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1.  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
2.  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
3.  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
4.  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
5.  The effect of strabismus on object detection in the ring scotoma of a monocular bioptic telescope 
Purpose
People with reduced visual acuity are permitted to drive with the aid of bioptic telescopes in the USA, The Netherlands, and Canada. When viewing through a monocular bioptic telescope, suppression of the deviating eye in strabismus may reduce the ability of the non-telescope eye to detect objects whose images fall in the ring scotoma area of the telescope eye, which could impair detection of traffic-relevant events. This ability to detect stimuli in the ring scotoma area was compared for strabismic and non-strabismic patients.
Methods
Ten strabismic and six non-strabismic patients with bilaterally reduced visual acuity (6/12 to 6/60) participated. A dichoptic perimeter presented stimuli to the fellow (non telescope) eye in the area of the ring scotoma under binocular viewing. Fellow-eye detection rates were determined with and without a bioptic, on uniform and patterned backgrounds, while performing passive (viewing a cross) and active (reading letters) fixation tasks.
Results
All strabismic patients were found to have anomalous retinal correspondence. Both non-strabismic and strabismic patients had lower fellow-eye detection rates on patterned than on uniform backgrounds, and while performing the active task. In addition, strabismic patients had lower detection with than without the bioptic on the patterned background. They also had a larger decrease in detection from the uniform to the patterned background than non-strabismic patients (26% vs 8%). Depending on the angle and direction of the deviation relative to the target side, strabismus either increased or decreased fellow-eye stimulus eccentricity on the retina. Larger detection rate reductions between the uniform and patterned backgrounds were associated with more eccentric stimulus locations (rho = 0.606, p = 0.013).
Conclusions
Both strabismic patients and non-strabismic patients were able to detect stimuli with the fellow eye in the ring scotoma area, demonstrating successful bi-ocular multiplexing. However, strabismic patients generally had a greater reduction in detection performance from the uniform to the patterned background than non-strabismic patients, which was accounted for in part by differences in stimulus eccentricities on the retina (that varied with the angle and direction of the strabismus). However, a study with a larger sample, including participants with strabismus and normal retinal correspondence, is needed before our findings can be generalized.
doi:10.1111/opo.12067
PMCID: PMC3809061  PMID: 23639041
low vision; rehabilitation; vision multiplexing; driving
6.  Vertical and Oblique Saccade Disconjugacy in Strabismus 
Purpose.
Previous studies have shown that horizontal saccades are disconjugate in humans and monkeys with strabismus. The present study was designed to extend these results to vertical and oblique saccades. A major goal was to assess the conjugacy in terms of both amplitude and direction.
Methods.
Saccadic eye movements were recorded binocularly in three adult monkeys. One had normal eye alignment, one had exotropia resulting from a bilateral medial rectus tenotomy in the first week of life, and one had esotropia resulting from prism rearing during the first 3 months of life. We assessed the conjugacy of saccades in various directions by comparing both amplitude and direction.
Results.
Saccades in the strabismic monkeys were disconjugate in terms of both amplitude and direction. These effects were as large for vertical and oblique saccades as for horizontal ones. However, the pattern of disconjugacy often varied as a function of saccade direction. In some cases, saccades that appeared to be conjugate in terms of amplitude differed substantially when direction was taken into account.
Conclusions.
These data indicate that the assessment of saccade disconjugacy in strabismus may yield misleading results if direction is not considered. The complex pattern of disconjugacy suggests that strabismus is associated with substantial abnormalities within the circuitry controlling saccades. Neurophysiological studies are needed to identify the specific neural substrates for these behavioral effects.
We quantified the conjugacy of saccades in various directions in three monkeys (one normal, one exotrope, and one esotrope). For both strabismic animals, saccades in the two eyes often differed notably, in terms of both amplitude and direction.
doi:10.1167/iovs.13-13473
PMCID: PMC3891270  PMID: 24346173
saccade; strabismus; exotropia; esotropia; eye movement
7.  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
8.  Stimulation of Pontine Reticular Formation in Monkeys With Strabismus 
Purpose.
