effects of strabismic amblyopia and strabismus without amblyopia...
TRANSCRIPT
Eye Movement, Strabismus, Amblyopia, and Neuro-Ophthalmology
Effects of Strabismic Amblyopia and Strabismus withoutAmblyopia on Visuomotor Behavior, I: Saccadic EyeMovements
Ewa Niechwiej-Szwedo,1 Manokaraananthan Chandrakumar,1 Herbert C. Goltz,1,2
and Agnes M. F. Wong1,2
PURPOSE. It has previously been shown that anisometropicamblyopia affects the programming and execution of saccades.The aim of the current study was to investigate the impact ofstrabismic amblyopia on saccade performance.
METHODS. Fourteen adults with strabismic amblyopia, 13 adultswith strabismus without amblyopia, and 14 visually normaladults performed saccades and reach-to-touch movements totargets presented at 658 and 6108 eccentricity duringbinocular and monocular viewing. Latency, amplitude, andpeak velocity of primary and secondary saccades weremeasured.
RESULTS. In contrast to visually normal participants who hadshorter primary saccade latency during binocular viewing, nobinocular advantage was found in patients with strabismuswith or without amblyopia. Patients with amblyopia had longersaccade latency during amblyopic eye viewing (P < 0.0001);however, there were no significant differences in saccadeamplitude precision among the three groups across viewingconditions. Further analysis showed that only patients withsevere amblyopia and no stereopsis (n ¼ 4) exhibited longerlatency (which was more pronounced for more central targets;P < 0.0001), and they also had reduced amplitude precisionduring amblyopic eye viewing. In contrast, patients with mildamblyopia (n ¼ 5) and no stereopsis had normal latency andreduced precision during amblyopic eye viewing (P < 0.001),whereas those with gross stereopsis (n¼5) had normal latencyand precision. There were no differences in peak velocityamong the groups.
CONCLUSIONS. Distinct patterns of saccade performance accord-ing to different levels of visual acuity and stereoscopic losses instrabismic amblyopia were found. These findings were incontrast to those in anisometropic amblyopia in which thealtered saccade performance was independent of the extent ofvisual acuity or stereoscopic deficits. These results were most
likely due to different long-term sensory suppression mecha-nisms in strabismic versus anisometropic amblyopia. (Invest
Ophthalmol Vis Sci. 2012;53:7458–7468) DOI:10.1167/iovs.12-10550
Amblyopia is a neural disorder caused by inadequate visualstimulation during the early critical period of develop-
ment.1 Amblyopia is commonly associated with two riskfactors: strabismus (eye misalignment) and anisometropia(difference in refractive errors between the eyes).2 Patientswith amblyopia have reduced visual acuity and contrastsensitivity, as well as other perceptual deficits,3–10 which aremost pronounced during amblyopic eye viewing; however,they are also evident during fellow eye viewing, albeit to alesser extent.11–13
The effects of amblyopia on visuomotor behavior have notbeen examined as extensively as the sensory/perceptualdeficits. This is surprising because a fundamental function ofthe brain is to use sensory information from all modalities tomake purposeful, goal-directed behaviors through the processof sensorimotor integration. Vision provides critical informa-tion about the location and properties of objects that we wantto interact with or avoid. To see an object in detail, the fovea—the area of highest resolution on the retina—has to be directedtoward the object, which is achieved via saccadic eyemovements. Visual information is combined across eyemovements to form internal spatial representations of theexternal world.14,15 Thus, saccadic eye movements are anessential component of the action–perception loop, and playan important role in guiding flexible behaviors while peopleinteract with objects in dynamic environments.
Our group has been studying the effects of impairedspatiotemporal visual functions in amblyopia on motorbehavior. In a series of detailed investigations, we haverecently reported the impact of anisometropic amblyopia onsaccadic eye movements,16 reaching movements of the upperlimb,17,18 and eye–hand coordination19 during visually guidedreaching. Specifically, we have shown that patients withanisometropic amblyopia had significantly longer and morevariable saccade latency during amblyopic eye viewing,16
lower peak acceleration and a longer acceleration phase duringreaching,18 and a different temporal pattern of eye–handcoordination.19 Importantly, the effects of amblyopia onreaching movements were evident not only during amblyopiceye viewing, but also during binocular and fellow eye viewing.
As a next step in our systematic investigations, weexamined whether different subtypes of amblyopia affectmotor behaviors differentially. Previous studies have demon-strated several differences in perceptual deficits amongpatients with anisometropic versus strabismic amblyopia. Forexample, patients with anisometropic amblyopia exhibited
From the 1Department of Ophthalmology and Vision Sciences,The Hospital for Sick Children, Toronto, Ontario, Canada; and the2University of Toronto, Toronto, Ontario, Canada.
Supported by Canadian Institutes of Health Research GrantMOP 106663, a Leaders Opportunity Fund grant from the CanadianFoundation for Innovation, and a grant from the Department ofOphthalmology and Vision Sciences at The Hospital for SickChildren.
Submitted for publication July 9, 2012; revised August 22 andOctober 1, 2012; accepted October 2, 2012.
Disclosure: E. Niechwiej-Szwedo, None; M. Chandrakumar,None; H.C. Goltz, None; A.M.F. Wong, None
Corresponding author: Agnes M. F. Wong, Department ofOphthalmology and Vision Sciences, The Hospital for Sick Children,555 University Avenue, Toronto, Ontario, Canada M5G 1X8;[email protected].
