Alternating Fixation and Saccade Behavior in Nonhuman Primates with Alternating Occlusion–Induced Exotropia

Purpose: Nonhuman primates reared with daily alternating monocular occlusion (AMO) during their first few months of life develop large horizontal strabismus, A/V patterns and dissociated vertical deviation (DVD). In addition, these animals often alternate or switch the fixating eye during binocular viewing. The purpose of this study was to characterize the alternating fixation behavior of these animals during visually guided saccade tasks. Methods: Binocular eye movements were measured in two monkeys with AMO-induced exotropia as they performed a visually guided saccade task (random target presentation over a ±15° grid horizontally and vertically) during either monocular or binocular viewing. Results: During binocular viewing, large target steps into the temporal hemifield of the nonfixating eye (nasal retina of the nonfixating eye) produced fixation switches. Target steps into the nasal hemifield of the nonfixating eye (temporal retina of the nonfixating eye) tended not to produce a fixation switch. There were no significant differences in the amplitude–peak velocity or amplitude–duration main sequence relationships between alternating (binocular viewing) and nonalternating saccades (monocular or binocular viewing). Saccade latency tended to be greater during binocular viewing than during monocular viewing. Conclusions: This study shows that the AMO model for strabismus may be used for studying neural circuits involved in generating alternating fixation and alternating saccade behavior. Since patterns of alternating fixation are likely to be influenced by patterns of visual suppression, alternating saccade behavior may also be used as a probe to study mechanisms of visual suppression in strabismus

Investigating mechanisms of strabismus in nonhuman primates

Strabismus affects 2% to 4% of the infant population, with infantile esotropia being the most common form in Western populations.1, 2 Investigations of strabismus found in the literature are primarily oriented toward describing different forms of strabismus and evaluating outcomes of surgical intervention. However, there are a small number of research groups that have tried to improve our basic understanding of strabismus mechanisms by performing studies in nonhuman primates. In this issue of the Journal, one of the leading groups, led by Dr. Larry Tychsen of Washington University in St. Louis, describes their studies examining properties of naturally occurring esotropia in macaque monkeys.3 They have used a comprehensive approach in their investigation by examining eye alignment and eye movement behavior in the strabismic monkeys followed by the use of anatomical methods to analyze binocularity in primary visual cortex (area V1) and the use of anatomical and magnetic resonance imaging methods to analyze extraocular muscles. They make several important points

Responses of Cells in the Midbrain Near-Response Area in Monkeys with Strabismus

Purpose: To investigate whether neuronal activity within the supraoculomotor area (SOA—monosynaptically connected to medial rectus motoneurons and encode vergence angle) of strabismic monkeys was correlated with the angle of horizontal misalignment and therefore helps to define the state of strabismus. Methods: Single-cell neural activity was recorded from SOA neurons in two monkeys with exotropia as they performed eye movement tasks during monocular viewing. Results: Horizontal strabismus angle varied depending on eye of fixation (dissociated horizontal deviation) and the activity of SOA cells (n = 35) varied in correlation with the angle of strabismus. Both near-response (cells that showed larger firing rates for smaller angles of exotropia) and far-response (cells that showed lower firing rates for smaller angles of exotropia) cells were identified. SOA cells showed no modulation of activity with changes in conjugate eye position as tested during smooth-pursuit, thereby verifying that the responses were related to binocular misalignment. SOA cell activity was also not correlated with change in horizontal misalignment due to A-patterns of strabismus. Comparison of SOA population activity in strabismic animals and normal monkeys (described in the literature) show that both neural thresholds and neural sensitivities are altered in the strabismic animals compared with the normal animals. Conclusions: SOA cell activity is important in determining the state of horizontal strabismus, possibly by altering vergence tone in extraocular muscle. The lack of correlated SOA activity with changes in misalignment due to A/V patterns suggest that circuits mediating horizontal strabismus angle and those that mediate A/V patterns are different

