Introduction
The vision of newborn infants is crude. As infants experience the normal visual environment, their vision rapidly improves, with different visual capabilities emerging at different ages. Determining the exact timing for the behavioral onset of specific visual functions and identifying the critical factors that limit their development have been the primary focus of perceptual and physiologic studies on vision development. Although immaturities of the physiologic optics and ocular motility are known to affect infant’s vision soon after birth the maturation of the retina and, to a greater extent, the visual brain (i.e., the striate and extrastriate visual cortex) largely set a limit on their normal perceptual development. The binocular and monocular receptive-field (RF) properties of neurons in the primary visual cortex (V1) and secondary visual area V2 of infant monkeys are qualitatively “adult-like” near birth. However, the responsiveness of these neurons is quite low, reflecting, in part, retinal immaturity. The weak and sluggish signaling of V1 and V2 neurons and the delayed maturation of higher-order visual areas are thought to be largely responsible for the slower perceptual development.
The neuronal connections of the visual cortex are malleable for a considerable period of time after birth, the “critical” (“sensitive” or “plastic”) period of development. The postnatal development of the visual cortex, therefore, requires normal visual experience and precise matching of the images in the two eyes. Experiencing binocularly discordant images early in life, binocular imbalance , has devastating effects on the development of the visual system because after eye opening, the neurons in the highly plastic visual cortex receive signals from the two eyes that do not match. Binocular imbalance commonly results from monocular form deprivation owing to congenital cataract or ptosis, chronic monocular defocus caused by large interocular differences in refractive power (anisometropia), and/or large misalignment of visual axes (strabismus). Experiencing binocular imbalance during early infancy causes binocular vision disorders, and, if untreated, amblyopia and/or abnormal binocular integration is likely to develop.
Topics in this chapter cover what we currently know about the perceptual consequences of early abnormal visual experience, the neural basis of altered vision, and the synaptic and molecular mechanisms of cortical plasticity. Macaque monkeys are ideal animal models for exploring the neural mechanisms underlying developmental vision disorders in humans. The anatomical and physiologic organizations of their visual system are nearly identical to humans. Perceptual studies in normal mature monkeys have documented extensively the striking similarities in monocular and binocular visual capabilities between macaque monkeys and humans. The relative (scaled) time course of normal visual development in macaque monkeys parallels that of humans. The primate visual cortex is structurally and functionally more developed at or near birth than the visual cortex in lower species. Many important discoveries on vision development have been made on subprimate species. However, in lower animals it is not always possible to establish a link between neural and perceptual deficits resulting from early abnormal visual experience. This chapter, therefore, primarily reviews studies on nonhuman primates . Studies with human infants are mentioned when appropriate, and research in subprimate species is described in detail mostly where the neural and molecular basis of cortical plasticity is discussed.
Effects of early monocular form deprivation
Constant monocular form deprivation
Monocular form deprivation can result from an occlusion of the image in one eye or from a severely degraded image in the affected eye. Congenital dense cataracts and ptosis are the common causes of monocular form deprivation in human infants. To create primate models of monocular form deprivation, the eyelids of infant monkeys are surgically closed or, more recently, by wearing diffuser lenses in front of one eye.
Perceptual deficits
All binocular functions, including local/global stereopsis and binocular summation of contrast sensitivity, are severely compromised or lost following early monocular form deprivation. The visual sensitivity of the deprived eye is dramatically reduced or virtually lost—form deprivation amblyopia ( Fig. 40.1A ). Importantly, the severity of the contrast sensitivity loss resulting from monocular form deprivation is directly related to the degree of retinal image degradation during early infancy ( Fig. 40.1B ).
Monocular deprivation also leads to an abnormal elongation of the eyes, hence the development of myopic refractive errors. The deleterious effects of early monocular deprivation on spatial vision development are generally far more severe than the anomalies resulting from form deprivation in both eyes, bilateral form deprivation ( Fig. 40.2 ). As in monkeys with monocular form deprivation, bilateral form deprivation leads to a significant loss of binocular functions, including the detection of stereoscopic cues and binocular summation of contrast sensitivity ( Fig. 40.2 ). In these binocularly deprived monkeys, the binocular contrast sensitivity function ( Fig. 40.2 , green square symbols) overlaps with the better eye’s monocular sensitivity function ( Fig. 40.2 , blue circle symbols).
