Sunday, May 11, 2025
5/11/2025
Binocular Coordination of Eye Movements - Abstract High visual acuity, binocular alignment and binocular coordination of eye movements are important in foveate species and are susceptible to visual development disruptions leading to enormous negative impact on public health and the economy. Thus, developmental loss of sensory or motor fusion leads to ocular misalignment (strabismus) and associated binocular oculomotor disturbances in as much as 5% of all children and amblyopia is the leading cause of monocular visual impairment in the U.S., disabling over two million children. In Aim 1, we investigate how strabismic subjects orient their eyes to visual targets within their environment. We will build upon our recent work, recording from the superior colliculus in non-human primate models for strabismus, that has focused on a curious gaze orienting behavior, wherein under binocular viewing, many strabismic subjects choose their eye of fixation depending upon location of the eccentric visual target. In the proposed experiments, we will investigate the contribution of a critical area for visual target selection, the Frontal Eye Fields and use a unique stimulus (the double-step paradigm) to test the validity of a competition framework as the basis for gaze orienting behavior in alternating strabismus. In Aim 2, we will test, in the monkey, an innovative new therapeutic approach to treat MD amblyopia that has demonstrated remarkable recovery of vision in the MD eye, involving temporarily inactivating the fellow eye by intravitreal injection of a low volume of low concentration tetrodotoxin (TTX). If TTX therapy were shown to be an effective and safe substitute for patching therapy, it would foster a revolutionary advance in treatment of amblyopia. Following induction of amblyopia via MD in infant NHP, TTX will be injected into the vitreous cavity of the good eye. Rigorous vision testing will be performed after MD to establish the severity of amblyopia and repeated after TTX treatment to test treatment efficacy. Within this specific aim, we will also determine whether TTX microinjection is safe and has no permanent effects on eye function or structure. Our approach to investigating parameter space will include experiments in animals at two ages (within and outside the critical period), at two dosage levels and with two frequencies of application. Control experiments will include sham injections and a reverse occlusion cohort. Before and after each round of TTX injection, visual function testing will be conducted, including visual acuity evaluation via VEP or CSF testing, testing of stereo function, evaluation of the pupil, refraction, ERG, bio-microscopy, biometry, and OCT retinal nerve fiber layer/optic nerve imaging. Finally histologic evaluation of the eyes will evaluate any evidence of TTX-induced damage and histological evaluation of brain will evaluate support for amblyopia recovery. Thus, each of the two aims leverage our unique expertise in working with monkey models for visual development disorders and is likely to significantly advance understanding of mechanisms underlying neural circuitry. Moreover, this project has the potential to help guide the development of rationally based therapies for amblyopia.
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