Amblyopia is one of the most common forms of visual impairment, arising from an early functional imbalance between the two eyes. It is currently accepted that, due to a lack of neural plasticity,amblyopia is an untreatable pathology in adults. Environmental enrichment (EE) emerged as a strategy highly effective in restoring plasticity in adult animals, eliciting recovery from amblyopia through a reduction of intracortical inhibition. It is unknown whether single EE components are able to promote plasticity in the adult brain, crucial information for designing new protocols of environmental stimulation suitable for amblyopic human subjects. Here, we assessed the effects of enhanced physical exercise,increased social interaction, visual enrichment or perceptual learning on visual function recovery in adult amblyopic rats. We report a complete rescue of both visual acuity and ocular dominance in exercised rats, in animals exposed to visual enrichment and in animals engaged in perceptual learning.These effects were accompanied by a reduced inhibition/excitation balance in the visual cortex. In contrast, we did not detect any sign of recovery in socially enriched rats or in animals practicing a purely associative visual task. These findings could have a bearing in orienting clinical research in the field of amblyopia therapy.

Brain aging is characterized by functional deterioration across multiple systems, associated to a progressive decay of neural plasticity. Here, we explored environmental enrichment (EE), a condition of enhanced sensory-motor and cognitive stimulation, as a strategy to restore plasticity processes in the old brain. Visual system is one of the paradigmatic models for studying experience-dependent plasticity. While reducing input from one eye through monocular deprivation induces a marked ocular dominance (OD) shift of neurons in the primary visual cortex during development, the same manipulation is totally ineffective after the closure of the critical period. We show that EE is able to reactivate OD plasticity in the visual cortex of aging rats, as assessed with both visual-evoked potentials and single-unit recordings. A marked reduction in intracortical GABAergic inhibition and a remodeling of extracellular matrix accompany this effect. The non-invasive nature of EE makes this paradigm eligible for human application.

The influence of maternal environment on fetal development is largely unexplored, the available evidence concerns only the deleterious effects elicited by prenatal stress. Here we investigated the influence of prenatal enrichment on the early development of the visual system in the fetus. We studied the anatomical development of the rat retina, by analyzing the migration of neural progenitors and the process of retinal ganglion cell death, which exerts a key role in sculpturing the developing retinal system at perinatal ages. The number of apoptotic cells in the retinal ganglion cell layer was analyzed using two distinct methods: the presence of pyknotic nuclei stained for cresyl violet and the appearance of DNA fragmentation (Tunel method). We report that environmental enrichment of the mother during pregnancy affects the structural maturation of the retina, accelerating the migration of neural progenitors and the dynamics of natural cell death. These effects seem to be under the control of insulin-like growth factor-I: its levels, higher in enriched pregnant rats and in their milk, are increased also in their offspring, its neutralization abolishes the action of maternal enrichment on retinal development and chronic insulin-like growth factor-I injection to standard-reared females mimics the effects of enrichment in the fetuses. Thus, the development of the visual system is sensitive to environmental stimulation during prenatal life. These findings could have a bearing in orienting clinical research in the field of prenatal therapy.

Loss of visual acuity caused by abnormal visual experience during development (amblyopia) is an untreatable pathology in adults. We report that environmental enrichment in adult amblyopic rats restored normal visual acuity and ocular dominance. These effects were due to reduced GABAergic inhibition in the visual cortex, accompanied by increased expression of BDNF and reduced density of extracellular-matrix perineuronal nets, and were prevented by enhancement of inhibition through benzodiazepine cortical infusion.

Down syndrome (DS) is the most common genetic disorder associated with mental retardation. It has been repeatedly shown that Ts65Dn mice, the prime animal model for DS, have severe cognitive and neural plasticity defects due to excessive inhibition. We report that increasing sensory-motor stimulation in adulthood through environmental enrichment (EE) reduces brain inhibition levels and promotes recovery of spatial memory abilities, hippocampal synaptic plasticity, and visual functions in adult Ts65Dn mice.

