Effects of Enucleation of the Fixating Eye on Strobismic Amblyopio in Monkeys

Transcription

1 Effects of Enucleation of the Fixating Eye on Strobismic Amblyopio in Monkeys Ronald S. Horwerrh,* Earl L. Smith, III,* Gary C. Duncan,* M. L. J. Crawford,t and Gunrer K. von Noorden^: The effects of enucleation of the fixating eye on the visual function of the deviating eye were studied in two rhesus monkeys with strabismic amblyopia. An esotropia was surgically induced when the monekys were approximately 1 mo of age, and the fixating eyes were then enucleated at age 3 yr 11 mo. Four measures of visual function (photopic increment-threshold spectral sensitivity, scotopic spectral sensitivity, spatial modulation sensitivity, and temporal modulation sensitivity) were determined for both eyes prior to enucleation and for the deviating eyes over an 11-month period following the surgical removal of the fixating eye. Both monkeys showed some recovery of contrast sensitivity of their deviating eyes. The extrapolated cut-off values for their spatial modulation sensitivity functions increased from.27 to 2.8 c/deg for one animal and from.28 to 6.3 c/deg for the other. The extrapolated cut-off frequencies for the temporal modulation sensitivity functions of both animals showed an increase of Hz compared to the pre-enucleation values. The spectral sensitivity functions of one monkey recovered to near normal values following enucleation, while both the photopic and scotopic functions of the other animal remained at pre-enucleation levels. Overall, the results of the experiments indicate that the removal of the fixating eyes of monkeys with strabismic amblyopia can result in significant improvements in the functional capacity of their deviating eyes. Invest Ophthalmol Vis Sci 27: , 1986 Interocular suppression mechanisms are generally considered to play an important role in the subnormal visual acuity of amblyopic eyes. 1 " 4 In addition to being involved in the development of amblyopia, suppression mechanisms may also continue to affect the vision of the amblyopic eye after the organism is past the "critical period" for visual system development. 5 " 10 For example, several studies have shown that the nondeprived eyes of monocularly lid-sutured cats continue to exert an inhibitory or suppressive influence upon the deprived eyes well past the classical critical period. 6 " 10 Moreover, psychophysical studies of human amblyopes have demonstrated that inhibitory binocular interactions are present in adult subjects"" 13 and that the visual acuity of the amblyopic eye sometimes improves following the loss of the nonamblyopic eye. 414 " 16 The role of post-critical period suppression is probably not the same in all types of amblyopia. In our previous study of stimulus deprivation amblyopia in From the University of Houston-University Park, College of Optometry,* University of Texas at Houston, Graduate School of Biomedical Sciences, Sensory Sciences Center, f Baylor College of Medicine, Cullen Eye Institute,:): Houston, Texas. Supported by Research Grants EY-01139, EY-03611, and EY from the National Eye Institute and NIH/UH-BRSG Grant S07 RR to the University of Houston. Submitted for publication: February 5, Reprint requests: Ronald S. Harwerth, OD, PhD, College of Optometry, University of Houston-University Park, 4800 Calhoun, Houston, TX monkeys, 17 it was shown that enucleation of the nondeprived eye did not result in any recovery of visual function in the amblyopic eye over a 9-mo recovery period. These results indicate that post-critical period interocular inhibition did not substantially affect the functional capacity of an eye with severe stimulus deprivation amblyopia. However, it is possible that abnormal binocular interactions may be more important in other forms of amblyopia such as strabismic amblyopia. Therefore, the present study was undertaken to investigate the effects of enucleating the fixating eyes on the visual capability of the amblyopic eyes in monkeys reared with surgically induced, unilateral esotropia. Prior to the removal of the fixating eyes, the sensory deficits of the deviating amblyopic eyes, as assessed by psychophysical measures of spatial and temporal modulation sensitivity and increment-threshold spectral sensitivity, were quite similar to those resulting from monocular deprivation produced by lid suture. 18 " 20 Therefore, any recovery seen for these strabismic amblyopes following enucleation of the fixating eye can be directly compared to the previous results for stimulus deprivation amblyopes. Materials and Methods All of the experimental and animal care procedures conformed to the ARVO Resolution on the Use of Animals in Research and were strictly in adherence with the NIH guide for the Care and Use of Laboratory 246

