Microstimulation of Interstitial Nucleus of Cajal Evokes Directionally Disconjugate Eye Movements in Monkeys With Pattern Strabismus.

Purpose: Pattern strabismus is characterized by a horizontal misalignment of the eyes that varies with vertical eye position. This disorder has traditionally been described, and treated, as overaction or underaction of the oblique muscles. In recent years, evidence has accumulated that indicate that the disorder is associated with abnormal cross-talk between brainstem pathways that contribute to the horizontal and vertical components of eye movements. The present study was designed to investigate the hypothesis that the key abnormalities are at the level of, or downstream from, the interstitial nucleus of Cajal (INC). Methods: Microstimulation was applied to the INC in two mature rhesus monkeys with "A" pattern strabismus that was experimentally induced in infancy. We asked whether the evoked movements would be vertical and conjugate, as has been previously reported in normal monkeys, or would be directionally disconjugate (i.e. with oblique or horizontal movement observed for at least one eye). Results: Evoked movements were conjugate and vertical for a minority of sites but, for most sites, the evoked movements were directionally disconjugate. Moreover, there was typically a convergent change in horizontal strabismus when the evoked movements were upward and a divergent change when the evoked movements were downward. Conclusions: Microstimulation of INC in monkeys with A-pattern strabismus evokes movements with the expected directional disconjugacies, implying that the key neural abnormalities are within, or downstream from, this structure. High site-to-site variability in the conjugacy/disconjugacy of evoked movements rules out the hypothesis that the abnormalities are solely peripheral.

Abnormal Tuning in Nucleus Prepositus Hypoglossi of Monkeys With "A" Pattern Exotropia.

Purpose: In many individuals with pattern strabismus, the vertical misalignment varies with horizontal eye position. It has been proposed that these cross-axis effects result from abnormal cross-talk between brainstem structures that would normally encode horizontal and vertical eye position and velocity. The nucleus prepositus hypoglossi (NPH) is an ideal structure to test this overarching hypothesis. Neurons in the NPH are believed to mathematically integrate eye velocity signals to generate a tonic signal related to horizontal eye position. We hypothesized that, in monkeys with A-pattern exotropia and vertical inconcomitance, these neurons would show an abnormally large sensitivity to vertical eye position. Methods: Three rhesus monkeys (1 normal and 2 with A-pattern exotropia) were trained to maintain fixation on a visual target as it stepped to various locations on a tangent screen. Extracellular neural activity was recorded from neurons in the NPH. Each neuron's sensitivity to horizontal and vertical eye position was estimated using multiple linear regression and preferred directions computed for each eye. Results: Unexpectedly, the mean preferred directions for the left eye were normal in the monkeys with A-pattern exotropia. For the right eye, there was a clear upward deviation for the right NPH and a downward deviation for the left NPH. In addition, the R2 values were significantly lower for model fits for neurons recorded from the exotropic monkeys. Conclusions: We suggest that vertical inconcomitance results from inappropriate vertical-to-horizontal cross-talk that affects the two eyes differently.

Abnormal Eye Position Signals in Interstitial Nucleus of Cajal in Monkeys With "A" Pattern Strabismus.

Purpose: Pattern strabismus is characterized by a cross-axis pattern of horizontal and vertical misalignments. In A-pattern strabismus, for example, a divergent change in the horizontal misalignment occurs on downgaze. Work with nonhuman primate models has provided evidence that this disorder is associated with abnormal cross-talk between brainstem pathways that normally encode horizontal and vertical eye position and velocity. Neurons in the interstitial nucleus of Cajal (INC) are normally sensitive to vertical eye position; in the present study, we test the hypothesis that, in monkeys with pattern strabismus, some INC neurons will show an abnormal sensitivity to horizontal eye position. Methods: Monkeys were rewarded for fixating a visual target that stepped to various locations on a tangent screen. Single neurons were recorded from INC in one normal monkey, and two with A-pattern strabismus. Multiple linear regression analysis was used to estimate the preferred direction for each neuron. Results: In the normal monkey, all INC neurons had preferred directions within 20° of pure vertical (either up or down). The preferred directions were significantly more variable in the monkeys with pattern strabismus, with a minority being more sensitive to horizontal eye position than vertical eye position. In addition, the vertical eye position sensitivity was significantly less in the monkeys with strabismus. Conclusions: In pattern strabismus, neurons in INC show neurophysiological abnormalities consistent with a failure to develop normal tuning properties. Results were consistent with the hypothesis that, in pattern strabismus, INC receives an abnormally strong signal related to horizontal eye position.

A Rhesus Monkey With a Naturally Occurring Impairment of Disparity Vergence. I. Behavioral Comparisons to Vergence in a Normal Animal.