Neural deficits
The most consistent effect of early monocular form deprivation on development is the anomalous changes in the ocular dominance distribution of V1 neurons ( ocular dominance plasticity ). During the critical period of development, the afferent fibers from the lateral geniculate nucleus (LGN) representing the two eyes compete for consolidation of functional connections in V1 ( binocular competition ). This early binocular competition is activity dependent, hence depriving normal signals from one eye puts the affected eye into competitive disadvantage and leads to a severe loss of functional connections in V1 from the deprived eye. The ocular dominance columns of the input layer in V1 (layer 4 C) representing the deprived eye exhibit a substantial shrinkage. The axon arbors of the afferent fibers from the LGN in the deprived columns show abnormal structural changes, and the intrinsic long-range horizontal connections extending over multiple ocular dominance columns reorganize their wiring pattern in the cat primary visual cortex.
Electrophysiological studies consistently report the severe loss of binocularly driven cells (i.e., neurons that can be activated by stimulation of either eye). Moreover, there is a clear shift in the ocular dominance distribution of cortical neurons away from the deprived eye. Specifically, the percentage of V1 neurons that can be activated or dominated by stimulation of the deprived eye is significantly decreased ( Fig. 40.3 ). The reduced functional innervation from the deprived eye is, at least in part, the neural basis for “undersampling” of visual scenes by the affected eye in form-deprivation amblyopia.
For subcortical structures, there is a mild shrinkage of cell bodies of LGN neurons that receive input signals from the deprived eye. However, the response properties of these primate LGN neurons are largely unaffected by early monocular form deprivation. Interestingly, there is considerable evidence for functional alterations in the cat LGN due to early abnormal visual experience. In the primate retina there is no significant structural or functional abnormality due to early monocular form deprivation. Together, major neural changes resulting from early monocular form deprivations in primates occur beyond the LGN, that is, they begin in the primary visual cortex.
Intermittent monocular deprivation
Experiencing “normal vision” during early monocular form deprivation ( intermittent monocular form deprivation ) reduces some of the deleterious effects of early constant monocular form deprivation. The effects of early intermittent deprivations have been studied using different rearing regimens including daily alternating monocular deprivation, reverse occlusion, and monocular form deprivation with daily brief periods of unrestricted vision.
Alternating monocular deprivation
Daily alternation of form deprivation between the two eyes has very little impact on the perceptual development of either eye in cats. Consistent with this observation, the spatial RF properties such as orientation selectivity are normal. However, the same daily alternating deprivation devastates the development of binocular vision. Local stereopsis is lost and the proportion of binocularly driven neurons in area 17 is severely reduced. In monkeys, daily alternating monocular occlusion beginning at birth leads to a variety of abnormal eye positions and eye movements including strabismus and/or saccadic disconjugacy, that is, the amplitudes of saccades in the occluded eye are less than that in the viewing eye.
Reverse occlusion
The effects of constant form deprivation in one eye, including spatial contrast sensitivity loss and ocular dominance shift in V1 away from the deprived eye, can be reversed if vision of the originally deprived eye is restored early in development and the fellow nondeprived eye is occluded—a reverse occlusion ( Fig. 40.4 ). The timing of the reverse occlusion is critical in determining the effectiveness of this procedure because the “recovery” of functions in the originally deprived eye may occur at the expense of the originally nondeprived eye. For example, contrast sensitivity can be restored if reverse occlusion occurs relatively early in the critical period, that is, if the original deprivation is short (e.g., 15 or 30 days). However, this early reversal leads to a loss of contrast sensitivity in the newly deprived (or originally nondeprived) eye ( red circles in Fig. 40.4A ) and causes a corresponding shift in the ocular dominance distribution of V1 neurons favoring the initially deprived eye. There is an optimal time for the reversal of monocular occlusion in order to achieve near-normal contrast sensitivity for both eyes (e.g., after 90 days of original monocular deprivation [ Fig. 40.4B ]). In all cases, the binocular functions are diminished. Similar effects of reverse occlusion have been studied extensively in cats, and the results have contributed to advancing our understanding of the neural mechanisms underlying the breakdown and recovery of visual functions from early monocular form deprivation. The clinical significance of these findings is that this kind of animal study could provide key information for developing an effective clinical strategy for treating amblyopia with various patching regimens .
