Abnormal Visual Input Research Articles

The Role of Retinal Dysfunction in Myopia Development.

Myopia is a refractive disorder arising from a mismatch between refractive power and relatively long axial length of the eye. With its dramatically increasing prevalence, myopia has become a pervasive social problem. It is commonly accepted that abnormal visual input acts as an initiating factor of myopia. As the first station to perceive visual signals, the retina plays an important role in myopia etiology. The retina is a fine-layered structure with multitudinous cells, processing intricate visual signals via numerous molecular pathways. Accordingly, dopaminergic mechanisms, contributions of rod and cone photoreceptors, myopic structural changes of retinal pigment epithelium (RPE) and neuro-retinal layers have all suggested a vital role of retinal dysfunction in myopia development. Herein, we separately discuss myopia-related retinal dysfunction and current dilemmas by different levels, from molecules to cells, with the hope that the comprehensive delineation could contribute to a better understanding of myopia etiology, indicate novel therapeutic targets, and inspire future studies.

Critical Periods in Vision Revisited.

For four decades, investigations of the biological basis of critical periods in the developing mammalian visual cortex were dominated by study of the consequences of altered early visual experience in cats and nonhuman primates. The neural deficits thus revealed also provided insight into the origin and neural basis of human amblyopia that in turn motivated additional studies of humans with abnormal early visual input. Recent human studies point to deficits arising from alterations in all visual cortical areas and even in nonvisual cortical regions. As the new human data accumulated in parallel with a near-complete shift toward the use of rodent animal models for the study of neural mechanisms, it is now essential to review the human data and the earlier animal data obtained from cats and monkeys to infer general conclusions and to optimize future choice of the most appropriate animal model.

Optical Coherence Tomography Analysis of Macular Thickness in Children with Amblyopia

Purpose: To compare central, inner and outer ring macular thickness measured with optic coherence tomography (OCT) in children with unilateral amblyopia. To analyze the differences in retinal structure among strabismic, anisometropic and combined (strabismus + anisometropia) amblyopia. Background: Amblyopia is a reduction of visual acuity in one or both eyes due to an abnormal visual input during the development of the visual system. It is mainly caused by strabismus, anisometropia or high bilateral refractive errors, and visual deprivation. Although it has been always said that the amblyopic eye is an otherwise healthy eye, the imaging techniques developed lately, especially OCT and angio OCT, may show differences in retinal structures that could have a role in the development of amblyopia and/or its response to treatment. Methods: Retrospective review of amblyopic children followed up in our hospital. 60 children with unilateral amblyopia due to anisometropia and/or strabismus, with a good quality OCT exam, were included. We analyzed 9 thickness measurements: central macular thickness (1mm ring) and 4 sectors in inner (3mm) and outer (6mm) rings. Results: Data from 60 children is included. Mean retinal thickness at the central 1mm ring was 249.15µm for amblyopic eyes vs 238.3µm for fellow eye (p=0.000). For the thickness in the other 8 sectors for inner and outer rings no statistically significant differences were found. The central retina measurement was thicker in the anisometropic amblyopia group (p=0.003), but no statistically significant difference was found in the strabismic (p=0.066) and combined group (p=0.055). Conclusions: Central retinal thickness was significantly greater in amblyopic eyes compared to fellow eyes. This difference in thickness is also statistically significant in patients with anisometropia but not in those with strabismus or strabismus + anisometropia. Further studies with more patients are recommended.

Tract-based spatial statistics analysis of white matter changes in children with anisometropic amblyopia

Amblyopia is a neurological disorder of vision that follows abnormal binocular interaction or visual deprivation during early life. Previous studies have reported multiple functional or structural cortical alterations. Although white matter was also studied, it still cannot be clarified clearly which fasciculus was affected by amblyopia. In the present study, tract-based spatial statistics analysis was applied to diffusion tensor imaging (DTI) to investigate potential diffusion changes of neural tracts in anisometropic amblyopia. Fractional anisotropy (FA) value was calculated and compared between 20 amblyopic children and 18 healthy age-matched controls. In contrast to the controls, significant decreases in FA values were found in right optic radiation (OR), left inferior longitudinal fasciculus/inferior fronto-occipital fasciculus (ILF/IFO) and right superior longitudinal fasciculus (SLF) in the amblyopia. Furthermore, FA values of these identified tracts showed positive correlation with visual acuity. It can be inferred that abnormal visual input not only hinders OR from well developed, but also impairs fasciculi associated with dorsal and ventral visual pathways, which may be responsible for the amblyopic deficiency in object discrimination and stereopsis. Increased FA was detected in right posterior part of corpus callosum (CC) with a medium effect size, which may be due to compensation effect. DTI with subsequent measurement of FA is a useful tool for investigating neuronal tract involvement in amblyopia.

