Ronald G. Boothe - US grants

eye coordination disorder; amblyopia; vision disorders; animal developmental psychology; infant animal; vision tests; biological models;

The objective of this research is to develop and study nonhuman primate models of strabismus. Four specific monkey models are proposed: 1) surgical, 2) optical, 3) neurotoxin, and 4) natural. Each monkey model will be tested behaviorally to determine what impairments in visual functions result from the strabismus. Specific impairments to the looked for are amblyopia and loss of binocular stereoscopic vision. Experiments are designed to determine both the magnitude of any impairments and also the time course over which they develop. These measurements will be used to provide information about the "sensitive period" associated with strabismus. Macaque monkeys are chosen as the model species because information about sensitive periods can be extrapolated to humans with more confidence than from any non primate model.

model design /development; amblyopia; lens disorder;

Until recently, unilateral infantile cataracts were considered to be untreatable because lack of form or pattern vision during the early postnatal months inevitably resulted in profound, irreversible amblyopia from unbalanced visual inputs. However, in recent years a number of laboratory and clinical reports have indicated that it might be possible to maintain functional vision in these eyes by prompt surgical removal of the cataract, correction of the resulting aphakia, and aggressive occlusion of the opposite eye. We have developed a monkey model with which we can study these treatments. We conduct a lensectomy shortly after birth on deeply anesthetized monkeys using sterile procedures similar to those that would be used with human babies. Then we fit the infant monkeys with extended-wear contact lenses that are manufactured in our own laboratory specifically for infant monkey eyes. Some contact lenses provide an optical correction to the eye, allowing that eye to see more clearly. Other lenses defocus, diffuse, or occlude light, thus forcing the animal to use its opposite eye. Studies conducted in our laboratories have determined that continuous occlusion for long periods is always detrimental to visual function in the occluded eye and often leads to ocular misalignment. Therefore, our current research focus is on treatments that involve either minimal occlusion or no occlusion. Complete ophthalmic examinations are conducted on our animals at regular intervals to document the clinical status of our treatment groups. Behavioral outcome measures include assessments of visual functions including acuity, contrast sensitivity, spatial localization, spatial phase sensitivity, and extent of the visual fields. Visually evoked potentials (VEPs) will also be measured periodically and related to the behavior results. At the end of the rearing period, neuroanatomical studies will be conducted so that each treatment paradigm can be evaluated in terms of the correlations between visual function and central nervous system changes. The results of these studies will provide direct information about deficits in the central visual pathways that result from infantile aphakia in monkeys. These results can also be extrapolated to human infants with aphakic amblyopia because of the close similarities of macaque monkey and human visual systems. Therefore, our studies have direct clinical relevance for devising treatments of human infants who are born with unilateral cataracts.

DESCRIPTION: The aphakic amblyopia that develops in children after the removal of a cataract is particularly difficult to treat. One reason for the recalcitrance to respond to treatment is the early onset of the deprivation: the developing infant's brain has little opportunity to experience the normal binocular stimulation that is needed for proper development of the visual system. The objectives of this project are to understand the neural bases for this and related disorders and, ultimately, to design treatments for amblyopia that are based on sound scientific knowledge. Systematic studies of infant monkeys with extended wear contact lenses that simulate certain aspects of the visual deprivation experienced by children with an early onset infantile cataract corroborate the clinical findings in children that no schedules of patching, even those that maintain relatively good acuity, are successful at maintaining normal binocular function in these children. The proposed studies are designed specifically to better understand the neural mechanisms involved in the loss of binocular function. The primary probe will be a neurological deficit involving motion processing that is linked to loss of binocular function following neonatal deprivation. A combination of behavioral, electrophysiological and anatomical methods will be used to correlate the behavioral deficits to alterations in specific neural subsystems of the brain and to test specific hypotheses about the underlying neurodevelopmental mechanisms. The results will provide direct information about alterations in the central visual pathways of monkeys following early visual deprivation that can also be extrapolated to human infants with aphakic amblyopia, because of the close similarities between this condition as it occurs naturally in humans and experimentally in our monkeys.

The overall goal of this project is to discover better ways to prevent and treat conditions that lead to blinding disorders in human children. We focus on neural and behavioral abnormalities associated with conditions such as congenital cataracts that occur during the neonatal period. During the past year we have continued to study abnormalities in motion processing, oculomotor behavior, and regulation of eye growth that occur following neonatal visual deprivation, but not during visual deprivation initiated somewhat later during postnatal development. These include abnormal growth of the eye leading to anisometropia, and asymmetrical responses to horizontal motion as assessed with visually evoked potentials and oculomotor measures. Monkeys reared under conditions of neonatal visual deprivation in previous years continue to be studied for the long-term presence of all of these disorders. Five new animals were reared under conditions of restricted binocular expo sure duri ng the past year, and those infants will be tested with ophthalmological, electrophysiological, psychophysical, and oculomotor methods during the coming year. FUNDING NIH EY05975 $166,645 7/1/95 - 6/30/00 PUBLICATIONS Boothe, R.G. and Fulton, A.B. Amblyopia. In Principles and Practice of Ophthalmology, 2nd Edition, D.M. Albert and F.A. Jakobiec (Eds.), W.B. Saunders Company, (In press). Bradley, D.V., Fernandes, A., Lynn, M., Tigges, M. and Boothe, R.G. Emmetropization in the rhesus monkey (Macaca mulatta) Birth to young adulthood. Invest. Ophthalmol. Vis. Sci. (In press). Bradley, D.V., Fernandes, A. and Boothe, R.G. The refractive development of untreated eyes of rhesus monkeys varies according to the treatment received by their fellow eyes. Vision Res. (In press). Brown, R.J., Wilson, J.R., Norcia, A.M. and Boothe, R.G. Development of directional motion symmetry in the monocular visually evoked potential of infant monkeys. Vision Res. 38:1253-1263, 1998. Wilson, J.R., Noyd, W.W., Aiyer, A.D., Norcia, A.M., Mustari, M.J. and Boothe, R.G. Asymmetric responses in cortical visually evoked potentials to motion are not derived from eye movements. Invest. Ophthalmol. Vis. Sci. (In press). P51RR00165-38 1/1/98 - 12/31/98 Yerkes Regional Primate Research Center

transplantation; psychology; prosthesis; growth factor; congenital disorders; Mammalia; Primates; eye; nervous system; behavioral /social science research tag;