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The Distribution of Cones in the Primate Retina V. HUGH PERRY Every student of vision is aware that the sampling of an image by the photoreceptors imposes important limitations on the information that is available at every subsequent stage of processing along the visual pathways. Despite the importance of knowing the receptor distribution, the actual data base for the primate retina has been remarkably small until the recent publication of a number of papers that have sought to rectify this and that have brought to light new and interesting points. This paper will bring together some of the main points, but no attempt is made to give all the quantitative values since these are readily available in the primary sources. TISSUE PREPARATION Assessing the distribution of photoreceptors across the retina would appear to be a relatively trivial problem. However, it must be recognized that the preparation of any tissue for microscopic examination usually involves some sort of processing, and this processing commonly results in shrinkage of the tissue. Unless the shrinkage is taken into account by making appropriate measurements at the various stages of preparation, the value of receptor counts from such material is limited. The fact that the receptor density changes dramatically with eccentricity also requires that the sampling eccentricity be exactly known. The use of whole-mounted retinas greatly reduces many of the problems associated with using sectioned retinas and allows accurate estimates of retinal shrinkage. The identification of rods and cones in the primate retina poses few problems (Figure 1~. The classic study of Osterberg (1935) described the distribution of rods and cones over a large part of a single human retina. Polyak (1957) described the density of cones in monkey (M. mulatta) and human retinas 105

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106 A Kit HUGH PERRY FIGURE 1A Photomicrograph of foveal cones in a horizontal section through the inner segments. The retina is from an M. fasciculans monkey. The field is a little more than 1 deg across (201 M/degree from Peny and Cowey, 1985~. but largely restricted his observations to the fovea and perifovea. More recent studies on a small number of retinas have also been restricted to the fovea or central few degrees (Miller, 1979; de Monasterio et al., 1985~. The foveal cone density has attracted much attention, in no small part because of the interest of many visual scientists in measurements of threshold vision. What was required was a study of cone density distribution in a sufficient number of retinas to give an idea of the variability between individuals. Rolls and Cowey (1970) examined a number of retinas from M. mulatto and S. sciureus along the horizontal meridian, but they used vertical sections of retina and were well aware of the problems in extracting accurate estimates from such material. My co-workers and I examined, in whole-mounted retinas, the distri- bution of cones along the horizontal and vertical meridians in four retinas from M. mulatta (Perry and Cowey, 1985~. In these preparations the shrink- age was minimal. Estimates of the foveal cone density were made from horizontal sections that passed through the inner segments. The shrinkage of the sections was known. In one case the entire retina was sampled except for the fovea itself. A number of important points came out of this study. The cone density changes very rapidly over the central 1 deg of the visual field (Figure 1A) and continues to decline rapidly over the central

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THE DIST~B=ION OF CONES IN THE PLATE ~TINA 107 Bma ~ _ ~~ i. FIGURE 1B A field centered on 1 deg from the center of the fovea (M. fasciculans). 5 degrees (Figures 1B and 1C). The change in the size of the cones and the increasing number of rods are easily seen in these photomicrographs. There was a clear nasotemporal asymmetry in the cone distribution outside the central 10 deg or so of the retina; the cone density declined more slowly along the nasal horizontal meridian of the retina than along the other axes. The asymmetry in cone density was somewhat smaller than that seen for the ganglion cells (Perry et al., 1984~. This asymmetry is consistent with psychophysical observations of acuity and sensitivity being superior in the temporal field. In addition, we found differences in foveal cone density between species (see also Rolls and Cowey, 1970; Borwein et al., 1980~. While these data provide a useful basis for comparison with physiological and psychophysical studies on monkeys, it remained to be shown how the cone density varied in the primate for which we have so much psychophysical data the human. CONE DENSITY Curcio et al. (1987b) have provided the first complete maps of the retinal cone distribution in humans. The same laboratory has also shown that the density of cones varies with age (Yuodelis and Hendrickson, 1986~. Bearing in mind that the number of retinas examined is small, Yuodelis