Gross topographic organization in the corpus callosum is preserved despite abnormal visual input.

Gross topographic organization in the corpus callosum is preserved despite abnormal visual input.

Visual deprivation: mechanism and practical applications

AbstractMaturation of the visual system is incomplete at birth. Visual deprivation mechanism, amblyopia, or ocular misalignment, leads to abnormalities in visual development, including abnormal eyeball growth and neurological changes. The current knowledge on ocular conditions related to abnormal visual development in infants, includes prevalence, risk factors, causes, and mechanisms involved. The role of eyeball growth with pathologic mechanism of visual deprivation and development of amblyopia in infants appears essential to be analyzed. Particular developmental issues in preterm neonates, methods of visual assessment and screening, diagnosis, treatment, and nutritional issues will be discussed. Visual deprivation mechanism, amblyopia, or ocular misalignment, leads to abnormalities in visual development, including abnormal eyeball growth and neurological changes. Abnormal visual input can lead to abnormalities in visual development, which can become permanent visual impairment if left untreated. Reduce the risk of abnormal visual development and prevent long‐term or permanent visual deficits needs an early screening and a better understanding of the complex impairment mechanisms.

The case from animal studies for balanced binocular treatment strategies for human amblyopia

Although amblyopia typically manifests itself as a monocular condition, its origin has long been linked to unbalanced neural signals from the two eyes during early postnatal development, a view confirmed by studies conducted on animal models in the last 50 years. Despite recognition of its binocular origin, treatment of amblyopia continues to be dominated by a period of patching of the non-amblyopic eye that necessarily hinders binocular co-operation. This review summarizes evidence from three lines of investigation conducted on an animal model of deprivation amblyopia to support the thesis that treatment of amblyopia should instead focus upon procedures that promote and enhance binocular co-operation. First, experiments with mixed daily visual experience in which episodes of abnormal visual input were pitted against normal binocular exposure revealed that short exposures of the latter offset much longer periods of abnormal input to allow normal development of visual acuity in both eyes. Second, experiments on the use of part-time patching revealed that purposeful introduction of episodes of binocular vision each day could be very beneficial. Periods of binocular exposure that represented 30-50% of the daily visual exposure included with daily occlusion of the non-amblyopic could allow recovery of normal vision in the amblyopic eye. Third, very recent experiments demonstrate that a short 10 day period of total darkness can promote very fast and complete recovery of visual acuity in the amblyopic eye of kittens and may represent an example of a class of artificial environments that have similar beneficial effects. Finally, an approach is described to allow timing of events in kitten and human visual system development to be scaled to optimize the ages for therapeutic interventions.

Sparse Coding Can Predict Primary Visual Cortex Receptive Field Changes Induced by Abnormal Visual Input

Receptive fields acquired through unsupervised learning of sparse representations of natural scenes have similar properties to primary visual cortex (V1) simple cell receptive fields. However, what drives in vivo development of receptive fields remains controversial. The strongest evidence for the importance of sensory experience in visual development comes from receptive field changes in animals reared with abnormal visual input. However, most sparse coding accounts have considered only normal visual input and the development of monocular receptive fields. Here, we applied three sparse coding models to binocular receptive field development across six abnormal rearing conditions. In every condition, the changes in receptive field properties previously observed experimentally were matched to a similar and highly faithful degree by all the models, suggesting that early sensory development can indeed be understood in terms of an impetus towards sparsity. As previously predicted in the literature, we found that asymmetries in inter-ocular correlation across orientations lead to orientation-specific binocular receptive fields. Finally we used our models to design a novel stimulus that, if present during rearing, is predicted by the sparsity principle to lead robustly to radically abnormal receptive fields.

Postural stability changes during large vertical diplopia induced by prism wear in normal subjects.