Investigative Ophthalmology & Visual Science, November 2012, Vol. 53, No. 12
7458 Copyright 2012 The Association for Research in Vision and Ophthalmology, Inc.
deficits in contrast detection8 and spatial localization across theentire visual field,20 whereas patients with strabismic ambly-opia exhibited more pronounced deficits in the central visualfield than those in the peripheral visual field. A study of 427amblyopic patients has also shown distinctive patterns of visualdeficits among different amblyopia subtypes.13 Patients withanisometropic amblyopia and moderate loss of acuity hadnormal/subnormal contrast sensitivity and were more likely tohave gross stereopsis, whereas those with strabismic ambly-opia and moderate loss of acuity had better than normalcontrast sensitivity at low spatial frequencies and were morelikely to have reduced/absent stereopsis.
The effects of strabismic amblyopia on saccadic eyemovements have only been investigated in two previousstudies. Schor21 examined saccades in five patients using apredictable, square-wave stimulus to elicit saccades. Hereported no difference in latency and a significant increase inamplitude variability when patients viewed with their ambly-opic eye. Ciuffreda and colleagues22 tested six patients usingan unpredictable stepping target and found longer saccadelatencies in some patients. However, they21,22 did not include avisually normal control group and their sample size was small,which precluded a more detailed analysis of the effects ofvisual acuity or stereoacuity on saccade performance. Previousstudies of children with strabismus without amblyopia foundno difference in saccade latency between children with andwithout binocular vision23 and in comparison to children withnormal vision.24 However, adults with strabismus showed animpairment in binocular coordination of saccades that wasmost pronounced in patients without binocular vision.25
The objective of the current study was to investigatesaccadic eye movements during a visually guided reaching taskin patients with strabismic amblyopia, as well as the effects ofvisual acuity and stereoacuity deficits on saccade performance.We hypothesized that impairments in saccade performancewould be largest in patients with amblyopia during amblyopiceye viewing. We also hypothesized that patients’ performancewould be affected by their level of visual acuity andstereoacuity deficits. Specifically, we hypothesized that sac-cades will be delayed and have reduced precision in patientswith poorer acuity and negative stereopsis. Results of thereaching movement are the focus of our next study.
METHODS
Participants
All participants were adults and underwent a complete orthoptic
assessment by a certified orthoptist, which included visual acuity
(Snellen chart), prism cover test (simultaneous and alternate) of eye
alignment, and measurement of stereoacuity using the Titmus test.
Exclusion criteria were any ocular cause for reduced visual acuity,
previous intraocular surgery, or any neurologic disease. All participants
were right-handed to reduce the variability in motor performance.26
Fourteen patients with strabismic amblyopia (6 females; age: 31.7
6 9.9 years; see Table 1 for clinical characteristics) were recruited.
Strabismic amblyopia was defined as an interocular acuity difference
‡2 lines on a Snellen chart, and subjects with a history of childhood
strabismus and manifest eye deviation. Visual acuity was tested with
current refractive correction. The difference in refractive error
between the two eyes was �1 diopter (D) of spherical or cylindrical
power, to rule out a potentially amblyogenic astigmatic component
(i.e., to rule out mixed-mechanism amblyopia). When stereopsis was
absent, the presence or absence of sensory fusion was determined
using Worth’s 4-dot test and Bagolini-striated glasses. Ten patients had
mild amblyopia, with acuity in the amblyopic eye ranging from 20/30
to 20/60. Five of the patients with mild amblyopia had gross stereopsis
(range: 120–800 seconds of arc), whereas the other five patients had
negative stereopsis. Four patients had severe amblyopia (20/200 in the
amblyopic eye) and negative stereopsis. Visual acuity in the fellow eye
was 20/20 or better in all patients.
Thirteen patients with strabismus without amblyopia (acuity 20/25
or better in both eyes) were also recruited (6 females; age: 30.1 6 4.0
years; see Table 1 for clinical characteristics). All patients had manifest
eye deviation. Nine patients were tested negative for stereopsis, two
had stereoacuity of 3000 seconds of arc, and the remaining two had
stereoacuity of 50 and 80 seconds of arc.
Fourteen visually normal participants (6 females; age: 31.7 6 9.9
years) with corrected-to-normal visual acuity (20/20 or better) in both
eyes and stereoacuity � 40 seconds of arc were recruited. Eye
dominance in visually normal participants was determined using the
Dolman ‘‘hole-in-card’’ test.27
The study was approved by the Research Ethics Board at The
Hospital for Sick Children, and all protocols adhered to the guidelines
of the Declaration of Helsinki. Informed consent was obtained from
each participant.
Apparatus and Experimental Protocol
Details of the apparatus and experimental procedure have been
described in a previous article.16 Briefly, the visual target was a white
square (visual angle: 0.58) presented on a black background on a
cathode ray tube computer monitor (Diamond Pro 2070SB, resolution
1600 3 1200 at 85 Hz; NEC/Mitsubishi Electric Visual Systems, Tokyo,
Japan). Testing was conducted in a dimly lit room. Eye movements
were recorded binocularly at 200 Hz using a video-based pupil/iris
tracking system (Chronos Vision, Berlin, Germany). Reaching move-
ments of the upper limb were also recorded simultaneously at 200 Hz
using an infrared illumination-based motion-capture system (Optotrak
Certus; Northern Digital, Waterloo, Canada).
