Effects of experimental strabismus on the architecture of macaque monkey striate cortex.

Strabismus, a misalignment of the eyes, results in a loss of binocular visual function in humans. The effects are similar in monkeys, where a loss of binocular convergence onto single cortical neurons is always found. Changes in the anatomical organization of primary visual cortex (V1) may be associated with these physiological deficits, yet few have been reported. We examined the distributions of several anatomical markers in V1 of two experimentally strabismic Macaca nemestrina monkeys. Staining patterns in tangential sections were related to the ocular dominance (OD) column structure as deduced from cytochrome oxidase (CO) staining. CO staining appears roughly normal in the superficial layers, but in layer 4C, one eye's columns were pale. Thin, dark stripes falling near OD column borders are evident in Nissl-stained sections in all layers and in immunoreactivity for calbindin, especially in layers 3 and 4B. The monoclonal antibody SMI32, which labels a neurofilament protein found in pyramidal cells, is reduced in one eye's columns and absent at OD column borders. The pale SMI32 columns are those that are dark with CO in layer 4. Gallyas staining for myelin reveals thin stripes through layers 2-5; the dark stripes fall at OD column centers. All these changes appear to be related to the loss of binocularity in cortical neurons, which has its most profound effects near OD column borders.

Visual response properties of neurons in the LGN of normally reared and visually deprived macaque monkeys.

It is now well appreciated that parallel retino-geniculo-cortical pathways exist in the monkey as in the cat, the species in which parallel visual pathways were first and most thoroughly documented. What remains unclear is precisely how many separate pathways pass through the parvo- and magnocellular divisions of the macaque lateral geniculate nucleus (LGN), what relationships-homologous or otherwise-these pathways have to the cat's X, Y, and W pathways, and whether these are affected by visual deprivation. To address these issues of classification and trans-species comparison, we used achromatic stimuli to obtain an extensive set of quantitative measurements of receptive field properties in the parvo- and magnocellular laminae of the LGN of nine macaque monkeys: four normally reared and five monocularly deprived of vision by lid suture near the time of birth. In agreement with previous studies, we find that on average magnocellular neurons differ from parvocellular neurons by having shorter response latencies to optic chiasm stimulation, greater sensitivity to luminance contrast, and better temporal resolution. Magnocellular laminae are also distinguished by containing neurons that summate luminance over their receptive fields nonlinearly (Y cells) and whose temporal response phases decrease with increasing stimulus contrast (indicative of a contrast gain control mechanism). We found little evidence for major differences between magno- and parvocellular neurons on the basis of most spatial parameters except that at any eccentricity, the neurons with the smallest receptive field centers tended to be parvocellular. All parameters were distributed unimodally and continuously through the parvo- and magnocellular populations, giving no indications of subpopulations within each division. Monocular deprivation led to clear anatomical effects: cells in deprived-eye laminae were pale and shrunken compared with those in nondeprived eye laminae, and Cat-301 immunoreactivity in deprived laminae was essentially uniformly abolished. However, deprivation had only subtle effects on the response properties of LGN neurons. Neurons driven by the deprived eye in both magno- and parvocellular laminae had lower nonlinearity indices (i.e., summed signals across their receptive fields more linearly) and were somewhat less responsive. In magnocellular laminae driven by the deprived eye, neuronal response latencies to stimulation of the optic chiasm were slightly shorter than those in the nondeprived laminae, and receptive field surrounds were a bit stronger. No other response parameters were affected by deprivation, and there was no evidence for loss of a specific cell class as in the cat.

Visual motion analysis for pursuit eye movements in area MT of macaque monkeys.

