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1From the Department of Neurophysiology, Max-Planck-Institute for Brain Research, Frankfurt, Germany; the 2Department of Biological Psychology, Institute for Psychology, J. W. Goethe-University, Frankfurt, Germany; the 3Department of Biomedical Engineering, College of Engineering, Boston University, Boston, Massachusetts; and the 4Department of Biophysics, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.
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METHODS. Seventeen experimental subjects were asked to describe and sketch their perception of simple geometric pattern, as perceived through their amblyopic eyes. A subgroup of 15 subjects participated in a psychophysical experiment, in which the two-dimensional displacement maps were determined by asking the subjects to reconstruct, point-by-point, memorized circles of different radii. The results of these displacement maps were related to the clinical characteristics and the perceptual descriptions of the same subjects.
RESULTS. Twelve of the 17 investigated subjects experienced spatial distortions; six subjects perceived temporal instabilities, either in addition, or in the absence of spatial distortions. Objectively determined spatial displacement and spatial uncertainty were significantly larger in subjects with a history of strabismus and a deep acuity loss than in subjects with refractive etiology and a mild acuity loss. Subjects experiencing temporal instability showed more spatial uncertainty in the amblyopic eye than did subjects with a stable perception.
CONCLUSIONS. These results suggest that a history of strabismus and a deep amblyopia are more likely to be associated with temporal misperceptions than a refractive etiology and a mild acuity loss. A temporally unstable perception may be related to a more profound disorganization of the central neural pathways connected to the amblyopic eye.
Hess et al.5 were the first to capture the amblyopic perception of patches of sinusoidal gratings (4° or 20° in diameter), by asking their subjects to describe and sketch their perceptions through the amblyopic eye. They found that the spatial "aberrations" perceived by amblyopic subjects affected mainly gratings with higher spatial frequencies.
Sireteanu et al.10 asked their subjects to describe and sketch their perceptions of simple, two-dimensional, spatially extended geometric patterns (square-wave gratings of low and high spatial frequencies, checkerboards, and grids). The drawings were completed by the experimenters and then compared with computer-reconstructions of the same patterns, based on a point-by-point mapping of the central 12° of the visual field of each subject.9 Sireteanu et al.10 found that the subjectively experienced spatial distortions cannot be completely predicted by the computer-reconstructed images. They concluded that the two methods may tap onto different levels of the amblyopic visual pathway.
More recently, Barrett et al.19 asked a large group of amblyopic subjects to draw small patches (3.2° in diameter) of Gaussian-modulated sinusoidal gratings of different orientations and spatial frequencies. They described five distinct classes of anomalous perception: (1) wavy appearance of straight gratings; (2) a "jagged" type with abrupt positional shifts orthogonal to the grating orientation; (3) errors in perceived orientation; (4) fragmented perception, in which the gratings appear broken; and (5) scotomatous distortions showing large gaps in the gratings. For most subjects, the type of perceptual distortion was constant over time, but not across different spatial frequencies or orientations. Barrett et al. suggest that these misperceptions may originate from errors in the neural coding of orientation in the primary visual cortex.19 21
In the present study, we were interested in the temporal instabilities that occur in amblyopic vision. Our main questions were: How often do temporal instabilities occur in amblyopic vision? Are there different types of temporal instability? Do the temporal instabilities affect amblyopic subjects with an etiology of strabismus more often than those in whom amblyopia is caused by an early deficit in ocular refraction? Is there any relationship between the stability of the perceived image and other clinical data of the affected subjects?
We performed two experiments: in the first experiment, we constructed digitalized, animated graphic illustrations of the spatial distortions and the temporal instabilities of subjects with well-defined clinical data. We attempted to categorize these images and to relate them to the clinical data of each subject. In the second experiment, we investigated whether there was a quantitative relationship between the perceived temporal instabilities and the objectively determined disorganization of the representation of visual space of each subject. To correlate the subjective images with the objectively determined spatial distortions of each amblyopic subject, we used a fine-grained, two-dimensional psychophysical mapping procedure, based on a method previously developed in our laboratory.9 10 To distinguish between the subjective perceptual distortions and those assessed in the psychophysical mapping experiment, the latter shall be called "spatial displacements." The quantitative results of the spatial displacement mappings were analyzed in relation to the etiology of the subjects, their acuity loss and the occurrence of temporal instability.
