What simple brains teach us about how vision works. Amblyopia usually derives from conditions of early functional imbalance between the two eyes, owing to anisometropia, strabismus, or congenital cataract, and results in a pronounced reduction of visual acuity and severe deficits in contrast sensitivity and stereopsis. It is widely accepted that, due to a lack of sufficient plasticity in the adult brain, amblyopia becomes untreatable after the closure of the critical period in the primary visual cortex.
"Adult amblyopia treatment," recent results obtained both in animal models and in clinical trials have challenged this view, unmasking a previously unsuspected potential for promoting recovery even in adulthood. In this context, non invasive procedures based on visual perceptual learning, i. This review will survey recent work regarding the impact of visual perceptual learning on amblyopia, with a special focus on a new experimental model of perceptual learning in Adult amblyopia treatment amblyopic rat.
The rare amblyogenic condition called congenital or early-acquired media opacity causes a form of amblyopia Adult amblyopia treatment deprivation amblyopia, the most severe and damaging type of amblyopia.
In this case, cataracts, corneal lesions, or ptosis "Adult amblyopia treatment" or distort retinal image formation. Regardless of its etiology, amblyopia is usually unilateral: Associated Adult amblyopia treatment include poor stereoscopic depth perception, and low contrast sensitivity and reduced motion sensitivity in the weaker eye.
In the clinical setting, however, the damage produced by amblyopia is generally expressed as a loss of visual acuity in an apparently healthy eye, despite appropriate optical corrections. In contrast with early investigations indicating the retina as the primary site of amblyopia Hess,many studies have confirmed that the retina exhibits normal physiology in amblyopic subjects Sherman and Stone, ; Kratz et al.
The current consensus, however, is that amblyopia mostly originates from alterations in neural circuitries in the primary visual cortex V1; Levi and Harwerth, ; Blakemore and Vital-Durand, ; Hess, ; Barrett et al.
Development of visual system circuits depends on the interaction between genetic Adult amblyopia treatment and experience-driven plasticity processes Goodman and Shatz, ; Katz and Shatz,the latter being "Adult amblyopia treatment" for a proper refinement of neural circuits Weliky, ; Lewis and Maurer, Critical periods CPs are time windows in early postnatal life during which plasticity is enhanced and neural circuits display a heightened sensitivity to acquire instructive and adaptive signals from the external environment.
CPs for experience-dependent plasticity are widespread in the animal kingdom Berardi et al. It is now clear that there are different CPs not only for different functions even within the same sensory system; e.
The CP is not a simple, age-dependent maturational process, but is rather a series of critical developmental events "Adult amblyopia treatment" in a use-dependent manner. In agreement with this concept, a total absence of sensory inputs leads to a delay in the functional and anatomical maturation of the visual system. Moreover, animals reared from birth in complete darkness have a delayed CP time course, with abnormal levels of plasticity persisting into adulthood Mower, ; Fagiolini et al.
The CP for the development of amblyopia closes around 6—8 years of age in humans Worth, ; von Noorden, Alterations in visual experience caused by strabismus or high anisometropia with onset beyond this age do not result either in the severe loss of visual acuity for the affected eye or in the severe reduction in binocular vision caused by altered visual experience with an earlier onset.
What is more important, however, Adult amblyopia treatment that if the correction of strabismus or anisometropia is delayed past this age, recovery of visual acuity and binocular vision is almost absent; indeed, the magnitude of the recovery is progressively reduced as the corrective intervention is made at progressively increasing ages during childhood, with negligible recovery obtained after 8 years of age. That is, in addition to the occurrence of a CP for the establishment of amblyopia, there is also a sensitive period for a successful treatment of this pathology see Lewis and Maurer, Much of our current understanding of the neural mechanisms underlying amblyopia derives from studies on animal models, revealing that major pathological changes in this pathology occur at the cortical level.
