Roger W. Li

Removing brakes on adult brain plasticity: from molecular to behavioral interventions.

Adult brain plasticity, although possible, remains more restricted in scope than during development. Here, we address conditions under which circuit rewiring may be facilitated in the mature brain. At a cellular and molecular level, adult plasticity is actively limited. Some of these “brakes” are structural, such as perineuronal nets or myelin, which inhibit neurite outgrowth. Others are functional, acting directly upon excitatory-inhibitory balance within local circuits. Plasticity in adulthood can be induced either by lifting these brakes through invasive interventions or by exploiting endogenous permissive factors, such as neuromodulators. Using the amblyopic visual system as a model, we discuss genetic, pharmacological, and environmental removal of brakes to enable recovery of vision in adult rodents. Although these mechanisms remain largely uncharted in the human, we consider how they may provide a biological foundation for the remarkable increase in plasticity after action video game play by amblyopic subjects.

Video-game play induces plasticity in the visual system of adults with amblyopia.

A pilot study suggests that playing video games may enhance a range of spatial vision functions in adults with amblyopia.

Improving the performance of the amblyopic visual system

Experience-dependent plasticity is closely linked with the development of sensory function; however, there is also growing evidence for plasticity in the adult visual system. This review re-examines the notion of a sensitive period for the treatment of amblyopia in the light of recent experimental and clinical evidence for neural plasticity. One recently proposed method for improving the effectiveness and efficiency of treatment that has received considerable attention is ‘perceptual learning’. Specifically, both children and adults with amblyopia can improve their perceptual performance through extensive practice on a challenging visual task. The results suggest that perceptual learning may be effective in improving a range of visual performance and, importantly, the improvements may transfer to visual acuity. Recent studies have sought to explore the limits and time course of perceptual learning as an adjunct to occlusion and to investigate the neural mechanisms underlying the visual improvement. These findings, along with the results of new clinical trials, suggest that it might be time to reconsider our notions about neural plasticity in amblyopia.

Characterizing the mechanisms of improvement for position discrimination in adult amblyopia

Adult amblyopes can improve positional acuity through practice; however, the neural mechanisms underlying this improvement are still not clear. In this study, seven adult amblyopes repeatedly practiced a position discrimination task in the presence of positional noise. We found that six of the seven showed systematic and significant improvements in position acuity that were both eye and orientation specific. Using a position-averaging model, we were able to parse the improvement in performance with practice into two factors: improvement in sampling efficiency and reduction of equivalent input noise. Three of the seven showed improved efficiency with no change in equivalent noise, two showed a significant reduction in equivalent noise with no change in efficiency, and one showed both improved efficiency and reduced equivalent noise. Interestingly, all observers showed substantial improvement in visual acuity, and one observer showed substantial improvement in stereoacuity. Three observers were also tested on a counting task, and all three improved after practicing positional discrimination. Our results reveal the mechanisms underlying perceptual learning in amblyopic vision, and may provide a basis for developing more effective and efficient strategies for the treatment of amblyopia.

Prolonged Perceptual Learning of Positional Acuity in Adult Amblyopia: Perceptual Template Retuning Dynamics

Amblyopia is a developmental abnormality that results in physiological alterations in the visual cortex and impairs form vision. It is often successfully treated by patching the sound eye in infants and young children, but is generally considered to be untreatable in adults. However, a number of recent studies suggest that repetitive practice of a visual task using the amblyopic eye results in improved performance in both children and adults with amblyopia. These perceptual learning studies have used relatively brief periods of practice; however, clinical studies have shown that the time-constant for successful patching is long. The time-constant for perceptual learning in amblyopia is still unknown. Here we show that the time-constant for perceptual learning depends on the degree of amblyopia. Severe amblyopia requires >50 h (≈35,000 trials) to reach plateau, yielding as much as a five-fold improvement in performance at a rate of ≈1.5%/h. There is significant transfer of learning from the amblyopic to the dominant eye, suggesting that the learning reflects alterations in higher decision stages of processing. Using a reverse correlation technique, we document, for the first time, a dynamic retuning of the amblyopic perceptual decision template and a substantial reduction in internal spatial distortion. These results show that the mature amblyopic brain is surprisingly malleable, and point to more intensive treatment methods for amblyopia.

Crowding between first- and second-order letter stimuli in normal foveal and peripheral vision.

Evidence that the detection of first- and second-order visual stimuli is processed by separate pathways abounds. This study asked whether first- and second-order stimuli remain independent at the stage of processing where crowding occurs. We measured thresholds for identifying a first-order (luminance defined) or second-order (contrast defined) target letter in the presence of two second- or first-order flanking letters. For comparison, we also measured thresholds when the target and flanking letters were all first or second order. Contrast of the flankers was 1.6 times their respective contrast thresholds. Measurements were obtained at the fovea and 10 degrees in the lower visual field of four normally sighted observers. Two observers were also tested at 10 degrees nasal visual field. As expected, in both the fovea and periphery, the magnitude of crowding (threshold elevation) was maximal at the closest letter separation and decreased as letter separation increased. The magnitude of crowding was greater for second- than for first-order target letters, independent of the order type of flankers; however, the critical distance for crowding was similar for first- and second-order letters. Substantial crossover crowding occurred when the target and flanking letters were of different order type. Our finding of substantial interaction between first- and second-order stimuli suggests that the processing of these stimuli is not independent at the stage of processing at which crowding occurs.

