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Neuroplasticity, Amblyopia and Emerging Treatments

2 CPD in Australia | 1CD in New Zealand | 1 March 2018

 

 

By Dr. Brian Dornbos and Dr. Tuan Tran 

In recent years, amblyopia treatment, beyond patching or strabismus surgery, has attracted the attention of both the medical and research communities. Advances in technology and scientific knowledge have led to the development of new treatment methods that focus on neuroplasticity.

LEARNING OBJECTIVES

1. Understand the complex process of visual development

2. Give an account of traditional methods of amblyopia therapy

3. Identify downfalls of traditional methods of amblyopia therapy

4. Discuss the benefits and downfalls to binocular therapy for amblyopia

5. Analyze benefits and shortcomings of early studies on dichoptic therapies

6. Explain what benefit virtual reality offers beyond more traditional methods of amblyopic treatment.

 

Amblyopia is defined as a 2-line difference between the eyes and is characterised as a neurodevelopmental disorder due to abnormal visual experience early in life. The amblyogenic agent is often ametropia or strabismus and less likely deprivation due to media opacity or blepharoptosis. Amblyogenic agents not only prevent images from being properly focused on the macula of the eye but also disrupt binocular vision. Population-based studies of children show a mean prevalence of 2.4 per cent for amblyopia and 2.8 per cent for strabismus.1 The Sydney Paediatric Eye Disease Study found comparable prevalence with amblyopia discovered in nearly 2 per cent of a sample of Australian preschool children.2 Amblyopia is one of the leading causes of visual impairment in Australian children, second only to refractive error.3

Development and Critical Periods

Infants have a rather disorganised visual system at birth which develops rather rapidly in the weeks and months following birth. This is followed by a slower maturation phase over the first few years of life.4 Physical postnatal visual development consists of eyeball growth, central retina maturation and organization, and neuron proliferation, maturation and myelination. Organisation of the macula becomes crucial for colour vision, contrast sensitivity, and stereopsis.5

This developing visual system is highly influenced by environment. The importance of a rich, visually stimulating environment is not a new concept;  Bennett and colleagues reported that rats raised in cages containing toys and puzzles performed better in standardised maze tests versus rats raised in a cage without an enriched environment. Not only did the rats in an enriched environment test better, the brain of these rats was actually heavier than the brain of their counterparts.6 As neurons grow and develop new synapses and connections, functional networks, such as ocular dominance columns, begin to form. The process of refinement and pruning now begins, and becomes a critical component for the developing binocular visual system.4

Preferential looking tasks in clinical and research studies have utilised visual evoked potential (VEP) measurements and have provided insight into the visual ability of infants. VEP information specifically studying the infant contrast sensitivity function affords an estimation of infant visual acuity. It is now apparent that low spatial frequency sensitivity develops rapidly over the first months of life, with adult-like levels discernible between six and eight months of age.7 High spatial frequency sensitivity develops much slower and reaches adult-like levels around four years of age.4 Just as binocular vision requires the additive principles of simultaneous perception, fusion, and then stereopsis, VEP measurement shows that infants develop fusion and stereopsis in sequence. Development of fusion and stereopsis occurs between 2–4 and 6–7 months, respectively.8,9 Stereoacuity continues to improve and reaches adult-like levels around age three.10

These temporal periods of rapid growth and change in sensitivity followed by a slower tapering, or fine-tuning, of the visual system provide the basis for our understanding of the critical period of visual development. Hubel and Wiesel’s 1970 animal studies afforded a look at the structural changes that a visual system suffers when one eye is deprived of sight.11 Not surprisingly, there is not a single critical period, but rather multiple periods whereby neural networks required for different visual functions such as acuity, motions sensitivity, stereopsis and other visual skills mature and develop.12,13 The concept of a critical period, or perhaps better described as periods of extensive neural growth and development, is not unique to the visual system. Indeed, language, motor skills, and many other abilities follow a similar time and environment dependent pattern as the visual system.14,15 Lewis and Maurer offer a slightly different thought on the critical period from their studies on visually deprived children. They fragment the critical period of the visual system into three stages. The first is a period of visually-driven normal development, wherein a portion of the visual system fails to develop due to a lack of stimulus. The second period is the period of damage. Here the visual system is approaching adult-like function, but a deficient visual experience leads to changes in structure and function. The last stage is a period of recovery; here the visual system is able to recover from the abnormal visual input.12 Although the original focus of these concepts was primarily applied to deprivation, the idea of irreversible and reversible damage to the visual system can be extrapolated to our expanding knowledge on the plasticity of the human visual system.

