Responses to visual motion of neurons in the extrastriate visual cortex of macaque monkeys with experimental amblyopia.

Amblyopia is a developmental disorder that results from abnormal visual experience in early life. Amblyopia typically reduces visual performance in one eye. We studied the representation of visual motion information in area MT and nearby extrastriate visual areas in two monkeys made amblyopic by creating an artificial strabismus in early life, and in a single age-matched control monkey. Tested monocularly, cortical responses to moving dot patterns, gratings, and plaids were qualitatively normal in awake, fixating amblyopic monkeys, with primarily subtle differences between the eyes. However, the number of binocularly driven neurons was substantially lower than normal; of the neurons driven predominantly by one eye, the great majority responded only to stimuli presented to the fellow eye. The small population driven by the amblyopic eye showed reduced coherence sensitivity and a preference for faster speeds in much the same way as behavioral deficits. We conclude that, while we do find important differences between neurons driven by the two eyes, amblyopia does not lead to a large scale reorganization of visual receptive fields in the dorsal stream when tested through the amblyopic eye, but rather creates a substantial shift in eye preference toward the fellow eye.

Developmentally stable representations of naturalistic image structure in macaque visual cortex.

To determine whether post-natal improvements in form vision result from changes in mid-level visual cortex, we studied neuronal and behavioral responses to texture stimuli that were matched in local spectral content but varied in "naturalistic" structure. We made longitudinal measurements of visual behavior from 16 to 95 weeks of age, and of neural responses from 20 to 56 weeks. We also measured behavioral and neural responses in near-adult animals more than 3 years old. Behavioral sensitivity reached half-maximum around 25 weeks of age, but neural sensitivities remained stable through all ages tested. Neural sensitivity to naturalistic structure was highest in V4, lower in V2 and inferotemporal cortex (IT), and barely discernible in V1. Our results show a dissociation between stable neural performance and improving behavioral performance, which may reflect improved processing capacity in circuits downstream of visual cortex.

Development of radial frequency pattern perception in macaque monkeys.

Infant primates see poorly, and most perceptual functions mature steadily beyond early infancy. Behavioral studies on human and macaque infants show that global form perception, as measured by the ability to integrate contour information into a coherent percept, improves dramatically throughout the first several years after birth. However, it is unknown when sensitivity to curvature and shape emerges in early life or how it develops. We studied the development of shape sensitivity in 18 macaques, aged 2 months to 10 years. Using radial frequency stimuli, circular targets whose radii are modulated sinusoidally, we tested monkeys' ability to radial frequency stimuli from circles as a function of the depth and frequency of sinusoidal modulation. We implemented a new four-choice oddity task and compared the resulting data with that from a traditional two-alternative forced choice task. We found that radial frequency pattern perception was measurable at the youngest age tested (2 months). Behavioral performance at all radial frequencies improved with age. Performance was better for higher radial frequencies, suggesting the developing visual system prioritizes processing of fine visual details that are ecologically relevant. By using two complementary methods, we were able to capture a comprehensive developmental trajectory for shape perception.

Developmentally stable representations of naturalistic image structure in macaque visual cortex.

We studied visual development in macaque monkeys using texture stimuli, matched in local spectral content but varying in "naturalistic" structure. In adult monkeys, naturalistic textures preferentially drive neurons in areas V2 and V4, but not V1. We paired behavioral measurements of naturalness sensitivity with separately-obtained neuronal population recordings from neurons in areas V1, V2, V4, and inferotemporal cortex (IT). We made behavioral measurements from 16 weeks of age and physiological measurements as early as 20 weeks, and continued through 56 weeks. Behavioral sensitivity reached half of maximum at roughly 25 weeks of age. Neural sensitivities remained stable from the earliest ages tested. As in adults, neural sensitivity to naturalistic structure increased from V1 to V2 to V4. While sensitivities in V2 and IT were similar, the dimensionality of the IT representation was more similar to V4's than to V2's.

Attention in visually typical and amblyopic children.

