ABSTRACT

Recent research on amblyopia has highlighted new concepts and a better understanding of this common vision-threatening clinical condition. The primary dysfunction within the amblyopic visual system occurs in the primary visual area or striate cortex (V1) area, and the amblyopic effect can be amplified in the higher areas of brain processing. Various simple and complex visual functions are affected in amblyopia, and significant clinical and functional differences exist in the patterns of visual loss among the clinically defined categories of amblyopia. Nevertheless, the substantial neural plasticity in the amblyopic brain beyond the "critical period" can potentially open the door for various treatments for amblyopia, even in teens and adults.

Keywords: Amblyopia; Strabismus; Anisometropia; Vision, Binocular.

RESUMO

Pesquisas recentes sobre a ambliopia enfatizaram novos conceitos e levaram a uma melhor compreensão dessa condição clínica comum que compromete a visão. A disfunção primária no sistema visual ambliópico ocorre na área visual primária ou córtex estriado (V1) e o efeito ambliópico pode ser amplificado nas áreas superiores do processamento cerebral. Várias funções visuais simples e complexas são afetadas na ambliopia e existem diferenças clínicas e funcionais significativas nos padrões de perda visual entre as categorias clinicamente definidas da ambliopia. Entretanto, a plasticidade neural significativa no cérebro ambliópico fora do "período crítico" tem o potencial de abrir as portas para vários tratamentos para a ambliopia, mesmo em adolescentes e adultos.

Palavras-chave: Ambliopia; Estrabismo; Anisometropia; Visão Binocular.

RESUMEN

Investigaciones recientes sobre la ambliopía han puesto de relieve nuevos conceptos y así se ha alcanzado una mejor comprensión de esa condición clínica común que compromete la visión. La disfunción primaria en el sistema visual ambliópico ocurre en el área visual primaria también conocida como córtex estriado (V1) y el efecto ambliópico pode amplificarse en las áreas superiores del procesamiento cerebral. Se afectan varias funciones visuales sencillas y complejas en la ambliopía y hay distinciones clínicas e funcionales significativas en los estándares de pérdida visual entre las categorías clínicamente definidas de la ambliopía. Sin embargo, la plasticidad neural significativa en el cerebro ambliópico fuera del "período crítico" tiene el potencial de abrir puertas a varias terapias para el cuidado de la ambliopía, aun en adolescentes y adultos.

Palabras-clave: Ambliopía; Estrabismo; Anisometropía; Visión Binocular.

INTRODUCTION

Definition

Amblyopia is clinically defined as the reduction of visual acuity (VA) in one or both eyes caused by abnormal binocular interaction during the critical period of visual development that cannot be attributed to any ocular or visual system abnormality or refractive error¹. The American Academy of Ophthalmology considers amblyopia to be an interocular difference of two lines or more on the VA chart (without specifying any) or a VA worse than or equal to 20/30 with the best optical correction².

With a prevalence of 3%-6%, amblyopia is the second most common cause of low VA in children and adults and affects them economically and socially^3,4. Individuals with amblyopia often have restricted career options and reduced quality of life owing to less social contact, cosmetic distress (if associated with strabismus), low self-esteem, visual disorientation, and fear of losing vision in the other eye^5-8.

Physiopathology

Classically, amblyopia is defined as a decrease in VA, decrease in contrast sensitivity of high spatial frequencies, and binocular vision deficit; however, it can also affect the development of a broad range of neural, sensory, oculomotor, and perceptual functions of vision^9-11.

Notably, various visual functions are underdeveloped at birth. The complete development of these functions during the critical period of visual development in infancy depend on the following three fundamental conditions: adequate stimuli received from each eye, ocular parallelism (corresponding images), and integrity of the visual pathways.

However, disturbances in the input of stimuli received by the visual cortex during this plastic and unstable stage of visual development prevent the proper use of input from the affected eye, thereby resulting in amblyopia. The effects of the visual system are closely related to the time of the advent of visual disturbance along with its intensity, type, and duration.

When the visual stimulus disorder is precocious, severe, unidentified, and not reversed during the first months or years of life, it can lead to profound structural modification of visual neuronal circuit, causing definitive morphological changes in cortical structures of lateral geniculate nucleus and the visual cortex, leading to definite alterations in the final visual function¹².

Nevertheless, when the visual stimulus disorder develops and is less intense, the normal anatomy of the visual system is maintained, albeit with the possibility of active inhibition from neurons of the normal eye on neurons of the affected eye, which also results in functional amblyopia. In such instances, the neurological mechanism inhibits the image formed in the affected eye to facilitate undisturbed processing of the normal eye¹³.

Because amblyopia is a visual development disorder, early diagnosis of ocular changes associated with amblyopia is crucial for an excellent visual prognosis by allowing treatment at a stage where the visual neurological pathways are still amenable to stimulation, recovery, and reversal of the cortical damage.

The main ocular alterations that predispose to amblyopia are as follows: deprivation of visual stimuli (pupil occlusion by ptosis, opacities of optical media, nystagmus, and several others), alteration of sharpness of visual stimuli owing to refractive changes (high ametropia or anisometropia), and non-corresponding images received by each eye (strabismus).

 

TYPES OF AMBLYOPIA

Deprivation amblyopia

Deprivation happens when eye diseases prevent the light stimulus from reaching the retina, thereby preventing the normal visual process and can cause amblyopia if it occurs during the critical period of visual development. The deprivation is primarily caused by diseases, such as congenital cataract, blepharoptosis, and persistent fetal vasculature.

Seminal studies by Hubel and Wiesel had demonstrated that suturing the eyelid of cats deprived the eye of visual stimuli and led to several anatomical and functional changes in the cortical visual pathways. Moreover, these changes were observed to be more drastic if the deprivation occurred earlier in life and was more intense and prolonged^14-21.

Similarly, several authors have proven that deprivation adversely affects children's vision variously, and the period and severity of deprivation can result in various deficits in the final visual function^22,23.

The ideal period to treat the causes of deprivation in humans is within the sixth month of life because the effectiveness of treatment and ability to achieve normal results decrease rapidly after that period²⁴. Notably, the severity of deprivation makes a difference in these first 6 months. For instance, dense bilateral cataracts not treated by 3 months of age will undoubtedly lead to the development of nystagmus, which will severely limit the VA permanently²⁵.

Deprivation amblyopia causes profound anatomical changes in the visual circuitry and has the greatest influence on the VA and all other visual functions. Therefore, its treatment is challenging, with less successful results compared with other forms of amblyopia^4,24,26.

Anisometropic amblyopia

Anisometropia is the difference of at least 1 diopter in the states of refraction between the two eyes²⁷. The prevalence of anisometropic amblyopia is about 4.7% in children and can be myopic, astigmatic, or hypermetropic.

