IOVS Papers in Press. Published on September 1, 2010 as Manuscript iovs Crossland et al. Task specific preferred retinal loci 1

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1 Page 1 of 22 IOVS IOVS Papers in Press. Published on September 1, 2010 as Manuscript iovs Crossland et al. Task specific preferred retinal loci 1 Task specific fixation behaviour in macular disease Michael D. Crossland PhD MCOptom FAAO 1,2 David P. Crabb PhD 3 Gary S. Rubin PhD 1,2 1: UCL Institute of Ophthalmology, London, UK 2: NIHR BMRC for Ophthalmology, London, UK 3: Department of Optometry and Visual Science, City University London, UK Grant information: funded by National Institute for Health Research, UK, Fellowship PDF/01/2008/011. Date of original submission: 2 March 2010 Date of resubmission with edits: 14 July 2010 Date of resubmission with minor edits: 9 August 2010 Final version uploaded: 18 August 2010 Word count: 3635 Copyright 2010 by The Association for Research in Vision and Ophthalmology, Inc.

2 IOVS Page 2 of 22 Crossland et al. Task specific preferred retinal loci Abstract 2 Purpose People with central scotomas frequently use a preferred retinal locus (PRL) in place of the damaged fovea in order to fixate a target. Here we use a novel statistical technique to determine whether the retinal locus used for fixating a point target is the same as that used for reading words. Methods Nine subjects with established macular disease and bilateral central scotomas were recruited. The retinal area used for fixating a point target and words of text was measured using a microperimeter (MP-1, Nidek Technologies, Italy). A nonparametric spatial statistical technique was used to identify whether fixation points were the same for each of these two tasks. Results The spatial distribution of fixation points was different for point fixation and word reading in all subjects with macular disease (p<0.01). Fixation stability was also poorer for the word reading task than the fixation task (p<0.05). For control subjects without macular disease, the distribution of fixation was the same for each task (p>0.3). Conclusions Fixation behaviour in people with macular disease is not the same for fixating a point target and for fixating words in a reading task. It can not be assumed that measuring a patient s fixation to a discrete point target accurately simulates their fixation performance on other tasks.

3 Page 3 of 22 IOVS Crossland et al. Task specific preferred retinal loci 3 People with central scotomas caused by macular disease are not able to see an object if it is viewed with the fovea. In order to observe a target, it is necessary to make an eye movement and to use peripheral retina in place of the damaged fovea. 1 Most people with macular disease use a specific retinal area for this task, known as the preferred retinal locus, or PRL. 2-7 If people with good vision are forced to use peripheral retina by an experimentally induced artificial scotoma, reading is most efficient when the text is fixated with retina superior to the fovea: that is, by making an eye movement upward and moving the fovea above the word of interest in visual field space. 8 However, this finding has not been replicated in people with macular disease: in a large study of 829 patients, Fletcher and Schuchard did not find any significant differences in reading speed based on the location of the preferred retinal locus. 4 More recent research has also failed to find a relationship between fixation position and reading speed. 3, 7 A possible explanation for the lack of relationship between PRL position and reading speed in patients with macular disease is that the PRL is not often assessed during a reading task. Generally, the preferred retinal locus is assessed by asking the person to look towards a point target. 3 However, it is known that changing the fixation target can cause different regions of retina to be used: for example, when viewing a dim target rather than a bright target. 9 It has also been shown that multiple preferred retinal loci can be elicited during complex tasks such as reading. 10 Studies which have measured fixation position during reading give equivocal results. In an early study, Timberlake and colleagues found that the same retinal area is used for reading scrolled text and for fixating a point target, 11 although the same author has recently identified some patients who use different retinal loci for reading text and fixating a target. 6 Some authors report the use of multiple preferred retinal loci when reading a