We asked whether the dynamics of target motion are represented in visual area MT and how information about image velocity and acceleration might be extracted from the population responses in area MT for use in motor control. The time course of MT neuron responses was recorded in anesthetized macaque monkeys during target motions that covered the range of dynamics normally seen during smooth pursuit eye movements. When the target motion provided steps of target speed, MT neurons showed a continuum from purely tonic responses to those with large transient pulses of firing at the onset of motion. Cells with large transient responses for steps of target speed also had larger responses for smooth accelerations than for decelerations through the same range of target speeds. Condition-test experiments with pairs of 64 msec pulses of target speed revealed response attenuation at short interpulse intervals in cells with large transient responses. For sinusoidal modulation of target speed, MT neuron responses were strongly modulated for frequencies up to, but not higher than, 8 Hz. The phase of the responses was consistent with a 90 msec time delay between target velocity and firing rate. We created a model that reproduced the dynamic responses of MT cells using divisive gain control, used the model to visualize the population response in MT to individual stimuli, and devised weighted-averaging computations to reconstruct target speed and acceleration from the population response. Target speed could be reconstructed if each neuron's output was weighted according to its preferred speed. Target acceleration could be reconstructed if each neuron's output was weighted according to the product of preferred speed and a measure of the size of its transient response.

Factors limiting contrast sensitivity in experimentally amblyopic macaque monkeys.

Contrast detection is impaired in amblyopes. To understand the contrast processing deficit in amblyopia, we studied the effects of masking noise on contrast threshold in amblyopic macaque monkeys. Amblyopia developed as a result of either experimentally induced strabismus or anisometropia. We used random spatiotemporal broadband noise of varying contrast power to mask the detection of sinusoidal grating patches. We compared masking in the amblyopic and non-amblyopic eyes. From the masking functions, we calculated equivalent noise contrast (the noise power at which detection threshold was elevated by square root of 2) and signal-to-noise ratio (the ratio of threshold contrast to noise contrast at high noise power). The relation between contrast threshold and masking noise level was similar for amblyopic and non-amblyopic eyes. Although in most cases there was some elevation in equivalent noise for amblyopic compared to fellow eyes, signal-to-noise ratio showed greater variation with the extent of amblyopia. These results support the idea that the contrast detection deficit in amblyopia is a cortical deficit.

Pattern adaptation and cross-orientation interactions in the primary visual cortex.

The responsiveness of neurons in the primary visual cortex (V1) is substantially reduced after a few seconds of visual stimulation with an effective pattern. This phenomenon, called pattern adaptation, is uniquely cortical and is the likely substrate of a variety of perceptual after-effects. While adaptation to a given pattern reduces the responses of V1 neurons to all subsequently viewed test patterns, this reduction shows some specificity, being strongest when the adapting and test patterns are identical. This specificity may indicate that adaptation affects the interaction between groups of neurons that are jointly activated by the adapting stimulus. We investigated this possibility by studying the effects of adaptation to visual patterns containing one or both of two orientations--the preferred orientation for a cell, and the orientation orthogonal to it. Because neurons in the primary visual cortex are sharply tuned for orientation, stimulation with orthogonal orientations excites two largely distinct populations of neurons. With intracellular recordings of the membrane potential of cat V1 neurons, we found that adaptation to the orthogonal orientation alone does not evoke the hyperpolarization that is typical of adaptation to the preferred orientation. With extracellular recordings of the firing rate of macaque V1 neurons, we found that the responses were not reduced by adaptation to the orthogonal orientation alone nearly as much as by adaptation to the preferred orientation. In the macaque we also studied the effects of adaptation to plaids containing both the preferred and the orthogonal orientations. We found that adaptation to these stimuli could modify the interactions between orientations. It increased the amount of cross-orientation suppression displayed by some cells, even turning some cells that showed cross-orientation facilitation when adapted to a blank stimulus into cells that show cross-orientation suppression. This result suggests that pattern adaptation can affect the interaction between the groups of neurons tuned to the orthogonal orientations, either by increasing their mutual inhibition or by decreasing their mutual excitation.

