IUSO Bill Swanson PubMed Papers June 28, 2012

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1 1. Malik R, Swanson WH, Garway-Heath DF. 'Structure-function relationship' in glaucoma: past thinking and current concepts. Clin Experiment Ophthalmol May;40(4): doi: /j x. Epub 2012 Apr 12.PMID: [PubMed - in process] An understanding of the relationship between functional and structural measures in primary open-angle glaucoma is necessary for both grading the severity of disease and for understanding the natural history of the condition. This article outlines the current evidence for the nature of this relationship and highlights the current mathematical models linking structure and function. Large clinical trials demonstrate that both structural and functional change are apparent in advanced stages of disease, and at an individual level, detectable structural abnormality may precede functional abnormality in some patients, whereas the converse is true in other patients. Although the exact nature of the 'structure-function' relationship in primary open-angle glaucoma is still the topic of scientific debate and the subject of continuing research, this article aims to provide the clinician with an understanding of the past concepts and contemporary thinking in relation to the structure-function relationship in primary open-angle glaucoma The Authors. Clinical and Experimental Ophthalmology 2012 Royal Australian and New Zealand College of Ophthalmologists. 2. Keltgen KM, Swanson WH. Estimation of spatial scale across the visual field using sinusoidal stimuli. Invest Ophthalmol Vis Sci Dec 13. [Epub ahead of print] PMID: [PubMed - as supplied by publisher] PURPOSE: To characterize contrast sensitivity for sinusoidal stimuli across the central visual field and help bridge the gap between perimetry and visual psychophysics by developing a contrast-sensitivity template for spatial scale (experiment 1) and testing it on a new dataset (experiment 2). METHODS: In experiment 1, 40 subjects free of eye disease, ages 43 to 84 years, had one eye tested. Twenty-three locations along the horizontal and vertical meridians were tested with sinusoidal stimuli having peak spatial frequencies of 0.5, 1.0, and 2.0 cpd and a spatial bandwidth of 1.0 octave. Contrast sensitivity functions were fit with a lowpass template slid horizontally on a log-log plot by a spatial scale factor. In experiment 2, 29 of the original subjects had one eye tested. Twenty-six locations in grid form were tested with sinusoidal stimuli having peak spatial frequencies of 0.375, 0.53, 0.75, and 1.5 cpd. Spatial scale values were predicted using the cpd data and template and compared to empirical values determined from the remaining data. RESULTS: In experiment 1, the change in spatial scale alone fit the mean sensitivities well (residual sum of squares = 0.01 log unit). Spatial scale increased with eccentricity except for horizontal nasal displacements between 3 and 15. In experiment 2, differences between empirical and predicted spatial scale values were within ±0.1 log unit (mean and SEM: 0.00 ± 0.01 log unit). CONCLUSIONS: Spatial scale characterized the visual field tested in perimetry well and can contribute to further linkage between clinical perimetry and basic vision science. 3. Gardiner SK, Demirel S, Johnson CA, Swanson WH. Assessment of linearscale indices for perimetry in terms of progression in early glaucoma. Vision Res Aug 15;51(16): Epub 2011 Jun 16. PMID:

2 [PubMed - indexed for MEDLINE] PMCID: PMC [Available on 2012/8/15] Currently, global indices that summarize the visual field combine sensitivities on a logarithmic (decibel) scale. Recent structure-function models for glaucoma suggest that contrast sensitivity should be converted to a linear scale before averaging across visual field locations, to better relate sensitivity with the number of surviving retinal ganglion cells (RGCs). New indices designed to represent the number of RGCs already lost are described. At least one was found to be a significantly better predictor of subsequent rate of change than traditional Mean Deviation (p=0.014) in participants with glaucomatous optic neuropathy. Issues concerning the creation of optimal global indices are discussed.copyright 2011 Elsevier Ltd. All rights reserved. 4. Shafi A, Swanson WH, Dul MW. Structure and function in patients with glaucomatous defects near fixation. Optom Vis Sci Jan;88(1): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: To assess relations between perimetric sensitivity and neuroretinal rim area using high-resolution perimetric mapping in patients with glaucomatous defects within 10 of fixation. METHODS: One eye was tested in each of 31 patients with open-angle glaucoma enrolled in a prospective study of perimetric defects within 10 of fixation. Norms were derived from 110 control subjects free of eye disease, aged 21 to 81 years. Perimetric sensitivity was measured using the 10-2 test pattern with the Swedish Interactive Threshold Algorithm (SITA) standard algorithm on the Humphrey Field Analyzer (HFA) II-i; Carl Zeiss Meditec), stimulus size III. Area of the temporal neuroretinal rim was measured using the Heidelberg retina tomograph 3. Decibel values were converted into linear units of contrast sensitivity averaged across locations corresponding to the temporal rim sector. Both measures were expressed as percent of mean normal, and the Bland-Altman method was used to assess agreement. Perimetric locations corresponding to the temporal sector were determined for six different optic nerve maps. RESULTS: Contrast sensitivity was moderately correlated with temporal rim area (r2 >30%, p < 0.005). For all six optic nerve maps, Bland-Altman analysis found good agreement between perimetric sensitivity and rim area with both measures expressed as fraction of mean normal and confidence limits for agreement that were consistent with normal between-subject variability in control eyes. CONCLUSIONS: By using high-resolution perimetric mapping in patients with scotomas within 10 of fixation, we confirmed findings of linear relations between perimetric sensitivity and area of temporal neuroretinal rim and showed that the confidence limits for agreement in patients with glaucoma were consistent with normal between-subject variability. 5. Swanson WH, Sun H, Lee BB, Cao D. Responses of primate retinal ganglion cells to perimetric stimuli. Invest Ophthalmol Vis Sci Feb 9;52(2): Print 2011 Feb. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article 2

