October 2018
Volume 59, Issue 12
Open Access
Research Highlight  |   October 2018
Visualizing Neuronal Adaptation Over Time After Treatment of Strabismus
Author Affiliations
  • Jérome Fleuriet
    Washington National Primate Research Center, University of Washington, Seattle, Washington, United States
    Department of Ophthalmology, University of Washington, Seattle, Washington, United States
  • Linda K. McLoon
    Department of Ophthalmology and Visual Neurosciences, Minneapolis, Minnesota, United States; mcloo001@umn.edu
    Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota, United States
Investigative Ophthalmology & Visual Science October 2018, Vol.59, 5022-5024. doi:https://doi.org/10.1167/iovs.18-25651
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      Jérome Fleuriet, Linda K. McLoon; Visualizing Neuronal Adaptation Over Time After Treatment of Strabismus. Invest. Ophthalmol. Vis. Sci. 2018;59(12):5022-5024. https://doi.org/10.1167/iovs.18-25651.

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      © ARVO (1962-2015); The Authors (2016-present)

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Despite the frequency of developmental strabismus, we do not understand the primary cause of eye misalignment in otherwise normal children. Since the 1800s, strabismus has been treated using similar methods and rationale. The first current approach includes spectacle correction or eye patching, which fails to result in normal alignment in 40% of the children treated.1 If patching fails, a surgical alteration of eye alignment is performed, where the muscles are made “stronger” or “weaker” by changing their effective length and/or the site of their insertions onto the sclera. For many of these children, these approaches produce successful outcomes, including orthotropic eye alignment and normal binocular vision. However, there are many children for whom surgical treatment fails.2 Longitudinal studies have shown that over 10 and 20 year periods, the failure rates are as high as 50% to 80%.36 There are almost 9000 published studies on the effects of strabismus surgery, yet the fundamental cause(s) of its failure to produce and maintain long-term, normal eye alignment is still not understood. The publication by Pullela et al.7 provides us great insight into the process of neuronal changes that occurs longitudinally, both acutely and chronically, after resection/recession surgery using a well-established model for infantile strabismus.8 
Recent studies have examined changes to the extraocular muscle structure after various types of strabismus surgery and demonstrated that there was significant adaptation of the operated extraocular muscles.9,10 In resected, recessed, or tenotomized muscles, myofiber cross-sectional areas decreased within 7 days of surgery. There was also an increase of labeled muscle precursor cells into the myofibers of the operated muscles at a rate 10 times that seen in control muscles.9,10 This rapid muscle remodeling corresponds to the 1-week time point shown in an earlier report from the Das laboratory,11 where there was already close to a 10 degree worsening of the surgically-induced improvement in eye alignment. What was perhaps more compelling were the coordinated alterations in the unoperated muscle discovered on the contralateral side.10,12 The manifestation of bilateral changes in muscle size and myosin expression corresponds to the bilateral change in the postsurgical eye alignment within even this 1-week time period.7,8 
In a series of studies, it has been clearly shown that the angle of misalignment is driven by the motor neurons,13,14 which in turn are driven by supranuclear areas that project onto these motor neurons.1520 The power of the study by Das and colleagues is based on their ability to record changes to motor neuron activity before and after a corrective surgery and correlate this activity with changes in eye alignment in adult non-human primates.7 The results show that the neuronal drive to the “strengthened” medial rectus muscle is actually reduced, which would drive the eye alignment back into a more exotropic state, thus “undoing” the effects of muscle surgery. By 6 months, neuronal drive had returned to presurgical values, maintaining the original exotropia in these monkeys. Interestingly the second monkey showed a different pattern of neuronal drive changes. In this case, the oculomotor system increased the neuronal drive to the “weakened” muscle, again negating the effect of the attempted correction by recession on this muscle and pushing the alignment back to a more exotropic state. These studies provide important perspectives on how eye alignment is controlled. First, the ocular motor system detects changes in muscle force generation after surgery and actively works to return the eyes to their original angle of misalignment. Second, there appears to be significant plasticity in how the oculomotor system responds to perturbations, with two very different patterns of changes in neuronal drive. Both of these changes yielded the same net result, which worked against the initial corrective surgical intervention. These observations are extremely important because they suggest that the most efficacious way to ensure a permanent correction of childhood onset strabismus deserves further study. For example, determining how to “readapt” the visuo- and oculomotor systems to the surgically or pharmacologically altered “new” eye alignment could significantly improve efficacious outcomes. 
