Spiking Noise and Information Density of Neurons in Visual Area V2 of Infant Monkeys.

Encoding of visual information requires precisely timed spiking activity in the network of cortical neurons; irregular spiking can interfere with information processing especially for low-contrast images. The vision of newborn infants is impoverished. An infant's contrast sensitivity is low and the ability to discriminate complex stimuli is poor. The neural mechanisms that limit the visual capacities of infants are a matter of debate. Here we asked whether noisy spiking and/or crude information processing in visual cortex limit infant vision. Since neurons beyond the primary visual cortex (V1) have rarely been studied in neonates or infants, we focused on the firing pattern of neurons in visual area V2, the earliest extrastriate visual area of both male and female macaque monkeys (Maccaca mulatta). For eight stimulus contrasts ranging from 0% to 80%, we analyzed spiking irregularity by calculating the square of the coefficient of variation (CV2) in interspike intervals, the trial-to-trial fluctuation in spiking (Fano factor), and the amount of information on contrast conveyed by each spiking (information density). While the contrast sensitivity of infant neurons was reduced as expected, spiking noise, both the magnitude of spiking irregularity and the trial-to-trial fluctuations, was much lower in the spike trains of infant V2 neurons compared with those of adults. However, information density for V2 neurons was significantly lower in infants. Our results suggest that poor contrast sensitivity combined with lower information density of extrastriate neurons, despite their lower spiking noise, may limit behaviorally determined contrast sensitivity soon after birth.SIGNIFICANCE STATEMENT Despite >50 years of investigations on the postnatal development of the primary visual cortex (V1), cortical mechanisms that may limit infant vision are still unclear. We investigated the quality and strength of neuronal firing in primate visual area V2 by analyzing contrast sensitivity, spiking variability, and the amount of information on contrast conveyed by each action potential (information density). Here we demonstrate that the firing rate, contrast sensitivity, and dynamic range of V2 neurons were depressed in infants compared with adults. Although spiking noise was less, information density was lower in infant V2. Impoverished neuronal drive and lower information density in extrastriate visual areas, despite lower spiking noise, largely explain the impoverished visual sensitivity of primates near birth.

Long-term histological changes in the macaque primary visual cortex and the lateral geniculate nucleus after monocular deprivation produced by early restricted retinal lesions and diffuser induced form deprivation.

Ocular dominance (OD) plasticity has been extensively studied in various mammalian species. While robust OD shifts are typically observed after monocular eyelid suture, relatively poor OD plasticity is observed for early eye removal or after tetrodotoxin (TTX) injections in mice. Hence, abnormal binocular signal interactions in the visual cortex may play a critical role in eliciting OD plasticity. Here, we examined the histochemical changes in the lateral geniculate nucleus (LGN) and the striate cortex (V1) in macaque monkeys that experienced two different monocular sensory deprivations in the same eye beginning at 3 weeks of age: restricted laser lesions in macular or peripheral retina and form deprivation induced by wearing a diffuser lens during the critical period. The monkeys were subsequently reared for 5 years under a normal visual environment. In the LGN, atrophy of neurons and a dramatic increase of GFAP expression were observed in the lesion projection zones (LPZs). In V1, although no obvious shift of the LPZ border was found, the ocular dominance columns (ODCs) for the lesioned eye shrunk and those for the intact eye expanded over the entirety of V1. This ODC size change was larger in the area outside the LPZ and in the region inside the LPZ near the border compared to that in the LPZ center. These developmental changes may reflect abnormal binocular interactions in V1 during early infancy. Our observations provide insights into the nature of degenerative and plastic changes in the LGN and V1 following early chronic monocular sensory deprivations.

Observations on the relationship between anisometropia, amblyopia and strabismus.