Notably, hypermetropic anisometropia is the most likely cause of amblyopia because the retina of the more ametropic eye never receives a clear and defined image. Typically, the fovea of the normal eye is focused, and there will be no stimulus of accommodative effort to adjust the focus of the more hyperopic eye. In myopic anisometropia, the more ametropic eye can be used for near vision, preventing the same levels of amblyopia experienced with hyperopia^1,28,29.

Anisometropia may be considered a moderate form of deprivation of visual stimulus because the more ametropic eye is deprived of receiving a good-quality stimulus in the retina. Anatomical and functional changes owing to deprivation can, therefore, be expected in anisometropic amblyopia^30,31.

The severity of amblyopia is not directly related to the magnitude of the refractive degree but to the amount of anisometropia between the two eyes, thereby suggesting that mechanisms other than an optical blur, especially abnormal binocular interactions, are involved in the risk of amblyopia^31,32.

Despite differences in the inputs received from each eye, in anisometropia, both eyes receive congruent images, and unlike strabismus, there is no stimulation of non-corresponding retinal areas^33,34. Therefore, pure anisometropic amblyopia classically leads to substantial VA deficits compatible with the loss of contrast sensitivity of all spatial frequencies; however, with relative sparing of binocular vision^10,35,36.

Anisometropic amblyopia has the best prognosis among all amblyopia types, with sometimes an unexpected recovery of VA with only the use of adequate correction and even with later treatments³⁷. Studies have shown that the presence of preserved or subnormal binocular function is a crucial factor for the recovery of the visual system, although these researches have shown that besides the conventional monocular occlusive treatment, other forms of balanced binocular (dichoptic) treatment are ideal for restoring the normal visual functions^38-40.

Strabismic amblyopia

Strabismus is the deviation of one eye with loss of eye parallelism. Consequently, the eyes do not receive corresponding images, forcing the visual system to adapt to this change¹.

When the visual system is completely formed (adults), the perception of non-corresponding images by two eyes leads to double vision but when the visual system is in its critical period of development (childhood), the brain is still capable of using mechanisms to avoid diplopia or rivalry by inhibiting the activation of the retinocortical pathways originating from the fovea of the deviating eye. Even though this adaptive mechanism prevents diplopia, it causes a restructuring of the visual cortical circuits in the visual cortex, thereby causing amblyopia.

Tychsen et al. have demonstrated several visual function alterations in monkeys with strabismus and loss of V1 binocular connections^17-19,41. Notably, the severity of motor ocular changes and the loss of V1 binocular connections increased as a function of the decorrelation duration, in that the animals treated until 3 weeks of decorrelation recovered these functions.

Strabismus causes changes in the cortical spatial information pathways or a loss of connectivity to it, altering the spatial summation and side inhibitions of the stimuli received, which consequently prevents the integration of contours and shapes. The spatial vision is, therefore, distorted, which interferes with numerous discriminatory visual tasks, such as VA, Vernier VA (alignment accuracy), and crowding^42-47.

In strabismus, there is no binocular facilitation for any form of stimulus, and the suppression is constant and strong³⁴. Suppression is also seen in the fovea of the normal eye when the amblyopic eye is fixing, thereby indicating that the lost VA is not solely related to suppression. Thus, it is suppression that leads to amblyopia in an individual who has strabismus and not vice versa because the inactivity of the system may interfere with the process of synaptic development⁴⁸.

In strabismus, the different stimuli received by the eyes prevent normal image fusion compromising binocular vision, summation, and the ability to discriminate disparity and depth of vision with altered stereoscopic VA (stereopsis) and even postural stability^6,49-56.

Mixed amblyopia

Mixed amblyopia occurs when two amblyogenic factors are involved, with the most common being the combination of anisometropic and strabismic amblyopia is common, primarily observed in partially accommodative esotropia, microtropia, and monofixation syndrome^1,36.

Clinically, mixed amblyopia is more severe with several visual function deficits, besides an exacerbation of VA loss, contrast sensitivity, and typically extinction of stereopsis. However, the magnitude of the effect on each visual function depends on the simultaneous onset or on the different times at which each ocular change occurs⁶.

 

OTHER CORTICAL AREAS AND COMPLEX FUNCTIONS AFFECTED BY AMBLYOPIA

Amblyopia is, therefore, a neural disorder resulting from abnormal brain stimulation during the critical period of visual development. Several studies have indicated that the primary cortical area affected by amblyopia is V1. Amblyopes have decreased binocular neurons and neurons responsible for the amblyopic eye in V1 besides having active binocular suppression^14,41,57-63.

Recent research has shown that despite the well-known visual processing deficits, amblyopic patients present with alterations in visual processing of high-order cortical functions⁶⁴, such as a deficiency in movement integration⁶⁵, perception and processing of shape and global contour^66-69, altered perception of alignment (Vernier acuity), and symmetry^70,71. In addition, deficits have been observed in tasks involving high-order attention components^45,72-79, such as enumeration of objects, prolonged attentional blinking, the "crowding" phenomenon, reading process, and visual decision-making. Recent evidence shows that the perceptual influence of amblyopia extends beyond vision to multisensory processing⁸⁰, with abnormalities evident in the audiovisual speech perception^81-83, spatial audiovisual localization⁸⁴, and temporal judgment tasks⁸⁵.

Furthermore, these high-order deficits are observed in the fellow eye^{45,86-88,89,90} and during binocular vision^75,80,91,92.

The common element in all these affected sensory-motor tasks is that they are not limited to acuity and require both local and global cortical processing^67,93 and involve extraction and segregation of a background noise signal^94-96, clearly implicating high-order visual processes^35,97-99.

Studies have used functional magnetic resonance imaging to confirm the different effects on the visual cortex related to different types of amblyopia. Recent findings have suggested more profound disorganization of the cortical arrangement in patients with strabismic amblyopia, wherein the interhemispheric asymmetry for parvo- and magnocellular input processing was lost, whereas normal cortical asymmetry was present in those with anisometropic amblyopia^100-102.

Recent research has shown that amblyopia causes abnormality in multisensory brain processing that persists even in binocular condition. Experiments of Richards et al. have demonstrated alterations in the temporal, spatial, and speech audiovisual perception in amblyopic subjects, indicating that amblyopia causes not only unisensory visual impairment but also alterations in multisensorial brain processing^80,84,85.

 

DIAGNOSIS

Despite the variations in visual function deficits, amblyopia is still diagnosed by measuring the VA on an eye chart by using optotype-based recognition.

Preverbal children who cannot complete this task are diagnosed using behavioral methods, such as the fixation preference, which is performed by observing the vigor with which the child objects to the occlusion of one eye relative to the other. Grading schemes can be used to quantitatively measure the fixation preference¹⁰³, besides doing the grating acuity test by using the Teller acuity cards¹⁰⁴. Recognition VA testing based on optotypes (letters, numbers, or symbols) must be done as soon as the child can perform this task reliably¹⁰⁵.

Because amblyopia is a common and preventable visual deficit, there is immense concern regarding its early diagnosis and in determining more effective treatments for the condition. The American Academy of Pediatrics recommends pediatricians or family care practitioners to screen the child for amblyopia as part of the regular well-child visit, including the use of instrument-based vision screening techniques for preverbal children¹⁰⁶.