Based on these results, we suggest a mechanism that may account for the genesis of the misperceptions in amblyopic vision, and possibly reconcile controversial reports in the literature. Preliminary accounts of part of the results of this study were presented elsewhere.22 23 24 25 26 27
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To be included in the study, the amblyopic subjects had to have little or no stereopsis (cutoff disparity was 250 minutes, measured with the TNO test) and an acuity of not more than a 0.5 decimal acuity in the most affected eye, measured with the Landolt C test for single optotypes (1.0 corresponds to 6/6 visual acuity). To be deemed anisometropic, amblyopic subjects were required to have a minimum difference in refraction of 1.5 D spherical equivalent between the two eyes.
Before psychophysical testing, the subjects’ contrast sensitivity was tested for far (3 m) and near (40 cm). Testing was done monocularly using the Vistech Contrast Sensitivity Test (VCTS 600 charts).
Testing of the subjects was performed in accordance with the tenets of the Declaration of Helsinki. Written informed consent was obtained from all subjects after the nature and purpose of the study had been fully explained. The study was approved by the Ethics Committee of Frankfurt University.
Experiment 1: Graphic Illustration of Nonveridical Perception and Relationship to Clinical Data
Seventeen experimental subjects aged from 22 to 58 years participated in the experiment: 14 subjects with amblyopia of different etiologies and 3 with alternating fixation and good vision in both eyes. Table 1 provides an overview of the clinical data of all experimental subjects.
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For the assessment of the temporal distortions, the subjects were asked to describe verbally whether the perceived spatial distortions were stable or changed over time. They had to describe whether temporal instabilities appeared in addition to or in the absence of spatial distortions, if there was a special "type" of instability occurring in the stimuli, and for how long the instability was perceived.
Based on the verbal descriptions and the sketches by the subjects, one of the authors (CB) completed the drawings in pencil, which were then drawn in ink and scanned. Based on the digitalized drawings and on the verbal descriptions of the subjects, animated images were generated for each pattern and each amblyopic subject, which were then validated by the subjects. Animation was performed with standard manipulation software (Photoshop, ver .7, and ImageReady, v.7; Adobe Systems, San Jose CA).
Experiment 2: Objectively Determined, Two-Dimensional Spatial Displacement Maps in Amblyopic Vision
The results of the second experiment are based on data from 15 of the 17 experimental subjects investigated in the first experiment. Two subjects from the previous sample (AF and GP) were not available for investigation (see Table 1 ). Ten naïve normally sighted observers aged between 21 and 40 years (5 women and 5 men) were included as control subjects.
The method was based on that developed by Lagrèze and Sireteanu,9 but with a finer grain of the tested points and an improved testing protocol. The subjects were seated in front of a computer monitor, in a darkened room. The observer’s head was placed on a chin rest, to keep an eye-to-monitor distance of 57 cm. The subjects were asked to fixate monocularly a small cross (25 arcmin arm length and 4 arcmin arm width) at the center of the screen, after which a circle centered on the fixation cross was presented for 5 seconds. The radius of the circle could be 1°, 2°, 3°, 4°, 5° or 6°. The subjects were asked to memorize the radius of the circle, after which they heard a number ranging from 1 to 12, similar to the hours on an analog watch. The task of the subjects was to move a small target (a disc with a diameter of 30 arcmin), under the control of the amblyopic or the dominant eye, from the fixation point to the imagined position on the memorized circumference of the circle. The test point could be moved only after the memorization period of 5 seconds was completed. The final position of the test point was recorded. The subjects were asked to keep fixation on the central cross throughout this procedure.
To ensure that the stimuli were visible only to one eye at a time, the subjects wore red-green goggles. The stimuli on the screen were presented in colors perfectly matched to the colors of the goggles. The fixation cross and the circles to be memorized were shown only to the fixating eye, while the test dot could be shown to each eye in turn. The acoustically presented numbers, which indicated the angular position of the target, had been recorded on tape. The numbers were heard through speakers placed symmetrically on the right and left of the screen. A control experiment ensured that all numbers could be understood perfectly by all subjects. Data collection lasted approximately 1.5 hours, with breaks whenever necessary. To avoid the effects of fatigue, the experiment was performed in the sequence ABBA in one experimental session and BAAB in the next.
