Roger S. Anderson

The psychophysics of glaucoma: improving the structure/function relationship.

Perimetry of some kind remains an important tool in the detection, diagnosis and monitoring of glaucomatous damage to the visual pathway. However, recent studies have served to reinforce the suspicion that conventional perimetry does not possess the sensitivity to detect the earliest signs of functional loss resulting from glaucoma. The relationship between differential light threshold and ganglion cell loss is extremely weak and, in the early stages of glaucoma, non-existent. Alternative, more novel perimetric techniques seem to offer promise of better detectability for early loss by claiming to tap in to one or other of the separate parallel pathways of the visual system. While some of these tests show potential for better detection and monitoring of glaucoma, the reasons why this might be so are not always clearly formulated or represented. This leads to misunderstanding of what the test actually measures and of the glaucomatous disease process itself. This paper seeks to revisit and review the theory underlying psychophysical testing of visual function related to glaucoma and stresses the importance of developing tests that are based on a firm theoretical understanding of visual function and processing in order to both detect glaucoma at an earlier stage and better understand the mechanisms of loss from the disease process.

Psychophysical evidence for a selective loss of M ganglion cells in glaucoma

We measured resolution acuity at 12 different retinal locations using sinusoidal gratings in a group of normals, ocular hypertensives and glaucoma patients. Resolution was measured using both stationary gratings, which selectively stimulate parvocellular ganglion cells (P cells), and gratings which phase reversed at 30 Hz, which selectively stimulate a higher proportion of magnocellular ganglion cells (M cells). With stationary gratings, peripheral resolution was found to be significantly reduced in glaucoma patients and, to a lesser extent, in ocular hypertensives. When the stimuli phase reversed at 30 Hz these differences between groups were larger. The ratio of resolution with and without phase reversal also showed a significant difference between the three groups. These results provide strong psychophysical evidence for a selective loss of M ganglion cell density over P ganglion cell density in glaucoma.

Psychophysical localization of the human visual streak.

In a topographical study of the human retina, Curcio and Allen documented the presence of the human visual streak, which they described as a prominent nasotemporal asymmetry in ganglion cell density. This asymmetry could also be expected to be measurable in any visual function limited by ganglion cell density. By using an interferometer we sought to test the hypothesis of Thibos et al. that peripheral resolution acuity is limited by the spacing of ganglion cells and should therefore reflect the anatomical asymmetry of the visual streak, once the attenuating effects of the eyes optics have been removed. This proved to be the case and differences predicted by a ganglion cell density of 2:1 were easily measurable. This study has potential clinical implications for the detection of disease or abnormalities of the visual system that cause death or dysfunction of retinal ganglion cells.

Sensitivity loss in early glaucoma can be mapped to an enlargement of the area of complete spatial summation.

PURPOSE The area of complete spatial summation (Riccos area) is the largest stimulus size for which area × intensity is constant at threshold. The authors sought to investigate whether Riccos area changes in early glaucoma to account for the decreased visual signal/noise ratio that may accompany retinal ganglion cell loss. METHODS Spatial summation functions were measured, and Riccos area was determined at four 10° retinal locations in 24 patients with early glaucoma (total deviation at test locations, mean, -1.3 dB; range, +2 dB to -8 dB) and 26 age-similar healthy subjects under achromatic and S-cone isolation conditions. Achromatic grating resolution acuity was measured at the same locations to estimate functional ganglion cell density. RESULTS Riccos area was enlarged in patients compared with controls for both achromatic (enlarged by: superior field, 0.57 log units, P < 0.01; inferior field, 0.72 log units, P < 0.01) and chromatic (enlarged by: superior field, 0.26 log units, P < 0.01; inferior field, 0.25 log units, P = 0.065) stimuli, with negligible vertical summation curve shifts along the intensity axis. Resolution acuity was significantly reduced in glaucoma patients in both hemifields (P < 0.001). There was a weak, but significant, relationship between Riccos area and resolution acuity. CONCLUSIONS Enlargement of Riccos area completely compensates for reduced perimetric sensitivity in early glaucoma to maintain constant threshold at Riccos area, suggesting an increase in signal pooling in response to ganglion cell loss. The rightward displacement of the spatial summation curve indicates that perimetric stimuli should be capable of modulating in size as well as/instead of contrast, which may boost the glaucoma signal within measurement noise.

Investigation of changes in the myopic retina using multifocal electroretinograms, optical coherence tomography and peripheral resolution acuity

We investigated relationships between retinal structure using optical coherence tomography (OCT) and retinal function using peripheral resolution acuity and multifocal electroretinograms (mfERG) in 56 subjects with a range of refractive errors (+0.50 to -15.00 D). Retinal thinning occurred in moderate and high myopia which appeared to be primarily due to reduced thickness of the middle to inner retina (MIR) (outer plexiform layer to the nerve fiber layer). MIR thickness was correlated with reduced spatial resolution and delayed mfERG timing in the peripheral retina. The findings suggest the structure and function of the post-receptor retina is susceptible to disruption in moderately and highly myopic eyes.

Relationship between acuity for gratings and for tumbling-E letters in peripheral vision.