Randomized longitudinal studies have shown that screening improves vision outcomes and decreases the prevalence of amblyopia by as much as 60%¹⁰⁷. Moreover, novel technologies, such as instrument-based devices (vision screeners), enable primary care providers to diagnose amblyopia in the early stages and refer children for specialized ophthalmologic care^108-110. Early detection can facilitate timely treatment and result in better outcomes for children¹¹¹.

 

TREATMENT

The gold standard treatment for amblyopia is patching the better eye to force the brain to use the weaker eye. Depriving the fellow or fixating eye of vision forces the amblyopic eye to strike suppression and use the visual cortex corresponding to the eye to recover connections for better vision. Alternatives to patching are optical penalization with atropine eye drops, filters to blur the better eye, optical defocus using glasses or contact lenses, and dichoptic video games.

In the last 20 years, groups such as PEDIG (Pediatric Eye Disease Investigator Group)^112,113 and MOTAS (Monitored Occlusion Treatment of Amblyopia Study)¹¹⁴ have conducted randomized clinical trials to address the primary issues of occlusive treatment and define the optimal treatment protocols.

The PEDIG studies have published 17 Amblyopia Treatment Studies (ATS), which have evaluated the amblyopic treatment for children aged 3 to 17 years, and the significant results to date are as follows:

1. Optical correction alone is successful in improving the amblyopia in nearly one-third of patients^37,115.

2. Patching is an effective treatment for amblyopia¹¹⁶.

3. The ideal number of hours of patching was evaluated. Children aged 3 to 7 years with moderate amblyopia were randomized to 2 hours of patching per day compared with 6 hours of patching daily. Although the 6-hour occlusion group had faster improvement, at the end of 4 months of treatment both groups achieved similar VA (20/30 VA or at least an improvement of three lines from baseline), with no statistically significant intergroup difference¹¹⁷. Another ATS evaluated severe amblyopia (20/100 to 20/400) and compared between groups using 6 hours of patching and full-time patching. At the end of the treatment period, both groups had favorable outcomes with an average improvement in VA of 4.8 lines (6 hours) and 4.7 lines (full time) with no statistically significant intergroup difference¹¹⁸. Nevertheless, higher hours of patching were associated with worse compliance, with only 6% of patients complying with the prescribed time¹¹⁹. These studies provide useful information regarding the effect of the prescribed number of hours on the VA. However, it is imperative to follow prudence by customizing patching treatment for each patient based on the time of onset of amblyopia and the different etiologies³.

4. Atropine for penalization proved to be as effective as occlusion. Although the occlusion group had a quicker improvement in the VA, at the end of 6 months of treatment both the two groups had an equal improvement in the VA, which was maintained over a long term of follow-up (up to 15 years). In addition to daily atropine, the use of atropine once a week showed improvement in the VA and better compliance among patients¹²⁰.

5. Treatment of amblyopia is most effective under 7 years of age. Children up to 13 years of age showed significant improvement in vision with patching, albeit with a slower rate of response to treatment, a higher dose of patching, and incomplete recovery¹²¹.

6. Amblyopia treatment, with both occlusion and atropine, had an identical high rate of recurrence (approximately 25%) at the end of treatment. Notably, this rate was four times higher in children who did not have a gradual taper of their treatment for at least 5 weeks after the resolution of amblyopia. The other factors linked with the high recurrence rates were better VA at the end of treatment, a greater number of lines of improvement, and previous history of recurrence^122,123.

7. Children who performed near work for a better part of their patching time had more improvement than children who did no near work as part of the patching regimen^124,125.

Nonetheless, the results of this series of studies should be analyzed with caution because no individual analysis is available for each type of amblyopia, dysfunctions of earlier or later onset, or factors that cause diverse dysfunctions in visual functions with different prognosis.

Therefore, more than proposing new regimens of patching treatment hours, the study data help us to understand the effect of the prescribed occlusion hours. Thus, the conventional treatment regimens remain valid, and each case must be analyzed and treated individually.

 

NEW PERSPECTIVES IN AMBLYOPIA

Over the years, the study of amblyopia has enabled to understand the brain function better. The study of Hubel and Wiesel on animal models demonstrated anatomical and functional alterations in the primary visual cortex owing to amblyopia. However, since then, much has been discovered regarding the effect of amblyopia on the visual system and the significance of the critical period of cerebral plasticity on the effectiveness of treatment. Nevertheless, these research have caused two major shifts in the paradigm concerning amblyopia, namely the perspectives that successful treatment of amblyopia is possible beyond the critical period and amblyopia is more of a binocular disease than a monocular one¹²⁶.

Treatment of amblyopia outside the critical period

It is well-known that the young brain is more plastic than an adult brain, but also known is the fact that the adult brain is still capable of learning and recovering after an injury. Thus, there is plasticity at the synaptic level, cellular level, and the level of cortical representation. One interpretation of this context is that the critical period ends with an increased threshold for plasticity rather than complete closure; therefore, it is necessary to find stimuli and ways to stimulate the specific plasticity of the adult brain^11,126.

Intracortical inhibitory circuitry was discovered to be a key factor in defining the limits of cortical plasticity. A brief reduction of GABAergic inhibition in the brains of rats was shown to be able to reopen a window of plasticity in the visual system well after the normal closure of the critical period¹²⁷. Therefore, several intrinsic and extrinsic modes of augmentation of plasticity have been employed to facilitate amblyopia therapy beyond the critical period of development.

Intrinsic augmentation can be achieved by manipulating the neurotransmitter systems that regulate synaptic plasticity environmentally or behaviorally. One can stimulate this system through environmental enrichment (exercise and visual enrichment), prolonged dark exposure, caloric restriction, and with new or challenging visual tasks (perceptual learning)^11,128-132.

Extrinsic augmentation involves exogenous manipulation of the endogenous neuromodulatory system. One of these methods is pharmacological, and the most commonly used drug for this purpose is levodopa. However, a randomized, placebo-controlled clinical trial conducted by PEDIG showed that the improvement in VA with levodopa did not have a statistically significant difference compared to the placebo, and the improvement in vision in the levodopa group was not sustained during follow-up after stopping the medication¹³³.

Notwithstanding, another possibility would be to use medications that alter the expression of genes to remove the molecular "brakes" on cortical plasticity^134-137.

The neuromodulatory system can also be accessed through direct and noninvasive activation by using subthreshold electric current or transcranial magnetic stimulation. Transcranial direct current stimulation and transcranial magnetic stimulation have been employed to facilitate plasticity in stroke patients and patients with amblyopia. Both techniques have shown improved contrast sensitivity in amblyopic patients and facilitated stereopsis, albeit with clinically insignificant results¹³⁸.

