My graduate work began under R.D. Freeman 1,3,4 with a study of amblyopia, one of the most intriguing visual dysfunctions known to clinical optometry. Amblyopia is characterized by a loss of visual acuity for no apparent reason and our experiments were aimed at establishing where in the visual pathways lies the defect responsible for this condition. Using a combination of psychophysical and electrodiagnostic techniques, we examined a particular kind of amblyopia, for which vision is acute when patterns are at one orientation but not at another. Since this condition occurs only in persons with strong ocular astigmatism during childhood, the working hypothesis was that uncorrected astigmatism during the critical period of development produces a deprived visual environment which eventually leads to a permanent visual disability. Our experimental results provided the first direct evidence from humans to support this hypothesis and pointed to the initial stages of the visual system, possibly the retina, as the locus of meridional amblyopia.
Some years later, I was awarded an NIH postdoctoral fellowship to join W.R. Levick in Australia to test this idea in the cat animal model. We found that the simplest hypothesis, that the receptive fields of retinal neurons are modified by astigmatic visual deprivation, is not correct 12. Since we also found no optical defect from the deprived rearing conditions, we concluded that meridional amblyopia is an abnormality of the brain, not the eye. Only recently have A. Bradley and I arrived, by quite different paths, at yet another retinal hypothesis for amblyopia based on the idea of retinal undersampling which we are currently exploring.
Levick and I also studied the problem of pigment-related visual dysfunction. Albinism is a genetic abnormality in which a lack of the pigment melanin is associated with a misrouting of optic nerve fibers: axons of retinal ganglion cells project to the wrong side of the brain. This curious association between pigment production and disorganization of the visual pathway led us to study the blue-eyed white-cat, another variety which lacks pigment but is not albino. Surprisingly, our neurophysiological experiments indicated that the white cat has normal visual pathways 8. To solve this puzzle we undertook further histological experiments to determine the basis for hypopigmentation in the two types of cat. We found that the white cat lacks the melanocytes necessary for pigment production, whereas the albino has melanocytes but these cells fail to synthesize melanin, evidently because they lack the enzyme tyrosinase 9. Since the white cat has normal tyrosinase (as indicated by normal pigmentation of the retinal epithelial cells), we suggested that abnormal development of the visual pathways may depend fundamentally on a defective enzyme, and that reduced pigmentation is merely one reflection of that defect.
A third class of retinal disorders are the acquired and disease processes. Cats are particularly susceptible to dietary insufficiency of the amino acid taurine which leads to photoreceptor death and blindness in the central region of the retina. While I was in Australia, Levick and I began a long-term neurophysiological and histological study of this disease with the goal of understanding the consequences of photoreceptor death and the loss of photic input to retinal ganglion cells. Results so far indicate that ganglion cells outside the photoreceptor lesion have normal response properties, cells inside the lesion are blind, and cells on the border of the lesion have abnormal sensitivity and unusual receptive fields.5B Surprisingly, conduction of nerve action potentials by optic nerve fibers was normal despite the fact that some cells had probably not generated an action potential spontaneously for several years prior to our experiments.