We investigated the potential causal relationships between anisometropia, amblyopia and strabismus, specifically to determine whether either amblyopia or strabismus interfered with emmetropization. We analyzed data from non-human primates that were relevant to the co-existence of anisometropia, amblyopia and strabismus in children. We relied on interocular comparisons of spatial vision and refractive development in animals reared with 1) monocular form deprivation; 2) anisometropia optically imposed by either contact lenses or spectacle lenses; 3) organic amblyopia produced by laser ablation of the fovea; and 4) strabismus that was either optically imposed with prisms or produced by either surgical or pharmacological manipulation of the extraocular muscles. Hyperopic anisometropia imposed early in life produced amblyopia in a dose-dependent manner. However, when potential methodological confounds were taken into account, there was no support for the hypothesis that the presence of amblyopia interferes with emmetropization or promotes hyperopia or that the degree of image degradation determines the direction of eye growth. To the contrary, there was strong evidence that amblyopic eyes were able to detect the presence of a refractive error and alter ocular growth to eliminate the ametropia. On the other hand, early onset strabismus, both optically and surgically imposed, disrupted the emmetropization process producing anisometropia. In surgical strabismus, the deviating eyes were typically more hyperopic than their fellow fixating eyes. The results show that early hyperopic anisometropia is a significant risk factor for amblyopia. Early esotropia can trigger the onset of both anisometropia and amblyopia. However, amblyopia, in isolation, does not pose a significant risk for the development of hyperopia or anisometropia.

Noisy Spiking in Visual Area V2 of Amblyopic Monkeys.

Interocular decorrelation of input signals in developing visual cortex can cause impaired binocular vision and amblyopia. Although increased intrinsic noise is thought to be responsible for a range of perceptual deficits in amblyopic humans, the neural basis for the elevated perceptual noise in amblyopic primates is not known. Here, we tested the idea that perceptual noise is linked to the neuronal spiking noise (variability) resulting from developmental alterations in cortical circuitry. To assess spiking noise, we analyzed the contrast-dependent dynamics of spike counts and spiking irregularity by calculating the square of the coefficient of variation in interspike intervals (CV2) and the trial-to-trial fluctuations in spiking, or mean matched Fano factor (m-FF) in visual area V2 of monkeys reared with chronic monocular defocus. In amblyopic neurons, the contrast versus response functions and the spike count dynamics exhibited significant deviations from comparable data for normal monkeys. The CV2 was pronounced in amblyopic neurons for high-contrast stimuli and the m-FF was abnormally high in amblyopic neurons for low-contrast gratings. The spike count, CV2, and m-FF of spontaneous activity were also elevated in amblyopic neurons. These contrast-dependent spiking irregularities were correlated with the level of binocular suppression in these V2 neurons and with the severity of perceptual loss for individual monkeys. Our results suggest that the developmental alterations in normalization mechanisms resulting from early binocular suppression can explain much of these contrast-dependent spiking abnormalities in V2 neurons and the perceptual performance of our amblyopic monkeys. SIGNIFICANCE STATEMENT: Amblyopia is a common developmental vision disorder in humans. Despite the extensive animal studies on how amblyopia emerges, we know surprisingly little about the neural basis of amblyopia in humans and nonhuman primates. Although the vision of amblyopic humans is often described as being noisy by perceptual and modeling studies, the exact nature or origin of this elevated perceptual noise is not known. We show that elevated and noisy spontaneous activity and contrast-dependent noisy spiking (spiking irregularity and trial-to-trial fluctuations in spiking) in neurons of visual area V2 could limit the visual performance of amblyopic primates. Moreover, we discovered that the noisy spiking is linked to a high level of binocular suppression in visual cortex during development.

Early monocular defocus disrupts the normal development of receptive-field structure in V2 neurons of macaque monkeys.