4 IOVS Page 4 of 22 Crossland et al. Task specific preferred retinal loci 4 single word: for example, using a larger PRL with poorer resolution to observe word shape and position, and then a smaller locus with better resolution to identify characters within the word. 10 To assess accurately the retinal area used for fixating a target, a device is required which simultaneously presents stimuli and images the retina. Although a direct ophthalmoscope or fundus camera can be used for this task, 7 most research in this area has used a confocal Scanning Laser Ophthalmoscope (cslo) equipped with a visible Helium-Neon 4, 6, laser such as the Rodenstock SLO-101. The HeNe laser in the cslo can create very bright stimuli but this Rodenstock cslo is limited to producing only monochromatic red targets, the image can suffer from visible raster artefacts, and the retinal image produce has some raster distortion. 15 Whilst other scanning laser ophthalmoscopes do not have these limitations, the Rodenstock cslo has been used most commonly for published work examining fixation behaviour in vision rehabilitation research. The MP-1 microperimeter (Nidek Technologies, Italy) is a clinical instrument which can display dynamic stimuli on a LCD display to a subject whilst simultaneously imaging the retina using an infrared camera. Unlike the Rodenstock confocal scanning laser ophthalmoscope, this instrument can display full colour stimuli which more accurately simulate reading at contrast and luminance levels more similar to conventional reading. As the text presented is black on a white background, at approximately equivalent luminance to reading a hardback book under good lighting, this simulates the glare and intraocular scatter experienced by patients when performing a real reading task. In this paper we describe a technique to enable this instrument to be used for fixation analyses whilst people perform more complex tasks such as fixating words. We compare

5 Page 5 of 22 IOVS Crossland et al. Task specific preferred retinal loci 5 the locus of fixation used when fixating a point target and when fixating words for a group of subjects with macular disease. We then apply a novel statistical test to compare the parameters of fixation for these two tasks. Whilst word fixation is not the same as reading continuous text, we believe that investigating fixation whilst observing words can aid our understanding of the reading process. Method Participants and ethical approval Nine people with central scotomas were recruited from the low vision and medical retina clinics at Moorfields Eye Hospital, London. All participants had at least one year history of bilateral central vision loss and had attended a low vision clinic to ensure the optimal spectacle correction and low vision aids were dispensed. The study was approved by the Moorfields and Whittington Research Ethics committee and conformed to the Declaration of Helsinki. Participants gave their informed consent prior to data collection. Stimulus display system and calibration All stimuli were presented on the internal display of Nidek MP-1 microperimeter. This MP-1 microperimeter comprises a LCD display for stimulus presentation, an infrared video retinal camera to monitor eye position, and a colour fundus camera for capturing a still retinal image. The optics of the MP-1 allow an almost Maxwellian view. 16 Stimuli were generated on a supplementary laptop computer (MacBook Pro, Apple, Cupertino, CA) running Matlab (Mathworks, Natick, MA) and elements of the Psychophysics toolbox. 17 The video output of this laptop was connected to the VGA input on the side of the MP-1. A switch box allowed the video input to be changed between the laptop and the MP-1 control

6 IOVS Page 6 of 22 Crossland et al. Task specific preferred retinal loci computer. This technique allows the eyetracking and retinal imaging capabilities of the 6 microperimeter to be used whilst any image (or video) created on the laptop is shown on the MP-1 display. We have previously described a method for calculating the parameters of the MP-1 screen and presenting stimuli on the screen using a supplementary computer. 18 Briefly, the centre of the MP-1 internal display screen was found by interpolating the centre of a circle which encompasses all of the pixels visible on the display when looking into the microperimeter. Following this, the relationship between pixel position on the internal display and eye position (in degrees) was calculated by measuring the eye position, using the eyetracking facility of the microperimeter, whilst five control subjects observed targets created by the supplementary computer presented at specified locations on the internal display. Finally, eye position was measured and a retinal image was captured (using the onboard fundus camera of the MP-1) whilst the subjects observed the same targets to determine the retinal coordinates of the eye position data recorded by the MP-1 eyetracker. This analysis has shown that, for our microperimeter, the screen centre is at pixel position (367, 249); that each pixel of target decentration leads to a 0.085º movement to be recorded in the fixation file (95% CI: 0.081º-0.088º); and that each pixel of target decentration causes a 2.37 movement on the image file (95% CI: pixels). There were no significant differences in these values between five observers (p>0.5 in all cases). Knowledge of these parameters makes it straightforward to relate fixation position, (from the MP-1 fixation data file) to fixation position on the retinal image captured on the MP-1. The luminance of the internal display was measured at the exit pupil of the instrument using a photometer supplied by Nidek and was 126 cd/m 2 at maximum brightness.

