Amblyopia, or “lazy eye,” is defined as decreased vision either without a structural abnormality or with a structural abnormality that does not impair visual acuity.1 It is common in adults, with a 5% prevalence, and is the primary cause of monocular reduced vision.2 The condition usually does not affect daily life, except for specialized skills such as acquiring a commercial driver's license. However, in addition to reduced monocular vision, individuals with amblyopia suffer from subnormal or non-binocular perceptual performance.3 Additionally, they suffer from sensory deficits such as reduced position acuity and contrast sensitivity.4 The subtle perceptual dysfunctions in amblyopia cover a broad spectrum that includes abnormal spatial processing, abnormal activities in specific cortical areas, and abnormal integration of visual information over space and time.5
To date, it is unclear whether amblyopia also affects higher cognitive functions, especially in individuals with primarily visuospatial demands. A study of patients with congenital strabismus provided initial insight6: the subgroup of patients with amblyopia showed lower intelligence quotient scores than individuals without amblyopia. However, the differences were not significant and intelligence was assessed with Wechsler intelligence scales,7 which only partly addressed visuospatial abilities.
One test that explicitly measures planning and problem solving requiring visuospatial information processing is the Tower of London (ToL) test.8 The ToL test was originally developed to assess planning deficits in patients with frontal lobe lesions,9 and it was found to depend on activity in the dorsolateral prefrontal cortex.10,11 For the tower transformation task, patients rearrange three colored balls on three pegs from an initial state to a given goal state. The required planning ability is fundamentally associated with fluid intelligence12 and shows a corresponding age-dependent trajectory. The development of planning abilities continues until the third decade of life13 and then linearly decreases from the fourth to the eighth decade.14
These cognitive properties make the ToL test ideal to answer the question: does monocular amblyopia have an impact on planning and problem solving in the adult population? The ToL test can determine whether higher visuospatial abilities are affected by amblyopia.
Patients and Methods
The participants in the current study were from a subgroup of the Gutenberg Health Study. To avoid misclassification bias caused by age-related medical conditions (eg, cataract), we restricted our analysis to the youngest subgroup (aged 35 to 44 years at baseline examination). The recruitment and testing of the cohort have been described in detail elsewhere.15 All participants provided written informed consent. The study design was in accordance with the tenets of the Declaration of Helsinki. The study was approved by the Ethics Commission of the State Chamber of Physicians of Rhineland-Palatinate and by the local and federal data safety commissioners.
Definition of Amblyopia
Amblyopia was defined as a visual acuity of 0.63 or worse (worse eye) with the presence of an amblyogenic factor (strabismus, anisometropia, or deprivation). Further details are published elsewhere.2 The prevalence of amblyopia was 5% in our study sample. To compare the participants with amblyopia to controls, we classified three groups: with amblyopia (n = 78), without amblyopia with a visual acuity of 0.63 or worse (worse eye) (n = 65), and without amblyopia with a visual acuity of better than 0.63 (worse eye) (n = 1,426).
ToL–Freiburg Version (ToL-F) Test
The ToL-F test16 was implemented as a computerized pseudorealistic representation of the original wooden configuration of the ToL test. The tower configuration consists of three rods of different heights, with the left, middle, and right rod being capable of accommodating up to three, two, and one balls, respectively. The tower configuration further comprises three balls colored red, yellow, and blue.
Patients were required to transform the start state into the goal state with the fewest number of moves, which was indicated to the left of the start state in the ToL-F test. The balls were moved with fingers on a touchscreen. Patients were instructed as follows: only one ball may be moved at a time, balls cannot be placed beside the rods, and only the topmost ball can be moved. The computer program does not allow these rules to be broken and it records any attempts to do so. Participants were advised to solve problems with the fewest number of moves and to plan each movement before execution.
The time limit was 1 minute for each test item, and the time limit for the entire assessment was 20 minutes. The ToL problem set consisted of an optimized selection of four-, five-, and six-move problems (eight problems each), providing a monotonic increase in problem difficulty. For the analysis of planning performance, a ToL test score ranging from 0 to 24 was computed by summing the number of problems that were solved with the fewest moves.
Participants were tested individually in a quiet, air-conditioned room at the Gutenberg Health Study Center at the University Medical Center Mainz in Mainz, Germany. Each participant was instructed by an experienced examiner who was present throughout the testing session. A detailed description of the ToL test as implemented in the current study can be found in Kaller et al.14 Sex, age, and socioeconomic status are factors known to influence ToL planning performance,9 so they were considered confounders. Socioeconomic status was defined according to Lampert's and Kroll's scores of socioeconomic status ranging from 3 to 27, where 3 indicated the lowest socioeconomic status and 27 indicated the highest socioeconomic status.17
The authors used a multiple linear regression analysis with amblyopia classification (with amblyopia, without amblyopia with a visual acuity of 0.63 or worse [worse eye], and without amblyopia with a visual acuity of better than 0.63 [worse eye]), age, sex, and socioeconomic status as predictors and the number of correctly solved planning tasks (ToL) as the dependent variable.
