Vision Research 114 (2015) 1–3

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Vision Research

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Preface A window into visual cortex development and recovery of vision: Introduction to the Vision Research special issue on

Normal visual development requires unimpeded and coordi- developmental ages on the structure and function of primary nated input from each eye to the visual cortex during an early crit- visual cortex (Hubel & Weisel, 2004). More recently, work in this ical period of cortical maturation. Disrupted area has provided new insights into the impact of abnormal visual during this critical period, due to visual deprivation (e.g. congenital experience on the development of extrastriate visual brain areas cataract), misalignment of the eyes () or unequal refrac- (Bi et al., 2011; El-Shamayleh et al., 2010) and provided unex- tive error (anisometropia), can lead to amblyopia, a neurodevelop- pected evidence that vision can indeed be recovered in the ambly- mental disorder of vision (Daw, 2014; Holmes & Clarke, 2006). opic eyes of visually mature animals (Duffy & Mitchell, 2013; Amblyopia is characterized by a loss of visual acuity in the affected Murphy et al., 2015). This suggests that critical periods are not eye and impaired or absent binocular visual function in the absolute. Recovery of vision has also been demonstrated in adult absence of any ocular disease or abnormality. humans with amblyopia, further supporting this idea (Astle, Amblyopia has been the focus of two parallel and complemen- Webb, & McGraw, 2011; Hess, Thompson, & Baker, 2014; Levi & tary lines of research for many decades: one clinical and one neu- Li, 2009). roscientific. Clinically, amblyopia represents the most common The breadth and momentum of amblyopia research was cause of visual impairment in childhood (Wong, 2012) and has a recently recognized by joint mini-symposia organized by the Eye significant impact on quality of life (Carlton & Kaltenthaler, Movements/Strabismus/Amblyopia/Neuro-ophthalmology (EY) 2011). The current evidence-based treatment for amblyopia and Visual Psychophysics/Physiological Optics (VI) sections of the involves refractive correction (Cotter et al., 2006; Writing Association for Research in Vision and Ophthalmology (ARVO), Committee for the Pediatric Eye Disease Investigator et al., 2012) held at the 2014 ARVO annual meeting. The symposia brought followed by occlusion or penalization of the non-amblyopic eye together researchers whose combined expertise spanned both to encourage use of the amblyopic eye (Pediatric Eye Disease the clinical and neuroscientific areas of amblyopia research and Investigator Group, 2002). This treatment can induce recovery of provided the inspiration for this special issue. amblyopic eye visual acuity if implemented at an early age The special issue highlights a number of key themes in ambly- (Wallace et al., 2006); however improvements in binocular vision opia research that bring together these two important lines of are often limited (Birch, 2013). research. The first relates to the nature of the structural and func- In humans, early monocular deprivation has catastrophic conse- tional abnormalities that underlie the visual deficits caused by quences for the final level of vision the deprived eye can obtain, amblyopia. With regards to cortical structure, Allen et al. (2015) while the same type of deprivation introduced later in childhood used diffusion tensor imaging to identify and assess white matter has a diminishing impact and little or no effect at all beyond tracts within the visual pathways in a group of adult patients with around 9 years of age (Vaegan & Taylor, 1979). This transition from amblyopia and a group of controls. Patients with amblyopia exhib- severe early impairments to virtually no effect on acuity later in ited increased mean diffusivity in thalamo-cortical visual path- development delimits the duration of visual system susceptibility ways, but no significant differences between patients and to abnormal visual experience – the so-called ‘critical period’. controls were observed in cortico-cortical pathways. This suggests This window is thought to reflect a changing balance of influence that amblyopia may alter the white matter properties of early between visual mechanisms of plasticity and stability. Currently, visual pathways. there are no treatments for adults with amblyopia that are in gen- A number of advances in understanding the neural changes that eral clinical use. This reflects the rather entrenched view that occur in amblyopia are also reported in the special issue. Using amblyopia is intractable in older patients. Once the period of vul- multi-electrode