A randomised clinical trial objectively comparing the effect of patching therapy with video gaming for amblyopia

Amblyopia affects 3% of the children and is caused by strabismus (misaligned),
anisometropia (unequal refractive error) or both. The standard treatment is
glasses and patching therapy preferably before 8 years old. From North-America,
behavioural training, i.e. dichoptic training , perceptual learning and video
gaming, has become increasingly popular. The rationale behind these games is by
using dichoptic stimulation (using both eyes), with the contrast of the stimuli
presented to the good eye reduced to match the appearance of the same stimuli
when shown to the amblyopic eye, suppression can be alleviated. The many
studies now conducted in the USA demonstrate improvement in visual acuity with
the games, the effect however is limited to an average of 1.8 lines, while
visual acuity improvement with patching therapy is up 7 lines. Nevertheless,
the speed of improvement is markedly quicker with gaming: 17 hours of gaming
compared to 142 hours of patching is necessary to achieve one line of visual
acuity improvement. In these studies, prescribed patching-time was compared to
realised game-time. As we have previously demonstrated the average level of
compliance with patching therapy is only 50% and 9% of the children are not
patched at all. Because of a patent-issue we can only measure compliance
electronically in Europe using the ODM. It seems only logical that we conduct
this study in which we compare the effect of both treatments. It would have
serious consequences if all newly diagnosed amblyopic children would receive
gaming therapy whilst in the studies prescribed patching time was compared to
realised game-time. In addition, there is no information available about
patient preferences and experiences of video gaming as amblyopia treatment. As
video gaming may be a future treatment performed by orthoptics, it is important
that orthoptists can inform patients not only about the effect, but also on
other aspects of the treatment, such as the impact of the treatment on daily
life. Moreover in order to support patient participation in clinical
decision-making, we need to know their information needs.

.

To achieve a valid comparison of the effect of gaming and patching therapy on
visual acuity, with compliance measured electronically.

The study design will be a prospective randomized clinical trial. All newly
diagnosed amblyopic children will be recruited (see also study population).
After written consent is obtained the participants will be randomized to either
the patching or video game treatment by the independent researcher (the PhD
student). Both treatments will continue on for 24 weeks.

At the start of the treatment periods and after every two weeks visual acuity,
stereo acuity and contrast sensitivity will be assessed by the researcher
orthoptist who is blinded as to randomization and treatment. A treatment period
of 24 weeks is adopted as the literature has shown that most of the children
achieved their best visual acuity with 150 to 250 hours' cumulative dose of
patching.The fastest improvement in visual acuity occurred in the first six
weeks of patching. For the dichoptic action video game it has been demonstrated
(in adults) to show an improvement after 17 hours of training, however
participants continued to improve after 26 hours as well. This would involve a
schedule of at least one hour of training per week.

In addition together with some basic characteristics a validated questionnaire
will be assessed, in order to collect information about the impact of the
amblyopia and the treatment on vision-related quality of life. To adult
participants, the A&SQ (van de Graaf et al. 2004) will be sent to their home
and collected at the first visit at the HU. Children and their parents will be
interviewed face to face when they visit the HU following the CVFQ (Felius et
al. 2004) clinic and their parents will be asked to fill in the CVFQ (Felius et
al. 2004) which will be sent to their home in advance of their visit. Also, the
CAT-QoL will be assessed together with eight additional questions.

Treatment:
1) Patching therapy
The non-amblyopic eye will be patched for two hours per day. Compliance with
therapy will be monitored with the ODM.

2) Video game
A dichoptic custom-made Unreal Tournament video game was developed by Levi*s
group. The game is played under dichoptic viewing conditions in order to reduce
suppression and promote fusion, while challenging the amblyopic eye with an
embedded perceptual learning task.
The important aspect of this video game is that it presents the same image to
each eye (except for Gabor patches and suppression checks) with reduced
luminance/contrast in the fellow eye, in an attempt to promote binocular
fusion, whereas other dichoptic video game studies have presented different
game elements to each eye so that binocular combination is required to play the
game.11
There is also a YouTube about the previous version of the game:
https://www.youtube.com/watch?v=71RML96XxCI

3) fMRI scans
In collaboration with the Netherlands Institute for Neuroscience in Amsterdam
functional magnetic resonance imaging (fMRI) scans will be conducted on 10
adult subjects, prior to the treatment, and after completing the treatment (see
Fig. 1). The scans will take place on a 3T scanner.

