The goal of this research is to determine if maldeveloped brain circuits in infants with strabismus can be repaired by early eye realignment surgery. Non-randomized studies of a small number of strabismic human infants have reported improved alignment and stereopsis after early surgery. However, early surgery is not the standard of care. It is clinically burdensome and the efficacy is controversial. The limitations of human study preclude gathering the detailed knowledge of repair efficacy that would help settle the controversy. Nonhuman primates (NHPs) develop strabismus when they experience sensorial binocular decorrelation in the first weeks of life. The animals display each of the behaviors of the human infantile strabismus syndrome, providing an excellent model for a study of functional-structural repair. In the proposed research, visuomotor behaviors, cortical activity, and cortical connections will be measured after surgery in NHPs randomized to early vs. delayed treatment groups. The following hypotheses will be tested in each animal: Hypothesis 1. Early surgical correction of strabismus promotes repair of a constellation of visuomotor behaviors. The infantile strabismus syndrome includes anomalies of stereopsis, motion perception, fusional vergence, and horizontal gaze-stabilizing, pursuit, optokinetic and ocular following movements. Strabismus will be corrected surgically after durations of 10 and 30 weeks, the equivalent of age 10 mos. (early surgery), and 3.5 years (delayed surgery) in children. After eye realignment, each behavior will be recorded. If the behavioral measures approximate normal values in monkeys realigned earlier, early realignment will be considered to achieve functional repair. Hypothesis 2. fMRI cerebral gaze BOLD signals are unbalanced/asymmetric in infantile strabismus;earlier surgical correction promotes symmetry. Visual areas V1, MT and MST are implicated as the loci of the horizontal gaze/visual motion processing asymmetries that typify infantile strabismus. Symmetry of motion-evoked fMRI signals in V1/MT/MST contralateral and ipsilateral to the viewing eye will be measured with and without eye tracking. If fMRI signals are more symmetric in monkeys realigned earlier, early realignment will be considered important for repair of gaze pathways. Hypothesis 3: Strabismic primates have structural abnormalities in V1 that: a) correlate with behavioral deficits, and b) can be repaired by realignment of the eyes;earlier realignment promotes substantial repair, delayed re-alignment promotes partial repair. Ocular dominance columns (ODCs) in V1 will be injected using neuroanatomic labels to reveal monocular and binocular excitatory connections. Suppression of ODC activity and inhibitory connections will also be examined using cytochrome- oxidase and GABA histochemistry. If binocular excitatory connections are more numerous, and ODC suppression/inhibitory connections less numerous in monkeys realigned earlier, early strabismus surgery will be considered to achieve structural repair.

Public Health Relevance

Strabismus (crossed-eyes) is a major pediatric health problem, causing permanent visual impairment in ~ 4-5 % of children worldwide. Surgical correction early in infancy is clinically burdensome and the efficacy controversial. Infants with minimal brain dysfunction due to prematurity or other birth-related troubles are at especially high risk. Early-onset strabismus devastates perception of depth, motion, and eye tracking. It is a leading cause of permanent vision loss due to interocular suppression (amblyopia). The animal model will help us improve surgical and neuropharmacological treatments for these disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
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Central Visual Processing Study Section (CVP)
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Araj, Houmam H
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Washington University
Schools of Medicine
Saint Louis
United States
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Hoekel, James; Chisholm, Smith Ann; Al-Lozi, Amal et al. (2014) Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome. J AAPOS 18:461-465.e1
Ghasia, Fatema; Tychsen, Lawrence (2014) Horizontal and vertical optokinetic eye movements in macaque monkeys with infantile strabismus: directional bias and crosstalk. Invest Ophthalmol Vis Sci 55:265-74
Tychsen, Lawrence; Richards, Michael; Wong, Agnes et al. (2010) The neural mechanism for Latent (fusion maldevelopment) nystagmus. J Neuroophthalmol 30:276-83
Hasany, A; Wong, A; Foeller, P et al. (2008) Duration of binocular decorrelation in infancy predicts the severity of nasotemporal pursuit asymmetries in strabismic macaque monkeys. Neuroscience 156:403-11
Tychsen, Lawrence; Richards, Michael; Wong, Agnes et al. (2008) Spectrum of infantile esotropia in primates: Behavior, brains, and orbits. J AAPOS 12:375-80
Richards, Michael; Wong, Agnes; Foeller, Paul et al. (2008) Duration of binocular decorrelation predicts the severity of latent (fusion maldevelopment) nystagmus in strabismic macaque monkeys. Invest Ophthalmol Vis Sci 49:1872-8
Tychsen, Lawrence (2007) Causing and curing infantile esotropia in primates: the role of decorrelated binocular input (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc 105:564-93
Lim, Key Hwan; Poukens, Vadims; Demer, Joseph L (2007) Fascicular specialization in human and monkey rectus muscles: evidence for anatomic independence of global and orbital layers. Invest Ophthalmol Vis Sci 48:3089-97
Narasimhan, Anita; Tychsen, Lawrence; Poukens, Vadims et al. (2007) Horizontal rectus muscle anatomy in naturally and artificially strabismic monkeys. Invest Ophthalmol Vis Sci 48:2576-88
Shiels, Alan; Bennett, Thomas M; Prince, Jessica B et al. (2007) X-linked idiopathic infantile nystagmus associated with a missense mutation in FRMD7. Mol Vis 13:2233-41

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