3 PURPOSE: Perimetry is used clinically to assess glaucomatous ganglion cell loss. It has been proposed that frequency-doubling stimuli are better than the conventional size III perimetric stimulus in preferentially stimulating magnocellular (M) versus parvocellular (P) ganglion cells. However, little is known about how primate ganglion cells respond to perimetric stimuli. The authors recorded contrast responses of M and P ganglion cells to size III and frequency-doubling stimuli and compared contrast gain of M and P cells to these stimuli to assess the ability of these stimuli to preferentially stimulate M versus P cells. METHODS: Data were recorded from 69 macaque retinal ganglion cells, by an in vivo preparation, at eccentricities of 5 to 15. The size III stimulus was a circular luminance increment 26 min arc in diameter, 200 ms in duration. The frequency-doubling stimulus was a sinusoidal grating (0.5 cyc/deg) temporally modulated in counterphase at 13 Hz. A Michaelis-Menten function was fit to each cell's contrast responses to assess contrast gain. RESULTS: For both size III and frequency-doubling stimuli, ganglion cell responses increased linearly at low contrasts, and then the increase slowed at high contrasts (saturation). The mean (± SE) difference in estimated log contrast gain between M and P cells for the size III stimulus was significantly higher than that for the frequencydoubling stimulus (1.24 ± 0.09 vs ± 0.13; P < 0.01). CONCLUSIONS: The size III stimulus was superior to the frequency-doubling stimulus in preferentially stimulating M cells versus P cells. Comment in Frequency-doubling technology and parasol cells. [Invest Ophthalmol Vis Sci. 2011]Frequency-doubling technology and parasol cells. Maddess T. Invest Ophthalmol Vis Sci.2011 May; 52(6):3759; author reply Epub 2011Jun1. 6. Stark LR, Kruger PB, Rucker FJ, Swanson WH, Schmidt N, Hardy C, Rutman H, Borgovan T, Burke S, Badar M, Shah R. Potential signal to accommodation from the Stiles-Crawford effect and ocular monochromatic aberrations. J Mod Opt Nov;56(20): PMID: [PubMed] PMCID: PMC Free PMC Article The purpose of this study is to determine if cues within the blurred retinal image due to the Stiles-Crawford (SC) effect and the eye's monochromatic aberrations can drive accommodation with a small pupil (3 mm) that is typical of bright photopic conditions.the foveal, psychophysical SC function (17 min arc) and ocular monochromatic aberrations were measured in 21 visually normal adults. The retinal image of a 10.2 min arc disc was simulated for spherical defocus levels of -1 D, 0 D and +1 D in each of four conditions consisting of combinations of the presence or absence of the individual SC function and monochromatic aberrations with a 3 mm pupil. Accommodation was recorded in eleven participants as each viewed the simulations through a 0.75-mm pinhole.the SC effect alone did not provide a significant cue to accommodation. Monochromatic aberrations provided a statistically significant but rather small cue to monocular accommodation. 3

4 7. Patel S, Schwartz SH, Swanson WH. Differential vertical visual latency as determined with a simultaneity paradigm. Vision Res Mar 5;50(5): Epub 2009 Dec 23. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article Behavioral studies, as well as anatomical and physiological data, suggest differences in functionality for inferior and superior visual fields. Previous investigations comparing latencies of the two fields have employed motor reaction times. This approach is of limited usefulness in elderly clinical populations where various degrees of motor impairment may be present. In this report, we describe a simultaneity paradigm that allows the determination of relative latencies without dependence on motor reaction times. A slightly, but statistically significant, shorter latency (3.9+/-5.9ms) was found for the superior visual field. The results are not affected by age, and both within- and between-session variability are low. 8. Gardiner SK, Swanson WH, Demirel S, McKendrick AM, Turpin A, Johnson CA. A two-stage neural spiking model of visual contrast detection in perimetry. Vision Res Aug;48(18): Epub 2008 Jul 21. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article Perimetry is a commonly used clinical test for visual function, limited by high variability. The sources of this variability need to be better understood. In this paper, we investigate whether noise intrinsic to neural firing could explain the variability in normal subjects. We present the most physiologically accurate model to date for stimulus detection in perimetry combining knowledge of the physiology of components of the visual system with signal detection theory, and show that it requires that detection be mediated by multiple cortical cells in order to give predictions consistent with psychometric functions measured in human observers. 9. Chen Y, Wyatt HJ, Swanson WH, Dul MW. Rapid pupil-based assessment of glaucomatous damage. Optom Vis Sci Jun;85(6): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: To investigate the ability of a technique employing pupillometry and functionally-shaped stimuli to assess loss of visual function due to glaucomatous optic neuropathy. METHODS: Pairs of large stimuli, mirror images about the horizontal meridian, were displayed alternately in the upper and lower visual field. Pupil diameter was recorded and analyzed in terms of the "contrast balance" (relative sensitivity to the upper and lower stimuli), and the pupil constriction amplitude to upper and lower stimuli separately. A group of 40 patients with glaucoma was tested twice in a first session, and twice more in a second session, 1 to 3 weeks later. A group of 40 normal subjects was tested with the same protocol. RESULTS: Results for the normal subjects indicated functional symmetry in upper/lower retina, on average. Contrast balance results for the patients with glaucoma differed from normal: half the normal subjects had contrast balance within 0.06 log unit of equality and 80% had contrast balance within 0.1 log unit. Half the patients had contrast 4

