The role of GABAergic inhibition in the function and dysfunction of the human binocular visual system

When you catch a ball in mid-air, or point your finger to press a button, you are using your sensation of depth. The most precise sensation of depth, called 'binocular' depth, comes from using our two eyes together. The two eyes at the front of the face allow two views of the world, with one view slightly shifted to the side with respect to the other. During early childhood, the brain learns to combine these two images to form a single image seen in depth. To do this successfully, the eyes have to point in the same direction and give equally clear images. If the eyes point in different directions, or one eye gives a very blurry image, children can develop a 'lazy eye' where one eye works better than the other. This leads to the weaker eye being ignored by the brain. Lazy eye is one of the most common visual problem in children.

Scientists think that one of the reasons why the weak eye is ignored by the brain is because of a neurochemical in the brain called GABA. GABA is an inhibitory neurochemical, which means that it can weaken the signal from other brain cells. We think that GABA weakens the signal from the 'lazy eye' because it is less useful than the other eye. More generally, GABA may actively control what we see and do not see. It is important, therefore, to understand the role of GABA in vision. We will do this by measuring how changing GABA levels in the brain change the way we see in binocular depth.

We will use a brain scanner and a method to measure GABA in the living human brain, known as MR Spectroscopy. We aim to determine the importance of GABA in binocular vision using three studies. In Study 1, the goal is to test whether increasing GABA with a prescription drug, known as clobazam, improves binocular depth perception. This may also make brain cells more selective to visual input in general. To ensure that any differences are exclusively due to the drug, we will also ask the same participants to take a placebo pill while repeating the experiments on another day. Comparing drug to placebo data will reveal the contribution of the increase in GABA. In study 2, we will train adults with lazy eye to learn to use their eyes together, by performing a visual task for an hour each day for 2 weeks. This has been shown to improve the ability of the eyes to work together. We will measure the level of GABA before and after training, which will show whether GABA level is related to improvements due to training, and the places in the brain where any activity changes occurred.

In the final study, we will recruit children aged 6-13 who are at risk of developing lazy eye. Such children usually wear a patch for 6 months over their stronger eye for several hours a day to try to prevent the development of lazy eye. This 'occlusion therapy' helps the weaker eye work better as it is the only eye that is seeing, and the brain is forced to use its signal. We will scan 30 of these children, along with age-matched children with healthy vision, to test whether patching therapy changes the GABA concentration in the visual brain. We will also test whether improvement in vision is related to changes in GABA levels. Understanding the way in which patching therapy shapes the child brain can improve future treatment regimes.

This series of studies focusing on the role of GABA in the brain will allow us to design treatments to help improve binocular vision for children and adults.

The ability to see in-depth using two eyes is acquired early in development, and critically requires normal binocular visual experience. Abnormal binocular experience, through a squint or unequal refraction, causes long-lasting and severe deficits in visual perception. This condition called Amblyopia, affects around 3% of the population. As binocular vision is achieved by the brain, amblyopia is a disorder not of the eyes but of the brain. One of the key elements in determining experience-dependent plasticity in the binocular visual system is the inhibitory neurotransmitter GABA. This programme of research is designed to determine the role of GABA in binocular function and dysfunction in the human visual cortex.

The proposed research aims to use multi-modal magnetic resonance imaging (MRI) to determine (i) whether pharmacologically modulating GABA levels in the brain interferes with binocular functions; (ii) whether a binocular visual training leads to a reduction in GABA in amblyopes that is correlated with improvement in binocular vision and; (iii) how the visual system of children at risk of amblyopia differs from those without binocular deficits and how patching therapy changes cortical structure and function underlying binocular vision.

In combination, we will non-invasively quantify the concentration of GABA in the visual cortex, obtain population receptive field measures of depth and assess binocular vision acuity to determine the relationship between neurochemistry, neural organisation and perception. By performing experiments in healthy adults, adults with amblyopia and children at risk of amblyopia, we aim to build a unifying framework that can account for changes during early development and in adulthood. Not only will these studies provide important data for improving therapy for amblyopia, but the binocular vision system can act as a model for neurodevelopmental disorders of higher cognitive function, such as autism or schizophrenia.