The radii of the circles, the different positions, and the colors corresponding to the two eyes were intermixed randomly. Each target position was recorded five times for each eye. After completion of the experiment, the means and standard deviations (SDs) of the radial and angular settings were calculated for all 72 positions of each eye and each subject. The deviations of the mean positions of the amblyopic eyes from the mean positions of the dominant eyes were used to build a two-dimensional vectorial map of the spatial distortions of each subject.7 Two-dimensional SD areas (expressed in deg2) were calculated by multiplying the radial with the angular SDs for each position and each eye of each subject (green and red areas in Fig. 5 ).
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level was set at 0.05 for omnibus tests, Wilk’s 
was used as a test statistic. Separate error terms and Bonferroni adjustments were used for planned comparisons and contrasts. |
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We replicated these findings with the more clinical approach of the charts (VisTech Consultants, Dayton, OH). In addition to the already described types of contrast sensitivity loss, we identified another type, in which contrast sensitivity was subnormal in both eyes. The first three types were designated high-spatial-frequency loss, high and low spatial frequency loss, and no contrast sensitivity loss. The last type was designated bilateral contrast sensitivity loss. The contrast sensitivities of all amblyopic subjects are shown in Figs. 2 3 and 4 .
Experiment I: Spatial and Temporal Misperceptions in Amblyopic Vision
Two of the 14 amblyopic subjects did not report any perceptual distortions (AF and MH). The three strabismic subjects with alternating fixation (RF, MO, JZ) also did not report any misperceptions. Of the 12 subjects who reported anomalous perception, 6 perceived temporal instability of the original patterns, either in the absence (MK, DS) or in addition to spatial distortions (GP, BB, CL, TS). The remaining six subjects perceived spatial distortions but no temporal instability.
Although we are aware that any classification may be somewhat arbitrary, we collapsed the subjects into two groups, according to presumed major etiology: amblyopic subjects with a history of strabismus (strabismic and strabismic-anisometropic amblyopia) and subjects with a refractive history (bilaterally ametropic and purely anisometropic amblyopia). The two bilaterally ametropic subjects had some strabismus, presumably secondary to their refractive anomaly.
Spatial Distortions
Examples of the graphic illustrations of the spatial distortions and the contrast sensitivities of the two groups of subjects are shown in Figures 2 and 3 . Despite the different stimuli and the different experimental procedure, we identified in our sample the five spatial distortion categories proposed by Barrett et al.19 Several subjects showed distortions belonging to more than one category.
In most subjects, when distortions were experienced for the low-spatial-frequency grating or checkerboard, distortions were also perceived for the high-spatial-frequency grating and grid, respectively. There was a strong relationship between the spatial frequency and the appearance and severity of the spatial misperception: spatial distortions were more pronounced for the higher spatial frequencies (1.6 and 3.2 cyc/deg) than for the low-spatial-frequency patterns.
Temporal Instability.
Temporal instability was described by six subjects (MK, DS, GP, BB, CL, and TS), either in addition, or in the absence of spatial distortions. Instability was perceived only for the higher spatial frequency grating and grid, the 0.4 cyc/deg spatial frequency patterns had a stable appearance. The temporal instabilities fell into two categories. In the first one, the whole pattern was perceived as moving or flickering, whereas in the second, moving lines pervaded the pattern. Examples for the first category—the whole-pattern flicker—were slightly more common (four of six subjects).
In this category, subjects GP and BB perceived all stripes as vibrating in the high-spatial-frequency grating; subject CL saw them as moving from one side to the other. In the first two subjects the stripes flickered on a short time scale, while in subject CL a sideways movement, from left to right, of the whole grating was experienced. CL also perceived a jerky movement of the whole pattern in the grid, but in the direction opposite to that in the grating. Subject DS perceived a movement of the grid as well; in his case the pattern was moving upward. All these subjects had a history of strabismus (subjects DS and GP were strabismic; subjects BB and CL were strabismic-anisometropic).
