammation. Subsequently, intermediate AMD can differentiate into either geographic atrophy (GA) or neovascular AMD, both of which result in severe visual impairment. Approximately 0.37% of the World population has late AMD [1]; for comparison, the prevalence in the Scandinavian countries is 0.94% [224], 0.7% in a German population [231] and 1.5% in the USA [223].

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Table 7.2 Clinical classification of AMD as proposed by Ferris et al [230]. Definition Classification of AMD No apparent ageing changes Normal ageing changes Early AMD Intermediate AMD Late AMD

(Lesions assessed within 2 disc diameters of the fovea in either eye)

No drusen and no AMD pigmentary abnormalities Only drupelets (small drusen ≤63μm) and no AMD pigmentary abnormalities Medium drusen >63μm and ≤125μm and no AMD pigmentary abnormalities Large drusen >125μm and/or any AMD pigmentary abnormalities Neovascular AMD and/or any geographic atrophy of the RPE

Geographic atrophy manifests as a loss of the RPE, outer layers of the neurosensory retina [225 (p.123)] and can be clearly seen using fundus autofluorescence (FAF). This is an imaging technique that can reveal the variation in concentration of lipofuscin in the retina and thus areas of atrophy or areas in which active degeneration is present. If neovascular changes do not ensue, GA signals the end stage of dry AMD and accounts for approximately 20% of AMD patients who are classified as blind [225 (p.122)]. It is often the case that both eyes are affected [232] and due to the presence of central scotomata, patients develop one or more extra-foveal fixation sites or preferred retinal loci (PRL) in order to perform various visual tasks [233, 234]. Given that the resolution capabilities of the peripheral retina are much lower than in the fovea, visual function in the PRL will also reflect this. Neovascular AMD is a potentially serious condition caused by choroidal neovascularization (CNV) in which new blood vessels form and grow through defects in Bruch’s membrane and usually continue to do so below the RPE. Initial vison loss results from leakage of blood and serum under the retina, into the retina (causing macular oedemia) and under the RPE [7 (p.636)]. At this stage patients report reduced visual acuity, metamorphopsia (visual distortion) and possibly the presence of a positive central scotoma (or dark spot in the central field visible to the patient). Confirmation of the presence of the CNV is by means of fluorescein angiography (FA) or Indocyanine green angiography (ICG). Prior to the discovery of anti-vascular endothelial growth factor (anti-VEGF) drugs, neovascular AMD accounted for approximately 90% of cases of severe vision loss due to AMD [235]. Untreated neovascular

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AMD is associated with an extremely poor visual prognosis due to complications such as haemorrhagic pigment epithelial detachment (PED) or vitreous hemorrhage which in turn result in retinal detachment [7 (p.636)]. Stargardt macular dystrophy Stargardt macular dystrophy (SMD) is the most common autosomal recessive macular dystrophy, affecting roughly between 1 in 8000 to 10000 and accounts for ~7% of all retinal disease [236, 237]; men and women are affected equally. SMD usually debuts in the first or second decades of life [7 (p.670), 237, 238] and is sometimes termed juvenile macular degeneration; it shares many clinical signs and symptoms of AMD. First described by Carl Stargardt in 1909 as a flecked retina disease, patients with Stargardt disease initially complain of bilateral reduced vision, even those with seemingly normal acuity [238]. During the early stages of the disease, the foveolar light reflex diminishes and characteristic yellowish-white flecks appear around the macular, or may alternatively encompass the posterior pole. The flecks are round, linear or pisciform (fish-like) in shape and average 100-200 μm in size and contain a lipofuscin-like substance. Over time the accumulation of this material within the RPE instigates cell death, atrophy of the RPE and choriocapiliaris, much like the changes leading to geographic atrophy. As with GA, central visual function is compromised and patients adopt an eccentric fixation and PRL due to the presence of bilateral scotomata. Peripheral visual function is said to be largely unaffected though darkadaptation times are sometimes delayed [239]. Fundus flavimaculatus (FFM), a variant of SMD, usually shows a slower progression and somewhat better long-term visual prognosis. This may reflect the fact that some cases of FFM do not present until the fourth or fifth decades of life [240, 241]. Fundus autofluorescence is also useful when examining patients with SMD or FFM; autofluorescence levels are often abnormal in both conditions [240, 242]. Lebers hereditary optic atrophy Lebers hereditary optic atrophy (LHON) is an uncommon, maternally inherited mitochondrial genetic disease, with 70% of cases due to the 11778point mutation in the mitochondrial DNA [243]. LHON is characterised by sudden and painless monocular loss of central vision, however after a few weeks or months the second eye will also be affected; 97% of those affected have bilateral central visual field loss within one year of initial onset of the first eye being involved [244]. The prevalence of LHON has been reported to be approximately one in 31000 to 50000 with males more often affected than females, constituting 80-90% of all cases [245].