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~- a: ~ ~ HUGH PERRY FIGURE 1C A field centered on a point 5 deg Tom the center of the fovea (M. mulatta). The estimated linear shrinkage of A and B during processing was about 15 percent; no correction has been applied to the scaling. Scale bar = 25 ,um. and Hendrickson have shown that the foveal cone density in the newborn is relatively low; density then increases for at least the next 4 or more years. The density may fall again in aged subjects. It is believed that the increase in cone density in the postnatal period is accomplished by the migration of cones toward the center of the fovea (Hendrickson and Kupfer, 1976; Yuodelis and Hendrickson, 1986~. The loss of cones in the aging eye may be a result of cell death. Not only is there a change in cone density with age, Curcio et al. (1987b) have shown that the foveal density may vale by as much as a factor of 3 in normal adult human eyes. A sample of four retinas from subjects aged 27 to 44 years was studied. There was considerably less variation in density outside the central 1 deg. The cone distribution in the human eye has a similar but not as pronounced nasotemporal asymmetry as described for the monkey with the higher densities in the nasal retina. The large variation in foveal cone density cannot be readily attributed to differential tissue shrinkage. The method of clearing the tissue and viewing it under Normaski optics greatly reduced processing distortion (Curcio et al., 1987a) and the authors estimate the shrinkage as varying from 2 to 12 percent. It could be argued, however, that the large variation in cone density was due to the fact that human eyes are not always obtained

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THE DISTRIBUTION OF CONES IN THE PRIMATE RETINA D I., 109 ---~d~D ~ ~~.~. .~ ~ Act_ - ~ ~ Y f A \~ ' ~ V - hi. ' ~1~ ~ ~ ~ t~ Ad' ~~-._~N A. ~~ /~ . ~ t! /~ - ~ . - ~ ~ Y Y ~ ~ ~ ~ ~ ~ v - v He's'' ~ ~ .~ ~ ~? ~~ ~ _~J ~ f ~ MA ~ ~ ~ ~ I ~ ~ - (< _ V1~ -7 /~ ~ ~ ~ ~ \. ~ _ ~) - #_ ~ ~ ~ 4~-~ Y<\ 2 it,/ ff i' ~ FIGURE ID, E Analysis of cone mosaics to demonstrate the local triangular lattice at the fovea and how it degenerates with eccentricity. See text for details.

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110 ~ mu_ _ ~ HUGH PERRY ~~ r Afar FIGURE IF Analysis of cone mosaics to demonstrate the local triangular lattice at the fovea and how it degenerates with eccentncity. See text for details. under conditions for tissue histology, and it is generally agreed that the fovea is particularly vulnerable to postmortem artefacts. We therefore undertook a study of eyes from M. fascicular~s, where the eyes could all be obtained immediately postmortem following fixation in situ by perfusion (Hawker et al., 1988~. Each eye was subsequently processed in as near identical fashion as possible following the method of Curcio et al. (1987a). Counts of the cone density were made throughout the central degree and at selected intervals out to the periphery. There would appear to be no a priori reason why the size of the sampling area chosen for counting should be of any particular dimensions. In Figure 1A it is clear that the density is changing very rapidly across the central 1 deg. The sample area used by Perry and Cowey (1985) of About 0.45 x 0.45 deg was almost certainly slightly too large. Some of the variability among different studies can, in part, be accounted for by differences in the sampling area. Pokorny (1968) has examined how grating acuity changes with the size of the target viewed, and his results suggest that an area about 0.125 x 0.125 deg would be appropriate. This was the area we used. A sample of our data is shown in Figure 2, where the cone density along the temporal horizontal meridian in eight retinas is plotted. In six of the retinas there is a rapid decline in cone density with eccentricity, as we

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THE DISTRIBUTfON OF CONES IN THE PRIMATE RETINA ~ o 5 - - sin _' i 104 o 10 111 , , , , I, . . . 0 1 10 100 ECCENTRI C I TY ~ deg. arc ~ FIGURE 2 Density of cones at the fovea and along the temporal horizontal meridian in retinas from M. fasciculans monkeys. expected from previous studies. The variation is similar in these six retinas across the eccentricities we have examined. In contrast, two of the retinas (- and o) showed quite clear reductions in density within the central 0.5 deg. In these animals we could observe no pathology or distortion of the tissue, and indeed it was clear that the inner segments of the cones were themselves larger than in the retinas with higher densities. If these low counts resulted from distortion of the tissue, we might expect to see anomalies at further eccentricities; this was not the case. Despite having low densities in the foveal center, these two animals would still theoretically have a cone density at O.S deg. sufficient to resolve about 30 cycles/degree. The highest and lowest foveal counts give about a sixfold range in peak density. It would be interesting to know how these anatomical results compared with behavioral measures of acuity in M. fascicularis, but unfortunately no large sample is available. However, behavioral measures of acuity in M. mulatta, which