In animal models, amblyopia can be easily induced by imposing a reduction of inputs from one by lid suture monocular deprivation, MD during the CP.
This treatment dramatically decreases V1 binocularity, shifting the physiological responsiveness of visual cortical neurons towards the open eye.
In their pioneering experiments, Hubel and Wiesel observed that, in kittens, the susceptibility to the effects of MD starts suddenly near the beginning of the fourth
Adult amblyopia treatment of life, remains robust between the sixth and eighth weeks, and then declines completely after the third month, thus defining a CP for MD effectiveness.
MD starting in adulthood produced no detectable outcome Hubel and Wiesel, ; Olson and Freeman, While the effects of MD can be reversed to Adult amblyopia treatment limited extent during the CP by reversing the condition of visual deprivation, the same deficits become irreversible later on Wiesel and Hubel, ; Movshon, ; Van Sluyters, ; Blakemore et al. At least in the mouse, this is due to a rapid weakening of the deprived-eye responses, accompanied by a delayed strengthening the open-eye responses which results from mechanisms of homeostatic plasticity Frenkel and Bear, ; Kaneko et al.
Anatomical changes accompany functional plasticity in the developing visual cortex of the mouse, as they do in higher mammals Antonini et al. Theoretically, the basic strategy for treating Adult amblyopia treatment is to provide a clear retinal image, and Adult amblyopia treatment to Adult amblyopia treatment the OD deficit, as early as possible, during the period of visual cortex plasticity. Occlusion therapy with patching of the dominant eye has been widely used as the primary treatment for amblyopia Loudon and Simonsz, The success of patching seems to correlate with the actual number of hours that the eye is patched Loudon et al.
Atropine penalization is recognized as a valid alternative to patching for amblyopia therapy Foley-Nolan et al.
Atropine paralyzes accommodation and blurs near vision, encouraging the use of the amblyopic eye. It has been reported that atropine is as effective as patching, but that patching effects are initially faster, while atropine displays Adult amblyopia treatment better compliance Pediatric Eye Disease Investigator Group, Another major difference between the two treatments is that in atropine penalization vision is binocular in the sense that the image at the fovea of the dominant eye is degraded, while input to the amblyopic eye is not affected; in contrast, binocularity is impaired in the patching treatment.
A better strategy might be to couple passive methods with treatments in which certain tasks are prescribed to be performed by the patient: Pleoptics is a method for visual diagnosis and training that employs monocular techniques for the detection and elimination of eccentric fixation and amblyopia: Typically, pleoptic treatments have to be performed several times a week in order to effectively enhance the Adult amblyopia treatment elicited by occlusion therapy.
Most practitioners, however, have found pleoptics to be no better than standard occlusion therapy VerLee and Iacobucci, ; Fletcher et al. Another proposed active procedure was the so called CAM treatment Campbell,consisting in a high contrast square wave grating that rotates slowly, at
Adult amblyopia treatment one revolution per minute. The treatment was based on the findings that spatial frequency and orientation-specific filters, in the visual system, are activated by rotation.
The CAM treatment was found not effective Keith et al. It has been established that Adult amblyopia treatment stimulation may be important for the treatment of amblyopia; indeed, animal research indicates that binocular stimulation promotes binocular cortical connections during recovery from deprivation amblyopia Mitchell and Sengpiel, Experimental models of patching therapy for amblyopia applied to animals rendered amblyopic by a prior period of early MD Adult amblyopia treatment that the benefits of a patching therapy can be heightened when combined with critical amounts of binocular visual input each day and Sengpiel, Recent studies Baker et al.
While amblyopia can often be reversed when treated early Wu and Hunter,successful treatments are not generally possible in adults. Treatments for amblyopia in adulthood are focused on promoting cortical plasticity by reducing those factors that actively limit adult plasticity, or by exploiting endogenous permissive factors; under Adult amblyopia treatment favorable conditions, circuit rewiring may be facilitated in the mature brain, inducing recovery from amblyopia.