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Spontaneous visual recovery has been reported within the first year following vision loss, but is less common in the 11778 mutation than for other mutations (for example the 14484 or 3460 mutations). Unfortunately, the harsh reality is that visual acuity will decrease to below 0.1 (1.0 logMAR) in the majority of cases and patients will develop large central visual field defects [244]. Fundus examination during the initial phase may fail to elicit any disc abnormalities, even though it is more common to see disc hyperaemia and diffuse disc margins reminiscent of pseudopapilledema. Thereafter severe optic atrophy ensues, giving rise to a waxy, pale disc appearance and pronounced cupping due to the loss of retinal ganglion cells. Peripheral vision is usually intact and therefore visual rehabilitation targeted at enhancing peripheral visual function is a clinically viable option, especially as most LHON patients are young and particularly amenable to training [246]. Progressive cone-rod dystrophy Cone-rod dystrophies (CRDs) are also a group of rare inherited diseases leading to CFL with a prevalence of 1/40,000. The earliest symptoms, usually occurring during the first decade of life, are a reduction in visual acuity and increased photophobia (sensitivity to light). Children adopt a noticeable deviated gaze to counteract the bilateral central scotomata by making use of the intact peripheral retina. Colour vision deteriorates as the disease progresses, and later, night blindness becomes a problem subsequent to rod involvement [247, 248]. End-stage visual acuity is usually in the order of 0.05 (1.3 logMAR).

7.2

Medical treatment options

With the exception of neovascular AMD, there are very few surgical or medical treatment options for the other causes of CFL discussed above. Instead, the goal of CFL rehabilitation from the perspective of an optometrist is to improve remaining peripheral visual function and help the patient utilize this to its full potential. Prior to the advent of antiangiogenic agents (also anti-VEGF), neovascular AMD was treated in an aggressive manner using laser photocoagulation and from the late 1990’s, photodynamic therapy (PDT) with Verteporfin® [249]. Despite improved visual outcomes with PDT compared with photocoagulation, visual acuity continued to deteriorate and there were other adverse effects such as photosensitivity, headaches and chorioretinal atrophy [250]. Anti-VEGF agents were seen as a breakthrough as visual function in the majority of patients was actually shown to improve following

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administration of the drug and further deterioration of vision greatly reduced [249, 251]. Macugen (pegaptanib) was the first anti-VEGF agent to be given FDA approval in 2004 and since then, Lucentis (ranibizumab), Avastin (bevacizumab) and Eylea (aflibercept) have also been used to treat CNV [225 (p.248), 235]. These are administered by way of injection into the vitreous chamber via the sclera, posterior to the ciliary body. The need to perforate the eye, along with the necessity for frequent retreatments and high cost of treatment are seen as the major drawbacks of using antiVEGF agents. Despite this they are now firmly established as the standard of care, although in developing countries the high cost prohibits their use. For a more thorough discussion of treatment options see Lim et al (2012) [235]. In addition to the pharmaceutical treatment of neovascular AMD, it is important to mention the Age-related Eye Disease Studies (AREDS and AREDS2) in which randomized clinical trials of antioxidant vitamins, minerals and omega-3 fatty acids and their effects on AMD and cataract were conducted. The initial AREDS study showed that a combination of vitamins C and E, beta-carotine, zinc oxide and cupric oxide, taken orally, reduced the relative risk in patients with monocular, intermediate or advanced AMD of developing advanced AMD in contralateral eye by 25% at five years. The risk for subsequent vision loss of three or more lines was also decreased by nearly 20% [252]. There are currently no approved pharmaceutical treatments for SMD, LHON or CRD, but trials of the drug Idebenon (Raxone) for LHON are currently in progress within Europe. Results from the initial phase of the study showed that Raxone appears to prevent further vision loss in the better eye of patients with unequal acuities [253]. The possibility of retinal gene therapy is also one being considered for a number of the conditions mentioned above; a concise review of these as of 2012 was published by Boye et al [254]. Having read this chapter one may be left feeling that the situation for patients with CFL is rather dire and gloomy, but headway is being made. The number of people with incipient neovascular AMD who progress to become severely visually impaired or blind should also decline with the advent of antiVEGF treatment. In addition, there are other options to ameliorate remaining visual function, by giving optimal optical correction, prescribing magnification and/or filter lenses in combination with compensatory techniques. These will be the subject of the following chapter.

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8. VISUAL REHABILITATION OF PATIENTS WITH CFL Bilateral central vision loss leads to difficulties in performing everyday tasks such as recognizing faces [255], reading or driving. Patients with CFL find reading demanding and a large proportion (87.5%) are reported to cease reading altogether [256]. The presence of an absolute central scotoma necessitates the adoption of eccentric viewing strategies so that relatively healthy areas of the peripheral retina are used instead for visual tasks; in effect moving the scotoma out of the line of sight (See figure 8.1)

Figure 8.1 The concept of eccentric viewing and use of a preferred retinal locus (PRL). a) Central scotoma impeding vision. b) Eccentric viewing in which the scotoma is displaced upwards, away from the text, and a PRL below the scotoma is used.