Brief unrestricted vision during monocular deprivation
Providing brief daily periods of normal vision (unrestricted vision) to the deprived eye during early monocular deprivation prevents or reduces the severity of form-deprivation amblyopia in monkeys. Constant form deprivation (0 hour of unrestricted vision), as previously described, causes severe amblyopia of the deprived eye and a large shift in the ocular dominance of V1 neurons away from the deprived eye. However, only 1 hour of unrestricted (normal) vision every day during the deprivation period (12 hours/day) dramatically improves the contrast sensitivity of the deprived eye, reducing the severity of form deprivation amblyopia. In these monkeys, the extent of abnormal ocular dominance shift in V1 is significantly reduced. In stark contrast, the same “preventive” measure, even with 4 hours of daily unrestricted vision during the 12-hour deprivation period, does not prevent a severe loss of disparity-sensitive neurons, highlighting the extremely fragile nature of developing binocular connections in V1. Finally, constant monocular form deprivation leads to an elongation of the eye and thus the development of myopic refractive errors in the deprived eye. However, a brief period of unrestricted vision during the deprivation period reduces the degree of myopic refractive error. The clinical relevance of these studies is that the timely removal of the conditions that produce degradation of images or image occlusion (e.g., severe hyperopic anisometropia, cataract, or ptosis) is critically important for the prevention of amblyopia. If that is not immediately possible, “stopgap manipulations” such as lifting a drooping eyelid or keeping corrective lenses even for a short period of time every day are likely to have preventive effects against form-deprivation amblyopia and development of myopic refractive errors.
Critical period
The critical (sensitive or plastic) period of vision development is traditionally defined as the postnatal period during which visual deprivation leads to long-term or permanent structural and/or functional changes of the visual system. The critical period differs substantially between species, the visual functions affected by deprivation, sites of neural alterations, and the nature of the visual deprivation (e.g., dark rearing, monocular form deprivation), monocular defocus, or ocular misalignment. For example, the critical period for primates, unlike subprimate species, begins at or near birth. Binocular functions are generally more readily disrupted by early visual deprivations than monocular spatial vision. The critical period for experience-dependent changes differs between cortical sites (e.g., V1, V2, V4, or MT [middle-temporal area or V5]), and between cortical layers within a given cortical site. The higher stages of processing (e.g., supra- and infragranular layers), compared with input layer within V1 or cortical sites later in the hierarchy of extrastriate visual areas, appear to have longer periods of plasticity.
Critical period for monocular form deprivation
There are multiple “plastic” periods for different visual functions in macaque monkeys ( Fig. 40.5 ). Spectral sensitivity functions have relatively short critical periods that begin soon after birth and last for 3 months for scotopic spectral sensitivity and 6 months for photopic spectral sensitivity. The critical period for visual acuity loss is much longer, lasting over 24 months. Binocular vision development can be disrupted by monocular deprivation starting as late as 25 months of age (roughly equivalent to 8 years in humans).
Because the sensitivity of the visual cortex to deprivations varies substantially during the critical periods, the timing of deprivation (i.e., onset and duration ) has significant effects on the severity of perceptual and neural deficits. At what age is monocular form deprivation likely to have the most damaging effects in monkeys? The perceptual development of contrast sensitivity and visual acuity in macaque monkeys is most vulnerable to monocular form deprivation during the first 5 postnatal months. A sharp drop of sensitivity to deprivation occurs after this initial period of heightened sensitivity, followed by a gradual decline over an extended period of time (i.e., >24 months) ( Fig. 40.5 ).
For ocular dominance plasticity in V1 of monkeys, the most severe shrinkage of ocular dominance columns for the deprived eye occurs with the earliest -onset age (e.g., 1 week of age). The degree of shrinkage becomes progressively smaller as the onset of deprivation is delayed, and there is no obvious shrinkage if the onset is set at the 12th postnatal week. Thus, contrary to a classical observation, the ocular dominance columns in layer 4 C of monkey V1 are most sensitive to monocular deprivation right after birth.
