Development of Higher-Level Vision: A Network Perspective.

Most studies on the development of the visual system have focused on the mechanisms shaping early visual stages up to the level of primary visual cortex (V1). Much less is known about the development of the stages after V1 that handle the higher visual functions fundamental to everyday life. The standard model for the maturation of these areas is that it occurs sequentially, according to the positions of areas in the adult hierarchy. Yet, the existing literature reviewed here paints a different picture, one in which the adult configuration emerges through a sequence of unique network configurations that are not mere partial versions of the adult hierarchy. In addition to studying higher visual development per se to fill major gaps in knowledge, it will be crucial to adopt a network-level perspective in future investigations to unravel normal developmental mechanisms, identify vulnerabilities to developmental disorders, and eventually devise treatments for these disorders.

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.

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.

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.

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.

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.

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.

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.

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.

From local to global processing: the development of illusory contour perception.

Global visual processing is important for segmenting scenes, extracting form from background, and recognizing objects. Local processing involves attention to the local elements, contrast, and boundaries of an image at the expense of extracting a global percept. Previous work is inconclusive regarding the relative development of local and global processing. Some studies suggest that global perception is already present by 8 months of age, whereas others suggest that the ability arises during childhood and continues to develop during adolescence. We used a novel method to assess the development of global processing in 3- to 10-year-old children and an adult comparison group. We used Kanizsa illusory contours as an assay of global perception and measured responses on a touch-sensitive screen while monitoring eye position with a head-mounted eye tracker. Participants were tested using a similarity match-to-sample paradigm. Using converging measures, we found a clear developmental progression with age such that the youngest children performed near chance on the illusory contour discrimination, whereas 7- and 8-year-olds performed nearly perfectly, as did adults. There was clear evidence of a gradual shift from a local processing strategy to a global one; young children looked predominantly at and touched the "pacman" inducers of the illusory form, whereas older children and adults looked predominantly at and touched the middle of the form. These data show a prolonged developmental trajectory in appreciation of global form, with a transition from local to global visual processing between 4 and 7 years of age.

"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.

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.

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.

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.

Linking structure and function: development of lateral spatial interactions in macaque monkeys.

Lateral spatial interactions among elements of a scene, which either enhance or degrade visual performance, are ubiquitous in vision. The neural mechanisms underlying lateral spatial interactions are a matter of debate, and various hypotheses have been proposed. Suppressive effects may be due to local inhibitory interactions, whereas facilitatory effects are typically ascribed either to the function of long-range horizontal projections in V1 or to uncertainty reduction. We investigated the development of lateral spatial interactions, facilitation and suppression, and compared their developmental profiles to those of potential underlying mechanisms in the visual system of infant macaques. Animals ranging in age from 10 weeks to 3 years were tested with a lateral masking paradigm. We found that suppressive interactions are present from very early in postnatal life, showing no change over the age range tested. However, facilitation develops slowly over the first year after birth. Our data suggest that the early maturation of suppressive interactions is related to the relatively mature receptive field properties of neurons in early visual cortical areas near birth in infant macaques, whereas the later maturation of facilitation is unlikely to be explained by development of local or long-range connectivity in primary visual cortex. Instead our data favor a late developing feedback or top-down cognitive process to explain the origin of facilitation.

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.

Global visual processing in macaques studied using Kanizsa illusory shapes.

The ability to extract form information from a visual scene, for object recognition or figure-ground segregation, is a fundamental visual system function. Many studies of nonhuman primates have addressed the neural mechanisms involved in global form processing, but few have sought to demonstrate this ability behaviorally. In this study, we probed global visual processing in macaque monkeys (Macaca nemestrina) using classical Kanizsa illusory shapes as an assay of global form perception. We trained three monkeys on a "similarity match-to-sample" form discrimination task, first with complete forms embedded in fields of noncontour-inducing "pacman" elements. We then tested them with classic Kanizsa illusory shapes embedded in fields of randomly oriented elements. Two of the three subjects reached our criterion performance level of 80% correct or better on four of five illusory test conditions, demonstrating clear evidence of Kanizsa illusory form perception; the third subject mastered three of five conditions. Performance limits for illusory form discrimination were obtained by manipulating support ratio and by measuring threshold for discriminating "fat" and "thin" illusory squares. Our results indicate that macaque monkeys are capable of global form processing similarly to humans and that the perceptual mechanisms for "filling-in" contour gaps exist in macaques as they do in humans.

Development of sensitivity to visual texture modulation in macaque monkeys.

In human and non-human primates, higher form vision matures substantially later than spatial acuity and contrast sensitivity, as revealed by performance on such tasks as figure-ground segregation and contour integration. Our goal was to understand whether delayed maturation on these tasks was intrinsically form-dependent or, rather, related to the nature of spatial integration necessary for extracting task-relevant cues. We used an intermediate-level form task that did not call for extensive spatial integration. We trained monkeys (6-201 weeks) to discriminate the orientation of pattern modulation in a two-alternative forced choice paradigm. We presented two families of form patterns, defined by texture or contrast variations, and luminance-defined patterns for comparison. Infant monkeys could discriminate texture- and contrast-defined form as early as 6 weeks; sensitivity improved up to 40 weeks. Surprisingly, sensitivity for texture- and contrast-defined form matured earlier than for luminance-defined form. These results suggest that intermediate-level form vision develops in concert with basic spatial vision rather than following sequentially. Comparison with earlier results reveals that different aspects of form vision develop over different time courses, with processes that depend on comparing local image content maturing earlier than those requiring "global" linking of multiple visual elements across a larger spatial extent.