2 No. 2 EFFECTS OF ENUCLEATION ON STRADISMIC AMDLYOPIA / Horwerrh er ol. 247 Animals (NIH Publication No ). The subjects for the experiments were two well-trained rhesus monkeys (Macaca mulatto). Experimental esotropia was induced when the animals were 3-4 wk of age (see Table I for the pertinent details of the treatment sequence) using surgical procedures similar to those previously described. 21 The resulting strabismus was incomitant, constant, and unilateral with an angle of deviation in excess of 50 prism diopters. In order to facilitate psychophysical testing, the angle of deviation was reduced by a second surgical procedure when the animals were approximately 1 yr of age. Immediately following the second surgery, both animals were nearly orthotropic. The eye position of one of the animals (subject 7606) remained straight throughout the duration of the experiments, but within the first year following the second surgery the other animal (subject 7605) developed a secondary exotropia of prism diopters which was subsequently constant in magnitude and direction. The fixating right eyes of both monkeys were enucleated under asceptic operating room conditions using standard surgical procedures when they were 3 yr 11 mo of age. Both monkeys recovered from the surgery without any apparent adverse physiological or behavioral effects. The refractive errors were determined under cycloplegia at one year intervals by retinoscopy and with an infrared optometer (Bausch and Lomb Ophthalmetron; Rochester, NY). The refractive error measurements at ages 1 yr 1 mo (at the time of eye alignment surgery) and at 3 yrs 11 mo (at the time of enucleation) are presented in Table 2. It is interesting that the spherical equivalent refractive errors of the deviating eyes were nearly constant over this period while the refractive errors of the fixating eyes changed 2.25 to 2.50 diopters in the less hyperopic (7905) or more myopic (7906) direction. The refractive errors were corrected with ophthalmic lenses during the experimental sessions. The monkeys viewed all of the stimuli through natural pupils. The fixation behavior of the subjects was not objectively monitored during the experiments. The apparatus and methodology have been previ- Table 1. Treatment sequence Subject Date of birth 2/26/79 3/8/79 Age at eye deviation 34 days 24 days Age at eye alignment 1 yr 1 mo 1 yr 1 mo Age at enucleation 3 yr 11 mos 3 yrs 11 mos ously described 18 " 2022 and were identical to those of our previous study of the effects of enucleating the nondeprived eye on stimulus deprivation amblyopia. 17 The contrast sensitivity stimuli were generated on the CRT of an oscilloscope using standard methods. 23 The stimulus field subtended a 4 visual angle at the 114 cm viewing distance and had a mean luminance of 40 cd/m 2. In the spatial modulation sensitivity experiments, the detection stimuli were stationary vertical sinusoidal gratings presented for 500 msec with squarewave onset and offset properties. In the temporal modulation sensitivity experiments, the luminance of the entire screen was sinusoidally modulated about its mean luminance to produce a uniform field flicker. The viewing duration for the flickering stimuli was 1 sec. The optical system used in the spectral sensitivity experiments was a 2-channel Maxwellian view system with a 2.5-mm exit pupil. The source for both channels was a 1000-W, heat-filtered xenon arc lamp. The background and test fields subtended visual angles of 10 and 2, respectively. The test flash duration was 50 msec. The monochromatic test stimuli, obtained by a Jarrel-Ash Mark X monochromator (Fisher Scientific; Orangeburg, NY) with a 10-nm half-band width, were superimposed on a 3000 troland achromatic background in the photopic sensitivity studies. For the scotopic sensitivity studies the background channel was blocked, and the spectral test stimuli were presented to the dark-adapted eye. Threshold estimates were determined by a descending methods of limits using a criterion response-time paradigm. The monkeys were trained to press and hold down a response lever at the beginning of each trial, which was signalled by the onset of an auditory cue. The lever press initiated a variable interval foreperiod Table 2. Vision characteristics of subjects Extrapolated spatial frequency cut-off values Extrapolated temporal frequency cut-off values Subject Eye Refractive error at eye alignment Refractive error at enucleation post- enucleation preenucleation post- enucleation preenucleation 7905 OD-fixating OS-deviating X X DS pi -0.50X c/deg 0.27 c/deg 2.8 c/deg 93 Hz 33 Hz 58 Hz 7906 OD-fixating OS-deviating piano DS DS X c/deg 0.28 c/deg 6.3 c/deg 84 Hz 43 Hz 64 Hz