Amblyopia as a binocular disease

Amblyopia typically affects the VA in one eye and was always considered a monocular disease. Accordingly, the primary treatment is often the occlusion of the fellow eye to improve the monocular function of the amblyopic eye. However, several studies have demonstrated that the deficit in amblyopia extends beyond monocular VA impairment and into higher-order functions, such as binocular vision, fixation instability, and visuomotor activities owing to abnormal interocular interactions^10,139,140. The common element in these additional deficits in amblyopia is that they are not acuity-limited tasks; instead, they require integration of information over relatively large regions of space and time and involve extracting a signal from noise⁶². These deficits are not corrected by monocular treatment and remain even when the VA recovers after patching.

Based on these findings, it has been argued that amblyopia is intrinsically a binocular problem and that the suppression should be addressed first during the treatment of amblyopia, rather than hoping to restore binocular vision after monocular acuity improvement with occlusion therapy. Based on this suggestion, new binocular treatments have been proposed. Hess, Mansouri, and Thompson proposed a treatment based on strengthening binocular combination through a gradual reduction in suppression^38,141,142. Using this binocular approach, they demonstrated that individuals with strabismic amblyopia could combine the information normally between their eyes when the suppression was reduced by presenting stimuli of different contrasts to each eye through dichoptic viewing⁶. Based on these findings, these authors proposed a new type of treatment for amblyopia, commonly called the dichoptic treatment. The treatment strategy aims to stimulate the two eyes simultaneously, thereby promoting the possibility of improvement of monocular VA of the amblyopic eye besides combating the suppression and working to normalize binocular interactions for recovery of binocular vision.

This concept has been applied to passive and active forms of training for amblyopia. Passive training modalities include watching movies under dichoptic viewing conditions³⁹. Active training applies perceptual learning using hand-held tablets, which when combined with red-green glasses, presents video games that require a binocular function to complete the game's objective^40,143-145. Both active and passive strategies of dichoptic treatment have shown favorable results with the improvement of the VA and in several cases resulted in normalization or recovery of binocular vision, including in adult individuals.

Given these promising results, PEDIG conducted a large, randomized, controlled trial on patients aged 5 to 13 years to compare between playing 1 hour of falling blocks game daily and patching for 2 hours daily over 16 weeks. The study revealed a poor adherence to the game regimen prescribed and the improvement in the VA, for this particular game, was not as good as that with 2 hours of prescribed daily patching¹⁴⁶. Similar results were observed in another well-designed, multi-center randomized clinical trial (BRAVO study)¹⁴⁷.

Albeit these disappointing results, the authors encourage new research using more engaging gameplay to reduce noncompliance owing to the nature of the game, like the falling blocks game, which is not appealing to children. Nevertheless, new protocols with different and more engaging games, such as action-oriented adventure games, first-person shooter games, virtual reality, and 3-dimensional gaming platforms are being analyzed for this purpose^148-150.

Although the dichoptic treatment did not show substantial improvement in the VA and stereopsis, all protocols showed improved contrast processing during the games, which suggest better binocular interaction and decreased suppression. Therefore, it is imperative to evaluate the improvement in other visual functions that are altered in amblyopia, which depend directly on the normal binocular interaction, such as Vernier acuity, contrast sensitivity of different levels of complexity, global movement tasks, fixation stability, and even quality of life through questionnaires to assess the subjective perception of each individual regarding their vision changes.

A more meticulous, global study of individuals with amblyopia can provide explanations regarding the high variability of response to treatment in these individuals. Moreover, it can help us define, understand, and categorize amblyopia better, thereby helping to prepare a more customized treatment for each patient¹⁵¹.

 

CONCLUSION

Recent research on amblyopia has introduced new concepts and provided a better understanding regarding this common vision-threatening clinical condition. Therefore, we now know that the primary dysfunction within the amblyopic visual system first occurs in V1 area and the effect caused by amblyopia can be amplified in the higher areas of processing. In addition, we are aware of the significant clinical and functional differences in the patterns of visual loss among the clinically defined categories of amblyopia. Most importantly, we comprehend that substantial neural plasticity exists in the amblyopic brain beyond the "critical period," which can potentially facilitate the use of different treatments of amblyopia, even during teens and adulthood.

 

REFERENCES

1. von Noorden GK, Campos EC. Binocular Vision and Ocular Motility. 6ª ed. St. Louis, MO: Mosby, Inc; 2002.

2. Zhao PF, Zhou YH, Wang NL, Zhang J. Study of the wavefront aberrations in children with amblyopia. Chin Med J (Engl). 2010 Jun;123(11):1431-5.

3. Gunton KB. Advances in amblyopia: What have we learned from PEDIG trials?. Pediatrics. 2013 Mar;131(3):540-7.

4. Billson FA, Fitzgerald BA, Provis JM. Visual deprivation in infancy and childhood: clinical aspects. Aust N Z J Ophthalmol. 1985 Aug;13(3):279-86.

5. Van De Graaf ES, Van Der Sterre GW, Polling JR, Van Kempen H, Simonsz B, Simonsz HJ. Amblyopia & Strabismus Questionnaire: design and initial validation. Strabismus. 2004 Sep;12(3):181-93.

6. Wong AM. New concepts concerning the neural mechanisms of amblyopia and their clinical implications. Can J Ophthalmol. 2012 Oct;47(5):399-409.

7. Carlton J, Kaltenthaler E. Amblyopia and quality of life: A systematic review. Eye (Lond). 2011 Apr;25(4):403-13.

8. Webber AL. The functional impact of amblyopia. Clin Exp Optom. 2018 Jul;101(4):443-50.

9. Wong EH, Levi DM, McGraw PV. Spatial interactions reveal inhibitory cortical networks in human amblyopia. Vision Res. 2005 Oct;45(21):2810-9.

10. Birch EE. Amblyopia and binocular vision. Prog Retin Eye Res. 2013 Mar;33:67-84.

11. Levi DM. Prentice award lecture 2011: Removing the brakes on plasticity in the amblyopic brain. Optom Vis Sci. 2012 Jun;89(6):827-38.

12. Davis AR, Sloper JJ, Neveu MM, Hogg CR, Morgan MJ, Holder GE. Differential changes of magnocellular and parvocellular visual function in early- and late-onset strabismic amblyopia. Invest Ophthalmol Vis Sci. 2006 Nov;47(11):4836-41.

13. Sloper J. The other side of amblyopia. J AAPOS. 2016 Feb;20(1):1.e1-13.

14. Wiesel TN, Hubel DH. Effects of visual deprivation on morphology and physiology of cells in. J Neurophysiol. 1963 Nov;26:978-93.

15. Hubel DH, Wiesel TN. Effects of monocular deprivation in kittens. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol. 1964 Aug;248:492-7.

16. Wiesel TN, Hubel DH. Comparison of the effects of unilateral and bilateral eye closure on cortical unit responses in kittens. J Neurophysiol. 1965 Nov;28(6):1029-40.