It is known that amblyopia becomes less responsive to conventional treatment as a patient ages.16 Besides our knowledge of development and critical periods, advances in neuroimaging have greatly expanded our ability to visualise the structure of an amblyopic brain and visual system. A key method utilises diffusion magnetic resonance imaging (dMRI). Diffusion MRI is non-invasive and affords a view of the structural integrity of white matter in a subject.17 When comparing the anatomy and structure of white matter of anisometropic and strabismic amblyopes to normal subjects, dMRI studies have suggested reduced structural integrity in multiple areas of the visual system. This includes the optic radiations, inferior longitudinal fasciculus, vertical occipital fasciculus, and corpus callosum.18,19 Interestingly, the primary and secondary visual cortex was not remarkable for significant changes between amblyopes and normal controls.20 As the human brain ages, functional changes within the existing system replace the ability to create new neural structures. Since the adult amblyopic brain is essentially playing from behind, the ability to manipulate the visual system of older amblyopic patients from a functional standpoint has become a topic of interest.

In a thorough review of adult brain plasticity, Bavelier and colleagues highlight the importance of altering the release of excitatory and inhibitory neurotransmitters.21 N-Methyl-D-aspartic acid (NMDA) and gamma-Aminobutyric acid (GABA) pathways appear to play important roles in the functional plasticity in a developing visual system.22 GABA-mediated channels specifically may play a role in both neuroplasticity as well as in suppression.23 Building on the evolving understanding of neuroplasticity, new amblyopia treatments have emerged that challenge conventional treatment.21-23

Treatment

Standard treatment of amblyopia consists of optical correction for refractive error to provide the amblyopic eye with a clear retinal image. This is followed by penalisation therapy to correct for ocular imbalance by means of either part-time patching or using a cycloplegic ophthalmic drop, such as atropine, on the dominant eye. Refractive correction alone may suffice to correct both amblyopia or strabismus; however, strabismic patients (amblyopic or not) may undergo extraocular muscle surgery to align the eyes. Strabismus surgery alone often does not result in functional binocular vision.24 Interestingly, a large multicenter study by Simonsz investigated binocular ability in 231 post-strabismus surgery children at around four years of age. Only 3.9 per cent of the patients recognized the Titmus housefly test when examined at the age of six, even though 65.2 per cent of the children had a post-surgical deviation of less than 10 degrees.25

If initiated at an early age, intervention by means of occlusion or penalisation therapy can result in an average gain in 3 lines of visual acuity in approximately 75 per cent of patients;26 the ability of the amblyopic visual system to improve declines with age.16 However, the literature is lacking in studies regarding traditional treatment on adult amblyopia. This is due to the fact that the adult visual system has long been considered to be beyond the period of recovery.27 In fact, all too frequently adult amblyopic patients are under the impression that there is no chance of recovering any amount of vision.

Aside from declining efficacy with age, traditional amblyopia therapy fails to address other deficits within the visual system of an amblyope. Traditional therapy focuses on improvement in monocular visual acuity and thus fails to address amblyopia as a disorder that affects both monocular and binocular vision. In fact, oculomotor abnormalities,1,28 visual processing deficits,29 suppression,27 and stereopsis1 are often abnormal in amblyopes. Not surprisingly, these visual skills are often intertwined. The linking factor to this list is that each of these items are properties of a binocular system. With neuroplasticity in mind, treatment focused on rehabilitating the binocular system as a whole has emerged. Reducing suppression and/or enhancing stereopsis are new focal points of therapy.30,31

New Treatment Thoughts

Pharmacological manipulation of neuroplasticity through neural excitation has been a topic of interest. Dopamine is a neurotransmitter that not only plays a critical role in reward centres of the brain, but also in visual processing and retinal function. The precursor molecule, levodopa, is able to cross the blood-brain barrier where it is then converted to dopamine. It was postulated that co-treatment of amblyopes with levodopa and patching would enhance visual rehabilitation. However, the Pediatric Eye Disease Investigator Group (PEDIG) tested this theory and found the addition of levodopa to patching therapy no better than patching alone.32 Citicoline is a supplement thought to increase dopamine receptors on cell membranes. It has also been attempted as adjuvant therapy to patching; however, the results were similar to levodopa treatment.33

Restore Binocular Function to Drive Visual Acuity Improvements

Perceptual learning within amblyopia rehabilitation involves repetition of a visual task with the improvement of visual skills extending to multiple visual abilities. Often the task was monocular and attempted with the non-amblyopic eye patched. Indeed, repetition in a task such as contrast detection has transferred to improvement in visual acuity.34 The principles of perceptual learning have been extended to activities requiring the use of both eyes with the intent of rebalancing binocular input and forcing the visual system to use both eyes together. In essence, restore binocular function and visual acuity will follow.