3 248 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1986 Vol. 27 preceding the presentation of the detection stimulus. If the monkey released the lever within a specific response period following the onset of the stimulus (ie, the limited-hold period), it was assumed that he had detected the stimulus (a hit) and he was rewarded with a conditioned reinforcer (a tone) after each trial and with an unconditioned reinforcer (orange drink) on approximately 70% of the hit trials. Conversely, if the monkey failed to release the lever within the limitedhold period, it was considered that he had failed to detect the stimulus. The threshold was operationally defined as the stimulus level for which the monkey failed to release the lever within the criterion response period in two consecutive trials. However, to maintain stimulus control of the animal's behavior, the stimulus intensity was not predictably increased after two consecutive misses, but rather, the second and each subsequent miss had a 0.5 probability of resetting it. The final threshold estimates were derived from the geometric mean of 12 threshold measurements with resulting standard errors of approximately 0.05 log units for both contrast thresholds and the spectral sensitivity thresholds. The psychophysical functions were determined for each eye prior to enucleation of the fixating eye and then as quickly as possible after enucleation in the following order: (1) photopic increment-threshold spectral sensitivity, (2) spatial modulation sensitivity, (3) temporal modulation sensitivity, and (4) scotopic spectral sensitivity. About 1 wk of time was required for the measurement of each function. Subsequently, the same functions, except for the scotopic spectral sensitivity measurements, were determined at 3-mo intervals in the same order. The scotopic spectral sensitivity functions which were determined only at 5 wk and 11 mo post-enucleation. Results Increment-Threshold Spectral Sensitivity 900 SSO '00 Fig. 1. Pre-enucleation increment-threshold spectral sensitivity functions for the 2 subjects for a 3000 td achromatic background. Data are shown for the fixating (open circles) and deviating eyes (filled circles). The curves drawn through the data for the fixating eyes and at long wavelengths for the deviating eyes were derived from the linear, subtractive-interaction equations proposed by Sperling and Harwerth. 27 The curve superimposed on the data of the deviating eyes for the shorter wavelengths (570 nm) is the CIE scotopic luminosity curve. The pre-enucleation increment-threshold spectral sensitivity functions for each eye of both subjects are shown in Figure 1. The sensitivity data for the fixating eyes conform to the broad, three-peaked functions that are typical for data obtained from both humans 24 " 26 and macaque monkeys 27 ' 28 when a photopic, achromatic background field is employed. The curves drawn through the data points for the fixating eyes were visually fit with template curves generated from the linear, subtractive-interaction model of spectral sensitivity functions proposed by Sperling and Harwerth. 27 In contrast, the spectral sensitivity data for the deviating eyes (filled circles) are not adequately described by "typical" photopic spectral sensitivity functions and, in comparison to the data for the fixating eyes, exhibit about a 2-log unit reduction in sensitivity for the middle wavelengths. These spectral sensitivity functions are, in most respects, similar to those obtained for monkeys with stimulus deprivation amblyopia. The data for wavelengths shorter than 570 nm form a broad spectral sensitivity function which has a peak in the nm region and which is well-described by the CIE scotopic luminosity function 29 (as represented by the curve drawn through the data points), even