17. Tychsen L. Causing and curing infantile esotropia in primates: the role of decorrelated binocular input (an American Ophthalmological Society thesis). Trans Am Ophthalmol Soc. 2007 Dec;105:564-93.

18. Tychsen L, Richards M, Wong AM, Demer J, Bradley D, Burkhalter A, et al. Decorrelation of cerebral visual inputs as the sufficient cause of infantile esotropia. Am Orthopt J. 2008;58:60-9.

19. Tychsen L, Richards M, Wong A, Foeller P, Burhkalter A, Narasimhan A, et al. Spectrum of infantile esotropia in primates: Behavior, brains, and orbits. J AAPOS. 2008 Aug;12(4):375-80.

20. Marg E. Prentice-Memorial Lecture: Is the animal model for stimulus deprivation amblyopia in children valid or useful?. Am J Optom Physiol Opt. 1982 Jun;59(6):451-64.

21. Headon MP, Sloper JJ, Hiorns RW, Powell TPS. Effects of monocular closure at different ages on deprived and undeprived cells in the primate lateral geniculate nucleus. Brain Res Dev Brain Res. 1985 Feb;18(1-2):57-78.

22. Lewis TL, Maurer D. Multiple sensitive periods in human visual development: evidence from visually deprived children. Dev Psychobiol. 2005 Apr;46(3):163-83.

23. Ellemberg D, Lewis TL, Maurer D, Brent HP. Influence of monocular deprivation during infancy on the later development of spatial and temporal vision. Vision Res. 2000 Feb;40(23):3283-95.

24. Birch EE, Stager DR. The critical period for surgical treatment of dense congenital unilateral cataract. Invest Ophthalmol Vis Sci. 1996 Jul;37(8):1532-8.

25. Hamm L, Chen Z, Li J, Black J, Dai S, Yuan J, et al. Interocular suppression in children with deprivation amblyopia. Vision Res. 2017 Apr;133:112-20.

26. Hamm LM, Chen Z, Li J, Dai S, Black J, Yuan J, et al. Contrast-balanced binocular treatment in children with deprivation amblyopia. Clin Exp Optom. 2018 Jul;101(4):541-52.

27. DK P. Anisometropia. Brookman KE. Boston: Butterman-Heinemann; 1996. p.99-121.

28. Copps LA. Vision in Anisometropia. Am J Ophth. 1944;27(6):641-4.

29. Toor S, Horwood AM, Riddell P. Asymmetrical accommodation in hyperopic anisometropic amblyopia. Br J Ophthalmol. 2018 Jun;102(6):772-8.

30. McKee SP, Levi DM, Movshon JA. The pattern of visual deficits in amblyopia. J Vis. 2003;3(5):380-405.

31. Levi DM, McKee SP, Movshon JA. Visual deficits in anisometropia. Vision Res. 2011 Jan;51(1):48-57.

32. Helveston EM. Relationship between degree of anisometropia and depth of amblyopia. Am J Ophthalmol. 1966 Oct;62(4):757-9.

33. Harrad RA, Hess RF. Binocular integration of contrast information in amblyopia. Vision Res. 1992 Nov;32(11):2135-50.

34. Harrad R. Psychophysics of suppression. Eye (Lond). 1996; 10(Pt 2):270-3.

35. Muckli L, Kiess S, Tonhausen N, Singer W, Goebel R, Sireteanu R. Cerebral correlates of impaired grating perception in individual, psychophysically assessed human amblyopes. Vision Res. 2006 Feb;46(4):506-26.

36. Weakley Junior DR. The association between nonstrabismic anisometropia, amblyopia, and subnormal binocularity. Ophthalmology. 2001 Jan;108(1):163-71.

37. Cotter SA, Pediactric Eye Disease Investigator Group, Edwards AR, Wallace DK, Beck RW, Arnold RW, Astle WF, et al. Treatment of anisometropic amblyopia in children with refractive correction. Ophthalmology. 2006 Jun;113(6):895-903.

38. Hess RF, Mansouri B, Thompson B. Restoration of binocular vision in amblyopia. Strabismus. 2011 Sep;19(3):110-8.

39. Li SL, Reynaud A, Hess RF, Wang YZ, Jost RM, Morale SE, et al. Dichoptic movie viewing treats childhood amblyopia. J AAPOS. 2015 Oct;19(5):401-5.

40. Birch EE, Li SL, Jost RM, Morale SE, De La Cruz A, Stager D, et al. Binocular iPad treatment for amblyopia in preschool children. J AAPOS. 2015 Feb;19(1):6-11.

41. Tychsen L, Wong AMF, Burkhalter A. Paucity of horizontal connections for binocular vision in V1 of naturally strabismic macaques: Cytochrome oxidase compartment specificity. J Comp Neurol. 2004 May;474(2):261-75.

42. Hess RF, Campbell FW, Greenhalgh T. On the nature of the neural abnormality in human amblyopia; neural aberrations and neural sensitivity loss. Pflügers Arch. 1978 Nov;377(3):201-7.

43. Hess RF, Holliday IE. The spatial localization deficit in amblyopia. Vision Res. 1992 Jul;32(7):1319-39.

44. Hess RF, Wang YZ, Demanins R, Wilkinson F, Wilson HR. A deficit in strabismic amblyopia for global shape detection. Vision Res. 1999 Mar;39(5):901-14.

45. Levi DM, Klein SA. Vernier acuity, crowding and amblyopia. Vision Res. 1985;25(7):979-91.

46. Bonneh YS, Sagi D, Polat U. Spatial and temporal crowding in amblyopia. Vision Res. 2007 Jun;47(14):1950-62.

47. Chung STL, Li RW, Levi DM. Crowding between first- and second-order letters in amblyopia. Vision Research. 2008 Mar;48(6):788-98.

48. Sengpiel F, Blakemore C. The neural basis of suppression and amblyopia in strabismus. Eye (Lond). 1996;10(Pt 2):250-8.

49. Hubel DH, Wiesel TN. Binocular interaction in striate cortex of kittens reared with artificial squint. J Neurophysiol. 1965 Nov;28(6):1041-59.

50. Barlow HB, Blakemore C, Pettigrew JD. The neural mechanism of binocular depth discrimination. J Physiol. 1967 Nov;193(2):327-42.

51. Blakemore C. The conditions required for the maintenance of binocularity in the kitten's visual cortex. J Physiol. 1976 Oct;261(2):423-44.

52. Hoyt CS. Amblyopia: a neuro-ophthalmic view. J Neuroophthalmol. 2005 Sep;25(3):227-31.

53. Norcia AM, Hale J, Pettet MW, McKee SP, Harrad RA. Disparity tuning of binocular facilitation and suppression after normal versus abnormal visual development. Invest Ophth Vis Sci. 2009 Mar;50(3):1168-75.

54. O'Connor AR, Birch EE, Anderson S, Draper H. Relationship between binocular vision, visual acuity, and fine motor skills. Optom Vis Sci. 2010 Dec;87(12):942-7.