These behavioral and anatomical studies reinforce the clinical view that the removal of dense congenital cataracts combined with high optical quality lenses or the correction of ptosis at the earliest possible postnatal time is essential to minimize the negative impact of monocular form deprivation in humans.
The critical period for ocular dominance in cats begins at about 3 to 4 weeks of age when the optics of their eyes becomes relatively clear, peaks at around 6 to 8 weeks, and gradually decreases during the next 12 to 14 weeks. Similar but earlier and shorter critical periods of plasticity for monocular deprivation have been reported for mice, rats, and ferrets, with minor variations. The critical period is longer for monkeys than in lower species and appears to be generally correlated with animal life expectancy. It is difficult to determine the precise critical period of vision development for humans, in part because of the difficulties associated with conducting experiments on human infants and dependence on clinical observations for data collection. Although the critical period for humans varies considerably for specific visual tasks and type of visual deprivation as evidenced in animal studies, the critical period for experience-dependent changes in human is thought to begin soon after birth (within 6 months or earlier), peak at around 1 to 3 years of age, and decline slowly until 7 to 8 years of age or later (also see Chapter 38 ). Finally, recent evidence suggests that the “sensitive”/“plastic” period in human does not completely close during early development. Instead, “residual” cortical plasticity extends into adulthood, as it does in nonhuman primates and lower species.
Molecular mechanisms of experience-dependent ocular dominance plasticity
The molecular mechanisms of experience-dependent ocular dominance plasticity have been extensively studied in rodents because the visual cortex of rodents is, in general, organized similarly to that of higher mammals and a wide range of genetic manipulations are readily accessible in rodents. As described previously for higher species, synaptic events following monocular deprivation ( binocular competition ) consist of an initial reversible reduction in functional connections to the deprived eye and rewiring of the upper-layer long-range connections. These are followed by extended periods of strengthening of the responses to the nondeprived eye and an eventual structural reorganization ( Fig. 40.6A ).
Multiple cellular and circuit mechanisms are involved in ocular dominance plasticity in V1: Hebbian synaptic plasticity, homeostatic synaptic plasticity, and neuromodulator mechanisms ( Fig. 40.6B ).
Hebbian synaptic plasticity
The initial rapid changes occur as a result of imbalance in the strength of the input signals between the deprived and the nondeprived eyes. This imbalance disrupts the timing of the firing of action potentials between the presynaptic (LGN) and postsynaptic (V1) neurons for the deprived eye. Uncorrelated firing of action potentials between the presynaptic and postsynaptic neurons in V1 leads to a weakening of synaptic connections for the deprived eye while well-timed firing between the pre- and postsynaptic cells strengthens the synapses for the nondeprived eye. The timing of presynaptic and postsynaptic neuronal spiking is also modulated by inhibitory neurons in the circuitry. These activity-dependent changes in synaptic strength involve long-term potentiation (LTP) of input signals from the nondeprived eye and long-term depression (LTD) of signals from the deprived eye.
Closely associated with LTP and LTD synaptic plasticity is the role of glutamate receptors in cortical neurons, in particular n-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and γ-aminobutyric-acid (GABA) receptors ( Fig. 40.6B ). Excitatory synaptic transmission is mediated by NMDA and AMPA receptors, whereas inhibitory synaptic transmission is regulated by GABA Aα receptors. Each of these glutamate receptors has a broad range of critical roles in regulating the balance between excitation and inhibition and ocular dominance plasticity.
NMDA receptors are made up of three types of subunits (NR1, NR2A, and NR2B). The normal postnatal changes in the expression of NR1 and NR2A or NR2B subunits (e.g., the NR2A/NR2B ratio being low at birth and gradually increasing during postnatal development) are also experience dependent. As a result, the developmental changes of the NMDA subunit expression owing to monocular deprivation (i.e., the activity-dependent regulation of the NR2A/NR2B ratios) are intimately involved in regulating the plasticity of the visual cortex. For example, an increase in the NR2A or NR2A/2B ratios leads to the induction of LTP and to a heightened sensitivity of synapses to modification.