Saccade disconjugacy in strabismus could result from any of a number of factors, including abnormalities of eye muscles, the plant, motoneurons, near response cells, or atypical tuning of neurons in saccade-related areas of the brain. This study was designed to investigate the possibility that saccade disconjugacy in strabismus is associated with abnormalities in paramedian pontine reticular formation (PPRF).
Methods.
We applied microstimulation to 22 sites in PPRF and 20 sites in abducens nucleus in three rhesus macaque monkeys (one normal, one esotrope, and one exotrope).
Results.
When mean velocity was compared between the two eyes, a slight difference was found for 1/5 sites in the normal animal. Significant differences were found for 5/6 sites in an esotrope and 10/11 sites in an exotrope. For five sites in the strabismic monkeys, the directions of evoked movements differed by more than 40° between the two eyes. When stimulation was applied to abducens nucleus (20 sites), the ipsilateral eye moved faster for 4/6 sites in the normal animal and all nine sites in the esotrope. For the exotrope, however, the left eye always moved faster, even for three sites on the right side. For the strabismic animals, stimulation of abducens nucleus often caused a different eye to move faster than stimulation of PPRF.
Conclusions.
These data suggest that PPRF is organized at least partly monocularly in strabismus and that disconjugate saccades are at least partly a consequence of unbalanced saccadic commands being sent to the two eyes.
Stimulation of paramedian pontine reticular formation evokes disconjugate movements in monkeys with experimentally-induced strabismus. These data suggest a possible neurophysiologic basis for saccade disconjugacy in human patients with infantile strabismus.
doi:10.1167/iovs.13-12924
PMCID: PMC3813322  PMID: 24114541
strabismus; exotropia; esotropia; saccadic eye movements; PPRF
9.  CAUSING AND CURING INFANTILE ESOTROPIA IN PRIMATES: THE ROLE OF DECORRELATED BINOCULAR INPUT (AN AMERICAN OPHTHALMOLOGICAL SOCIETY THESIS) 
Purpose: Human infants at greatest risk for esotropia are those who suffer cerebral insults that could decorrelate signals from the 2 eyes during an early critical period of binocular, visuomotor development. The author reared normal infant monkeys, under conditions of binocular decorrelation, to determine if this alone was sufficient to cause esotropia and associated behavioral as well as neuroanatomic deficits.
Methods: Binocular decorrelation was imposed using prism-goggles for durations of 3 to 24 weeks (in 6 experimental, 2 control monkeys). Behavioral recordings were obtained, followed by neuroanatomic analysis of ocular dominance columns and binocular, horizontal connections in the striate visual cortex (area V1).
Results: Concomitant, constant esotropia developed in each monkey exposed to decorrelation for a duration of 12 to 24 weeks. The severity of ocular motor signs (esotropia-angle; dissociated vertical deviation; latent nystagmus; pursuit/optokinetic tracking asymmetry; fusional vergence deficits), and the loss of V1 binocular connections, increased as a function of decorrelation duration. Stereopsis was deficient and motion visual evoked potentials were asymmetric. Monkeys exposed to decorrelation for 3 weeks showed transient esotropia but regained normal visuomotor behaviors and binocular V1 connections.
Conclusions: Binocular decorrelation is a sufficient cause of infantile esotropia when imposed during a critical period of visuomotor development. The systematic relationship between severity of visuomotor sign, and severity of V1 connectivity deficit, provides a neuroanatomic mechanism for several of these signs. Restoration of binocular fusion and V1 connections, after short durations of decorrelation, helps explain the benefits of early repair in human strabismus.
PMCID: PMC2258131  PMID: 18427630
10.  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
11.  Binocular Summation and Other Forms of Non-Dominant Eye Contribution in Individuals with Strabismic Amblyopia during Habitual Viewing 
PLoS ONE  2013;8(10):e77871.
Background
Adults with amblyopia (‘lazy eye’), long-standing strabismus (ocular misalignment) or both typically do not experience visual symptoms because the signal from weaker eye is given less weight than the signal from its fellow. Here we examine the contribution of the weaker eye of individuals with strabismus and amblyopia with both eyes open and with the deviating eye in its anomalous motor position.