5 balances more than 0.1 log unit from equality. Patient contrast balances were moderately correlated with predictions from perimetric data (r = 0.37, p < ). Contrast balances correctly classified visual field damage in 28 patients (70%), and response amplitudes correctly classified 24 patients (60%). When contrast balance and response amplitude were combined, receiver operating characteristic area for discriminating glaucoma from normal was CONCLUSIONS: Pupillary evaluation of retinal asymmetry provides a rapid method for detecting and classifying visual field defects. In this patient population, classification agreed with perimetry in 70% of eyes. 10. Sun H, Swanson WH, Arvidson B, Dul MW. Assessment of contrast gain signature in inferred magnocellular and parvocellular pathways in patients with glaucoma. Vision Res Nov;48(26): Epub 2008 May 23. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: Contrast gain signatures of inferred magnocellular and parvocellular postreceptoral pathways were assessed for patients with glaucoma using a contrast discrimination paradigm developed by Pokorny and Smith. The potential causes for changes in contrast gain signature were investigated using model simulations of ganglion cell contrast responses. METHODS: Foveal contrast discrimination thresholds were measured with a pedestal- Delta-pedestal paradigm developed by Pokorny and Smith [Pokorny, J., & Smith, V. C. (1997). Psychophysical signatures associated with magnocellular and parvocellular pathway contrast gain. Journal of the Optical Society of America A, 14(9), ]. Stimuli were 27 ms luminance increments superimposed on 227 ms pulsed Deltapedestals. Contrast thresholds and contrast gain signatures mediated by the inferred magnocellular (MC) and parvocellular (PC) pathways were assessed using linear fits to contrast discrimination thresholds at either lower or higher Delta-pedestal contrasts, respectively. Twenty-seven patients with glaucoma were tested, as well as 16 agesimilar control subjects free of eye disease. RESULTS: Contrast sensitivity and contrast gain signature mediated by the inferred MC pathway were lower for the glaucoma group, and reduced contrast gain signature was correlated with reduced contrast sensitivity (r(2)=45%, p<.0005). These two parameters mediated by the inferred PC pathway were little affected for the glaucoma group. Model simulations suggest that the reduced contrast sensitivity and contrast gain signature were consistent with the hypothesis that reduced MC ganglion cell dendritic complexity can lead to reduced effective retinal illuminance, and hence increased semi-saturation contrast of the ganglion cell contrast response functions. CONCLUSIONS: The contrast sensitivity and contrast gain signature of the inferred MC pathway were reduced in patients with glaucoma. The results were consistent with a model of ganglion cell dysfunction due to reduced synaptic density. 11. Swanson WH, Pan F, Lee BB. Chromatic temporal integration and retinal eccentricity: psychophysics, neurometric analysis and cortical pooling. Vision Res Nov;48(26): Epub 2008 Apr 15. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article 5

6 Psychophysical chromatic sensitivity deteriorates in peripheral retina, even after appropriate size scaling of targets. This decrease is more marked for stimuli targeted at the long- (L) to middle-wavelength (M) cone opponent system than for stimuli targeted at short-wavelength (S) pathways. Foveal chromatic mechanisms integrate over several hundred milliseconds for pulse detection. If the time course for integration were shorter in the periphery, this might account for sensitivity loss. Psychophysical chromatic temporal integration (critical duration) for human observers was estimated as a function of eccentricity. Critical duration decreased by a factor of 2 (from approximately 200 to approximately 100 ms) from the fovea to 20 degrees eccentricity. This partly (but not completely) accounts for the decrease in /L-M/ sensitivity in the periphery, but almost completely accounts for the decrease in S-cone sensitivity. Some loss of /L-M/I sensitivity thus has a cortical locus. In a physiological analysis, we consider how the /L- M/ cone parvocellular pathway integrates chromatic signals. Neurometric contrast sensitivities of individual retinal ganglion cells decreased with the square-root of stimulus duration (as expected from Poisson statistics of ganglion cell firing). In contrast, psychophysical data followed an inverse linear relationship (Bloch's law). Models of cortical pooling mechanisms incorporating uncertainty as to stimulus onset and duration can at least partially account for this discrepancy. 12. Hot A, Dul MW, Swanson WH. Development and evaluation of a contrast sensitivity perimetry test for patients with glaucoma. Invest Ophthalmol Vis Sci Jul;49(7): Epub 2008 Mar 31. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: To design a contrast sensitivity perimetry (CSP) protocol that decreases variability in glaucomatous defects while maintaining good sensitivity to glaucomatous loss. METHODS: Twenty patients with glaucoma and 20 control subjects were tested with a CSP protocol implemented on a monitor-based testing station. In the protocol 26 locations were tested over the central visual field with Gabor patches with a peak spatial frequency of 0.4 cyc/deg and a two-dimensional spatial Gaussian envelope, with most of the energy concentrated within a 4 degrees circular region. Threshold was estimated by a staircase method: Patients and 10 age-similar control subjects were also tested on conventional automated perimetry (CAP), with the 24-2 pattern with the SITA Standard testing strategy. The neuroretinal rim area of the patients was measured with a retinal tomograph (Retina Tomograph II [HRT]; Heidelberg Engineering, Heidelberg, Germany). A Bland-Altman analysis of agreement was used to assess test-retest variability, compare depth of defect shown by the two perimetric tests, and investigate the relations between contrast sensitivity and neuroretinal rim area. RESULTS: Variability showed less dependence on defect depth for CSP than for CAP (z = 9.3, P < 0.001). Defect depth was similar for CAP and CSP when averaged by quadrant (r = 0.26, P > 0.13). The relation between defect depth and rim area was more consistent with CSP than with CAP (z = 9, P < 0.001). CONCLUSIONS: The implementation of CSP was successful in reducing test-retest variability in glaucomatous defects. CSP was in general agreement with CAP in terms of depth of defect and was in better agreement than CAP with HRT-determined rim area. 6