The second category—line moving only—was reported by the two strabismic amblyopic subjects MK and DS. They reported fine threads crossing the high-spatial-frequency grating and moving constantly on a small spatial range. In both subjects, the threads distorted the pattern on the horizontal axis, they moved unpredictably, either sideways or up and down. Unlike in the perception of patterns in the whole-pattern flicker category, here the grating itself remained undistorted.
The temporal misperception of the anisometropic subject TS was difficult to allocate to one of the proposed instability categories. TS perceived squares propagating from the inside-out of the grating field. After focusing on the high-spatial-frequency pattern, the subject saw an unstable, ovally shaped, small diameter area in the center of the grating. This area of temporal instability expanded progressively as it propagated to the periphery of the grating field. The stripes of the high-spatial-frequency grating itself remained undistorted.
Generally, in the whole-pattern instability category, spatial distortions were perceived in addition to the temporal ones, while in the line-moving category no spatial distortions were perceived. Here, temporal misperception occurred solely.
Anomalous Color Perception.
One unexpected finding was that four of our subjects (MK, DS, BB, and CL) reported, in addition to temporal instability, perception of colored contours for the high-spatial-frequency patterns. All four subjects had a history of strabismus (MK and DS: strabismic; BB and CL: strabismic-anisometropic). Subjects MK and DS perceived the moving lines pervading the grating in rainbow-like or red-and-green colors, respectively. Subject BB had a perception of vibrating lines, appearing in red and yellow. For subject CL, the stripes in the higher spatial frequency grating appeared also in basic rainbow colors—similar to subject MK’s perception—whereas the cubicles in the grid pattern were perceived in greenish color (not illustrated).
In sum, there seem to be two types of color misperceptions accompanying the perception of temporal instability: in the first one, all kinds of colors in the rainbow spectrum were perceived. In the second, only one or two colors (green, red, yellow, or blue) were reported. There was no relationship between the color misperceptions and the category or type of temporal misperception.
Eye Dominance.
An intriguing relationship was seen between the side of the amblyopic eye and the type of distortion, meaning that when the right eye of right-handed subjects (or the left eye of left-handed subjects) was the amblyopic eye, temporal distortions were more likely to occur. Temporal instabilities were reported by four of the six right-handed subjects with an amblyopic right eye (MK, DS, GP, and BB), but only by one of the six right-handed amblyopic subjects with a left amblyopic eye (CL). Thus, it seems that crossed eye–hand dominance may favor the occurrence of temporal instabilities.
Relationship to Clinical Condition
Most subjects reporting temporal instabilities were either strabismic (MK, DS, and GP) or strabismic and anisometropic (BB and CL). Only one subject perceiving temporal instability (the anisometropic amblyopic subject TS) did not have a known history of strabismus (albeit his eccentric fixation made us wonder whether he may have had undetected microstrabismus). Of the six subjects reporting spatial distortions only, five had a history of refraction anomaly, either bilateral (the two ametropic amblyopic subjects RS and SB) or unilateral (the three subjects with anisometropic amblyopia HL, JB, and MB). Only subject LP was purely strabismic. Thus, although the correlation is not perfect, it seems that a history of strabismus, either alone or in combination with anisometropia, may be a good predictor of the occurrence of a temporally unstable perception, whereas a refractive etiology may lead to spatial, but not temporal, misperceptions.
The visual acuities of the subjects experiencing no perceptual distortions (n = 2) or stable distortions without (n = 6) or with (n = 6) temporal instability were completely overlapping (Table 1) . Thus, there was no clear relationship between type and occurrence of distortions and the amount of visual acuity loss.
Type and amount of contrast sensitivity loss also did not predict accurately the occurrence and severity of distortions (Fig. 4) . Of the subjects with undistorted perception, subject AF showed only a mild contrast sensitivity loss (type 3: both eyes were in the normal range), while MH showed a deeper loss affecting mainly the higher spatial frequencies (type 1: see top panels in Fig. 4 ). It is not clear why these subjects showed reduced visual acuity. A deep loss, affecting both higher and lower spatial frequencies, was often associated with distorted vision, but did not predict whether a purely spatial or a combination of spatial and temporal distortion was going to occur. Even in the same subjects, alike stimuli can be perceived in very different ways. For instance, several subjects had very different spatial misperceptions for the checkerboard and the low-spatial-frequency grating, although these patterns have the same fundamental spatial frequency (Figs. 2 3) .