Methodology/Results
The task consisted of a blue-on-yellow detection task along a horizontal line across the central 50 degrees of the visual field. We compare the results obtained in ten individuals with strabismic amblyopia with ten visual normals. At each field location in each participant, we examined how the sensitivity exhibited under binocular conditions compared with sensitivity from four predictions, (i) a model of binocular summation, (ii) the average of the monocular sensitivities, (iii) dominant-eye sensitivity or (iv) non-dominant-eye sensitivity. The proportion of field locations for which the binocular summation model provided the best description of binocular sensitivity was similar in normals (50.6%) and amblyopes (48.2%). Average monocular sensitivity matched binocular sensitivity in 14.1% of amblyopes’ field locations compared to 8.8% of normals’. Dominant-eye sensitivity explained sensitivity at 27.1% of field locations in amblyopes but 21.2% in normals. Non-dominant-eye sensitivity explained sensitivity at 10.6% of field locations in amblyopes but 19.4% in normals. Binocular summation provided the best description of the sensitivity profile in 6/10 amblyopes compared to 7/10 of normals. In three amblyopes, dominant-eye sensitivity most closely reflected binocular sensitivity (compared to two normals) and in the remaining amblyope, binocular sensitivity approximated to an average of the monocular sensitivities.
Conclusions
Our results suggest a strong positive contribution in habitual viewing from the non-dominant eye in strabismic amblyopes. This is consistent with evidence from other sources that binocular mechanisms are frequently intact in strabismic and amblyopic individuals.
doi:10.1371/journal.pone.0077871
PMCID: PMC3812153  PMID: 24205005
12.  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
13.  Horizontal Rectus Muscle Anatomy in Naturally and Artificially Strabismic Monkeys 
Purpose
Structural abnormalities of extraocular muscles (EOMs) or their pulleys are associated with some forms of human strabismus. This experiment was conducted to investigate whether such abnormalities are associated with artificial or naturally occurring strabismus in monkeys.
Methods
Binocular alignment and grating visual acuities were determined in 10 monkeys representing various species using search coil recording and direct observations. Four animals were orthotropic, two had naturally occurring “A”-pattern esotropia, two had concomitant and one had “V”-pattern esotropia artificially induced by alternating or unilateral occlusion in infancy, and one had “A”-pattern exotropia artificially induced by prism wear. After euthanasia, 16 orbits were examined by high-resolution magnetic resonance imaging (MRI) in the quasicoronal plane. Paths and sizes of horizontal rectus EOMs were analyzed quantitatively in a standardized coordinate system. Whole orbits were then serially sectioned en bloc in the quasicoronal plane, stained for connective tissue, and compared with MRI. Nerve and EOM features were analyzed quantitatively.
Results
Quantitative analysis of MRI revealed no significant differences in horizontal rectus EOM sizes or paths among orthotropic or naturally or artificially strabismic monkeys. Histologic examination demonstrated no differences in EOM size, structure, or innervation among the three groups, and no differences in connective tissues in the pulley system. The accessory lateral rectus (ALR) EOM was present in all specimens, but was small, inconsistently located, and sparsely innervated. Characteristics of the ALR did not correlate with strabismus.
Conclusions
Major structural abnormalities of horizontal rectus EOMs and associated pulleys are unrelated to natural or artificial horizontal strabismus in the monkeys studied. The ALR is unlikely to contribute to horizontal strabismus in primates. However, these findings do not exclude a possible role of pulley abnormalities in disorders such as cyclovertical strabismus.
doi:10.1167/iovs.06-0662
PMCID: PMC1975407  PMID: 17525187
14.  Differences in Gene Expression between Strabismic and Normal Human Extraocular Muscles 
Purpose.
Strabismic extraocular muscles (EOMs) differ from normal EOMs in structural and functional properties, but the gene expression profile of these two types of EOM has not been examined. Differences in gene expression may inform about causes and effects of the strabismic condition in humans.