though the function was determined at a moderately intense photopic adaptation level (3000 td). The data for wavelengths longer than 570 nm deviate from the scotopic luminosity function suggesting that photopic mechanisms, although reduced in sensitivity, determine the spectral sensitivity over the long wavelength region of the spectrum. Although the photopic mechanisms revealed at the long wavelength end of the spectral sensitivity function cannot be identified with certainty, the data points can be adequately fit by functions similar to those used to describe the long wavelength sensitivity of the fixating eye. If such an interpellation of the data is correct, it suggests that both the long- and middlewavelength sensitive cones are involved in the determination of long wavelength spectral sensitivity. In an attempt to define more clearly the nature of the photopic mechanisms underlying the long wavelength sensitivity in the amblyopic eyes, a set of selective chromatic adaptation experiments were conducted. The results for blue light adaptation (Oriel narrow-band interference filter, 480 nm peak wavelength) are presented in Figure 2. Data are shown for adaptation levels of 3000 td (circles), 9000 td (squares), and 27,000 td (triangles). The shapes of the spectral sensitivity func-

4 No. 2 EFFECTS OF ENUCLEATION ON STRADISMIC AMDLYOPIA / Horwerrh er ol. 249 tions for the 3000 and 9000 td blue light adaptation levels are virtually identical to the functions for the 3000 td achromatic adaptation condition (Fig. 1, filled circles). Moreover, even with the threefold increase in the adapting field intensity, there was no appreciable reduction in sensitivity (the two lower curves in Fig. 2A-B were each displaced downward by 0.5-log units for clarity). However, with an additional threefold increase in adapting field intensity the spectral sensitivity curves became flatter and, as illustrated by the three curves superimposed on the data, 28 the shapes are compatible with the explanation that for the 27,000 td blue background the spectral sensitivity is determined by the upper envelope of the 3 individual cone receptor mechanisms. Although the intense blue adaptation suggests the presence of three color vision mechanisms, the adaptation properties of the deviating eye are clearly abnormal since, in the normal eye, this level of blue light has been shown to be sufficient to selectively adapt the short- and middle-wavelength sensitive cones and to reveal the isolatd sensitivity function of the longwavelength sensitive cones. 18 ' 28 The spectral sensitivity functions obtained after enucleation of the fixating eyes are shown for subject 7906 in Figure 3 and subject 7905 in Figure 4. There is an obvious difference between the two monkeys in the recovery effects following enucleation of the fixating eye. For subject 7906 (Fig. 3) the earliest spectral sensitivity measurements demonstrated a 1-log unit increase in sensitivity and a change in the shape of the function from an apparently rod dominated function to a 3-peaked cone dominated function that is very similar in shape to the function which had previously been measured for the fixating eye under these conditions. Subsequent sensitivity measurements for the deviating eye of subject 7906 confirmed that even though the shape of the spectral sensitivity curve is essentially normal, the absolute sensitivity of the amblyopic eye is still approximately 1 log unit lower than was found for the fixating eye. In contrast, the postenucleation spectral sensitivity measurements for subject 7905 (Fig. 4) do not show any evidence of recovery. The function determined in the second wk after enucleation of the fixating eye (panel A) is at approximately the same level of sensitivity as the pre-enucleation function, and the only substantive difference between the pre- and post-enucleation data is that the photopic intrusion at long wavelengths is absent in the post-enucleation curves. The later spectral sensitivity determinations (Fig. 4, panels B-D) reveal a small increase in sensitivity during the first 3 mo after enucleation of the fixating eye but, in general, the shapes of the curves were essentially constant over the 9-mo period in which the sensitivity was followed. Therefore, the incrementthreshold spectral sensitivity experiments show that s-«subject: 7«O«SUBJECT: 780 Fig. 2. Increment-threshold spectral sensitivity for the 2 subjects with blue (480 nm) light adaptation. Data are shown for background intensities of 3000 td (circles), 9000 td (squares), and 27,000 td (triangles). The data for the 9000 td and 27,000 td background conditions have been displaced downward by 0.5 and 1.0 log units respectively. The curves drawn through the upper two sets of data for each animal are the same curves used in Figure 1. The three curves drawn through the lower sets of data represent the three cone sensitivities obtained for monkeys by selective chromatic adaptation. 