Participants were seated at a table with their heads stabilized on a
chin rest. They fixated a cross at the beginning of each trial. The
viewing distance was 42 cm. After a variable delay of 1.5 to 3 seconds,
the fixation cross was extinguished and one visual target appeared
randomly at one of four eccentricities at 658 or 6108 along the
horizontal axis. There was no temporal delay between the offset of the
fixation point and the presentation of the target (simultaneous fixation
offset and target onset). Participants were instructed to look at the
target and to make a reaching movement to touch the target with their
index finger as quickly and as accurately as possible. Details of the
reaching task have been described previously.18 In 50% of the trials, the
target was switched off at the onset of hand movement. For the other
50% of the trials, the target remained on the screen. Trials with and
without visual feedback of the target were randomized on a trial-by-trial
basis.
Participants performed the experiment in three viewing conditions:
(1) binocular viewing; (2) monocular viewing with the dominant eye
(i.e., the fellow eye for patients with amblyopia, and the nondeviating
eye for patients with strabismus without amblyopia); and (3)
monocular viewing with the nondominant eye (i.e., the amblyopic
eye for patients with amblyopia, and the deviating eye for patients with
strabismus without amblyopia). Data were collected in blocks for each
viewing condition, and the order of viewing conditions was
randomized across participants. All participants completed 10 trials
in each combination of the experimental conditions for a total of 240
trials/session. Practice trials were completed before the experiment
was begun to familiarize the participants with the experimental
procedure. All data were collected in one session (1–1.5 hours), which
included calibration of the apparatus, practice, and experimental trials.
Analysis: Saccadic Eye Movements
Eye position data were low-pass filtered using a second-order dual-pass
Butterworth filter with a cutoff frequency of 50 Hz. Eye velocity was
obtained using a two-point differentiation method. A custom-written
IOVS, November 2012, Vol. 53, No. 12 Saccadic Eye Movements in Strabismic Amblyopia 7459
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7460 Niechwiej-Szwedo et al. IOVS, November 2012, Vol. 53, No. 12
script (Matlab; The MathWorks, Natick, MA) was used to identify
primary saccades using a velocity threshold of 20 deg/s. All trials were
inspected visually to ensure that saccades were identified correctly by
the computer script. We examined the recordings of the right and left
eyes during the binocular viewing condition and found no difference in
saccade kinematics between eyes. Therefore, only one eye was
included in the statistical analysis. During monocular viewing
conditions, only the viewing eye was analyzed. Outcome measures
for primary saccades were mean latency, amplitude, and peak velocity.
The variability (SD) of primary saccade amplitude was also calculated.
All trials were inspected for the presence of secondary saccades
that were marked manually for each trial. Secondary saccades that
occurred within 250 ms of the primary saccades were defined as
corrective saccades. The outcome measures for secondary saccades
were frequency in each viewing condition, as well as mean saccade
latency, amplitude, and peak velocity. In addition, we calculated the
precision (i.e., variability) of the final amplitude after secondary
saccades were executed. The final amplitude was defined as the
algebraic sum of primary and secondary saccade amplitudes. The final
saccade amplitude precision was used to examine whether secondary
saccades were generated to correct the error in position that remained
after the primary saccade.
Statistical Analysis
All continuous dependent variables were submitted to repeated-
measures ANOVA with one between-subjects factor: Group (strabismic
amblyopia, strabismus without amblyopia, visually normal) and three
within-subjects factors: Viewing Condition (binocular, monocular
dominant eye [fellow eye for patients with amblyopia], and monocular
nondominant eye [amblyopic eye for patients with amblyopia]), Target
Location (58, 108), and Visual Feedback of Target (on, off).
The frequency of corrective saccades was compared using
Pearson’s v2 statistic. The frequency of saccades was first compared
between patients and visually normal participants, then the effect of
Viewing Condition was examined within each group, both using
Pearson’s v2 statistic.
All statistical analyses were performed using a commercial statistical
analysis software program (SAS Software, version 9.2; SAS Institute Inc.,
Cary, NC). Descriptive statistics were reported as the mean and
corresponding SD. All main effects and interactions were analyzed
further using Tukey–Kramer post hoc tests to adjust for multiple
comparisons. The significance level was set at P < 0.05. Preliminary
analysis of all the data showed that Visual Feedback of Target had no
significant effect on any outcome measures; therefore, data with or
without visual feedback were collapsed for subsequent analysis and
reporting. Saccades to the left and right targets at each eccentricity
were pooled together for statistical analysis.
Effects of Severity of Amblyopia and Stereopsis. To investigate
further the effects of severity of amblyopia and stereopsis, a separate
repeated-measures analysis was performed on each outcome measure.