Amblyopia is the most common form of impairment of visual function affecting one eye, with a prevalence of about 1-5% of the total world population. This pathology is caused by early abnormal visual experience with a functional imbalance between the two eyes owing to anisometropia, strabismus, or congenital cataract, resulting in a dramatic loss of visual acuity in an apparently healthy eye and various other perceptual abnormalities, including deficits in contrast sensitivity and in stereopsis. It is currently accepted that, due to a lack of sufficient plasticity within the brain, amblyopia is untreatable in adulthood. However, recent results obtained both in clinical trials and in animal models have challenged this traditional view, unmasking a previously unsuspected potential for promoting recovery after the end of the critical period for visual cortex plasticity. These studies point toward the intracortical inhibitory transmission as a crucial brake for therapeutic rehabilitation and recovery from amblyopia in the adult brain.

One major goal in Neuroscience is the development of strategies promoting neural plasticity in the adult central nervous system, when functional recovery from brain disease and injury is limited. New evidence has underscored a pivotal role for cortical inhibitory circuitries in regulating plasticity both during development and in adulthood. This paper summarizes recent findings showing that the inhibition-excitation balance controls adult brain plasticity and is at the core of the pathogenesis of neurodevelopmental disorders like autism, Down syndrome, and Rett syndrome.

A crucial issue in neurobiology is to understand the main mechanisms restricting neural plasticity to brief windows of early postnatal life. The visual system is one of the paradigmatic models for studying experience-dependent plasticity. The closure of one eye (monocular deprivation, MD) causes a marked ocular dominance (OD) shift of neurons in the primary visual cortex only during the critical period. Here, we report that environmental enrichment (EE), a condition of increased sensory-motor stimulation, reactivates OD plasticity in the adult visual cortex, as assessed with both visual evoked potentials and single-unit recordings. This effect is accompanied by a marked increase in cerebral serotonin (5-HT) levels. Blocking 5-HT enhancement in the visual cortex of EE rats completely prevents the OD shift induced by MD. We also found that EE leads to a reduced intracortical GABAergic inhibition and an increased BDNF expression and that the modulation of these molecular factors is neutralized by cortical infusion of the 5-HT synthesis inhibitor pCPA. Our results show that EE rejuvenates the adult visual cortex and that 5-HT is a crucial factor in this process, triggering a cascade of molecular events that allow the reinstatement of neural plasticity. The non-invasive nature of EE makes this paradigm particularly eligible for clinical application.

Experience is required for the shaping and refinement of developing neural circuits during well defined periods of early postnatal development called critical periods. Many studies in the visual cortex have shown that intracortical GABAergic circuitry plays a crucial role in defining the time course of the critical period for ocular dominance plasticity. With the end of the critical period, neural plasticity wanes and recovery from the effects of visual defects on visual acuity (amblyopia) or binocularity is much reduced or absent. Recent results pointed out that intracortical inhibition is a fundamental limiting factor for adult cortical plasticity and that its reduction by means of different pharmacological and environmental strategies makes it possible to greatly enhance plasticity in the adult visual cortex, promoting ocular dominance plasticity and recovery from amblyopia. Here we focus on the role of intracortical GABAergic circuitry in controlling both developmental and adult cortical plasticity. We shall also discuss the potential clinical application of these findings to neurological disorders in which synaptic plasticity is compromised because of excessive intracortical inhibition.