Methods.
EOM samples were obtained during corrective surgery from patients with horizontal strabismus and from deceased organ donors with normal EOMs. Microarrays and quantitative PCR identified significantly up- and down-regulated genes in EOM samples. Analysis was performed on probe sets with more than 3-fold differential expression between normal and strabismic samples, with an adjusted P value of ≤ 0.05.
Results.
Microarray analysis showed that 604 genes in these samples had significantly different expression. Expression predominantly was upregulated in genes involved in extracellular matrix structure, and down-regulated in genes related to contractility. Expression of genes associated with signaling, calcium handling, mitochondria function and biogenesis, and energy homeostasis also was significantly different between normal and strabismic EOM. Skeletal muscle PCR array identified 22 (25%) of 87 muscle-specific genes that were significantly down-regulated in strabismic EOMs; none was significantly upregulated.
Conclusions.
Differences in gene expression between strabismic and normal human EOMs point to a relevant contribution of the peripheral oculomotor system to the strabismic condition. Decreases in expression of contractility genes and increases of extracellular matrix-associated genes indicate imbalances in EOM structure. We conclude that gene regulation of proteins fundamental to contractile mechanics and extracellular matrix structure is involved in pathogenesis and/or consequences of strabismus, suggesting potential novel therapeutic targets.
Strabismic human extraocular muscles show significant changes in gene expression with upregulation of genes related to extracellular matrix and downregulation of myosin genes. The strabismic transcriptome suggests a major contribution of the muscle to strabismus, as well as new therapeutic targets.
doi:10.1167/iovs.12-9785
PMCID: PMC3416046  PMID: 22786898
15.  A Perioculomotor Nitridergic Population in the Macaque and Cat  
Purpose.
We determined the distribution of cells containing synthetic enzymes for the unconventional neurotransmitter, nitric oxide, with respect to the known populations within the oculomotor complex.
Methods.
The oculomotor complex was investigated in monkeys and cats by use of histochemistry to demonstrate nicotinamide adenine dinucleotide phosphate diaphorase positive (NADPHd+) cells and antibodies to localize neuronal nitric oxide synthase positive (NOS+) cells. In some cases, wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) was injected into extraocular muscles to allow comparison of retrogradely labeled and NADPHd+ cell distributions.
Results.
The distribution of the NADPHd+ and NOS+ neurons did not coincide with that of preganglionic and extraocular motoneurons in the oculomotor complex. However, labeled perioculomotor neurons were observed. Specifically, in monkeys, they lay in an arc that extended from between the oculomotor nuclei into the supraoculomotor area (SOA). Comparison of WGA-HRP–labeled medial and superior rectus motoneurons with NADPHd staining confirmed that the distributions overlapped, but showed that the C- and S-group cells were not NADPHd+. This suggested that NADPHd+ cells are part of the centrally projecting Edinger-Westphal population (EWcp). Examination of the NADPHd+ cell distribution in the cat showed that these cells were indeed found primarily within its well-defined EWcp.
Conclusions.
Based on their similar distributions, it appears that the peptidergic EWcp neurons, which project widely in the brain, also may be nitridergic. While the preganglionic and C- and S-group motoneuron populations do not use this nonsynaptic neurotransmitter, nitric oxide produced by surrounding NADPHd+ cells may modulate the activity of these motoneurons.
The centrally projecting Edinger-Westphal nucleus (EWcp) in both the macaque monkey and cat contains a nitridergic cell population. The motoneurons in the preganglionic Edinger Westphal nucleus (EWpg) and the oculomotor nucleus are not nitridergic.
doi:10.1167/iovs.12-10287
PMCID: PMC3426346  PMID: 22836763
16.  Spectrum of Infantile Esotropia in Primates: Behavior, Brains and Orbits 
Introduction
Recent studies of human infants have described a spectrum of early-onset esotropia, from small-variable-angle to large heterotropias.1 We report here a similar spectrum of early-onset esotropia in infant monkeys, with emphasis on the relationship between visuomotor deficits, central nervous system (CNS) circuitry and orbital anatomy.