For this analysis, patients with amblyopia were stratified into three
subgroups: (1) mild amblyopia (i.e., acuity �20/60) and gross
stereopsis (mild�stereoþ; Table 1: patients 1–5); (2) mild amblyopia
and negative stereopsis (mild�stereo�; Table 1: patients 6–10); and (3)
severe amblyopia (i.e., acuity 20/200) and negative stereopsis (Table 1:
patients 11–14). Since the number of subjects in each subgroup was
small, a nonparametric approach was used. All data were transformed
to ranks and then submitted to a repeated-measures ANOVA following
the procedure developed by Conover and Iman.28 The ANOVA had
Subgroup as a between-subjects factor (i.e., mild�stereoþ,
mild�stereo�, severe) and two within-subjects factors: Viewing
Condition (binocular, monocular fellow eye, and monocular amblyopic
eye) and Target Location (58, 108).
Effects of Stereopsis in Patients with Strabismus without
Amblyopia. To investigate the effects of stereopsis in patients with
strabismus without amblyopia, a separate repeated-measures ANOVA
on the ranked data28 was performed on each outcome measure. For
this analysis, patients with strabismus without amblyopia were divided
into two subgroups: stereo positive (n¼4), and stereo negative (n¼9).
The ANOVA had Subgroup as a between-subjects factor (i.e., stereoþ,
stereo�) and two within-subjects factors: Viewing Condition (binocular,
monocular dominant eye, and monocular nondominant eye) and Target
Location (58, 108).
Effects of Strabismic Eye Deviation. Spearman correlation
analysis was performed to investigate the relation between the amount
of eye deviation and primary saccade outcome measures (latency,
amplitude accuracy [mean] and precision [SD], peak velocity). The
correlation coefficient was calculated separately for patients with
strabismic amblyopia and patients with strabismus without amblyopia
for the different viewing conditions.
RESULTS
Primary Saccades
Figure 1 shows representative eye velocity tracings from avisually normal participant and individual patients withstrabismic amblyopia (mild�stereoþ, mild�stereo�, severe),and strabismus without amblyopia (stereoþ, stereo�). Thevisually normal participant showed highly stereotypical sac-cades in all viewing conditions. The largest deviation from thestereotypical saccade behavior was seen in the patient withsevere amblyopia (negative stereopsis) during amblyopic eyeviewing and in the patient with strabismus without amblyopia(negative stereopsis) in all viewing conditions. Both patientsshowed delayed and highly variable saccades.
Latency. The main effect of Viewing Condition (F2,76 ¼16.81; P < 0.0001) and the interaction between Group andViewing Condition were significant (F4,76 ¼ 6.92; P < 0.0001;Fig. 2A). Post hoc tests revealed that mean saccade latencyincreased significantly when patients with strabismic ambly-opia viewed with their amblyopic eye (218 6 49 ms),compared with viewing with their fellow eye (172 6 36 ms)or binocularly (177 6 39 ms). Patients with strabismus withoutamblyopia had comparable saccade latency in all viewingconditions (binocular: 191 6 29 ms; dominant eye: 190 6 23ms; nondominant eye: 198 6 32 ms). In contrast, visuallynormal participants had significantly shorter saccade latencywhen viewing binocularly (173 6 27 ms), compared withmonocular viewing with the dominant eye (190 6 25 ms) ornondominant eye (191 6 26 ms).
The three-way interaction between Group (strabismicamblyopia, strabismus without amblyopia, visually normal),Viewing Condition, and Target Location was also significant(F6,76 ¼ 5.12; P ¼ 0.0002; Fig. 3A). Post hoc testing indicatedthat patients with strabismic amblyopia had significantly longerlatency during amblyopic eye viewing for saccades to the 58target (227 6 52 ms) compared with the 108 target (209 6 44ms). Target Location did not affect saccade latency in patientswith strabismus without amblyopia and visually normalparticipants in any viewing condition.
The comparison among patients within the amblyopiasubgroup (mild�stereoþ, mild�stereo�, severe) showed asignificant interaction between Subgroup and Viewing Condi-tion (F4,22¼9.34; P < 0.0001, Fig. 2B). Post hoc tests indicatedthat patients with severe amblyopia had significantly longersaccade latency when viewing with the amblyopic eye (273 636 ms), compared with binocular (165 6 41 ms) or fellow eyeviewing (160 6 33 ms), and to the other subgroups (i.e., mildamblyopia with and without stereopsis). Patients with mildamblyopia and negative stereopsis also had significantly longersaccade latency during amblyopic eye viewing (187 6 34 ms),compared with binocular (165 6 23 ms) or fellow eye viewing(165 6 35 ms). In contrast, patients with mild amblyopia and
IOVS, November 2012, Vol. 53, No. 12 Saccadic Eye Movements in Strabismic Amblyopia 7461
FIGURE 1. Representative eye velocity tracings from individual trials during monocular viewing with the nondominant/amblyopic eye (left
column), monocular viewing with the dominant/fellow eye (middle column), and binocular viewing (right column) when the target was shown108 to the right. Top row: a visually normal participant; second row: a patient with mild amblyopia and gross stereopsis (200 seconds of arc) (Table1, ID 4); third row: a patient with mild amblyopia and negative stereopsis (Table 1, ID 6); fourth row: a patient with severe amblyopia and negativestereopsis (Table 1, ID 14); fifth row: a patient with strabismus and stereopsis (80 seconds of arc) (Table 1, ID 16); last row: a patient withstrabismus without amblyopia and negative stereopsis (Table 1, ID 21).