Earlier studies have reported that grating resolution is sampling-limited in peripheral vision but that letter acuity is generally poorer than grating acuity. These results suggest that peripheral resolution of objects with rich Fourier spectra may be limited by some factor other than neural sampling. To examine this suggestion we formulated and tested the hypothesis that letter acuity in the periphery is sampling-limited, just as it is for extended and truncated gratings. We tested this hypothesis with improved methodology to avoid the confounding factors of target similarity, alphabet size, individual variation, peripheral refractive error, and stimulus size. Acuity was measured for an orientation-discrimination task (horizontal versus vertical) for a three-bar resolution target and for a block-E letter in which all strokes have the same length. We confirmed previous reports in the literature that acuity for these targets is worse than for extended sinusoidal gratings. To account for these results quantitatively, we used difference-spectrum analysis to identify those frequency components of the targets that might form a basis for performing the visual discrimination task. We find that discrimination performance for the three-bar targets and the block-E letters can be accounted for by a sampling-limited model, provided that the limited number of cycles that are present in the characteristic frequency of the stimulus is taken into account. Quantitative differences in acuity for discriminating other letter pairs (e.g., right versus left letters E or characters with short central strokes) could not be attributed to undersampling of either the characteristic frequency or the frequency of maximum energy in the difference spectrum. These results suggest additional tests of the sampling theory of visual resolution, which are the subject of a companion paper.

Effect of window size on detection acuity and resolution acuity for sinusoidal gratings in central and peripheral vision

Detection and resolution of square patches of sinusoidal gratings were measured in central and peripheral vision (30 degrees horizontal temporal visual field) for high-contrast gratings as a function of the number of cycles in the stimulus. We determined performance in a forced-choice paradigm for a fixed number of stimulus cycles by arranging for stimulus diameter to vary inversely with spatial frequency. For both psychophysical tasks and for both target locations, the psychometric function relating performance to log spatial frequency shifted to higher frequencies without changing slope significantly as the number of cycles in the stimulus was increased. Thus the entire effect could be captured by an analysis of spatial acuity, which increased with increasing number of grating cycles over the range 0.5-6 cycles but remained constant over the range 6-14 cycles. In the central field, resolution acuity and detection acuity were equal regardless of the number of cycles in the stimulus. In the peripheral field, detection acuity exceeded resolution acuity and perceptual aliasing occurred for stimuli in the range 1-14 cycles. From this result we conclude that resolution acuity is sampling limited in the periphery, provided that the stimulus contains at least one full cycle of the grating. Essential features of the results could be accounted for by Fourier analysis of the stimulus.

What limits detection and resolution of short-wavelength sinusoidal gratings across the retina?

Peripheral resolution acuity for achromatic gratings is known to be limited by the density of the underlying ganglion cell sampling array. After confirming isolation of the short-wavelength sensitive (SWS) system using chromatic adaptation methods, we wished to determine if resolution is limited by blue/yellow ganglion cell sampling (evidenced by a superiority of detection over resolution acuity and the perception of aliasing) and thus directly related to SWS-driven ganglion cell density. We measured detection and resolution acuity between 0 degrees and 35 degrees, using blue sinusoidal gratings superimposed on a yellow adapting background which ranged in intensity from 2.5 to 4.7logTrolands. At all locations, a break could be observed in the acuity vs. illumination curves followed by a plateau. Detection and resolution acuity were the same for low background intensities, but resolution acuity was lower than detection at higher intensities, accompanied by observations of chromatic aliasing. SWS resolution is sampling-limited across the retina and agrees well with predicted performance based on anatomical estimates of small bistratified ganglion cell density.

Spatial summation of S-cone ON and OFF signals: Effects of retinal eccentricity

We studied spatial summation for S-cone ON and OFF signals as a function of retinal eccentricity in human subjects. S-cone isolation was obtained by the two-colour threshold method of Stiles, modified by adding blue light to the yellow background. Test stimuli were blue light increments or decrements within a circular area of variable size. These were presented for 100 ms at 0 to 20 deg along the horizontal temporal retinal meridian. Riccos area of complete spatial summation was measured from the threshold vs. area curves. This was nearly constant and approximately the same for both types of stimuli within the 0-5 deg range and increased beyond this range. The decremental area increased faster, suggesting that separate mechanisms, presumably ON and OFF, integrate S-cone increments and decrements. The results appear to provide new evidence for the existence of separate S-cone ON and OFF pathways. We compare the data with known morphology of primate retina and assume that, if S-cone decrements are detected via separate OFF cells, these should differ in density and dendritic field size from the S-cone ON cells, but only in the retinal periphery.

Carotenoids and Co-Antioxidants in Age-Related Maculopathy: Design and Methods

Age-related macular degeneration (AMD), is the leading cause of blind registration in the Western World among individuals 65 years or older. Early AMD, a clinical state without overt functional loss, is said to be present clinically when yellowish deposits known as drusen and/or alterations of fundus pigmentation are seen in the macular retina. Although the etiopathogenesis of AMD remains uncertain, there is a growing body of evidence in support of the view that cumulative oxidative damage plays a causal role. Appropriate dietary antioxidant supplementation is likely to be beneficial in maintaining visual function in patients with AMD, and preventing or delaying the progression of early AMD to late AMD. The Carotenoids in Age-Related Maculopathy (CARMA) Study is a randomized and double-masked clinical trial of antioxidant supplementation versus placebo in 433 participants with either early AMD features of sufficient severity in at least one eye or any level of AMD in one eye with late AMD (neovascular AMD or central geographic atrophy) in the fellow eye. The aim of the CARMA Study is to investigate whether lutein and zeaxanthin, in combination with co-antioxidants (vitamin C, E, and zinc), has a beneficial effect on visual function and/or prevention of progression from early to late stages of disease. The primary outcome is improved or preserved distance visual acuity at 12 months. Secondary outcomes include improved or preserved interferometric acuity, contrast sensitivity, shape discrimination ability, and change in AMD severity as monitored by fundus photography. This article outlines the CARMA Study design and methodology, including its rationale.