Mean contrast sensitivity of subjects experiencing spatial distortions only and that of those reporting temporal instabilities, with or without spatial distortions, were practically identical (Fig. 4 , bottom), and similar to those of the subjects not experiencing any perceptual distortions (Fig. 4 , top).
Thus, neither severity of amblyopia nor contrast sensitivity loss are good predictors of the presence of temporal misperceptions in amblyopic vision. Also, there was no clear correlation between pattern of distortion and angle of strabismus, presence of eccentric fixation, type of correspondence, or early therapy.
Absence of stereopsis or total exclusion of the amblyopic eye from binocular vision are not prerequisites for the occurrence of spatial distortions: all four purely anisometropic subjects showed some degree of spatial distortion, albeit three of them (HL, JB, MB) had some residual binocular function. But the loss of binocular function may favor the occurrence of temporal instabilities. Indeed, all subjects reporting temporal instabilities, but only half of those without temporal instability showed a complete loss of binocular function. Although the number of subjects in each category is too small to warrant a statistical analysis, these results suggest that the loss of binocularity may have been involved in the emergence of temporal misperceptions.
In general, temporal instabilities were perceived in addition to spatial distortions. Especially puzzling was the occurrence of temporal instabilities without spatial distortions. Both subjects presenting this pattern had strabismic amblyopia with high ametropia (bilateral hyperopia and astigmatism). One of them (MK) had a high-spatial-frequency only (type 1) contrast sensitivity loss; in the other (DS), contrast sensitivity was subnormal in both eyes (type 4).
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Almost half (6 [43%] of 14) of the amblyopic subjects in our sample reported temporal instabilities, either in addition (four cases) or in the absence of spatial misperception (two cases). This relatively high incidence is unlikely to have been inflated by our selection criteria (little or no residual stereopsis, relatively deep amblyopia). To our knowledge, this is the first study to give a detailed description of the temporal instabilities and their possible relationship to other deficits in amblyopic vision.
Temporal instabilities could be of two types: either the whole pattern, or only part of it, were perceived as moving. Four of the six subjects with strabismic amblyopia experiencing temporal instabilities also reported perceiving illusory colors. The occurrence, type, and severity of perceptual instability do not seem to be directly related to the loss of acuity or contrast sensitivity. Temporal instabilities were always associated with a complete breakdown of binocularity. This association may indicate a fundamental role of binocularity loss in the emergence of a more pronounced disorganization of the cortical maps in the amblyopic brain. This disorganization may in turn lead to unstable perception. A prominent role of the loss of binocularity in the functional deficits in amblyopia was suggested recently.28
The correlation between the occurrence of temporal instability and the pattern of eye-hand dominance is intriguing and deserves further investigation. Crossed dominance (opposite sides of the dominant eye and the dominant hand) has been reported in other neurodevelopmental disorders, such as developmental dyslexia.29
The results of this experiment show that temporal instabilities occur more frequently in amblyopic subjects with a history of strabismus than in amblyopic subjects with a refractive etiology. It thus appears that a history of strabismus may lead to a temporally unstable, in addition to a spatially distorted visual world.
Experiment II: Two-Dimensional Spatial Displacement Maps
In the second experiment, we investigated whether the temporal instability experienced in strabismic amblyopia may be related to a more profound misrepresentation of visual space. To quantify the spatial distortions in amblyopic subjects, we used a fine-grained, two-dimensional mapping procedure, based on a method previously developed in our laboratory.9 10 The results of these mappings were then correlated with the clinical data and with the occurrence of temporal instability in these subjects.
Individual Data
To enable a quantitative comparison of the results, we calculated for each subject the average vector length (AVL), the mean SD area of the dominant and the nondominant eye (SDdom and SDn-dom), and the ratio of the mean SD areas (SDratio = SDn-dom/SDdom) over all tested positions (n = 72). The vector length is a measure of the spatial displacements of the subject, whereas the SD area gives a measure of the spatial uncertainty. The ratio of the SD areas (SDratio) is a measure the relative precision of the settings of the nondominant eyes. The data of all subjects (including the 10 normally sighted control subjects) are included in Table 2 .
