Can ocular dominance plasticity provide a general index to visual plasticity to personalize treatment in amblyopia?

Purpose: Recently, Lunghi et al showed that amblyopic eye's visual acuity per se after 2 months of occlusion therapy could be predicted by a homeostatic plasticity, i.e., the temporary shift of ocular dominance observed after a 2-hour monocular deprivation, in children with anisometropic amblyopia (Lunghi et al., 2016). In this study, we assess whether the visual acuity improvement of the amblyopic eye measured after 2 months of occlusion therapy could be predicted by this plasticity. Methods: Seven children (6.86 {+/-} 1.46 years old; SD) with anisometropic amblyopia participated in this study. All patients were newly diagnosed and had no treatment history before participating in our study. They had finished 2 months of refractive adaptation and then received a 4-hour daily fellow eye patching therapy with an opaque patch for a 2-month period. Best-corrected visual acuity of the amblyopic eye was measured before and after the patching therapy. The homeostatic plasticity was assessed by measuring the temporary shift of ocular dominance observed after 2 hours of occlusion for the amblyopic eye before the treatment started. A binocular phase combination paradigm was used for this test. Results: We found that there was no significant correlation between the temporary shift of ocular dominance observed after 2 hours of occlusion for the amblyopic eye before the treatment started and the visual acuity gain obtained by the amblyopic eye from 2-month of classical patching therapy. This result involving the short-term patching of the amblyopic eye is consistent with a reanalysis of Lunghi et al's data. Conclusions: Ocular dominance plasticity does not provide an index of cortical plasticity in the general sense such that it could be used to predict acuity outcomes from longer term classical patching.


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There is a considerable variability in the response to amblyopic treatment, be it classical 47 occlusion therapy (Stewart et al., 2005)  leading us to the inescapable conclusion that some amblyopes have brains that are more 51 capable of change, in other words, more plastic, than others. Unfortunately, there is no way 52 of knowing which patients are more likely to respond to the treatment before the therapy 53 begins, in the main (though see, (Stewart et al., 2007a)) it is not until the end that the 54 responders can be separated from the non-responders. If we had some general measure of 55 visual cortical plasticity it may be possible to personalize the present treatment and avoid 56 subjecting patients who are unlikely to respond to months or years of the sort of disruption 57 that patching the one good eye produces. areas of the brain are and as such could provide a measure that might allow greater 71 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/10.1101/2020.03.26.20044701 doi: medRxiv preprint predictability for more long-term procedures such as amblyopia patching therapy which is 72 currently associated with a high level of variability in terms of its effectiveness across a 73 population of amblyopes. If this was the case, patching therapy could be personalized using 74 the measure, ocular dominance plasticity in terms of hours per day and total duration. One 75 study has addressed this very interesting question using the measure, short-term ocular 76 dominance plasticity, and concluded that children who exhibit a higher degree of short-term 77 ocular dominance plasticity (determined after a 2-hour period of patching session) go on to 78 obtain larger amblyopic eye "recovery rate" after a long-term (months) patching procedures 79 (Lunghi et al., 2016). It should be noted that, the amblyopic eye "recovery rate" was defined 80 as the absolute final visual acuity after the long-term patching in Lunghi et al's study (Lunghi 81 et al., 2016). It would be interesting to further investigate whether large changes in ocular 82 dominance plasticity were able to predict large improvements (i.e., difference between initial 83 acuity before occlusion therapy and that found after occlusion therapy) in visual acuity (i.e., 84 the effects of patching therapy) as a result of long-term patching. 85 We directly tested this idea in this study. Initially we measured ocular dominance plasticity 86 by patching the amblyopic eye for 2 hours. Second, classical occlusion therapy with an opaque 87 patch occluding the fellow eye (4hrs/day for 2 months) was undertaken in 7 newly diagnosed 88 patients. Any patient who needed an update to the spectacle correction was allowed a 2-89 month period before undertaking the experiment. Seven children (6.86 ± 1.46 years old; SD) who had anisometropic or ametropic 94 amblyopia and were able to perform the binocular phase combination task after practice 95 participated in this study. All patients were newly diagnosed and had no treatment history 96 before participated in our study. The clinical details of the patients and their visual acuity before 97 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

Apparatus 105
The stimuli for the short-term monocular deprivation measurement were generated and 106 In this study, the treatment effect of 2 months patching therapy (4-hour daily fellow eye 116 patching with an opaque patch) was tested after a 2-month of refractive adaptation. The short-117 term monocular deprivation effect was quantified in an initial experiment by the shift of ocular 118 dominance in binocular phase combination after 2-hour of amblyopic eye patching (Zhou et al., 119 2013c). An illustration of the experimental design is provided in Figure 1. 120 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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Seven newly diagnosed child amblyopes (6.86 ± 1.46 years old; SD) participated, in which the treatment 123 effect of 2 months patching therapy (4-hour daily patching with an opaque patch) was tested after a 2-124 month of refractive adaptation. The short-term monocular deprivation effect was quantified by the shift 125 of ocular dominance in binocular phase combination after 2-hour of amblyopic eye patching before the 126 initial of the treatment.