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

Amblyopia is a developmental disorder of pattern vision. After surgical creation of esotropic strabismus in the first weeks of life or after wearing -10 diopter contact lenses in one eye to simulate anisometropia during the first months of life, macaques often develop amblyopia. We studied the response properties of visual cortex neurons in six amblyopic macaques; three monkeys were anisometropic, and three were strabismic. In all monkeys, cortical binocularity was reduced. In anisometropes, the amblyopic eye influenced a relatively small proportion of cortical neurons; in strabismics, the influence of the two eyes was more nearly equal. The severity of amblyopia was related to the relative strength of the input of the amblyopic eye to the cortex only for the more seriously affected amblyopes. Measurements of the spatial frequency tuning and contrast sensitivity of cortical neurons showed few differences between the eyes for the three less severe amblyopes (two strabismic and one anisometropic). In the three more severely affected animals (one strabismic and two anisometropic), the optimal spatial frequency and spatial resolution of cortical neurons driven by the amblyopic eye were substantially and significantly lower than for neurons driven by the nonamblyopic eye. There were no reliable differences in neuronal contrast sensitivity between the eyes. A sample of neurons recorded from cortex representing the peripheral visual field showed no interocular differences, suggesting that the effects of amblyopia were more pronounced in portions of the cortex subserving foveal vision. Qualitatively, abnormalities in both the eye dominance and spatial properties of visual cortex neurons were related on a case-by-case basis to the depth of amblyopia. Quantitative analysis suggests, however, that these abnormalities alone do not explain the full range of visual deficits in amblyopia. Studies of extrastriate cortical areas may uncover further abnormalities that explain these deficits.

Functional organization of owl monkey lateral geniculate nucleus and visual cortex.

The nocturnal, New World owl monkey (Aotus trivirgatus) has a rod-dominated retina containing only a single cone type, supporting only the most rudimentary color vision. However, it does have well-developed magnocellular (M) and parvocellular (P) retinostriate pathways and striate cortical architecture [as defined by the pattern of staining for the activity-dependent marker cytochrome oxidase (CO)] similar to that seen in diurnal primates. We recorded from single neurons in anesthetized, paralyzed owl monkeys using drifting, luminance-modulated sinusoidal gratings, comparing receptive field properties of M and P neurons in the lateral geniculate nucleus and in V1 neurons assigned to CO "blob," "edge," and "interblob" regions and across layers. Tested with achromatic stimuli, the receptive field properties of M and P neurons resembled those reported for other primates. The contrast sensitivity of P cells in the owl monkey was similar to that of P cells in the macaque, but the contrast sensitivities of M cells in the owl monkey were markedly lower than those in the macaque. We found no differences in eye dominance, orientation, or spatial frequency tuning, temporal frequency tuning, or contrast response for V1 neurons assigned to different CO compartments; we did find fewer direction-selective cells in blobs than in other compartments. We noticed laminar differences in some receptive field properties. Cells in the supragranular layers preferred higher spatial and lower temporal frequencies and had lower contrast sensitivity than did cells in the granular and infragranular layers. Our data suggest that the receptive field properties across functional compartments in V1 are quite homogeneous, inconsistent with the notion that CO blobs anatomically segregate signals from different functional "streams."

Spacing of cytochrome oxidase blobs in visual cortex of normal and strabismic monkeys.

Some models of visual cortical development are based on the assumption that the tangential organization of V1 is not determined prior to visual experience. In these models, correlated binocular activity is a key element in the formation of visual cortical columns, and when the degree of interocular correlation is reduced the models predict an increase in column spacing. To examine this prediction we measured the spacing of columns, as defined by cytochrome oxidase (CO) blobs, in the visual cortex of monkeys whose binocular vision was either normal or disrupted by a strabismus. The spatial distribution of blobs was examined in seven normal and five strabismic macaques. Tangential sections through the upper layers of the visual cortex were stained to reveal the two-dimensional (2D) pattern of CO blobs. Each blob was localized and their center-to-center spacing, packing arrangement and density were calculated using 2D nearest-neighbor spatial analyses. The mean center-to-center spacing of blobs (590 microm for normally reared and 598 microm for strabismic macaques) and the mean density of blobs (3.67 blobs/mm2 for normally reared and 3.45 blobs/mm2 for strabismic macaques) were not significantly different. In addition, the 2D packing arrangement of the blobs was not affected by strabismus. While it is clear that neural activity plays a key role in the elaboration and refinement of ocular dominance cortical modules, we conclude that it does not determine the spatial period of the pattern of CO blobs. This suggests that aspects of the neural circuitry underlying the columnar architecture of the visual cortex are established prenatally and its fundamental periodicity is not modifiable by experience.