recordings from V1 and V2 in macaques with nerability had passed, it was assumed that plasticity was limited experimentally induced amblyopia, Shooner et al. (2015) demon- in scope and, as a result, treatment would be ineffective. strated that more information from the amblyopic eye is available From a neuroscientific perspective, amblyopia is a preeminent at an early stage of cortical processing than would be expected model for exploring cortical development and plasticity in both based on behavioral contrast sensitivity losses. This implies deficits animals and humans. Nobel prize winners Hubel and Wiesel in downstream processing. Shooner et al. (2015) identified a reduc- famously used experimentally induced amblyopia in monkeys to tion in the relative proportion of signals passing to extrastriate investigate the impact of altered visual input at different areas due to sub-optimal pooling of neural information from the http://dx.doi.org/10.1016/j.visres.2015.06.002 0042-6989/Ó 2015 Elsevier Ltd. All rights reserved. 2 Preface / Vision Research 114 (2015) 1–3 amblyopic eye within V1 and V2 as a potential mechanism for this novel hypothesis that interocular could be used to dif- effect. In a neurobiological study, Williams et al. (2015) investi- ferentiate amblyopia from myopia in the context of vision screen- gated the changes that occur within V1 in a cat model of monocu- ing. They found that a measure of interocular inhibition was highly lar deprivation amblyopia and found a rapid loss of AMPA receptor accurate in discriminating amblyopic eyes from myopic eyes with proteins across all of V1, that was followed by a more gradual or without the presence of refractive correction. With respect to recovery in peripheral visual field representations. The net result the treatment of amblyopia, Kelly et al. (2015) used visually was a loss of AMPA receptors that persisted only in the central evoked potentials (VEPs) to investigate the effect of occlusion ther- region of V1. Importantly, Williams et al. (2015) propose a link apy on the cortical response to information from the amblyopic between the deprivation-induced loss of AMPA receptors in V1 eye. Prior to treatment, amblyopic eye VEPs exhibited a poorer sig- and visual acuity impairments in the central field that were appar- nal-to-noise ratio, a longer latency and increased phase misalign- ent even under binocular viewing conditions in monocularly ment relative to fellow eye VEPs. Each of these measures deprived animals. Also using a cat model of amblyopia, Crewther improved with occlusion therapy, revealing a change in visual cor- and Crewther (2015) report neurophysiological and modeling evi- tex function that was partially related to improved temporal syn- dence indicating that differences in the timing of signals from each chronization of neural activity. eye propagating from LGN to V1 play a role in the loss of visual The final three research papers within the detection and treat- function associated with strabismic amblyopia. In particular, an ment theme all involve binocular treatment of amblyopia. Duffy increased temporal dispersion of signals from the amblyopic eye et al. (2015) build on their earlier finding that exposure to com- relative to the fellow eye was evident in single cell extracellular plete darkness enabled recovery of vision in kittens with monocu- recordings made from the LGN. lar deprivation amblyopia (Duffy & Mitchell, 2013) by asking The second theme relates to the impact of amblyopia on visual whether binocular eyelid closure initiates the same effect. functions over and above the loss of visual acuity in the amblyopic Although binocular eyelid closure led to anatomical recovery of eye. Using retinal imaging, Chung et al. (2015) investigated the neuron soma size in deprived layers of the LGN, no behavioral effect of strabismic and anisometropic amblyopia on fixational improvements occurred. Subsequent exposure to complete dark- eye movements. While fixational eye movements in the non-am- ness led to recovery of vision in the deprived eye, suggesting that blyopic eyes of patients were not different from controls, ambly- a complete absence of binocular visual input is required for the opic eyes exhibited abnormal fixational eye movements, an effect behavioral therapeutic effect. Using an active intervention strategy that was particularly pronounced in patients with strabismic in human patients, Li et al. (2015) report significant improvements amblyopia. Further, Chung et al. (2015) highlighted the functional in amblyopic eye contrast sensitivity in adult patients following relevance of eye-movement anomalies in amblyopia by identifying treatment with a dichoptic video game based therapy developed the characteristics