Dichoptic treatment refers to visual activities in which different elements of a scene or game are seen by each eye. When the visual system is working together, the entire visual scene is completed; however, if an eye is suppressed, portions of the scene are missing. A classical approach to obtaining dichoptic viewing requires the use of anaglyph glasses in activities such as GTVT anti-suppression chart or a TV trainer. Newer dichoptic treatment modalities have used active shutter 3D glasses and virtual reality (VR). Dichoptic therapy has even been combined with perceptual learning tasks (Figure 1), which may produce an improvement in stereoacuity and a reduction in interocular suppression.35

Figure 1. Dichoptic viewing illustration inside a virtual reality headset. The amblyopic eye (LE) sees the markers within the white rings, and the fellow eye (RE) sees the spaceship.

 

The importance of excitement or engagement in an activity should not be overlooked. You will see in the next few paragraphs not just the concept of dichoptic image presentation, but the use of media within visual rehabilitation. Weber and colleagues expanded on the work of Hungarian psychologist Mihaly Csikszentmihalyi’s concept of flow - a theory meshing happiness and optimal experience. We can extract key components of flow in regards to visual rehabilitation. A therapy would require:

  • A challenging task
  • The possession of appropriate level of visual skills for the task
  • Concentration to complete the task
  • A pleasant experience for the patient
  • A feeling of gratification or constructive feedback.

Weber argued that “If an individual is exposed to flow inducing stimuli and flow occurs, then specific attentional and (neural) reward networks synchronize.”36 Although theoretical, it is interesting to think of how this concept could tie into visual rehabilitation, neural excitation, and plasticity.21 Could it be that excitement and engagement in a task could actually enhance neuroplasticity?

Video Game Play

Video games have significantly improved in quality over the years. Video games are a unique form of entertainment – they require allocation of attention with the added benefit of providing engagement and challenge to individuals of all ages. As such, the use of video games for amblyopia rehabilitation has been a topic of interest. Video games have the potential to be used for monocular, dichoptic, perceptual learning, and stereoscopic training tools.

Over a decade ago, the Interactive Binocular Treatment (I-BiT) system was developed in the United Kingdom. The I-BiT system was the first to use VR and dichoptic gameplay for amblyopia rehabilitation, although the prototype used by the I-BiT team was much larger and not exactly portable.37 A pilot study using the I-BiT system investigated the effect of dichoptic treatment on 12 patients ages six to 11 years was favourable – seven of the 12 children had sustained improvement in high- and low-contrast visual acuity. Mean acuity improvement was greater than 1.7 lines. In addition, four patients displayed improvement in stereoacuity.38 A later randomized trial using the I-BiT system and shutter glasses compared dichoptic movie watching and dichoptic video game play to non-dichoptic gameplay. Although compliance was excellent and treatment was entertaining, mean visual acuity improvement was only one line in the movie group. Acuity was not significantly improved in other groups, and stereoacuity was not significantly improved in the entire cohort.39 An important observation to make within these studies is that no attempt to balance visual input between the eyes was made, nor were adjustments for a strabismic amblyope’s angle of deviation.

More recent work consisted of video game gameplay using a dichoptic falling blocks stimulus. The game could be utilised with lenticulars in a clinical setting or as home-based therapy using red-green anaglyphs. Subjects first performed a dichoptic global motion test using a random dot kinematogram. The contrast was adjusted until vision was balanced between the amblyopic eye and the normal eye. Both lenticular and anaglyph versions of the activity afforded an average gain of greater than one line of visual acuity. Mean stereoacuity improved from 1388 arc seconds to 344 arc seconds.40

Building off a smaller study, PEDIG used the anaglyphic version of the falling blocks games adapted for an iPad and compared dichoptic gameplay to traditional patching. Subjects were randomised and were assigned to either play the game for one hour per day, 7 days a week for 16 weeks or to patch two hours per day. As the game progressed, the contrast between the amblyopic eye and the normal eye would adjust based on game performance. Statistical analysis slightly favoured patching to the dichoptic iPad game. Unfortunately, the trial was disadvantaged due to poor compliance, as only 22.2 per cent of subjects completed more than 75 per cent of the recommended treatment.41 A larger randomised trial of patients ages seven to adult used a similar game and suffered similar issues with compliance.42