The total number of participants was 1,569 and 811 (51.7%) of those were women. Seventy-eight participants suffered from monocular amblyopia with a visual acuity of 0.63 or worse (worse eye). An additional 65 participants without amblyopia demonstrated a visual acuity of 0.63 or worse (worse eye). The main cause of reduced visual acuity was eye trauma. The overall mean ± standard deviation for socioeconomic status was 14.45 ± 3.86, and it was significantly lower in participants with amblyopia (13.42 ± 3.49) and participants with monocular-reduced visual acuity (13.89 ± 4.08). The difference was not significant.
On a descriptive level, the mean ± standard deviation of ToL performance was 15.31 ± 3.29 in individuals without amblyopia with a visual acuity of worse than 0.63, 14.56 ± 3.76 in individuals with amblyopia, and 15.14 ± 3.65 in individuals without amblyopia with a visual acuity of 0.63 or better (worse eye) (Table 1).
The results of the linear regression model are presented in Table 2. Sex and socioeconomic status were significantly associated with planning performance (both P < .0001), but no significant effect was identified for amblyopia (P = .20). As expected from previous data and indicated by the prefixes of the beta estimates (Table 2), better planning performance was observed in men and in participants with a higher socioeconomic status. No significant difference in planning ability was found between participants with and without amblyopia.
Results of Regression Analysis With Planning Performance as the Dependent Variable
The main result of the current study is the independence of amblyopia and visuospatial planning performance as assessed by the ToL test. This point is important when considering the prognosis and the burden of amblyopia.
Our results are supported by neuroimaging studies. In addition to abnormal responses in the primary and secondary visual areas and for the visual pathways within the parieto-occipital and temporal cortices, a recent review reported no abnormalities in the pre-frontal cortices.18 In a resting-state functional magentic resonance imaging study, spontaneous brain activity in children and adults with anisometropic amblyopia revealed differences from controls only in posterior areas such as the bilateral calcarine, middle occipital, or precuneus cortices.19 No activation differences were found in the frontal areas. Consequently, our behavioral results are in accordance with neural findings because the ToL planning task is intimately linked to prefrontal functioning.
However, the question remains: why can higher-order cognition be intact in adulthood when basic visuospatial processing is already impaired in early childhood? One possible explanation is brain plasticity with regard to behavioral manifestations (eg, perceptual learning). The effects of perceptual learning have been well documented in individuals with amblyopia, which makes perceptual learning attractive as a potential therapy.18 An alternative explanation is that higher abstract cognition can develop independently of basal visual processing and, thus, seems to be unaffected in adults with amblyopia. Because both explanations are speculative, further studies are needed to assess the trajectory of basal and higher-order visuospatial abilities in individuals with amblyopia longitudinally from childhood until adulthood, combined with neuroimaging methods.
As expected, we found effects of sex and socioeconomic status on visuospatial planning but no association with age. Men scored significantly higher than women (15.82 ± 3.43 vs 14.74 ± 3.14, respectively), and higher socioeconomic status was associated with better planning performance. These findings concur with previous observations9 and confirm the external validity of the current study. The lack of age-related effects can be explained by the narrow age range in the analyzed sub-cohort.
Although amblyopia is a lifelong condition that affects many aspects of minor visual function, our study did not find a relationship between amblyopia and cognitive function in adulthood. This point is important when considering prognosis and the burden of amblyopia.
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|Variable||All (N = 1,569)||Amblyopia (n = 78)||No Amblyopia, Worse Eye > 0.63 (n = 1,426)||No Amblyopia, Worse Eye ≤ 0.63 (n = 65)|
|Age (y)||45.2 ± 2.6||45.5 ± 2.6||45.2 ± 2.6||45.7 ± 2.7|
|Socioeconomic status||14.45 ± 3.86||13.42 ± 3.49||14.53 ± 3.86||13.89 ± 4.08|
|Visual acuity OD||1.00 ± 0.18||0.69 ± 0.30||1.03 ± 0.13||0.67 ± 0.25|
|Visual acuity OS||1.01 ± 0.18||0.69 ± 0.32||1.04 ± 0.13||0.72 ± 0.26|
|ToL performance||15.26 ± 3.33||14.56 ± 3.76||15.31 ± 3.29||15.14 ± 3.65|
Results of Regression Analysis With Planning Performance as the Dependent Variable
|Characteristic||Beta Estimate||Lower 95% CI||Upper 95% CI||P|
|Sex (female)||−0.92||−1.24||−0.60||< .0001a|
|Socioeconomic status||0.17||0.13||0.22||< .0001a|