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The vectorial subtraction maps of the amblyopic subjects showed idiosyncratic patterns of expansion, contraction or torsion of portions of the visual field, confirming previous studies9 10 (Fig. 5) .
In subjects with strabismic and strabismic–anisometropic amblyopia, both the vector lengths and the SD areas were larger and more irregular than in control subjects. In the four subjects with anisometropia without strabismus, vectorial displacements and SD areas were comparable to those of normally sighted subjects. Particularly pronounced distortions were shown by the two subjects with a bilateral ametropic amblyopia (RS and SB). Both subjects showed large mapping errors and enormous SD areas, affecting both eyes. One of the three subjects with alternating fixation and good vision in both eyes (RF) showed larger displacements and SD areas than the normal control subjects, comparable to those of some subjects with strabismic amblyopia. This subject was previously strabismic–anisometropic amblyopic, treated by pleoptic therapy at an early age. It appears that an early treatment may be beneficial for visual acuity, but less efficient in eliminating the spatial misperceptions which accompany an early strabismic amblyopia.
Group Data
Figure 6 shows the dependence of the individual AVLs and the ratios of the mean SD areas (SDratio) on the visual acuity of the nondominant eye of each subject. Subjects with different etiologies are indicated by different symbols. Subjects who had reported a stable perception in Experiment I are indicated by open symbols and subjects experiencing temporal instabilities by filled symbols.
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To verify the statistical significance of these observations, the data of all subjects were grouped according to different criteria: visual acuity loss (left clusters in Fig. 7 ), etiology (middle clusters), and temporal stability (right clusters). The top panels in Figure 7 indicate the AVLs of the different groups and the bottom panels the ratios of the SD areas of the same groups (SDratios).
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Subjects with a deep amblyopia showed significantly larger spatial displacements (mean AVL, 0.43°) than the normally sighted observers (0.27°; t(16) = 3.5, P < 0.01), but the difference was not significant in subjects with a moderate or no acuity loss (0.34°; t(15) = 1.7, P = 0.10).
SDratio for the subjects with deep amblyopia was 1.45, which was significantly higher than for normally sighted observers (1.07; t(16) = 2.9, P = 0.01). SDratios of subjects with a moderate acuity loss (1.14) did not differ significantly from those of normally sighted control subjects. Mean SDratio of subjects with deep amblyopia was higher than that for subjects with moderate or no amblyopia, but this difference did not reach statistical significance (t(13) = 1.7, P = 0.10).
Relationship between the Magnitude of Spatial Displacements and Etiology.
To quantify the spatial displacements of subjects with different etiologies, we compared the results of subjects with a history of strabismus (strabismic amblyopia, strabismic–anisometropic amblyopia, and strabismus with alternating fixation; n = 9) with those with a refractive etiology (bilaterally ametropic and anisometropic amblyopia; n = 6; Fig. 7 , middle clusters).
AVLs were significantly larger in subjects with a history of strabismus (0.40°) than in normally sighted observers (0.27°; t(17) = 3.1, P < 0.01). The difference was not statistically significant in subjects with a refractive error etiology (0.38°; t(14) = 2.0, P = 0.06). There was no significant difference between the AVLs of the subjects with a history of strabismus and those of subjects with a refractive error etiology (Fig. 7a) .
SDratios of the subjects with a history of strabismus were significantly higher (1.48) than those of the subjects with a refractive etiology (1.04; t(13) = 2.8, P = 0.01) and of the normally sighted observers (1.07; t(17) = 3.1, P < 0.01). SDratios on the amblyopic subjects with a refractive etiology did not differ significantly from those of the control subjects (see Fig. 7b ).
Thus, it seems that both a deep acuity loss and a history of strabismus are related to increased spatial displacements and higher spatial uncertainty.
Relationship between Spatial Displacements and Temporal Instability.
We wondered whether the temporal instability experienced by amblyopic subjects may be related to an increased disorder of the spatial map experienced by these subjects. Inspection of Figures 5 and 6 suggests that a simple correlation is unlikely. Indeed, the subjects showing the most pronounced displacements (RS, SB, and RF) did not report any temporal instability (Fig. 6) . Also, the mean spatial displacements of the subjects experiencing temporal instability (Fig. 6a , filled symbols) were not higher than those of the subjects with a stable perception (Fig. 6a , open symbols).