Procedure and stimuli 128
Similar to our previous studies (Zhou et al., 2013a), the short-term monocular deprivation 129 effect was tested with a binocular phase combination task. In the measure, two horizontal 130 sine-wave gratings (1 cycle/°, 2° × 2°), with equal and opposite phase shifts (+22.5° and -131 22.5°) relative to the center of the screen were dichoptically presented to the two eyes. The 132 perceived phase of fused stimuli was 0° when the two eyes contributed equally to binocular 133 fusion. The interocular contrast ratio at that condition was the balance point in binocular phase 134 combination. We firstly tested this balance point for each patient with the contrast of the stimuli 135 in the amblyopic eye set as 100%. This was achieved by measuring individual's binocularly 136 perceived phase at interocular contrast ratios of 0, 0.1, 0.2, 0.4, 0.8 and 1; and the binocularly 137 perceived phase vs. interocular contrast ratio (PvR) curve was fitted with a contrast-gain 138 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is trials were provided before we conducted of the main study to make sure patients understood 140 the task and had a reliable performance in the binocular phase combination task. Individuals' 141 PvR curves measured before treatment are provided in Figure 1. The balance points of 142 patients before treatment are provided in Table 1. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/10.1101/2020.03.26.20044701 doi: medRxiv preprint For the best-corrected visual acuity measure, we asked patients to read the optotypes 166 one after another and stopped when they could not respond within 10 s. We calculated their 167 percentage correct at different lines of the Logarithmic visual acuity Chart. We then used linear 168 interpolation to calculate the score associated with 75% correct judgments. This score was 169 defined as patients' visual acuity. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/10.1101/2020.03.26.20044701 doi: medRxiv preprint Pearson correlation analysis showed that the correlation between the amblyopic eye acuity 198 improvement after 2 months of treatment and the normalized ocular dominance index 199 difference after 2 hrs of amblyopic patching was not significant: r = 0.20, P = 0.66. 200 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

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We show that there was no significant correlation between the amblyopic eye acuity 222 improvement after 2 months of occlusion treatment and the normalized ocular dominance (OD) 223 index difference associated with the OD plasticity resulting from the amblyopic eye being 224 subjected to 2 hrs of short-term deprivation. dominance (OD) against the absolute acuity at end of treatment. This is because they defined 230 the effects of occlusion treatment (the "recovery rate") in terms of the absolute visual acuity of 231 the amblyopic eye measured after 2 months of treatment. We believe that this prediction is 232 not interesting because clinically, in patients with amblyopia, their final visual acuity is best 233 predicted by their initial visual acuity before. This is also true in Lunghi et al's study. According 234 to Table 1 in Lunghi et al's paper, there is a strong correlation between the amblyopic eye's 235 visual acuity before and after 2-month of treatment: r = 0.731, P = 0.016. The p-value is even 236 smaller than that reported in Lunghi et al's paper using the homeostatic plasticity (rho = -0.65, 237 P = 0.04). This suggests that if one's objective was to predict amblyopic eye's visual acuity 238 after 2-month of occlusion therapy, one can simply rely on patients' initial visual acuity rather 239 than a complicated psychophysics measure. What one really wants to do is to predict what 240 change will occur in acuity as a result of treatment. That is what we set out to do. 241 Thus, our purpose was to investigate the relationship between the effects of the occlusion 242 therapy, in terms of the visual acuity improvement (i.e., the acuity benefit) of the amblyopic 243 eye measured after 2 months of treatment, and the short-term monocular deprivation induced 244 visual plasticity. Therefore, we plotted the change in ocular dominance from short-term 245 deprivation against the change in acuity from classical patching, as this is the only valid way 246 of assessing whether changes in short term plasticity can predict improvements in long term 247 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is valid conclusion based on a correlation analysis, e.g., why 10 is enough, while 7 is not 297 acceptable? This itself is tightly linked to the question that one asks. In particular, for the 298 question that we asked, whether the homeostatic plasticity predicts the recovery rate (or the 299 effects of occlusion therapy; or the visual acuity improvement), both Lunghi et al's and our 300 study failed to reach a significant correlation. Thus, both of these two studies suggest that the 301 All rights reserved. No reuse allowed without permission. the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.
The copyright holder for this preprint (which was not peer-reviewed) is . https://doi.org/10.1101/2020.03.26.20044701 doi: medRxiv preprint homeostatic plasticity might not be able to predict the acuity improvements from occlusion 302 therapy. Considering that this conclusion relies on 2 studies (Lunghi et al's and ours) with 17 303 patients (10 in Lunghi et al's and 7 in ours) from 2 independent groups using different 304 techniques, we believe that this strengthens the conclusion. In other words, if one has to get 305 a large sample to reach significance in this kind of correlation analysis, it's hard to believe that 306 we can use the homeostatic plasticity as a prediction index in clinical practice. 307 Short-term ocular dominance plasticity does not provide an index of cortical plasticity in 308 the general sense, such that it could be used to predict acuity improvement outcomes from 309 classical patching. This conclusion is robust to the type of measurement method used, the 310 degree of amblyopia treated and the eye that is occluded (i.e., fixing vs amblyopic) in the short-311 term OD measurement. In some ways this general conclusion is unsurprising because short 312 term OD plasticity is a very specific homeostatic form of plasticity(Min et al., 2018), which may 313 be quite different from the type of plasticity that underlies monocular patching therapy. While 314 it may not predict monocular outcomes in patching therapy, it is yet to be determined if this is 315 also true for purely binocular outcomes, using purely binocular therapy (Hess and Thompson, 316 2015), or changes of neural transmitter concentration (e.g. GABA(Lunghi et al., 2015b)), etc. 317 All that can be said is that there appears to be no simple straightforward prediction from the 318 extent of ocular dominance change from short-term occlusion and the acuity benefit of long-319 term occlusion therapy. 320

DATA AVAILABILITY 321
The datasets generated for this study are available on request to the corresponding author. 322

ETHICS STATEMENT 324
This study was carried out in accordance with the recommendations of the ethics committee 325 of the Wenzhou Medical University, with written informed consent from all subjects after 326