Methods
Eye movements were recorded in macaque monkeys with natural, infantile-onset esotropia (n=7) and in control monkeys (n=2) to assess alignment, latent nystagmus, dissociated vertical deviation (DVD), and pursuit/optokinetic nystagmus (OKN) asymmetries. Acuity was measured by preferential-looking technique or spatial sweep VEP (SSVEP). Geniculo-striate pathways were then analyzed with neuroanatomic tracers and metabolic labels. Extraocular muscles were examined by high-resolution magnetic resonance imaging (MRI) and anatomic sectioning of whole orbits.
Results
Esotropia ranged from 4-13.5° (7-24 prism diopters [PD]) with fixation preference (if any) varying idiosyncratically (as in human). Severity of ocular motor dysfunction (i.e. nystagmus velocity, DVD amplitude, pursuit-OKN nasal bias index), increased as the magnitude of esotropia angle. Animals with greater ocular motor deficits tended to have greater visual area V1 (striate cortex) neuroanatomic deficits, evident as fewer binocular horizontal connections in V1. Orbital MRI/anatomic analysis showed no difference in horizontal rectus cross sectional areas, muscle paths, innervation densities or cytoarchitecture compared to normal animals.
Conclusion
The infantile esotropia spectrum in non-human primates is remarkably similar to that reported in human infants. Concomitant esotropia in these primates cannot be ascribed to abnormalities of the extraocular muscles or orbit. These findings, combined with epidemiologic studies of human, suggest that perturbations of CNS binocular pathways in early development are the primary cause of the infantile esotropia syndrome.
doi:10.1016/j.jaapos.2007.11.010
PMCID: PMC2637440  PMID: 18289896
17.  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
18.  Brief Daily Periods of Unrestricted Vision Preserve Stereopsis in Strabismus 
In this study, stereopsis was preserved in optically strabismic infant monkeys by brief daily periods of normal binocular vision. This result indicates that the temporal integration properties of mechanisms responsible for vision development ensure that binocular vision development proceeds normally despite episodes of abnormal vision, but also implies that stereopsis may be preserved in human strabismic infants by providing brief daily periods of fusion prior to alignment surgery.
Purpose.
This study examines whether brief periods of binocular vision could preserve stereopsis in monkeys reared with optical strabismus.
Methods.
Starting at 4 weeks of age, six infant monkeys were reared with a total of 30 prism diopters base-in split between the eyes. Two of the six monkeys wore prisms continuously, one for 4 weeks and one for 6 weeks. Four of the six monkeys wore prisms but had 2 hours of binocular vision daily, one for 4, one for 6, and two for 16 weeks. Five normally reared monkeys provided control data. Behavioral methods were used to measure spatial contrast sensitivity, eye alignment, and stereopsis with Gabor and random dot targets.
Results.
The same pattern of results was evident for both local and global stereopsis. For monkeys treated for 4 weeks, daily periods of binocular vision rescued stereopsis from the 10-fold reduction observed with continuous optical strabismus. Six weeks of continuous strabismus resulted in stereo blindness, whereas daily periods of binocular vision limited the reduction to a twofold loss from normal. Daily periods of binocular vision preserved stereopsis over 16 weeks of optical strabismus for one of the two monkeys.
Conclusions.
Two hours of daily binocular vision largely preserves local and global stereopsis in monkeys reared with optical strabismus. During early development, the effects of normal vision are weighed more heavily than those of abnormal vision. The manner in which the effects of visual experience are integrated over time reduces the likelihood that brief episodes of abnormal vision will cause abnormal binocular vision development.
doi:10.1167/iovs.10-6891
PMCID: PMC3175955  PMID: 21398285
19.  Smooth Pursuit Eye Movements in Children with Strabismus and in Children with Vergence Deficits 
PLoS ONE  2013;8(12):e83972.
Purpose
The objective of our study was to examine horizontal smooth pursuit performance in strabismic children and in children with vergence deficits, and to compare these data with those recorded in a group of control age-matched children.