The other important discovery in this publication by Das and colleagues is the demonstration that the neuronal drive to the unoperated muscles on the contralateral side also changes.7 These changes are coordinated and opposite to those seen in the neuronal drive to the treated muscles. Similar types of coordinated changes to untreated extraocular muscles on the contralateral side also have been demonstrated following growth factor treatment of extraocular muscles in adult strabismic monkeys.21 These data also indicate why surgery of only one muscle can be effective for treating strabismus.22,23 
How these changes in post-surgical eye alignment are controlled at the motor neuron and muscle level are not understood. One prediction is that strabismus surgery results in altered levels of neurotrophic factors within the muscles and/or motor neurons. Mechanism of action could include anterograde and/or retrograde transport of these molecules, which have the potential to alter properties of both neuronal and muscle cell structure and function. So far, little work has been reported to assess how various neurotrophic factors changed as a result of extraocular muscle resection or recession. However, it is known that when limb skeletal muscles were either unweighted or overloaded, altered levels of a number of neurotrophic factors occurred.24,25 A number of studies have demonstrated that the extraocular motor system, including both neurons and muscles, express higher levels of neurotrophins compared to brainstem and spinal cord motor systems.26 More support for neurotrophins playing a role in the onset and/or maintenance of strabismus comes from microarray studies showing dysregulation of ciliary neurotrophic factor and glial derived neurotrophic factor, among others, in muscles from strabismic humans.27,28 Complementary studies show the ability of increases in various neurotrophic factors to induce strabismus in infant monkeys (McLoon LK, et al. IOVS 2016;56:ARVO E-Abstract 1395).29 Finally, oculomotor neuronal drive based on visual error from upstream visual structures may also be at play in working against successful correction after surgical alignment, and understanding these mechanisms could offer an extraordinary asset for clinicians. 
The strength of the study by Das and colleagues lies in the ability to correlate pre- and postsurgical eye alignment with neuronal recordings performed pre- and postsurgically over a period of 6 months in the treated monkeys.7 Although the ophthalmology field has hypothesized that the failure of strabismus surgery may lie in the inability of the oculomotor system to adapt to a significant alteration in eye alignment produced by the surgical manipulation, this is the first demonstration that the motor neurons specifically alter their firing rates and actively compensate for what was perceived by the visuo- and oculomotor systems as an “incorrect” eye position. This study answers a basic and long-standing question but also raises interesting new hypotheses that can be tested. How does vision affect these changes? It has been shown that even transient strabismus induced by surgery results in a breakdown of cortical binocularity.30 Would the neuronal drive change if the monkeys were placed in the dark? Would visual therapy be possible to readapt the system to the altered visual field being seen after surgery? If the surgery had resulted in a fully corrected eye alignment, would the end result have been more stable? Does the age of the animal and cause and duration of the strabismus affect these results? As these strabismic monkeys were prism-reared as infants to induce their exotropia, it seems reasonable to extrapolate findings to naturally occurring strabismus. However, the reversal to the corrective effect reported here might not exactly match the challenge clinicians face after surgical manipulation of the extraocular muscles. For that matter, the etiology of strabismus is often unknown and could include different critical variables. 
