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Thesis (Ph. D.)--Washington State University, May 2008. / Includes bibliographical references.

Thesis (M.S.)--Baylor University, 2008. / Includes bibliographical references (p. 31-35)

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [105]-116).

Note:

Yes / Purpose To record transient ERGs from the lightadapted human retina using silent substitution stimuli which selectively reflect the activity of rod photoreceptors. We aim to describe the morphology of these waveforms and examine how they are affected by the use of less selective stimuli and by retinal pathology. Methods Rod-isolating stimuli with square-wave temporal profiles (250/250 ms onset/offset) were presented using a 4 primary LED ganzfeld stimulator. Experiment 1: ERGs were recorded using a rodisolating stimulus (63 ph Td, rod contrast, Crod = 0.25) from a group (n = 20) of normal trichromatic observers. Experiment 2: Rod ERGs were recorded from a group (n = 5) using a rodisolating stimulus (Crod = 0.25) which varied in retinal illuminance from 40 to 10,000 ph Td. Experiment 3: ERGs were elicited using 2 kinds of nonisolating stimuli; (1) broadband and (2) rod-isolating stimuli which contained varying degrees of L- and M-cone excitation. Experiment 4: Rod ERGs were recorded from two patient groups with rod monochromacy (n = 3) and CSNB (type 1; n = 2). Results The rod-isolated ERGs elicited from normal subjects had a waveform with a positive onset component followed by a negative offset. Response amplitude was maximal at retinal illuminances\100 ph Td and was virtually abolished at 400 ph Td. The use of non-selective stimuli altered the ERG waveform eliciting more photopic-like ERG responses. Rod ERGs recorded from rod monochromats had similar features to those recorded from normal trichromats, in contrast to those recorded from participants with CSNB which had an electronegative appearance. Conclusions Our results demonstrate that ERGs elicited by silent substitution stimuli can selectively reflect the operation of rod photoreceptors in the normal, light-adapted human retina. / Deutsche Forschungsgemeinschaft (DFG) (KR1317/13-1) and Bundesministerium für Bildung und Forschung (BMBF) (01DN14009) provided financial support for JK.

Yes / The purpose of this paper is to demonstrate: 1) that silent substitution stimuli can be used generate electro-retinograms (ERGs) that effectively isolate rod photoreceptor function in humans without the need for dark adaptation and 2) that this approach constitutes a viable alternative to current clinical standard testing protocols. Rod-isolating and non-isolating sinusoidal flicker stimuli were generated on a 4 primary LED ganzfeld stimulator to elicit ERGs from non-dark adapted participants with normal and compromised rod function. Responses were subjected to Fourier analysis and the amplitude and phase of the fundamental were used to examine temporal frequency and retinal illuminance response characteristics. ERGs elicited by rod isolating silent substitution stimuli exhibit low-pass temporal frequency response characteristics with an upper response limit of 30Hz. Responses are optimal between 5 – 8 Hz and between 10-100 photopic Td. There is a significant correlation between the response amplitudes obtained with the silent substitution method and current standard clinical protocols. Analysis of signal to noise ratios reveals significant differences between subjects with normal and compromised rod function. Silent substitution provides an effective method for the isolation of human rod photoreceptor function in subjects with normal as well as compromised rod function when stimuli are used within appropriate parameter ranges. Translational Relevance: This method of generating rod ERGs rod isolation can be achieved without time consuming periods of dark adaptation and provides improved isolation of rod- from cone-based activity and will lead to the development of faster clinical electro-physiological testing protocols with improved selectivity.

Retinal degeneration is the progressive loss of neurons lining the posterior surface of the eye. Loss of a certain group of neurons called rod photoreceptors can occur as the result of genetic mutation. In humans, and in mammalian models of retinal degeneration, the death of these cells is permanent, and often followed by cone photoreceptor death, which leads to blindness. As a step towards understanding the implications of rod cell death in the retina, we generated transgenic X. laevis that expressed a novel form of caspase-9, with binding domains specific to the compound AP20187. We treated these transgenic animals with AP20187 and caused rod cell death by apoptosis in tadpoles and post metamorphic animals. Peak rod apoptosis occurred two days after drug exposure. We adapted an electroretinography apparatus, and protocols designed for mammals to measure functional changes in X. laevis rod and cone derived responses. We observed delayed secondary cone cell dysfunction after induced rod cell apoptosis, which was subsequently restored. These animals provide a simple and clinically relevant model of diseases like Retinitis pigmentosa, in which we will be able to probe in detail the mechanisms that govern cone cell dysfunction as a consequence of rod apoptosis. The unique ability of this species to recover from this insult will provide clues towards initiating similar recovery in humans.

Recently, a novel optical imaging technique was successfully used in measuring the functional response of living retinal tissues. The technique, functional ultra high resolution optical coherence tomography, measures localized differential changes in the retina reflectivity over time resulting from external white light stimulation. This result can be used to develop a non-invasive diagnostic method for the early detection of retinal diseases. However, the physiological causes of the experimentally observed optical signals, most of which originate from the photoreceptors layer, are still not well understood. Due to the complexity of the photoreceptors, using purely experimental methods to isolate the changes in light reflectivity corresponding to individual physiological processes is not feasible. Therefore, we have employed the finite-difference time-domain method to model the changes in light scattering patterns of the photoreceptor cells caused by light-induced physiological processes. Processes such as cell swelling, cell elongation and hyperpolarization of doublelipid membrane structures were simulated by changing the size parameters and optical properties of the cells components. Simulation results show that the hyperpolarization of double-lipid membranous structures and cell swelling are the most likely causes for the experimentally observed changes in optical reflectivity. A number of experiments were suggested to verify the conclusions drawn from this numerical work. This numerical work includes an analysis of various errors in FDTD computational models.

Recently, a novel optical imaging technique was successfully used in measuring the functional response of living retinal tissues. The technique, functional ultra high resolution optical coherence tomography, measures localized differential changes in the retina reflectivity over time resulting from external white light stimulation. This result can be used to develop a non-invasive diagnostic method for the early detection of retinal diseases. However, the physiological causes of the experimentally observed optical signals, most of which originate from the photoreceptors layer, are still not well understood. Due to the complexity of the photoreceptors, using purely experimental methods to isolate the changes in light reflectivity corresponding to individual physiological processes is not feasible. Therefore, we have employed the finite-difference time-domain method to model the changes in light scattering patterns of the photoreceptor cells caused by light-induced physiological processes. Processes such as cell swelling, cell elongation and hyperpolarization of doublelipid membrane structures were simulated by changing the size parameters and optical properties of the cells components. Simulation results show that the hyperpolarization of double-lipid membranous structures and cell swelling are the most likely causes for the experimentally observed changes in optical reflectivity. A number of experiments were suggested to verify the conclusions drawn from this numerical work. This numerical work includes an analysis of various errors in FDTD computational models.