To test the effect of double vision on postural stability, we measured postural stability by electric stabilometry before prism-wearing and immediately, 15, 30, and 60min after continuous prism-wearing with 6 prism diopters in total (a 3-prism-diopter prism placed with the base up in front of one eye and with the base down in front of the other eye) in 20 normal adult individuals with their eyes open or closed. Changes in stabilometric parameters in the time course of 60min were analyzed statistically by repeated-measure analysis of variance. When subjectsｾ eyes were closed, the total linear length (cm) and the unit-time length (cm/sec) of the sway path were significantly shortened during the 60-minute prism-wearing (p＜0.05). No significant change was noted in any stabilometric parameters obtained with the eyes open during the time course. In conclusion, postural stability did not change with the eyes open in the condition of large vertical diplopia, induced by prism-wearing for 60min, while the stability became better when measured with the eyes closed. A postural control mechanism other than that derived from visual input might be reinforced under abnormal visual input such as non-fusionable diplopia.

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%1-3, the majority of cases being monocular2. Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation. Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself4,5 . Amblyopia is characterized by both monocular and binocular deficits6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions8. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia9,10 . Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations. In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15.

The Measurement and Treatment of Suppression in Amblyopia

Amblyopia, a developmental disorder of the visual cortex, is one of the leading causes of visual dysfunction in the working age population. Current estimates put the prevalence of amblyopia at approximately 1-3%1-3, the majority of cases being monocular2. Amblyopia is most frequently caused by ocular misalignment (strabismus), blur induced by unequal refractive error (anisometropia), and in some cases by form deprivation.Although amblyopia is initially caused by abnormal visual input in infancy, once established, the visual deficit often remains when normal visual input has been restored using surgery and/or refractive correction. This is because amblyopia is the result of abnormal visual cortex development rather than a problem with the amblyopic eye itself4,5 . Amblyopia is characterized by both monocular and binocular deficits6,7 which include impaired visual acuity and poor or absent stereopsis respectively. The visual dysfunction in amblyopia is often associated with a strong suppression of the inputs from the amblyopic eye under binocular viewing conditions8. Recent work has indicated that suppression may play a central role in both the monocular and binocular deficits associated with amblyopia9,10 .Current clinical tests for suppression tend to verify the presence or absence of suppression rather than giving a quantitative measurement of the degree of suppression. Here we describe a technique for measuring amblyopic suppression with a compact, portable device11,12 . The device consists of a laptop computer connected to a pair of virtual reality goggles. The novelty of the technique lies in the way we present visual stimuli to measure suppression. Stimuli are shown to the amblyopic eye at high contrast while the contrast of the stimuli shown to the non-amblyopic eye are varied. Patients perform a simple signal/noise task that allows for a precise measurement of the strength of excitatory binocular interactions. The contrast offset at which neither eye has a performance advantage is a measure of the "balance point" and is a direct measure of suppression. This technique has been validated psychophysically both in control13,14 and patient6,9,11 populations.In addition to measuring suppression this technique also forms the basis of a novel form of treatment to decrease suppression over time and improve binocular and often monocular function in adult patients with amblyopia12,15,16 . This new treatment approach can be deployed either on the goggle system described above or on a specially modified iPod touch device15.

Plasticity and Stability of the Visual System in Human Achiasma

The absence of the optic chiasm is an extraordinary and extreme abnormality in the nervous system. The abnormality produces highly atypical functional responses in the cortex, including overlapping hemifield representations and bilateral population receptive fields in both striate and extrastriate visual cortex. Even in the presence of these large functional abnormalities, the effect on visual perception and daily life is not easily detected. Here, we demonstrate that in two achiasmic humans the gross topography of the geniculostriate and occipital callosal connections remains largely unaltered. We conclude that visual function is preserved by reorganization of intracortical connections instead of large-scale reorganizations of the visual cortex. Thus, developmental mechanisms of local wiring within cortical maps compensate for the improper gross wiring to preserve function in human achiasma.

The Effect of Video Game Training on the Vision of Adults with Bilateral Deprivation Amblyopia

Amblyopia is a condition involving reduced acuity caused by abnormal visual input during a critical period beginning shortly after birth. Amblyopia is typically considered to be irreversible during adulthood. Here we provide the first demonstration that video game training can improve at least some aspects of the vision of adults with bilateral deprivation amblyopia caused by a history of bilateral congenital cataracts. Specifically, after 40 h of training over one month with an action video game, most patients showed improvement in one or both eyes on a wide variety of tasks including acuity, spatial contrast sensitivity, and sensitivity to global motion. As well, there was evidence of improvement in at least some patients for temporal contrast sensitivity, single letter acuity, crowding, and feature spacing in faces, but not for useful field of view. The results indicate that, long after the end of the critical period for damage, there is enough residual plasticity in the adult visual system to effect improvements, even in cases of deep amblyopia caused by early bilateral deprivation.