Methods
Binocular eye movements were recorded by video-oculography in ten strabismic children (mean age: 9.8±0.8) and seven children with vergence deficits (mean age: 10.8±0.6). Data were compared to that of age-matched control children (mean age: 9.8±0.8 years).
Results
Catch-up saccades amplitude in strabismic children and in children with vergence deficits were significantly higher than in control age-matched children. Moreover, in strabismic children the amplitude of catch-up saccades was significantly higher in rightward than in leftward direction. The number of catch-up saccades was also significantly higher in rightward than in leftward direction. The gain value of pursuits in rightward direction was significantly higher in the right eye than in the left one; for the right eye, the gain value was significantly higher in rightward than in leftward direction. Binocular coordination of pursuit was better in control age-matched children than in children with vergence deficits and than in strabismic children.
Conclusions
Binocular coordination of pursuit is abnormal in children with vergence deficits and worse in strabismic children. Binocular vision plays an important role in improving binocular coordination of pursuit.
doi:10.1371/journal.pone.0083972
PMCID: PMC3869866  PMID: 24376777
20.  The Final Version of the Distance Randot Stereotest: Normative data, reliability, and validity 
Purpose
Measurement of distance stereoacuity may be useful in assessing strabismic patients, especially those with intermittent exotropia. We developed the Distance Randot Stereotest as an easily administered quantitative test for distance stereoacuity in children. Using a prototype,1 we reported testability, validity, and normative data. Here we report normative and validity data for the final, commercially available version of the test.
Method
We administered both the Prototype and the Final Version Distance Randot Stereotest to 156 normal volunteers (2–40 years of age) and 77 strabismic patients (4–62 years of age). Test–retest data were collected for the Final Version.
Results
Normative Final Version scores were similar to those obtained with the Prototype; 96% were ≤100 arcsec. Test–retests were identical in 82% and within one disparity level in 100%. Final Version scores were correlated with Prototype scores (rs = 0.64, p < 0.05). Among strabismic patients, 62.3% had abnormal stereoacuity; those with normal scores had incomitant or intermittent deviations. Nil stereoacuity was found in 27 patients, confirmed in 90.9%of retests; 17 had measurable stereoacuity, confirmed in 96.3%of retests. Patients with constant strabismus were more likely to have nil stereoacuity than patients who had intermittent strabismus (95% vs 12.2%).
Conclusions
Distance Randotscores from normal subjects have low variability within each age group and high test–retest reliability. There is little overlap between Distance Randot® scores from normal controls and strabismic patients. The Distance Randot Stereotest is a sensitive measurement of binocular sensory status that may be useful in monitoring progression of strabismus and/or recovery following strabismus surgery.
doi:10.1016/j.jaapos.2009.12.159
PMCID: PMC2866770  PMID: 20199880
21.  Comparison of psychosocial and emotional consequences of childhood strabismus on the families from rural and urban India 
Indian Journal of Ophthalmology  2009;57(4):285-288.
Purpose:
To compare the psychosocial consequences of horizontal comitant strabismus in children between the families of urban and rural India.
Materials and Methods:
In this cohort study, an eight-question quality-of-life instrument was administered by trained staff to the guardians of strabismic children from rural and urban areas by a live interview.
Results:
This study included 93 strabismic-children aged 4-16 years of which 52 were females. Forty-one had esodeviation and 52 had exodeviation. Seventy per cent parents were extremely distressed due to squint, 65% were extremely distressed due to people's remarks, 65% were extremely worried, 55% children were extremely distressed due to people's remarks, 57% children were severely ostracized, 38% had severe difficulty in communication and 50% had difficulty to cope; 64% parents were not advised a corrective surgery. The difference between families from rural and urban areas, or whether a male child was affected or a female child or for an esodeviation or an exodeviation was statistically not significant. The questionnaire had a good internal consistency (Cronbach's Alpha = 0.71).