Amblyopia is a cortical visual disorder caused by unequal visual input to the brain from the two eyes during development. Amblyopes show reduced visual acuity and contrast sensitivity and abnormal binocularity, as well as more "global" perceptual losses, such as figure-ground segregation and global form integration. Currently, there is no consensus on the neural basis for these higher-order perceptual losses. One contributing factor could be that amblyopes have deficiencies in attention, such that the attentional processes that control the selection of information favor the better eye. Previous studies in amblyopic adults are conflicting as to whether attentional deficits exist. However, studies where intact attentional ability has been shown to exist were conducted in adults; it is possible that it was acquired through experience. To test this hypothesis, we studied attentional processing in amblyopic children. We examined covert endogenous attention using a classical spatial cueing paradigm in amblyopic and visually typical 5- to 10-year old children. We found that all children, like adults, independently of visual condition, benefited from attentional cueing: They performed significantly better on trials with an informative (valid) cue than with the uninformative (neutral) cue. Response latencies were also significantly shorter for the valid cue condition. No statistically significant difference was found between the performance of the amblyopic and the visually typical children or between dominant and nondominant eyes of all children. The results showed that covert spatial attention is intact in amblyopic and visually typical children and is therefore not likely to account for higher-order perceptual losses in amblyopic children.

Understanding the development of amblyopia using macaque monkey models.

Amblyopia is a sensory developmental disorder affecting as many as 4% of children around the world. While clinically identified as a reduction in visual acuity and disrupted binocular function, amblyopia affects many low- and high-level perceptual abilities. Research with nonhuman primate models has provided much needed insight into the natural history of amblyopia, its origins and sensitive periods, and the brain mechanisms that underly this disorder. Amblyopia results from abnormal binocular visual experience and impacts the structure and function of the visual pathways beginning at the level of the primary visual cortex (V1). However, there are multiple instances of abnormalities in areas beyond V1 that are not simply inherited from earlier stages of processing. The full constellation of deficits must be taken into consideration in order to understand the broad impact of amblyopia on visual and visual-motor function. The data generated from studies of animal models of the most common forms of amblyopia have provided indispensable insight into the disorder, which has significantly impacted clinical practice. It is expected that this translational impact will continue as ongoing research into the neural correlates of amblyopia provides guidance for novel therapeutic approaches.

Altered functional interactions between neurons in primary visual cortex of macaque monkeys with experimental amblyopia.

Amblyopia, a disorder in which vision through one of the eyes is degraded, arises because of defective processing of information by the visual system. Amblyopia often develops in humans after early misalignment of the eyes (strabismus) and can be simulated in macaque monkeys by artificially inducing strabismus. In such amblyopic animals, single-unit responses in primary visual cortex (V1) are appreciably reduced when evoked by the amblyopic eye compared with the other (fellow) eye. However, this degradation in single V1 neuron responsivity is not commensurate with the marked losses in visual sensitivity and resolution measured behaviorally. Here we explored the idea that changes in patterns of coordinated activity across populations of V1 neurons may contribute to degraded visual representations in amblyopia, potentially making it more difficult to read out evoked activity to support perceptual decisions. We studied the visually evoked activity of V1 neuronal populations in three macaques (Macaca nemestrina) with strabismic amblyopia and in one control animal. Activity driven through the amblyopic eye was diminished, and these responses also showed more interneuronal correlation at all stimulus contrasts than responses driven through the fellow eye or responses in the control animal. A decoding analysis showed that responses driven through the amblyopic eye carried less visual information than other responses. Our results suggest that part of the reduced visual capacity of amblyopes may be due to changes in the patterns of functional interaction among neurons in V1.NEW & NOTEWORTHY Previous work on the neurophysiological basis of amblyopia has largely focused on relating behavioral deficits to changes in visual processing by single neurons in visual cortex. In this study, we recorded simultaneously from populations of primary visual cortical (V1) neurons in macaques with amblyopia. We found changes in the strength and pattern of shared response variability between neurons. These changes in neuronal interactions could impair the visual representations of V1 populations driven by the amblyopic eye.