Processing of first- and second-order motion signals by neurons in area MT of the macaque monkey.

Extrastriate cortical area MT is thought to process behaviorally important visual motion signals. Psychophysical studies suggest that visual motion signals may be analyzed by multiple mechanisms, a "first-order" one based on luminance, and a "second-order" one based upon higher level cues (e.g. contrast, flicker). Second-order motion is visible to human observers, but should be invisible to first-order motion sensors. To learn if area MT is involved in the analysis of second-order motion, we measured responses to first- and second-order gratings of single neurons in area MT (and in one experiment, in area V1) in anesthetized, paralyzed macaque monkeys. For each neuron, we measured directional and spatio-temporal tuning with conventional first-order gratings and with second-order gratings created by spatial modulation of the flicker rate of a random texture. A minority of MT and V1 neurons exhibited significant selectivity for direction or orientation of second-order gratings. In nearly all cells, response to second-order motion was weaker than response to first-order motion. MT cells with significant selectivity for second-order motion tended to be more responsive and more sensitive to luminance contrast, but were in other respects similar to the remaining MT neurons; they did not appear to represent a distinct subpopulation. For those cells selective for second-order motion, we found a correlation between the preferred directions of first- and second-order motion, and weak correlations in preferred spatial frequency. These cells preferred lower temporal frequencies for second-order motion than for first-order motion. A small proportion of MT cells seemed to remain selective and responsive for second-order motion. None of our small sample of V1 cells did. Cells in this small population, but not others, may perform "form-cue invariant" motion processing (Albright, 1992).

Peripheral and central factors limiting the development of contrast sensitivity in macaque monkeys.

The aim of this study was to evaluate the contribution of peripheral and central factors to the development of visual sensitivity. We used the approach of (Pelli, 1981, 1990) to evaluate the hypothesis that intrinsic noise is high in infants compared with adults, and therefore sets an important limit on contrast sensitivity in infants. We measured contrast thresholds in the presence of various levels of dynamic spatiotemporal broadband noise in infant monkeys, and evaluated the developmental changes in contrast threshold and intrinsic noise. Our data show that intrinsic noise is high in infants and falls with contrast threshold during development. However, contrast thresholds in high-contrast noise also fall during development, although by a smaller amount. Therefore, while changes in intrinsic noise set an important limit on the development of contrast sensitivity across spatial frequencies, changes in non-additive sources of noise also contribute, particularly at high spatial frequencies. We interpret these results in terms of Pelli's hypothesis about the sources of additive and non-additive noise affecting visual detection. In these terms, additive noise reflects peripheral factors and non-additive noise reflects central ones. Our results suggest that changes in peripheral sources of noise represent an important limit for the development of visual sensitivity.

Linearity and normalization in simple cells of the macaque primary visual cortex.

Simple cells in the primary visual cortex often appear to compute a weighted sum of the light intensity distribution of the visual stimuli that fall on their receptive fields. A linear model of these cells has the advantage of simplicity and captures a number of basic aspects of cell function. It, however, fails to account for important response nonlinearities, such as the decrease in response gain and latency observed at high contrasts and the effects of masking by stimuli that fail to elicit responses when presented alone. To account for these nonlinearities we have proposed a normalization model, which extends the linear model to include mutual shunting inhibition among a large number of cortical cells. Shunting inhibition is divisive, and its effect in the model is to normalize the linear responses by a measure of stimulus energy. To test this model we performed extracellular recordings of simple cells in the primary visual cortex of anesthetized macaques. We presented large stimulus sets consisting of (1) drifting gratings of various orientations and spatiotemporal frequencies; (2) plaids composed of two drifting gratings; and (3) gratings masked by full-screen spatiotemporal white noise. We derived expressions for the model predictions and fitted them to the physiological data. Our results support the normalization model, which accounts for both the linear and the nonlinear properties of the cells. An alternative model, in which the linear responses are subject to a compressive nonlinearity, did not perform nearly as well.