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112 ~ HUGH PERRY were refracted and optically corrected, showed considerable variation (N Cowey, personal communication). Thus, we are able to confirm the results of Curcio et al. namely, that cone density varies substantially at the fovea between individual eyes. The reason that some animals have a low density is unclear, but it may well be that the late migration of cones into the foveal region (Hendrickson and Kupfer, 1976; Yuodelis and Hendrickson, 1986) is particularly susceptible to environmental, nutritional, and mechanical factors. How the variation in the foveal cone density is related to the refractive state of the eye was, unfortunately, not examined in this study but certainly merits further study. The anatomical data suggest that we can give no single value as the cone spacing at the human fovea. Ideally, we would like to look at the cone separation in the living eye and compare the results obtained with those found in whole-mount preparations. Using laser interferometric methods, it is possible to do just this (Williams, 1985, 1988~. Using this technique the data suggest that there is rather little variability in cone spacing. The discrepancy between the anatomical and psychophysical results may be more apparent than real at this time, since only small numbers of subjects have been examined in both instances. Williams (1988) does report that at least one subject found the moire patterns produced by the interference fringes difficult to see, which may reflect some anomaly in this subject's cone packing. IMAGE SAMPLING The way in which cones are packed at the fovea is also a matter of some interest since positional disorder in the elements sampling an image will degrade the high frequencies in an image (French et al., 1977; Hirsch and Hylton, 1984~. Once again, for this analysis we chose only those preparations where the distortion was minimized. Figure 1A shows that the cones are regularly packed but gives the impression of short-range order and little long-range order. This is simply demonstrated in Figure ID. A spot was placed in the center of each cone shown in Figure 1, and a straight line was drawn through as many spots as could be joined. If the cone mosaic was perfectly regular, the lines would cross the entire field. This is clearly not the case; the cone mosaic divides into "islands" in which the cones are arranged in a triangular lattice with fractures between the islands. The largest islands are about 10 x 20 cones. We adopted the same procedure for cones centered on a region 1 and 5 deg from the center of the fovea. Larger spots were used at 5 deg to allow for the fact that the cones themselves were substantially larger that at the fovea. The regularity of the mosaic clearly degenerates with eccentricity. The islands are less obvious, and the number of cones contributing to each of them is greatly

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THE DISTRIBUTION OF CONES IN THE PRIMATE RETINA 113 reduced. Williams (1988) has shown that in the human eye, again using interference fringes, the orientations of the moire patterns observed are of a form consistent with triangular packing of the cones with local but not long-range order. The extent of the regular packing predicted by his studies is in good agreement with the size of the largest islands and the rapid degeneration of the regularity with distance from the foveal center. If the cones are arranged in a crystalline lattice in the fovea, it would be of interest to know whether the different types of cones long-, medium-, and short-wavelength sensitive (here referred to as red, green, and blue cones) are also distributed in regular patterns. The blue cones, which can be identified by staining with Procion dyes, are organized In a regular lattice (de Monasterio et al., 1985~. Unfortunately, there is no simple anatomical method for discriminating between red and green cones in the primate. The only study that successfully differentially labeled the red and green cones in a primate was in the baboon retina (Marc and Sperling, 1977~. Their results showed that the two types of cones were randomly arrayed. It has been suggested that not only are the red and green cones randomly arrayed but also that the cells of the inner retinal layers are not able to distinguish between the two cone types during development (Shapley and Perry, 1986~. How then are color-opponent ganglion cells generated? We hypothesize that a midget bipolar cell contacting a single cone and connected to a single one of the smallest P ganglion cells (so- called midget ganglion cells; Polyak, 1941) would provide the central input to a cell with color-opponent receptive field. The surround of this cell might receive inputs from both red and green cones and, depending on the relative proportions of them, would appear as a more or less color- opponent cell. Across the whole population of color-opponent P ganglion cells, the neutral point to these cells would vary, as is found to be the case (Zrenner, 1983~. It will be of considerable interest to know just how and in what proportions these two cone types are distributed in the retina and whether this is consistent with this the "hit-or-miss" hypothesis. At the fovea the cells of the inner nuclear and ganglion cell layers are laterally displaced; in order that the cones might contact the cells of the inner nuclear layer, there is a long process, known as a fiber of Henle, that courses in the outer fiber layer and terminates in a pedicle to make synaptic contact in the outer plexiform layer (Polyak, 1941~. The length of these fibers and their arrangement around the fovea will not only be important for the preservation of the sampled image but will also determine the numerical relationship between the number of cones and ganglion cells sampling a given point of visual space. The fibers of Henle of foveal cones in the monkey retina are at least 400 Em in length (Boycott et al., 1987; Perry and Cowey, 1988~. Cones immediately adjacent to the central foveal cones have slightly shorter fibers