28 enucleation of the fixating eyes of monkeys with strabismic amblyopia can result in considerable recovery, but that this outcome is not consistent since the sensitivity of the second animal remained essentially at pre-enucleation levels. SUBJECT: 7906 INH) C. «MOS. POST - ENUCLEATION \ LOG SENSITIVITY \ z.7- /-N-YS VENUMBER (CM-') Fig. 3. Post-enucleation increment-threshold spectral sensitivity functions for subject 7906 for a 3000 td achromatic background. Data are shown for the four post-enucleation periods indicated on the graphs. \

5 Al 250 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1986 Vol. 27 SUBJECT: 7S03 A. 1 WEEK 5 POST-ENUCLEATi ION *\ x / \ VENUM8EH (CM-'I C. 0MOS. P09T-ENUCLEAT1 TIV SENS O * O "" - 0 S. 1U09. POST-ENUCtElTUN \ / V / \. vv WAVELENGTH (NM) VENUMBERICM-'I. SMOS. POST- ENUCIEATION ments was also found for the animals' scotopic mechanisms (Fig. 5). Prior to enucleation of the fixating eyes, the sensitivities of the scotopic mechanisms of the deviating eyes (filled circles) were log units lower than those of the fixating eyes (open circles). When the dark-adapted spectral sensitivity functions were measured 5 wk after enucleation of the fixating eyes, complete recovery of scotopic sensitivity had occurred for subject The post-enucleation sensitivity for his deviating eye, represented by the diamonds in Fig. 5, was at the same level as the pre-enucleation data for his fixating eye. However, the scotopic sensitivity for the other subject changed very little from the pre-enucleation levels at either 5 wk (diamonds) or 11 mo (squares) after enucleation. Therefore, spectral sensitivity measurements involving both the photopic and scotopic mechanisms are in agreement in showing significant recovery of visual function for one subject (7906) and an absence of recovery for the other subject (7905). Fig. 4. Post-enucleation increment-threshold spectral sensitivity functions for subject 7905 for a 3000 td achromatic background. Data are shown for the four post-enucleation periods indicated on the graphs. Scotopic Spectral Sensitivity A difference in recovery between the two animals, similar to that found for the photopic mechanisms in the increment-threshold spectral sensitivity experi- Fig. 5. Spectral sensitivity functions obtained under dark adapted conditions for the two subjects. Data are shown for the fixating (open circles) and deviating eyes (filled circles) prior to enucleation of the fixating eye. The diamonds and squares (subject 7905 only) represent data collected 5 wk and 11 mo after enucleation. The curves superimposed on the data are the CIE scotopic luminosity function. Spatial Modulation Sensitivity The effects of enucleation of the fixating eyes on the spatial modulation sensitivity of the deviating eyes are presented in Figure 6. The pre-enucleation data (Panels A and B), as previously reported, 19 show that esotropia surgically induced at 1 mo of age causes a profound reduction of contrast sensitivity in the deviating eyes. The extrapolated cut-off spatial frequencies for these functions (see Table 2) are more than 6 octaves lower for the deviating eyes than for the fixating eyes of both animals. The spatial modulation sensitivity functions determined at 3 wk (diamonds), 3.5 mo (squares), 6.5 mo (triangles), and 9.5 mo (inverted triangles) after enucleation of the fixating eyes are shown in the lower panels of Figure 6. For comparison purposes, the preenucleation data for the deviating eyes (filled circles) have also been replotted along with ± 1.0 SD of these data. The data for subject 7906 show only a very small improvement at 3 wk post-enucleation, but between 3 wk and 3.5 mo a relatively large increase in contrast sensitivity was evident. Thereafter, the functions are relatively constant with an extrapolated cut-off spatial frequency of 6.3 c/deg (approximately 20/100 Snellen acuity) for the function determined 9.5 mo after enucleation. However, even though the range of spatial frequencies which the animal could detect increased from 0.3 c/deg to 6 c/deg, the function is very flat on the low spatial frequency side and the peak of the function is more than 1.0 log unit below the pre-enucleation values for the fixating eye. Typically, contrast sensitivity functions have a more pronounced low spatial frequency roll-off, even if the subject is amblyopic and