Perhaps because of my engineering background, I became especially attracted as a graduate student to those tractable problems of retinal research which appear amenable to quantitative analysis. For my dissertation research I took up the challenge of quantifying F.S. Werblin's well-known, qualitative model of neural adaptation in the vertebrate retina based on studies of the mudpuppy. The basic idea was that if sustained adaptation of bipolar and ganglion cells is mediated by lateral antagonism occurring at the outer plexiform layer from the network of horizontal cells, then the graded antagonism measured in bipolar and ganglion cells should be closely correlated with the graded responses of horizontal cells. Similarly, the transient adaptation of ganglion cells by the network of amacrine cells at the inner plexiform layer should be correlated with the response properties of amacrine cells. By independently measuring the adaptation effects and the response properties of the antagonistic neurons over a broad range of stimulus parameters and configurations, I was able to give quantitative support to Werblin's model 5,6 Furthermore, analysis of the data indicated that the apparently nonlinear (divisive) nature of adaptation in bipolar cells could be explained by a linear (subtractive) feed-back synaptic-mechanism at the outer plexiform layer. On the other hand, transient adaptation of ganglion cells appeared to be due to a linear, feed forward mechanism at the inner plexiform layer
Following my graduate work on amphibian retina I moved to Australia to learn the mammalian preparation from one of the world's experts, W.R. Levick. Together we explored for eight years the rich field of spatial information processing by receptive fields of retinal ganglion cells. At that time a definitive scheme for classifying retinal ganglion cells had just been proposed by Cleland and Levick for the cat and we aimed to see if the same scheme could be applied also to the rabbit, an animal thought by some to have quite a different retinal organization. Although obvious quantitative differences emerged, we found that the qualitative behavior of ganglion cells in rabbit and cat were quite similar 11 , thus supporting the emerging generalization that the mammalian nervous system contains not one visual pathway but several distinct, parallel visual projections from retina to brain.1B
In order to assess the functionality of the various parallel pathways of the cat retina, we set out to characterize the response properties of the major classes of retinal ganglion cells from within the conceptual framework of spatial frequency analysis. In this context, the long-term goal is to describe neural responses to the sinusoidal grating stimulus as a function of spatial frequency, contrast, orientation and phase, for a variety of cell locations across the visual field. As a first step we showed that different cell types identified by Cleland and Levick, based on the qualitative assessment of response to simple geometrical targets like spots, bars and disks of light, can also be distinguished with sinusoidal gratings.14 Within a given functional class, response properties varied systematically with eccentricity of the cell from the central area. At any given eccentricity, each class gives a distinctly different weighting to the spatial frequency spectrum and each has a characteristic limit to the finest detectable grating. Thus we developed the viewpoint that each functional class of retinal ganglion cell filters the retinal image differently and so passes on its unique view of the visual world to the brain.
Several of our experiments produced results which challenged established views on the functional architecture of the retina. One of the more interesting examples concerned the basic structure of the concentric type of receptive field. Since its first discovery over 30 years ago, the concentric field has been described as the union of two distinct components, the center and antagonistic surround, both of which are roughly circular in shape and concentrically positioned. However, we found that a number of cells had double-centers which were characterized by unusual behavior for high-frequency gratings that was reminiscent of spurious resolution in optical systems. 16
Perhaps the most interesting feature of retinal organization we uncovered in the cat is radial tuning. Previously it had generally been assumed that receptive fields of retinal ganglion cells are circular, but we found that most fields are actually elliptical. Furthermore, these elongated fields are systematically organized across the retina with the long axis of the ellipse oriented radially like the spokes of a wheel with its hub centered on the region of highest density of retinal ganglion cells, where the cat has it's greatest visual acuity. 10,13,17 This discovery led to subsequent work by others indicating that elongation of dendritic fields is the anatomical basis for radial tuning in ganglion cells and that similar tuning occurs also in primate retina and cat visual cortex. Those results have led in turn to several interesting hypotheses about the developmental mechanisms responsible for radial tuning and the role of radial tuning in the establishment of orientation columns in visual cortex. In my own work, the possibility of radial tuning in humans led to new experiments on peripheral vision at Indiana University described further on.
Another line of investigation that Levick and I pursued was to establish the physical and biological factors which limit the ultimate sensitivity of retinal neurons for detecting dim flashes of light. We approached this problem from within the conceptual framework of signal detection theory, as developed for the context of neural signals by T.E. Cohn. As a graduate student, I had developed some appreciation for the power of this approach in a psychophysical study with Cohn in which we showed that, for a simple detection task, the human observer acts like an ideal photodetector with imperfect memory for stimulus parameters. 2 To set the stage for the corresponding experiment on single neurons, it was necessary for us to first advance the theory of ideal detectors of Poisson signals. 7 We were then in a position to test the hypothesis that detection of brief increments and decrements of light by ganglion cells is limited only by the inherent, quantal fluctuations in the light itself. The results showed that although quantal fluctuations are an important limiting factor, quantitative agreement between theory and experiment was possible only when a second, biological source of noise was postulated. 15 As a result of these experiments, it became necessary to reassess the broader issue of the meaning of the term "quantum efficiency" and to develop a new method of approach which incorporates both the physical and biological limits to detection. 2B
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