For a quantitative comparison, we grouped together the subjects who reported experiencing temporal instability in the previous experiment (n = 6) and those with a stable perception (six amblyopic subjects and three strabismic subjects with alternating fixation; n = 9). The results are shown in the right clusters in Figure 7 .
The mean vector lengths of the subjects experiencing temporal instability and those with a stable perception were identical (mean AVL was 0.39° in both groups). Both were significantly higher than the mean AVL of the normally sighted subjects (0.27°; t(17) = 2.4, P < 0.05 for subjects with a stable perception and t(14) = 3.0, P < 0.01 for subjects experiencing temporal instability; Fig. 7a ).
Subjects experiencing temporal instability showed significantly higher spatial uncertainties (the averaged SDratio was 1.60) than subjects with a stable perception (1.11; t(13) = 3.4, P < 0.01) and normally sighted subjects (1.07; t(14) = 4.0, P = 0.001). Subjects with a stable perception did not differ significantly from normal control subjects (see Fig. 7b ).
These results demonstrate that, while all groups of experimental subjects showed abnormally large spatial displacements, only subjects experiencing temporal instability also had an increased positional uncertainty in the amblyopic eyes. One possible interpretation of these results is that a system that perceives visual stimuli as unstable may be more likely to mislocalize these stimuli. Thus, temporal instability may be causally related to the increased spatial imprecision in amblyopic vision.
In this experiment, we refined the two-dimensional mapping procedure of the amblyopic displacements suggested earlier,9 10 using a finer grain of the experimental data collection. As reported in previous studies,6 7 8 9 10 we found that amblyopic subjects showed idiosyncratic expansions, shrinkages, or torsions of portions of the visual field. In addition, the precision of the settings through the amblyopic eyes was dramatically impaired. These impairments affected mainly subjects with a history of strabismus and a deep amblyopia, rather than those with a refractive etiology and mild acuity loss. Subjects with a temporally unstable perception showed more spatial uncertainty in the affected eye than did subjects with a stable perception.
These findings complement the results of the first experiment, in which we reported that a temporally unstable perception is more frequently seen in amblyopic subjects with a history of strabismus and a complete breakdown of binocularity than in amblyopic subjects with a refractive etiology and some residual binocularity.
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Several hypotheses have been put forward to explain the neural substrate of the amblyopic deficit. Hess et al.5 proposed a neural scrambling model (uncalibrated neural disarray), in which the normally accurate retinotopic map of the visual world is disturbed. Levi and Klein30 and Sharma et al.31 posited that the amblyopic deficit results from a thinning out of the cortical neurons representing the amblyopic eye ("sparse sampling," "undersampling"). In previous studies, Sireteanu et al.32 33 34 35 proposed that constant spatial errors in subjects with strabismus may be caused by a systematic shift in the neural map, caused by different patterns of retinal correspondence in the central versus the peripheral visual field; this in turn is related to the different grain of the different retinal regions. Barrett et al.19 20 suggested that the nonveridical spatial perception in amblyopia has its origin in errors in the neural coding of orientation in the primary visual cortex. They proposed a model in which the amblyopic eye perceives two orientations at once. Some of the distortions presented herein may be accounted for in terms of neural scrambling or undersampling. However, the spectacular, idiosyncratic, colored, and moving patterns described by amblyopic subjects are difficult to explain by thinning out, disorganization, or consistent shift of the spatial coordinates of otherwise normally functioning neurons. In the following, we propose an alternative explanation that may account for the misperceptions described in the different studies.
We suggest that, like other neurodevelopmental disorders, amblyopia may be a two-step process. A minority of newborns come into the world with a still-unexplained, presumably genetically determined, weakness of the cortical mechanisms responsible for binocular fusion. If these newborns encounter another visual problem, like an early ocular misalignment, anisometropia, a high bilateral ametropia, or a combination of these, the central pathway of one eye (typically, the more affected one) is chronically eliminated from further processing.