7 Page 7 of 22 IOVS Crossland et al. Task specific preferred retinal loci 7 Point fixation task The fixation target used was a black circle of diameter 1º with a central white detail of 0.3º diameter, displayed against a full white background of 126 cd/m 2. Subjects were asked to look at the centre of the fixation target so that it was as clear as possible. Once the participant reported being able to see the target clearly, they were asked to hold their eye still for a period of thirty seconds, during which eye position was recorded. Word fixation task Four word sentences were constructed using a random sentence generator which we have previously described. 19 Each sentence was presented, one word at a time, centred at the middle of the display, using a rapid serial visual presentation technique (RSVP). 20 Words were presented in black Courier font, against a white background, with x-height of three times visual acuity. Subjects were asked to read each word of each sentence silently. Reading speed was altered for each sentence by manipulating word presentation duration using the psychophysical method of constant stimuli. Each subject read four sentences at each of eight word presentation durations. These exposure durations were 0.083, 0.13, 0.2, 0.32, 0.5, 1, 2 and 4 seconds, corresponding to a reading speed of 720 to 15 words/minute. Not all subjects were able to read words at the fastest exposure duration, but all could read comfortably at the slowest reading speed. Threshold reading speed was, therefore, between the slowest and fastest exposure duration. Multiple eye position files of thirty seconds duration were recorded during the word fixation task. Procedure The eye with better visual acuity was assessed for all subjects, with the dominant eye used if visual acuity was equal. The contralateral eye was occluded in all cases. Participants were asked to fixate the standard fixation cross (generated with the supplied

8 IOVS Page 8 of 22 Crossland et al. Task specific preferred retinal loci MP-1 software) and eye position was measured. Following this, eye position was 8 measured as the subject viewed the same stimulus produced by the supplementary computer, to determine any offset in display position between stimuli presented with each computer. Each subject performed the point fixation and the word fixation task once, in counterbalanced order. Finally, a retinal photograph was taken. Statistical analysis Eye position data files were analysed retrospectively. Eye position was converted to retinal coordinates, and the retinal location corresponding to the centre of the fixation target for each recorded fixation was plotted on the retinal image (see figure 1). Fixation stability was recorded for each trial by measuring the area of an ellipse which encompasses 68% of fixation positions (bivariate contour ellipse area, BCEA). 21 An analysis adopted from spatial statistics was used to assess if participants used the same regions of the retina for fixating points and fixating words. The data arising from this experiment are a random variable from a spatial point process and, therefore, an appropriate method from the catalogue of methods for analyzing spatial statistics is required. In this analysis the fixations recorded in two-dimensional space are assumed to be values generated from a multivariate spatial point process with each point being one of two qualitatively distinguishable types. Spatial segregation is assumed to occur if within some area particular types of points predominate rather than being randomly intermingled. A technique modified from Diggle et al 22 and implemented in the spatialkernel and splancs packages, 1 using the open-source statistical programming environment R Barry Rowlingson, Peter Diggle, adapted, packaged for R by Roger Bivand, pxp functions by Giovanni Petris and goodness of fit byt Stephen Eglen. splancs: spatial and space-time point pattern analysis, R package version

9 Page 9 of 22 IOVS Crossland et al. Task specific preferred retinal loci 9 was used to assess this segregation of the fixation points. The purpose written R script is given as a supplementary file and is illustrated using data from the two control subjects and two of the patients. In short, this method gives a probability value against the null hypothesis that the fixation co-ordinates from the different tasks are yielded from the same spatial point process and are, therefore, not segregated. Some modifications from the original method were made. First, several fixations fall on exactly the same location (having the same co-ordinates) because of the measurement precision of the instrumentation. Moreover, the technique is very sensitive to small levels of segregation especially when the sample of points is large as in the case with these data. To overcome these limitations, random Gaussian noise was first added to every recorded (x,y) fixation both for controls and patients. This also has the effect of randomly mixing the two spatial processes further. For the purpose of this analysis it is assumed that if a statistically significant effect remains after this mixing then it provides clear evidence that the fixations for the two tasks are indeed generated from a different spatial process. The method uses a Monte-Carlo technique to derive probability values against the null hypothesis. Results Fixation position The segregation analysis indicated that there was overwhelming evidence for the participants with macular disease using different regions of retina for each task. For 8 out of the 9 subjects with macular disease the segregation analysis returned p=0.001 against the null hypothesis that the regions were coincident (not segregated). For one subject (M5) the segregation analysis returned a slightly higher probability value (0.008), but this still represents considerable statistical evidence. The p values were estimated from n=1000