Experiencing different quality images in the two eyes soon after birth can cause amblyopia, a developmental vision disorder. Amblyopic humans show the reduced capacity for judging the relative position of a visual target in reference to nearby stimulus elements (position uncertainty) and often experience visual image distortion. Although abnormal pooling of local stimulus information by neurons beyond striate cortex (V1) is often suggested as a neural basis of these deficits, extrastriate neurons in the amblyopic brain have rarely been studied using microelectrode recording methods. The receptive field (RF) of neurons in visual area V2 in normal monkeys is made up of multiple subfields that are thought to reflect V1 inputs and are capable of encoding the spatial relationship between local stimulus features. We created primate models of anisometropic amblyopia and analyzed the RF subfield maps for multiple nearby V2 neurons of anesthetized monkeys by using dynamic two-dimensional noise stimuli and reverse correlation methods. Unlike in normal monkeys, the subfield maps of V2 neurons in amblyopic monkeys were severely disorganized: subfield maps showed higher heterogeneity within each neuron as well as across nearby neurons. Amblyopic V2 neurons exhibited robust binocular suppression and the strength of the suppression was positively correlated with the degree of hereogeneity and the severity of amblyopia in individual monkeys. Our results suggest that the disorganized subfield maps and robust binocular suppression of amblyopic V2 neurons are likely to adversely affect the higher stages of cortical processing resulting in position uncertainty and image distortion.

Oblique effect in visual area 2 of macaque monkeys.

The neural basis of an oblique effect, a reduced visual sensitivity for obliquely oriented stimuli, has been a matter of considerable debate. We have analyzed the orientation tuning of a relatively large number of neurons in the primary visual cortex (V1) and visual area 2 (V2) of anesthetized and paralyzed macaque monkeys. Neurons in V2 but not V1 of macaque monkeys showed clear oblique effects. This orientation anisotropy in V2 was more robust for those neurons that preferred higher spatial frequencies. We also determined whether V1 and V2 neurons exhibit a similar orientation anisotropy soon after birth. The oblique effect was absent in V1 of 4- and 8-week-old infant monkeys, but their V2 neurons showed a significant oblique effect. This orientation anisotropy in infant V2 was milder than that in adults. The results suggest that the oblique effect emerges in V2 based on the pattern of the connections that are established before birth and enhanced by the prolonged experience-dependent modifications of the neural circuitry in V2.

Receptive-field subfields of V2 neurons in macaque monkeys are adult-like near birth.

Infant primates can discriminate texture-defined form despite their relatively low visual acuity. The neuronal mechanisms underlying this remarkable visual capacity of infants have not been studied in nonhuman primates. Since many V2 neurons in adult monkeys can extract the local features in complex stimuli that are required for form vision, we used two-dimensional dynamic noise stimuli and local spectral reverse correlation to measure whether the spatial map of receptive-field subfields in individual V2 neurons is sufficiently mature near birth to capture local features. As in adults, most V2 neurons in 4-week-old monkeys showed a relatively high degree of homogeneity in the spatial matrix of facilitatory subfields. However, ∼25% of V2 neurons had the subfield map where the neighboring facilitatory subfields substantially differed in their preferred orientations and spatial frequencies. Over 80% of V2 neurons in both infants and adults had "tuned" suppressive profiles in their subfield maps that could alter the tuning properties of facilitatory profiles. The differences in the preferred orientations between facilitatory and suppressive profiles were relatively large but extended over a broad range. Response immaturities in infants were mild; the overall strength of facilitatory subfield responses was lower than that in adults, and the optimal correlation delay ("latency") was longer in 4-week-old infants. These results suggest that as early as 4 weeks of age, the spatial receptive-field structure of V2 neurons is as complex as in adults and the ability of V2 neurons to compare local features of neighboring stimulus elements is nearly adult like.

Dynamics of spatial frequency tuning in mouse visual cortex.

Neuronal spatial frequency tuning in primary visual cortex (V1) substantially changes over time. In both primates and cats, a shift of the neuron's preferred spatial frequency has been observed from low frequencies early in the response to higher frequencies later in the response. In most cases, this shift is accompanied by a decreased tuning bandwidth. Recently, the mouse has gained attention as a suitable animal model to study the basic mechanisms of visual information processing, demonstrating similarities in basic neuronal response properties between rodents and highly visual mammals. Here we report the results of extracellular single-unit recordings in the anesthetized mouse where we analyzed the dynamics of spatial frequency tuning in V1 and the lateromedial area LM within the lateral extrastriate area V2L. We used a reverse-correlation technique to demonstrate that, as in monkeys and cats, the preferred spatial frequency of mouse V1 neurons shifted from low to higher frequencies later in the response. However, this was not correlated with a clear selectivity increase or enhanced suppression of responses to low spatial frequencies. These results suggest that the neuronal connections responsible for the temporal shift in spatial frequency tuning may considerably differ between mice and monkeys.