7462 Niechwiej-Szwedo et al. IOVS, November 2012, Vol. 53, No. 12
gross stereopsis had similar saccade latencies across all viewing
conditions (binocular viewing: 200 6 43 ms; fellow eye
viewing: 190 6 35 ms; amblyopic eye viewing: 205 6 29 ms).
The three-way interaction between Amblyopia Subgroup
(mild�stereoþ, mild�stereo�, severe), Viewing Condition, andTarget Location was also significant (F6,22 ¼ 2.88; P ¼ 0.0315;
Fig. 3B). Post hoc testing indicated that only patients withsevere amblyopia had significantly longer latency during
amblyopic eye viewing for saccades to the 58 targets (294 6
7 ms) compared with the 108 targets (252 6 21 ms). Targetlocation did not affect saccade latency in patients with
amblyopia who had mild acuity deficits with and withoutstereopsis.
There was no significant difference among patients withstrabismus without amblyopia with and without stereopsis for
saccade latency in any viewing condition. There was no
relation between the extent of eye deviation and latency inboth patient groups.
Amplitude. There was a significant main effect of targetlocation for saccade amplitude (F1,38 ¼ 1255.91; P < 0.0001).Saccades to the 108 target had higher amplitude than those tothe 58 target in all experimental conditions for visually normalparticipants and all patients (Table 2). No other significantmain effects or interactions were present for mean saccadeamplitude. There were also no differences among patients withamblyopia. The distribution of primary saccade amplitude foreach target location across viewing conditions for a fewrepresentative participants in each subject group is shown inSupplemental Figure S1 (see Supplementary Material andSupplementary Fig. S1, http://www.iovs.org/lookup/suppl/doi:10.1167/iovs.12-10550/-/DCSupplemental).
Saccade amplitude precision (i.e., variability) was notsignificantly different when patients with amblyopia werecompared with visually normal participants and patients withstrabismus without amblyopia (F4,76¼ 3.12; P¼ 0.064). Therewas a main effect of target location (F1,38 ¼ 114.08; P <0.0001); however, interaction between Group and Target
FIGURE 2. Mean saccade latencies as a function of viewing condition. (A) Latencies were significantly longer for patients with strabismic amblyopia(shown in red) during amblyopic eye viewing (P < 0.0001). Visually normal participants (shown in black) had shorter saccade latencies duringbinocular viewing compared with monocular viewing. In contrast, all patients had comparable saccade latency during binocular and fellow(nondeviated) eye viewing (i.e., no binocular advantage). Patients with strabismus without amblyopia (shown in green) had similar saccade latencyin all viewing conditions. (B) Saccade latencies were significantly longer only for patients with severe amblyopia (blue lines, visual acuity 20/200,negative stereopsis) during amblyopic eye viewing (P < 0.0001).
FIGURE 3. Mean saccade latency as a function of target eccentricity across viewing conditions. (A) Patients with strabismic amblyopia (shown inred) had longer saccade latency during amblyopic eye viewing for the 58 target compared with the 108 target (P¼ 0.0002). (B) Further subgroupanalysis revealed that only patients with severe visual acuity deficits due to amblyopia and negative stereopsis (shown in blue) had a significantlonger saccade latency (P¼ 0.0315) during amblyopic eye viewing to targets located closer to fixation compared with more peripheral targets.
IOVS, November 2012, Vol. 53, No. 12 Saccadic Eye Movements in Strabismic Amblyopia 7463
Location did not reach significance (F2,38¼2.33; P¼0.056). Allsubjects exhibited larger variability for the 108 target (visuallynormal: 1.07 6 0.528; patients with strabismic amblyopia: 1.326 0.658; patients with strabismus without amblyopia: 1.50 60.688) compared with the 58 target (visually normal: 0.68 60.318; patients with strabismic amblyopia: 0.88 6 0.488;patients with strabismus without amblyopia: 0.85 6 0.428).
There was a significant interaction between AmblyopiaSubgroup and Viewing Condition (F4,22¼6.89; P¼0.0009; Fig.4A) for saccade amplitude precision. Post hoc testing showedthat patients with severe amblyopia had significantly reducedprecision of saccade amplitude during amblyopic eye viewing(2.08 6 0.868) compared with binocular (1.12 6 0.528) orfellow eye viewing (0.71 6 0.328). Similarly, patients with mildamblyopia and negative stereopsis had reduced saccadeamplitude precision during amblyopic eye viewing (1.62 60.558) compared with binocular (1.18 6 0.328) or fellow eyeviewing (1.07 6 0.468). In contrast, patients with mildamblyopia and gross stereopsis had similar saccade amplitudeprecision across viewing conditions (binocular viewing: 0.816 0.608; fellow eye viewing: 1.18 6 0.648; amblyopic eyeviewing: 0.77 6 0.258), which was comparable to visuallynormal participants (binocular viewing: 0.94 6 0.648; domi-nant eye viewing: 0.83 6 0.378; nondominant eye viewing:0.94 6 0.528) and to patients with strabismus withoutamblyopia (binocular viewing: 1.27 6 0.768; dominant eyeviewing: 1.21 6 0.738; nondominant eye viewing: 1.16 60.578).
There was no significant difference among patients withstrabismus without amblyopia with and without stereopsis forsaccade amplitude in any viewing condition. There was norelation between the extent of eye deviation and amplitude orprecision in both patient groups.