Cortical correlates of amblyopia.

There are many levels of disorder in amblyopic vision, from basic acuity and contrast sensitivity loss to abnormal binocular vision and global perception of motion and form. Amblyopia treatment via patching to restore acuity often leaves other aspects of vision deficient. The source for these additional deficits is unclear. Neural correlates of poor binocular function and acuity loss are found in V1 and V2. However, they are generally not sufficient to account for behaviorally measured vision loss. This review summarizes the known cortical correlates of visual deficits found in association with amblyopia, particularly those relevant to binocular vision and higher-order visual processing, in striate and extrastriate cortex. Recommendations for future research address open questions on the role of suppression and oculomotor abnormalities in amblyopic vision, and underexplored mechanisms such as top-down influences on information transmission in the amblyopic brain.

Endogenous attention improves perception in amblyopic macaques.

Amblyopia, a developmental disorder of vision, affects many aspects of spatial vision as well as motion perception and some cognitive skills. Current models of amblyopic vision based on known neurophysiological deficiencies have yet to provide an understanding of the wide range of amblyopic perceptual losses. Visual spatial attention is known to enhance performance in a variety of detection and discrimination tasks in visually typical humans and nonhuman primates. We investigated whether and how voluntary spatial attention affected psychophysical performance in amblyopic macaques. Full-contrast response functions for motion direction discrimination were measured for each eye of six monkeys: five amblyopic and one control. We assessed whether the effect of a valid spatial cue on performance corresponded to a change in contrast gain, a leftward shift of the function, or response gain, an upward scaling of the function. Our results showed that macaque amblyopes benefit from a valid spatial cue. Performance with amblyopic eyes viewing showed enhancement of both contrast and response gain whereas fellow and control eyes' performance showed only contrast gain. Reaction time analysis showed no speed accuracy trade-off in any case. The valid spatial cue improved contrast sensitivity for the amblyopic eye, effectively eliminating the amblyopic contrast sensitivity deficit. These results suggest that engaging endogenous spatial attention may confer substantial benefit to amblyopic vision.

Development of visual cortical function in infant macaques: A BOLD fMRI study.

Functional brain development is not well understood. In the visual system, neurophysiological studies in nonhuman primates show quite mature neuronal properties near birth although visual function is itself quite immature and continues to develop over many months or years after birth. Our goal was to assess the relative development of two main visual processing streams, dorsal and ventral, using BOLD fMRI in an attempt to understand the global mechanisms that support the maturation of visual behavior. Seven infant macaque monkeys (Macaca mulatta) were repeatedly scanned, while anesthetized, over an age range of 102 to 1431 days. Large rotating checkerboard stimuli induced BOLD activation in visual cortices at early ages. Additionally we used static and dynamic Glass pattern stimuli to probe BOLD responses in primary visual cortex and two extrastriate areas: V4 and MT-V5. The resulting activations were analyzed with standard GLM and multivoxel pattern analysis (MVPA) approaches. We analyzed three contrasts: Glass pattern present/absent, static/dynamic Glass pattern presentation, and structured/random Glass pattern form. For both GLM and MVPA approaches, robust coherent BOLD activation appeared relatively late in comparison to the maturation of known neuronal properties and the development of behavioral sensitivity to Glass patterns. Robust differential activity to Glass pattern present/absent and dynamic/static stimulus presentation appeared first in V1, followed by V4 and MT-V5 at older ages; there was no reliable distinction between the two extrastriate areas. A similar pattern of results was obtained with the two analysis methods, although MVPA analysis showed reliable differential responses emerging at later ages than GLM. Although BOLD responses to large visual stimuli are detectable, our results with more refined stimuli indicate that global BOLD activity changes as behavioral performance matures. This reflects an hierarchical development of the visual pathways. Since fMRI BOLD reflects neural activity on a population level, our results indicate that, although individual neurons might be adult-like, a longer maturation process takes place on a population level.

Asymmetric Dichoptic Masking in Visual Cortex of Amblyopic Macaque Monkeys.