55. Baker DH, Meese TS, Mansouri B, Hess RF. Binocular summation of contrast remains intact in strabismic amblyopia. Invest Ophthalmol Vis Sci. 2007 Nov;48(11):5332-8.

56. Zipori AB, Colpa L, Wong AMF, Cushing SL, Gordon KA. Postural stability and visual impairment: Assessing balance in children with strabismus and amblyopia. PLoS One. 2018 Oct;13(10):e0205857.

57. Wiesel TN. Postnatal development of the visual cortex and the influence of environment. Nature. 1982 Oct;299(5884):583-91.

58. Movshon JA. Cortical effects of monocular deprivation: suppression or deafferentation?. Nature. 1981;291:284-5.

59. Hubel DH, Wiesel TN, LeVay S. Plasticity of ocular dominance columns in monkey striate cortex. Philos Trans R Soc Lond B Biol Sci. 1977 Apr;278(961):377-409.

60. Kiorpes L, Kiper DC, O'Keefe LP, Cavanaugh JR, Movshon JA. Neuronal correlates of amblyopia in the visual cortex of macaque monkeys with experimental strabismus and anisometropia. J Neurosci. 1998 Aug;18(16):6411-24.

61. Kiorpes L, McKee SP. Neural mechanisms underlying amblyopia. Curr Opin Neurobiol. 1999 Aug;9(4):480-6.

62. Kiorpes L. Visual processing in amblyopia: animal studies. Strabismus. 2006 Mar;14(1):3-10.

63. Horton JC, Hocking DR. Pattern of ocular dominance columns in human striate cortex in strabismic amblyopia. Vis Neurosci. 1996 Jul/Aug;13(4):787-95.

64. Bi H, Zhang B, Tao X, Harwerth RS, Smith EL, Chino YM. Neuronal responses in visual area V2 (V2) of macaque monkeys with strabismic amblyopia. Cereb Cortex. 2011 Sep;21(9):2033-45.

65. Simmers AJ, Ledgeway T, Hess RF. The influences of visibility and anomalous integration processes on the perception of global spatial form versus motion in human amblyopia. Vision Res. 2005 Feb;45(4):449-60.

66. Levi DM, Waugh SJ, Beard BL. Spatial scale shifts in amblyopia. Vision Res. 1994 Dec;34(24):3315-33.

67. Levi DM, Yu C, Kuai SG, Rislove E. Global contour processing in amblyopia. Vision Res. 2007 Feb;47(4):512-24.

68. Polat U, Sagi D, Norcia AM. Abnormal long-range spatial interactions in amblyopia. Vision Res. 1997 Mar;37(6):737-44.

69. Hamm LM, Black J, Dai S, Thompson B. Global processing in amblyopia: a review. Front Psychol. 2014 Jun;5:583.

70. Hess RF, Howell ER. The threshold contrast sensitivity function in strabismic amblyopia: evidence for a two type classification. Vision Res. 1977;17(9):1049-55.

71. Hou C, Good WV, Norcia AM. Validation study of VEP vernier acuity in normal-vision and amblyopic adults. Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4070-8.

72. Sharma V, Levi DM, Klein SA. Undercounting features and missing features: evidence for a high-level deficit in strabismic amblyopia. Nat Neurosci. 2000 May;3(5):496-501.

73. Levi DM. Crowding-an essential bottleneck for object recognition: a mini-review. Vision Res. 2008 Feb;48(5):635-54.

74. Popple AV, Levi DM. The attentional blink in amblyopia. J Vis. 2008 Oct;8(13):12.1-9.

75. Kanonidou E, Proudlock FA, Gottlob I. Reading strategies in mild to moderate strabismic amblyopia: an eye movement investigation. Invest Ophthalmol Vis Sci. 2010 Jul;51(7):3502-8.

76. Kugathasan L, Partanen M, Chu V, Lyons C, Giaschi D. Reading ability of children treated for amblyopia. Vision Res. 2019 Mar;156:28-38.

77. Birch EE, Castaneda YS, Cheng-Patel CS, Morale SE, Kelly KR, Beauchamp CL, et al. Self-perception of School-aged Children With Amblyopia and Its Association With Reading Speed and Motor Skills. JAMA Ophthalmol. 2019 Feb;137(2):167-73.

78. Farzin F, Norcia AM. Impaired visual decision-making in individuals with amblyopia. J Vis. 2011 Dec;11(14):pii:6.

79. Ho CS, Paul PS, Asirvatham A, Cavanagh P, Cline R, Giaschi DE. Abnormal spatial selection and tracking in children with amblyopia. Vision Res. 2006 Nov;46(19):3274-83.

80. Richards MD, Goltz HC, Wong AMF. Audiovisual perception in amblyopia: A review and synthesis. Exp Eye Res. 2019 Jun;183:68-75.

81. Burgmeier R, Desai RU, Farner KC, Tiano B, Lacey R, Volpe NJ, et al. The effect of amblyopia on visual-auditory speech perception why mothers may say "Look at me when I'm talking to you". JAMA Ophthalmol. 2015 Jan;133(1):11-6.

82. Narinesingh C, Goltz HC, Raashid RA, Wong AMF. Developmental Trajectory of McGurk Effect Susceptibility in Children and Adults With Amblyopia. Invest Ophthalmol Vis Sci. 2015 Mar;56(3):2107-13.

83. Putzar L, Goerendt I, Heed T, Richard G, Buchel C, Roder B. The neural basis of lip-reading capabilities is altered by early visual deprivation. Neuropsychologia. 2010 Jun;48(7):2158-66.

84. Richards MD, Goltz HC, Wong AMF. Optimal Audiovisual Integration in the Ventriloquism Effect But Pervasive Deficits in Unisensory Spatial Localization in Amblyopia. Invest Ophthalmol Vis Sci. 2018 Jan;59(1):122-31.

85. Richards MD, Goltz HC, Wong AMF. Alterations in audiovisual simultaneity perception in amblyopia. PloS One. 2017 Jun;12(6): e0179516.

86. Mansouri B, Allen HA, Hess RF. Detection, discrimination and integration of second-order orientation information in strabismic and anisometropic amblyopia. Vision Res. 2005 Aug;45(18):2449-60.

87. Wong EH, Levi DM, McGraw PV. Is second-order spatial loss in amblyopia explained by the loss of first-order spatial input?. Vision Res. 2001 Oct;41(23):2951-60.

88. Kiorpes L, Tang C, Movshon JA. Sensitivity to visual motion in amblyopic macaque monkeys. Vis Neurosci. 2006 Mar/Apr;23(2): 247-56.

89. Hayward J, Truong G, Partanen M, Giaschi D. Effects of speed, age, and amblyopia on the perception of motion-defined form. Vision Res. 2011 Oct;51(20):2216-23.

90. Meier K, Giaschi D. Unilateral Amblyopia Affects Two Eyes: Fellow Eye Deficits in Amblyopia. Invest Ophth Vis Sci. 2017 Mar;58(3):1779-800.