Conclusions:
There was a significant negative psychosocial and emotional impact of childhood strabismus that was not affected by the rural or urban location of the family or the gender of the strabismic child or type of the deviation. The quality-of-life instrument can be used as part of the clinical examination for strabismic children.
doi:10.4103/0301-4738.53053
PMCID: PMC2712697  PMID: 19574696
Children; quality of life; squint
22.  Duration of Binocular Decorrelation in Infancy Predicts the Severity of Nasotemporal Pursuit Asymmetries in Strabismic Macaque Monkeys 
Neuroscience  2008;156(2):403-411.
Purpose
Strabismus in human infants is linked strongly to nasotemporal asymmetries of smooth pursuit, but many features of this co-morbidity are unknown. The purpose of this study was to determine how the duration of early-onset strabismus (or timeliness of repair) affects the severity of pursuit asymmetries in a primate model.
Methods
Binocular image decorrelation was imposed on infant macaques by fitting them with prism goggles on day 1 of life. The goggles were removed after 3 weeks (n=2), 12 weeks (n=2) or 24 weeks (n=3), emulating surgical repair of strabismus in humans at 3, 12, and 24 months of age, respectively. Two control monkeys wore plano lenses. Several months after the goggles were removed, horizontal smooth pursuit was recorded using binocular search coils and a nasal-bias index (NBI) was calculated.
Results
Each animal in the 12- and 24-week groups developed a constant, alternating esotropic strabismus and a nasotemporal asymmetry of pursuit when viewing with either eye. Spatial vision was normal (no amblyopia). The 3-week duration monkeys were indistinguishable from control animals; they had normal eye alignment and symmetric pursuit. In the 12- and 24-week monkeys, the longer the duration of binocular decorrelation, the greater the pursuit asymmetry: for 15 deg/s target motion, the NBI in the 12-week and 24-week animals was 16 X and 22 X greater respectively, than that in the 3 week animals (ANOVA, p = 0.03).
Conclusions
Binocular decorrelation in primates during an early period of fusion development causes permanent smooth pursuit asymmetries when the duration exceeds the equivalent of 3 months in human. These findings support the conclusion that early correction of infantile strabismus promotes normal development of cerebral gaze pathways.
doi:10.1016/j.neuroscience.2008.06.070
PMCID: PMC2632802  PMID: 18708128
visual development; ocular motor system; fusion; esotropia; visual cortex; brain repair
23.  Origins of strabismus and loss of binocular vision 
Strabismus is a frequent ocular disorder that develops early in life in humans. As a general rule, it is characterized by a misalignment of the visual axes which most often appears during the critical period of visual development. However other characteristics of strabismus may vary greatly among subjects, for example, being convergent or divergent, horizontal or vertical, with variable angles of deviation. Binocular vision may also vary greatly. Our main goal here is to develop the idea that such “polymorphy” reflects a wide variety in the possible origins of strabismus. We propose that strabismus must be considered as possibly resulting from abnormal genetic and/or acquired factors, anatomical and/or functional abnormalities, in the sensory and/or the motor systems, both peripherally and/or in the brain itself. We shall particularly develop the possible “central” origins of strabismus. Indeed, we are convinced that it is time now to open this “black box” in order to move forward. All of this will be developed on the basis of both presently available data in literature (including most recent data) and our own experience. Both data in biology and medicine will be referred to. Our conclusions will hopefully help ophthalmologists to better understand strabismus and to develop new therapeutic strategies in the future. Presently, physicians eliminate or limit the negative effects of such pathology both on the development of the visual system and visual perception through the use of optical correction and, in some cases, extraocular muscle surgery. To better circumscribe the problem of the origins of strabismus, including at a cerebral level, may improve its management, in particular with respect to binocular vision, through innovating tools by treating the pathology at the source.
doi:10.3389/fnint.2014.00071
PMCID: PMC4174748  PMID: 25309358
children; early strabismus; binocular vision; brain development; critical period
24.  Insulin-like Growth Factor-1 and Cardiotrophin 1 Increase Strength and Mass of Extraocular Muscle in Juvenile Chicken 
Juvenile strabismic extraocular muscles may benefit from treatment with trophic factors, but only embryonic and adult muscles have previously been examined. Here the authors show in an animal model that juvenile muscles respond to two trophic factors with significant increases in force, and they determined which muscle parameters and segments are altered to achieve increases in force.