In amblyopia, abnormal visual experience leads to an extreme form of eye dominance, in which vision through the nondominant eye is degraded. A key aspect of this disorder is perceptual suppression: the image seen by the stronger eye often dominates during binocular viewing, blocking the image of the weaker eye from reaching awareness. Interocular suppression is the focus of ongoing work aimed at understanding and treating amblyopia, yet its physiological basis remains unknown. We measured binocular interactions in visual cortex of anesthetized amblyopic monkeys (female Macaca nemestrina), using 96-channel "Utah" arrays to record from populations of neurons in V1 and V2. In an experiment reported recently (Hallum et al., 2017), we found that reduced excitatory input from the amblyopic eye (AE) revealed a form of balanced binocular suppression that is unaltered in amblyopia. Here, we report on the modulation of the gain of excitatory signals from the AE by signals from its dominant fellow eye (FE). Using a dichoptic masking technique, we found that AE responses to grating stimuli were attenuated by the presentation of a noise mask to the FE, as in a normal control animal. Responses to FE stimuli, by contrast, could not be masked from the AE. We conclude that a weakened ability of the amblyopic eye to modulate cortical response gain creates an imbalance of suppression that favors the dominant eye.SIGNIFICANCE STATEMENT In amblyopia, vision in one eye is impaired as a result of abnormal early visual experience. Behavioral observations in humans with amblyopia suggest that much of their visual loss is due to active suppression of their amblyopic eye. Here we describe experiments in which we studied binocular interactions in macaques with experimentally induced amblyopia. In normal monkeys, the gain of neuronal response to stimulation of one eye is modulated by contrast in the other eye, but in monkeys with amblyopia the balance of gain modulation is altered so that the weaker, amblyopic eye has little effect while the stronger fellow eye has a strong effect. This asymmetric suppression may be a key component of the perceptual losses in amblyopia.

Altered Balance of Receptive Field Excitation and Suppression in Visual Cortex of Amblyopic Macaque Monkeys.

In amblyopia, a visual disorder caused by abnormal visual experience during development, the amblyopic eye (AE) loses visual sensitivity whereas the fellow eye (FE) is largely unaffected. Binocular vision in amblyopes is often disrupted by interocular suppression. We used 96-electrode arrays to record neurons and neuronal groups in areas V1 and V2 of six female macaque monkeys (Macaca nemestrina) made amblyopic by artificial strabismus or anisometropia in early life, as well as two visually normal female controls. To measure suppressive binocular interactions directly, we recorded neuronal responses to dichoptic stimulation. We stimulated both eyes simultaneously with large sinusoidal gratings, controlling their contrast independently with raised-cosine modulators of different orientations and spatial frequencies. We modeled each eye's receptive field at each cortical site using a difference of Gaussian envelopes and derived estimates of the strength of central excitation and surround suppression. We used these estimates to calculate ocular dominance separately for excitation and suppression. Excitatory drive from the FE dominated amblyopic visual cortex, especially in more severe amblyopes, but suppression from both the FE and AEs was prevalent in all animals. This imbalance created strong interocular suppression in deep amblyopes: increasing contrast in the AE decreased responses at binocular cortical sites. These response patterns reveal mechanisms that likely contribute to the interocular suppression that disrupts vision in amblyopes.SIGNIFICANCE STATEMENT Amblyopia is a developmental visual disorder that alters both monocular vision and binocular interaction. Using microelectrode arrays, we examined binocular interaction in primary visual cortex and V2 of six amblyopic macaque monkeys (Macaca nemestrina) and two visually normal controls. By stimulating the eyes dichoptically, we showed that, in amblyopic cortex, the binocular combination of signals is altered. The excitatory influence of the two eyes is imbalanced to a degree that can be predicted from the severity of amblyopia, whereas suppression from both eyes is prevalent in all animals. This altered balance of excitation and suppression reflects mechanisms that may contribute to the interocular perceptual suppression that disrupts vision in amblyopes.

Global and local visual processing in autism: An objective assessment approach.