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8.1

The preferred retinal locus (PRL)

The areas in the periphery that are used when bilateral central scotomata are present are called “preferred retinal loci” (PRL) [257] and are defined by Crossland et al [234] as, “one or more circumscribed regions of functioning retina, repeatedly aligned with a visual target for a specified task, that may also be used for attentional deployment and as the oculomotor reference”. Patients adopt a PRL, often within 2-3° from the edge of a scotoma without formal training or instruction [257-259]. Fletcher & Schuchard [260] indicate that the majority of patients with AMD, in the order of 85%, develop a PRL. Development of a PRL occurs remarkably rapidly, often over the course of one to six months [261]. Using a scanning laser ophthalmoscope (SLO) and a technique called microperimetry it is possible to determine the size and extent of the scotoma and to measure fixation stability (the ability of the eye to maintain fixation within the PRL). Guez et al [262] and Schuchard et al [232] found that the scotomata of AMD patients varied in both size and shape, with an average angular diameter between 10.3° to 21.8° and having a slight horizontal elliptical shape. Scotoma characteristics are etiology-dependent. Patients with LHON generally present with caecocentral scotoma (a central scotoma extending from the fovea to the blind spot), this gradually enlarging after the initial acute phase of the disease. In comparison, patients with atrophic AMD may initially develop a perifoveal horseshoe-shaped scotoma with a small island of intact central vision; the areas of atrophy coalescing with time, creating a dense central scotoma [259]. Studies investigating the fixation stability of AMD patients show large individual variation and generally much poorer fixation than for healthy subjects. Crossland and Rubin [263] and Crossland [264] showed that bivariate contour ellipse area (BCEA) fixation stability in healthy individuals is approximately 100 to 650 arcmin2 (equating to circles with a diameter of 0.2° to 0.5°). In comparison, the fixation stability of patients with AMD ranges from near-normal values to in excess of 30000 arcmin2 [265-268]. One study by Whittaker et al [269] showed a positive correlation between increasing scotoma size and fixation instability, whereas Crossland [265] and Timberlake [270] observed no such relationship. As one would expect, fixation stability generally improves over time [261, 265, 268]; being better for patients who lose visual function relatively early in life. In addition, the number of PRLs used by a patient decreases with time,

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even though many patients retain and use two or more functional PRL for different visual activities [265, 271-273]. Multiple PRLs are seen more frequently in the presence of larger central scotomata [269]. It has been speculated that the position of a PRL may affect certain visual tasks, such as reading and locomotion. The location of a PRL is unpredictable [260, 274], varying between individuals and CFL etiology. Patients with Stargardt often develop a PRL some distance below the scotoma [267, 275], whereas the majority with geographic atrophy tend to choose locations to the left or right of the scotoma, followed by positions below the scotoma [260, 261, 276, 277]. Guez et al [262] suggest that PRL locations inferior to a scotoma are important for locomotion and it is important to note that reading proficiency may not be the major factor regulating PRL location. One would intuitively expect that reading should be easiest when the PRL is located below the scotoma as the horizontal span of letters will not be affected by the scotoma. A number of investigators have shown that active eccentric viewing training, eye-movement training and eccentric viewing awareness can help to improve reading rates [178, 261, 278-283]. Eccentric viewing training in Sweden was first described by Inde [284], later resulting in the book “Low Vision Training” by Bäckman and Inde [246]. Since then, many different approaches have been employed. Nilsson et al [280] trained individuals to read magnified, scrolled text at “a more favorable retinal locus” or trained retinal locus (TRL) and saw a seven-fold improvement in reading speeds (from barely 10 words per minute to 68 words per minute). Using fixation stability training strategies, Tarita-Nistor [285] also showed improvements in reading speed, as did Seiple et al [286] who used eye-movement training. Younger individuals generally appear to adapt and learn these strategies more rapidly than elderly [261, 264]. No clear evidence has been provided showing the advantage of one training method over another; a combination of different strategies may be the best option [287]. In addition, training a TRL as opposed to an existing PRL may not lead to improved reading speed as a subject who is concentrating on his/her eccentric viewing strategy may actually read more slowly [261]. Improvements in fixation stability and saccadic control following training may be the underlying factor governing reading performance [288], this theory corroborated by Crossland and Seiple [289] who show that reading speed is reduced with increasing fixation instability. As it is impossible to discuss the various training strategies in depth within the scope of this thesis, I recommend the three excellent review articles by Howe [287], Gaffney [290] and Pijnaker [288] in which these are discussed.

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Ultimately many patients become unaware that they are using eccentric viewing strategy [261, 291]. This occurs when the eccentric viewing angle becomes manifest and the PRL acts as the new oculomotor fixation-locus from which eye movements are initiated; at this stage the patient can truly be said to be using eccentric fixation. Patients who are unconscious that they a using a PRL read more rapidly than those who are concentrating on their eccentric viewing [261] which suggests a more complete adaptation to their central field loss.

