Neuronal correlates of amblyopia in the visual cortex of macaque monkeys with experimental strabismus and anisometropia

Abstract

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.

Fig. 1.

Spatial contrast sensitivity functions for a normally reared control monkey (A) and for six amblyopic monkeys (B, C). In each panel, data from the nonamblyopic eye are represented by filled symbols, and data from the amblyopic eye are represented byopen symbols. The smooth curves represent the function described in the text; these curves were used to estimate the optimal spatial frequency, peak contrast sensitivity, and spatial resolution (the spatial frequency at which extrapolated sensitivity falls to 1). The number at the bottom left of each panel is the value of an amblyopia index, calculated by taking the area between the two fitted functions (plotted on linear frequency and logarithmic sensitivity coordinates) and dividing it by the area under the function for the nonamblyopic eye. The data shown for LF and OC were collected at a luminance of 250 cd/m²; the other data were collected at 60 cd/m².

Fig. 2.

Amblyopia index as a function of age for the six amblyopic monkeys. Each monkey is represented by a different symbol (filled, strabismics; open, anisometropes); points connected by solid lines are repeated measures for the same monkey. Isolated pointson the right show the age at recording for each animal; the amblyopia indices for these points are those shown in Figure 1, which are from the age closest to recording.

Fig. 3.

Distributions of cortical eye dominance from eight control monkeys (A) and from the six amblyopic monkeys (B, C). Eye dominance is represented using the seven-point scale of Hubel and Wiesel (1962). For the control monkeys, group 1 represents dominance by the contralateral eye (C), and group 7 represents dominance by the ipsilateral eye (I). For the amblyopic monkeys, data collected from the two hemispheres are combined so that group 1 represents dominance by the treated eye (T) and group 7 represents dominance by the untreated eye (U). The tophistograms in B and C show distributions pooled across the three monkeys in each group; the bottom small histograms show the individuals’ data. Only neurons with receptive fields representing the central visual fields are included; 76 units recorded from the representation of the peripheral visual field in monkey FT are excluded. In monkey FP, 35 units recorded in V2 are included; these were statistically indistinguishable from 62 other units recorded in V1. All other recordings were from V1.

Fig. 4.

The proportion of units dominated by the amblyopic eye is plotted against an amblyopia index (a measure of the severity of amblyopia that is described earlier). The normal situation is indicated by the open square; the value of the amblyopia index for three normal monkeys was 0.024, 0.061, and 0.074. Data from the strabismic monkeys in this study are shown by filled circles; data from anisometropic monkeys are shown byopen circles. Also included are data from three more profoundly amblyopic monkeys in which we measured cortical eye dominance (crosses) (Fenstemaker et al., 1997). Substantial amblyopia can evidently occur with or without a shift in cortical eye dominance, but the most severe amblyopes experienced a loss of effective input from the amblyopic eye.

Fig. 5.

Data from a complex cell recorded in an anisometropic monkey (OC). For this binocularly activated unit, quantitative data were measured with stimulation of each eye. Data taken through the amblyopic eye are shown by open symbols, and data taken from the nonamblyopic eye are shown byfilled symbols. A, Orientation and direction selectivity measured with high-contrast drifting gratings whose orientation was orthogonal to the direction plotted; the spatial and temporal frequencies were optimal for the eye being tested.B, Spatial frequency tuning measured with high-contrast gratings of optimal orientation, direction, and temporal frequency.C, Temporal frequency tuning measured with high-contrast gratings of optimal orientation and spatial frequency.D, Contrast response measured with gratings of optimal orientation and spatial and temporal frequency. Error bars indicate SE of the mean spike count per stimulus cycle. Dashed linesindicate spontaneous activity.

Fig. 6.

Spatial frequency tuning and contrast sensitivity data for neurons recorded from the three strabismic monkeys. Data for the amblyopic eye are shown in red, and data for the nonamblyopic eye are shown in green. A, Scatter diagrams in which each neuron is represented by a point plotted at its optimal spatial frequency and contrast sensitivity (i.e., the inverse of its threshold contrast). Bars on the abscissa and ordinate indicate the interquartile ranges (i.e., the bounds of the central 50% of the observed values) for each eye. B, Distributions of optimal spatial frequency, contrast sensitivity, and spatial resolution for neurons tested through each eye. The boundary between adjacent pairs of bins represents the center of the class interval. The three monkeys’ data are ordered vertically in the same way as in Figure 1B. For monkey FT, only data obtained from foveal recordings are included.

Fig. 7.

Spatial frequency tuning and contrast sensitivity data for neurons recorded from the three anisometropic monkeys. Data for the amblyopic eye are shown in red, and data for the nonamblyopic eye are shown in green; the format is identical to Figure 6. The three monkeys’ data are ordered vertically in the same way as in Figure 1C. For monkey FP, 35 units recorded in V2 are included; these were statistically indistinguishable in their properties from the 67 other units recorded from V1.

Fig. 8.

Diagrams in the format of Figure 6 and 7representing data from units recorded in strabismic monkey FT from the representation of the peripheral visual field in V1. The receptive fields of these units were located in the lower visual quadrant, between 16 and 23° from the fovea.

Fig. 9.

A comparison of interocular differences in spatial frequency tuning and contrast sensitivity with the severity of amblyopia. Filled symbols indicate data from the strabismic monkeys, and open symbols indicate data from the anisometropic monkeys. The ordinate in each plot is the ratio of the geometric population means of the values of the listed parameter for units tested through each of the eyes, with data from the nonamblyopic eye placed in the numerator.

Fig. 10.

A comparison of behavioral and neurophysiological assessments of interocular differences in spatial frequency selectivity and contrast sensitivity. The ordinate of each graph plots the same ratio of population geometric means shown on the ordinate of Figure 9. The abscissa indicates the ratio of the same values from the behavioral measurements of spatial contrast sensitivity shown in Figure1.