We examined global and local visual processing in autism spectrum disorder (ASD) via a match-to-sample task using Kanizsa illusory contours (KIC). School-aged children with ASD (n = 28) and age-matched typically developing controls (n = 22; 7-13 years) performed a sequential match-to-sample between a solid shape (sample) and two illusory alternatives. We tracked eye gaze and behavioral performance in two task conditions: one with and one without local interference from background noise elements. While analyses revealed lower accuracy and longer reaction time in ASD in the condition with local interference only, eye tracking robustly captured ASD-related global atypicalities across both conditions. Specifically, relative to controls, children with ASD showed decreased fixations to KIC centers, indicating reduced global perception. Notably, they did not differ from controls in regard to fixations to local elements or touch response location. These results indicate impaired global perception in the absence of heightened local processing in ASD. They also underscore the utility of eye-tracking measures as objective indices of global/local visual processing strategies in ASD. Autism Res 2017, 10: 1392-1404. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Covert spatial attention is functionally intact in amblyopic human adults.

Certain abnormalities in behavioral performance and neural signaling have been attributed to a deficit of visual attention in amblyopia, a neurodevelopmental disorder characterized by a diverse array of visual deficits following abnormal binocular childhood experience. Critically, most have inferred attention's role in their task without explicitly manipulating and measuring its effects against a baseline condition. Here, we directly investigate whether human amblyopic adults benefit from covert spatial attention-the selective processing of visual information in the absence of eye movements-to the same degree as neurotypical observers. We manipulated both involuntary (Experiment 1) and voluntary (Experiment 2) attention during an orientation discrimination task for which the effects of covert spatial attention have been well established in neurotypical and special populations. In both experiments, attention significantly improved accuracy and decreased reaction times to a similar extent (a) between the eyes of the amblyopic adults and (b) between the amblyopes and their age- and gender-matched controls. Moreover, deployment of voluntary attention away from the target location significantly impaired task performance (Experiment 2). The magnitudes of the involuntary and voluntary attention benefits did not correlate with amblyopic depth or severity. Both groups of observers showed canonical performance fields (better performance along the horizontal than vertical meridian and at the lower than upper vertical meridian) and similar effects of attention across locations. Despite their characteristic low-level vision impairments, covert spatial attention remains functionally intact in human amblyopic adults.

The Puzzle of Visual Development: Behavior and Neural Limits.

The development of visual function takes place over many months or years in primate infants. Visual sensitivity is very poor near birth and improves over different times courses for different visual functions. The neural mechanisms that underlie these processes are not well understood despite many decades of research. The puzzle arises because research into the factors that limit visual function in infants has found surprisingly mature neural organization and adult-like receptive field properties in very young infants. The high degree of visual plasticity that has been documented during the sensitive period in young children and animals leaves the brain vulnerable to abnormal visual experience. Abnormal visual experience during the sensitive period can lead to amblyopia, a developmental disorder of vision affecting ∼3% of children. This review provides a historical perspective on research into visual development and the disorder amblyopia. The mismatch between the status of the primary visual cortex and visual behavior, both during visual development and in amblyopia, is discussed, and several potential resolutions are considered. It seems likely that extrastriate visual areas further along the visual pathways may set important limits on visual function and show greater vulnerability to abnormal visual experience. Analyses based on multiunit, population activity may provide useful representations of the information being fed forward from primary visual cortex to extrastriate processing areas and to the motor output.

A Window into brain development: hdEEG methods to track visual development in nonhuman primates.