8.2

Optical correction and stimulus motion

As previously discussed in Chapters 2, 3, and 6, off-axis optical errors lead to reduced contrast and quality of the retinal image. As contrast sensitivity in the peripheral visual field is already lower than in the fovea it is important to ensure that optical errors are fully corrected, and that suitable levels of magnification are provided if peripheral vision is to be utilized to its full potential. Prior to the case study by Gustafsson [292], most research had evaluated the effect of eccentric correction on individuals with normal foveal vision [38, 85, 88, 151, 194]. The conclusion made by Millodot [85], Rempt [216] and Wang et al [87, 88] was that off-axis correction was of limited value as they observed no improvement in visual function. A number of years later, Gustafsson [292], undeterred by these results, became the first to apply knowledge concerning eccentric refraction in a group having the potential to benefit most, namely those with CFL using an eccentric PRL. Gustafsson [292] evaluated the effect of off-axis correction on resolution acuity and contrast sensitivity in a subject with central field loss. He found that both these measures improved by 0.1 log units with off-axis correction as opposed to central correction.Since this ground-breaking study, only a limited number of studies investigating the effect of off-axis correction on peripheral visual function have been conducted; the majority of these representing modifications to the initial study as new and better instrumentation became available. On a larger group of subjects with CFL, Gustafsson & Unsbo [293] saw improvements in visual acuity (0.13 logMAR) and contrast sensitivity (0.15 log units) with eccentric correction. In 2005, Lundström, Gustafsson & Unsbo [294] used a Hartman-Shack (HS) sensor to measure the off-axis optical errors in the PRL of six patients with CFL. A few years later, Lundström et al [83] evaluated the effect of eccentric wavefront correction at the PRL of seven CFL patients, and at 20° eccentricity in a control group of four subjects with normal vision. Visual function for resolution and detection improved with HS-eccentric correction for all CFL subjects; by comparison, high-contrast resolution was unaffected in normally-sighted subjects.

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In Paper II [217], we compared the effect of an eccentric refractive correction and full adaptive-optics (AO) aberration correction in the PRL of a patient with long-standing CFL due to Stargardt disease. The AO-correction resulted in better visual acuity at all contrast levels tested (100%, 25% and 10%). The improvements over standard eccentric correction attributable to the correction of higher order aberrations, primarily coma. By fully correcting the refractive error present off-axis, the subject’s high-contrast acuity improved by 0.06 logMAR, and her low-contrast (25%) acuity improved 0.16 logMAR compared to her habitual correction. After further correction of the higherorder aberrations the total improvement in visual acuity for high-contrast was 0.14 logMAR and 0.27 logMAR for low-contrast. This shows the importance of correcting off-axis refractive errors, and also highlights the fact that HOA’s also contribute to the reduction in visual performance in the peripheral field. Paper V also confirms that the correction of off-axis refractive errors is important, serving to improve peripheral resolution acuity and contrast sensitivity in five subjects with CFL. Without off-axis correction, only three of five subjects could resolve gratings at 25% contrast; following correction all subjects were able to resolve them. Contrary to expectations, high-contrast visual acuity also improved significantly with off-axis correction; researchers have discounted the benefit of peripheral optical correction on high-contrast acuity [84, 85, 87, 189]. On the other hand, Lundström et al [83] and Baskaran et al [27] also experienced similar results on subjects with CFL. This indicates that subjects with CFL, who concurrently have lower contrast sensitivity, gain more from off-axis corrections. This could be as a result of poorer contrast sensitivity for subjects using a peripheral retinal location than subjects with healthy eyes, as is evident when comparing the results of Papers IV and V. Optical errors would then be expected to further reduce contrast sensitivity and thus visual function is no longer sampling-limited, rather it becomes contrast-limited [83]. In addition to studying the effects of optical correction in Paper V, we also investigated the influence of stimulus motion on resolution contrast sensitivity. The main findings were that stimulus motion of 7.5 Hz resulted in improved contrast sensitivity for stimuli of low spatial frequency, and that high contrast acuity was generally unaffected by stimulus motion. That stimulus motion lead to improved contrast sensitivity for stimuli of low spatial frequency is interesting in light of previous studies investigating the effect of motion on visual function. Gustafsson and Inde [178] utilized dynamic text presentation as a method of pre-optical reading training; with suitable magnification (6x-13x), fixation lines, and horizontally scrolled text, their CFL subjects achieved significantly improved reading rates of between 10 and 90 extra words per minute.

