James Cavanaugh

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.

Subcortical Modulation of Attention Counters Change Blindness

Change blindness is the failure to see large changes in a visual scene that occur simultaneously with a global visual transient. Such visual transients might be brief blanks between visual scenes or the blurs caused by rapid or saccadic eye movements between successive fixations. Shifting attention to the site of the change counters this “blindness” by improving change detection and reaction time. We developed a change blindness paradigm for visual motion and then showed that presenting an attentional cue diminished the blindness in both humans and old world monkeys. We then replaced the visual cue with weak electrical stimulation of an area in the monkeys brainstem, the superior colliculus, to see if activation at such a late stage in the eye movement control system contributes to the attentional shift that counters change blindness. With this stimulation, monkeys more easily detected changes and had shorter reaction times, both characteristics of a shift of attention.

Attentional modulation of thalamic reticular neurons.

The major pathway for visual information reaching cerebral cortex is through the lateral geniculate nucleus (LGN) of the thalamus. Acting on this vital relay is another thalamic nucleus, the thalamic reticular nucleus (TRN). This nucleus receives topographically organized collaterals from both thalamus and cortex and sends similarly organized projections back to thalamus. The inputs to the TRN are excitatory, but the output back to the thalamic relay is inhibitory, providing an ideal organization for modulating visual activity during early processing. This functional architecture led Crick in 1984 to hypothesize that TRN serves to direct a searchlight of attention to different regions of the topographic map; however, despite the substantial influence of this hypothesis, the activity of TRN neurons has never been determined during an attention task. We have determined the nature of the response of visual TRN neurons in awake monkeys, and the modulation of that response as the monkeys shifted attention between visual and auditory stimuli. Visual TRN neurons had a strong (194 spikes/s) and fast (25 ms latency) transient increase of activity to spots of light falling in their receptive fields, as well as high background firing rate (45 spikes/s). When attention shifted to the spots of light, the amplitude of the transient visual response typically increased, whereas other neuronal response characteristics remained unchanged. Thus, as predicted previously, TRN activity is modified by shifts of visual attention, and these attentional changes could influence visual processing in LGN via the inhibitory connections back to the thalamus.

Optogenetic Inactivation Modifies Monkey Visuomotor Behavior

A critical technique for understanding how neuronal activity contributes to behavior is determining whether perturbing it changes behavior. The advent of optogenetic techniques allows the immediately reversible alteration of neuronal activity in contrast to chemical approaches lasting minutes to hours. Modification of behavior using optogenetics has had substantial success in rodents but has not been as successful in monkeys. Here, we show how optogenetic inactivation of superior colliculus neurons in awake monkeys leads to clear and repeatable behavioral deficits in the metrics of saccadic eye movements. We used our observations to evaluate principles governing the use of optogenetic techniques in the study of the neuronal bases of behavior in monkeys, particularly how experimental design must address relevant parameters, such as the application of light to subcortical structures, the spread of viral injections, and the extent of neuronal inactivation with light.

Thalamic pathways for active vision

Active vision requires the integration of information coming from the retina with that generated internally within the brain, especially by saccadic eye movements. Just as visual information reaches cortex via the lateral geniculate nucleus of the thalamus, this internal information reaches the cerebral cortex through other higher-order nuclei of the thalamus. This review summarizes recent work on four of these thalamic nuclei. The first two pathways convey internal information about upcoming saccades (a corollary discharge) and probably contribute to the neuronal mechanisms that underlie stable visual perception. The second two pathways might contribute to the neuronal mechanisms underlying visual spatial attention in cortex and in the thalamus itself.

Enhanced Performance with Brain Stimulation: Attentional Shift or Visual Cue?

The premotor theory of visual spatial attention proposes that the same brain activity that prepares for saccades to one part of the visual field also facilitates visual processing at that same region of the visual field. Strong support comes from improvements in performance by electrical stimulation of presaccadic areas, including the frontal eye field and superior colliculus (SC). Interpretations of these stimulation experiments are hampered by the possibility that stimulation might be producing an internal visual flash or phosphene that attracts attention as a real flash would. We tested this phosphene hypothesis in the SC by comparing the effect of interchanging real visual stimuli and electrical stimulation. We first presented a veridical visual cue at the time SC stimulation improved performance; if a phosphene improved performance at this time, a real cue should do so in the same manner, but it did not. We then changed the time of SC visual-motor stimulation to when we ordinarily presented the veridical visual cue, and failed to improve performance. Last, we shifted the site of SC stimulation from the visual-motor neurons of the SC intermediate layers to the visual neurons of the superficial layers to determine whether stimulating visual neurons produced a larger improvement in performance, but it did not. Our experiments provide evidence that a phosphene is not responsible for the shift of attention that follows SC stimulation. This added evidence of a direct shift of attention is consistent with a key role of the SC in the premotor theory of attention.