Functional MRI is a neuroimaging procedure using MRI technology that indirectly
measures brain activity by detecting changes associated with blood oxygenation.
This measure correlates well with the underlying neuronal activity and has been
used in a multitude of studies to further our knowledge of brain function. In
this study we are specifically interested in how video-game training / patching
affects the basic neural representation of visual stimuli in cortex. We will
use both artificial stimuli, such as gratings, which can be well controlled, as
well as naturalistic stimuli to study the daily visual experience of the
patients. We will examine the fMRI response to stimuli presented to either eye
in isolation and the two eyes simultaneously before and after patching therapy
/ gaming. We are particularly interested in studying at which level in the
cortical visual hierarchy therapy induced changes occur. Does video game
training/patching lead to enhancements in low level visual areas only, or are
neural representations of visual stimuli in high-level visual areas also
affected? To answer this question we will use state-of-the-art multi-voxel
pattern classification techniques to *decode* which visual stimulus was
presented, and to which eye. As an input to the decoders we will use the fMRI
activity patterns from low-level or high-level visual areas. If video-game
training / patching leads to strengthened or more reliable neural coding of the
stimulus this should lead to better decoding. Furthermore, we aim to link the
improvements in decoding accuracy observed in the fMRI experiments with the
clinically measured improvements in visual acuity.

4) Qualitative Study
Based on the outcome of the additional questionnaire a heterogenic sample of
children and adult participants (i.e. various age, gender, visual acuity,
treatment preference etc.) will be selected for an additional interview at the
end of both treatments for a more in-depth analyses of their experiences and
preferences of the amblyopia treatments. Topics in the interview guide will
include the impact of each amblyopia treatment on social and emotional aspects
of the child*s life and family life, the impact of the treatment on
participation of the child for example at school or daycare and the view of the
parents on compliance to the suggested therapy. In addition, information needs
form patients to support patient participation in clinical decision making will
be investigated. Each interview will be analyzed and based on the results, the
interview guide for the next interview will be adapted. More interviews will be
planned until the information is only confirmatory.

1) Patching therapy
The non-amblyopic eye will be patched two hours per day. Compliance with
therapy will be monitored with the ODM.

2) Video game
A dichoptic custom-made Unreal Tournament video game was developed by Levi*s
group. The game is played under dichoptic viewing conditions in order to reduce
suppression and promote fusion, while challenging the amblyopic eye with an
embedded perceptual learning task. See fig 3.

By proper extensive screening and (orthoptic) examination of participants there
are no potential risks associated with fMRI and the video games. There are no
risks in wearing the ODM.

There are no physical or psychological risks involved in the behavioural tasks.
The subject is seated comfortably, visual stimuli are presented on a computer
monitor set at a comfortable light level and the button press response requires
a minimal amount of effort. Possible fatigue may occur due to the
repetitiveness of the task but the subject may discontinue an experimental run
at any time and may take breaks between runs.

There are minimal risk associated with playing video games. The frequent use of
joystick may cause slight mechanical fatigue: finger irritation from repetitive
use of the joystick has been reported in a console player. Participants may
develop an interest in video game playing and may continue playing video games
after the conclusion of the study on their own time. Since the modified kids
friendly game that we have designed does not include any violence, there is no
risk which may typically be associated with violent action games. Some
participants may experience mild to moderate nausea as a result of the virtual
motion associated with action game play. Nausea usually subsides after the
first few training sessions and participants who do not feel well are permitted
to end a session early and make up training time later.

Numerous studies have demonstrated a positive effect of gaming on visual acuity
improvement. Thereby, the speed of the improvement is markedly quicker with
gaming compared to patching therapy. The main issue these studies is that
compliance in patching therapy is not measured electronically, thus
objectively. It would have serious consequences if all newly diagnosed
amblyopic children would receive gaming therapy whilst in the studies
prescribed patching time was compared to realised game-time.

Our study will be the first study to compare the effect of patching therapy,
using the ODM to objectively measure compliance, with the effect of a novel
dichoptic action video game in children as well as in adults. In addition, the
adult participants will undergo fMRI scans to document any changes in the
visual cortex before and after either therapy. This study will first provide
evidence on the speed of visual acuity improvement comparing both treatments,
and then shed further light on the plasticity of the brain in adults.