The Role of Suppression in Amblyopia

Eye Movements, Strabismus, Amblyopia, and Neuro-Ophthalmology The Role of Suppression in Amblyopia

Jingrong Li,1 Benjamin Thompson,2 Carly S. Y. Lam,3,4 Daming Deng,1 Lily Y. L. Chan,3,4 Goro Maehara,5 George C. Woo,3 Minbin Yu,1 and Robert F. Hess5

PURPOSE. This study had three main goals: to assess the degree uppression plays a key role in the amblyopic syndrome. Its of suppression in patients with strabismic, anisometropic, and Sclinical importance was recognized more than 60 years ago mixed amblyopia; to establish the relationship between sup- by the pioneering work of Travers,1 Jampolsky,2 and later, pression and the degree of amblyopia; and to compare the Pratt-Johnson and Wee,3,4 who showed that its regional distri- degree of suppression across the clinical subgroups within the bution (visual field topography) depends on the type of stra- sample. bismus present. More recently, this approach has been carried on by Joosse et al.5–7 whose innovative work has highlighted METHODS. Using both standard measures of suppression (Bago- the different types of suppression that occur in strabismic lini lenses and neutral density [ND] filters, Worth 4-Dot test) amblyopia and how it varies within any one strabismic subpop- and a new approach involving the measurement of dichoptic ulation. motion thresholds under conditions of variable interocular Although we now have a better idea of the position and contrast, the degree of suppression in 43 amblyopic patients shape of suppressed scotomata, we are still ignorant of their with strabismus, anisometropia, or a combination of both was role and importance in the amblyopia syndrome, a condition in quantified. which there is loss of vision of a nonorganic nature, secondary RESULTS. There was good agreement between the quantitative to strabismus, anisometropia or form deprivation. There are measures of suppression made with the new dichoptic motion some fundamental questions that remain unanswered, the threshold technique and measurements made with standard most important of which relates to whether suppression is of clinical techniques (Bagolini lenses and ND filters, Worth 4-Dot primary or secondary importance to amblyopia. For example, test). The degree of suppression was found to correlate directly suppression could simply follow as a consequence of amblyo- with the degree of amblyopia within our clinical sample, pia as a way of ensuring that the input from a weaker eye does whereby stronger suppression was associated with a greater not disrupt binocular perception. This view is compatible with current treatment approaches that focus on patching or penal- difference in interocular acuity and poorer stereoacuity. Sup- ization as a first step without any regard for suppression, which pression was not related to the type or angle of strabismus is often not quantified clinically and is rarely treated as a when this was present or the previous treatment history. separate entity. The idea that amblyopia and suppression are CONCLUSIONS. These results suggest that suppression may have separate entities gains some support from the suggestion that a primary role in the amblyopia syndrome and therefore have there is a reciprocal relationship between the strength of implications for the treatment of amblyopia. (Invest Ophthal- suppression and the degree of amblyopia; the greater the mol Vis Sci. 2011;52:4169–4176) DOI:10.1167/iovs.11-7233 amblyopia, the less suppression is needed to eliminate that eye’s input from the binocular mix.8 The opposite view, however, is that suppression causes the visual dysfunction in amblyopia. In this scenario, the suppression develops due to a 1 From the State Key Laboratory of Ophthalmology, Zhongshan disruption of binocular function (strabismus or anisometropia), Ophthalmic Center, Sun Yat-sen University, Guangzhou, People’s Re- and it is the chronic suppression itself that results in amblyo- public of China; the 2Department of Optometry and Vision Science, Faculty of Science, The University of Auckland, Auckland, New Zea- pia. This alternative view gains some support from the recent land; the 3School of Optometry, and the 4The Hong Kong Jockey Club finding that, even in adults using repetitive transcranial mag- Sports Medicine and Health Sciences Centre, Faculty of Health and netic stimulation (rTMS), a noninvasive means of transiently Social Sciences, The Hong Kong Polytechnic University, Hong Kong altering neural excitability in the human cortex, a 10-minute SAR, China; and the 5Department of Ophthalmology, McGill Univer- application of TMS can temporarily improve contrast sensitiv- sity, Montreal, Quebec, Canada. ity in amblyopia,9 suggesting that visual function is not lost but Supported by equipment/resources donated by The Hong Kong suppressed. Further support comes from the finding that anti- Jockey Club Charities Trust, Hong Kong Polytechnic University Inter- suppression therapy not only results in improved binocular nal Competitive Research Grant CRG G-YH71 (CSYL), University of function but also in improved monocular functioning of the Auckland Faculty Development Research Fund Award (BT), CIHR 10 Grants MOP 53346 and PPP93073 (RFH), the Fundamental Research adult amblyopic eye. However, before one can accept that Funds of the State Key Lab of Ophthalmology, Sun Yat-sen University suppression is of primary importance in the amblyopic syn- (JL), a Thrasher Research Fund Early Career Award (JL), and the drome, the issue of the relationship between the degree of Guangdong Province International Collaboration Project Grant amblyopia and the strength of suppression should be re- 2010B050100014 (DD). opened, for it is only if there is a direct relationship between Submitted for publication January 15, 2011; revised February 27, these two clinical features that it would be reasonable to 2011; accepted March 16, 2011. assume that suppression is of primary importance. The present Disclosure: J. Li, None; B. Thompson, None; C.S.Y. Lam, None; support for a reciprocal relationship rests on only a small , None; , None; , None; , D. Deng L.Y.L. Chan G. Maehara G.C. Woo sample of patients with clinical suppression (n ϭ 10), only two None; M. Yu, None; R.F. Hess, None of whom had visual acuity worse than 20/30 in the amblyopic Corresponding author: Minbin Yu, Department of Glaucoma, De- 8 partment of Optometry and Vision Science, Zhongshan Ophthalmic eye. Center, Guangzhou 510060, People’s Republic of China; Recently a novel method of quantifying binocular combina- [email protected]. tion in the normal visual system has been developed,11 and we