Functional Maturation of the Macaque's Lateral Geniculate Nucleus

Vision in infant primates is poor, but it is not known which structures in the eye or brain set the main limits to its development. We studied the visual response properties of 348 neurons recorded in the lateral geniculate nucleus (LGN) of macaque monkeys aged 1 week to adult. We measured spatial and temporal frequency tuning curves and contrast responses with drifting achromatic sinusoidal gratings. Even in animals as young as 1 week, the main visual response properties of neurons in the magnocellular (M) and parvocellular (P) divisions of the LGN were qualitatively normal, including the spatial organization of receptive fields and the characteristic response properties that differentiate M- and P-cells. At 1 and 4 weeks, spatial and temporal resolution were less than one-half of adult values, whereas contrast gain and peak response rates for optimal stimuli were about two-thirds of adult values. Adult levels were reached by 24 weeks. Analysis of correlations between S-potentials representing retinal inputs and LGN cells suggested that the LGN follows retinal input as faithfully in infants as in adults, implicating retinal development as the main driving force in LGN development. Comparisons with previously published psychophysical data and ideal observer models suggest that the relatively modest changes in LGN responses during maturation impose no significant limits on visual performance. In contrast to previous studies, we conclude that these limits are set by neural development in the visual cortex, not in or peripheral to the LGN.

Saccadic Corollary Discharge Underlies Stable Visual Perception

Saccadic eye movements direct the high-resolution foveae of our retinas toward objects of interest. With each saccade, the image jumps on the retina, causing a discontinuity in visual input. Our visual perception, however, remains stable. Philosophers and scientists over centuries have proposed that visual stability depends upon an internal neuronal signal that is a copy of the neuronal signal driving the eye movement, now referred to as a corollary discharge (CD) or efference copy. In the old world monkey, such a CD circuit for saccades has been identified extending from superior colliculus through MD thalamus to frontal cortex, but there is little evidence that this circuit actually contributes to visual perception. We tested the influence of this CD circuit on visual perception by first training macaque monkeys to report their perceived eye direction, and then reversibly inactivating the CD as it passes through the thalamus. We found that the monkeys perception changed; during CD inactivation, there was a difference between where the monkey perceived its eyes to be directed and where they were actually directed. Perception and saccade were decoupled. We established that the perceived eye direction at the end of the saccade was not derived from proprioceptive input from eye muscles, and was not altered by contextual visual information. We conclude that the CD provides internal information contributing to the brains creation of perceived visual stability. More specifically, the CD might provide the internal saccade vector used to unite separate retinal images into a stable visual scene. SIGNIFICANCE STATEMENT Visual stability is one of the most remarkable aspects of human vision. The eyes move rapidly several times per second, displacing the retinal image each time. The brain compensates for this disruption, keeping our visual perception stable. A major hypothesis explaining this stability invokes a signal within the brain, a corollary discharge, that informs visual regions of the brain when and where the eyes are about to move. Such a corollary discharge circuit for eye movements has been identified in macaque monkey. We now show that selectively inactivating this brain circuit alters the monkeys visual perception. We conclude that this corollary discharge provides a critical signal that can be used to unite jumping retinal images into a consistent visual scene.

Modulation of Shifting Receptive Field Activity In Frontal Eye Field by Visual Salience

In the monkey frontal eye field (FEF), the sensitivity of some neurons to visual stimulation changes just before a saccade. Sensitivity shifts from the spatial location of its current receptive field (RF) to the location of that field after the saccade is completed (the future field, FF). These shifting RFs are thought to contribute to the stability of visual perception across saccades, and in this study we investigated whether the salience of the FF stimulus alters the magnitude of FF activity. We reduced the salience of the usually single flashed stimulus by adding other visual stimuli. We isolated 171 neurons in the FEF of 2 monkeys and did experiments on 50 that had FF activity. In 30% of these, that activity was higher before salience was reduced by adding stimuli. The mean magnitude reduction was 16%. We then determined whether the shifting RFs were more frequent in the central visual field, which would be expected if vision across saccades were only stabilized for the visual field near the fovea. We found no evidence of any skewing of the frequency of shifting receptive fields (or the effects of salience) toward the central visual field. We conclude that the salience of the FF stimulus makes a substantial contribution to the magnitude of FF activity in FEF. In so far as FF activity contributes to visual stability, the salience of the stimulus is probably more important than the region of the visual field in which it falls for determining which objects remain perceptually stable across saccades.

Suppressive Surrounds of Receptive Fields In Monkey Frontal Eye Field

A critical step in determining how a neuron contributes to visual processing is determining its visual receptive field (RF). While recording from neurons in frontal eye field (FEF) of awake monkeys (Macaca mulatta), we probed the visual field with small spots of light and found excitatory RFs that decreased in strength from RF center to periphery. However, presenting stimuli with different diameters centered on the RF revealed suppressive surrounds that overlapped the previously determined excitatory RF and reduced responses by 84%, on average. Consequently, in that overlap area, stimulation produced excitation or suppression, depending on the stimulus. Strong stimulation of the RF periphery with annular stimuli allowed us to quantify this effect. A modified difference of Gaussians model that independently varied center and surround activation accounted for the nonlinear activity in the overlap area. Our results suggest that (1) the suppressive surrounds found in FEF are fundamentally the same as those in V1 except for the size and strength of excitatory and suppressive mechanisms, (2) methodically assaying suppressive surrounds in FEF is essential for correctly interpreting responses to large and/or peripheral stimuli and therefore understanding the effects of stimulus context, and (3) regulating the relative strength of the surround clearly changes neuronal responses and may therefore play a significant part in the neuronal changes resulting from visual attention and stimulus salience.