10 IOVS Page 10 of 22 Crossland et al. Task specific preferred retinal loci Monte-Carlo trials. Figure 1 shows the fixation positions superimposed onto the retinal 10 image for all of the participants with macular disease. For comparison, data for two control subjects are shown in figure 2. Control subjects data were collected under identical conditions except that words were not presented at exposure durations of 1, 2 and 4 seconds. Instead, exposures of 0.016, 0.033, and 0.05 were added, such that subjects observed words corresponding to a reading speed of 3750 to 120 words/minute. It can be seen that the fixation position for both tasks is the same and coincident with the foveal centre in these observers without eye disease. The segregation analysis supported this visual impression with no evidence that the fixations for each task come from different spatial processes in these subjects (p=0.76 for control subject C1 and p=0.34 for control subject C2). Table 2 shows the distance between the centre of the fixation locus for each task for every subject. The mean separation of the centre of each locus was 2.8º for those with macular disease and 0.2º for the control subjects. Fixation stability Fixation was less stable for the word fixation task than for the point fixation task, with a mean BCEA for point fixation of 6078 minarc 2 ; and a mean BCEA for word fixation of 16,300 minarc 2 (matched pairs, p<0.05). Table 2 show fixation stability data for all participants. Discussion

11 Page 11 of 22 IOVS Crossland et al. Task specific preferred retinal loci 11 In this sample all nine subjects with macular disease used a different retinal region for point fixation and for word fixation. This indicates that for people with macular disease, it can not be assumed that the PRL used for fixating a point target is necessarily the same as the retinal point used for any other task. We have used a novel application of a statistical test to analyse eye position files. This procedure is nonparametric and makes no assumption about the underlying shape of the distributions generated by the point process, which is appropriate as many authors have shown that fixation data are rarely normally distributed. 21, 26 This test appears to be sensitive to small changes between the distributions, but the fact that our control subjects were shown to use the same retinal area for word fixation and point fixation with this technique indicates that the differences found in our patient data are unlikely to be caused by type I error. The technique presented here may have other applications when examining spatial distributions of fixation points and we encourage other resesearchers to use and adapt our code (see Supplementary Files). Why is the fixation area used different for the two tasks? Examination of figure 1 shows that for some participants, such as M1 and M4, fixating the centre of a word at the same location as the point fixation target would cause some letters of the word to fall within the scotoma. In this case a small horizontal or vertical eye movement is an appropriate strategy to enable the entire word to be read at one fixation. Throughout this manuscript we have referred to the task when identifying a word as word fixation. However, we did not ask our subjects just to maintain fixation on a word, we asked them to read it. Although it would be inappropriate to describe this RSVP task as reading, word fixation is also slightly misleading in that it implies we asked people not to make intra-word

12 IOVS Page 12 of 22 Crossland et al. Task specific preferred retinal loci saccades. This was not the case: indeed we expected our subjects to make intra-word 12 saccades and fixations as part of their reading strategy. For other subjects, for example M8 and M9, if the retinal area for point fixation were used for reading, the entire word would fall into relatively healthier retina. We speculate that the reason for the distribution being different for the two tasks here is a consequence of a reduced visual span: that is, if the visual span is smaller than the word length, an additional eye movement is needed to read an entire word. This extra fixation would lead to a different fixation distrubution for word reading. In people with macular disease, visual span is approximately halved. 27 Although the mean word length of our sentences was only 3.5 letters, some words were considerably longer (eg leading, 7 letters). Whilst a seven letter word is likely to fall within the visual span of someone with good vision, 28 at least one eye movement would be required if the visual span was beneath this value. This is the likely reason for the greater horizontal extent of the fixation pattern for word fixation in subjects M1, M7 and M8. Unfortunately we did not measure visual span in our subjects. Some subjects (such as M5 and M6) show retinal fixation loci which are centred at similar points but which have different distrubutions. In each case, fixation is more stable for the point target than for the word. Our statistical technique shows that these distributions are significantly different for the two tasks. Whilst the fixation location was statistically different in those subjects who used a different retinal area for each task, figure 1 shows that none moved fixation into different quadrants of retina. Therefore, our results do not wholly explain the poor relationship between PRL position and reading speed found in previous studies. This is likely to be due to the fact that RSVP is not an accurate simulation of reading continuous text. We used RSVP text