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have applied it to quantifying the strength of suppression in Suppression Measurement both strabismic and anisometropic amblyopes,12,13 using a global motion stimulus in which signal elements moving in a The Worth-4-Dot Test. The Worth-4-Dot test was performed at coherent direction are seen by one eye and noise elements near (33 cm) and far (6 m) test distances. The filters were placed, moving in random directions are seen by the other eye. This according to convention: red over the right eye and green over the left method is an accurate way, within the context of signal/noise eye. To ensure the visibility of each filter, the participants’ eyes were analysis, of measuring12,13 and treating10 suppression within covered alternately to ensure that each eye was visibly aware of the red the central field. In this study we used this approach to assess and green filters. When this testing was performed monocularly, all the strength of suppression in a group of anisometropic, participants reported seeing two red dots when the left eye was mixed, and strabismic amblyopes. The method provides a occluded (right eye wearing the red filter) and three green dots when more quantitative means (better resolution) of measuring the the right eye was occluded (left eye wearing the green filter). Partici- degree of suppression compared with the Worth 4-Dot test or pants were asked to report the number and color of the dots they saw Ͻ the use of a red filter and neutral density wedge. We first under photopic (118 lux) followed by scotopic ( 0.1 lux) conditions. assessed the relationship between this new signal/noise A scoring system was assigned to grade the depth and the size of the method that can precisely quantify suppression and more tra- suppression scotoma. For example, a four-dot response with the white ditional, relatively coarse, measures of suppression (Worth dot at the bottom was given a score of 0 (no suppression), while a two- 4-Dot test and modified Bagolini test). We then addressed the or three-dot response received a score of 2 (complete suppression). A following two questions: What is the relationship between score of 1 (partial suppression) was assigned to observers who re- visual losses in amblyopia (acuity and stereo) and the degree of ported that they saw four dots, with the color of the bottom white dot suppression? How does suppression vary within the amblyopic being perceived as either green or red. The sum of near and far scores, clinical population? The answers to these questions bear on the which could range from 0 to 4, was used to represent the overall level issue of whether suppression plays a causal role in the visual of suppression as measured by this test, as we found no reliable ϭ loss that characterizes amblyopia. difference between the near and far measurements (sign test, P 1.0). The Neutral-Density Filter with the Bagolini Striated Lens Test. The relative depth of suppression in the amblyopic eye METHODS was assessed by combining the Bagolini striated lenses test with neutral-density (ND) filters.15 Each observer viewed a light source (30 Participants cd/m2) held at 33 cm while wearing Bagolini striated lenses under low ambient room illumination (5 lux). Under normal viewing conditions, A total of 43 amblyopic observers (23 females, 20 males), between the participants with normal binocular function perceive an X, represent- ages of 9 and 56 years (mean age, 20.7 Ϯ 11.9), and 10 normal seen by the گ ing the combination of the / seen by one eye and the observers (4 females, 6 males), between the ages of 20 to 35 years (گ other. However, for participants with suppression, only one line (/ or (mean age, 29.20 Ϯ 5.39), who met the inclusion criteria were en- is perceived within the region affected by the suppression scotoma. To rolled. Clinical details for the amblyopic observers are provided in measure the strength of this suppression, progressively stronger ND Table 1. filters can be placed over the fellow eye until the imbalance in lumi- The normal observers acted as the control group and had equal nance between the two eyes is sufficiently strong to overcome the visual acuity in each eye of at least 20/20; absence of any ocular, suppression and allow for the percept of the X. To achieve this, ND oculomotor, or binocular abnormalities; normal stereoacuity (Յ20 filters (Wratten; Eastman Kodak Company, Rochester, NY), increasing seconds of arc); and a spherical equivalent refractive error of between in 0.3-log-unit increments were mounted on a bar. The filters ranged ϩ1.00 and Ϫ3.00 D, with an unequal spherical equivalent of not more from 0.3 to 3 log units and had a transmittance ranging from 50% to than a 1-D difference between the eyes detected during a standard 0.1%. The ND filter bar was held vertically in front of the fellow fixing ocular examination; and a cylindrical correction of less than 1 D. The (fixating) eye and moved upward to increase the strength of the ND amblyopic group was defined according to the Preferred Practice filter. Participants were asked to report when they could perceive an Protocol (PPP) of The American Academy of Ophthalmology14 and X. The end point of this test was defined as the ND filter strength at classified under one of the following clinical conditions: strabismic which the intensity of the line seen by the amblyopic eye was per- amblyopia (with an angle of strabismus of less than 35⌬), anisome- ceived as the same or slightly stronger than the line seen by the fellow tropic amblyopia with a visual acuity loss in the worse eye of no worse fixing (fixating) eye. To ensure the accuracy of this end point, the ND than 20/100, and mixed (those that met the criteria for both types of filter strength was increased by an additional 0.6 log units below this amblyopia). Subjects with strabismus due to ocular albinism, diplopia, balance point, and the end point was measured again from seeing to anomalous correspondence, or a medical history of seizures were nonseeing until a balanced reversal point was achieved. excluded. All tests were conducted at a constant room luminance, measured with a digital lux meter (TES Electronic Corp., Taipei, Tai- wan). This study complied with the Declaration of Helsinki and was Dichoptic Motion Coherence approved by the Ethics Committee of Zhongshan Ophthalmic Center Threshold Measurements and The Hong Kong Polytechnic University. Informed consent was obtained from all participants before data collection. On the basis of The method we used for measuring interocular suppression using 13 previous data from both amblyopic observers13 and observers with random-dot kinematograms has been described in detail elsewhere. normal binocular vision (Thompson, unpublished data, 2010), we Briefly, stimuli were displayed using a video goggle apparatus (Z800 3D estimated a difference in fellow fixing eye contrast at a balance point Visor; eMagin Corp., Washington, DC) driven by a laptop computer of 70% contrast between controls and observers with amblyopia with (MacBook Pro; Apple Computer, Cupertino, CA, running MatLab; The a maximum SD of 17%. To detect this difference at a significance level MathWorks, Natick, MA) and the Psychophysics Toolbox, version 12,13,16 of P Ͻ 0.01 with a power of 0.99 would require three participants per 3. This apparatus allowed for separate images to be presented to group. Our smallest subgroup contained 10 participants. each eye and for the images in each eye to be aligned by the participants, using routines within the stimulus presentation software. Stim- Stereo Acuity Test uli were random-dot kinematograms, which consisted of a population of signal dots, all moving in a common direction, and a population of Stereoacuity was assessed using the Randot stereo graded circle test noise dots, that moved randomly. Dots were bright against a mean (Random Dot 2 Acuity Test, Vision Assessment Corp., Elk Grove Vil- luminance background (35 cd/m2). The luminance modulation (Mi- lage, IL). These values are reported in Table 1. chelson contrast) and hence the visibility of the dots could be varied by