7 13. Yang A, Swanson WH. A new pattern electroretinogram paradigm evaluated in terms of user friendliness and agreement with perimetry. Ophthalmology Apr;114(4): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: To assess ease of use of the pattern electroretinogram optimized for glaucoma screening (PERGLA) paradigm by a novice operator; to study test-retest variability of the PERGLA parameters; and to compare results from the PERGLA to those from perimetry. DESIGN: Cohort study. PARTICIPANTS: Twelve healthy control subjects and 16 patients with moderate to advanced glaucoma in at least 1 eye. METHODS: Pattern electroretinograms were recorded simultaneously from both eyes using a commercially available testing station. Each participant underwent PERGLA procedures in 2 sessions. One eye of each subject was tested on contrast sensitivity perimetry (CSP) in which a 0.4 cycles/degree Gabor patch served as a stimulus. Central visual fields results from conventional automated perimetry (CAP) were obtained from patients' records. Bland-Altman analysis was performed on PERGLA results to assess normal test-retest variability. Differences from mean normal (in decibels [db]) were compared for PERGLA versus CSP and CAP. MAIN OUTCOME MEASURES: Pattern electroretinogram amplitude, noise, phase, and test-retest variability (coefficient of variation); contrast sensitivity from CSP; perimetric sensitivity from CAP; and differences from mean normal for PERGLA, CSP, and CAP. RESULTS: The mean log amplitude (0.08+/-0.12 log muv) and the mean phase (1.92+/-0.07 pi rad) for the control group were consistent with published PERGLA norms, as was test-retest variability for both amplitude (coefficient of variation [CV] = 8.2+/-7.0%) and phase (CV = 1.1+/-0.9%). The mean signal-to-noise ratio (8.7+/-4.5) was lower than published norms. The test-retest variability increased as PERGLA log amplitude decreased (R2>0.12, P<0.05). On average, differences from mean normal were similar for PERGLA versus CSP and for PERGLA versus CAP (mean differences<0.5 db) with 95% confidence intervals near +/-4 db in both comparisons. CONCLUSIONS: A novice operator successfully replicated published PERGLA norms in a young control group for amplitude, phase, and repeatability. Higher test-retest variability was found in eyes with smaller signals. On average, PERGLA results were in reasonable agreement with those from perimetry, although there existed large individual differences which may limit the usage of PERGLA in screening or in following progression of glaucoma. 14. Wyatt HJ, Dul MW, Swanson WH. Variability of visual field measurements is correlated with the gradient of visual sensitivity. Vision Res Mar;47(7): Epub 2007 Feb 23. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article Conventional static automated perimetry provides important clinical information, but its utility is limited by considerable test-retest variability. Fixational eye movements during testing could contribute to variability. To assess this possibility, it is important to know how much sensitivity change would be caused by a given eye movement. To investigate this, we have evaluated the gradient, the rate at which sensitivity changes with location. 7

8 We tested one eye each, twice within 3 weeks, of 29 patients with glaucoma, 17 young normal subjects and 13 older normal subjects. The 10-2 test pattern with the SITA Standard algorithm was used to assess sensitivity at locations with 2 degrees spacing. Variability and gradient were calculated at individual test locations. Matrix correlations were determined between variability and gradient, and were substantial for the patients with glaucoma. The results were consistent with a substantial contribution to test-retest variability from small fixational eye movements interacting with visual field gradient. Successful characterization of the gradient of sensitivity appears to require sampling at relatively close spacing, as in the 10-2 test pattern. 15. Pan F, Swanson WH. A cortical pooling model of spatial summation for perimetric stimuli. J Vis Oct 13;6(11): PMID: [PubMed - indexed for MEDLINE] Free full text Contemporary models of perimetric sensitivity assume probability summation of retinal ganglion cell sensitivities, ignoring cortical processing. To assess the role of cortical processing in perimetric spatial summation, we used a common form of multiplemechanism spatial vision model in which the stimulus is sampled by receptive fields analogous to those of simple cells in primary visual cortex. Psychophysical threshold was computed by probability summation across the receptive fields. When the receptive fields were nonoriented (like ganglion cells), the spatial summation function had a large nonmonotonic transitional region that was inconsistent with perimetric spatial summation data. When the receptive fields were orientation tuned (like cortical cells), the model was able to give good fits to perimetric spatial summation data. The predictions of the model were evaluated with a masking study, in which noise masks either enlarged the critical area or changed the shape of the spatial summation functions. We conclude that cortical pooling by multiple spatial mechanisms can account for perimetric spatial summation, whereas probability summation across ganglion cells cannot. 16. Chung I, Bartolone A, Swanson WH, Thau AP. A clinical evaluation of proview pressure phosphene tonometry in children. Optom Vis Sci Nov;83(11): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: The Proview tonometer measures intraocular pressure by inducing a pressure phosphene through the eyelid and, if reliable and valid, may offer a quick, nonthreatening and noninvasive alternative method of obtaining intraocular pressures (IOPs) without the use of eye drops. This study compares the IOP measurements obtained in children using Proview pressure phosphene tonometry (PPPT) and Goldmann tonometry (GT). METHODS: One hundred four 5- to 12-year-old patients of the University Optometric Center/SUNY College of Optometry participated in the study. Subjects were randomized to receive, by different investigators, either PPPT or GT first. Two measurements with each instrument were attempted on each eye of all subjects. A subgroup of 41 subjects was asked which of the two methods was preferred. RESULTS: Seven percent of the subjects did not report a pressure phosphene response compared with 12% of the subjects on whom the investigators were unable to 8