Purpose: Human children with disorders affecting vergence eye movements have difficulty during close work, such as reading. Patients with convergence insufficiency show a receded near point and an exophoria that is greater at near than at far. Neurologic abnormalities may underlie these symptoms, but it is difficult to test this idea directly because there is no animal model for this disorder. In the present case report, we describe behavioral testing in a rhesus monkey with a naturally occurring impairment of vergence eye movements (monkey CI). Methods: Three monkeys were trained to perform a variety of oculomotor tasks that required saccades, vergence, and/or smooth tracking of a visual target moving in depth. Results: Two of the monkeys (N1 and N2) were able to perform these tasks correctly. The third, monkey CI, was able to correctly perform these tasks when the required vergence angle was ≤5° but had difficulty when the task required larger convergence. This animal showed a consistent exodeviation that worsened as the target drew closer. When a variable prism was used to test disparity vergence in monkey CI, the animal showed an unstable convergence response (maximum 6°) that increased with prism correction, up to 12 prism diopters. By comparison, monkey N1 was able to achieve stable, appropriate convergence up to 26 prism diopters. Monkey CI's performance on vergence tasks improved when a large-field random checkerboard pattern was used to provide additional depth cues. Conclusions: Monkey CI appears to have a naturally occurring disorder of vergence eye movements.

A Rhesus Monkey With a Naturally Occurring Impairment of Disparity Vergence. II. Abnormal Near Response Cell Activity in the Supraoculomotor Area.

Purpose: Convergence insufficiency is a very common disorder that can have significant adverse effects on school performance. When reading, children with this disorder often experience diplopia and headaches. We have recently obtained a rhesus monkey with a naturally occurring impairment of vergence eye movements. In the companion paper, we report behavioral testing that shows a pattern of impairments similar to what clinicians observe in human children with convergence insufficiency, including a receded near point, an exophoria that increases as target distance decreases, and difficulty maintaining an appropriate vergence angle when presented with a large field stimulus at near. For the present case report, we wondered whether these behavioral deficits would be associated with abnormal discharge patterns in brainstem neurons related to vergence eye movements. Methods: Single unit activity was recorded from near and far response cells in the supraoculomotor area in the vergence-impaired monkey, while he performed a smooth vergence tracking task or fixated visual targets at different distances. Results: We found an abnormally weak sensitivity to both vergence angle and vergence velocity. Nonetheless, these neurons modulated in association with contextually inappropriate slow vergence movements that occurred in the absence of saccades but not for slow divergence drifts that immediately followed converging saccades. Modulation of activity was more robust when additional depth cues were available. Conclusions: These data suggest that disorders affecting vergence eye movements may be associated with impoverished sensory input to the near and far response cells and, perhaps, aberrant tuning in vergence-related neurons.

Activity of near-response cells during disconjugate saccades in strabismic monkeys.

Infantile strabismus is a common disorder characterized by a chronic misalignment of the eyes, impairment of binocular vision, and oculomotor abnormalities. Nonhuman primates with strabismus, induced in infancy, show a pattern of abnormalities similar to those of strabismic children. This allows strabismic nonhuman primates to serve as an ideal animal model to examine neural mechanisms associated with aberrant oculomotor behavior. Here, we test the hypothesis that impairment of disparity vergence and horizontal saccade disconjugacy in exotropia and esotropia are associated with disrupted tuning of near- and far-response neurons in the supraoculomotor area (SOA). In normal animals, these neurons carry signals related to vergence position and/or velocity. We hypothesized that, in strabismus, these neurons modulate inappropriately in association with saccades between equidistant targets. We recorded from 62 SOA neurons from 4 strabismic animals (2 esotropes and 2 exotropes) during visually guided saccades to a target that stepped to different locations on a tangent screen. Under these same conditions, SOA neurons in normal animals show no detectable modulation. In our strabismic subjects, we found that a subset of SOA neurons carry weak vergence velocity signals during saccades. In addition, a subset of SOA neurons showed clear modulation associated with slow fluctuations of horizontal strabismus angle in the absence of a saccade. We suggest that abnormal SOA activity contributes to fixation instability but plays only a minor role in the horizontal disconjugacy of saccades that do not switch fixation from one eye to the other. NEW & NOTEWORTHY The present study is the first to investigate the activity of neurons in the supraoculomotor area (SOA) during horizontally disconjugate saccades in a nonhuman primate model of infantile strabismus. We report that fluctuations of horizontal strabismus angle, during fixation of static targets on a tangent screen, are associated with contextually inappropriate modulation of SOA activity. However, firing rate modulation during saccades is too weak to make a major contribution to horizontal disconjugacy.

Response of supraoculomotor area neurons during combined saccade-vergence movements.

