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1From the School of Optometry and the 2Helen Wills Neuroscience Institute, University of California-Berkeley, Berkeley, California.
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30%) after a short period (15 hours, 4000 trials) of perceptual learning. The present study was conducted to determine whether extended training is necessary for optimal treatment of amblyopia. METHODS. Two children, aged 9 and 12 years, with previously untreated severe amblyopia (Snellen acuity, 20/100–20/125) practiced a position-discrimination task repeatedly over 3 months (100 hours, >25,000 trials by each observer). The task was to judge which of three pairings of two groups of eight Gabor patches was misaligned. Positional noise was used to investigate the neural mechanisms involved in learning position discrimination.
RESULTS. After practice both observers showed substantial recovery in both positional and letter acuities (60% and 2–4 chart lines) and both also regained significant stereoacuity. In the first 20 hours, the recovery rate was comparable to that of 12 previously treated amblyopes. However, extending the treatment dosage for an additional 30 hours resulted in substantially greater plateau improvements. These improvements were primarily the results of a marked increase in sampling and processing ability and, to a lesser degree, to a decrease in spatial distortion.
CONCLUSIONS. The results show that in two juvenile amblyopes, perceptual learning extended over an accumulated dosage of 50 hours may be an efficient and effective adjunct to occlusion for reversing amblyopia. When combined with occlusion, perceptual learning may significantly speed up the time to recovery in children with amblyopia.
One recently proposed method for improving the effectiveness and efficiency of treatment that has received considerable attention is "perceptual learning," (i.e., repeated practice of a visual task). For example, practicing Vernier acuity,15 16 position discrimination,17 contrast detection,18 19 20 grating resolution20 and letter recognition21 22 all induce some degree of recovery of vision in adults with amblyopia, often (though not always) with transfer to visual acuity. It is important to note that during the training sessions, the nonamblyopic eye is occluded, and so the improvements most likely result from the combined effects of occlusion and perceptual learning.
One might expect that young children, whose developing brain should be more plastic, would show greater improvement than adults after perceptual learning. However, we found a similar degree of improvement in children as in adults after perceptual learning.23 It is worth noting that those children had already undergone occlusion therapy before the start of the experiments. It is possible that prior treatment may have already resulted in improvement in vision, leaving limited room for further improvement.
In the present study, we sought to explore the limits and time course of perceptual learning as an adjunct to occlusion in two previously untreated childhood amblyopes (9- and 12-year-old) and to investigate the neural mechanisms underlying the visual improvement using positional noise. In our previous studies,23 observers underwent a 10-session training course (15 hours). Given the fact that the effects of occlusion only plateau after 100 to 400 hours,5 12 13 in this present study we extended the period of training to 50 to 60 sessions (90–100 hours) and compared the dose–response relationship of occlusion combined with perceptual learning with that of occlusion therapy reported from previous studies.
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20/16) in the fellow sound eyes. They also presented mild crowding deficits (about 1 letter line), meaning they had better visual acuity when isolated letters were presented.24 Both of them failed stereo tests, indicating that they had no gross stereopsis (or >400 arcsec). Their clinical data are summarized in Table 1 . In this study, visual acuity was measured using Bailey-Lovie logMAR letter charts (National Vision Research Institute of Australia, 1978). Stereotests (Randot [Stereo Optical Co., Inc., Chicago, IL] and Frisby [Clement-Clarke Ltd., Harlow, UK]) were used to measure stereoacuity for observers AL and SG, respectively. Neither of the observers had prior experience in psychophysical experiments.
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15–30 min). Testing and training were performed with the observer wearing best optical correction, and the visual acuity values reported throughout the paper are for best corrected acuity. All testing was performed in the Amblyopia Research Laboratory at the University of California-Berkeley. The research adhered to the tenets of the Declaration of Helsinki. The experimental procedures were approved via the University Committee for Protection of Human Subjects. Assent was obtained from child observers, and informed consent was obtained from their parents before the children began the study.
Position Discrimination
The stimuli and methods are essentially identical to those used in a previous study of perceptual learning in childhood amblyopia23 and are described briefly as follows. A three-alternative, forced-choice (3AFC) procedure was used to determine the position-discrimination threshold. As illustrated in Figure 1 , the observer’s task was to select the one misaligned pair of Gabor patch groupings out of three choices (top, middle, or bottom). Each grouping consisted of eight discrete Gabor patches (carrier spatial frequency = 5 cyc/deg; 
= 12 arcmin) arranged in a horizontal row.
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A modified interleaved staircase method was adopted to control the offset magnitude between the two Gabor patch groupings and track the individual thresholds.23 The response data were fit with a Weibull psychometric function, and positional threshold was defined as the offset at which 66% correct responses were obtained.
Observers were trained at three (AL) or four (SG) positional noise levels (including zero); 132 responses were required for each noise level. Each session consisted of 396 and 528 trials for observers AL and SG, respectively. Fewer positional noise levels and trials were required from observer AL because of his younger age. Viewing was monocular at 2 m, and the eye not being tested was covered with a standard black eye patch. The experiment was self-paced, and a break was given whenever the subject requested one. More than 25,000 trials were performed by each observer over a 3-month period (90–100 hours in total).