Purpose.
Insulin-like growth factor 1 (IGF1) and cardiotrophin 1 (CT1) are known to increase the strength of extraocular muscles in adult and embryonic animals, but no information is available for the early postnatal period, when strabismus treatment in humans is most urgent. Here the authors sought to determine whether these trophic factors strengthen juvenile maturing extraocular muscles and gain insight into mechanisms of force increase.
Methods.
After two injections of IGF1, CT1, or both with different dosages in posthatch chickens, the authors quantified five parameters of the superior oblique extraocular muscle at 2 weeks of age: contractile force, muscle mass, total myofiber area, myofiber diameter, and number of proliferating satellite cells labeled by bromodeoxyuridine.
Results.
Treatment with IGF1, CT1, and combination of IGF1 and CT1 significantly increased contractile force by 14% to 22%. CT1 and combination treatment significantly increased muscle mass by 10% to 24%. IGF1/CT1 combination treatment did not have additive effects on strengthening muscles, compared with single-drug treatments. Myofiber area increased significantly with IGF1 and CT1 treatment in proximal, but not distal, parts of the muscle and this was due to increased fiber numbers or length (IGF1) or increased diameters of global layer myofibers (CT1). Trophic factors increased the number of proliferating (bromodeoxyuridine-labeled) satellite cells in proximal and middle segments of muscles.
Conclusions.
Exogenous IGF1 and CT1 strengthen extraocular muscles during maturation. They predominantly remodel the proximal segment of juvenile extraocular muscles. This information about muscle plasticity may aid the design of pharmacologic treatment of strabismus in children during the “critical period” of oculomotor maturation.
doi:10.1167/iovs.09-4414
PMCID: PMC2868486  PMID: 20007833
25.  Dissociated vertical deviation: an exaggerated normal eye movement used to damp cyclovertical latent nystagmus. 
PURPOSE: Dissociated vertical deviation (DVD) has eluded explanation for more than a century. The purpose of this study has been to elucidate the etiology and mechanism of DVD. METHODS: Eye movement recordings of six young adults with DVD were made with dual-coil scleral search coils under various conditions of fixation, illumination, and head tilt. Horizontal, vertical, and torsional eye movements were recorded for both eyes simultaneously. Analyses of the simultaneous vertical and torsional movements occurring during the DVD response were used to separate and identify the component vergence and version eye movements involved. RESULTS: Typically, both horizontal and cyclovertical latent nystagmus developed upon occlusion of either eye. A cycloversion then occurred, with the fixing eye intorting and tending to depress, the covered eye extorting and elevating. Simultaneously, upward versions occurred for the maintenance of fixation, consisting variously of saccades and smooth eye movements, leading to further elevation of the eye behind the cover. The cyclovertical component of the latent nystagmus became partially damped as the DVD developed. CONCLUSIONS: In patients with an early-onset defect of binocular function, the occlusion of one eye, or even concentration on fixing with one eye, produces unbalanced input to the vestibular system. This results in latent nystagmus, sometimes seen only with magnification. The cyclovertical component of the latent nystagmus, when present, is similar to normal vestibular nystagmus induced by dynamic head tilting about an oblique axis. Such vestibular nystagmus characteristically produces a hyperdeviation of the eyes. In the case of cyclovertical latent nystagmus, the analogous hyperdeviation will persist unless corrected by a vertical vergence. A normal, oblique-muscle-mediated, cycloversion/vertical vergence is called into play. This occurs in the proper direction to correct the hyperdeviation, but it occurs in an exaggerated form in the absence of binocular vision, probably as a learned response. The cycloversion/vertical vergence helps damp the cyclovertical nystagmus (a cyclovertical "nystagmus block-age" phenomenon), aiding vision in the fixing eye. But this mechanism also produces unavoidable and undesirable elevation and extortion of the fellow eye, which we call DVD.
PMCID: PMC1298405  PMID: 10360299

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