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TABLE 1. Clinical Details for the Observers with Amblyopia

Cycloplegic LogMAR LogMAR Age Refractive Visual Visual Acuity Ocular Dev. Stereopsis Observer Sex (y) Type Error (OD/OS) Acuity (OD) (OS) (Prism D) History (sec arc)

01 F 17 A ϩ3.35Ϫ0.50x145 0.09 Ϫ0.08 4XP Diagnosed: 7 years old 100 ϩ1.25Ϫ0.50x110 (ϩ) Patched: 4 years 02 F 11 A ϩ2.00Ϫ0.25x161 0.04 Ϫ0.18 4XP Diagnosed: 8 years old 50 Ϫ1.25Ϫ0.75x178 (ϩ) Patched: 2 years 03 F 43 A Ϫ0.75 DS 0 0.15 0 Diagnosed: 43 years old 40 ϩ3.25ϩ0.50x076 No treatment 04 F 56 A ϩ4.75 DS 0 0.15 0 No detection 70 ϩ7.50Ϫ3.00x040 No treatment 05 F 34 A ϩ2.75Ϫ0.50x170 0 0.18 0 No detection 400 ϩ6.00Ϫ1.50x013 No treatment 06 F 17 A Ϫ2.50 DS 0 0.52 0 Diagnosed: 17 years old Suppression ϩ4.50ϩ2.50x095 No treatment 07 F 11 A Plano DS 0 0.40 0 Diagnosed: 11 years old 200 ϩ4.25ϩ2.00x155 No treatment 08 F 13 A ϩ0.50DS Ϫ0.18 0.70 0 Diagnosed: 13 years old Suppression ϩ4.50DS No treatment 09 F 13 A Plano DS Ϫ0.08 0.15 0 Diagnosed: 13 years old 70 ϩ2.50Ϫ3.50x175 No treatment 10 F 32 A ϩ5.50ϩ1.00x165 0.30 0 0 Diagnosed: 6 years old Suppression Ϫ1.00Ϫ0.75x175 (ϩ) Patched: 6 years 11 F 24 A ϩ5.00Ϫ1.50x021 0 0.10 0 Diagnosed: 6 years old 70 ϩ6.75Ϫ1.75x170 (ϩ) Patched: 4 years 12 M 43 A Ϫ1.00DS 0 0.40 0 No detection 100 ϩ2.25DS No treatment 13 M 19 A Plano DS Ϫ0.08 0.70 0 No detection Suppression ϩ7.00ϩ0.75x180 No treatment 14 M 15 A Ϫ1.00Ϫ0.50x180 0.14 0 0 Diagnosed: 15 years old 80 ϩ2.50ϩ1.00x180 No treatment 15 M 21 A ϩ1.00ϩ3.50x165 0.15 0.08 0 Diagnosed: 21 years old 100 Plano DS No treatment 16 M 15 A ϩ0.50ϩ0.50x175 Ϫ0.18 0.70 0 Diagnosed: 15 years old Suppression ϩ7.50ϩ1.25x75 No treatment 17 M 19 A Ϫ1.25Ϫ0.50x065 0 0.30 0 Diagnosed: 7 years old 120 ϩ3.50ϩ1.25x175 (ϩ) Patched: 4 years 18 M 21 A ϩ3.50 DS 0.15 Ϫ0.08 0 No detection 100 Plano DS No treatment 19 M 40 A Ϫ0.50 DS 0 0.10 0 No detection 100 ϩ2.50 DS No treatment 20 M 37 A ϩ3.50ϩ1.00x100 0.30 0 0 No detection 200 Plano DS No treatment 21 M 10 A ϩ1.25 DS 0 0.70 0 Diagnosed: 8 years old 200 ϩ4.50 DS (ϩ) Patched: 2 years 22 M 18 A ϩ5.00Ϫ0.50x130 0 0.10 0 No detection 200 ϩ4.25ϩ0.50x010 No treatment 23 F 10 AS ϩ6.50Ϫ1.50x177 0.10 0 0* Diagnosed: 3 years old 30 ϩ4.50Ϫ2.00x175 (ϩ) Patched: 2 years (ϩ) Surgery at 7 years old 24 F 48 AS ϩ5.00Ϫ0.50x130 0.70 0 20ET, 35ETЈ Diagnosed: 6 years old Suppression ϩ3.25Ϫ0.75x090 (ϩ) Patched (ϩ) Surgery 25 M 10 AS ϩ1.00Ϫ0.75x005 Ϫ0.08 0.05 0* Diagnosed: 6 years old 20 ϩ2.75Ϫ1.75x170 (ϩ) Surgery at 5 years old 26 M 17 AS Ϫ1.25 DS 0 0.22 0* Diagnosed: 6 years old Suppression ϩ4.25ϩ1.00x165 (ϩ) Patched (ϩ) Surgery at 7 years old 27 M 15 AS ϩ1.25ϩ1.00x175 0 0.70 0, 20XTЈ No detection Suppression ϩ6.50ϩ2.25x165 No treatment 28 M 26 AS ϩ5.25ϩ2.00x165 0.52 Ϫ0.08 10XT, 15XTЈ No detection Suppression Plano DS No treatment 29 M 29 AS Ϫ1.25 DS Ϫ0.18 0.05 15ET Diagnosed: 5 years old 70 ϩ2.00ϩ1.00x165 (ϩ) Patched (ϩ) Surgery 30 F 10 S Ϫ7.00Ϫ2.25x010 0 0.4 0* Diagnosed: 6 years old 100 Ϫ8.00Ϫ2.50x170 (ϩ) Patched (ϩ) Surgery (continues)