As with any paradigm-shifting research, this study indicates that to improve the outcomes of strabismus surgery, we must learn how to modulate the brain's solution to dealing with the lack of normal eye alignment. To do this, we need to fully understand the way oculomotor neurons control the eye muscles and the resultant eye position and eye movements in both health and disease. For example, a series of recent studies have focused on using retrogradely transported neurotrophic factors to modulate the central control of eye muscles and eye position and cause or treat strabismus.21,3133 This paper from the Das laboratory provides significant support for the quest to develop methods to modulate motor neuron functional properties to find a successful and long-lasting treatment for childhood onset strabismus. 
Acknowledgments
Supported by EY15313 (LKM), P30 EY11375, EY06069 (Michael Mustari), P30 EY001730 (University of Washington), ORIP P51OD010425, Washington National Primate Research Center, the Minnesota Lions Foundation, and unrestricted grants to the Departments of Ophthalmology (University of Minnesota and University of Washington) from Research to Prevent Blindness, Inc. 
Disclosure: J. Fleuriet, None; L.K. McLoon, None 
References
Flynn JT, Schiffman J, Feuer W, Corona A. The therapy of amblyopia: an analysis of the results of amblyopia therapy utilizing the pooled data of published studies. Trans Am Ophthalmol Soc. 1998; 96: 431–450.
Vroman DT, Hutchinson AK, Saunders RA, Wilson ME. Two-muscle surgery for congenital esotropia: rate of reoperation in patients with small versus large angles of deviation. J AAPOS. 2000; 4: 267–270.
Livir-Rallatos G, Gunton KB, Calhoun JH. Surgical results for large-angle exotropia. J AAPOS. 2002: 6: 77–80.
Louwagie CR, Diehl NN, Greenberg AE, Mohney BG. Long-term follow-up of congenital esotropia in a population-based cohort. J AAPOS. 2009; 13: 8–12.
Ekdawi NS, Nusz KJ, Diehl NN, Mohney BG. Postoperative outcomes in children with intermittent exotropia from a population-based cohort. J AAPOS. 2009; 13: 4–7.
Pineles SL, Ela-Dalman N, Zvansky AG, Yu F, Rosenbaum AL. Long-term results of the surgical management of intermittent exotropia. J AAPOS. 2010; 14: 298–304.
Pullela M, Ağaoğlu MN, Joshi AC, Agaoglu S, Coats DK, Das VE. Neural plasticity following surgical correction of strabismus in monkeys. Invest Ophthalmol Vis Sci. 2018; 59: 5011–5021.
Yildirim C, Tychsen L. Effect of infantile strabismus on visuomotor development in the squirrel monkey (Saimiri sciureus): optokinetic nystagmus, motion VEP and spatial sweep VEP. Strabismus. 1999; 7: 211–219.
Christiansen SP, McLoon LK. The effect of resection on satellite cell activity in rabbit extraocular muscle. Invest Ophthalmol Vis Sci. 2006; 47: 605–613.
Christiansen SP, Antunes-Foschini RS, McLoon LK. Effects of recession versus tenotomy surgery without recession in adult rabbit extraocular muscle. Invest Ophthalmol Vis Sci. 2010; 51: 5646–5656.
Pullela M, Degler BA, Coats DK, Das VE. Longitudinal evaluation of eye alignment and eye movements following surgical correction of strabismus in monkeys. Invest Ophthalmol Vis Sci. 2016; 57: 604–6047.
Christiansen SP, Madhat M, Baker L, Baker R. Fiber hypertrophy in rat extraocular muscle following lateral rectus resection. J Pediatr Ophthalmol Strabismus. 1988; 25: 167–171.
Joshi AC, Das VE. Responses of medial rectus motoneurons in monkeys with strabismus. Invest Ophthalmol Vis Sci. 2011; 52: 6697–6705.
Walton MM, Mustari MJ, Willoughby CL, McLoon LK. Abnormal activity of neurons in abducens nucleus of strabismic monkeys. Invest Ophthalmol Vis Sci. 2014; 56: 10–19.