AMPA receptors, composed of GluR2 and either GluR1 or GluR3 subunits, are also involved in synaptic plasticity. Synaptic strength is determined by the AMPA receptor density and calcium permeability. Repetitive activation of synapses leads to increased insertion of AMPA subunits into postsynaptic neuronal membrane, resulting in LTP, whereas reductions in synaptic activation (e.g., by monocular deprivation) remove AMPA receptors, leading to LTD. Such redistribution of AMPA receptors is mediated by expression of the immediate gene Arc. Prolonged LTD leads to structural changes (e.g., loss of synaptic contacts from the deprived eye). Synaptic depolarization via activation of NMDA and AMPA receptors induces calcium influx and activates an intracellular signaling cascade. The second-messenger molecules that are directly involved in synaptic strength and ocular dominance plasticity include protein kinase (PKA), calcium/calmodulin-dependent protein kinase II (CaMKII), extracellular signal–regulated kinase 1,2 (ERK), cyclic AMP–responsive element-binding protein (CREB), and protein synthesis machinery. PKA, CaMKII, and ERK rapidly promote ocular dominance plasticity by modulating synaptic strength by phosphorylating plasticity-regulating molecules in glutamate or GABA receptors. This kinase signaling leads to the activation of CREB. The changes initiated by activation of intracellular second-messenger molecules, along with the action of brain-derived neurotrophic factor (BDNF), leads to the enhanced expression of molecules that act on tissue plasminogen activation (tPA). BDNF and tPA can initiate the changes of dendritic spine motility, spine density and extracellular matrix that ultimately result in rewiring of cortical circuits favoring the nondeprived eye.
Homeostatic synaptic mechanisms
Because a single V1 neuron receives diverse multiple inputs, including the feedforward thalamic projection (e.g., intrinsic and feedback connections), Hebbian synaptic plasticity for a given neuron is strongly influenced by the level of past and current activity of all synapses in its neural circuit to maintain its stability (homeostatic synaptic plasticity). There are two major theories on homeostatic plasticity. According to the “sliding threshold” or Bienenstock, Cooper, Munro (BCM) theory, a sustained period of high activity in neuronal network raises the threshold for LTP induction, resulting in LTD, whereas a prolonged period of low activity lowers the threshold and leads to LTP induction. Another way that Hebbian synaptic plasticity can be influenced is to alter the “gain” of synapses (Scaling model). Such gain control stabilizes the overall firing rate (i.e., prolonged high activity downscales excitatory synaptic events whereas prolonged low activity upscales them), thus adjusting average synaptic strength and maintaining the overall firing rate at a “normal” level.
Neuromodulator mechanisms
Another class of molecules involved in synaptic plasticity are the neuromodulators , including acetylcholine (Ach), noradrenaline (NA), and serotonin. These molecules are abundantly present throughout the cortex and have strong influence over ocular dominance plasticity. For example, enhanced cholinergic or adrenergic systems facilitate LTP induction. Changes in the expression of neuromodulators influence the level of LTP and/or LTD induction by modifying the intracellular calcium concentration by second-messenger pathways, resulting in the associated structural reorganizations of local connections to the visual cortex. Acetylcholine in V1 modulates the gain of geniculate inputs in layer 4 C and exerts inhibitory influence over intracortical synaptic events, controlling the excitatory/inhibitory (E/I) balance in V1 during early development. Cholinergic inputs facilitate the activity of somatostatin (SOM)-containing inhibitory neurons. SOM inhibitory neurons are known to inhibit parvalbumin-expressing inhibitory (PV) neurons and pyramidal neurons, leading to “disinhibition” by PV neurons over pyramidal neurons. Such disinhibition influences ocular dominance plasticity and the temporal dynamics of neuronal activity, leading to “improved” information processing in V1. Finally, increasing evidence suggests that microglia (innate immune cells) modulate synaptic remodeling and plasticity by interacting with NE modulator and homeostatic synaptic mechanisms.
GABA-mediated inhibition is important not only in maintaining the balance between cortical excitation and inhibition but also in regulating the timing of ocular dominance plasticity. Manipulation of normal levels of GABAergic transmission by PV-expressing inhibitory neurons in the developing brain can delay or advance the onset of the critical period by altering E/I balance in V1. Preventing the maturation of GABA-mediated transmission or dark rearing delays the critical period. Enhancing GABA transmission by infusing a GABA agonist (e.g., benzodiazepines) or facilitating the growth of GABAergic interneurons by BDNF can advance the onset of critical period. The clinical significance of these manipulations to “reset” the excitatory and inhibitory balance in V1 by various pharmacologic methods is that the results may provide new insights into the mechanisms underlying critical periods, and potential means to promote functional recovery in adults with developmental vision disorders (but see further on “recovery from amblyopia”).