Binocular maps in Xenopus tectum: Visual experience and the development of isthmotectal topography

Xenopus frogs have a prominent binocular field that develops as a consequence of the migration of the eyes during the remodeling of the head during and after metamorphosis. In the optic tectum, a topographic representation of the ipsilateral eye develops during this same period. It is relayed indirectly, via the nucleus isthmi. In the early stages of binocular development, the topographic matching of the ipsilateral input to the retinotectal input from the contralateral eye is largely governed by chemical cues, but the ultimate determinant of the ipsilateral map is binocular visual input. Visual input is such a dominant factor that abnormal visual input resulting from unilateral eye rotation can induce isthmotectal axons to alter their trajectories dramatically, even shifting their terminal zones from one pole of the tectum to the other. This plasticity normally is high only during a 3-4-month critical period of late tadpole-early juvenile life, but the critical period can be extended indefinitely by dark-rearing. N-methyl-D-aspartate (NMDA) receptors are involved in this process; plasticity can be blocked or promoted by chronic treatment with NMDA antagonists or agonists, respectively. Cholinergic nicotinic receptors on retinotectal axons are likely to play an essential role as well. Modifications in the polysialylation of neural cell adhesion molecule are correlated with the state of plasticity. The circuitry underlying binocular plasticity is not yet fully understood but has proved not to be a simple convergence of ipsilateral and contralateral inputs onto the same targets.

Visual development in infants: physiological and pathological mechanisms

This review summarizes current knowledge on ocular conditions related to abnormal visual development in infants, including prevalence, risk factors, causes, and mechanisms involved. We discuss the role of eyeball growth with pathologic mechanism of visual deprivation and development of amblyopia in infants, particular developmental issues in preterm neonates, methods of visual assessment and screening, diagnosis, treatment, and nutritional issues. Visual development is incomplete at birth, particularly in premature infants; maturation of the visual system--including neurological and ocular components--is influenced by many factors including prenatal and postnatal nutrition and postnatal visual stimulation. In early life, particularly during sensitive periods of development, abnormal visual input, for example caused by visual deprivation mechanism, amblyopia, or ocular misalignment, leads to abnormalities in visual development, including abnormal eyeball growth and neurological changes. Untreated anomalies or abnormal visual development can result in long-term or even permanent visual impairment. Nutrition plays a key role in visual development: infant formulas containing nutrients essential for normal visual development (specifically omega-3 fatty acid docosahexaenoic acid and omega-6 fatty acid arachidonic acid) may protect nonbreast-fed infants against visual development abnormalities. Problems related to visual anomalies are common among young children, particularly in preterm neonates. Screening to enable early diagnosis and correction of visual deficiency is important as abnormal visual input can lead to abnormalities in visual development, which can become permanent visual impairment if left untreated. Optimized nutrition can help to reduce the risk of abnormal visual development and prevent long-term or permanent visual deficits.

Cortical Maps and White Matter Tracts following Long Period of Visual Deprivation and Retinal Image Restoration

Abnormal visual input during development has dramatic effects on the visual system. How does the adult visual system respond when input is corrected? MM lost his left eye and became blind in the right due to corneal damage at the age of 3. At age 46, MM regained his retinal image, but his visual abilities, even seven years following the surgery, remain severely limited, and he does not rely on vision for daily life. Neuroimaging measurements reveal several differences among MM, sighted controls, sighted monocular, and early blind subjects. We speculate that these differences stem from damage during the critical period in development of retinal neurons with small, foveal receptive fields. In this case, restoration of functional vision requires more than improving retinal image contrast. In general, visual restoration will require accounting for the developmental trajectory of the individual and the consequences of the early deprivation on cortical circuitry.