Cells in the supraoculomotor area in monkeys with strabismus show activity related to the strabismus angle

We have earlier shown that monkeys reared with daily alternating monocular occlusion for the first few months of life develop large horizontal strabismus, A/V patterns, dissociated vertical deviation (DVD), and dissociated horizontal deviation (DHD). Here, we present results from neurophysiological experiments that show that neuronal activity of cells within the supraoculomotor area (SOA) of juvenile strabismic monkeys is correlated with the angle of strabismus. There was no modulation of SOA cell activity with conjugate eye position as tested during horizontal smooth pursuit. Comparison of SOA population activity in these strabismic animals and normal monkeys (described in the literature) suggests that both vergence (misalignment in the case of the strabismic animals) thresholds and vergence position sensitivities are different in the strabismic animals compared to the normals. Our data suggest that activity within the SOA cells is important in determining the state of horizontal strabismus possibly by altering vergence tone in extraocular muscle

Correlation of Cross-Axis Eye Movements and Motoneuron Activity in Non-Human Primates with “A” Pattern Strabismus

Purpose: The authors showed earlier that animals reared with certain types of visual sensory deprivation during their first few months of life develop large horizontal strabismus, A/V patterns, and dissociated vertical deviation (DVD). Cross-axis eye movements were observed in the nonfixating eye that reflected pattern strabismus and DVD. The purpose of this study was to investigate whether neuronal activity within the oculomotor nucleus could be driving the abnormal cross-axis eye movements observed in the nonfixating eye. Methods: Burst-tonic activity was recorded from oculomotor nucleus neurons in three animals with A-pattern exotropia as they performed horizontal or vertical smooth pursuit during monocular viewing. Two animals were reared by alternate monocular occlusion for 4 months, and one animal was reared by binocular deprivation for 3 weeks. Results: In this study, efforts were focused on neurons modulated for vertical eye movements. Vertical burst-tonic motoneurons were strongly correlated with vertical eye movements regardless of whether the movement was purposeful, as in vertical smooth pursuit, or whether it was inappropriate, as in a vertical component observed in the nonfixating eye during horizontal smooth pursuit. Quantitative analysis of position and velocity sensitivities of the cells measured during the different tracking conditions suggested that motoneuron activity was sufficient to account for most of the inappropriate vertical cross-axis component. Conclusions: Results suggest that, in animals with sensory-induced strabismus, innervation to extraocular muscles from motor nuclei produce the inappropriate cross-axis eye movements, resulting in change in ocular misalignment with gaze position associated with pattern strabismus and DVD

Influence of Target Parameters on Fixation Stability in Normal and Strabismic Monkeys

Purpose: The purpose of this study was to assess the effect of fixation target parameters on fixation instability in strabismic monkeys. Methods: One normal and three exotropic monkeys were presented with four differently shaped fixation targets, with three diameters, during monocular or binocular viewing. Fixation targets were white on a black background or vice versa. Binocular eye movements were recorded using the magnetic search coil technique and fixation stability quantified by calculating the bivariate contour ellipse area (BCEA). Results: Fixation instability was greater in all the strabismic monkeys compared with the normal monkey. During monocular viewing, strabismic monkeys showed significantly greater instability in the covered eye compared to the fixating eye. Multifactorial ANOVA suggested statistically significant target parameter influences, although effect sizes were small. Thus, a disk-shaped target resulted in greater instability than other target shapes in the viewing eyes of the normal monkey and two of three strabismic monkeys. A similar target-shape effect was also observed in the covered eye. Least instability was elicited with a 0.5° target in the normal monkey and a 1.0° target in the strabismic monkeys, both in the viewing and the covered eye. Target/background polarity effects were idiosyncratic. In strabismic monkeys, stability of the fixating eye during binocular viewing was not different from the stability of the same eye during monocular viewing. Conclusions: Abnormal drifts and nystagmus contribute to increased fixation instability in strabismic monkeys. Target parameters (shape and size) that influence fixation stability in a normal animal also affected fixation stability in our sample of strabismic monkeys

Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology Responses of Cells in the Midbrain Near-Response Area in Monkeys with Strabismus

PURPOSE. To investigate whether neuronal activity within the supraoculomotor area (SOA-monosynaptically connected to medial rectus motoneurons and encode vergence angle) of strabismic monkeys was correlated with the angle of horizontal misalignment and therefore helps to define the state of strabismus. METHODS. Single-cell neural activity was recorded from SOA neurons in two monkeys with exotropia as they performed eye movement tasks during monocular viewing. RESULTS. Horizontal strabismus angle varied depending on eye of fixation (dissociated horizontal deviation) and the activity of SOA cells (n ¼ 35) varied in correlation with the angle of strabismus. Both near-response (cells that showed larger firing rates for smaller angles of exotropia) and far-response (cells that showed lower firing rates for smaller angles of exotropia) cells were identified. SOA cells showed no modulation of activity with changes in conjugate eye position as tested during smooth-pursuit, thereby verifying that the responses were related to binocular misalignment. SOA cell activity was also not correlated with change in horizontal misalignment due to A-patterns of strabismus. Comparison of SOA population activity in strabismic animals and normal monkeys (described in the literature) show that both neural thresholds and neural sensitivities are altered in the strabismic animals compared with the normal animals. CONCLUSIONS. SOA cell activity is important in determining the state of horizontal strabismus, possibly by altering vergence tone in extraocular muscle. The lack of correlated SOA activity with changes in misalignment due to A/V patterns suggest that circuits mediating horizontal strabismus angle and those that mediate A/V patterns are different. (Invest Ophthalmol Vis Sci. 2012;53:3858-3864) DOI:10.1167/iovs.11-9145 I nfantile forms of strabismus occur in as much as 5% of all children. 1-3 The exact cause of strabismus is often unknown. 3-5 Many diverse factors, including refractive errors (anisometropia); visual acuity factors (congenital cataracts); genetic factors (congenital fibrosis of extraocular muscle, Marfan's syndrome); brainstem pathology (Duane's syndrome); and muscle pathology (dysthyroid opthalmopathy), likely trigger a cascade of events that result in misaligned eyes. 2,16,17 In cases of strabismus that is not due to an obvious paralytic or restrictive factor, a common feature among the different trigger factors and correspondingly the different approaches to producing animal models for strabismus is that binocular vision is disrupted in early life due to breakdown in either motor fusion (e.g., surgical strabismus models) or sensory fusion (e.g., optically induced strabismus). Although motoneurons showed correlated activity with abnormal alignment and abnormal eye movements associated with strabismus, it is unlikely that they are the source of the problem. Central structures are likely providing aberrant inputs to motoneurons. When considering sources of such aberrant input to the motoneurons, the supraoculomotor area (SOA) is implicated because of its purported role in binocular eye movements. The SOA is the area immediately adjacent to the oculomotor nucleus. Neurons in this area receive major projections from the fastigial nucleus and the posterior interposed nucleus in the cerebellum, and also project monosynaptically to the medial rectus motoneurons in the oculomotor nucleus

Motion Information via the Nonfixating Eye Can Drive Optokinetic Nystagmus in Strabismus