Cortical and subcortical connections of V1 and V2 in early postnatal macaque monkeys.

Connections of primary (V1) and secondary (V2) visual areas were revealed in macaque monkeys ranging in age from 2 to 16 weeks by injecting small amounts of cholera toxin subunit B (CTB). Cortex was flattened and cut parallel to the surface to reveal injection sites, patterns of labeled cells, and patterns of cytochrome oxidase (CO) staining. Projections from the lateral geniculate nucleus and pulvinar to V1 were present at 4 weeks of age, as were pulvinar projections to thin and thick CO stripes in V2. Injections into V1 in 4- and 8-week-old monkeys labeled neurons in V2, V3, middle temporal area (MT), and dorsolateral area (DL)/V4. Within V1 and V2, labeled neurons were densely distributed around the injection sites, but formed patches at distances away from injection sites. Injections into V2 labeled neurons in V1, V3, DL/V4, and MT of monkeys 2-, 4-, and 8-weeks of age. Injections in thin stripes of V2 preferentially labeled neurons in other V2 thin stripes and neurons in the CO blob regions of V1. A likely thick stripe injection in V2 at 4 weeks of age labeled neurons around blobs. Most labeled neurons in V1 were in superficial cortical layers after V2 injections, and in deep layers of other areas. Although these features of adult V1 and V2 connectivity were in place as early as 2 postnatal weeks, labeled cells in V1 and V2 became more restricted to preferred CO compartments after 2 weeks of age.

Effects of brief daily periods of unrestricted vision during early monocular form deprivation on development of visual area 2.

PURPOSE: Providing brief daily periods of unrestricted vision during early monocular form deprivation reduces the depth of amblyopia. To gain insights into the neural basis of the beneficial effects of this treatment, the binocular and monocular response properties of neurons were quantitatively analyzed in visual area 2 (V2) of form-deprived macaque monkeys. METHODS: Beginning at 3 weeks of age, infant monkeys were deprived of clear vision in one eye for 12 hours every day until 21 weeks of age. They received daily periods of unrestricted vision for 0, 1, 2, or 4 hours during the form-deprivation period. After behavioral testing to measure the depth of the resulting amblyopia, microelectrode-recording experiments were conducted in V2. RESULTS: The ocular dominance imbalance away from the affected eye was reduced in the experimental monkeys and was generally proportional to the reduction in the depth of amblyopia in individual monkeys. There were no interocular differences in the spatial properties of V2 neurons in any subject group. However, the binocular disparity sensitivity of V2 neurons was significantly higher and binocular suppression was lower in monkeys that had unrestricted vision. CONCLUSIONS: The decrease in ocular dominance imbalance in V2 was the neuronal change most closely associated with the observed reduction in the depth of amblyopia. The results suggest that the degree to which extrastriate neurons can maintain functional connections with the deprived eye (i.e., reducing undersampling for the affected eye) is the most significant factor associated with the beneficial effects of brief periods of unrestricted vision.

Receptive-field properties of V1 and V2 neurons in mice and macaque monkeys.