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This positive effect of stimulus motion has also been reported by Macedo et al [179] and Watson et al [295]. Macedo et al [179] showed that retinal image slip had a positive effect on peripheral acuity for isolated targets, though this effect was negated by crowding. Watson et al [295] on the other hand saw improvements in word recognition and the ability to discriminate facial expressions when images were “jittered” on the computer screen and suggested that jittered stimuli produce a sustained neuronal response allowing for more efficient processing of the low-spatial frequency images best seen by patients with CFL. Combined, these results provide strong evidence that a certain amount of stimulus motion is advantageous, enhancing the perception of large objects (containing low spatial frequency information) in the peripheral field.

8.3

Magnification

As previously alluded to in section 8.2 and in chapter 3, magnification is required to counteract the low resolution capacity of the peripheral retina when using a PRL. Three options are available when it comes to magnification: enlarge the object to be seen (object magnification), reduce the viewing distance, thereby increasing the angular subtense of the object at the retina (relative distance magnification), or use an optical system to create angular magnification (See figure 8.2 a-c). Proximal magnification or Relative distance magnification (see Fig 8.2b) is the simplest form of magnification, and is achieved by moving the object closer to the eye. For highly myopic or young patients with sufficient remaining accommodation, a reading addition may not be required to compensate for the relatively short working distances. In other instances a reading addition will be necessary; this being the reciprocal of the actual viewing distance (in meters). It is common to specify magnification relative to a fixed distance, usually 25cm which necessitates an Add of +4.00D. The magnification level relative to 25 cm is thus 1x. Halving the reading distance to 12.5cm requires the use of a +8.00D Add, and will give a relative magnification of 2x. Following this logic one can see that magnification (relative to 25cm) is the dioptric power of the near addition (F) divided by 4. Object magnification or Relative size magnification is achieved by physically enlarging the text or object (see Fig 8.2a). Prior to the advent of smart-phones and tablets, electronic video magnifiers and large-print books were the most common low vision devices for creating object magnification at close distance. Inexpensive modern technology has made object magnification much

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more accessible. It is possible to take photos of both near and distance objects and enlarge these sufficiently by simply increasing the level of zoom.

Figure 8.2 Three methods of achieving the same level of magnification: a) Object magnification, b) Proximal magnification and c) Telescopic magnification. The red letter “A” is the original object (and retinal image), the black letter “A”, the new object size/distance and corresponding retinal image. The grey letter, the magnified virtual image produced by the telescope. The third method of providing angular magnification (see Fig 8.2c), is via telescopic devices. The ratio of the angle subtended by the image through the optical system to that subtended by the object when viewed directly gives the angular enlargement; the vergence of light may remain unaltered which makes this method the most effective for achieving magnification at greater distances. These devices can also be used at shorter distances by adding a plus-powered reading ‘cap’ [296 (p.192)]. There are numerous methods of determining the presumptive magnification requirement for reading; these often based on either the distance or near visual acuity, for example, the Kestenbaum method, Mehr & Freid’s method, Lighthouse method, Newman’s reciprocal of vision, Equivalent viewing distance and the proximal magnification method. Many of these bear semblance to one another, differing only in terms of whether distance or near acuities are used as a starting point [297]. A comparison of eight different methodologies was performed by Wolffson & Eperjesi, and the difference between predicted- and prescribed was smallest for the Kestenbaum method

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and proximal magnification methods. Greater differences were observed when magnification requirements were higher [297]. Calculation of predicted magnification using the Kestenbaum method involves taking the reciprocal of the decimal or Snellen distance acuity [297] or alternatively 10logMAR (distance visual acuity). For example a patient with a distance acuity of 0.1 (6/60) will require an Add of approximately +10.00D and will consequently read at a distance of 10cm. It is often the case that prescribed and predicted magnifications using this method do not fully correspond due to differences in task complexity or other patient-specific factors. As such, predicted magnification can only ever be a starting point from which optimal magnification devices are determined [297]. The proximal magnification method simply involves determining the reading addition required to accomplish near acuity as described earlier in this section. This process can be further simplified by using Inde and Gustafssons’ SEnior training manual titled “Come closer” [298]. One determines the magnification required in order to read text at a distance of 25cm with a +4.00D reading addition, and thereafter reduce the reading distance (and give correct addition) as specified in the manual. One final method of calculating the required magnification is to compare the measured acuity with the required acuity and depending on requirements, provide a slight magnification reserve in addition to this. For example, a patient with a distance acuity of 0.1, wanting to see detail corresponding to 0.5 will require 5x magnification (with an additional magnification reserve if necessary). The same approach applies for reading; a patient with an acuity of 24p who wants to read 8p text will require at least 3x magnification to resolve the letters, and somewhat more (a reserve of 2:1 to 3:1) for fluent reading [299 (pp.475-497)]. In summary, the visual rehabilitation of patients with CFL can be considered a multi-stage process in which the following (and other stages) are included: 1) Various training strategies to improve fixation stability, 2) Determination of the optimal eccentric correction(s) to improve acuity and contrast sensitivity, 3) Prescribing magnification to counteract the effects of poor peripheral resolution. 4) Evaluate the effect of image motion on visual performance. 5) Prescribe optical filter lenses to improve image contrast. For CFL subjects, the beneficial effects of optical correction were clearly evident in papers II and V, as was the benefit of stimulus motion on contrast sensitivity in paper V.