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TABLE 1 (continued). Clinical Details for the Observers with Amblyopia

Cycloplegic LogMAR LogMAR Age Refractive Visual Acuity Visual Acuity Ocular Dev. Stereopsis Observer Sex (y) Type Error (OD/OS) (OD) (OS) (Prism D) History (sec arc)

31 F 10 S Ϫ0.50Ϫ1.50x178 0.14 0 15XT, 10XTЈ (ϩ) Surgery at 6 years old 40 Ϫ0.50Ϫ0.50x178 (ϩ) Patched (ϩ) Surgery 32 F 26 S Ϫ1.75Ϫ1.00x032 Ϫ.04 0.10 10XT, 15XTЈ Detection N/A 40 Ϫ4.25Ϫ0.75x161 (ϩ) Vision training treatment 33 F 9 S Ϫ2.00Ϫ1.50x010 0.16 0 10ET, 15ETЈ No detection 25 Ϫ4.00Ϫ0.50x166 No treatment 34 F 12 S ϩ1.25 DS 0 0.10 0, 10XTЈ Detection N/A 200 Plano DS (ϩ) Patched (ϩ) Surgery at 7 years 35 F 16 S Plano DS 0.10 0 15XT, 10XTЈ No detection 120 Planoϩ0.50x175 No treatment 36 F 15 S Ϫ0.50 DS 0.16 0 20ET Diagnosed: 8 years old 200 ϩ1.25ϩ0.50x175 (ϩ) Surgery at 10 years old 37 F 15 S ϩ1.00ϩ0.50x030 0 0.22 35ET, 35ETЈ No detection 400 ϩ2.00ϩ0.50x145 No treatment 38 F 12 S Plano DS 0 0.15 25ET, 15ETЈ No detection 80 Plano DS No treatment 39 M 14 S ϩ0.75 DS 0 0.15 30XT, 25XTЈ Diagnosed: 6 years old 100 ϩ0.75 DS No treatment 40 M 12 S ϩ1.00 DS Ϫ0.08 0.10 30XT, 25XTЈ No detection 140 Ϫ0.25 DS No treatment 41 M 12 S Ϫ0.25 DS Ϫ0.08 0.10 20ET, 15ETЈ Diagnosed: 4 years old 80 ϩ0.50 DS (ϩ) Surgery at 6 years old 42 M 32 S ϩ0.50 DS 0 0.15 30ET, 35ETЈ No detection 70 Ϫ0.75 DS No treatment 43 F 10 S Ϫ4.00Ϫ2.75x002 0.05 0.15 15XT, 10XTЈ No detection 30 Ϫ4.25Ϫ2.75x002 No treatment

Ocular dev., ocular deviation; A, anisometropia; AS, mixed amblyopia with anisometropia and strabismus; S, strabismic amblyopia; plano, plain lens; ET, esotropia; XP, exophoria; XT, exotropia; DS, diopter sphere. * Strabismus that has been surgically corrected; (ϩ), a positive therapeutic outcome. If the strabismus was different, at distance and near, both deviations are supplied, the top one being distance.