6 No. 2 EFFECTS OF ENUCLEATION-ON STRADISMIC AMDLYOPIA / Horwerrh er ol. 251 their contrast sensitivity function exhibits a cut-off spatial frequency similar to that demonstrated by this subject ' 31 The post-enucleation spatial modulation sensitivity data for the other subject (Fig. 6D) are generally similar to those of subject 7906 except that the time course was slower and the final cut-off spatial frequency was lower (2.8 c/deg or approximately 20/215 Snellen acuity). Therefore, even though the spectral sensitivity experiments failed to show any recovery of visual function for subject 7905, the spatial modulation sensitivity functions show a definite, though incomplete, recovery following enucleation of the fixating eye. A. SUBJECT: 7906 PRE-ENUCLEATION C. SUBJECT: 7906 POST-ENUCLEATION B. SUBJECT: 7905 PRE-ENUCLEATION SUBJECT: 7905 POST-ENUCLEATION Temporal Modulation Sensitivity The results of the investigation of temporal modulation sensitivities following enucleation of the fixating eyes are presented in Figure 7, using the same format as that used for the spatial modulation sensitivity results (Fig. 6). The pre-enucleation data (Panels A and B) have also been previously reported 20 and show a lower temporal modulation sensitivity for the deviating eyes than for the fixating eyes at all temporal frequencies (the extrapolated cut-off temporal frequencies are listed in Table 2). The extent of recovery of temporal modulation sensitivity of the deviating eyes following enucleation of the fixating eyes is shown for the two animals in panels C and D of Figure 7 for post-enucleation intervals of 1 mo (diamonds), 4 mo (squares), 7 mo (triangles), and 10 mo (inverted triangles). The temporal contrast sensitivity measurements show some recovery of function for all temporal frequencies for both animals, but the most significant changes were observed for the higher temporal frequencies. The extrapolated cut-off temporal frequencies from the final functions determined 10 mo after the enucleation surgery demonstrate that the temporal resolution limit had increased by Hz for both animals. However, the final temporal modulation sensitivities for the deviating eyes were still approximately 0.4 log units below those obtained for the fixating eyes at all temporal frequencies. Therefore, both the temporal modulation sensitivity data and the spatial modulation sensitivity data are consistent in showing measureable, but incomplete, recovery of visual function for the deviating eyes, presumably as a result of removing the suppressive influences of the fixating eyes. Discussion The results of these experiments have shown that enucleation of the fixating eye can produce a marked V\»\ SPATIAL FREQUENCY (C/DEG) Fig. 6. Spatial modulation sensitivity functions for the two observers. Panels A and B show the pre-enucleation data for the fixating (open circles) and deviating eyes (filled circles). Panels C and D show a comparison of the pre- and post-enucleation data for the deviating eyes. The filled circles are the pre-enucleation data replotted from above and the lines connect the ± 1 SD values of these data. The diamonds, squares, triangles, and inverted triangles represent data collected at 3 wk, 3.5 mo, 6.5 mo, and 9.5 mo after enucleation, respectively. p loo- A. SUBJECT: 7906 PRE - ENUCLEATION TEMPORAL FREQUENCY (Hz) B. SUBJECT: 7905 PRE - ENUCLEATION D. SUBJECT: 79OS POST - ENUCLEATION TEMPORAL FREQUENCY (Hz) Fig. 7. Temporal modulation sensitivity functions for the two subjects. Panels A and B show the pre-enucleation data for the fixating (open circles) and deviating eyes (filled circles). Panels C and D show a comparison of the pre- and post-enucleation data for the deviating eyes. The filled circles are the pre-enucleation data replotted from above and the lines connect the ± 1 SD values of these data. The diamonds, squares, triangles, and inverted triangles represent data collected at 1 mo, 4 mo, 7 mo, and 10 mo after enucleation, respectively.

