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1.  Spatial Patterns of Fixation-Switch Behavior in Strabismic Monkeys 
Purpose.
Patients with strabismus perceptually suppress information from one eye to avoid double vision. Mechanisms of visual suppression likely lead to fixation-switch behavior wherein the subject acquires targets with a specific eye depending on target location in space. The purpose of this study was to investigate spatial patterns of fixation-switch behavior in strabismic monkeys.
Methods.
Eye movements were acquired in three exotropic and one esotropic monkey in a binocular viewing saccade task. Spatial patterns of fixation were analyzed by calculating incidence of using either eye to fixate targets presented at various gaze locations.
Results.
Broadly, spatial fixation patterns and fixation-switch behavior followed expectations if a portion of the temporal retina was suppressed in exotropia and a portion of the nasal retina was suppressed in esotropia. Fixation-switch occurred for horizontal target locations that were approximately greater than halfway between the lines of sight of the foveating and strabismic eyes. Surprisingly, the border between right eye and left eye fixation zones was not sharply defined and there was a significant extent (>10°) over which the monkeys could acquire a target with either eye.
Conclusions.
We propose that spatial fixation patterns in strabismus can be accounted for in a decision framework wherein the oculomotor system has access to retinal error information from each eye and the brain chooses between them to prepare a saccade. For target locations approximately midway between the two foveae, strength of retinal error representations from each eye is almost equal, leading to trial-to-trial variability in choice of fixating eye.
Spatial fixation patterns in esotropic and exotropic monkeys are likely driven by visual suppression mechanisms. They can be accounted for in a decision framework where the oculomotor system has access to retinal error associated with each eye and chooses between the two errors to prepare a saccade.
doi:10.1167/iovs.13-13460
PMCID: PMC3943416  PMID: 24508786
eye movements; strabismus; monkeys; visual suppression; visual fixation
2.  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.
The author shows that neurons in the midbrain near-response area adjacent to the oculomotor nucleus, that are known to encode vergence in normal monkeys show activity related to strabismus angle in monkeys with a sensory-induced strabismus.
doi:10.1167/iovs.11-9145
PMCID: PMC3390217  PMID: 22562519
3.  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.
doi:10.1111/j.1749-6632.2011.06146.x
PMCID: PMC3285100  PMID: 21950980
strabismus; oculomotor; neurophysiology; near response area; vergence
4.  Responses of Medial Rectus Motoneurons in Monkeys with Strabismus 
The authors show that central innervation to extraocular muscle is responsible for setting the state of horizontal misalignment and also generating abnormal cross-axis eye movements that result in A or V patterns of strabismus.
Purpose.
Monkeys reared under conditions of alternating monocular occlusion during their first few months of life show large horizontal strabismus, “A” patterns, and dissociated vertical deviation. “A” patterns manifest as an inappropriate horizontal component in the deviated eye during vertical eye movements (cross-axis movement). The objective of this study was to investigate response properties of medial rectus motoneurons (MRMNs) in relation to strabismus properties.
Methods.
Burst-tonic activity of 21 MRMNs in the oculomotor nucleus were recorded from two monkeys with exotropia as they performed horizontal and vertical smooth pursuit (0.2 Hz, ±10°) under monocular viewing conditions. Neuronal responses and horizontal component of eye movements were used to identify regression coefficients in a first-order model for each tracking condition.
Results.
Comparison of position, velocity, and constant parameter coefficients, estimated from horizontal tracking data with either eye viewing, showed no significant differences (P > 0.07), indicating that neuronal activity could account for the horizontal misalignment. Comparison of the position, velocity, and constant parameter coefficients estimated from horizontal tracking and the cross-axis condition showed no significant differences (P > 0.07), suggesting that motoneuron activity could account for most of the inappropriate horizontal cross-axis movement observed in the covered eye during vertical smooth pursuit.
Conclusions.