Learning to Identify Near-Threshold Luminance-Defined and Contrast-Defined Letters in Observers with Amblyopia

We assessed whether or not the sensitivity for identifying luminance-defined and contrast-defined letters improved with training in a group of amblyopic observers who have passed the critical period of development. In Experiment 1, we tracked the contrast threshold for identifying luminance-defined letters with training in a group of 11 amblyopic observers. Following training, six observers showed a reduction in thresholds, averaging 20%, for identifying luminance-defined letters. This improvement transferred extremely well to the untrained task of identifying contrast-defined letters (average improvement=38%) but did not transfer to an acuity measurement. Seven of the 11 observers were subsequently trained on identifying contrast-defined letters in Experiment 2. Following training, five of these seven observers demonstrated a further improvement, averaging 17%, for identifying contrast-defined letters. This improvement did not transfer to the untrained task of identifying luminance-defined letters. Our findings are consistent with predictions based on the locus of learning for first- and second-order stimuli according to the filter-rectifier-filter model for second-order visual processing.

Characteristics of fixational eye movements in amblyopia: Limitations on fixation stability and acuity?

Persons with amblyopia, especially those with strabismus, are known to exhibit abnormal fixational eye movements. In this paper, we compared six characteristics of fixational eye movements among normal control eyes (n=16), the non-amblyopic fellow eyes and the amblyopic eyes of anisometropic (n=14) and strabismic amblyopes (n=14). These characteristics include the frequency, magnitude of landing errors, amplitude and speed of microsaccades, and the amplitude and speed of slow drifts. Fixational eye movements were recorded using retinal imaging while observers monocularly fixated a 1° cross. Eye position data were recovered using a cross-correlation procedure. We found that in general, the characteristics of fixational eye movements are not significantly different between the fellow eyes of amblyopes and controls, and that the strabismic amblyopic eyes are always different from the other groups. Next, we determined the primary factors that limit fixation stability and visual acuity in amblyopic eyes by examining the relative importance of the different oculomotor characteristics, adding acuity (for fixation stability) or fixation stability (for acuity), and the type of amblyopia, as predictive factors in a multiple linear regression model. We show for the first time that the error magnitude of microsaccades, acuity, amplitude and frequency of microsaccades are primary factors limiting fixation stability; while the error magnitude, fixation stability, amplitude of drifts and amplitude of microsaccades are the primary factors limiting acuity. A mediation analysis showed that the effects of error magnitude and amplitude of microsaccades on acuity could be explained, at least in part, by their effects on fixation stability.

Learning to identify near-acuity letters, either with or without flankers, results in improved letter size and spacing limits in adults with amblyopia.

Amblyopia is a developmental abnormality that results in deficits for a wide range of visual tasks, most notably, the reduced ability to see fine details, the loss in contrast sensitivity especially for small objects and the difficulty in seeing objects in clutter (crowding). The primary goal of this study was to evaluate whether crowding can be ameliorated in adults with amblyopia through perceptual learning using a flanked letter identification task that was designed to reduce crowding, and if so, whether the improvements transfer to untrained visual functions: visual acuity, contrast sensitivity and the size of visual span (the amount of information obtained in one fixation). To evaluate whether the improvements following this training task were specific to training with flankers, we also trained another group of adult observers with amblyopia using a single letter identification task that was designed to improve letter contrast sensitivity, not crowding. Following 10,000 trials of training, both groups of observers showed improvements in the respective training task. The improvements generalized to improved visual acuity, letter contrast sensitivity, size of the visual span, and reduced crowding. The magnitude of the improvement for each of these measurements was similar in the two training groups. Perceptual learning regimens aimed at reducing crowding or improving letter contrast sensitivity are both effective in improving visual acuity, contrast sensitivity for near-acuity objects and reducing the crowding effect, and could be useful as a clinical treatment for amblyopia.

The expandability of the eye in childhood myopia.

Purpose. While intraocular pressure has been shown to have some influence on eye growth, the stress exerted on the outer wall of the eye and the rigidity of the outer coats of the eye may be of greater importance. No studies have assessed the significance of both of these variables in terms of childhood myopia and its progression. Methods. Twenty myopic and twenty non-myopic children aged 8 to 12 years participated in the study. Refractive error (including refractive error shift over the past year), ocular dimensions (anterior chamber, lens thickness, vitreous chamber, axial length), intraocular pressure, equatorial scleral rigidity, and outer wall thickness were measured for right eyes. Outer wall stress was calculated using the approximation, p = IOP*r/2t. Results. The myopic group was 3.43D more myopic and had 1.43 mm longer eyes on average than the non-myopic group. The myopic children had experienced a mean refractive shift of -0.30 D/yr over the past year. Equatorial wall thickness was significantly less in myopes than non-myopes (difference of 0.09 mm, p = 0.02) and in the combined sample was correlated to refractive error (r = 0.312, p = 0.05), but not refractive error shift. Ocular rigidity and eye wall stress values were similar in the two groups. The refractive shift increased as wall stress increased both in the combined sample (r = -0.386, n = 35, p = 0.022) and the myopic group (r = -0.600, n = 16, p = 0.014). Conclusion. We did not find large differences in wall thickness, ocular rigidity, or wall stress in myopic and non-myopic children. While reduced ocular rigidity, increased wall stress and scleral thinning may have a role in myopia progression in childhood we were not able to clearly show this in our study of 40 children.