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9. SUMMARY OF PAPERS This thesis expands the knowledge within the field of peripheral visual function with emphasis on the optical correction of off-axis refractive errors and dynamic viewing conditions. For all studies, ethical approval was obtained from either the local ethics committee (Ethical Advisory Board in South East Sweden, Karlskrona), or regional ethics committee (Regional Ethical Review Board, Linköping and/or Stockholm). Informed consent was obtained from all participants in agreement with the tenets of the Declaration of Helsinki.

9.1

Paper I: Resolution of static and dynamic stimuli in the peripheral visual field.

This study evaluated the effect of stimulus motion on high-contrast visual acuity in the periphery. Resolution acuity of the right eye of ten young emmetropes was measured at seven locations along the horizontal visual field: in the fovea, 10°, 20° and 30°; both nasally and temporally. Stimuli were high contrast Gabor gratings made to appear to drift within the Gaussian envelope. Three drift velocities were evaluated: 0°/s, 1°/s, and 2/°s. The results showed no difference between static and dynamic resolution acuity in the peripheral field for either velocity. In the fovea, static resolution acuity was better than dynamic resolution acuity. There was a clear naso-temporal asymmetry in resolution acuity (both static and dynamic) beyond 10°. The author was responsible for study design, subject recruitment, data collection, data analysis and writing the manuscript.

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9.2

Paper II: Benefit of Adaptive Optics Aberration Correction at Preferred Retinal Locus.

In this case study, the effect on vision of optical correction in the PRL of a subject with central field loss was investigated. The 68 year-old subject with bilateral central scotoma subsequent to Stargardt disease used a PRL situated 25° nasally from the non-functional fovea of the left eye. High (100%) and low contrast (10% and 25%) static grating resolution acuity was measured under sphero-cylindrical correction as well as aberration correction (utilizing adaptive optics). The results showed that aberration correction gave improvements (approximately 0.10 logMAR) in both high- and low contrast resolution acuity compared with sphero-cylindrical correction. At 10% contrast it was not possible to measure resolution acuity without aberration correction. The author was involved in study design, collection of fixation-stability data, mapping of the PRL, fundus photography and assisting in writing the manuscript.

9.3

Paper III: Objectively Determined Refraction Improves Peripheral Vision.

The purpose of this study was to assess the impact of objectively obtained offaxis correction on peripheral vision. Peripheral low-contrast (10%) grating resolution acuity was evaluated both with and without refractive correction at 20° in the nasal visual field of 10 emmetropic subjects. The correction was obtained using a commercial wavefront sensor (COAS-HD VR aberrometer). The results showed that there was a strong correlation between improvement in low-contrast resolution and off-axis astigmatism. Subjects with off-axis astigmatism ≥ 1.50 D showed an average improvement of 0.1 logMAR with refractive correction. The study concluded that there are tangible benefits in correcting even moderate amounts of off-axis refractive errors and that the process of determining these could be simplified using commercial available open-field aberrometers. The author was responsible for study design, subject recruitment, data collection, data analysis and writing the manuscript.

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9.4

Paper IV: Peripheral contrast sensitivity for drifting stimuli.

The aim of this paper was to investigate the shape of the spatio-temporal contrast sensitivity function in the peripheral visual field of healthy subjects. High contrast grating resolution acuity as well as grating contrast sensitivity were evaluated on three experienced subjects at 10° in the nasal visual field. First, the off-axis refractive errors were corrected (obtained with the COAS aberrometer). Second, resolution acuity was measured at four temporal frequencies: 0, 5, 10 and 15 Hz. Contrast sensitivity was then determined for the same temporal frequencies at 0.5 cpd and at three additional spatial frequencies (these based on subjects resolution cutoff). The results showed a significant difference in the CSF; changing from band-pass to low-pass with stimulus motion, with the peak CS shifted towards lower spatial frequencies. The greatest improvement with motion was observed at the lowest spatial frequency for movement of 5 and 10 Hz. There was no significant effect of stimulus motion on high-contrast resolution. This study concluded that contrast sensitivity in the peripheral visual field is better with moving stimuli, especially for low spatial frequencies. The author was jointly responsible for study design, subject recruitment, data collection, and assisting in writing the manuscript.

9.5

Paper V: Optical correction and stimulus motion improves peripheral vision in eyes with central scotoma.