Environmental enrichment strongly affects visual system maturation both at retinal and cortical levels. Which molecular pathways are activated by an enriched environment (EE) to regulate visual system development has not been clarified. Here, we show that early [postnatal day 1 (P1) to P7] insulin-like growth factor 1 (IGF-1) injections in the eyes of non-EE rat pups mimic EE effects both in increasing BDNF levels in the retinal ganglion cell layer at P10 and in determining a more adult-like retinal acuity, assessed with pattern electroretinogram at P25. Blocking IGF-1 action in EE animals during the same early postnatal time window by injecting the IGF-1 receptor antagonist JB1 prevents EE effects both on BDNF expression and on retinal acuity maturation. Reducing BDNF expression in the retina of IGF-1-treated rats prevents IGF-1 effects on retinal acuity development. Finally, we show that tyrosine hydroxylase (TH) expression is increased in the retina of P10 EE and IGF-1-treated rats and that blocking TH expression in EE animals prevents EE from affecting retinal acuity development. Thus, early levels of IGF-1 play a key role in mediating EE effects on retinal development through an action that requires BDNF and involves dopaminergic amacrine cell network.

Amblyopia is one of the most common forms of visual impairment, arising from an early functional imbalance between the two eyes. It is currently accepted that, due to a lack of neural plasticity,amblyopia is an untreatable pathology in adults. Environmental enrichment (EE) emerged as a strategy highly effective in restoring plasticity in adult animals, eliciting recovery from amblyopia through a reduction of intracortical inhibition. It is unknown whether single EE components are able to promote plasticity in the adult brain, crucial information for designing new protocols of environmental stimulation suitable for amblyopic human subjects. Here, we assessed the effects of enhanced physical exercise,increased social interaction, visual enrichment or perceptual learning on visual function recovery in adult amblyopic rats. We report a complete rescue of both visual acuity and ocular dominance in exercised rats, in animals exposed to visual enrichment and in animals engaged in perceptual learning.These effects were accompanied by a reduced inhibition/excitation balance in the visual cortex. In contrast, we did not detect any sign of recovery in socially enriched rats or in animals practicing a purely associative visual task. These findings could have a bearing in orienting clinical research in the field of amblyopia therapy.

Brain aging is characterized by functional deterioration across multiple systems, associated to a progressive decay of neural plasticity. Here, we explored environmental enrichment (EE), a condition of enhanced sensory-motor and cognitive stimulation, as a strategy to restore plasticity processes in the old brain. Visual system is one of the paradigmatic models for studying experience-dependent plasticity. While reducing input from one eye through monocular deprivation induces a marked ocular dominance (OD) shift of neurons in the primary visual cortex during development, the same manipulation is totally ineffective after the closure of the critical period. We show that EE is able to reactivate OD plasticity in the visual cortex of aging rats, as assessed with both visual-evoked potentials and single-unit recordings. A marked reduction in intracortical GABAergic inhibition and a remodeling of extracellular matrix accompany this effect. The non-invasive nature of EE makes this paradigm eligible for human application.

This study examined the effects of amblyopia on perceptual decision-making processes to determine the consequences of visual deprivation on the development of higher level cortical networks outside of the visual cortex. A variant of the Eriksen flanker task was used to measure response time and accuracy for decisions made in the presence of response-selection conflict. Performance of adults with amblyopia was compared to that of neurotypical participants of the same age. Additionally, simple and choice reaction time tasks presented in the visual and the auditory modality were used to control for factors such as feature visibility, crowding, and motor execution speed. A selective deficit in response time for visual decisions was found when individuals with amblyopia used either the amblyopic or non-amblyopic (dominant) eye, and this deficit was independent of visual acuity, motor time, and performance accuracy. In trial conditions that provoked response-selection conflict, responses were significantly delayed in amblyopic relative to neurotypical participants and were not subject to standard trial sequence effects. Our results indicate that, beyond the known effects of abnormal visual experience on visual cortex, suboptimal binocular input during a developmental critical period may also impact cortical connections to downstream areas of the brain, including parietal and frontal cortices, that are believed to underlie decision and response-selection processes.