9 perform GT. The remaining 85 subjects completed the subject protocol. Of the 41 subjects asked, 56% preferred PPPT, 24% had no preference, and 20% preferred GT. The coefficient of repeatability between the two readings was higher for PPPT (3-4 mm Hg) than for GT (1 mm Hg). Mean IOP was 4 mm Hg higher for PPPT than GT with the difference in readings between the two instruments increasing with higher IOPs (r >19%, p < 0.005). CONCLUSIONS: In our study of healthy young subjects, PPPT measurements of IOP appear to be repeatable within a few millimeters of mercury in most children, but for some children, variability in repeat measurements can be substantial. Our data showed a mean difference in readings of 4 mm Hg with a 95% confidence interval that the PPPT reading was between 12 mm Hg above GT and 4 mm Hg below GT. This wide range of values indicates that PPPT is not comparable to GT. However, because our study found that children can appreciate pressure phosphenes and most prefer PPPT over GT, the Proview monitor may have value as a noninvasive, portable screener in pediatric patients. To fully evaluate this potential, further studies are needed that include patients with high IOPs. 17. Pan F, Swanson WH, Dul MW. Evaluation of a two-stage neural model of glaucomatous defect: an approach to reduce test-retest variability. Optom Vis Sci Jul;83(7): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: The purpose of this study is to model perimetric defect and variability and identify stimulus conditions that can reduce variability while retaining good ability to detect glaucomatous defects. METHODS: The two-stage neural model of Swanson et al. was extended to explore relations among perimetric defect, response variability, and heterogeneous glaucomatous ganglion cell damage. Predictions of the model were evaluated by testing patients with glaucoma using a standard luminance increment 0.43 degrees in diameter and two innovative stimuli designed to tap cortical mechanisms tuned to low spatial frequencies. The innovative stimuli were a luminance-modulated Gabor stimulus (0.5 c/deg) and circular equiluminant red-green chromatic stimuli whose sizes were close to normal Ricco's areas for the chromatic mechanism. Seventeen patients with glaucoma were each tested twice within a 2-week period. Sensitivities were measured at eight locations at eccentricities from 10 degrees to 21 degrees selected in terms of the retinal nerve fiber bundle patterns. Defect depth and response (test-retest) variability were compared for the innovative stimuli and the standard stimulus. RESULTS: The model predicted that response variability in defective areas would be lower for our innovative stimuli than for the conventional perimetric stimulus with similar defect depths if detection of the chromatic and Gabor stimuli was mediated by spatial mechanisms tuned to low spatial frequencies. Experimental data were consistent with these predictions. Depth of defect was similar for all three stimuli (F = 1.67, p > 0.19). Mean response variability was lower for the chromatic stimulus than for the other stimuli (F = 5.58, p < 0.005) and was lower for the Gabor stimulus than for the standard stimulus in areas with more severe defects (t = 2.68, p < 0.005). Variability increased with defect depth for the standard and Gabor stimuli (p < 0.005) but not for the chromatic stimulus (slope less than zero). 9

10 CONCLUSIONS: Use of large perimetric stimuli detected by cortical mechanisms tuned to low spatial frequencies can make it possible to lower response variability without comprising the ability to detect glaucomatous defect. 18. Pearson PM, Schmidt LA, Ly-Schroeder E, Swanson WH. Ganglion cell loss and age-related visual loss: a cortical pooling analysis. Optom Vis Sci Jul;83(7): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSE: To evaluate the ability of the cortical pooling model to predict the effects of random, mild ganglion cell loss, we compared the predictions of the model with the agerelated loss and variability in achromatic and chromatic contrast sensitivity. METHODS: The relative sensitivity to small (0.5 degrees ) and large (3.0 degrees ) stimuli was compared in older (mean = 67 years, n = 27) and younger (mean = 23 years, n = 32) adults. Contrast sensitivity for modulations along the luminance, equiluminant L-cone, and equiluminant S-cone axes was assessed at the fovea and at four peripheral locations (12 degrees). RESULTS: When the stimuli were large, threshold measurements obtained from all participants were reliable and well within the range of modulations along the chromatic axes that could be produced by the phosphors of the CRT. For the large stimuli, neither long- nor short-term variability increased as a function of age. Increasing the size of the stimulus did not decrease the magnitude of the age-related losses when the stimulus was chromatic, and visual losses observed with large chromatic stimuli were not different from those obtained with small achromatic stimuli. Moreover, chromatic contrast sensitivity assessments identified significant visual losses in four individuals who were not identified by achromatic contrast sensitivity assessments and only missed identifying one individual with significant losses in achromatic contrast sensitivity. CONCLUSIONS: The declines in achromatic and chromatic sensitivity as a function of age ( db per decade) were similar to those obtained in previous studies of achromatic and chromatic perimetry and are consistent with the loss of retinal ganglion cells reported in histologic studies. The results of this study are consistent with the predictions the cortical pooling model makes for both variability and contrast sensitivity. These findings emphasize that selective visual impairments do not necessarily reflect preferential damage to a single ganglion cell class and that it is important to include the influence of higher cortical processing when quantifying the relation between ganglion cells and visual function. 19. Sun H, Dul MW, Swanson WH. Linearity can account for the similarity among conventional, frequency-doubling, and gabor-based perimetric tests in the glaucomatous macula. Optom Vis Sci Jul;83(7): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article PURPOSES: The purposes of this study are to compare macular perimetric sensitivities for conventional size III, frequency-doubling, and Gabor stimuli in terms of Weber contrast and to provide a theoretical interpretation of the results. METHODS: Twenty-two patients with glaucoma performed four perimetric tests: a conventional Swedish Interactive Threshold Algorithm (SITA) 10-2 test with Goldmann 10

