Lynne Kiorpes

Neuronal Correlates of Amblyopia in the Visual Cortex of Macaque Monkeys with Experimental Strabismus and Anisometropia

Amblyopia is a developmental disorder of pattern vision. After surgical creation of esotropic strabismus in the first weeks of life or after wearing −10 diopter contact lenses in one eye to simulate anisometropia during the first months of life, macaques often develop amblyopia. We studied the response properties of visual cortex neurons in six amblyopic macaques; three monkeys were anisometropic, and three were strabismic. In all monkeys, cortical binocularity was reduced. In anisometropes, the amblyopic eye influenced a relatively small proportion of cortical neurons; in strabismics, the influence of the two eyes was more nearly equal. The severity of amblyopia was related to the relative strength of the input of the amblyopic eye to the cortex only for the more seriously affected amblyopes. Measurements of the spatial frequency tuning and contrast sensitivity of cortical neurons showed few differences between the eyes for the three less severe amblyopes (two strabismic and one anisometropic). In the three more severely affected animals (one strabismic and two anisometropic), the optimal spatial frequency and spatial resolution of cortical neurons driven by the amblyopic eye were substantially and significantly lower than for neurons driven by the nonamblyopic eye. There were no reliable differences in neuronal contrast sensitivity between the eyes. A sample of neurons recorded from cortex representing the peripheral visual field showed no interocular differences, suggesting that the effects of amblyopia were more pronounced in portions of the cortex subserving foveal vision. Qualitatively, abnormalities in both the eye dominance and spatial properties of visual cortex neurons were related on a case-by-case basis to the depth of amblyopia. Quantitative analysis suggests, however, that these abnormalities alone do not explain the full range of visual deficits in amblyopia. Studies of extrastriate cortical areas may uncover further abnormalities that explain these deficits.

Neural mechanisms underlying amblyopia.

The nature of the neural basis of amblyopia is a matter of some debate. Recent neurophysiological data show correlates of amblyopia in the spatial properties of neurons in primary visual cortex. These neuronal deficits are probably the initial manifestation of the visual loss, but there are almost certainly additional deficits at higher levels of the visual pathways.

Visual Processing in Amblyopia: Animal Studies

In the past five years, substantial progress has been made in our knowledge of the neural basis of amblyopia. Recent advances based on animal models are described, along with new psychophysical data showing perceptual deficits in amblyopic animals that are not explained by simple losses in contrast sensitivity. Studies of contour integration and integration of motion and form signals in the presence of noise show that 1) there are fundamental losses in temporal as well as spatial vision, 2) the losses extend to the fellow eye in many cases, 3) amblyopic animals are especially impaired in the presence of background noise, and 4) these losses must depend on a process downstream from area V1 in the extrastriate cortex.

Does experimentally-induced amblyopia cause hyperopia in monkeys?

We assessed refractive errors in 19 monkeys (Macaca nemestrina) raised with experimentally produced strabismus or unilateral defocus. These procedures resulted in hyperopic anisometropia in 10 monkeys. All 10 of the hyperopic animals were amblyopic; the amblyopic eye was always the more hyperopic eye. The degree of anisometropia was correlated with the degree of amblyopia. Hyperopic anisometropia did not develop in non-amblyopic animals. There was an association between early onset of visual abnormality and later development of hyperopic anisometropia. Since the refractive changes were correlated with changes in axial length and vitreous chamber depth, we suggest that amblyopia may cause alterations in eye growth and late-onset hyperopia.

Contrast sensitivity and vernier acuity in amblyopic monkeys

Human psychophysical studies suggest that strabismic and anisometropic amblyopes may have characteristically different patterns of visual loss. In particular, anisometropic amblyopes often show deficits on spatial localization tasks that scale with their spatial resolution losses, whereas strabismic amblyopes can show localization deficits that are large relative to their losses in spatial resolution. We have compared the performance of non-human primates with experimentally-induced anisometropic and strabismic amblyopia on contrast detection and vernier acuity tasks. The performance of both groups of animals was fundamentally similar: both strabismic and anisometropic monkeys showed deficits in spatial localization that were large relative to their resolution losses, although the animals with the most disproportionate losses were strabismic. We investigated the extent to which contrast sensitivity losses accounted for the vernier acuity deficits. The results showed that, in most cases of either strabismic or anisometropic amblyopia, when the vernier stimuli for each eye were equated in terms of effective contrast, the extent of the vernier acuity deficit was reduced to approximately the extent of the spatial resolution deficit. In two cases, both of strabismic amblyopia, we found that equating the stimuli in this way was not sufficient to make the deficits equal, a pattern that has been described for human strabismic amblyopes.

