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Note to the Reader Visual Neuroscience (1991) 6: 403–406 © copyright http version by Robert W. Williams

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The Human Retina Has a Cone-Enriched Rim

Robert W. Williams
Department of Anatomy and Neurobiology, University of Tennessee, College of Medicine, Memphis, Tennessee 38163
(Received February 15, 1991, Accepted March 7, 1991)

Video-enhanced imaging of retinal wholemounts reveals an abrupt change in the composition of the photoreceptor mosaic at the edge of the human retina. Cone densities rise three-fold and rod densities fall ten-fold in a 1-mm-wide peripheral band. Antibodies directed against cones confirm the identification of the major subtypes of photoreceptors within this peripheral band. The cone-enriched rim is most highly developed along the nasal retinal margin, an area where the extreme lateral periphery of the visual field is imaged. This rim of cones may function as part of a rapid-acting alert mechanism under conditions of moderate and bright illumination.

   One of the most characteristic features of primate retina is the high density of rods throughout the periphery. In humans, for example, rods outnumber cones 25 to 1 in mid-peripheral retina (Curcio et al., 1990). This factor contributes to the superior light sensitivity of peripheral retina. The idea that rods maintain their dominance out to the extreme periphery is deeply entrenched (e.g., Polyak, 1941). However, little effort has actually been expended on the retinal edge, and even a brief survey of standard references reveals intriguing discrepancies. For instance, Schwalbe (1874) stated that density of rods fell sharply at the ora serrata, and Østerberg (1935) mentioned, almost in passing, that the density of cones rose at three sites near the ora on the nasal side of a single retina he studied.

Techniques introduced recently by Curcio and colleagues (1987) now make it practical to rapidly quantify the structure of the mosaic at any location in a number of glycerin-embedded retinal wholemounts. The method combines high-resolution video-enhanced differential interference contrast optic with a video-overlay system. This combination makes it possible to determine the structure of the mosaic around the entire perimeter of the retina.

Retinas from 9 humans were studied. The average age of material was 61 years (28-82 years). Retinas and the pars planae of the ciliary body were dissected and flattened between coverslips in a mixture of glycerin, water, and polyvinyl alcohol (Heimer & Taylor, 1974). There is no appreciable tissue shrinkage. Two retinas were reacted using polyclonal antibodies directed against cone opsins (see Lerea et al., 1989, for details). A total of 281 sites (6200 µm2 each) completely free of microcysts were analyzed in retinas from 8 individuals. Sites were quantified at 3500× using differential interference contrast optics, analog and digital video enhancement, and a long working distance oil-immersion objective from the edge of retina inward 2 mm (Wikler et al., 1990). Parts of the periphery were also embedded in plastic and semithin sections were cut to study lamination and cell morphology.

As described in the classical literature (Schwalbe, 1874; Salzmann, 1912) and as confirmed by the analysis of transverse plastic sections, all layers of the retina extend out to the extreme periphery. Layers are thinner; ganglion cells are widely spaced (Stone & Johnston, 1981). Microcysts are common within the outer layers of retina in the older human material (Ochi, 1927). Such microcystic regions were avoided. This report only covers the photoreceptor mosaic.

Distinguishing between rods and cones was not appreciably more difficult at the retinal rim than elsewhere in retina (Fig. 1, A and B). Cone inner segments are typically four times larger than those of neighboring rods (70 ± 16 µm2 vs. 18.2 ± 5.9 µm2). Cone inner segments at the retinal edge are somewhat smaller than those even 50 microns farther in. The size distribution of rods and cones shows no overlap at any eccentricity.

Human Cones Fig. 1. Photoreceptors at the extreme periphery of the human retina. A, The edge of photoreceptor mosaic of a 36-year-old human (nasal side). Almost the entire mosaic is occupied by cone inner segments. Several rods are marked by arrowheads. The large arrows mark the ora serrata, the retinal edge. Tissue was illuminated with a 50 watt high-pressure mercury bulb used with 546-nm interference filter. All photographs were taken directly from an RGB video monitor. B, Longitudinal optical section of photoreceptors at the dorsal margin of a human retina. In this video micrograph, rod and cone inner and outer segments are located just above the external limiting membrane. Large conical profiles of cone inner segments (IS) are obvious below the level of the line. Small rod inner segments are marked with asterisks. The large arrows indicate outer segments (OS) of both rods and cones. In these preparations, in which the pigment epithelium is removed, outer segments often fall over. 1700×. C, The nasal retinal edge of an immune-reacted wholemount (63-year-old male). The polyclonal antibodies directed against red and green cone opsins label outer segments of a majority of cones in this field at the dorsal nasal margin. In each case, the labeled outer segment could be traced in a through-focus series down to a large unlabeled inner segment. The edge is at the top. The focal plane is at or just above the level indicated by the line in B. 440x. D, Higher-power view of labeled cones outlined in C. Note the tight mosaic of cone inner segments and the overlying labeled outer segments. The arrow indicates one case in which the structural continuity between the labeled outer segment and the unlabeled inner segment is apparent even in a single focal plane. Not all outer segments are visible in this focal plane. 1000x.