Effects of Early Pattern Deprivation on Visual Development

Studies of children treated for dense cataract shed light on the extent to which pattern stimulation drives normal visual development and whether there are sensitive periods during which an abnormal visual environment is especially detrimental. Here, we summarize the findings to date into five general principles: (1) At least for low-level vision, aspects of vision that develop the earliest are the least likely to be adversely affected by abnormal visual input whereas those that develop later are affected more severely. (2) Early visual input is necessary to preserve the neural infrastructure for later visual learning, even for visual capabilities that will not appear until later in development. (3) The development of both the dorsal and ventral streams depends on normal visual input. (4) After monocular deprivation has been treated by surgical removal of the cataractous lens, the interactions between the aphakic and phakic eyes are competitive for low-level vision but are complementary for high-level vision. (5) There are multiple sensitive periods during which experience can influence visual development.The studies described here have important implications for understanding normal development. They indicate that patterned visual input immediately after birth plays a vital role in the construction and preservation of the neural architecture that will later mediate sensitivity to both basic and higher level aspects of vision. The period during which patterned visual input is necessary for normal visual development varies widely across different aspects of vision and can range from only a few months after birth to more than the first 10 years of life. The results point to new research questions on why early visual deprivation can cause later deficits, what limits adult plasticity, and whether effective rehabilitation in other areas can provide new clues for the treatment of amblyopia.

Paediatric cataract surgery

Bilateral congenital cataract is the most common cause of treatable childhood blindness. Nuclear cataract is usually present at birth and is non-progressive, while lamellar cataract usually develops later and is progressive. Prompt surgery has to be performed in cases with dense congenital cataract: if nystagmus has developed, the amblyopia is unfortunately irreversible. A treatment regime based on surgery within 2 months of life, combined with prompt optical correction of the aphakia and occlusion therapy with frequent follow-up, have been successful in both unilateral and bilateral cases. The surgery ought to include anterior and posterior capsulorexis in all children at the present time. Intraocular lens implantation has been safely performed below the age of 1 year and has also been successfully performed in bilateral cases. Anterior dry vitrectomy should be performed in preschool children to avoid visual axis opacification. Visual axis opacification is the most common complication found after cataract surgery in children. Secondary glaucoma is by far the most sight-threatening complication and is, unfortunately, common in the newborn so lifelong follow-up is essential in these cases.

Short periods of concordant binocular vision prevent the development of deprivation amblyopia

Based in part on deprivation studies, it is generally agreed that the development of vision and of the central visual pathways of higher mammals such as cats and primates is experience-dependent. Past deprivation experiments employed periods of exclusively abnormal early visual input. Because of the absence of any normal visual input, such studies indicate only the extremes to which the visual system can change in response to visually driven activity (i.e. its capabilities) rather than provide insight into the role of early visual input in normal development (i.e. what it actually does). We examined the possibility that certain visual input, i.e. normal concordant binocular vision, may be more efficacious than others with respect to its effects on the developing visual system and on vision. On a daily basis, one type of visual input, i.e. normal binocular experience (BE), was pitted against abnormal (monocular exposure, ME) input in order to see if one was more effective. We show that 2 h of daily normal concordant, but not discordant, BE outweighs or protects against as much as 5 h of daily abnormal input to permit the development of normal grating acuity and alignment accuracy in the two eyes. Further, we show that splitting the period of BE into two 1-h periods straddling the period of ME was ineffective, thereby indicating the 2 h of BE each day must be continuous to protect against the development of amblyopia.

Form deprivation modulates retinal neurogenesis in primate experimental myopia

Juvenile primates develop myopia when their visual experience is degraded by lid fusion. In response to this abnormal visual input, retinal neural networks cause an excessive growth of the postequatorial segment of the eye, but the mechanism underlying this axial elongation is unknown. After fusion of the lids in one eye of juvenile rhesus macaques and green monkeys, we combined cDNA subtractions, microarray profiling, and real-time PCR to compare gene expression in the retinas of the closed and open eyes. This molecular analysis showed up-regulation of a number of genes associated with cell division in the retina of the closed eye and differential expression of six genes localized to chromosomal loci linked to forms of human hereditary myopia. In addition, it substantiated a previous observation, based on immunocytochemistry, that synthesis of vasoactive intestinal polypeptide was increased upon lid fusion. Injection of 5-bromo-2'-deoxyuridine and immunocytochemistry showed that the primate retinal periphery harbors mitotically active neuroprogenitor cells that increase in number when the visual experience is altered by lid fusion. Furthermore, the number of dividing cells is highly correlated with axial elongation of the eye and the resulting myopic refractive error. Thus, the retina undergoes active growth during the postnatal development of the primate eye. This growth is modulated by the visual input and accelerates considerably when the eye develops axial myopia. Vasoactive intestinal polypeptide may be the molecule that stimulates retinal growth.