91. Mirabella G, Hay S, Wong AM. Deficits in perception of images of real-world scenes in patients with a history of amblyopia. Arch Ophthalmol. 2011 Feb;129(2):176-83.

92. Thompson B, Richard A, Churan J, Hess RF, Aaen-Stockdale C, Pack CC. Impaired spatial and binocular summation for motion direction discrimination in strabismic amblyopia. Vision Res. 2011 Mar;51(6):577-84.

93. Mansouri B, Hess RF. The global processing deficit in amblyopia involves noise segregation. Vision Res. 2006 Nov;46(24):4104-17.

94. Levi DM, Klein SA, Sharma V. Position jitter and undersampling in pattern perception. Vision Res. 1999 Feb;39(3):445-65.

95. Norcia AM, Sampath V, Hou C, Pettet MW. Experience-expectant development of contour integration mechanisms in human visual cortex. J Vis. 2005 Feb;5(2):116-30.

96. Popple AV, Levi DM. Amblyopes see true alignment where normal observers see illusory tilt. Proc Natl Acad Sci U S A. 2000 Oct;97(21):11667-72.

97. Van Essen DC, Anderson CH, Felleman DJ. Information processing in the primate visual system: an integrated systems perspective. Science. 1992 Jan;255(5043):419-23.

98. Hess RF, Thompson B, Gole GA, Mullen KT. The amblyopic deficit and its relationship to geniculo-cortical processing streams. J Neurophysiol. 2010 Jul;104(1):475-83.

99. Li X, Dumoulin SO, Mansouri B, Hess RF. Cortical deficits in human amblyopia: Their regional distribution and their relationship to the contrast detection deficit. Invest Ophth Vis Sci. 2007 Apr;48(4):1575-91.

100. Costa MF, Cunha G, Marques JPO, Castelo-Branco M. Strabismic amblyopia disrupts the hemispheric asymmetry for spatial stimuli in cortical visual processing. Br J Vis Impair. 2016 May;34(2):141-50.

101. Liang M, Xie B, Yang H, Yin X, Wang H, Yu L, et al. Altered interhemispheric functional connectivity in patients with anisometropic and strabismic amblyopia: a resting-state fMRI study. Neuroradiology. 2017 May;59(5):517-24.

102. Mi Young C, Lee KM, Hwang JM, Dong Gyu C, Dong Soo L, Ki Ho P, et al. Comparison between anisometropic and strabismic amblyopia using functional magnetic resonance imaging. Br J Ophthalmol. 2001 Sep;85(9):1052-6.

103. Birch EE, Holmes JM. The clinical profile of amblyopia in children younger than 3 years of age. J AAPOS. 2010 Dec;14(6):494-7.

104. Salomao SR, Ventura DF. Large sample population age norms for visual acuities obtained with Vistech-Teller Acuity Cards. Invest Ophthalmol Vis Sci. 1995 Mar;36(3):657-70.

105. Wallace DK, Repka MX, Lee KA, Melia M, Christiansen SP, Morse CL, et al. Amblyopia Preferred Practice Pattern^®. Ophthalmology. 2018 Jan;125(1):P105-P142.

106. O'Hara MA. Instrument-based pediatric vision screening. Curr Opin Ophthalmol. 2016 Sep;27(5):398-401.

107. Williams C, Harrad RA, Harvey I, Sparrow JM, Team AS. Screening for amblyopia in preschool children: results of a population-based, randomised controlled trial. ALSPAC Study Team. Avon Longitudinal Study of Pregnancy and Childhood. Ophthalmic Epidemiol. 2001 Dec;8(5):279-95.

108. Cotter SA, Varma R, Tarczy-Hornoch K, McKean-Cowdin R, Lin J, Wen G, et al. Risk factors associated with childhood strabismus: the multi-ethnic pediatric eye disease and Baltimore pediatric eye disease studies. Ophthalmology. 2011 Nov;118(11):2251-61.

109. Hunter DG, Nassif DS, Piskun NV, Winsor R, Gramatikov BI, Guyton DL. Pediatric Vision Screener 1: instrument design and operation. J Biomed Opt. 2004 Nov/Dec;9(6):1363-8.

110. Jesus DL. Rastreamento visual e por photoscreener em escolares do primeiro ano do ensino fundamental [tese]. São Paulo: Biblioteca Digital de Teses e Dissertações da USP; Universidade de São Paulo; Faculdade de Medicina; 2015.

111. Baker J. Screen Eyes Early (SEE) in the Medical Home. A New Standard of Care is Possible in 2017. San Francisco, CA: AAPOS CsEFo; 2017. Available from: https://www.childrenseyefoundation.org/see/

112. Pediatric Eye Disease Investigator Group (PEDIG). Manuscripts. Tampa, FL: JAEB Center for Health Research; 2019. Available from: https://public.jaeb.org/pedig/pubs

113. Pediatric Eye Disease Investigator Group (PEDIG). Manuscripts. Tampa, FL: JAEB Center for Health Research; 2019. Available from: https://public.jaeb.org/pedig/pubs

114. Stewart CE, Fielder AR, Stephens DA, Moseley MJ. Design of the Monitored Occlusion Treatment of Amblyopia Study (MOTAS). Br J Ophthalmol. 2002 Aug;86(8):915-9.

115. Writing Committee for the Pediatric Eye Disease Investigator Group, Cotter SA, Foster NC, Holmes JM, Melia BM, Wallace DK, Repka MX, et al. Optical treatment of strabismic and combined strabismic-anisometropic amblyopia. Ophthalmology. 2012 Jan; 119(1):150-8.

116. Wallace DK, Pediatric Eye Disease Investigator Group, Edwards AR, Cotter SA, Beck RW, Arnold RW, Astle WF, et al. A randomized trial to evaluate 2 hours of daily patching for strabismic and anisometropic amblyopia in children. Ophthalmology. 2006 Jun; 113(6):904-12.

117. Repka MX, Beck RW, Holmes JM, Birch EE, Chandler DL, Cotter SA, et al. A randomized trial of patching regimens for treatment of moderate amblyopia in children. Arch Ophthalmol. 2003 May;121(5):603-11.

118. Holmes JM, Kraker RT, Beck RW, Birch EE, Cotter SA, Everett DF, et al. A randomized trial of prescribed patching regimens for treatment of severe amblyopia in children. Ophthalmology. 2003 Nov;110(11):2075-87.

119. Gottlob I, Awan M, Proudlock F. The role of compliance in 2 vs 6 hours of patching in children with amblyopia. Arch Ophthalmol. 2004 Mar;122(3):422-3.

120. Repka MX, Kraker RT, Holmes JM, Summers AI, Glaser SR, Barnhardt CN, et al. Atropine vs patching for treatment of moderate amblyopia: follow-up at 15 years of age of a randomized clinical trial. JAMA Ophthalmol. 2014 Jul;132(7):799-805.