Peak Velocity. There was a significant main effect of targetlocation for saccade peak velocity (F1,38¼712.87; P < 0.0001).Saccades to the 108 target had higher peak velocity than thoseto the 58 target in all experimental conditions for visuallynormal participants and all patients. There was also a maineffect of viewing condition (F2,76 ¼ 4.67; P ¼ 0.012) for peakvelocity. Saccades had higher peak velocity during binocularviewing compared with monocular viewing, which was mostevident for saccades to the 108 target in all groups, except forpatients with strabismus without amblyopia and negativestereopsis (Table 2).
There was no significant difference among patients withstrabismus without amblyopia with and without stereopsis forpeak velocity in any viewing condition. There was no relationbetween the extent of eye deviation and peak velocity in bothpatient groups.
Secondary Corrective Saccades
Frequency. The overall frequency of corrective saccadeswas greater in patients with strabismic amblyopia (16.3%) andpatients with strabismus without amblyopia (15.1%) comparedwith visually normal participants (13.5%; v2
[df¼2] ¼ 8.61, P ¼0.013). However, there was no difference in the frequency ofsecondary saccades among viewing conditions for patientswith strabismic amblyopia (binocular viewing: 6.3%, fellow eyeviewing: 5.6%, amblyopic eye viewing: 4.4%), patients withstrabismus without amblyopia (binocular viewing: 5.8%;dominant eye viewing: 4.3%; nondominant eye viewing:4.9%), and visually normal participants (binocular viewing:4.1%; dominant eye viewing: 4.8%; nondominant eye viewing:4.6%).
Subgroup analysis of patients with amblyopia showed asignificant frequency difference in corrective saccade frequen-cy (v2
[df¼2]¼ 49.00, P < 0.001). Specifically, patients with mildTA
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7464 Niechwiej-Szwedo et al. IOVS, November 2012, Vol. 53, No. 12
amblyopia and gross stereopsis made fewer secondarysaccades (3.1%), compared with patients with mild amblyopiaand negative stereopsis (6.4%) and patients with severeamblyopia (6.8%). Differences among viewing conditions areshown in Table 3.
Latency. The latency of corrective saccades was compara-ble across all viewing conditions for patients with strabismicamblyopia, patients with strabismus without amblyopia, andvisually normal participants. The subanalysis of patients withamblyopia also yielded no significant differences.
Amplitude and Peak Velocity. There was a significantinteraction between Group and Viewing Condition forcorrective saccade amplitude (F4,62 ¼ 4.49; P ¼ 0.003). Posthoc testing indicated that patients with strabismic amblyopiahad significantly greater secondary saccade amplitudes duringamblyopic eye viewing (2.44 6 1.148) compared withbinocular (1.58 6 0.788) and fellow eye viewing (1.43 6
0.908), which were comparable to visually normal participants(binocular viewing: 1.39 6 0.928; dominant eye viewing: 1.346 0.618; nondominant eye viewing: 1.42 6 0.808) and topatients with strabismus without amblyopia (binocular view-ing: 1.72 6 0.928; dominant eye viewing: 1.37 6 0.668;nondominant eye viewing: 1.47 6 0.458). The interactionbetween Group and Viewing Condition for corrective saccadepeak velocity did not reach significance (F4,62 ¼ 1.97; P ¼0.111).
Further analysis of patients with amblyopia revealed a maineffect of Viewing Condition for secondary saccade amplitude(F2,11 ¼ 10.03; P ¼ 0.001) and peak velocity (F2,11 ¼ 4.70; P ¼0.024). Data presented in Table 3 indicate that patients withnegative stereopsis had significantly larger amplitude and peakvelocity of secondary saccades during amblyopic eye viewingcompared with binocular and fellow eye viewing.
Amplitude Variability after Secondary Saccade. Thecomparison between patients with amblyopia, patients withstrabismus without amblyopia, and visually normal participantswas not statistically significant. The mean precision of the finalamplitude after the secondary saccade was less than 18 for allgroups (range: 0.65–0.988). In contrast, analysis of patientswith amblyopia revealed a main effect of Subgroup (F2,11 ¼13.70; P ¼ 0.001). Post hoc analysis indicated that amplitudevariability after secondary saccade was larger in patients withmild amblyopia and negative stereopsis compared with theother groups in all viewing conditions, with the exception ofpatients with severe amblyopia during amblyopic eye viewing.There was also an interaction between Subgroup and ViewingCondition (F4,22¼ 8.91; P¼ 0.0002; Fig. 4B). Post hoc analysisindicated that patients with severe amblyopia had significantlylower precision (i.e., increased variability) of the finalamplitude after secondary saccade during amblyopic eyeviewing (1.33 6 0.228) compared with binocular (0.77 6
0.288) and fellow eye viewing (0.50 6 0.168), as well as with
TABLE 3. Frequency and Kinematics of Secondary Saccades for Patients with Strabismic Amblyopia
Mild�Stereoþ (n* ¼ 79) Mild–Stereo� (n* ¼ 163) Severe–Stereo� (n* ¼ 173)
Binocular
Fellow
Eye
Amblyopic
Eye Binocular
Fellow
Eye
Amblyopic
Eye Binocular
Fellow
Eye
Amblyopic
Eye
Frequency, % 5.0 2.0 2.4 6.5 3.9 7.3 7.5 11.4 3.0
Latency, ms 209 6 24 225 6 17 215 6 19 206 6 28 213 6 20 202 6 25 198 6 40 192 6 27 146 6 29
Amplitude, 8 1.65 6 0.71 1.27 6 0.24 1.78 6 0.59 1.90 6 0.83 1.78 6 1.30 2.79 6 0.96† 1.16 6 0.60 1.17 6 0.49 2.64 6 1.85†
Peak velocity, deg/s 122 6 43 102 6 24 131 6 39 125 6 43 112 6 48 161 6 48† 100 6 57 95 6 42 153 6 97†
* Total number of trials that contained secondary saccades in each group of patients.† Saccade amplitude and peak velocity were greater during amblyopic eye viewing for patients with amblyopia with negative stereopsis.