11 size III stimuli, two frequency-doubling tests (FDT 10-2, FDT Macula) with counterphase-modulated grating stimuli, and a laboratory-designed test with Gabor stimuli. Perimetric sensitivities were converted to the reciprocal of Weber contrast and sensitivities from different tests were compared using the Bland-Altman method. Effects of ganglion cell loss on perimetric sensitivities were then simulated with a two-stage neural model. RESULTS: The average perimetric loss was similar for all stimuli until advanced stages of ganglion cell loss, in which perimetric loss tended to be greater for size III stimuli than for frequency-doubling and Gabor stimuli. Comparison of the experimental data and model simulation suggests that, in the macula, linear relations between ganglion cell loss and perimetric sensitivity loss hold for all three stimuli. CONCLUSIONS: Linear relations between perimetric loss and ganglion cell loss for all three stimuli can account for the similarity in perimetric loss until advanced stages. The results do not support the hypothesis that redundancy for frequency-doubling stimuli is lower than redundancy for size III stimuli. 20. Malik R, Swanson WH, Garway-Heath DF. Development and evaluation of a linear staircase strategy for the measurement of perimetric sensitivity. Vision Res Sep;46(18): Epub 2006 Jun 9. PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article Perimetric sensitivity of patients with glaucoma has traditionally been measured in logarithmic (db) units, but linear sensitivity correlates better with conventional structural measures of glaucomatous damage. Monte Carlo simulations of perimetric algorithms were used to assess potential effects of logarithmic steps on bias and variability when perimetric sensitivity was represented in linear units, and to assess the potential benefits of algorithms using linear steps. Simulations predicted that linear staircases could reduce the sensitivity-dependence of bias, variability and efficiency. These predictions were supported by a perimetric study of 21 patients with glaucoma and 20 age-similar controls who made repeat visits over several weeks. 21. Schwartz SH, Swanson WH. Empiric determination of corrected visual acuity standards for train crews. Optom Vis Sci Aug;82(8): PMID: [PubMed - indexed for MEDLINE] PURPOSE: Probably the most common visual standard for employment in the transportation industry is best-corrected, high-contrast visual acuity. Because such standards were often established absent empiric linkage to job performance, it is possible that a job applicant or employee who has visual acuity less than the standard may be able to satisfactorily perform the required job activities. For the transportation system that we examined, the train crew is required to inspect visually the length of the train before and during the time it leaves the station. The purpose of the inspection is to determine if an individual is in a hazardous position with respect to the train. In this article, we determine the extent to which high-contrast visual acuity can predict performance on a simulated task. METHODS: Performance at discriminating hazardous from safe conditions, as depicted in projected photographic slides, was determined as a function of visual acuity. For 11

12 different levels of visual acuity, which was varied through the use of optical defocus, a subject was required to label scenes as hazardous or safe. RESULTS: Task performance was highly correlated with visual acuity as measured under conditions normally used for vision screenings (high-illumination and highcontrast): as the acuity decreases, performance at discriminating hazardous from safe scenes worsens. CONCLUSIONS: This empirically based methodology can be used to establish a corrected high-contrast visual acuity standard for safety-sensitive work in transportation that is linked to the performance of a job-critical task. 22. Chen Y, Wyatt HJ, Swanson WH. Pupillary evaluation of retinal asymmetry: development and initial testing of a technique. Vision Res Sep;45(19): PMID: [PubMed - indexed for MEDLINE] PMCID: PMC Free PMC Article Glaucomatous damage to upper and lower retina is often unequal. We have developed a rapid, objective, quantitative measure of asymmetry of retinal sensitivity, using infrared pupillometry and pairs of large stimuli that are symmetric about the horizontal meridian. Results for a group of 11 young subjects free of eye disease indicate that the distribution of asymmetry is close to a normal distribution centered near upper/lower symmetry. Some subjects showed modest amounts of asymmetry, which was relatively uniform within each eye, and between the two eyes, of the subject. This approach to determination of asymmetry within an eye is potentially applicable to testing patients with glaucoma. The narrowness of the distribution should make it possible to detect asymmetries caused by disease. 23. Swanson WH, Dul MW, Fischer SE. Quantifying effects of retinal illuminance on frequency doubling perimetry. Invest Ophthalmol Vis Sci Jan;46(1): PMID: [PubMed - indexed for MEDLINE] Free full text PURPOSE: To measure and quantify effects of variation in retinal illuminance on frequency doubling technology (FDT) perimetry. METHODS: A Zeiss-Humphrey/Welch Allyn FDT perimeter was used with the threshold N-30 strategy. Study 1, quantifying adaptation: 11 eyes of 11 subjects (24-46 years old) were tested with natural pupils, and then retested after stable pupillary dilation with neutral density filters of 0.0, 0.6, 1.2, and 1.6 log unit in front of the subject's eye. Study 2, predicting effect of reduced illuminance: 17 eyes of 17 subjects (26-61 years old) were tested with natural pupils, and then retested after stable pupillary miosis (assessed with an infrared camera). A quantitative adaptation model was fit to results of Study 1; the mean adaptation parameter was used to predict change in Study 2. RESULTS: Study 1: Mean defect (MD) decreased by 10 db over a 1.6 log unit range of retinal illuminances; model fits for all subjects had r2> 95%. Study 2: Change in MD (DeltaMD) ranged from -7.3 db to +0.8 db. The mean adaptation parameter from Study 1 accounted for 69% of the variance in DeltaMD (P <0.0005), and accuracy of the model was independent of the magnitude of DeltaMD (r2< 1%, P >0.75). CONCLUSIONS: The results confirmed previous findings that FDT perimetry can be dramatically affected by variations in retinal illuminance. Application of a quantitative 12