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114 ~ HUGH PERRY and so on, such that the length of the fibers decreases in a systematic fashion from the fovea out to about 15 deg eccentricity. The fibers radiate out from the center like the spokes from a wheel, and it is clear that adjacent cones have very similar lengths (PerIy and Cowey, 1988), so the topography of the cone mosaic at the level of the inner segments is preserved at the pedicles. There is, however, an interesting problem for those cones in the most central part of the fovea since the fibers of these cones project to all four quadrants around the fovea. Initially the cells to which these fibers are connected lay over the foveal center and migrated laterally during development; thus, it would appear that the topography was preserved. However, while this is in large part correct, there remains the problem that some fibers pass to either side of the vertical meridian. Ganglion cells on either side of the meridian send their axons to opposite sides of the brain. This poses a problem as to how the image is then retrieved, particularly with high spatial frequencies since these are poorly transmitted across the corpus callosum (Bernard) et al., 1987~. Williams (1988) has found that in some observers the cone spacing is larger in the horizontal direction than in the vertical direction. It seems possible that this may be related to the behavior of the fibers of Henle. GANGLION/FOVEAL CELL RATIO From our knowledge of the length of the fibers of Henle or by taking into account the fact that cone pedicles are at least twice the diameter of the cone inner segment (Boycott et al., 1987), it is possible to estimate the numerical relationship of ganglion cells to cones for the foveal retina. The present estimates show that the ratio of ganglion cells to cones is slightly greater than 2:1 for the central 1 dog (Perry and Cowey, 1988; Schein, 1988~. It has been shown that each cone pedicle is contacted by at least two bipolar cells, which themselves terminate at different levels in the inner plexiform layer (Kolb et al., 1969~. From what is known of the organization of other retinas, it seems likely that one of these bipolar cells contacts an ON-center ganglion cell, the other an OFF-center cell. A 2:1 ratio may be of little advantage with respect to the spatial sampling but may be an advantage for producing a system with a large dynamic range. The foveal cones have a fiber of Henle of the order of 400 Am long and about 2 to 3 sum in diameter. The conduction of a potential along such a process will result in both a decrement and temporal smearing of the signal. This is not likely to be an advantage. Polyak (1941) pointed out that Muller's fibers, the radial glia of the retina, appear to partially wrap themselves around the fibers of Henle. We have recently shown that adjacent Muller's fibers and fibers of Henle have very similar lengths at the same retinal eccentricities. It would appear that the Muller's fibers may act