121. Holmes JM, Lazar EL, Melia BM, Astle WF, Dagi LR, Donahue SP, et al. Effect of age on response to amblyopia treatment in children. Arch Ophthalmol. 2011 Nov;129(11):1451-7.

122. Holmes JM, Melia M, Bradfield YS, Cruz OA, Forbes B, Group PEDI. Factors associated with recurrence of amblyopia on cessation of patching. Ophthalmology. 2007 Aug;114(8):1427-32.

123. Birch EE, Fawcett SL, Morale SE, Weakley DR, Wheaton DH. Risk factors for accommodative esotropia among hypermetropic children. Invest Ophthalmol Vis Sci. 2005;46(2):526-9.

124. Pediatric Eye Diasease Group. A randomized trial of near versus distance activities while patching for amblyopia in children aged 3 to less than 7 years. Ophthalmology. 2008 Nov;115(11):2071-8.

125. Holmes JM, Edwards AR, Beck RW, Arnold RW, Johnson DA, Klimek DL, et al. A randomized pilot study of near activities versus non-near activities during patching therapy for amblyopia. J AAPOS. 2005 Apr;9(2):129-36.

126. Gaier ED, Hunter DG. Advances in Amblyopia Treatment: Paradigm Shifts and Future Directions. Int Ophthalmol Clin. 2017 Fall;57(4):117-28.

127. Harauzov A, Spolidoro M, DiCristo G, De Pasquale R, Cancedda L, Pizzorusso T, et al. Reducing intracortical inhibition in the adult visual cortex promotes ocular dominance plasticity. J Neurosci. 2010 Jan;30(1):361-71.

128. Baroncelli L, Bonaccorsi J, Milanese M, Bonifacino T, Giribaldi F, Manno I, et al. Enriched experience and recovery from amblyopia in adult rats: impact of motor, social and sensory components. Neuropharmacology. 2012 Jun;62(7):2388-97.

129. Kaneko M, Stryker MP. Sensory experience during locomotion promotes recovery of function in adult visual cortex. eLife. 2014 Jun;3:e02798.

130. Imamura K, Kasamatsu T. Interaction of noradrenergic and cholinergic systems in regulation of ocular dominance plasticity. Neurosci Res. 1989 Aug;6(6):519-36.

131. Duffy KR, Mitchell DE. Darkness alters maturation of visual cortex and promotes fast recovery from monocular deprivation. Curr Biol. 2013 Mar;23(5):382-6.

132. Spolidoro M, Baroncelli L, Putignano E, Maya-Vetencourt JF, Viegi A, Maffei L. Food restriction enhances visual cortex plasticity in adulthood. Nat Commun. 2011;2:320.

133. Repka MX, Kraker RT, Dean TW, Beck RW, Siatkowski RM, Holmes JM, et al. A randomized trial of levodopa as treatment for residual amblyopia in older children. Ophthalmology. 2015 May;122(5):874-81.

134. Morishita H, Hensch TK. Critical period revisited: impact on vision. Curr Opin Neurobiol. 2008 Feb;18(1):101-7.

135. Bavelier D, Levi DM, Li RW, Dan Y, Hensch TK. Removing brakes on adult brain plasticity: from molecular to behavioral interventions. J Neurosci. 2010 Nov;30(45):14964-71.

136. Putignano E, Lonetti G, Cancedda L, Ratto G, Costa M, Maffei L, et al. Developmental downregulation of histone posttranslational modifications regulates visual cortical plasticity. Neuron. 2007 Mar;53(5):747-59.

137. Baroncelli L, Scali M, Sansevero G, Olimpico F, Manno I, Costa M, et al. Experience Affects Critical Period Plasticity in the Visual Cortex through an Epigenetic Regulation of Histone Post-Translational Modifications. J Neurosci. 2016 Mar;36(12):3430-40.

138. Thompson B, Mansouri B, Koski L, Hess RF. From motor cortex to visual cortex: the application of noninvasive brain stimulation to amblyopia. Dev Psychobiol. 2012 Apr;54(3):263-73.

139. Levi DM, Knill DC, Bavelier D. Stereopsis and amblyopia: A mini-review. Vision Res. 2015 Sep;114:17-30.

140. Zhao W, Jia WL, Chen G, Luo Y, Lin B, He Q, et al. A complete investigation of monocular and binocular functions in clinically treated amblyopia. Sci Rep. 2017;7(1):10682.

141. Hess RF, Mansouri B, Thompson B. A binocular approach to treating amblyopia: antisuppression therapy. Optom Vis Sci. 2010 Sep;87(9):697-704.

142. Hess RF, Mansouri B, Thompson B. A new binocular approach to the treatment of amblyopia in adults well beyond the critical period of visual development. Restor Neurol Neurosci. 2010;28(6):793-802.

143. Hess RF, Thompson B. Amblyopia and the binocular approach to its therapy. Vision Res. 2015 Sep;114:4-16.

144. Li J, Thompson B, Deng D, Chan LY, Yu M, Hess RF. Dichoptic training enables the adult amblyopic brain to learn. Curr Biol. 2013 Apr;23(8):R308-9.

145. Li SL, Jost RM, Morale SE, Stager DR, Dao L, Stager D, et al. A binocular iPad treatment for amblyopic children. Eye (Lond). 2014 Oct;28(10):1246-53.

146. Holmes JM, Manh VM, Lazar EL, Beck RW, Birch EE, Kraker RT, et al. Effect of a Binocular iPad Game vs Part-time Patching in Children Aged 5 to 12 Years With Amblyopia: A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec;134(12):1391-400.

147. Gao TY, Guo CX, Babu RJ, Black JM, Bobier WR, Chakraborty A, et al. Effectiveness of a Binocular Video Game vs Placebo Video Game for Improving Visual Functions in Older Children, Teenagers, and Adults With Amblyopia: A Randomized Clinical Trial. JAMA Ophthalmol. 2018 Feb;136(2):172-81.

148. Kelly KR, Jost RM, Dao L, Beauchamp CL, Leffler JN, Birch EE. Binocular iPad Game vs Patching for Treatment of Amblyopia in Children: A Randomized Clinical Trial. JAMA Ophthalmol. 2016 Dec;134(12):1402-8.

149. Vedamurthy I, Knill DC, Huang SJ, Yung A, Ding J, Kwon OS, et al. Recovering stereo vision by squashing virtual bugs in a virtual reality environment. Philos Trans R Soc Lond B Biol Sci. 2016 Jun;371(1697):pii:20150264.

150. Žiak P, Holm A, Halička J, Mojžiš P, Piñero DP. Amblyopia treatment of adults with dichoptic training using the virtual reality oculus rift head mounted display: preliminary results. BMC Ophthalmol. 2017 Jun;17(1):105.

151. Holmes JM. Lessons From Recent Randomized Clinical Trials of Binocular Treatment for Amblyopia. JAMA Ophthalmol. 2018 Feb;136(2):181-3.

 

Received on: April 29, 2019.
Accepted on: August 13, 2019.