Amblyopia is a common disorder of neurodevelopment resulting from discordant binocular visual experience during the first years of life, affecting 2-3% of children. Randomized clinical trials (RCTs) show that current approaches to amblyopia treatment, most often patching the fellow eye, are effective in improving visual acuity. However, full recovery occurs in less than 50% of children. Standard-of-care patching treatment of amblyopia is effective but suffers from poor adherence, exhibits significant individual differences in response even when adherence is good, and fails to address the binocular dysfunction that is fundamental to amblyopia. There is a need for an alternative approach to occlusion therapy that improves adherence to maximize visual outcomes. Aim 1 will evaluate a novel, patch-free approach to occlusion therapy and determine whether it results in better adherence and visual acuity outcomes compared with patching in an RCT. Our patch-free treatment provides access to a variety of engaging activities for the child during occlusion time. Our hypothesis is that patch-free occlusion will lead to better adherence and better visual acuity improvement than standard-of-care patching. However, even excellent patching adherence does not ensure a good outcome; objectively monitored patching for200 hours resulted in visual acuity improvements ranging from 0.15-0.8 logMAR. Clearly, poor adherence is not the only factor influencing visual acuity outcome—other unidentified factors must contribute to individual differences. This argues for a personalized approach to amblyopia treatment, choosing among a variety of effective approaches to determine which works best for each child. In Aim 2, we propose to evaluate an alternative treatment approach based on spike-timing dependent plasticity (STDP) to shift the modification threshold for long-term potentiation (LTP). This neuroplasticity-based approach, prioritized in the NEI Strategic Plan, is targeted to strengthen amblyopic eye input to binocular neurons and improve not only visual acuity but also binocular function. In an RCT, we will determine whether this treatment results in better visual acuity and binocular outcomes compared with standard-of-care patching. Ourproposed clinical trials include anumber of technological innovations. Our conceptual approach is novel in that we not only evaluate vision outcomes, but also look at the effects of treatment on the whole child, including motor skills, self-perception, and quality of life.