13 adaptation model provided guidelines for estimating effects of pupil diameter and lens density on FDT perimetry. 24. Swanson WH, Felius J, Pan F. Perimetric defects and ganglion cell damage: interpreting linear relations using a two-stage neural model. Invest Ophthalmol Vis Sci Feb;45(2): PMID: [PubMed - indexed for MEDLINE] Free full text PURPOSE: To better understand the relations between glaucomatous perimetric defects and ganglion cell damage, a neural model was developed to interpret empiric findings on linear relations between perimetric defects and measures of ganglion cell loss. METHODS: A two-stage model computed responses of ganglion cell mosaics (first stage), then computed perimetric sensitivity in terms of processing by spatial filters (second stage) that pool the ganglion cell responses. Cell death and dysfunction were introduced in a local patch of the first-stage ganglion cell mosaic, and perimetric defect depth was computed for the corresponding region of the visual field. Calculations were performed for both sparse and dense ganglion cell mosaics and for spatial filters with peak frequencies from 0.5 to 4.0 cyc/deg. RESULTS: The model yielded nonlinear functions for perimetric defect depth in decibel versus the percentage of ganglion cell damage, but functions for lower spatial frequencies became linear when perimetric defect was expressed as a percentage of normal. The relations between perimetric defects and percentage of ganglion cell loss were determined primarily by spatial tuning of the second-stage spatial filters. For averaging sensitivities across different visual field locations, linear units (arithmetic mean) can more closely approximate mean ganglion cell loss than decibel units (geometric mean). Fits to data from experimental glaucoma required ganglion cell dysfunction in addition to ganglion cell loss. CONCLUSIONS: Pooling by second-stage spatial filters can account for empiric findings of linear relations between perimetric defects and measures of ganglion cell loss. 25. Felius J, Swanson WH. Effects of cone adaptation on variability in S-cone increment thresholds. Invest Ophthalmol Vis Sci Sep;44(9): PMID: [PubMed - indexed for MEDLINE] Free full text PURPOSE: Short-wavelength automated perimetry (SWAP) has gained popularity as a clinical tool for the assessment of short-wavelength-sensitive (S)-cone visual function, but has also been shown to have higher threshold variability than conventional achromatic perimetry, possibly due to an imbalance between S-cone adaptation and long (L)- and medium (M)-wavelength-sensitive cone adaptation. To investigate potential causes for this relatively high variability, we studied the effects of luminance and S-cone adaptation on variability in S-cone increment thresholds. METHODS: Foveal S-cone increment thresholds were measured on adapting backgrounds ranging from 1.17 to 4.17 log troland (Td) and from to 3.66 log S- cone trolands (Td(S)). Within-session variability (slope of the psychometric function) was evaluated in 2 trained and 15 inexperienced normal observers. Test-retest variability was evaluated in the 2 trained observers, and interobserver variability in the 13

14 group of 15 observers. Multiple linear regression was used to model the effects of log luminance, log S-cone adaptation, and second-site polarization (ratio of luminance and S-cone adaptation; log [Td/Td(S)]). RESULTS: Test-retest variability was lower for conditions with higher levels of S-cone adaptation (F = 9.04, P = 0.013, for the trained observers). Adaptation conditions with lower levels of polarization were associated with lower within-session variability (F = 6.9, P = 0.011; trained observers) and interobserver variability (F = 33.7, P = 0.004; group of 15 observers). CONCLUSIONS: Variability of S-cone increment thresholds can be reduced by using adaptation conditions with a higher level of S-cone adaptation and/or a more balanced ratio between luminance and S-cone adaptation than is used for SWAP. 26. Swanson WH, Cohen JM. Color vision. Ophthalmol Clin North Am Jun;16(2): Review. PMID: [PubMed - indexed for MEDLINE] Many visual disorders produce acquired color vision defects. Color vision theory emphasizes several stages of visual processing: prereceptoral filters (lens, macular pigment, pupil), cone photopigments (L-, M-, and S-cones), and postreceptoral processes (red-green, S-cone, and luminance channels). Congenital color defects, which affect 8% to 10% of males and 0.4% to 0.5% of females, result from alterations in the photopigment absorption spectra or the absence of one or more photopigments. The most common defects are color vision deficiencies (protan and deutan defects), which are milder than the rarer achromatopsias (complete loss of color vision). Acquired color vision defects can be attributed to a number of different causes: alteration of prereceptoral filters, reduced cone photopigment optical density, greater loss of one cone type than the others, and disruption of postreceptoral processes. Acquired color vision defects have been divided into three classes: type 1, red-green defect with scotopization; type 2, red-green defect without scotopization; and type 3, blue defects (with or without pseudoprotanomaly). Blue defects are usually type 3 acquired defects because congenital tritan defects have an incidence of one in several tens of thousands. Red-green defects can be acquired or congenital, and ruling out acquired defects can require a battery of tests (plates and arrangement tests, anomaloscopy, perhaps genetic analysis). Color vision tests must be administered carefully (with a standard illuminant and protocol), and pupillary miosis or high lens density should be noted and their possible effects considered when interpreting test results. Plate tests provide a simple screening method but do not provide a diagnosis. Arrangement tests and anomaloscope testing take more time and make greater demands on the tester, but they provide a more thorough evaluation. When standard protocols are followed and results are interpreted in terms of prereceptoral filters, photopigment optical density, cone loss, and disruption of postreceptoral processes, a battery of color vision tests can be useful in the differential diagnosis, after progression of the disease, and for evaluating the effectiveness of treatment. 27. White AJ, Sun H, Swanson WH, Lee BB. An examination of physiological mechanisms underlying the frequency-doubling illusion. Invest Ophthalmol 14