FIGURE 4. The precision (i.e., variability) of primary saccade amplitude across viewing conditions. (A) Patients with amblyopia and negativestereopsis (both mild [shown in green] and severe [shown in blue] acuity deficits) had significantly reduced primary saccade amplitude precision(i.e., greater SD) during amblyopic eye viewing (P < 0.0001) compared with patients with mild amblyopia and gross stereopsis (shown in red). (B)Only patients with severe amblyopia and negative stereopsis had lower final saccade amplitude precision after executing a secondary saccade,whereas patients with mild acuity deficits attained precision comparable to that of visually normal participants after executing a secondary saccade(P¼ 0.0002).
IOVS, November 2012, Vol. 53, No. 12 Saccadic Eye Movements in Strabismic Amblyopia 7465
patients with mild amblyopia with and without stereopsis, asillustrated in Figure 4B.
DISCUSSION
This study examined saccades in patients with strabismicamblyopia and compared their performance to that of patientswith strabismus without amblyopia and visually normalparticipants. The major findings are: (1) patients withstrabismic amblyopia and patients with strabismus withoutamblyopia showed no binocular advantage for saccadeinitiation; (2) latency and amplitude of primary saccades wereaffected by the severity of amblyopia and the presence ofstereopsis; (3) amblyopic patients without stereopsis initiatedsecondary saccades more frequently compared with visuallynormal participants. These secondary saccades improved thefinal precision of saccade amplitude; however, the precisionremained significantly worse in patients with severe amblyopiaduring amblyopic eye viewing; and (4) these findings wereunique to patients with strabismic amblyopia, because theywere not observed in patients with strabismus withoutamblyopia.
Patients Lack Binocular Advantage for SaccadeInitiation
Binocular advantage refers to improvements in performance(e.g., visual acuity, contrast sensitivity, and detection of dimstimuli) during binocular viewing compared with monocularviewing in normal people.29 It has been proposed that whensensory signals from the eyes are summated, uncorrelatedsignals (i.e., noise) cancel out and correlated signals areamplified (binocular summation).29,30 This binocular summa-tion, however, is impaired in patients with amblyopia. Levi andcolleagues31 found no improvement in contrast sensitivityduring binocular viewing compared with fellow eye viewing inthree patients with strabismic amblyopia and one patient withanisometropic amblyopia. Our findings provide additionalevidence that patients with strabismic amblyopia lack binoc-ular advantage in their oculomotor system; their saccadelatency was comparable during binocular and fellow eyeviewing.
We also found slightly higher peak velocity during binocularviewing compared with that during monocular viewing, whichwas evident in all groups, except for patients with strabismuswithout amblyopia and negative stereopsis. The difference wasstatistically significant, but it was quite small (~5% for 108saccades). Although we cannot explain this effect at present,we will continue to investigate it in the future by examiningthe saccade main sequence in patients to determine whetherviewing binocularly or monocularly affects the saturationvelocity of saccades.
Effects of Severity of Amblyopia and Stereopsis
Although the number of patients with strabismic amblyopia ineach subgroup was small in the current study, we foundsignificant differences in saccade latency and precision amongpatients with different levels of visual acuity and stereoacuitydeficits. With respect to acuity deficit, our analysis yielded twoimportant findings. First, saccade latency was prolonged onlyin patients with a severe acuity deficit (20/200) but not inpatients with a mild deficit (�20/60) during amblyopic eyeviewing. These results are in contrast to those in patients withanisometropic amblyopia who had significantly longer saccadelatencies during amblyopic eye viewing, irrespective ofwhether they had a mild or severe acuity deficit, using the
same criteria and experimental paradigm.16,32 Second, patientswith strabismic amblyopia and severe acuity deficits experi-enced more difficulty orienting to targets closer to centralfixation (i.e., the 58 vs. 108 target). This is in contrast topatients with anisometropic amblyopia whose saccade laten-cies were not affected by Target Location.16,32 Our current andprevious results16,32 can be interpreted as the motor conse-quences of different long-term sensory suppression mecha-nisms in strabismic versus anisometropic amblyopia.Suppression of the central field helps to eliminate centraldiplopia arising from eye misalignment and allows some degreeof peripheral fusion. In contrast, the prolonged saccade latencythat is independent of Target Location16,32 in patients withanisometropic amblyopia is consistent with sensory suppres-sion of a blurred image across the entire visual field.20
Interestingly, we found no correlation between the amountof strabismus and saccade latency for different target locations.A larger sample size is required for a more robust correlationanalysis.