The validity of morphological criteria used to classify rod and cones was corroborated using antibodies directed against cone opsins (Lerea et al., 1989). A subset of outer segments in the periphery was heavily labeled (Fig. 1., C and D). With antibodies directed against red and green opsins, up to 90% of large inner segments (putative cones) could be traced to labeled outer segments in well-reacted parts of the extreme periphery in humans. In many cases, however, cone inner segments could not be traced to labeled or unlabeled outer segments. The outer segment is especially sensitive to mechanical damage in postmortem immersion-fixed tissue, and it is also probable that some outer segments are short or have undergone senescent change (Salzmann, 1912). Small inner segments (rods) could never be traced to labeled outer segments. The blue cone opsin antibody labeled a very small number of outer segments in the extreme periphery. This immunological work unequivocally validates structural criteria used to distinguish rod and cone inner segments.

The peak packing density of cones at the edge of the retina consistently ranges between 10,000 and 15,000/mm2. This is 3 to 5 times higher than values in the mid-periphery (Curcio, 1990). The average within the outer 500 micron band is about 8,000 cones/mm2. Within this band the ratio of surface area occupied by cones and rods is about 8:1 (Fig. 2). This ratio is pertinent because it takes into account the much larger area—hence, light-gathering capacity—of cone inner segments, and provides a rough estimate of the proportion of photons initially captured by the two receptor systems. The cone-enriched rim contains as many as 250,000 cones. In comparison, human fovea contains in the neighborhood of 75,000 cones (Curcio et al. 1990, their fig. 6).

Fig 2


Fig. 2. Plot of the shift in the structure of the human photoreceptor mosaic from rod dominance (right side) to cone dominance near the retinal edge (left side). The photoreceptor coverage ratio used in this figure is the ratio between the surface area occupied by cones and that occupied by rods, here on a logarithmic y-axis. More than 1500 µm from the edge of the retina, rods typically occupy twice as much of the retina as do cones (log coverage ratio = -0.3). At a distance of 1000 microns, the retina is divided almost equally (log of the coverage ratio = 0), and within 250 microns of the edge, cones typically occupy 90% to 95% of the mosaic (log coverage ratio of 0). The fovea would be far to the right at about 22,000 microns. Data points are averages from 99 nasal sites, and 182 sites distributed equally in temporal, dorsal, and ventral quadrants from 8 human retinas. For purpose of analysis, values in excess of log 2 were treated as log 2. Only sites free of microcysts were analyzed. Such sites are prominent in aged material and can be readily recognized and avoided by focusing at the level of the outer plexiform layer. They appear as large tissue-free vacuoles. Bars on data points indicate the standard error of the mean.

The cone-enriched rim is most pronounced in the nasal and upper nasal part of the retina. In humans, the density along the nasal margin is typically 10,000/mm2 (range: 6,000/mm2 to 15,000/mm2), whereas the average in other parts of the retina is typically 8,000/mm2 (range: 3,000/mm2 to 12,000/mm2). Rods are present throughout most of the cone-enriched belt, but often at remarkably low densities. Within 500 microns of the edge the average rod density in humans is under 10,000/mm2, and along the nasal margin it is not uncommon to find fields in which densities are under 3,000/mm2 (Fig. 1A). In contrast, rod densities over most of the mid-periphery are well above 40,000/mm2.

Over what distance does the transition from rod to cone dominance occur? Within 1-2 mm of the edge, cone densities begin to rise (Fig. 2). The crossover point—the distance at which the retinal surface is partitioned equally between rods and cones—is located 1500 microns from the edge in the nasal sector and about 1000 microns elsewhere (Fig. 2). From this point moving outward, the change is rapid, and over a distance of only 800 microns, the ratio of the area covered by cones to that covered by rods increases from 1:1 to 10:1. Within 250 microns of the edge, cones occupied 10 times more area that rods. The remarkable switch from rod- to cone-dominated retina is as abrupt along the radial axis as that along the rim of the fovea.