These data suggest that, in animals with sensory-induced strabismus, central innervation to extraocular muscles is responsible for setting the state of strabismus. Mechanical factors such as muscle length adaptation (for horizontal misalignment) and pulley heterotopy or static torsion (for “A” patterns) likely do not play a major role in determining properties in a sensory-induced strabismus.
doi:10.1167/iovs.11-7402
PMCID: PMC3262551  PMID: 21743010
5.  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.
doi:10.1167/iovs.08-2772
PMCID: PMC2837805  PMID: 19279316
6.  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.
doi:10.1167/iovs.08-2686
PMCID: PMC2837806  PMID: 19029024
8.  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.
doi:10.1167/iovs.06-0249
PMCID: PMC2562537  PMID: 17251464
9.  Horizontal Saccade Disconjugacy in Strabismic Monkeys 
Purpose
Previous studies have shown that binocular coordination during saccadic eye movement is affected in humans with large strabismus. The purpose of this study was to examine the conjugacy of saccadic eye movements in monkeys with sensory strabismus.
Methods
The authors recorded binocular eye movements in four strabismic monkeys and one unaffected monkey. Strabismus was induced by first occluding one eye for 24 hours, switching the occluder to the fellow eye for the next 24 hours, and repeating this pattern of daily alternating monocular occlusion for the first 4 to 6 months of life. Horizontal saccades were measured during monocular viewing when the animals were 2 to 3 years of age.
Results
Horizontal saccade testing during monocular viewing showed that the amplitude of saccades in the nonviewing eye was usually different from that in the viewing eye (saccade disconjugacy). The amount of saccade disconjugacy varied among animals as a function of the degree of ocular misalignment as measured in primary gaze. Saccade disconjugacy also increased with eccentric orbital positions of the nonviewing eye. If the saccade disconjugacy was large, there was an immediate postsaccadic drift for less than 200 ms. The control animal showed none of these effects.
Conclusions
As do humans with large strabismus, strabismic monkey display disconjugate saccadic eye movements. Saccade disconjugacy varies with orbital position and increases as a function of ocular misalignment as measured in primary gaze. This type of sensory-induced strabismus serves as a useful animal model to investigate the neural or mechanical factors responsible for saccade disconjugacy observed in humans with strabismus.
doi:10.1167/iovs.06-0955
PMCID: PMC2562538  PMID: 17591880
10.  Incomitance in Monkeys with Strabismus 
Strabismus  2005;13(1):33-41.
Purpose
Rhesus monkeys reared with restricted visual environment during their first few months of life develop large ocular misalignment (strabismus). The purpose of this study was to describe ‘A and V’ patterns and DVD in these animals during fixation and eye movements and suggest that this form of rearing produces animals that are a suitable model to study mechanisms that might cause ‘A/V’ pattern incomitant strabismus and dissociated vertical deviation (DVD) in humans.
Methods
Eye movements were recorded during fixation, smooth-pursuit and saccades using binocular search coils in one monkey with esotropia, three monkeys with exotropia and one normal monkey.
Results
1) Monkeys reared with Alternating Monocular Occlusion or Binocular deprivation (tarsal plates intact) showed both horizontal and vertical misalignment during monocular and binocular viewing.
2) Large ‘A’ patterns were evident in 2 out of 3 exotropes while a ‘V’ pattern was observed in the esotrope.
3) Similar ‘A/V’ patterns were observed with either eye viewing and during fixation or eye movements.
4) The vertical misalignment, which consisted of the non-viewing eye being higher than the fixating eye, appeared to constitute a DVD.
Conclusion
Visual sensory deprivation methods that induce large strabismus also induce ‘A/V’ patterns and DVD similar to certain types of human strabismus. The source of the pattern strabismus could be central, i.e., altered innervation to extraocular muscles from motor nuclei, or peripheral, i.e., altered location of extraocular muscle pulleys.
doi:10.1080/09273970590910298
PMCID: PMC2553355  PMID: 15824015
A/V patterns; dissociated vertical deviation; eye movement; monkey; incomitant strabismus; esotropia; exotropia
11.  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.
Our study was designed to examine the adaptive capability of smooth pursuit during monocular viewing. The goal of this study was to determine whether monkeys with exotropic strabismus could adapt both eyes equally. We found that strabismic monkeys showed conjugate adaptation of smooth pursuit.