Purpose: Strabismic patients can perceptually suppress information from one eye to avoid double vision. However, evidence from prior studies shows that some parts of the visual field of the deviated eye are not suppressed. Our goal here was to investigate whether motion information available only to the deviated eye can be utilized by the oculomotor system to drive eye movements. Methods: Binocular eye movements were acquired in two exotropic monkeys in a dichoptic viewing task in which the fixating eye viewed a stationary spot and the deviated eye viewed a 10° × 10° stationary patch that contained a drifting grating stimulus moving at 10°/s to the right or left for 20 seconds. Spatial location and contrast of the grating were systematically varied in subsequent trials. For each trial, mean slow-phase velocity of the optokinetic nystagmus (OKN) elicited by grating motion was calculated. Results: We found that OKN responses can be elicited by a motion stimulus presented to the foveal region of the deviated eye. Optokinetic nystagmus magnitude varied depending on which eye was viewing the drifting grating and correlated well with fixation preference and fixation stability (indicators of amblyopia). The magnitude of OKN increased for increased relative contrast of the motion stimulus compared to the fixation spot. Conclusions: Our results show that motion information available only to the deviated eye can drive optokinetic eye movements. We conclude that the brain has access to visual information from portions of the deviated eye (including the fovea) in strabismus that it can use to drive eye movements

Applicability of Infrared Photorefraction for Measurement of Accommodation in Awake-Behaving Normal and Strabismic Monkeys

Purpose: This study was designed to use infrared photorefraction to measure accommodation in awake-behaving normal and strabismic monkeys and describe properties of photorefraction calibrations in these monkeys. Methods: Ophthalmic trial lenses were used to calibrate the slope of pupil vertical pixel intensity profile measurements that were made with a custom-built infrared photorefractor. Day to day variability in photorefraction calibration curves, variability in calibration coefficients due to misalignment of the photorefractor Purkinje image and the center of the pupil, and variability in refractive error due to off-axis measurements were evaluated. Results: The linear range of calibration of the photorefractor was found for ophthalmic lenses ranging from ?1 D to +4 D. Calibration coefficients were different across monkeys tested (two strabismic, one normal) but were similar for each monkey over different experimental days. In both normal and strabismic monkeys, small misalignment of the photorefractor Purkinje image with the center of pupil resulted in only small changes in calibration coefficients, that were not statistically significant (P > 0.05). Off-axis measurement of refractive error was also small in the normal and strabismic monkeys (?1 D to 2 D) as long as the magnitude of misalignment was <10°. Conclusions: Remote infrared photorefraction is suitable for measuring accommodation in awake, behaving normal, and strabismic monkeys. Specific challenges posed by the strabismic monkeys, such as possible misalignment of the photorefractor Purkinje image and the center of the pupil during either calibration or measurement of accommodation, that may arise due to unsteady fixation or small eye movements including nystagmus, results in small changes in measured refractive error

Conjugate Adaptation of Smooth Pursuit during Monocular Viewing in Strabismic Monkeys with Exotropia

Purpose: Humans and monkeys are able to adapt their smooth pursuit output when challenged with consistent errors in foveal/parafoveal image motion during tracking. Visual motion information from the retina is known to be necessary for guiding smooth pursuit adaptation. The purpose of this study is to determine whether retinal motion signals delivered to one eye during smooth pursuit produce adaptation in the fellow eye. We tested smooth pursuit adaptation during monocular viewing in strabismic monkeys with exotropia. Methods: To induce smooth pursuit adaptation experimentally, we used a step-ramp tracking with two different velocities (adaptation paradigm), where the target begins moving at one speed (25°/s) for first 100 ms and then changes to a lower speed (5°/s) for the remainder of the trial. Typically, 100 to 200 trials were used to adapt the smooth pursuit response. Control trials employing single speed step-ramp target motion (ramp speed = 25°/s) were used before and after adaptation paradigm to estimate adaptation. Results: The magnitude of adaptation as calculated by percentage change was not significantly different (P = 0.53) for the viewing (mean, 40.3% ± 5.9%) and the nonviewing (mean, 39.7% ± 6.2%) eyes during monocular viewing conditions, even in cases with large angle (18°–20°) strabismus. Conclusions: Our results indicate that animals with strabismus retain the ability to produce conjugate adaptation of smooth pursuit. Therefore, we suggest that a single central representation of retinal motion information in the viewing eye drives adaptation for both eyes equally