Individual variation within the cone belt is substantial but is no higher that that which characterizes human and monkey fovea (Curcio et al., 1990; Wikler et al., 1990). However, there was unexpected variation in the structure of the mosaic at neighboring sites in periphery. For example, in an extreme case, one field had cone and rod densities of 11,000/mm2 and 4,700/mm2, respectively, whereas an adjacent field had cone and rod densities of 6,600/mm2 and 12,200/mm2.

Each human retina had elevated cone densities, particularly along the nasal periphery. This region that corresponds to a 5- to 10-degree-wide swath of the extreme lateral part of the visual field (Donders, 1877; Drasdo & Fowler, 1974). In contrast, the elevation of cones was not as marked in non-nasal parts of retina. These non-nasal regions of the retinal margin are shielded by the eyebrow, the cheek, and the side of the nose. Consequently, peripheral vision at maturity does not normally extend much beyond 65 degrees in these directions, and a large peripheral sector, including much of the cone-enriched rim in temporal and ventral quadrants, does and probably do not have a role in vision at maturity. While it is far from proof, the fact that the most prominent part of the cone-enriched rim is optically aligned with the extreme temporal periphery suggests that these cones have functional significance. In this context, it is worth noting that I have also observed a prominent increase in cone coverage in the nasal periphery of several other Old World primates (R.W. Williams, unpublished).


Functional Considerations

Unlike the fovea, the periphery of the retina is primarily engaged in detection, not resolution. In this context, there are several reasons why a band of cones along the nasal edge of the retina might be advantageous. One possibility is that these cones are used to detect objects crossing into the visual field on the basis of color. Ferree and Rand (1927) demonstrated convincingly that color fields extend to the extreme periphery, provided that the stimulus is sufficiently large (5 degree diameter), but to date no abrupt change in color function, corresponding to the rim of cones, has been noted at the edge of the visual field. A second possible advantage is that cone responses are not saturated in bright light (Aguilar & Stiles, 1954). Consequently, this band of cones may ensure that peripheral stimuli evoke a strong response even in broad daylight. A third possible advantage is that the time response of cones is at least two times faster than that of rods even at moderate levels of illumination at which both types function (Conner, 1982), and cones in the periphery appear to have particularly rapid response times (Tyler, 1985). A fast-acting alert mechanism would have considerable adaptive value, particularly in primate species in which the lateral coverage of the visual field has been compromised by a large binocular field. Finally, it is also possible that the three-fold increase in the packing density of cones compensates for the steep drop in image magnification in the extreme periphery (Drasdo & Fowler, 1974) thereby maintaining a more nearly constant density of cones per steradian. This reduction in magnification in the periphery also increases the intensity of illumination at the edge, compensating somewhat for the pupillary vignetting. Because it is so technically demanding, psychophysical tests of retinal function have not yet been carried out in the extreme periphery of humans. It is clear that such work will be essential to test whether the cone enriched rim has a particular role in human vision.

[Motivated in part by this report, Mollon and colleagues (1998) looked for psychophysical correlates of the cone-enriched rim. They were unable to find any evidence for changes either in flicker detection or color naming for stimuli persented at very high eccentricity to two male subjects (26 and 53 years of age). While their results fail to support a functional role for the cone enriched rim, they note that "it remains possible that a (functional) discontinuity might be detected in younger subjects, or by a different measure."]

From a comparative view point it is of interest to note that the edge of the retina is highly specialized in some birds and lizard. In fact, in some species there is even be a second, far temporal fovea (Fite & Lister, 1981) related to frontal vision. This demonstrates that the optical quality of peripheral retina is not invariably poor.

Recent work on the growth of retina provides the basis for a model of the development of the cone-enriched rim. In mammals, rods are generated long after cones (e.g., LaVail et al., 1991). Rods appear to intercalate between cones as the retina expands (Fernald, 1988). There is a good possibility that the rim of the retina is stiff and does not expand much (Lia et al., 1987; Kelling et al, 1989) thereby preserving an initially high concentration of cones.



I thank the donors and their families for providing tissue and Dr. C. Lerea for generously providing antibodies. Human tissue was obtained with the help of K. Allen of the Lions Eye Banks, Seattle, Washington. My thanks to D. Turner, H. Zhou, and P. Nguyen for technical assistance; and D. Goldowitz, C. Johnson, and K. Graehl for stimulating discussion and comment on the manuscript. This work was supported by NEI 6627 and the University of Tennessee Center for Neuroscience.


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Since 11 August 98


Neurogenetics at University of Tennessee Health Science Center

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