increasing the luminance of the dots, with respect to the background, balance point contrast can be considered as a parametric measurement according to the following equation: of suppression.12 For the control group the nondominant eye, as defined by the hole-in-the-card test, was designated as the amblyopic ϭ Ϫ Dot luminance contrast (%) 100[(Ldots Lbackground)/(Lbackground)] eye for these measurements. The alignment of central nonius lines (one to each eye) was used to ensure accurate alignment of the stimulus fields seen by the right and left eyes. Subjects were asked to where Ldots and Lbackground are the dot and background luminance, respectively. Signal dots were presented to one eye, and noise dots attend to the central part of the stimulus field. The fact that for this were presented to the other eye. The task was to indicate the motion stimulus corresponding points are not stimulated (i.e., the signal and direction of the signal dots. A staircase procedure controlled the noise dots do not overlap in space) allows fusion to occur on a more relative proportion of signal-to-noise dots in the stimulus to allow for global level, and we believe it is this that makes its use as a treatment the measurement of a motion coherence threshold (the number of so effective. We view the point-wise suppression as more of V1 func- signal dots required for 71% correct performance; see Black et al.13 for tion and the global suppression more of extrastriate function. further details [their method 1] and illustrative figures of this technique). To measure suppression, the contrast of the dots presented to RESULTS the amblyopic eye was fixed at 100% whereas the contrast of the dots presented to the fellow fixing eye was varied across five contrast levels A one-way ANOVA conducted on the balance point data re- (100%, 80%, 50%, 25%, and 12.5% contrast, equivalent to dot lumi- vealed a significant main effect of group (control versus stra- 2 ϭ Ͻ nances of 70, 63, 52.5, 43.8, and 39.4 cd/m , respectively), using the bismic versus anisometropic versus mixed; F(3,49) 12.18, P method of constant stimuli. Within a single measurement session, 10 0.0001. Post hoc Bonferroni tests (corrected for multiple com- randomly interleaved staircases were presented, five for each contrast parison) revealed that the control group balance points were level with the signal dots shown to the amblyopic eye and five for the significantly higher than those of each of the three amblyopic signal dot presentation to the fellow fixing eye. Two measurement groups (strabismic P Ͻ 0.03; anisometropic P Ͻ 0.001; mixed sessions were conducted per patient separated by a 30-minute break. P Ͻ 0.001). The amblyopic groups did not differ significantly The fellow fixing eye contrast at which the motion coherence thresh- from one another (P Ͼ 0.05). The mean contrast presented to olds were the same irrespective of which eye saw the signal and which the fellow fixing (or dominant) eye at the balance point and the saw the noise was calculated by fitting linear functions to the average corresponding 95% confidence interval (CI) can be seen in threshold data for each eye as a function of fellow fixing eye contrast Figure 1. It is evident that amblyopic participants had a signif- and calculating the intersection of these fits.13 We refer to this dichop- icantly larger imbalance between the eyes than the control tic contrast offset as the “balance point,” as it represents the point at participants (i.e., lower fellow eye contrasts at balance point) which suppression has been overcome and information is being com- consistent with the presence of interocular suppression. The bined between the two eyes in a normal fashion.12,13 Therefore, the fact that control participants did have a small contrast offset