doi:10.1167/iovs.11-9011
PMCID: PMC3995563  PMID: 22410567
12.  Muscimol inactivation caudal to the interstitial nucleus of Cajal induces hemi-seesaw nystagmus 
Hemi-seesaw nystagmus (hemi-SSN) is a jerk-waveform nystagmus with conjugate torsional and disjunctive vertical components. Halmagyi et al. in Brain 117(Pt 4):789–803 (1994), reported hemi-SSN in patients with unilateral lesions in the vicinity of the Interstitial Nucleus of Cajal (INC) and suggested that an imbalance in projections from the vestibular nuclei to the INC was the source of the nystagmus. However, this hypothesis was called into question by Helmchen et al. in Exp Brain Res 119(4):436–452 (1998), who inactivated INC in monkeys with muscimol (a GABAA agonist) and induced failure of vertical gaze-holding (neural integrator) function but not hemi-SSN. We injected 0.1–0.2 μl of 2% muscimol into the supraoculomotor area, 1–2 mm dorso-lateral to the right oculomotor nucleus and caudal to the right INC. A total of seven injections in two juvenile rhesus monkeys were performed. Hemi-SSN was noted within 5–10 min after injection for six of the injections. Around the time the hemi-SSN began, a small skew deviation also developed. However, there was no limitation of horizontal or vertical eye movements, suggesting that the nearby oculomotor nucleus was not initially compromised. Limitations in eye movement range developed about ½–1 h following the injections. Clinical signs that were observed after the animal was released to his cage included a moderate to marked head tilt toward the left (contralesional) side, consistent with an ocular tilt reaction. We conclude that hemi-SSN can be caused by lesions just caudal to the INC, whereas lesions of the INC itself cause down-beat nystagmus and vertical gaze-holding failure, as demonstrated by Helmchen et al. Combined deficits may be encountered with lesions that involve several midbrain structures.
doi:10.1007/s00221-010-2376-2
PMCID: PMC2965773  PMID: 20686890
Hemi-seesaw nystagmus; Rhesus; Muscimol; Oculomotor
13.  Signal Processing and Distribution in Cortical-Brainstem Pathways for Smooth Pursuit Eye Movements 
Smooth pursuit (SP) eye movements are used to maintain the image of a moving object relatively stable on the fovea. Even when tracking a single target over a dark background, multiple areas including frontal eye fields (FEF), middle temporal (MT) and medial superior temporal (MST) cortex contribute to converting visual signals into initial commands for SP. Signals in the cortical pursuit system reach the oculomotor cerebellum through brainstem centers including the dorsolateral pontine nucleus (DLPN), nucleus reticularis tegmenti pontis (NRTP) and pretectal nucleus of the optic tract (NOT). The relative information carried in these parallel pathways remains to be fully defined. We used multiple linear-regression modeling to estimate the relative sensitivities of cortical (MST, FEF), pontine (NRTP, DLPN) and NOT neurons to eye- and retinal-error parameters (position, velocity and acceleration) during step-ramp SP of macaques (Macaca mulatta). We found that a large proportion of pursuit-related MST and DLPN neurons were most sensitive to eye-velocity or retinal error velocity. In contrast, a large proportion of FEF and rostral NRTP neurons were most sensitive to eye-acceleration. Visual neurons in MST, DLPN and NOT neurons were most sensitive to retinal image velocity.
doi:10.1111/j.1749-6632.2009.03859.x
PMCID: PMC3057571  PMID: 19645893
cerebral cortex; eye movements; macaque; pontine; pretectum
14.  Conjugate Adaptation of Saccadic Gain in Non-Human Primates With Strabismus 
Journal of neurophysiology  2003;91(2):1078-1084.
In this study, we have used the double-step paradigm to test saccadic gain adaptation during monocular viewing in one normal monkey, two monkeys with exotropia, and one monkey with esotropia. In this paradigm, the target for the saccade is displaced during the saccade, resulting in a consistent visual error. Studies in normal humans and monkeys have shown that the brain responds to this consistent visual error by gradually changing saccade gain. Using this technique, we were able to elicit adaptation in both the viewing eye and the nonviewing eye in the normal monkey and in monkeys with strabismus. The rate of adaptation was not significantly different in the viewing and nonviewing eyes in the normal and strabismic monkeys. The magnitude of adaptation as calculated by a percentage change in gain was also not significantly different in the viewing and the nonviewing eyes in the normal and strabismic monkeys. Our data show that animals with strabismus retain the ability to elicit a conjugate adaptation of saccades using this mechanism. We also suggest that the double-step paradigm elicits a conjugate adaptation of saccades whether the animal is viewing monocularly (our studies) or binocularly (data published in literature).
doi:10.1152/jn.00205.2003
PMCID: PMC2562043  PMID: 14586028

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