Concluding remarks on the Lasker/IRRF initiative on amblyopia.

All agree that amblyopia is a disorder that affects visual structures beyond the eye. Many simply say that amblyopia is a brain disorder. But the retina is part of the brain, pushed out into the eye during development. As someone who has long studied the retina, I wonder if the retina is at all affected. At first glance, retinal function appears normal in amblyopia, but is it totally unaltered? I am not convinced, but as yet, nothing of significance has been shown in this regard. The reasons I suggest this are three fold: first, there are centrifugal fibers from higher visual structures that innervate the retina and alterations in higher visual pathways could very well affect the retina. Second, as noted many times in this report, there are many visual deficits that occur in amblyopia—it is not just a defect in visual acuity but in contrast sensitivity, accommodation, fixation, binocularity, and so forth. Third, some visual alterations are seen in the other eye in unilateral amblyopia and suggest to me that a closer examination of retinal function in amblyopia might be useful to undertake. I am not suggesting that retinal changes are the major alterations in amblyopia; clearly, the major effects of amblyopia are manifest in the cortex. But where in the cortex? Beginning in area V1 but certainly in higher visual areas as well and even, probably, in other nonvisual areas. The bottom line is that amblyopia is a very complex disorder consisting of several different forms, each of which is expressed somewhat differently. Today, throughout the world, we are focusing enormous effort on studies of the brain structure and function, and many of the major issues regarding how the brain functions are the front and center in amblyopia research. In other words, findings in amblyopia research are instructive in terms of understanding the brain function and vice versa. A prime example is that of brain plasticity—how hard wired are our brains? Our views on this have changed dramatically over the past half century, beginning with the pioneering studies of Wiesel and Hubel on monocular visual deprivation in cats and monkeys. Dramatic changes in structure and function occur in area V1 of the cortex often after just a relatively short period of deprivation. And as was learned from the clinic, the changes in amblyopia occur most dramatically in the young, during the so-called critical period. It was also recognized in the clinic that if recovery was to be achieved, it happened most readily by interventions in the critical period. All of the above are certainly correct, but what has changed is our understanding of critical periods—when the nervous system is modifiable. Whereas it was once viewed that the critical period was finite, we now recognize that it is not. Brain plasticity can occur all of our lives, although as we grow older it does decline. As described in several of the reviews in this volume, critical periods can be extended and even reopened by various manipulations, by the administration of drugs and other neuroactive substances, by brain stimulation and even by environmental and behavioral treatments. Further, we now recognize that various visual phenomena have different critical periods in terms of timing. All of this research is beginning to have a clinical impact. It was believed that recovery from amblyopia in humans could not happen in adulthood; however, this view has now softened, and various approaches to this possibility are being explored. Clearly, there is great variability in the response of older individuals to these therapies, so we still have much to learn. That our brain circuitry can be altered throughout our lives by neurons growing new dendrites and forming new synapses, research pioneered by visual deprivation studies, has an impact far beyond amblyopia. Indeed, our view today is that the brain is continually changing by everything we do and experience. A paradigm shift in our thinking, it has immense implications on understanding how the brain develops, how it ages, and on how we treat various brain disorders and degenerative diseases. We hope this report will be useful not only for those studying amblyopia but for brain science in general. PersPective