Combined saccade-vergence movements allow humans and other primates to align their eyes with objects of interest in three-dimensions. In the absence of saccades, vergence movements are typically slow, symmetrical movements of the two eyes in opposite directions. However, combined saccade-vergence movements produce vergence velocities that exceed values observed during vergence alone. This phenomenon is often called "vergence enhancement", or "saccade-facilitated vergence," though it is important to consider that rapid vergence changes, known as "vergence transients," are also observed during conjugate saccades. We developed a visual target array that allows monkeys to make saccades in all directions between targets spaced at distances that correspond to ~1° intervals of vergence angle relative to the monkey. We recorded the activity of vergence-sensitive neurons in the supra-oculomotor area (SOA), located dorsal and lateral to the oculomotor nucleus while monkeys made saccades with vergence amplitudes ranging from 0 to 10°. The primary focus of this study was to test the hypothesis that neurons in the SOA fire a high frequency burst of spikes during saccades that could generate the enhanced vergence. We found that individual neurons encode vergence velocity during both saccadic and non-saccadic vergence, yet firing rates were insufficient to produce the observed enhancement of vergence velocity. Our results are consistent with the hypothesis that slow vergence changes are encoded by the SOA while fast vergence movements require an additional contribution from the saccadic system. NEW & NOTEWORTHY Research into combined saccade-vergence movements has so far focused on exploring the saccadic neural circuitry, leading to diverging hypotheses regarding the role of the vergence system in this behavior. In this study, we report the first quantitative analysis of the discharge of individual neurons that encode vergence velocity in the monkey brain stem during combined saccade-vergence movements.

Neural mechanisms of oculomotor abnormalities in the infantile strabismus syndrome.

Infantile strabismus is characterized by numerous visual and oculomotor abnormalities. Recently nonhuman primate models of infantile strabismus have been established, with characteristics that closely match those observed in human patients. This has made it possible to study the neural basis for visual and oculomotor symptoms in infantile strabismus. In this review, we consider the available evidence for neural abnormalities in structures related to oculomotor pathways ranging from visual cortex to oculomotor nuclei. These studies provide compelling evidence that a disturbance of binocular vision during a sensitive period early in life, whatever the cause, results in a cascade of abnormalities through numerous brain areas involved in visual functions and eye movements.

Target position relative to the head is essential for predicting head movement during head-free gaze pursuit.

Gaze pursuit is the coordinated movement of the eyes and head that allows humans and other foveate animals to track moving objects. The control of smooth pursuit eye movements when the head is restrained is relatively well understood, but how the eyes coordinate with concurrent head movements when the head is free remains unresolved. In this study, we describe behavioral tasks that dissociate head and gaze velocity during head-free pursuit in monkeys. Existing models of gaze pursuit propose that both eye and head movements are driven only by the perceived velocity of the visual target and are therefore unable to account for these data. We show that in addition to target velocity, the positions of the eyes in the orbits and the retinal position of the target are important factors for predicting head movement during pursuit. When the eyes are already near their limits, further pursuit in that direction will be accompanied by more head movement than when the eyes are centered in the orbits, even when target velocity is the same. The step-ramp paradigm, often used in pursuit tasks, produces larger or smaller head movements, depending on the direction of the position step, while gaze pursuit velocity is insensitive to this manipulation. Using these tasks, we can reliably evoke head movements with peak velocities much faster than the target's velocity. Under these circumstances, the compensatory eye movements, which are often called counterproductive since they rotate the eyes in the opposite direction, are essential to maintaining accurate gaze velocity.

Motion perception and visual signal design in Anolis lizards.

Anolis lizards communicate with displays consisting of motion of the head and body. Early portions of long-distance displays require movements that are effective at eliciting the attention of potential receivers. We studied signal-motion efficacy using a two-dimensional visual-motion detection (2DMD) model consisting of a grid of correlation-type elementary motion detectors. This 2DMD model has been shown to accurately predict Anolis lizard behavioural response. We tested different patterns of artificially generated motion and found that an abrupt 0.3° shift of position in less than 100 ms is optimal. We quantified motion in displays of 25 individuals from five species. Four species employ near-optimal movement patterns. We tested displays of these species using the 2DMD model on scenes with and without moderate wind. Display movements can easily be detected, even in the presence of windblown vegetation. The fifth species does not typically use the most effective display movements and display movements cannot be discerned by the 2DMD model in the presence of windblown vegetation. A number of Anolis species use abrupt up-and-down head movements approximately 10 mm in amplitude in displays, and these movements appear to be extremely effective for stimulating the receiver visual system.

Modeling and measuring the visual detection of ecologically relevant motion by an Anolis lizard.

Motion in the visual periphery of lizards, and other animals, often causes a shift of visual attention toward the moving object. This behavioral response must be more responsive to relevant motion (predators, prey, conspecifics) than to irrelevant motion (windblown vegetation). Early stages of visual motion detection rely on simple local circuits known as elementary motion detectors (EMDs). We presented a computer model consisting of a grid of correlation-type EMDs, with videos of natural motion patterns, including prey, predators and windblown vegetation. We systematically varied the model parameters and quantified the relative response to the different classes of motion. We carried out behavioral experiments with the lizard Anolis sagrei and determined that their visual response could be modeled with a grid of correlation-type EMDs with a spacing parameter of 0.3 degrees visual angle, and a time constant of 0.1 s. The model with these parameters gave substantially stronger responses to relevant motion patterns than to windblown vegetation under equivalent conditions. However, the model is sensitive to local contrast and viewer-object distance. Therefore, additional neural processing is probably required for the visual system to reliably distinguish relevant from irrelevant motion under a full range of natural conditions.