Adaptation to contingencies in macaque primary visual cortex.

We tested the hypothesis that neurons in the primary visual cortex (V1) adapt selectively to contingencies in the attributes of visual stimuli. We recorded from single neurons in macaque V1 and measured the effects of adaptation either to the sum of two gratings (compound stimulus) or to the individual gratings. According to our hypothesis, there would be a component of adaptation that is specific to the compound stimulus. In a first series of experiments, the two gratings differed in orientation. One grating had optimal orientation and the other was orthogonal to it, and therefore did not activate the neuron under study. These experiments provided evidence in favour of our hypothesis. In most cells adaptation to the compound stimulus reduced responses to the compound stimulus more than it reduced responses to the optimal grating, and the responses to the compound stimulus were reduced more by adaptation to the compound stimulus than by adaptation to the individual gratings. This suggests that a component of adaptation was specific to (and caused by) the simultaneous presence of the two orientations in the compound stimulus. To test whether V1 neurons could adapt to other contingencies in the stimulus attributes, we performed a second series of experiments, in which the component gratings were parallel but differed in spatial frequency, and were both effective in activating the neuron under study. These experiments failed to reveal convincing contingent effects of adaptation, suggesting that neurons cannot adapt equally well to all types of contingency.

Visual response properties of striate cortical neurons projecting to area MT in macaque monkeys.

We have previously shown that some neurons in extrastriate area MT are capable of signaling the global motion of complex patterns; neurons randomly sampled from V1, on the other hand, respond only to the motion of individual oriented components. Because only a small fraction of V1 neurons projects to MT, we wished to establish the processing hierarchy more precisely by studying the properties of those neurons projecting to MT, identified by antidromic responses to electrical stimulation of MT. The neurons that project from V1 to MT were directionally selective and, like other V1 neurons, responded only to the motion of the components of complex patterns. The projection neurons were predominantly "special complex," responsive to a broad range of spatial and temporal frequencies, and sensitive to very low stimulus contrasts. The projection neurons thus comprise a homogeneous and highly specialized subset of V1 neurons, consistent with the notion that V1 acts as clearing house of basic visual measurements, distributing information appropriately to higher cortical areas for specialized analysis.

Spike train encoding by regular-spiking cells of the visual cortex.

1. To study the encoding of input currents into output spike trains by regular-spiking cells, we recorded intracellularly from slices of the guinea pig visual cortex while injecting step, sinusoidal, and broadband noise currents. 2. When measured with sinusoidal currents, the frequency tuning of the spike responses was markedly band-pass. The preferred frequency was between 8 and 30 Hz, and grew with stimulus amplitude and mean intensity. 3. Stimulation with broadband noise currents dramatically enhanced the gain of the spike responses at low and high frequencies, yielding an essentially flat frequency tuning between 0.1 and 130 Hz. 4. The averaged spike responses to sinusoidal currents exhibited two nonlinearities: rectification and spike synchronization. By contrast, no nonlinearity was evident in the averaged responses to broadband noise stimuli. 5. These properties of the spike responses were not present in the membrane potential responses. The latter were roughly linear, and their frequency tuning was low-pass and well fit by a single-compartment passive model of the cell membrane composed of a resistance and a capacitance in parallel (RC circuit). 6. To account for the spike responses, we used a "sandwich model" consisting of a low-pass linear filter (the RC circuit), a rectification nonlinearity, and a high-pass linear filter. The model is described by six parameters and predicts analog firing rates rather than discrete spikes. It provided satisfactory fits to the firing rate responses to steps, sinusoids, and broadband noise currents. 7. The properties of spike encoding are consistent with temporal nonlinearities of the visual responses in V1, such as the dependence of response frequency tuning and latency on stimulus contrast and bandwidth. We speculate that one of the roles of the high-frequency membrane potential fluctuations observed in vivo could be to amplify and linearize the responses to lower, stimulus-related frequencies.