Development of vernier acuity and grating acuity in normally reared monkeys

The developmental time courses for vernier acuity and grating acuity were measured longitudinally in infant Macaca nemestrina monkeys. Behavioral measurements of vernier and grating acuity were made at regular intervals during development. Near birth, grating acuity is relatively more mature than vernier acuity. The proportional rate of vernier acuity development is faster than that for grating acuity. During the course of development, grating acuity improves approximately 15-fold whereas vernier acuity improves about 60-fold. Both visual functions approach adult levels at about the same age, around 40 weeks postnatally. Although grating acuity develops about four times faster in monkeys than in humans, vernier acuity development in monkeys and humans does not appear to reflect the same relationship. Adult levels of vernier acuity for the monkeys are about a factor of 2 poorer than are typically reported for humans. The differential development of vernier acuity and grating acuity does not necessarily reflect development at different levels of the visual system.

Operant measurements of contrast sensitivity in infant macaque monkeys during normal development.

The development of contrast sensitivity was measured longitudinally in seven Macaca nemestrina monkeys. Operant conditioning methods were used to train and then test infant monkeys from the ages of 1 to 12 months. Several changes were observed in the contrast sensitivity function, including an overall increase in sensitivity to contrast, a shift in the peak of the function toward higher spatial frequencies, and an increase in the cutoff spatial frequency. The time-courses for the changes in the contrast sensitivity function were characterized by rapid development during the first 10-20 weeks, followed by a gradual asymptotic development to adult levels over the remainder of the year. Sensitivity to contrast was found to develop with different time-courses for different spatial frequencies; sensitivity to low spatial frequencies reached adult levels much earlier than sensitivity to high spatial frequencies.

Visual Motion Processing by Neurons in Area MT of Macaque Monkeys with Experimental Amblyopia

Early experience affects the development of the visual system. Ocular misalignment or unilateral blur often causes amblyopia, a disorder that has become a standard for understanding developmental plasticity. Neurophysiological studies of amblyopia have focused almost entirely on the first stage of cortical processing in striate cortex. Here we provide the first extensive study of how amblyopia affects extrastriate cortex in nonhuman primates. We studied macaque monkeys (Macaca nemestrina) for which we have detailed psychophysical data, directly comparing physiological findings to perceptual capabilities. Because these subjects showed deficits in motion discrimination, we focused on area MT/V5, which plays a central role in motion processing. Most neurons in normal MT respond equally to visual stimuli presented through either eye; most recorded in amblyopes strongly preferred stimulation of the nonamblyopic (fellow) eye. The pooled responses of neurons driven by the amblyopic eye showed reduced sensitivity to coherent motion and preferred higher speeds, in agreement with behavioral measurements. MT neurons were more limited in their capacity to integrate motion information over time than expected from behavioral performance; neurons driven by the amblyopic eye had even shorter integration times than those driven by the fellow eye. We conclude that some, but not all, of the motion sensitivity deficits associated with amblyopia can be explained by abnormal development of MT.

Contour integration in amblyopic monkeys

Amblyopia is characterized by losses in a variety of aspects of spatial vision, such as acuity and contrast sensitivity. Our goal was to learn whether those basic spatial deficits lead to impaired global perceptual processing in strabismic and anisometropic amblyopia. This question is unresolved by the current human psychophysical literature. We studied contour integration and contrast sensitivity in amblyopic monkeys. We found deficient contour integration in anisometropic as well as strabismic amblyopic monkeys. Some animals showed poor contour integration in the fellow eye as well as in the amblyopic eye. Orientation jitter of the elements in the contour systematically decreased contour-detection ability for control and fellow eyes, but had less effect on amblyopic eyes. The deficits were not clearly related to basic losses in contrast sensitivity and acuity for either type of amblyopia. We conclude that abnormal contour integration in amblyopes reflects disruption of mechanisms that are different from those that determine acuity and contrast sensitivity, and are likely to be central to V1.

Sensitivity to visual motion in amblyopic macaque monkeys.

Amblyopia is usually considered to be a deficit in spatial vision. But there is evidence that amblyopes may also suffer specific deficits in motion sensitivity as opposed to losses that can be explained by the known deficits in spatial vision. We measured sensitivity to visual motion in random dot displays for strabismic and anisometropic amblyopic monkeys. We used a wide range of spatial and temporal offsets and compared the performance of the fellow and amblyopic eye for each monkey. The amblyopes were severely impaired at detecting motion at fine spatial and long temporal offsets, corresponding to fine spatial scale and slow speeds. This impairment was also evident for the untreated fellow eyes of strabismic but not anisometropic amblyopes. Motion sensitivity functions for amblyopic eyes were shifted toward large spatial scales for amblyopic compared to fellow eyes, to a degree that was correlated with the shift in scale of the spatial contrast sensitivity function. Amblyopic losses in motion sensitivity, however, were not correlated with losses in spatial contrast sensitivity. This, combined with the specific impairment for detecting long temporal offsets, reveals a deficit in spatiotemporal integration in amblyopia which cannot be explained by the lower spatial resolution of amblyopic vision.