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reflects the sensitivity of this test to eye dominance.11,17 The mean coherence thresholds (i.e., the number of signal dots) at the balance point (95% CI) were as follows: controls, 16 (14– 19); anisometropic, 10 (9–12); mixed, 11 (8–13); and strabismic, 13 (11–15). These results demonstrate that once balanced, the amblyopic participants performed no worse, in fact a little better, than the control observers; however, thresholds across the groups were generally comparable. The thresholds of amblyopic participants were very similar to those in previous reports using related techniques in a group of observers with amblyopia13 and a group of observers with normal binocular vision who were shown stimuli of equal contrast to both eyes.17 The relatively elevated thresholds we found for the control participants may reflect the fact that this technique is designed to measure suppression, and the use of a large range of contrasts may slightly bias motion coherence estimates when suppression is not present. As our group of observers with amblyopia included both adult and juvenile (Յ17 years of age) patients, we conducted a separate analysis to investigate the effect of age on the balance point data and on motion coherence thresholds. We found no difference between adults and juveniles for either the balance ϭ ϭ point data (t(41) 0.7, P 0.52; juvenile mean, 56.4 [SD 21.5]; adult mean, 52.7 [SD 15.3]) or the motion coherence threshold ϭ ϭ data (t(41) 0.53, P 0.60; juvenile mean, 11.5 [SD 3.8]; adult mean, 11.0 [SD 3.1]). We also found no correlation between age and either the balance point data (Spearman’s ␳ ϭϪ0.2, P ϭ 0.22) or the motion coherence data (Spearman’s ␳ ϭ 0.07, P ϭ 0.65). These analyses indicate that the patient’s age did not FIGURE 2. The relationship between the contrast presented to the fellow fixing eye at the balance point and suppression on the Worth systematically influence these variables. As such, the observers 4-Dot test (A) and the modified Bagolini striated lenses test (B). Higher with amblyopia were treated as a single group in subsequent numbers on both the Worth and Bagolini tests (x-axis) are indicative of analyses. greater suppression. Smaller contrast values for the balance point To compare the balance point test with clinical tests of (y-axis) are indicative of greater suppression, as a larger imbalance suppression, we correlated the results of the Worth 4-Dot test between the eyes is required for binocular combination to occur. (A) and the modified Bagolini striated lenses test with the balance Interval data on the abscissa and ordinal data on the ordinate axis. The point contrast. The near and far results for the Worth 4-Dot test statistical analysis for this comparison was nonparametric and con- were combined to give a score from 0 (no suppression for ducted on the ranked data using Spearman’s rho. either test) to 4 (full suppression on both tests). For both suppression measures, there was a significant negative correlation with the fellow fixing eye’s contrast at the balance point The contrast at the balance point also correlated signifi- ␳ ϭ ϭ (rank; Worth 4-Dot, ␳ ϭϪ0.57, P Ͻ 0.0001; modified Bagolini, cantly with both stereo sensitivity ( 0.47, P 0.002; the ␳ ϭϪ0.74, P Ͻ 0.0001; Fig. 2). This finding demonstrates that greater the stereo sensitivity, the less the difference in contrast the larger the difference in contrast between the two eyes that between the eyes) and the acuity difference in log units be- is necessary for normal binocular combination of motion sig- tween the eyes (␳ ϭϪ0.60, P Ͻ 0.001; the greater the acuity nals (i.e., the lower the contrast in the fellow eye; recall that difference, the greater the contrast difference). These correla- the contrast to the amblyopic eye remains fixed at 100%), the tions are shown in Figure 3. To assess whether the relationship larger the amount of suppression measured using standard and between these two variables and the contrast at balance point modified clinical tests. differed among anisometropic, mixed, and strabismic amblyopes, we performed a univariate general linear model analysis on the contrast at balance point data with amblyopia type (anisometropic versus mixed versus strabismic), acuity difference between the eyes, and stereo sensitivity as covariates. The model revealed a significant interaction between amblyopia type and acuity difference, F ϭ 10.02, P ϭ 0.003, demonstrating that the effect of visual acuity difference on balance point contrast varied across the different amblyopia subtypes. There was no significant interaction between amblyopia subtype and stereo sensitivity, suggesting that the effect of stereo sensitivity did not vary across the different amblyopia subtypes. To ex- plore the interocular visual acuity difference and amblyopia subtype interaction further, we correlated interocular visual acuity difference with balance point contrast separately for each amblyopia subtype. Both the strabismic and mixed am- FIGURE 1. The contrast presented to the fellow (or dominant) eye to blyopes showed significant negative correlations (strabismic: achieve balanced performance on the motion coherence task between ␳ ϭϪ ϭ ␳ ϭϪ ϭ the two eyes (i.e., the same motion coherence threshold was achieved 0.62, P 0.018, mixed: 0.82, P 0.023). The regardless of which eye was presented with noise and which with anisometropic amblyopes also showed a negative correlation, signal). Error bars, 95% CI of the mean. Controls, n ϭ 10, ani- but it did not quite reach significance (␳ ϭϪ0.42, P ϭ 0.053), sometropes, n ϭ 22; mixed, n ϭ 7; and strabismics, n ϭ 14. suggesting that the presence of strabismus influenced the

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FIGURE 4. The relationship between fellow eye contrast at balance point and the motion coherence threshold ratio between the eyes when 100% contrast was shown to both eyes. Larger threshold ratios and lower fellow eye contrasts indicate a greater deﬁcit for the amblyopic eye under dichoptic viewing conditions.

surements relative to the nontreated group (between-subjects t-tests, P Ͼ 0.05) and none of our outcome measures covaried with treatment and amblyopia subtype (univariate ANOVA with covariates of treatment type and amblyopia subtype). Figure 5 shows the mean contrast for the fellow fixing eye at balance point (Fig. 5A) and the mean interocular acuity difference (Fig. 5B) for each of the treatment groups (no treatment, patching only, surgery only, and both surgery and patching. FIGURE 3. The relationship between contrast in the fellow fixing Finally, we considered only the participants with strabismic eye at the balance point and stereo sensitivity (A) or acuity differ- or mixed amblyopia who still had strabismus to assess whether ence between the eyes ( ). Dashed lines: the best linear fit to the B the extent of strabismus was related to the strength of suppres- data. For stereo sensitivity (A) the negative correlation shows that the lower the balance point contrast in the fellow fixing eye (i.e., sion. The relationship between angle of deviation and suppres- the greater the difference between the eyes), the lower the stereo sion is shown in Fig. 6 for both the balance point measure (Fig. sensitivity. The positive correlation for acuity difference (B) dem- 6A) and the Bagolini measure (Fig. 6B) of suppression. Exo- onstrates that the greater the difference between the eyes at bal- tropes and esotropes are identified in these plots by the use of ance point contrast, the larger the acuity difference. filled and hollow markers, respectively. There were no reliable relationships between deviation angle and strength of suppres-