Effects of early-onset artificial strabismus on pursuit eye movements and on neuronal responses in area MT of macaque monkeys.

In humans, esotropia of early onset is associated with a profound asymmetry in smooth pursuit eye movements. When viewing is monocular, targets are tracked well only when they are moving nasally with respect to the viewing eye. To determine whether this pursuit abnormality reflects an anomaly in cortical visual motion processing, we recorded eye movements and cortical neural responses in nonamblyopic monkeys made strabismic by surgery at the age of 10-60 d. Eye movement recordings revealed the same asymmetry in the monkeys' pursuit eye movements as in humans with early-onset esotropia. With monocular viewing, pursuit was much stronger for nasalward motion than for temporalward motion, especially for targets presented in the nasal visual field. However, for targets presented during ongoing pursuit, temporalward and nasalward image motion was equally effective in modulating eye movement. Single-unit recordings made from the same monkeys, under anesthesia, revealed that MT neurons were rarely driven binocularly, but otherwise had normal response properties. Most were directionally selective, and their direction preferences were uniformly distributed. Our neurophysiological and oculomotor measurements both suggest that the pursuit defect in these monkeys is not due to altered cortical visual motion processing. Rather, the asymmetry in pursuit may be a consequence of imbalances in the two eyes' inputs to the "downstream" areas responsible for the initiation of pursuit.

Using computation to help relate neurobiology and behaviour.

Studies of the neural basis of perceptual experience must relate the activity of sensory neurons to the behaviour of observers. Computational techniques can provide an important tool to help bridge the wide gap that exists between these two kinds of information.

A computational analysis of the relationship between neuronal and behavioral responses to visual motion.

We have documented previously a close relationship between neuronal activity in the middle temporal visual area (MT or V5) and behavioral judgments of motion (Newsome et al., 1989; Salzman et al., 1990; Britten et al., 1992; Britten et al., 1996). We have now used numerical simulations to try to understand how neural signals in area MT support psychophysical decisions. We developed a model that pools neuronal responses drawn from our physiological data set and compares average responses in different pools to produce psychophysical decisions. The structure of the model allows us to assess the relationship between "neuronal" input signals and simulated psychophysical performance using the same methods we have applied to real experimental data. We sought to reconcile three experimental observations: psychophysical performance (threshold sensitivity to motion stimuli embedded in noise), a trial-by-trial covariation between the neural response and the monkey's choices, and a modest correlation between pairs of MT neurons in their variable responses to identical visual stimuli. Our results can be most accurately simulated if psychophysical decisions are based on pools of at least 100 weakly correlated sensory neurons. The neurons composing the pools must include a broader range of sensitivities than we encountered in our MT recordings, presumably because of the inclusion of neurons whose optimal stimulus is different from the one being discriminated. Central sources of noise degrade the signal-to-noise ratio of the pooled signal, but this degradation is relatively small compared with the noise typically carried by single cortical neurons. This suggests that our monkeys base near-threshold psychophysical judgments on signals carried by populations of weakly interacting neurons; these populations include many neurons that are not tuned optimally for the particular stimuli being discriminated.

Cortical oscillatory responses do not affect visual segmentation.

We tested the hypothesis that synchronization of oscillatory responses between populations of visually driven neurons could be the basis for visual segmentation and perceptual grouping. We reasoned that oscillations in response induced by flickering visual targets should have an effect on visual performance in these tasks. We therefore measured the psychophysical performance of human subjects in a texture segregation task. (Expt I) and in a perceptual grouping task (Expt II). In both experiments, the elements composing the stimuli were flickered and presented in a variety of flicker conditions. These experimental conditions were designed to either interfere with naturally occurring synchronization of oscillations, or to induce synchronization and bias a subject's perceptual judgment. Performance in these tasks was neither helped nor hindered by the temporal pattern of flicker. These results suggest that physiologically observed oscillatory responses are unrelated to the processes underlying visual segmentation and perceptual grouping.