The aim of this paper was to improve the remaining vision of CFL patients using a combination of stimulus motion and optical correction. First, the location and fixation stability of the most-used PRL was found. Second, offaxis refractive errors in the PRL were measured with the COAS aberrometer. Third, low contrast (LC), (25%), and high contrast (HC) resolution acuity for stationary gratings, with and without refractive correction were assessed at the PRL. HC acuity for moving gratings (7.5 Hz drift within a fixed window) as well as CS-measurements at 0.5 cpd and a number of additional spatial frequencies, for both stationary and moving gratings were performed with refractive correction. The results show that static LC resolution improves with refractive correction, as does HC resolution, in most cases. With stimulus motion, HC resolution was unaffected whereas the CS at 0.5 cpd improved. This study concluded that the remaining vision of patients with CFL can be improved by off-axis optical refractive correction and even further by moving the stimuli; with greatest benefits for stimuli of low contrast and low spatial frequencies. The author was responsible for study design, subject recruitment, data collection in Kalmar, data analysis and writing the manuscript.

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10.

CONCLUSIONS & OUTLOOK

The impetus behind this thesis and, in particular the focus on how stimulus motion may influence visual performance, originated following a conversation with a good friend, Krister Inde, who has long-standing central vision loss. His observations while sitting in the passenger seat of a car can be summarized as follows: “… when I’m sitting in a car that is in motion, I’m able to see road signs more easily than when the car is standing still…” Naturally the search for an explanation to this observation was warranted and this lead to the papers contained within this thesis. This thesis serves to expand the knowledge regarding the effects of optical correction and object motion on peripheral visual function. It also provides an elucidation of Krister’s observations. The most important result of this thesis is that contrast sensitivity in the peripheral field improves when optical errors are corrected, and that stimulus motion plays a vital role in enhancing visual performance in the periphery. The main conclusions of this thesis are the following: • The open-view COAS-HD aberrometer allows measurement of offaxis optical errors, accurate to within 1.00 D at 20°. Correction of these off-axis refractive errors leads to improved low contrast visual acuity in healthy subjects. • Optical refractive correction leads to improved high- and low-contrast acuity in subjects with CFL. • AO correction of optical errors, including HOA leads to improved high-contrast (~100%) and low-contrast acuity (25 % and 10 %) in the eccentric PRL of a subject with Stargardt disease. • Stimulus motion of up to ~15Hz does not affect high-contrast resolution acuity. • Stimulus motion equating to 7.5 Hz leads to improved contrast sensitivity in normal subjects and in subjects with CFL.

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The ramifications of these findings are that by providing magnification (to reduce the spatial frequency characteristics of objects) and suitable movement of objects it may be possible to enhance vision for people with CFL. A combination of off-axis optical correction, suitable magnification and stimulus motion may be the key to optimizing peripheral vision. In the future it would be interesting to conduct more detailed measurements of the spatio-temporal CSF on both healthy and CFL subjects at similar locations in the visual field to see if there are any differences between these two groups. Related to this, the controlled presentation of images within the PRL under conditions of “image-destabilisation” could also be an avenue worth studying. One possible option could be to incorporate image movement into electronic magnifying systems after magnifying the image sufficiently so that the predominant spatial frequencies coincide with the most sensitive region of the peripheral stCSF. Various options regarding type of image modulation could be evaluated; drift/scrolled motion or jitter. The latter has been shown to give improved word-recognition speeds and facial recognition in the study by Watson et al [295]. However they did not specify whether optical correction was used or not. As such it would be interesting to repeat aspects of their study using “real-world” visual tasks, incorporating off-axis refractive correction (and suitable addition for the reading distance if necessary) and image jitter. Obviously it would be interesting to see how optical correction and image motion influences facial recognition and reading speed. Finally, one other interesting question raised by this thesis is whether it is possible to incorporate an off-axis aberration correction into a contact lens and evaluate visual performance with this on the eye? Custom-made rotationallystable scleral lenses made using free-form lathing techniques may give us the opportunity to accomplish this at some time in the near future.

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11.

ACKNOWLEDGEMENTS

As the old adage goes - “time flies when you’re having fun”, and these past eight years have literally flown by while conducting my PhD studies. During this time I have had the opportunity to share many enjoyable moments with numerous people who have made it possible to complete this thesis without too many tears… I think it is fitting to dedicate a small section of this thesis to those “behind the scenes”. First, I would like to express my gratitude to Jörgen Gustafsson, for encouraging me to enter the field of “Visual impairment”. Initially I was more set on pursuing a PhD within sports-vision, but you managed to convince me that it is more fun to conduct studies on people who don’t see so well. I must say, you were right! I was sad to see you, as my main supervisor, leave for the West coast, but you’ve still been there for me when I’ve needed your help and advice. I’ve also really appreciated your, “from out of nowhere”, telephone calls asking how things are going – did I hear a slight tone of concern in your voice every now and then? Second, I feel honored that Peter Unsbo and Linda Lundström from The Royal Institute of Technology (KTH) in Stockholm took me under their experienced wings January 1st 2013 and offered to be my replacement supervisors when Jörgen chose his new calling. I’m always inspired having visited you both at Alba Nova; you both have an astonishing depth of knowledge regarding the eye and vision as a whole - there are not many physicists who can boast that! As supervisors, you’ve been more like friends; encouraging me and showing true concern for my wellbeing during periods when the workload was high. A very special word of thanks to you Linda, for your patience, kindness and hard work these past 12 months. It has been a true privilege to have you as a co-supervisor! To my co-authors from KTH, Robert Rosén and Abinaya Venkataraman… where would I be without you both? Robert, your enthusiasm is infectious. You are a ‘true researcher’, with a level of curiosity unsurpassed by many. I’m indebted to you for your Matlab programming