The visual stimuli remained on the screen until the observer gave a response, so that observers were able to analyze each pair of Gabor patch groupings carefully before responding. The adaptive staircase adjusts the visual task difficulty automatically according to the observer’s individual performance, so that most of the time the observers are challenged by stimuli that are close to their visual limit. Our experimental design involves the element of direct feedback and a computer game situation of competing for better scores. Trial-by-trial feedback was provided audiovisually following each trial to keep the child engaged.
Noise Averaging Modeling
A positional averaging model was used to quantify the effects of external noise (
e) on the threshold (th):
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i is the equivalent input noise (or uncalibrated internal spatial distortion), k is the number of samples extracted, and n is the total number of samples. The term 1/n is present in equation 1 because of the 0 mean adjustment of each Gabor patch grouping. In this study, each grouping consisted of eight Gabor patches; hence n = 8. For 66% correct response probability, the detectability (d') was 1.1.25 By measuring the thresholds at different external noise settings, i and k can be estimated with a least-squares algorithm. To quantify the ability to extract stimulus information for positional averaging, sampling efficiency (E) was defined as
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60% (AL: 65.2%; SG: 55.6%).
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Our TvN analysis shows that the improvement in positional acuity can be attributed primarily to a very marked increase in sampling efficiency. Sampling efficiency increased by a factor of 6.6 (red circle: from 2.1% to 13.8%) for AL, and by a factor of 3.2 (blue square: from 5.5% to 17.9%) for SG (Fig. 2E) , indicating that an increased number of target patches were extracted and used for positional processing and averaging after the course of training. In other words, after training, the observers were able to sample visual information more efficiently from the visual stimulus. This improvement, as a result of extended perceptual learning, is substantially greater than the approximately 1.33-fold (33%) improvements, as indicated by the black dashed line (Fig. 2E) , we have reported in earlier studies in a dozen amblyopes (five children and seven adults as shown by the filled symbols in Fig. 2E ) after 7 to 10 training sessions.23 26 In the present study, we also observed about a 20% decrease (from 2.1 to 1.6 arcmin) of additive internal spatial noise, or perceptual distortion, in observer SG (Fig. 2F , blue square).
Generalized Transfer of Learning to Letter Recognition and Depth Perception
We observed fast recovery of visual acuity over sessions in both observers (Fig. 3A) . Before the commencement of visual training, their isolated letter acuities were nearly identical (20/80), and both observers showed crowding27 Their isolated-letter acuity (open symbols) was better than their crowded line letter acuity (solid symbols). Both crowded and isolated letter acuities improved significantly while the observers were practicing position-discrimination tasks. The results are replotted as percent improvement versus cumulative training hours for crowded and isolated letters in Figures 3B and 3C , respectively. The solid lines show the exponential function fit to the visual acuity data in the figures.
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60% improvement (approximately 0.4 log unit or 4 letter lines on a logMAR letter chart), whereas SG showed a 37% improvement (2 letter lines) in both isolated and crowded letter acuities after 25 sessions (40–50 hours of training). An important question is whether this improvement can be simply attributed to the 40 to 50 hours of occlusion that accompanied the perceptual learning. Although we cannot rule this explanation out, we can compare the present results with the well-documented effects of occlusion. As noted earlier, the dose–response rate for occlusion (in patients aged 3–8 years) is 0.1 log unit/120 hours of occlusion,5 shown by the dashed in Figure 3B . Observer SG’s acuity improvement fell very close to the predicted effects of occlusion alone, but we note that SG (12 years old) was older than the original study group in Stewart et al.5 On the other hand, based on the dose–response curve for occlusion, it would require approximately 350 hours of occlusion alone to obtain the same amount of improvement demonstrated by AL in about one seventh of the time. As is evident in Figure 3B , the improvement in acuity of both observers in the first 20 hours was comparable to that of the dozen observers who participated in our previous studies26 28 : mean improvements of 27% and 33% for both childhood (Xs, 7–10 years old; n = 5) and adult (filled squares, 21–55 years old; n = 7) amblyopes, respectively. Note that all the childhood amblyopes in the earlier studies had already completed occlusion therapy before starting the learning experiments.
A comparison of Figures 3B and 3C suggests that single-letter acuity (Fig. 3C) recovered faster than did crowded-letter acuity (Fig. 3B) , and this observation is borne out by the time constants of the best fit exponential functions (solid lines). In the first 30 hours, the mean recovery rates were 15% per 10 hours for isolated letters and 12% per 10 hours for crowded letters (AL: 20.7%; SG: 9.4% for isolated and AL: 15.1%; SG: 8.6% for crowded). Each 15% improvement represents about 1 logMAR chart line. The time constants for isolated letters (AL: 10.1 hours; SG: 20.4 hours) were significantly shorter than those for crowded letters (AL: 25 hours; SG: 32.3 hours), implying that two different limiting mechanisms are involved and that more time is needed for the effects of crowding to be resolved.
To evaluate the long-term stability of the visual acuity outcome, we remeasured the visual acuity of AL after cessation of treatment and found that most of the acuity improvement was maintained 7 months after the training was completed (Fig. 3A , gray arrows).
