Acuity-independent effects of visual deprivation on human visual cortex

Visual development depends on sensory input during an early developmental critical period. Deviation of the pointing direction of the two eyes (strabismus) or chronic optical blur (anisometropia) separately and together can disrupt the formation of normal binocular interactions and the development of spatial processing, leading to a loss of stereopsis and visual acuity known as amblyopia. To shed new light on how these two different forms of visual deprivation affect the development of visual cortex, we used event-related potentials (ERPs) to study the temporal evolution of visual responses in patients who had experienced either strabismus or anisometropia early in life. To make a specific statement about the locus of deprivation effects, we took advantage of a stimulation paradigm in which we could measure deprivation effects that arise either before or after a configuration-specific response to illusory contours (ICs). Extraction of ICs is known to first occur in extrastriate visual areas. Our ERP measurements indicate that deprivation via strabismus affects both the early part of the evoked response that occurs before ICs are formed as well as the later IC-selective response. Importantly, these effects are found in the normal-acuity nonamblyopic eyes of strabismic amblyopes and in both eyes of strabismic patients without amblyopia. The nonamblyopic eyes of anisometropic amblyopes, by contrast, are normal. Our results indicate that beyond the well-known effects of strabismus on the development of normal binocularity, it also affects the early stages of monocular feature processing in an acuity-independent fashion.Over 50 y of research on experimental animal models has indicated that deprivation of normal visual experience during a developmental critical period perturbs both the structure and function of primary visual cortex (1–4). The animal models were developed to understand the underlying neural mechanisms of amblyopia, a common human developmental disorder of spatial vision associated with the presence of strabismus, anisometropia, or form deprivation during early life (5). Amblyopia is classically defined on the basis of poor visual acuity, but many other visual functions are known to be affected (6–8).The earliest experimental studies of visual deprivation focused on the effects of monocular lid suture, and these studies showed devastating effects on the ability of the deprived eye to drive neural responses, retain synaptic connections, and guide visual behavior (9–11). Later work studied less extreme forms of deprivation that are common in humans, such as the effects of strabismus (deviation of the pointing direction of the two eyes) (12, 13) or anisometropia (chronic optical blur) (14, 15). More recent studies (16, 17) have found that losses in cell responses in primary visual cortex appear to be insufficient to explain the magnitude of behaviorally measured deficits. Based on these results, a hypothesis has been put forward that these forms of deprivation have their primary effects in extrastriate cortex (16).Motivated by this idea, psychophysicists have sought evidence that extrastriate cortex is particularly impaired in human amblyopia. This work has used tasks whose execution is fundamentally limited by processing resources that single-cell physiology suggests are located in extrastriate cortex. As a second step, these studies have scaled stimuli based on visual acuity and compensated for contrast sensitivity losses to equate the output of early visual cortex from the amblyopic eye to that of normal-vision participants. Despite a nominal match at the level of early visual cortex outputs, patients with amblyopia still show deficits on illusory tilt perception (18), contour integration (19–23), global motion sensitivity (8, 24–28), object enumeration (29), and object tracking (7, 30). The impairments listed above have been interpreted to indicate that amblyopia may involve abnormalities in “higher-level” (e.g., extrastriate) neural processing that occur independent of any deficits in early processing stages (e.g., in striate cortex). A limitation of the existing psychophysical approaches has been the need to make an assumption that the stimulus scaling used to equate stimuli for visibility fully equilibrates the activity of early visual cortex. It would be preferable to take an approach that allows one to measure neural responses directly from both early and later stages of visual processing. Here we use event-related potentials (ERPs) and a stimulation paradigm that allow us to record responses from both early visual cortex and higher-level, extrastriate areas.Our approach is similar in spirit to existing psychophysical approaches: We use a stimulus configuration—illusory contours (ICs)—that previous single-unit studies have shown to be first extracted in extrastriate cortex (31–34). ICs, also referred to as subjective contours, render object borders that are perceptually vivid but that are created in the absence of luminance contrast or chrominance gradients (35). ICs have been widely used to study mechanisms of scene segmentation and grouping operations that are among the most fundamental tasks the visual system has to perform (36). ICs have garnered considerable interest because of their “inferential” nature—despite the lack of luminance edges, the visual system uses implicit configural cues to infer the presence of a contour. Finally, behavioral investigations in macaque suggest that IC perception is strongly dependent on higher visual areas, including V4 (37, 38) and inferotemporal (IT) cortex (39, 40).Instead of attempting to equate the visibility of stimuli in the amblyopic eye to that of normal control eyes, as has been typical practice in the study of amblyopia, we make a close analysis of the effects of deprivation that is based on ERP responses from the nonamblyopic eyes of patients with anisometropic or strabismic amblyopia. These eyes have normal visual acuity and normal or even supernormal contrast sensitivity (41), making the stimuli nominally equivisible without the need for scaling. We then measure evoked responses at early latencies before the time that IC selectivity arises to assess the integrity of early visual cortex, and compare these responses to those measured at longer latencies after robust IC selectivity has been established. Previous single-unit studies that have used ICs of the type used in the present study indicate that they are first extracted no later than V2 (31, 42, 43) or V4 (34). Given the difference in species and stimuli, we will refer in the following to evoked responses that lack IC sensitivity as having arisen in “early” visual cortex, rather than in specific visual areas. To further specify the site of deprivation effects, we also study a group of stereo-blind patients with strabismus who do not have amblyopia (normal visual acuity in each eye).A second goal of our study is to compare the effects of deprivation from unilateral blur (anisometropia) to that caused by strabismus. The human psychophysical literature has made a distinction in the pattern of visual loss associated with strabismus versus that associated with anisometropia (44). At least some of the differences in performance between these two types of deprivation can be explained on the level of residual stereopsis, which typically differs between these two populations (41). Whenever these two types of deprivation have been compared in terms of their effects on the monocular cell properties of V1, there has been little to differentiate the effects of the two types of deprivation (16, 45, 46). Unfortunately, there are relatively few studies of the effects of critical period deprivation on the cell-tuning properties in extrastriate cortex of any species (15, 17, 47), and there has been no comparison of the effects of strabismus vs. anisometropia in extrastriate cortex. The implication of the existing animal literature is that strabismus and anisometropia have comparable effects on early visual cortex and thus the divergence in their behavioral phenotype, as well as the major effects of deprivation, will lie in extrastriate cortex. Here we show that these two types of deprivation have differential effects very early in visual cortex, possibly as early as the transfer of information from V1 to V2.