13 Page 13 of 22 IOVS Crossland et al. Task specific preferred retinal loci 13 presentation to reduce the effect of eye movements, and to minimise the difficulties of determining which retinal position is attending to a given portion of continuous text at any given time. In previous control studies we have attempted to use the reverse correlation technique of Timberlake and colleagues on this instrument without success. It is tempting to speculate that if the PRL were measured for continuous text a third PRL would be identified, which may be in a different quadrant of retina. A potential confounding factor is that the words we presented were centred at the same point as the fixation target. It is known that the landing position of eye movements when reading continuous text is between the start and the centre of the word. 29 If our subjects were indeed observing to the left of the centre of the word, this would lead the word centre to fall to the right (in visual field) of the fixation point. On figure 1 this would be seen as the green dots appearing to the right of the black dots. This effect is only seen for subjects M1, M3 and M7, so it is clearly not a strategy for all of our patients. A reviewer of this manuscript commented that although neither of our control subjects exhibited this performance, it may be because the letters were too small to have observed this effect. A further experiment was performed where our control subjects observed words presented at x-height of 5º, so that differences in fixation distributions would be more apparent: a one-letter shift would be approximately the same distance as the diameter of the optic nerve head. The subjects were naïve to the purpose of this further experiment, and the instructions were identical as those given to the patients. Neither control subject was an author of the paper (one was a PhD student in a different lab and the other a departmental administrator). Results for this experiment data are shown in figure 3. It can be seen that there is no systematic shift in fixation position when observing

14 IOVS Page 14 of 22 Crossland et al. Task specific preferred retinal loci 14 larger text. This finding was confirmed statistically (p=0.19 for C1; p=0.48 for C2). If the magnitude of the offset between fixation positions was indeed related to the size of the letters then we would expect this offset to be correlated to visual acuity (as this is related to target size). This is not the case: linear regression does not show a significant correlation between visual acuity and the distance between the PRLs (r 2 =0.086, p=0.38). A further problem with our experimental design is that some of the word exposure durations were much longer than those needed to identify the word, and that eye movements can be made in this time. Data were collected across several trials rather than only when words were presented at or near threshold reading speed. This is a likely explanation for the poorer fixation stability for observing the words when compared to fixating the point target for our control subjects. Our control subjects were not age matched to our subjects with macular disease, but it is known that fixation stability does not 30, 31 deteriorate with age. We believe that this is the first time the MP-1 microperimeter has been used with a supplementary computer to generate stimuli whilst fixation position is recorded. A particular strength of this system is that the retina can be viewed whilst dynamic, full colour images of luminance similar to printed text are displayed. The possibility for this instrument to be used for observing the retinal location used by people with macular disease during a task such as watching a film is exciting and we encourage other researchers in the field to use this instrument modification in their studies. In conclusion, we have shown that fixation distributions are not the same when fixating a word as when fixating a point target. This indicates the position of the preferred retinal

15 Page 15 of 22 IOVS Crossland et al. Task specific preferred retinal loci 15 locus can not be defined solely from asking a patient to observe a point target or fixation cross. Rather, the PRL should be examined for each task separately, as it is likely to be different for each task. Acknowledgements The authors thank Barry Rowlingson (Department of Mathematics and Statistics, Lancaster University) for his suggestions for the R code for the segregation analysis. MDC was funded by National Institute for Health Research, UK, Fellowship PDF/01/2008/011. This report describes independent research arising from a grant supported by the National Institute for Health Research. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health. Elements of this work were presented at the American Academy of Optometry annual meeting, Orlando, Florida, November 2009.

16 IOVS Page 16 of 22 Crossland et al. Task specific preferred retinal loci 16 Subject Sex/Age (years) Diagnosis Visual acuity M1 Female/24 Best disease 0.78 logmar M2 Male/89 AMD 0.58 logmar M3 Female/86 AMD 0.90 logmar M4 Female/54 Stargardt disease 0.70 logmar M5 Female/71 AMD 0.76 logmar M6 Male/56 Chronic CSC 0.90 logmar M7 Female/76 AMD 0.40 logmar M8 Female/88 AMD 0.40 logmar M9 Male/72 AMD 1.26 logmar C1 Male/26 Control subject logmar C2 Male/32 Control subject logmar Table 1. Demographic and clinical data for each subject. AMD: Age-related macular disease. CSC: Central Serous Chorioretinopathy.

17 Page 17 of 22 IOVS Crossland et al. Task specific preferred retinal loci 17 Subject Distance between fixation and reading PRL (º) BCEA for fixation (minarc 2 ) BCEA for reading (minarc 2 ) M M M M M M M M M C C C1 (reading 5º letters) C2 (reading 5º letters) Table 2. Separation of the centres of the mean fixation position for fixation and reading, and fixation stability values for each task. BCEA: bivariate contour ellipse area.

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