Amblyopia is the most common form of impairment of visual function affecting one eye, with a prevalence of about 1-5% of the total world population. This pathology is caused by early abnormal visual experience with a functional imbalance between the two eyes owing to anisometropia, strabismus, or congenital cataract, resulting in a dramatic loss of visual acuity in an apparently healthy eye and various other perceptual abnormalities, including deficits in contrast sensitivity and in stereopsis. It is currently accepted that, due to a lack of sufficient plasticity within the brain, amblyopia is untreatable in adulthood. However, recent results obtained both in clinical trials and in animal models have challenged this traditional view, unmasking a previously unsuspected potential for promoting recovery after the end of the critical period for visual cortex plasticity. These studies point toward the intracortical inhibitory transmission as a crucial brake for therapeutic rehabilitation and recovery from amblyopia in the adult brain.

The rodents are an excellent model for understanding the development and plasticity of the visual system. In this study, we explored the feasibility of Mn-enhanced MRI (MEMRI) and diffusion tensor imaging (DTI) at 7 T for in vivo and longitudinal assessments of the retinal and callosal pathways in normal neonatal rodent brains and after early postnatal visual impairments. Along the retinal pathways, unilateral intravitreal Mn2+ injection resulted in Mn2+ uptake and transport in normal neonatal visual brains at postnatal days (P) 1, 5 and 10 with faster Mn2+ clearance than the adult brains at P60. The reorganization of retinocollicular projections was also detected by significant Mn2+ enhancement by 2%-10% in the ipsilateral superior colliculus (SC) of normal neonatal rats, normal adult mice and adult rats after neonatal monocular enucleation (ME) but not in normal adult rats or adult rats after monocular deprivation (MD). DTI showed a significantly higher fractional anisotropy (FA) by 21% in the optic nerve projected from the remaining eye of ME rats compared to normal rats at 6 weeks old, likely as a result of the retention of axons from the ipsilaterally uncrossed retinal ganglion cells, whereas the anterior and posterior retinal pathways projected from the enucleated or deprived eyes possessed lower FA after neonatal binocular enucleation (BE), ME and MD by 22%-56%, 18%-46% and 11%-15% respectively compared to normal rats, indicative of neurodegeneration or immaturity of white matter tracts. Along the visual callosal pathways, intracortical Mn2+ injection to the visual cortex of BE rats enhanced a larger projection volume by about 74% in the V1/V2 transition zone of the contralateral hemisphere compared to normal rats, without apparent DTI parametric changes in the splenium of corpus callosum. This suggested an adaptive change in interhemispheric connections and spatial specificity in the visual cortex upon early blindness. The results of this study may help determine the mechanisms of axonal uptake and transport, microstructural reorganization and functional activities in the living visual brains during development, diseases, plasticity and early interventions in a global and longitudinal setting.

BACKGROUND Non-invasive current stimulation can induce neuroplastic changes in the normal brain, including visual system structures. Because it is not known if such plasticity is of clinical value, we wished to learn if vision restoration can be induced after optic nerve damage. METHODS In an open-label, clinical observational study 446 patients with optic nerve lesions were treated with non-invasive repetitive transorbital alternating current stimulation (rtACS). Current bursts (<1000 μA, 5-20 Hz) were applied to induce phosphenes for one or two 10-day stimulation periods. Efficacy was assessed by monocular measurements of visual acuity and visual field (VF) size. EEG recordings at rest (n = 68) were made before and after treatment and global power spectra changes were analyzed. RESULTS rtACS improved VF size in the right and left eye by 7.1% and 9.3%(p < 0.001), respectively. VF enlargements were present in 40.4% of right and 49.5% of left eyes. Visual acuity (VA) significantly increased in both eyes (right = 0.02, left = 0.015; p < 0.001). A second 10-day course was conducted 6 months in a subset of 62 patients and resulted in additional significant improvements of VA. Analysis of EEG power spectra revealed that VA and VF improvements were associated with increased alpha power. Increased theta power was observed in patients that had only VF enlargements but no VA change. In contrast, non-responders had increased delta power spectra in frontal and occipital areas. CONCLUSIONS rtACS leads to long-lasting improvements in VA and VF size and after-effects in EEG power spectra. Because physiological and clinical parameters are correlated we hypothesize that rtACS enhances plasticity by inducing synchronization in different cortical regions, but the precise mechanisms needs further clarification. These encouraging results require confirmation by controlled clinical trials.