We report the results of extracellular single-unit recording experiments where we quantitatively analyzed the receptive-field (RF) properties of neurons in V1 and an adjacent extrastriate visual area (V2L) of anesthetized mice with emphasis on the RF center-surround organization. We compared the results with the RF center-surround organization of V1 and V2 neurons in macaque monkeys. If species differences in spatial scale are taken into consideration, mouse V1 and V2L neurons had remarkably fine stimulus selectivity, and the majority of response properties in V2L were not different from those in V1. The RF center-surround organization of mouse V1 neurons was qualitatively similar to that for macaque monkeys (i.e., the RF center is surrounded by extended suppressive regions). However, unlike in monkey V2, a significant proportion of cortical neurons, largely complex cells in V2L, did not exhibit quantifiable RF surround suppression. Simple cells had smaller RF centers than complex cells, and the prevalence and strength of surround suppression were greater in simple cells than in complex cells. These findings, particularly on the RF center-surround organization of visual cortical neurons, give new insights into the principles governing cortical circuits in the mouse visual cortex and should provide further impetus for the use of mice in studies on the genetic and molecular basis of RF development and synaptic plasticity.

Postnatal development of onset transient responses in macaque V1 AND V2 neurons.

Vision of newborn infants is limited by immaturities in their visual brain. In adult primates, the transient onset discharges of visual cortical neurons are thought to be intimately involved with capturing the rapid succession of brief images in visual scenes. Here we sought to determine the responsiveness and quality of transient responses in individual neurons of the primary visual cortex (V1) and visual area 2 (V2) of infant monkeys. We show that the transient component of neuronal firing to 640-ms stationary gratings was as robust and as reliable as in adults only 2 wk after birth, whereas the sustained component was more sluggish in infants than in adults. Thus the cortical circuitry supporting onset transient responses is functionally mature near birth, and our findings predict that neonates, known for their "impoverished vision," are capable of initiating relatively mature fixating eye movements and of performing in detection of simple objects far better than traditionally thought.

Effects of fixation instability on multifocal VEP (mfVEP) responses in amblyopes.

The cortical activity of subjects with compromised central vision (e.g., amblyopes) is thought to be much weaker for stimulation of the affected eye than in the fellow eye. Because these subjects are known to exhibit considerable difficulties in keeping steady fixation, we investigated the effects of anomalous fixation on their multifocal visual-evoked potential (mfVEP) responses using a dual Purkinje image (dPi) eye tracker. Our results show that mfVEP responses to stimulation of the central 5 degrees were depressed in the affected eye compared to those in the normal eye and the magnitude of response reductions was proportional to the degree of visual acuity loss in amblyopic subjects. Fixation was far less stable while viewing with the affected eye than with the fellow eye, some exhibiting jerk nystagmus and/or saccadic oscillations. Normal subjects with artificially imposed nystagmus showed similar reductions of VEP responses. The relative magnitudes of the deficits in mfVEP responses were tightly correlated with the degree of fixation instability. These results suggest that the interpretation of anomalous neural or perceptual processing in amblyopic subjects must take the effects of unsteady fixation during measurements into consideration in order to reveal the true nature and extent of sensory neural deficits.

Neuroscience: rewiring the adult brain.

Any analysis of plastic reorganization at a neuronal locus needs a veridical measure of changes in the functional output--that is, spiking responses of the neurons in question. In a study of the effect of retinal lesions on adult primary visual cortex (V1), Smirnakis et al. propose that there is no cortical reorganization. Their results are based, however, on BOLD (blood-oxygen-level-dependent) fMRI (functional magnetic resonance imaging), which provides an unreliable gauge of spiking activity. We therefore question their criterion for lack of plasticity, particularly in the light of the large body of earlier work that demonstrates cortical plasticity.

Directional bias of neurons in V1 and V2 of strabismic monkeys: temporal-to-nasal asymmetry?