of fixational eye movements that limit fixation by Hess and colleagues (Hess, Mansouri, & Thompson, 2010; To stability and acuity in amblyopic eyes. Amblyopia also disrupts et al., 2011). The treatment involves the dichoptic presentation of visuo-motor coordination; Grant and Conway (2015) investigated different game elements to each eye combined with an interocular the nature of this deficit by measuring reach-to-precision-grasp contrast difference that allows for information from the two eyes movements in patients with amblyopia and controls under differ- to be combined. In a complementary study, Vedamurthy et al. ent contrast and luminance conditions. Patients spent a signifi- (2015) report the effects of a binocular action video game treat- cantly longer time preparing their hand movements and in ment utilizing an interocular contrast difference as well as a applying their grip, while also making more reach and grasp errors. monocular perceptual learning task. Significant improvements in These effects were accentuated in patients for low-contrast objects, visual acuity, stereopsis, contrast sensitivity and reading speed suggesting that difficulties in acquiring reliable visual information resulted from the video game treatment. regarding the shape and location of target objects play a key role in Four reviews that focus on the treatment of amblyopia precede the visuo-motor control deficits associated with amblyopia. the research papers within this special issue. Hess and Thompson As studies in this issue highlight, the impact of amblyopia is not (2015) outline the development of their binocular approach to limited to the primary visual cortex, but extends to extrastriate amblyopia treatment and identify a number of possible mecha- visual cortex. This is evident in the performance of patients with nisms that may underlie the treatment effect. The importance of amblyopia on psychophysical tasks that are thought to require pro- considering binocular function when treating amblyopia is further cesses supported by extrastriate visual areas. Using this approach, emphasized by Levi, Knill, and Bavelier (2015) in a review of the Gao et al. (2015) employed a range of second-order stimuli extent to which stereopsis can be recovered in adults with ambly- (defined by textural cues rather than luminance boundaries) opia. Both of these reviews relate directly to the original research designed to target either the dorsal or ventral cortical streams. papers by Duffy et al. (2015), Li et al. (2015) and Vedamurthy When viewing with the amblyopic eye, patients exhibited deficits et al. (2015) outlined previously. In the next review, Wang across a wide range of second-order stimuli implicating both dor- (2015) addresses the issue of compliance with current amblyopia sal and ventral processing stream deficits. However, fellow eye treatments in a comprehensive summary of clinical studies on this viewing revealed deficits only for motion-defined form, suggesting topic. Compliance is identified as a key factor of treatment success that only dorsal stream deficits are common to both amblyopic and that represents a significant challenge to clinicians and parents of fellow eyes. Evidence supporting abnormal extrastriate function in children with amblyopia. Finally, Holmes (2015) provides an over- amblyopia is also provided by Giaschi et al. (2015) who report view of the issues that need to be considered when designing clin- impairments in motion-defined form perception and multiple ical trials of amblyopia treatments. This review lays out a object tracking in a group of children with amblyopia. Again, these framework for the potential translation of new therapies that are deficits were found in both amblyopic and fellow eyes. Crucially, emerging from basic science research to set a new agenda for evi- they were not improved by occlusion therapy, even when the acu- dence-based clinical practice. ity of the amblyopic eye improved significantly. The research highlighted by this special issue represents signif- Giaschi et al.’s (2015) findings link to the final theme within the icant advances in both our understanding of amblyopia and its special issue, which is the detection and treatment of amblyopia. treatment. However, many knowledge gaps remain and future Recently, binocular function and interocular suppression have research must continue to explore amblyopia as a unique window become a focus of research into new treatments for amblyopia. into visual cortex development and as a model for understanding Building on prior research in this area, Jia et al. (2015) tested the recovery of vision throughout the lifespan. Preface / Vision Research 114 (2015) 1–3 3

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