Effects of early monocular defocus
Constant monocular defocus
A less severe form of monocular image degradation results from large differences in refractive errors between the two eyes ( anisometropia ). Normal primates (including humans) begin their life with modest but binocularly balanced hyperopic refractive errors that decline to normal refractive state during early infancy ( emmetropization ). If infants have large differences in refractive state between the two eyes, they are unable to focus with both eyes at the same time. To avoid experiencing binocularly discordant images, infants focus with one eye (typically with the eye with a less severe refractive error), and as a result the other eye experiences a defocused image (chronic defocus). Monkey models of anisometropia are simulated by rearing infant monkeys with monocular defocusing lenses or by monocular atropinization.
Perceptual deficits
The perceptual consequences of untreated early anisometropia are generally similar to the anomalies found after early monocular form deprivation: impoverished binocular vision, reduced contrast sensitivity for high-spatial-frequency stimuli, and lower optotype acuity in the affected eye ( anisometropic amblyopia ). However, the perceptual deficits in anisometropes are generally less severe than in monocular form deprivation and are spatial-frequency dependent ( Fig. 40.7A ). Anomalies vary substantially between individuals depending on the etiological factors and rearing histories (e.g., the degree of defocus).
Neural deficits
Abnormal alterations in cortical physiology that result from early unilateral defocus are also similar to, but generally milder than, cortical deficits in monocularly form-deprived monkeys. The ocular dominance distribution of V1 neurons is marked by a substantial loss of binocularly balanced cells (ocular dominance between 3 and 5) and by a milder shift away from the affected eye ( Fig. 40.7B ). The sensitivity of V1 neurons to binocular disparity is substantially reduced, and complex cells are more severely affected than simple cells in V1 ( Fig. 40.7C ). The spatial resolution and contrast sensitivity of V1 neurons for the affected eye of severely anisometropic monkeys are moderately lower than those for the fellow eye.
In visual area 2 (V2), the ocular dominance shift away from the affected eye is more pronounced than that in V1 ( Fig. 40.7B ). Under binocular viewing, the disparity sensitivity of V2 neurons is significantly reduced, and this disparity sensitivity loss in V2 is more severe than that in V1 ( Fig. 40.7C ). Also, binocular suppression is highly prevalent in V2 as in V1. The monocular spatial RF properties of neurons driven by the affected eye (e.g., orientation bias, optimal spatial frequency, and RF center-surround sizes) are subnormal, and the overall sensitivity of those V2 neurons is lower than that of normal cells. Moreover, the RF spatial structure of V2 neurons, the “orderliness” in the spatial organization of RF “subfields,” is severely disrupted, and the degree of such RF disorganization is directly correlated with the magnitude of binocular suppression (see Fig. 40.16B ). Neurons in V2 exhibit elevated and “noisy” spontaneous activity and contrast-dependent noisy spiking during visual stimulation, for example, increased variations in interspike intervals (spiking irregularity) and trial-to-trial fluctuations in spiking (Fano factor). This noisy spiking is well correlated with the strength of binocular suppression ( Fig. 40.15C ). In MT of monkeys reared with monocular defocus, the ocular dominance distribution is shifted away from the affected eye, and the size of such shift is greater than that in V1. The affected MT neurons show abnormal motion sensitivity (e.g., elevated coherent motion threshold, increased preferred stimulus speed) and shorter integration time.
Alternating defocus
Early monocular defocus can be alternated daily between the two eyes to prevent the development of monocular perceptual deficits (e.g., amblyopia). If infant monkeys experience alternating defocus, the monocular response properties of V1 neurons, such as orientation selectivity, spatial-frequency tuning, and/or spatial resolution, do not show response alterations that favor one eye over the other, because each eye receives uninterrupted vision on alternate days during early infancy. However, daily alternating defocus leads to a spatial frequency–dependent loss of local stereopsis (elevated disparity threshold) ( Fig. 40.8B ). This reduction of local stereopsis is exaggerated for high-spatial-frequency stimuli because larger defocus generates greater conflicts between signals coming from the two eyes. Moreover, the disparity sensitivities of V1 neurons are significantly reduced in these monkeys, and this reduction is also spatial-frequency dependent.