Abnormal visual experience during a sensitive period of development disrupts neuronal circuitry in the visual cortex and results in abnormal spatial vision or amblyopia. Here we examined whether playing video games can induce plasticity in the visual system of adults with amblyopia. Specifically 20 adults with amblyopia (age 15-61 y; visual acuity: 20/25-20/480, with no manifest ocular disease or nystagmus) were recruited and allocated into three intervention groups: action videogame group (n = 10), non-action videogame group (n = 3), and crossover control group (n = 7). Our experiments show that playing video games (both action and non-action games) for a short period of time (40-80 h, 2 h/d) using the amblyopic eye results in a substantial improvement in a wide range of fundamental visual functions, from low-level to high-level, including visual acuity (33%), positional acuity (16%), spatial attention (37%), and stereopsis (54%). Using a cross-over experimental design (first 20 h: occlusion therapy, and the next 40 h: videogame therapy), we can conclude that the improvement cannot be explained simply by eye patching alone. We quantified the limits and the time course of visual plasticity induced by video-game experience. The recovery in visual acuity that we observed is at least 5-fold faster than would be expected from occlusion therapy in childhood amblyopia. We used positional noise and modelling to reveal the neural mechanisms underlying the visual improvements in terms of decreased spatial distortion (7%) and increased processing efficiency (33%). Our study had several limitations: small sample size, lack of randomization, and differences in numbers between groups. A large-scale randomized clinical study is needed to confirm the therapeutic value of video-game treatment in clinical situations. Nonetheless, taken as a pilot study, this work suggests that video-game play may provide important principles for treating amblyopia, and perhaps other cortical dysfunctions. TRIAL REGISTRATION: ClinicalTrials.gov NCT01223716.

Mucoceles are chronic non-neoplastic cystic lesions lined by mucus-secreting respiratory epithelium in the paranasal sinuses. Mucocele of the anterior clinoid process is a particularly rare entity most often presenting with rapidly progressive monocular blindness. The authors describe the case of a 32 year-old man who presented with acute painless visual loss in the left eye. Workup revealed an expansile lesion of the left anterior clinoid process with associated optic nerve compression. The patient underwent emergent endoscopic-assisted transnasal decompression of the optic nerve with full recovery of visual function. Early diagnosis and prompt surgical intervention optimizes the chances of functional regain of visual acuity.

Animal model studies of amblyopia have generally concluded that enduring effects of monocular deprivation (MD) on visual behavior (i.e., loss of visual acuity) are limited to the deprived eye, and are restricted to juvenile life. We have previously reported, however, that lasting effects of MD on visual function can be elicited in adulthood by stimulating visuomotor experience through the non-deprived eye. To test whether stimulating experience would also induce interocular plasticity of vision in infancy, we assessed in rats from eye-opening on postnatal day (P) 15, the effect of pairing MD with the daily experience of measuring thresholds for optokinetic tracking (OKT). MD with visuomotor experience from P15 to P25 led to a ~60% enhancement of the spatial frequency threshold for OKT through the non-deprived eye during the deprivation, which was followed by loss-of-function (~60% below normal) through both eyes when the deprived eye was opened. Reduced thresholds were maintained into adulthood with binocular OKT experience from P25 to P30. The ability to generate the plasticity and maintain lost function was dependent on visual cortex. Strictly limiting the period of deprivation to infancy by opening the deprived eye at P19 resulted in a comparable loss-of-function. Animals with reduced OKT responses also had significantly reduced visual acuity, measured independently in a discrimination task. Thus, experience-dependent cortical plasticity that can lead to amblyopia is present earlier in life than previously recognized.