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THE DISTRIBUTION OF CONES IN TlIE PRIMATE RETINA I15 as ensheathing glia and thus help to prevent the decrement of the signal as it passes from the cell body to the pedicle. A description of the distribution of the cones in the monkey and human eye is now available. This information should prove useful in showing the extent to which cone density limits visual performance across the visual field. The next important task is to discover from anatomical and physiological experiments how the information from the cones is used to construct the receptive field characteristics of the different types of ganglion cells. REFERENCES Bernadi, N., S. Bisti, and L. Maffei 1987 The transfer of visual information across the corpus callosum: spatial characteristics. Joumal of Physiology (London) 384:619-632. Borwein, B., D. Borwein, J. Medeiros, and J.W. McGowan 1980 The ultrastructure of monkey fovea photoreceptors, with special reference to the structure, shape, size and spacing of foveal cones. American Journal of Anatomy 159:125-146. Boycott, B.B., J.M. Hopkins, and H.G. Sperling 1987 Cone connections of the horizontal cells of the rhesus monkey's retina. Proceedings of the Royal Society B 229:345-379. Curcio, C.A., O. Packer, and R.E. Kalina 1987a A whole mount method for sequential analysis of photoreceptor and ganglion cell topography in a single retina. Vision Research 27:9-15. Curcio, C.A., K.R. Sloan, Jr., O. Packer, A.E. Hendrickson, and R.E. Kalina 1987b Distribution of cones in human and monkey retina: individual variability and radial asymmetry. Science (New York) 236:597-582. de Monasterio, F.M., E.P. McCrane, J.K, Newlander, and J.S. Schein 1985 Density profile of blue sensitive cones along the horizontal meridian of macaque retina. Investigative Ophthalmology and Visual Science 26:289-302. French, AS., A.W. Snyder, and D.G. Stavenga 1977 Image degradation lay an irregular retinal mosaic. Biological Cybemetics 27:22~233. Hawken, M.J., V.H. Perry, and A.J. parker 1988 Structural relationships of photoreceptors to VI receptive fields in primate. Invest. Ophthalm. V's. Sci 29(Supp.~:297. Hendrickson, A., and C. Kupfer 1976 The histogenesis of the fovea in the macaque monkey. Investigative Oph- thalmolo~y 15:746-756. Hirsch, J., and R. Hylton 1984 Quality of the primate receptor lattice and limits of spatial vision. Illusion Research 24:347-356. Kolb, H., B.B. Boycott, and J.E. Dowling 1%9 A second type of midget bipolar cell in the primate retina. Philosophical Transactions of the Royal Society B 225:177-184. Marc, R.E., and H.G. Sperling 1977 Chromatic organization of primate cones. Science 196:454-456.

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116 I! HUGH PERRY Miller, W.H. 1979 Ocular optica filtering. In Handbook of Sensory Physiology, vol. V11/6A. Berlin: Springer. Osterberg, G. 1935 Topography of the layer of rods and cones in the human retina. Acta OpAthalmologica Supplement 6:1-103. Perry, V.H., and A. Cowey 1985 The ganglion cell and cone distributions in the monkey's retina; implications for central magnification factors. I^sion Research 25:1795-1810. 1988 The lengths of the fibres of Henle in the retina of macaque monkeys: implications for vision. Neuroscience 25:225-236. Perry, V.H., R. Oehler, and ~ Cowey 1984 Retinal ganglion cells that project to the dorsal lateral geniculate nucleus in the macaque monkey. Neuroscience 12:1101-1023. Pokorny, J. 1968 The effect of target area on grating acuity. Vision Research 8:54~554. Polyak, S. 1941 The Retina. Chicago, Ill.: University of Chicago Press. 1957 The Herterbrate Usual System. Chicago, Ill.: University of Chicago Press. Rolls, E.T., and A Cowey 1970 Topography of the retina and striate cortex and its relationship to visual acuity in rhesus monkeys and squirrel monkeys. Experimental Brain Research 10 19~311. Schein, S.J. 1988 Anatomy of the macaque fovea and spatial densities of neurons in foveal representation. Journal of Comparative Neurology 269:479-505. Shapley, R.M., and V.H. Perry 1986 Cat and monkey retinal ganglion cells and their visual functional roles. Trends in Neuroscience 9:229-235. Williams, D.R. 1985 Aliasing in human foveal vision. Vision Research 25:195-205 1988 Topography of the foveal cone mosaic in the living human eye. Vision Research 28:433-454. Yuodelis, C., and ~E. Hendrickson 1986 A qualatative and quantitative analysis of the human fovea during develop- ment. Vision Research 26:847~55. Zrenner, E. 1983 Neurophysiological aspects of colour vision in primates. In Studies of Brain Function, vol. 9. Berlin: Springer-Verlag.