7 252 INVESTIGATIVE OPHTHALMOLOGY b VISUAL SCIENCE / February 1986 Vol. 27 improvement in the functional capacity of a strabismic subject's deviating amblyopic eye. The improvement was observed in both animals for measures of spatial and temporal modulation sensitivity, but only one animal showed recovery for measures of spectral sensitivity. It is puzzling that one animal (subject 7906) showed substantial recovery of both photopic and scotopic spectral sensitivity functions, while the other animal (subject 7905) failed to exhibit any improvement above the pre-enucleation levels. Kratz and Lemkuhle 32 have also reported that enucleating the nondeprived eye does not result in the recovery of visual function in some kittens with stimulus deprivation amblyopia. They hypothesized that their intersubject variability probably was a result of differences in the duration of the initial period of deprivation and the age at which the nondeprived eye was enucleated. However, in the present study the ages at which strabismus was induced and at which the fixating eyes were subsequently removed were essentially the same for both subjects. Moreover, the spectral sensitivity functions for both animals were nearly identical prior to the enucleation surgery, and ophthalmoscopic observations of the posterior segments of the monkeys' eyes also indicated that they were both normal and free from pathology. The recovery of contrast sensitivity for subject 7905 without the concurrent recovery of spectral sensitivity is somewhat difficult to explain. Since it is generally considered that, in comparison to spatial information, color information is processed at relatively peripheral sites in the nervous system, 33 " 35 one would not expect to observe any recovery of spatial vision in subjects with altered spectral sensitivity caused by a limiting anomaly early in the ascending visual pathway. However, like the anomalous spectral sensitivity functions previously observed in monkeys with severe stimulus deprivation amblyopia, 18 the alterations in spectral sensitivity observed in these esotropic subjects are similar in nature to those manifested by monkeys that have had their visual cortices surgically removed. 36 ' 37 Since the inputs from the deviating eyes are substantially reduced in monkeys reared with an esotropia, 38 it is reasonable to hypothesize that prior to enucleation when these strabismic monkeys were forced to use their deviating eyes, they were behaving like functionally decorticate monkeys. If that is the case, then the differences in recovery of spectral sensitivity between subjects 7905 and 7906 following enucleation of the fixating eyes may reflect differences in the degree of influence attained by the deviating eyes at some cortical level rather than differences in recovery at more peripheral sites in the visual pathway. Following the experiments reported here, a subsequent investigation (Crawford, in preparation) employing cytochrome oxidase staining methods 39 revealed that the horizontal extent of the ocular dominance columns for the deviating eyes in layer IVC of the striate cortex were the same for both subjects 7905 and It is not known to what extent that these column measurements reflect the functional integrity of connections from the deviating eyes to either infraor supra-granular layers within the striate cortex or to other cortical areas. Investigation of specific cortical areas which appear to be specialized for processing color information, eg, the cytochrome rich "blobs" of the striate cortex 40 ' 41 or cortical area V4 42 may reveal differences in recovery between subjects 7906 and However, based on the available evidence, it is impossible to explain the difference in the recovery patterns for the two esotropic subjects. The results of the present studies may be contrasted with our previous investigation 17 of stimulus deprivation amblyopia, although these comparisons should be viewed with some caution since the number of animals in each study was too small to access the variability of these findings. Prior to enucleation of the dominant eyes, the contrast sensitivity and spectral sensitivity deficits were very similar for the two groups of amblyopes. However, following enucleation of the dominant eyes, neither of the subjects with stimulus deprivation amblyopia showed any measureable recovery of visual function, while in the present study the subjects with strabismic amblyopia both demonstrated significant recovery, especially in their spatial (Fig. 6) and temporal resolving (Fig. 7) capabilities. The differences in the results of the two studies suggest that different neural mechanisms are involved in the two types of amblyopia; but it should also be noted that there were differences in the ages of the animals at the time of enucleation (57 mo for the lid sutured monkeys vs 47 mo for the strabismic monkeys), a difference which has been considered an important factor for cats. 32 However, since both the esotropic and lidsutured monkeys were well past the classical critical period at the time of enucleation, 43 we feel that the different recovery patterns observed in lid-sutured and strabismic monkeys reflect different neural mechanisms. In this respect, the findings of the present experiments are in accord with clinical evidence that inter-ocular suppression is more important in strabismic amblyopia than in anisometropic or stimulus deprivation amblyopia. 1 ' 4 ' 44 Clinicians have also observed that patients with strabismic amblyopia, who are well past the critical period of development, will often show considerable recovery of visual acuity if their good eye is lost as a result of injury or disease. 414 " 16 With respect to the degree and extent of recovery of spatial modulation sensitivity, the present results from