strength of the relationship between acuity difference and balance point contrast. We have shown that dichoptic motion coherence thresholds can be used to assess sensory ocular dominance in observers with normal binocular vision.18 Since the participants in this previous study did not have any interocular suppression, we did not vary contrast between the eyes but rather presented stimuli at 100% contrast to both eyes and calculated the motion coherence threshold ratio for signal dots presented to the left eye versus signal dots presented to the right eye. To assess the relationship between this measure and the balance point measure for amblyopic observers, for each participant, we calculated the threshold ratio when stimuli were presented at 100% contrast for both eyes and correlated the result with the balance point measure. The threshold ratio was calculated as amblyopic eye threshold/fellow eye threshold, and therefore larger ratios indicate a greater degree of suppression of the amblyopic eye. As shown in Figure 4 these two measures correlated signiﬁcantly (␳ ϭϪ0.77, P Ͻ 0.001). This relation- ϭ ship did not covary with amblyopia subtype (F(1,40) 0.17, P ϭ 0.69). Next, we assessed whether the amount of suppression was greater in participants who had never received treatment for their amblyopia. Within our sample, 16 anisometropic and 7 strabismic amblyopes had never received treatment, 6 anisometropic and 1 mixed amblyope had received patching only, 6 FIGURE 5. Mean fellow eye contrast at balance point (A) and intero- strabismic and 2 mixed amblyopes had received surgery only, cular acuity difference (B) for participants who had never received and 4 strabismic and 1 mixed amblyope had received both treatment (n ϭ 23), received patching only (n ϭ 7), received surgery patching and surgery. We found that the patients who had only (n ϭ 8), or received both patching and surgery (n ϭ 5). Errors received treatment showed no difference in any of our mea- bars, 95% CI.

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results suggest that this new approach has promise for quantifying suppression in binocular dysfunction and eye dominance in both clinical and normal populations.12,13,17 What is the relationship between visual losses in amblyopia (acuity and stereo) and the degree of suppression?We determined the extent to which the contrast of the stimuli (signal or noise) presented to the fellow fixing eye had to be reduced in order for normal sensory binocular combination to take place (the contrast of stimuli seen by the amblyopic eye was fixed at 100%). As discussed above, this measure of suppression is in close agreement with standard clinical measures. We found that the degree of suppression measured using this technique significantly correlated with the degree of amblyopia and stereo loss. In other words, the greater the suppression, the greater the amblyopia. This result is contrary to accepted wisdom8 that stronger suppression is associated with weaker amblyopia, but is consistent with previous reports demonstrating stronger suppression with deeper amblyopia.18–20 It should be noted that our study differed from that of Holopigian et al.8 in several ways. Our sample was larger and had a greater range of amblyopia severity than did the sample reported by Holopigian et al., which mainly contained patients with very mild amblyopia (visual acuity of 20/30Ϫ2 or better in the amblyopic eye). Also their sample contained a dispropor- tionate number of patients with alternating strabismus (8 patients in a sample of 10), which may represent a special category. A comparison of our findings with those of Holopi- gian et al. therefore raises the possibility that the suppression found in patients with amblyopia may differ from that in patients with alternating strabismus without amblyopia or in patients with very mild amblyopia. In addition, our primary FIGURE 6. The relationship between the angle of strabismus and measure of suppression differed from that used by Holopigian strength of suppression using the balance point measurement (A) and et al., who used monocular and dichoptic increment threshold the Bagolini method (B). The two larger circles indicate overlapping measurements for 3.3-cyc/deg sinusoidal gratings presented esotrope and exotrope data points. Dashed lines: indicate linear fits to foveally. Of note, their data show the same, albeit a weaker, the data. relationship between suppression and stereopsis that we report wherein stronger suppression results in reduced stereopsis, as one would expect. sion; however, in the esotropes there was a trend toward Our results, while being consistent with the idea that am- increasing suppression with increasing angle of deviation for blyopia results from suppression rather than the other way the balance point measure, which did not reach significance, around, do not in themselves prove a causal connection. It is probably due to the small sample size of this group (n ϭ 5; ␳ ϭ possible that they are positively correlated because both are Ϫ0.7, P ϭ 0.2). In addition, we found no relationship between the result of another factor, as yet unknown. What we can say angle of deviation and stereo acuity or interocular acuity difference (P Ͼ 0.05 for both). is that if suppression were simply a mechanism to stop the diplopic vision from an amblyopic eye from reaching perception, then a greater degree of suppression would be necessary DISCUSSION for mild compared with severe amblyopia. That is not what we found. In this study, we set out to answer the three questions detailed How does suppression vary among the amblyopic clinical below. population? Although it is commonly thought that the greatest How does the new balance point method compare with degree of suppression occurs in cases of strabismic amblyopia the current clinical standards (Worth 4-Dot test and modified Bagolini test) across a clinical population? Using a novel and the least in cases of anisometropia, we did not find any approach involving the measurement of dichoptic motion significant differences between the degree of suppression in thresholds for stimuli of different interocular contrast, we adults with strabismus, anisometropia, or mixed strabismus show that the degree of suppression is significant in strabis- and anisometropia using our balance point measurement. Fur- mus, anisometropia, and mixed amblyopia, but that there was thermore, we did not find that the degree of suppression no significant difference across our clinical sample in the dif- depended on the angle of the strabismus or the type of devia- 8,21–26 ferent subgroups (i.e., strabismics, anisometropes, and mixed). tion, in agreement with previous studies. However our We also demonstrate that this new quantitative approach to sample size was necessarily small, and therefore these results the measurement of suppression correlates strongly with tra- are not definitive. A caveat is needed here, because our method ditional, albeit qualitative, clinical measures. Finally, we show averages sensitivity over the central 20° and can only provide a significant correlation between the balance point measure a global measure of suppression. Since there is evidence that and a more abbreviated measurement based on the same prin- the size and extent of suppression scotomata depend on the ciple previously used to quantify sensory dominance in the type and angle of squint,1–4,7 a more localized measure is normal population.17 This conclusion is supported by data on needed to address this issue. We are currently investigating this eye dominance within the normal population.18 In all, these question.