Das VE, Mustari MJ. Correlation of cross-axis eye movements and motoneuron activity in non-human primates with “A” pattern strabismus. Invest Ophthalmol Vis Sci. 2007; 48: 665–674.
Das VE. Cells in the supraoculomotor area in monkeys with strabismus show activity related to the strabismus angle. Ann NY Acad Sci. 2011; 1233: 85–90.
Das VE. Responses of the cells in the midbrain near-response area in monkeys with strabismus. Invest Ophthalmol Vis Sci. 2012; 53: 3858–3864.
Joshi AC, Das VE. Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus. J Neurophysiol. 2103; 110: 1882–1291.
Walton MM, Mustari MJ. Abnormal tuning of saccade-related cells in pontine reticular formation of strabismic monkeys. J Neurophysiol. 2015; 114: 857–868.
Pallus AC, Walton MMG, Mustari MJ. Activity of near response cells during disconjugate saccades in strabismic monkeys [published online ahead of print August 15, 2018]. J Neurophysiol. https://doi.org/10.1152/jn.00219.2018
McLoon LK, Christiansen SP, Ghose GM, Das VE, Mustari JJ. Improvement of eye alignment in adult strabismic monkeys by sustained IGF-1 treatment. Invest Ophthalmol Vis Sci. 2016; 57: 6070–6078.
Jatla KK, Enzenauer RW. Strabismus outcomes/quality control: the application of statistical process control (SPC) to one muscle and two muscle simple horizontal strabismus of 25PD or less. Binocul Vis Strabismus Q. 2006; 21: 215–222.
Wang L, Nelson LB. One muscle strabismus surgery. Curr Opin Ophthalmol. 2010; 21: 335–340.
McMahon G, Morse CI, Burden A, Winwood K, Onambélé GL. Muscular adaptations and insulin-like growth factor-1 responses to resistance training are stretch-mediated. Muscle Nerve 2014; 49: 108–119.
Player DJ, Martin NR, Passey SL, Sharples AP, Mudera V, Lewis MP. Acute mechanical overload increases IGF-1 and MMP-9 mRNA in 3D tissue-engineered skeletal muscle. Biotechnol Lett. 2014; 36: 1113–1124.
Hernández RG, Silva-Hucha S, Morcuende S, de la Cruz RR, Pastor AM, Benítez-Temiño B. Extraocular motor system exhibits a higher expression of neurotrophins when compared with other brainstem motor systems. Front Neurosci. 2017; 11: 399.
Agarwal AB, Feng CY, Altick AL, et al. Altered protein composition and gene expression in strabismic human extraocular muscles and tendons. Invest Ophthalmol Vis Sci. 2016; 57: 5576–5585.
Altick AL, Feng CY, Schlauch K, Johnson LA, von Bartheld CS. Differences in gene expression between strabismic and normal human extraocular muscles. Invest Ophthalmol Vis Sci. 2012; 53: 168–177.
Willoughby CL, Fleuriet J, Walton MM, Mustari MJ, McLoon LK. Adaptability of the immature ocular motor control system: unilateral IGF-I medial rectus treatment. Invest Ophthalmol Vis Sci. 2015; 56: 3484–3496.
Sireteanu R, Singer W, Fronius M, et al. Eye alignment and cortical binocularity in strabismic kittens: a comparison between tenotomy and recession. Vis Neurosci. 1993; 10: 541–549.
Chen J, von Bartheld CS. Role of exogenous and endogenous trophic factors in the regulation of extraocular muscle strength during development. Invest Ophthalmol Vis Sci. 2004; 45: 3538–3545.
McLoon LK, Anderson BC, Christiansen SP. Increasing muscle strength as a treatment for strabismus: sustained release of insulin growth factor-1 results in stronger extraocular muscle. J AAPOS. 2006; 10: 424–429.
Li T, Feng CY, von Bartheld CS. How to make rapid eye movements “rapid”: the role of growth factors for muscle contractile properties. Pflugers Arch. 2011; 461: 373–386.
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