Thus, several pharmacological attempts have been done to enhance adult visual cortical plasticity, acting on factors which are also thought to contribute to its developmental time course. For example, the onset of visual cortical plasticity is delayed by genetic disruption of GABA synthesis or a slowing down of the maturational state of perisomatic inhibition Hensch, Conversely, application of benzodiazepines or other treatments that accelerate GABA circuit function trigger premature plasticity Di Cristo et al.
These manipulations are so powerful that animals of identical chronological age may be at the peak, before, or past their sensitive period, depending on how the maturational state of their GABA circuitry has been altered. In agreement with this, a
Adult amblyopia treatment study showed that a pharmacological reduction of intracortical inhibition obtained through the infusion of either Adult amblyopia treatment an inhibitor of GABA synthesis or picrotoxin a GABA A antagonist directly into the visual cortex reactivates OD plasticity in response to MD in adult rats
Adult amblyopia treatment et al.
In agreement with this, it has been demonstrated that chronic treatment with Adult amblyopia treatment selective serotonine-reuptake inhibitor SSRI fluoxetine reinstates OD plasticity following MD and promotes recovery of normal visual functions in adult amblyopic animals, acting through a pronounced reduction of intracortical inhibition Maya Vetencourt et al.
Another recent indication that neuromodulatory systems affect plasticity in adulthood comes from the demonstration that a genetic Adult amblyopia treatment of nicotinic cholinergic transmission promotes visual cortex plasticity after the end of the CP Morishita et al. On the basis of recent findings indicating that environmental experience can lead to epigenetic modifications of brain chromatin status, use of epigenetic drugs can be a promising strategy also for recovery from amblyopia Zhang and Meaney, It has been shown that a developmental downregulation of experience-dependent regulation of histone H3 and H4 is involved in the closure of the CP Putignano et al.
Recently, Silingardi et al. Finally, following the demonstration that extracellular matrix penineuronal nets PNNs drastically limit adult brain plasticity Pizzorusso et al. These authors also found that the decrease in spine density caused by long-term MD was recovered by the chondroitinase ABC treatment, suggesting that a possible mechanism underlying the recovery from amblyopia could be the formation of synaptic contacts on the newly formed spines by the inputs from the formerly deprived eye.
Some of the effects elicited by chondroitinase ABC could be mediated by modifications of intracortical inhibitory circuits occurring after PNN degradation, bringing parvalbumin PV interneurons back to a more juvenile-like status Hensch, Strikingly, a specific transfer of the orthodenticle homeobox 2 Otx2 homeoprotein into GABAergic interneurons expressing PV has been shown to be a critical trigger for both the opening and closure of the CP of plasticity in the developing mouse visual cortex Sugiyama et al.
Endogenous Otx2 is captured by specific binding sites in PNNs placed on the surfaces of PV cells, with a short aminoacidic domain containing an arginine-lysine doublet, called RK peptide, directly mediating Otx2 binding to PNNs Beurdeley et al.
A better strategy for amblyopia treatment would be that to induce an endogenous recapitulation of the brain states that promote plasticity in a non-invasive but Adult amblyopia treatment manner.
Amblyopic rats subjected to complete visual deprivation by dark exposure for 10 days recover significant Adult amblyopia treatment once allowed to see binocularly, acting through a modulation of the balance between excitation and inhibition He et al. However, translation of this treatment to humans is debatable as the proportional length of dark exposure required is likely to be quite long.
A more promising approach is environmental enrichment EE. EE is an experimental protocol specifically designed to investigate the influence of the environment on brain and behavior Rosenzweig and Bennett, ; van Praag et al. Thus, EE aims at optimizing environmental stimulation by providing the animals with the opportunity to attain high levels of voluntary physical activity, spontaneous exploration, cognitive activity and social interaction.