PURPOSE: Strabismus that develops shortly after birth is known to cause temporal-to-nasal eye movement asymmetries under monocular viewing. The neural mechanisms underlying this deficit are not well understood. In the current study, the hypothesis that this eye movement anomaly reflects a similar asymmetry in the directional response properties of neurons in the early stages of cortical processing was examined. METHODS: Strabismus was simulated with optical methods in infant monkeys between 4 and 14 weeks of age. When the monkeys were mature, microelectrode recording experiments were conducted in the primary visual cortex (V1) and visual area 2 (V2). After the spatial frequency of sine wave-grating stimuli for each neuron was optimized, each neuron's responsiveness to 24 directions of stimulus movement was measured. The preferred direction and the strength of directional bias were determined by a vector summation method: RESULTS: There was not an overabundance of neurons in V1 or V2 of strabismic monkeys preferring the temporal-to-nasal direction of stimulus movement. However, the average directional bias was significantly reduced in these strabismic monkeys. Interocular suppression was highly prevalent, and this suppression was stronger and more common in neurons dominated by the ipsilateral eye. CONCLUSIONS: The results suggest that the eye movement asymmetries in strabismic subjects do not result from similar asymmetries in the directional properties of V1 or V2 neurons, but rather reflect impoverished cortical signals to the brain stem nuclei that control eye movements.

Rapid plasticity of binocular connections in developing monkey visual cortex (V1).

The basic sets of cortical connections are present at birth in the primate visual system. The maintenance and refinement of these innate connections are highly dependent on normal visual experience, and prolonged exposure to binocularly uncorrelated signals early in life severely disrupts the normal development of binocular functions. However, very little is known about how rapidly these changes in the functional organization of primate visual cortex emerge or what are the sequence and the nature of the abnormal neural events that occur immediately after experiencing binocular decorrelation. In this study, we investigated how brief periods of ocular misalignment (strabismus) at the height of the critical period alter the cortical circuits that support binocular vision. After only 3 days of optically imposed strabismus, there was a striking increase in the prevalence of V1 neurons that exhibited binocular suppression, i.e., binocular responses were weaker than monocular responses. However, the sensitivity of these neurons to interocular spatial phase disparity was not significantly altered. These contrasting results suggest that the first significant change in V1 caused by early binocular decorrelation is binocular suppression, and that this suppression originates at a site(s) beyond where binocular signals are initially combined.

Effects of the duration of early strabismus on the binocular responses of neurons in the monkey visual cortex (V1).

PURPOSE: To determine how the duration of early strabismus influences the severity of loss of disparity sensitivity in V1 neurons and the effects of extensive poststrabismus visual experience on the maintenance of functional binocular connections. METHODS: Concomitant strabismus was optically simulated in 10 rhesus monkeys using a prism-rearing procedure. The onset of strabismus was kept constant at 4 weeks of age and the duration was maintained for 2, 4, or 8 weeks. In one group of monkeys (infants), the neurophysiological experiments were conducted immediately after the period of rearing with prisms. In another group (adults), after the termination of the prism-rearing regimen at either 8 or 12 weeks of age, the monkeys were kept in a normal housing environment until maturity and behavioral testing was conducted before the recording experiments to determine the animal's monocular and binocular visual capacities. To assess the effects of the period of early strabismus on binocular interactions in V1, extracellular single-unit recording methods were used in anesthetized and paralyzed monkeys, and dichoptic sine-wave gratings were used as stimuli. RESULTS: In all strabismic monkeys, the sensitivity of V1 units to interocular spatial phase disparity (disparity sensitivity) was significantly reduced, and the prevalence of binocular suppression was higher than that found in age-matched control animals. Although 8 weeks of strabismus resulted in a slightly larger loss of disparity sensitivity, the overall effects of the duration of strabismus were surprisingly small in infant strabismic monkeys. After poststrabismus visual experience, a small but significantly higher degree of disparity sensitivity was noted in V1 if prism-rearing was terminated after 4 weeks of strabismus (i.e., at 8 weeks of age), but not after 8 weeks of strabismus (i.e., at 12 weeks of age). CONCLUSIONS: A brief period (2 weeks) of misalignment after the emergence of stereopsis is sufficient to drastically reduce the functional binocular connections in V1, and longer periods of strabismus result in little additional loss in disparity sensitivity. Clinically, these results suggest that taking corrective measures for infantile esotropes before the known onset age for stereopsis may be important for maintaining better binocular sensory function and better interocular alignment at later stages of development.