Ophthalmology seminars

Photoreceptor loss is the primary cause behind vision impairment and blindness in diseases such as retinitis pigmentosa and age-related macular degeneration. However, the death of rods and cones allows retinoids to permeate the inner retina, causing retinal ganglion cells to become spontaneously hyperactive, severely reducing the signal-to-noise ratio, and creating interference in the communication between the surviving retina and the brain. Treatments aimed at blocking or reducing hyperactivity improve vision initiated from surviving photoreceptors and could enhance the signal fidelity generated by vision restoration methodologies.

Among all prevalent diseases with a central neurodegeneration, AMD can be considered the most promising in terms of prevention and early intervention, due to several factors surrounding the neural geometry of the foveal singularity. • Steep gradients of cell density, deployed in a radially symmetric fashion, can be modeled with a difference of Gaussian curves. • These steep gradients give rise to huge, spatially aligned biologic effects, summarized as the Center of Cone Resilience, Surround of Rod Vulnerability. • Widely used clinical imaging technology provides cellular and subcellular level information. • Data are now available at all timelines: clinical, lifespan, evolutionary • Snapshots are available from tissues (histology, analytic chemistry, gene expression) • A viable biogenesis model exists for drusen, the largest population-level intraocular risk factor for progression. • The biogenesis model shares molecular commonality with atherosclerotic cardiovascular disease, for which there has been decades of public health success. • Animal and cell model systems are emerging to test these ideas.

Abstract to follow.

Ophthalmology is ideally placed to benefit from recent advances in artificial intelligence. It is a highly image-based specialty and provides unique access to the microvascular circulation and the central nervous system. This talk will demonstrate diverse applications of machine learning and deep learning techniques in ophthalmology, including in age-related macular degeneration (AMD), the leading cause of blindness in industrialized countries, and cataract, the leading cause of blindness worldwide. This will include deep learning approaches to automated diagnosis, quantitative severity classification, and prognostic prediction of disease progression, both from images alone and accompanied by demographic and genetic information. The approaches discussed will include deep feature extraction, label transfer, and multi-modal, multi-task training. Cluster analysis, an unsupervised machine learning approach to data classification, will be demonstrated by its application to geographic atrophy in AMD, including exploration of genotype-phenotype relationships. Finally, mediation analysis will be discussed, with the aim of dissecting complex relationships between AMD disease features, genotype, and progression.

Deep learning techniques have revolutionized the field of image analysis and played a disruptive role in the ability to quickly and efficiently train image analysis models that perform as well as human beings. This talk will cover the beginnings of the application of deep learning in the field of ophthalmology and vision science, and cover a variety of applications of using deep learning as a method for scientific discovery and latent associations.

My research uses electrophysiological techniques to evaluate normal retinal function, dysfunction caused by blinding retinal diseases and the restoration of function using a variety of therapeutic strategies. We can use our understanding or normal retinal function and disease-related changes to construct optimal therapeutic strategies and evaluate how they ameliorate the effects of disease. Retinitis pigmentosa (RP) is a family of blinding eye diseases caused by photoreceptor degeneration. The absence of the cells that for this primary signal leads to blindness. My interest in RP involves the evaluation of therapies to restore vision: replacing degenerated photoreceptors either with: (1) new stem or other embryonic cells, manipulated to become photoreceptors or (2) prosthetics devices that replace the photoreceptor signal with an electronic signal to light. Glaucoma is caused by increased intraocular pressure and leads to ganglion cell death, which eliminates the link between the retinal output and central visual processing. We are parsing out of the effects of increased intraocular pressure and aging on ganglion cells. Congenital Stationary Night Blindness (CSNB) is a family of diseases in which signaling is eliminated between rod photoreceptors and their postsynaptic targets, rod bipolar cells. This deafferents the retinal circuit that is responsible for vision under dim lighting. My interest in CSNB involves understanding the basic interplay between excitation and inhibition in the retinal circuit and its normal development. Because of the targeted nature of this disease, we are hopeful that a gene therapy approach can be developed to restore night vision. My work utilizes rodent disease models whose mutations mimic those found in human patients. While molecular manipulation of rodents is a fairly common approach, we have recently developed a mutant NIH miniature swine model of a common form of autosomal dominant RP (Pro23His rhodopsin mutation) in collaboration with the National Swine Resource Research Center at University of Missouri. More genetically modified mini-swine models are in the pipeline to examine other retinal diseases.

John DowlingJohn E. Dowling received his AB and PhD from Harvard University. He taught in the Biology Department at Harvard from 1961 to 1964, first as an Instructor, then as assistant professor. In 1964 he moved to Johns Hopkins University, where he held an appointment as associate professor of Ophthalmology and Biophysics. He returned to Harvard as professor of Biology in 1971, was the Maria Moors Cabot Professor of Natural Sciences from 1971-2001, Harvard College professor from 1999-2004 and is presently the Gordon and Llura Gund Professor of Neurosciences. Dowling was chairman of the Biology Department at Harvard from 1975 to 1978 and served as associate dean of the faculty of Arts and Sciences from 1980 to 1984. He was Master of Leverett House at Harvard from 1981-1998 and currently serves as president of the Corporation of The Marine Biological Laboratory in Woods Hole. He is a Fellow of the American Academy of Arts and Sciences, a member of the National Academy of Sciences and a member of the American Philosophical Society. Awards that Dowling received include the Friedenwald Medal from the Association of Research in Ophthalmology and Vision in 1970, the Annual Award of the New England Ophthalmological Society in 1979, the Retinal Research Foundation Award for Retinal Research in 1981, an Alcon Vision Research Recognition Award in 1986, a National Eye Institute's MERIT award in 1987, the Von Sallman Prize in 1992, The Helen Keller Prize for Vision Research in 2000 and the Llura Ligget Gund Award for Lifetime Achievement and Recognition of Contribution to the Foundation Fighting Blindness in 2001. He was granted an honorary MD degree by the University of Lund (Sweden) in 1982 and an honorary Doctor of Laws degree from Dalhousie University (Canada) in 2012. Dowling's research interests have focused on the vertebrate retina as a model piece of the brain. He and his collaborators have long been interested in the functional organization of the retina, studying its synaptic organization, the electrical responses of the retinal neurons, and the mechanisms underlying neurotransmission and neuromodulation in the retina. Dowling became interested in zebrafish as a system in which one could explore the development and genetics of the vertebrate retina about 20 years ago. Part of his research team has focused on retinal development in zebrafish and the role of retinoic acid in early eye and photoreceptor development. A second group has developed behavioral tests to isolate mutations, both recessive and dominant, specific to the visual system.

Electrophysiology of eye and visual pathway is useful tool in ophthalmology and neurology. It covers a few examinations to find out if defect of vision is peripheral or central. Visual evoked potentials (VEP) are most frequently used in neurology and neuroophthalmology. VEP are evoked by flash or pattern stimulations. The combination of these both examinations gives more information about the visual pathway. It is very important to remember that VEP originate in the retina and reflect its function as well. In many cases not only VEP but also electroretinography (ERG) is essential for diagnosis. The seminar presents basic electrophysiological procedures used for diagnosis and follow-up of optic neuropathies and some of central nervous system diseases which affect vision (mostly multiple sclerosis, CNS tumors, stroke, traumas, intracranial hypertension).