As previously stated, patient engagement appears to be an important component of therapy. Even over a century ago, the importance of patient engagement regarding visual rehabilitative therapies was apparent. Ophthalmologist Claud Worth stated in his 1906 work that (the patient) “will, therefore, only permit the exercises so long as he finds them attractive and interesting.”43 This is becoming a new focus in visual rehabilitation. Use of child-friendly action games in concert with patching therapy significantly improved both visual acuity and stereoacuity relative to patching alone in a study of 40 amblyopic children.44 The adult amblyopic visual system also appears to respond to action video game gameplay. By meshing dichoptic stimuli and perceptual learning into action video game gameplay, adult amblyopes manifested improves in acuity, contrast sensitivity, reading speed, and stereoacuity relative to controls assigned to monocular movie viewing.45 Similar improvements were found in children. After four weeks of binocular video game treatment, a cohort of children showed nearly a two-line gain in acuity. The improvement may be due to better compliance with a more ‘exciting’ game.46

The level of immersion afforded by VR is an attractive method of rehabilitation. Current VR technology offers the added benefit of placing the patient in a true stereoscopic environment without the need for complicated stereoscopes or heavy, expensive equipment. Additionally, VR requires the use of binocular vision in order to maximise the VR experience. It is because of this that VR has a unique potential for use in visual rehabilitation. Although they did not utilise a conventional head-mounted display (HMD), Vedamurthy and colleagues designed the first three-dimensional VR stereopsis training program. Utilising a combination of monocular and binocular cues as well as tactile feedback, 11 amblyopic subjects were tasked with squashing virtual bugs that were projected onto a slanted surface with a plexiglass cylinder. Prior to the activity, visual input between the amblyopic eye and the normal eye were balanced by reducing contrast in the normal eye. This balancing of visual input helped a patient fuse images presented to each eye. Monocular depth cues then provided a base by which a patient could complete the bug squashing activity. As the subject progressed through the activity, there was a shift to pure stereo cue trials. This method of visual scaffolding combined with a perceptual learning task resulted in eight of the 11 subjects improving their reliance on stereoscopic cues and six subjects showing a slight improvement in visual acuity.47

Figure 2. Dichoptic viewing, interocular contrast adjustments, and other anti-suppression techniques can be implemented in virtual reality.

Advances in consumer grade VR hardware have removed barriers such as large, heavy equipment and high cost from being utilized in visual rehabilitation. Vivid Vision utilises a mixture of perceptual learning, dichoptic image display, and direct stereo training (Figure 2). A recently published pilot study of 17 adult amblyopic patients was promising. Subjects underwent eight 40-minute treatment sessions of VR video game gameplay. At the start of treatment, only eight subjects displayed measurable stereoacuity. At the conclusion of treatment, visual acuity improved by an average of 1.5 lines, and 15 of 17 subjects (88 per cent) showed measurable stereoacuity. Nine of these subjects displayed a significant improvement in stereoacuity.48

Conclusion

New treatment paradigms in amblyopia offer hope for older patients to obtain improvements in visual function, such as visual acuity and stereopsis. Newer research suggests that the critical period doesn’t end at childhood; rather a maximum neuroplasticity period. Dichoptic treatments involving the use of video games or VR combined with perceptual learning or stereoscopic training provide a unique tool for visual rehabilitation that was not widely available years ago.  


 

Dr. Brian Dornbos, OD, FAAO, is the Director of Optometry and Regulatory Compliance Officer at Vivid Vision, Inc. Dr. Dornbos has previously served a provider for the Indian Health Service and Department of Veterans Affairs, as well as clinical instructor for multiple US-based optometric programs. His interest includes new technologies in optometric and ophthalmic care, virtual reality, clinical optometry, and ophthalmic disease. 


 

Dr. Tuan Tran, OD, is one of the Co-Founders of Vivid Vision and acts as the Chief of Optometry. He is an associate clinical professor at Pennsylvania College of Optometry and Western University of Health Sciences. Dr. Tran completed a residency in Vision Therapy and Neuro-Rehabilitation through the Southern College of Optometry.

This education article was sponsored by France Medical.



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' As neurons grow and develop new synapses and connections, functional networks, such as ocular dominance columns, begin to form '