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CONCLUSIONS period of visual development. Restor Neurol Neurosci. 2010;28: 793–802. If it is indeed the case that suppression plays a causal role in 11. Hess RF, Hutchinson CV, Ledgeway T, Mansouri B. Binocular amblyopia, as our current data suggest, then there is an argu- influences on global motion processing in the human visual sys- ment to be made for incorporating therapeutic approaches that tem. Vision Res. 2007;47:1682–1692. directly target amblyopic eye suppression into amblyopia treat- 12. Mansouri B, Thompson B, Hess RF. Measurement of suprathresh- ment regimens. We have recently shown that repeated expo- old binocular interactions in amblyopia. Vision Res. 2008;48: sure to dichoptic motion coherence threshold stimuli can 2775–2784. effectively reduce suppression in adults with amblyopia, which 13. Black JM, Thompson B, Maehara G, Hess RF. A compact clinical in turn can improve visual acuity and stereopsis.10,27 These instrument for quantifying suppression. Optom Vis Sci. 2011;88: findings add further weight to the hypothesis that suppression E334–E343. plays a primary role in the amblyopia syndrome and the im- 14. American Academy of Ophthalmology. Preferred Practice Patterns. portance of considering suppression when treating amblyopia. Amblyopia PPP, September 2007. Available at http://www.aao.org/ These visual improvements are sustained and have so far been ppp. Accessed April 23, 2009. demonstrated in adults well beyond the critical period of visual 15. Steinman S, Steinman B, Garzia R. Foundations of Binocular development. We are presently developing a handheld, take Vision: a Clinical Perspective. McGraw-Hill Companies. 2000; home device on which the balance point principles are imple- 145–147. mented in the form of a video game, suitable for the younger 16. Brainard DH. The Psychophysics Toolbox. Spat Vis. 1997;10:433– age group. 436. 17. Li J, Lam CS, Yu M, et al. Quantifying sensory eye dominance in the References normal visual system: a new technique and insights into variation across traditional tests. Invest Ophthalmol Vis Sci. 2010;51:6875– 1. Travers T. Suppression of vision in squint and its association with 6881. retinal correspondence and amblyopia. Br J Ophthalmol. 1938;22: 18. Sireteanu R. Binocular vision in strabismic humans with alternating 577–604. fixation. Vision Res. 1982;22:889–896. 2. Jampolsky A. Characteristics of suppression in strabismus. Arch 19. Sireteanu R, Fronius M. Naso-temporal asymmetries in human Ophthalmol. 1955;54:683–696. amblyopia consequence of long-term interocular suppression. Vi- 3. Pratt-Johnson J, Wee HS. Suppression associated with exotropia. sion Res. 1981;21:1055–1063. Can J Ophthalmol. 1969;4:136–144. 20. Wong AM, Burkhalter A, Tychsen L. Suppression of metabolic 4. Pratt-Johnson JA, Wee HS, Ellis S. Suppression associated with activity caused by infantile strabismus and strabismic amblyopia in esotropia. Can J Ophthalmol. 1967;2:284–291. striate visual cortex of macaque monkeys. J AAPOS. 2005;9:37–47. 5. Joosse MV, Simonsz HJ, Spekreijse H, Mulder PG, van MindeRhout 21. Harrad R, Sengpiel F, Blakemore C. Physiology of suppression in HM. The optimal stimulus to elicit suppression in small-angle strabismic amblyopia. Br J Ophthalmol. 1996;80:373–377. convergent strabismus. Strabismus. 2000;8:233–242. 22. Hess RF. The site and nature of suppression in squint amblyopia. 6. Joosse MV, Simonsz HJ, van MindeRhout EM, Mulder PG, de Jong Vision Res. 1991;31:111–117. PT. Quantitative visual fields under binocular viewing conditions 23. Hofeldt TS, Hofeldt AJ. Measuring colour rivalry suppression in in primary and consecutive divergent strabismus. Graefes Arch Clin Exp Ophthalmol. 1999;237:535–545. amblyopia. Br J Ophthalmol. 1999;83:1283–1286. 7. Joosse MV, Simonsz HJ, van MindeRhout HM, de Jong PT, Noordzij 24. Joose MV, Simonsz HJ, de Jong PT. The visual field in strabismus: B, Mulder PG. Quantitative perimetry under binocular viewing a historical review of studies on amblyopia and suppression. Stra- conditions in microstrabismus. Vision Res. 1997;37:2801–2812. bismus. 2000;8:135–149. 8. Holopigian K, Blake R, Greenwald MJ. Clinical suppression and 25. Sengpiel F, Blakemore C. The neural basis of suppression and amblyopia. Invest Ophthalmol Vis Sci. 1988;29:444–451. amblyopia in strabismus. Eye (Lond). 1996;10:250–258. 9. Thompson B, Mansouri B, Koski L, Hess RF. Brain plasticity in the 26. Sireteanu R. Human amblyopia: consequence of chronic interocu- adult: modulation of function in amblyopia with rTMS. Curr Biol. lar suppression. Hum Neurobiol. 1982;1:31–33. 2008;18:1067–1071. 27. Hess RF, Mansouri B, Thompson B. A binocular approach to 10. Hess RF, Mansouri B, Thompson B. A new binocular approach to treating amblyopia: antisuppression therapy. Optom Vis Sci. 2010; the treatment of amblyopia in adults well beyond the critical 87:697–704.

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