We showed that EE promotes a complete recovery of visual acuity and OD in adult amblyopic animals Sale et Adult amblyopia treatment. Recovery of plasticity was associated with a marked reduction Adult amblyopia treatment GABAergic inhibition in the visual cortex, as assessed by brain microdialysis.
The reduction of cortical inhibition in EE rats was also paralleled by an increased expression of the neurotrophin BDNF and a lower density of PNNs in the visual cortex contralateral to the recovering previously amblyopic eye.
Perceptual learning PL is currently considered one of the most promising active strategies for treating amblyopia in adulthood. Perceptual learning is the improvement in performance on a variety of simple sensory tasks, following practice.
In visual perception, such tasks, often called discrimination tasks, involve identifying small differences in simple visual attributes, such as position, orientation, texture or shape.
Visual PL has been documented in a wide range of perceptual tasks: Training can improve the discrimination of small differences in the offset of two lines Vernier acuity Adult amblyopia treatment, even though initial thresholds are already in the hyperacuity range McKee and Westheimer, In addition, a number of studies indicate that visual acuity can improve with practice also in hyperacuity tasks Bennett Westheimer, ; Poggio et al.
An important component of visual PL is the rate at which learning occurs. For some visual tasks, the learning effect has been found to take
Adult amblyopia treatment within an hour or two Fiorentini and Berardi,; Shiu and Pashler, ; "Adult amblyopia treatment" et al. In some studies, learning is practically complete after a few hundreds of trials Fiorentini and Berardi, showing fast saturation. For other tasks, there is an initial fast saturating phase of learning, which is then followed by a slow phase where the performance
Adult amblyopia treatment to improve from one daily session to the next one, until a stable optimal level is reached Karni and Sagi, Interestingly, Karni and Sagi found that an improvement between sessions occurs only if the two sessions are separated by at least 68 h, suggesting the existence of a consolidation period.
Visual PL shows a high specificity for the features of the Adult amblyopia treatment used in the task. Many studies reported that the visual performance is typically improved on test trials that use the same stimuli as those used during training, and that the achieved performance often returns to baseline levels when test trials adopt even mildly different stimuli.
A specificity of Adult amblyopia treatment has been found for the orientation of lines and gratings Ramachandran and Braddick, ; McKee and Westheimer, ; Fiorentini and Berardi,; Karni and Sagi, ; Poggio et al. In most cases, visual PL is not restricted to the eye employed, i.
Texture discrimination is an exception in this respect, showing little interocular learning transfer Karni and Sagi, ; Schoups and Orban, The selectivity of visual PL for basic attributes of the stimuli, such as orientation Ramachandran and Braddick, ; McKee and Westheimer, ; Fiorentini and Berardi,; Karni and Sagi, Poggio et al.
The specificity of learning for basic visual features does not imply that the representations of learning occur only in the early stage of the visual system.
Cortical changes associated with PL can also occur in intermediate visual stages. Changes have been reported in the tuning Adult amblyopia treatment of cells in V4 in monkeys trained in an orientation discrimination task, whereas no such tuning changes were observed in V1 Ghose et al. Yang and Maunsell were the first to demonstrate that PL modifies basic neuronal response properties at an intermediate middle level of visual cortical processing V4. Adult amblyopia treatment found that an orientation discrimination task changes the response properties of V4 neurons: Moreover, neurons with preferred orientations, nearby the trained one, show the most relevant modifications.
The idea that changes associated with PL occur exclusively in early or intermediate visual areas has been challenged by the results of neurophysiological studies in monkeys Chowdhury and DeAngelis, ; Law and Gold, Given the importance of the potential for treatment of amblyopia in adulthood, it is crucial to understand the factors involved in adult amblyopia plasticity and.
Amblyopia is the most common form of impairment of visual function affecting one eye, with a prevalence of about % of the total world population.
Amblyopia. Studies on video games played by adults for the treatment of amblyopia have shown degree of visual restoration in the amblyopic eye [
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