The earlier the onset of this disuse and the longer its duration, the more likely cortical cells belonging to this pathway will fail to connect to each other and to cells from cortical areas subserving other modalities. Loss of resolution and contrast sensitivity may be the negative consequences of this disuse. But on the other hand, unchecked activity may lead to positive symptoms, which may become manifest as an activation that is not related to an actual stimulus in the outside world. Thus, the affected eye may perceive nonexisting contours, in the form of spatial distortions, nonexisting movement, temporal instability, or nonexisting colors.
This anomalous visual experience is reminiscent of the sensory hallucinations associated with some neuropsychiatric disorders. Visual hallucinations in schizophrenia, although relatively rare, have been shown to be associated with objectively measurable activity in higher-order visual areas on the extrastriate ventral visual pathway.36 Despite their very different etiologies, the neural mechanisms underlying anomalous visual perception in amblyopia and hallucinatory perception in developmental neuropsychiatric disorders, may have a similar neural substrate. This hypothetical scenario assumes that the loss of binocularity precedes and most likely causes the amblyopic deficit. We thus agree with a suggestion recently put forward by McKee et al. 28
Our suggested mechanism may reconcile conflicting results on the cortical activation in amblyopia. Several studies have described cortical deficits on stimulation of the amblyopic eye, although the effects were quite variable.37 38 39 40 41 Occasionally increased BOLD signals from the amblyopic eye, occurring in parts of areas V1 and V2 and affecting mainly the higher spatial frequencies, have also been described41 (first reported by Sireteanu R, et al. IOVS 1998;39:ARVO Abstract 909). We suggest that this apparent discrepancy may reflect the dual nature of the amblyopic deficit. While the thinning out of the cortical representation of the amblyopic eye may result in signal reduction, an increased attentional effort may produce the opposite effect. The resultant pattern may differ from one subject to the next.
We suggest that, due to increased attentional effort of an otherwise unchallenged central visual pathway, the requirement of the amblyopic eye on blood oxygenation in earlier areas may be, occasionally, higher than that of the fellow eye. (Indeed, normally sighted subjects show increased activation in area V1 when stimulated with patterns similar to those described by subjects with strabismic amblyopia.27 ) This paradoxically higher activation in part of areas V1 and V2 may occur in addition to the progressive disconnection of the amblyopic eye at higher cortical levels on the ventral pathway.42 43 This disconnection may be a consequence of the loss of synchronization between single cells fed by the amblyopic eye in the primary visual cortex.44
These effects may apply for the ventral, "what" visual cortical pathway, that leads from the primary area 17 to the inferotemporal cortex.45 46 47 On the other hand, cells on the dorsal "where" pathway, leading to the multisensory association areas in the posterior parietal cortex and responsible for localizing objects in space and for integrating vision with action, may also be affected. The unchecked activity of these cells may lead to the reported errors in localization,5 in appreciation of the continuity of contours,11 and in eye–hand coordination.48 They may also be responsible for the perception of illusory movement in the form of temporal instability.
We still do not know what happens in the visual areas on the dorsal pathway and especially in the motion areas MT and MST of amblyopic subjects. Although some psychophysical studies suggest that perception of motion is relatively spared in amblyopia,49 recent studies report that global motion and translation of vision into movement may be affected in amblyopic subjects as well.50 51 Such deficits imply that the dorsal "where" visual pathway leading to the posterior parietal cortex, may also be affected. Studies aimed directly at probing the function of the posterior parietal cortex in amblyopia have yielded conflicting results.52 53 Disruption of higher-order, integrative visual functions may reflect a functional loss in higher cortical areas on both visual pathways.54 55 56
If our scenario proves correct, an increased activation on the use of the amblyopic eye may be observed in the visual motion areas MT and MST in subjects experiencing temporal instability. Likewise, increased activation may be found in color-sensitive areas on the ventral pathway, in subjects experiencing spurious color perception. Further studies, incorporating a combination of psychophysical, computational, and functional imaging techniques, are needed to give an answer to these intriguing questions.
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Submitted for publication March 23, 2007; revised October 11, 2007, and January 13 and February 6, 2008; accepted May 27, 2008.
Disclosure: R. Sireteanu, None; C.C. Bäumer, None; A. Iftime, 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: Ruxandra Sireteanu, Max-Planck-Institut for Brain Research, Deutschordenstrasse 46, 60528 Frankfurt/Main, Germany; sireteanu{at}mpih-frankfurt.mpg.de.
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