Of interest, after practicing position discrimination, both observers also demonstrated measurable stereopsis (AL: 70 arcsec; SG: 85 arcsec). Note that neither demonstrated measurable stereoacuity (or >400 arcsec) before the commencement of the experiments.
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Discussion |
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Position Acuity
Both observers showed substantial improvement (60%) in position acuity at plateau, considerably greater than in our previous studies. In our previous study, using identical methods, we found that four of the five children showed improvements in position acuity, which averaged approximately 30%. Since the roughly 30% improvement in the first 15 hours in the present study was similar to that of previously treated amblyopes, we attribute the large increase at plateau to prolonged learning. As noted in Figure 2 , asymptotic learning was not achieved until 25 sessions (40–50 hours). This substantial improvement reflects primarily a three- to sixfold increase in sampling efficiency, much greater than observed in our earlier study. An important finding was that after learning, performance of the amblyopic eye was almost as good as (low noise) or better than (high noise) that of the fellow eye.
We postulate that the use of positional noise with feedback given to the observers’ responses could contribute to the reweighting of neural connections28 and the modest recalibration of the spatially distorted visual system. It would be interesting to record the retuning dynamics of behavioral receptive fields in amblyopic vision with the use of an efficient reverse-correlation technique.29
Letter Acuity
Similar to the results of our previous study, we found that the improvement in position acuity transferred to letter acuity. The plateau improvement in both isolated and crowded-letter acuity was considerably larger for AL than for SG. Amblyopes differ substantially in their individual responses to treatment, so we can only speculate about why our observers differed in their responses. It is worth noting that AL is considered to be still within, or at the limit of, the critical period, whereas SG is not. We suspect that the difference in their responses could be due in part to the age difference, since in prior studies, investigators have reported that the most effective timing of treatment may interact with the age at presentation.12 30
Comparing the present results with our previous studies,23 26 the rates of improvement were comparable to those of both amblyopic children and adults. However, the plateau improvements in position acuity for both observers, and in visual acuity for AL, are considerably greater. Thus, it is clear that more than the 10 sessions used in our previous studies23 26 are needed to reach steady plateau performance in patients with amblyopia. The present findings suggest that extended training sessions (>50 hours for severe amblyopia) are indicated for successful amblyopia treatment and maximizing visual outcomes.
Does Perceptual Learning Provide an Added Benefit?
Occlusion therapy is the "gold standard" method for treating amblyopia. In the present study, and all previous perceptual learning studies, the subjects wore occlusion while performing the visual task, and so it is reasonable to ask whether "active" perceptual learning actually provides an added benefit over occlusion alone.
We argue that perceptual learning does indeed provide an added benefit for the following reasons. First, in our previous study,23 we found that perceptual learning improved both position discrimination and letter acuity in amblyopes who were no longer responsive, or were nonresponsive, to occlusion, and demonstrated that even after occlusion therapy was terminated, room remained for visual improvement with perceptual learning. This finding reveals neural plasticity that might not be "taken up" completely by occlusion therapy. Second, a previous study showed that the dose–response rate for occlusion (in patients aged 3–8 years) is 0.1 log unit/120 hours of occlusion5 and to the extent that we can use it as a basis for comparison, it would require approximately 350 hours of occlusion alone to obtain the 0.4 log unit improvement demonstrated by AL in approximately one seventh of the time. It is important to note that there are individual differences in responding to occlusion therapy; 2 of 72 patients in the study by Stewart et al.5 showed recovery of as much as 4 and 8 chart lines after a cumulative dose of 100 hours of occlusion. Although we cannot rule out the possibility that AL was one of these rare "superresponders," we think it is more likely that the combination of occlusion and perceptual learning sped up his response. Finally, the effects of occlusion alone on position acuity have been shown to be modest,31 whereas the effects noted in this study were substantial.
We suggest that this new approach, combining occlusion with perceptual learning, may be a useful method for obtaining the optimal treatment outcome in the shortest possible time. Eliminating or reducing the need to wear an eye patch in public would eliminate, or at the very least reduce, the emotional stress that often accompanies occlusion therapy.32 We note that the in-house training itself is labor intensive and requires considerable parental dedication. Ultimately, a home-based training version involving the Internet may help to lessen the time commitment and the financial burden on parents. However, before this perceptual learning approach is used to treat amblyopia clinically, there are still many questions to be addressed. Only two amblyopic patients participated in the present study, and the response to treatment is likely to vary among individuals. Therefore a large-scale clinical study is needed to determine the dose–response function and compare that to the dose–response function of occlusion alone as well as to evaluate the prognosis for different types and depths of amblyopia.
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Acknowledgements |
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Footnotes |
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Submitted for publication March 16, 2007; revised May 30 and July 6 and 18, 2007; accepted August 23, 2007.
Disclosure: R.W. Li, None; A. Provost, None; D.M. Levi, None
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. 
1734 solely to indicate this fact.
Corresponding author: Roger W. Li, School of Optometry, University of California- Berkeley, Berkeley, CA 94720-2020; oroger{at}berkeley.edu.
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