Electroencephalography (EEG) is widely used to study human brain activity, and is a useful tool for bridging the gap between invasive neural recording assays and behavioral data. High-density EEG (hdEEG) methods currently used for human subjects for use with infant macaque monkeys, a species that exhibits similar visual development to humans over a shorter time course was adapted. Unlike monkeys, human subjects were difficult to study longitudinally and were not appropriate for direct within-species comparison to neuronal data. About 27-channel electrode caps, which allowed collection of hdEEG data from infant monkeys across development were designed. Acuity and contrast sweep VEP responses to grating stimuli was obtained and a new method for objective threshold estimation based on response signal-to-noise ratios at different stimulus levels was established. The developmental trajectories of VEP-measured contrast sensitivity and acuity to previously collected behavioral and neuronal data were compared. The VEP measures showed similar rates of development to behavioral measures, both of which were slower than direct neuronal measures; VEP thresholds were higher than other measures. This is the first usage of non-invasive technology in non-human primates. Other means to assess neural sensitivity in infants were all invasive. Use of hdEEG with infant monkeys opens many possibilities for tracking development of vision and other functions in non-human primates, and can expand our understanding of the relationship between neuronal activity and behavioral capabilities across various sensory and cognitive domains. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1342-1359, 2016.

"Global" visual training and extent of transfer in amblyopic macaque monkeys.

Perceptual learning is gaining acceptance as a potential treatment for amblyopia in adults and children beyond the critical period. Many perceptual learning paradigms result in very specific improvement that does not generalize beyond the training stimulus, closely related stimuli, or visual field location. To be of use in amblyopia, a less specific effect is needed. To address this problem, we designed a more general training paradigm intended to effect improvement in visual sensitivity across tasks and domains. We used a "global" visual stimulus, random dot motion direction discrimination with 6 training conditions, and tested for posttraining improvement on a motion detection task and 3 spatial domain tasks (contrast sensitivity, Vernier acuity, Glass pattern detection). Four amblyopic macaques practiced the motion discrimination with their amblyopic eye for at least 20,000 trials. All showed improvement, defined as a change of at least a factor of 2, on the trained task. In addition, all animals showed improvements in sensitivity on at least some of the transfer test conditions, mainly the motion detection task; transfer to the spatial domain was inconsistent but best at fine spatial scales. However, the improvement on the transfer tasks was largely not retained at long-term follow-up. Our generalized training approach is promising for amblyopia treatment, but sustaining improved performance may require additional intervention.

Population representation of visual information in areas V1 and V2 of amblyopic macaques.

Amblyopia is a developmental disorder resulting in poor vision in one eye. The mechanism by which input to the affected eye is prevented from reaching the level of awareness remains poorly understood. We recorded simultaneously from large populations of neurons in the supragranular layers of areas V1 and V2 in 6 macaques that were made amblyopic by rearing with artificial strabismus or anisometropia, and 1 normally reared control. In agreement with previous reports, we found that cortical neuronal signals driven through the amblyopic eyes were reduced, and that cortical neurons were on average more strongly driven by the non-amblyopic than by the amblyopic eyes. We analyzed multiunit recordings using standard population decoding methods, and found that visual signals from the amblyopic eye, while weakened, were not degraded enough to explain the behavioral deficits. Thus additional losses must arise in downstream processing. We tested the idea that under monocular viewing conditions, only signals from neurons dominated by - rather than driven by - the open eye might be used. This reduces the proportion of neuronal signals available from the amblyopic eye, and amplifies the interocular difference observed at the level of single neurons. We conclude that amblyopia might arise in part from degradation in the neuronal signals from the amblyopic eye, and in part from a reduction in the number of signals processed by downstream areas.

Visual development in primates: Neural mechanisms and critical periods.

Despite many decades of research into the development of visual cortex, it remains unclear what neural processes set limitations on the development of visual function and define its vulnerability to abnormal visual experience. This selected review examines the development of visual function and its neural correlates, and highlights the fact that in most cases receptive field properties of infant neurons are substantially more mature than infant visual function. One exception is temporal resolution, which can be accounted for by resolution of neurons at the level of the lateral geniculate nucleus (LGN). In terms of spatial vision, properties of single neurons alone are not sufficient to account for visual development. Different visual functions develop over different time courses. Their onset may be limited by the existence of neural response properties that support a given perceptual ability, but the subsequent time course of maturation to adult levels remains unexplained. Several examples are offered suggesting that taking account of weak signaling by infant neurons, correlated firing, and pooled responses of populations of neurons brings us closer to an understanding of the relationship between neural and behavioral development.