These observations support the traditional view that local stereopsis is spatial-frequency dependent, and that binocular disparity information is processed by independent channels tuned to different spatial frequencies. It is also evident that the local disparity processing mechanisms in V1 can be independently compromised by early abnormal visual experience depending on their spatial frequency–tuning properties. Finally, the effects of early alternating defocus on binocular vision development underscore the importance of having the normal presence of disparity-sensitive neurons in V1 for local stereopsis, although disparity-sensitive V1 neurons alone are not sufficient to support fine stereopsis (i.e., it requires further processing by extrastriate neurons).
Effects of early strabismus
Strabismus is a chronic deviation of the visual axes that emerges shortly after birth. The direction of the axis deviation can be convergent (esotropia), divergent (exotropia), or vertical (hypertropia). The etiology of infantile or congenital strabismus is not known. There is a clear familial tendency of developing strabismus, but the genetic factors responsible for infantile strabismus are not well understood. In monkeys and humans, a high degree of uncorrected hypermetropia soon after birth is known to result in esotropia (accommodative esotropia).
Perceptual deficits
Strabismic infants experience double vision (diplopia) immediately after the onset of misalignment. If “normal” alignment is not achieved in a timely manner, binocular vision anomalies, such as deficient stereoscopic vision ( Fig. 40.9 ), reduced binocular summation of contrast sensitivity, and clinical suppression, are likely to develop. Amblyopia may develop if strabismus is not treated for an extended period of time during the critical period.
Animal models of strabismus
The effects of experiencing early strabismus have been extensively studied in animals by artificially creating ocular misalignment shortly after birth. In monkey or cat models, human strabismus is commonly simulated by surgical or optical methods shortly after birth. The basic idea of either method is to disrupt binocular vision development. Also, alternating monocular occlusion (AOM) from birth leads to strabismus as mentioned previously, and these monkey models have served primarily for studies on ocular motility. For the surgical method, the extraocular muscle of one eye (the medial rectus muscle for exotropia and the lateral rectus muscle for esotropia) is sectioned and the opposing muscle (the lateral or medial rectus muscle, respectively) is tied to induce the misalignment. The surgical method creates a period of noncomitant or paralytic strabismus, that is, the angle of deviation changes with the field of gaze. This type of strabismus is less common in humans than comitant strabismus, that is, the angle of deviation does not change with the field of gaze. In monkeys with surgical strabismus, the manipulated eye is immediately placed at a competitive disadvantage and the nondeviating fellow eye becomes the “fixating” eye. As a result, the deviating eye is likely to develop amblyopia.
For the optical method, infant monkeys are fitted with a helmet with a pair of base-in or base-out prisms around 3 to 4 weeks of age. This method simulates comitant strabismus in humans. If the prism rearing begins at birth, ocular misalignment, exotropia or esotropia, develops. Neither eye is disadvantaged because their fixation frequently alternates between the two eyes, and thus the prism-reared monkeys are less likely to develop amblyopia. However, the effects of early surgical or optical strabismus are quite devastating on the perceptual and neural development of binocular vision.
Neural deficits
The proportion of V1 and V2 neurons that can be activated by stimulation of either eye (classically defined as “binocular cells”) is dramatically reduced in monkeys reared with surgical or optical strabismus ( Fig. 40.10A ). In monkeys reared with paralytic strabismus, the ocular dominance distribution of V1 neurons may slightly shift away from the deviating eye if strabismus is severe or does not shift at all ( Fig. 40.10A ). Larger shifts in ocular dominance distribution are evident in V2 ( Fig. 40.10A ) and the MT of monkeys with simulated paralytic strabismus. The proportion of disparity-sensitive neurons is drastically reduced in V1 of stereo-deficient monkeys reared with optical strabismus ( Figs. 40.10C, 40.11A, and 40.12B ), and in both V1 and V2 of monkeys reared with surgical strabismus ( Fig. 40.10C ).