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skills, your suggestion to use the ψ-method, and for introducing our family to “Tier auf tier” (Stack the animals). It has been great working with you too Abinaya; an optometrist among the physicists. I’m starting to think there’s something in the water at KTH as the environment produces so many great researchers, yourself included. Thanks for taking time from your family during the weekends to run experiments on CFL subjects, and for many relaxed and fruitful discussions about stCSF. To my colleagues, Peter Gierow, Baskar Theagarayan, Karthikeyan Baskaran, Jenny Roth, Carina Jonsson, Johanna Boström & Oskar Johansson, for being such a fun bunch of people to work and share “fikapauser” (coffee-breaks) with. A special thank you to the Indian contingent – I’ve seen you both become doctors during the course of my studies. We’ve shared many memorable “out of office” moments as friends together on Öland, and at our house during Christmas, Easter, or whenever - we always appreciate the authentic southern Indian cuisine you come with, making these occasions truly international. Krister Inde, for giving me first-hand insight into the World of vision “below 0.3”. In reality you belong to the group of colleagues above now, having taught our undergraduate students, and because you are now “one of the Doctors” at Linnæus University. I hope you’re not planning on retiring too soon as I would love to work together with you on one of your many projects To Sven Tågerud for your support during these past eight years; reading seven individual study plans (must almost be a record?) and for your reassuring and calming attitude. Staffan Carius for your supervision during the early stages of my PhD studies. Stefan Hagberg and Bo Molinder for being a fantastic ‘ground-crew’; finding creative solutions for making a curved back-drop in the lab. Also for your “cross-words” Stefan, which have expanded my Swedish vocabulary enormously. To the team from “Syncentralen” in Kalmar: in particular, Gun Olsson, Cilla Svanfeldt and Susanne Berggren for spreading the word that researchsubjects were required to participate in various projects, both within and parallel to this thesis. To the many anonymous subjects who partook in the experiments contained within Papers I-V, in particular the five who participated in the experiments of Paper V. Your contributions were invaluable in making it possible to find the connections between the other four papers and have helped expand our understanding of the effect of optics and motion on peripheral vision. The Swedish “Optikbranschen” who provided partial-funding during the first four years of my doctoral studies, making this journey happen, and to the Faculty of Health and Life sciences at Linnæus University who provided

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funding during the remaining four years, making it possible to complete the journey. The Berit and Carl-Johan Wettergren foundation for providing generous funding which, besides giving me the opportunity to meet so many inspiring subjects with CFL, allowed me to complete this thesis. All the other PhD candidates (unfortunately, too many to mention by name) who have made this journey enjoyable. For being great course mates, sharing a table in the coffee-room and paving the way. A big thanks to Antonio Macedo for providing Matlab routines for calculating fixation stability, and for adapting them according to my whims. It will be a pleasure to work and conduct research with you. Also to William Seiple for providing crucial information regarding details of the resolution of the OPKO OLED screen which was pivotal for calculating fixation stability for Paper V. To all the students who I’ve had the pleasure to teach during the past 12 years. For those of you who have endured long psychophysical experiments, and to those who have conducted pilot-studies in collaboration with me – especially to Hanna, Victoria, Robert, Caroline, Sofia. To all my relatives, both here in Sweden and New Zealand – thank you for your support during the years. A special mention to my parents, who have eagerly awaited the day that this thesis could be submitted. To my father, Alan, who repeatedly reminded me that “I’m not getting any younger – I won’t be able to come to your defence if you don’t get it finished soon…”, and for encouraging me to pursue an academic career. To my mother, Rosemary, who always has a listening ear – and sharp eyes for spelling/grammatical errors. I’ve definitely lost some of my English skills…. Most of all I want to thank my family who have been there to share the fun times (such as Captain’s Quarters, Florida 2012), and the hard times. Thank you David and Sofia for putting up with my mood-swings during the last critical phase of this journey. I’m still not sure if you know what I’ve been doing all this time, but it has to do with finding ways of helping people who don’t see so well, see better. Josefin, you have also had to endure periods where I’ve sat up really late, reading, writing and drawing pictures on the computer. You have not complained over the piles of papers and books cluttering much of the living room at home, and you’ve been a tremendous support when I’ve been contemplating throwing in the towel. You’re a great partner and wife , and without your love and support this thesis would never have eventuated! Thank you. Ps. - Our little dog Wilma also needs a special word of thanks… She has given me a reason to get a breath of fresh air every now and then, and her playfulness has helped reduce stress levels at crucial times…

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