15 Vis Sci Nov;43(11): PMID: [PubMed - indexed for MEDLINE] Free full text PURPOSE: The frequency-doubling illusion is an apparent doubling of spatial frequency when a sinusoidal grating is modulated rapidly in temporal counterphase. It has been proposed that the illusion arises from a spatially nonlinear ganglion cell class. The current study reexamines this possibility and investigates other mechanisms that may underlie the illusion. METHODS: Responses of macaque magnocellular (MC) retinal ganglion cells were recorded to counterphase-modulated sinusoidal gratings of various spatial frequencies, and linearity of spatial summation was assessed. Human psychophysical thresholds were measured for a variety of phase discrimination and matching tasks. RESULTS: Consistent with lateral geniculate recordings reported by other authors, no evidence was found of a separate nonlinear (M(y)) MC cell class. The small, spatially nonlinear responses found were least at the low spatial frequencies used in clinical testing. Further analysis showed that no spatially modulated signal can be expected from the nonlinear response of a ganglion cell; the nonlinearity of spatial summation gives a doubled response in time but not across space. Psychophysical performance was consistent with an inability to distinguish the temporal phase of counterphasemodulated gratings when the illusion occurs. From 4 to 40 Hz, the zero-crossings of the modulated sinusoidal grating provided a spatial cue and were matched to comparison patterns at twice the stimulus spatial frequency. CONCLUSIONS: These results are inconsistent with the hypothesis that spatially nonlinear (M(y)) retinal ganglion cells are the physiological substrate of the frequencydoubling illusion. A cortical loss of temporal phase discrimination may be the principle cause of the illusion. 28. Birch DG, Toler SM, Swanson WH, Fish GE, Laties AM. A double-blind placebo-controlled evaluation of the acute effects of sildenafil citrate (Viagra) on visual function in subjects with early-stage age-related macular degeneration. Am J Ophthalmol May;133(5): PMID: [PubMed - indexed for MEDLINE] PURPOSE: To assess the effects of a single 100-mg dose of sildenafil citrate on visual function in men with early-stage age-related macular degeneration. DESIGN: Randomized double-blind placebo-controlled clinical trial. METHODS: Nine men (mean age 71 years, range years) with early-stage (minimal visual impairment and large drusen in the macula) age-related macular degeneration and 20/40 or better-corrected visual acuity in at least one eye were prospectively randomized to receive either placebo or sildenafil citrate (Viagra; Pfizer Inc, New York, New York) 100 mg as a single oral dose. After 7-14 days, they received the alternate treatment. Subjects underwent visual acuity, Amsler grid, color discrimination (D15), traffic light, Humphrey perimetry, and photo-stress testing in each eye before and at specific intervals within 8 hours after dosing. RESULTS: Compared with placebo, no pattern of errors were evident in any visual function test following sildenafil administration. No statistically or clinically relevant changes from baseline were observed in visual acuity, Humphrey perimetry (corrected pattern standard deviation), D15 color discrimination, or photo-stress tests. No clinically 15

16 relevant changes were observed in the Amsler grid or traffic light tests. Sildenafil treatment was associated with transient mild or moderate headache, flushing, and rhinitis. There were no visual adverse events spontaneously reported to the investigator. CONCLUSION: A single 100-mg dose of sildenafil was well tolerated and produced no acute visual effects or exacerbation of preexisting visual impairment in nine men with early-stage age-related macular degeneration. 29. Pearson P, Swanson WH, Fellman RL. Chromatic and achromatic defects in patients with progressing glaucoma. Vision Res Apr;41(9): PMID: [PubMed - indexed for MEDLINE] To evaluate the pattern of losses associated with glaucomatous injury in patients with progressing glaucoma, functional losses were examined in 14 patients with progressing glaucoma using tests for which detection should be selectively mediated by one of three psychophysical mechanisms. Red-on-white increments, blue-on-white increments and critical flicker frequency were used to isolate the responses of the red-green chromatic mechanism, the blue-on chromatic mechanism, and the high-frequency flicker achromatic mechanism. For our 3.1 degrees circular stimuli, chromatic defects were found in a greater number of the patients with glaucoma than were achromatic defects. We evaluated these defects in terms of two existing hypotheses: preferential loss and reduced redundancy. The greater sensitivity to glaucomatous injury of chromatic tests, compared to achromatic tests, found in this and other studies and the apparent discrepancy between anatomical and psychophysical studies can be parsimoniously explained by differences in cortical summation of ganglion cell responses for the chromatic and achromatic pathways. 30. Swanson WH, Felius J, Birch DG. Effect of stimulus size on static visual fields in patients with retinitis pigmentosa. Ophthalmology Oct;107(10): PMID: [PubMed - indexed for MEDLINE] PURPOSE: To determine the effect of stimulus size on sensitivity of patients with retinitis pigmentosa (RP) as measured by automated static perimetry. DESIGN: Comparative case series. PARTICIPANTS: Thirty-nine patients with RP and a control group of 10 healthy volunteers. METHODS: Automated static perimetry (full threshold programs 24-2 or 30-2) was performed twice on one eye of each participant using stimulus sizes III (0.43 degrees diameter) and V (1.72 degrees diameter). Data from the same 50 test locations were used from each field. MAIN OUTCOME MEASURES: At each location, for each participant, the size effect was computed as the difference (in decibels) in sensitivities for sizes V and III, and the average sensitivity was computed as the mean of sensitivities for the two sizes. RESULTS: For both patient and control groups, the size effect was negatively correlated with average sensitivity (r(2) > 0.124; P: < 0.001). The mean size effect was significantly greater for the patient group than for the control group: 8.6 (+/- 3.6) db versus 5. 4 (+/- 2.2) db (t = 18.0; P: < 0.001). The percentage of abnormal locations (more than 8 db below mean normal) tended to be lower for size V than for size III, with a mean of 67% for size V versus 95% for size III. The percentage of absolute defects 16