The prolonged saccade latency for a more centrally locatedtarget is consistent with stronger sensory suppression of thecentral visual field in strabismic amblyopia as found in bothhumans33 and cats.34 This pattern of behavior is not likely to bedue to interocular suppression because longer latency wasfound only when patients were viewing with the amblyopiceye and not during binocular viewing. However, it is possiblethat the chronic suppression of the deviated eye duringbinocular viewing extends to the monocular viewing condi-tions.35 A previous brain imaging study36 showed a lower levelof cortical activation during foveal stimulation of the amblyopiceye, and may explain the longer saccade latency to morecentrally located targets.
A second important finding is that patients with negativestereopsis had significantly reduced precision of primarysaccades during amblyopic eye viewing, regardless of thevisual acuity deficit. In particular, we found that saccadeamplitude precision was significantly worse in patients withstrabismic amblyopia and negative stereopsis compared withpatients who had gross stereopsis and a similar acuity deficit. Itis possible that despite having good acuity in the amblyopiceye, the signal from the amblyopic eye in patients withnegative stereopsis may remain under suppression duringnatural binocular viewing, which also habitually extends tomonocular amblyopic eye viewing during the brief experimen-tal period. Our findings are consistent with a recentneuroimaging study37 on patients with strabismic amblyopia,which showed that the decrease in neural activation in V1/V2during amblyopic eye stimulation was dependent on thesuppressive effects of the fellow eye: activity was morereduced when the fellow eye was open than when it wasclosed. Taken together, our findings and those of others37
suggest that the amblyopic eye is under chronic suppressionduring both monocular and binocular viewing, albeit to adifferent extent.
Previous studies have used perceptual and psychophysicaltasks to demonstrate spatial localization deficits in ambly-opia.20,38,39 Patients showed a systematic localization bias inthe direction of the deviated eye, and exhibited increasedspatial uncertainty that was more pronounced in central visioncompared with the periphery. Using a saccade task, weprovide additional evidence that patients with amblyopia havedeficits in spatial localization as shown by increased variability(i.e., reduced precision) in primary saccade amplitudeespecially during amblyopic eye viewing. We also observed agradation of effects of strabismic amblyopia: in patients with asevere acuity deficit (and negative stereopsis), both detection(i.e., longer saccade latency) and localization (i.e., increasedsaccade amplitude variability) deficits were evident. In patients
7466 Niechwiej-Szwedo et al. IOVS, November 2012, Vol. 53, No. 12
with mild amblyopia and negative stereopsis, a localizationdeficit was evident but not a detection deficit (i.e., normalsaccade latency), whereas in those with mild amblyopia andgross stereopsis, no localization or detection deficit waspresent. The distinct pattern found in patients with mildamblyopia and negative stereopsis could be explained by aspeed–accuracy tradeoff: saccades were initiated with normallatency but with a greater than normal scatter of landingpositions. This behavior might have led to a large inaccuracy;however, the errors in primary saccade amplitude werecorrected by secondary saccades as discussed in the followingtext.
Secondary Saccades
Primary saccades have a tendency to undershoot the target byapproximately 10%.40,41 Secondary saccades are initiated tocorrect the amplitude error remaining after the primarysaccade. Two sources of error feedback have been proposedfor the generation of secondary saccades.40,42,43 One is basedon extraretinal information derived from the efference copy ofthe oculomotor command. Another is based on retinalfeedback derived from the position of the target image onthe retina at the end of the primary saccade.
Our data show two important findings. First, only patientswith amblyopia (mild and severe) and negative stereopsisinitiated secondary saccades more frequently. Second, saccadesinitiated by these patients with negative stereopsis duringamblyopic eye viewing had higher amplitudes and peakvelocities. Since we also found that these patients had lowerprimary saccade amplitude precision, these secondary sac-cades were initiated to correct the amplitude error remainingafter the primary saccade. Patients with mild amblyopia wereable to correct the error significantly more compared withpatients with severe amblyopia, as indicated by improved finalamplitude precision after the secondary saccade. These resultscan be interpreted by considering that the retinal feedback ismore impaired in patients with severe amblyopia. Consequent-ly, patients with less reliable retinal position error signals mayneed a larger visual error signal before initiating a secondarysaccade, which in turn leads to higher amplitude and, thus,peak velocity of the corrective eye movement. In addition, ourdata indicate that the error detection process is impaired inpatients with severe amblyopia because they made significantlyfewer secondary saccades during amblyopic eye viewing. Ourfindings highlight the importance of a reliable retinal feedbacksignal for the initiation of secondary corrective saccades.
In conclusion, our study adds to the growing body ofliterature that recognizes amblyopia as a heterogeneousdisorder of both visual and visuomotor functions.13,44–47 Wefound a distinct pattern of deficits in patients with strabismicamblyopia that, unlike that in anisometropic amblyopia, wasdependent on the level of visual acuity and stereoacuity losses.Gross stereopsis was associated with better saccade perfor-mance in terms of detection and localization, regardless ofviewing condition. In addition, these deficits were unique topatients with strabismic amblyopia, because they were notfound in patients with strabismus without amblyopia. Ourresults suggest that the evaluation of the effectiveness oftreatment regimens for amblyopia should also consider motorimprovement, rather than solely on visual acuity.
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