8 No. 2 EFFECTS OF ENUCLEATION ON STRABISMIC AMDLYOPIA / Horwerrh er ol. 253 strabismic monkeys are in better agreement with the results of other investigators' experiments with monocularly deprived cats 6 " 10 than our previous experiments with monocularly deprived monkeys. 17 Most of the experiments with cats reared with monocular lid suture have shown that the proportion of neurons in the striate cortex which responded to stimulation of the deprived eye increased dramatically following enucleation of the non-deprived eye. 6 " 8 In accord with the physiological findings, in cats a considerable amount of behavioral recovery in visual acuity has also been reported for the deprived eyes following the enucleation of the nondeprived eyes, 910 although there have also been some exceptions. 45 Therefore, removal of inhibitory influences of the non-amblyopic eye of either species results in some recovery of visual function in some types of amblyopia, but the time course for recovery appears to be much more rapid for cat 7 ' 9 than monkey. In cats recovery occurs immediately after enucleation of the nondeprived eye, 6 ' 7 but in monkey, recovery occurs much more slowly (see Fig. 6). Therefore, in cat the post-enucleation recovery appears to reflect the immediate release from an active inhibitory process, while in monkey the improvement of contrast sensitivity may be more related to the forced usage of the deviated eye. In this sense, the improvement in resolution capability for the monkey may be similar to the improvement of visual acuity of human amblyopes during orthoptic treatment. These differences indicate that different recovery mechanisms are involved for different species or types of amblyopia and further experimentation is required to determine which aspects of early abnormal visual experience, eg, age of onset, degree of amblyopia, etc, are most important in determining which aspects of visual function may recover if suppression is eliminated. Key words: amblyopia, strabismus, animal psychophysics, monkeys, contrast sensitivity, spectral sensitivity, enucleation References 1. von Noorden GK: Burian-von Noorden's Binocular Vision and Ocular Motility, Theory and Management of Strabismus. CV Mosby Co., St. Louis, 1980, pp Phelps G: Amblyopia: Theories on its etiology. Ophthalmic Seminars. 1:1, Crawford MLJ: The visual deprivation syndrome. Ophthalmology 85:465, von Noorden GK and Crawford MLJ: The sensitive period. Trans Ophthalmol Soc UK 99:942, Duffy FH, Snodgrass SR, Burchfield JL, and Conway JL: Bicuculline reversal of deprivation amblyopia in the cat. Nature 260:256, Kratz KE, Spear PD, and Smith DC: Postcritical-period reversal of effects of monocular deprivation on striate cortex cells in the cat. J Neurophysiol 39:501, Smith DC, Spear PD, and Kratz KE: Role of visual experience in postcritical-period reversal of effects of monocular deprivation in cat striate cortex. J Comp Neurol 178:313, Spear PD, Langstetmo A, and Smith DC: Age-related changes in effects of monocular deprivation on cat striate cortex neurons. J Neurophysiol 43:559, Smith DC: Functional restoration of vision in the cat after longterm monocular deprivation. Science 213:1137, Smith DC: Developmental alterations in binocular competitive interactions and visual acuity in visually deprived cats. J Comp Neurol 198:667, Awaya S and von Noorden GK: Visual acuity of amblyopic eyes under monocular and binocular conditions: Further observations. J Ped Ophthalmol 9:8, Levi DM, Harwerth RS, and Smith EL: Binocular interactions in normal and anomalous binocular vision. Doc Ophthalmol 49:302, Harwerth RS and Levi DM: Psychophysical studies of the binocular processes of amblyopes. Am J Optom Physiol Opt 60: 454, Burian HM: Pathophysiologic basis of amblyopia and its treatment. Am J Ophthalmol 67:1, Vereecken EP and Brabant P: Prognosis for vision in amblyopia after loss of the good eye. Arch Ophthalmol 102:220, Rabin J: Visual improvement in amblyopia after visual loss in the dominant eye. Am J Optom Physiol Opt 61:334, Harwerth RS, Smith EL, Crawford MLJ, and von Noorden GK: Effects of enucleation of the nondeprived eye on stimulus deprivation amblyopia in monkeys. Invest Ophthalmot Vis Sci 25: 10, Harwerth RS, Crawford MLJ, Smith EL, and Boltz RL: Behavioral studies of stimulus deprivation amblyopia in monkeys. Vision Res 21:779, Harwerth RS, Smith EL, Boltz RL, Crawford MLJ, and von Noorden GK: Behavioral studies on the effect of abnormal early visual experience in monkeys: spatial modulation sensitivity. Vision Res 23:1501, Harwerth RS, Smith EL, Boltz RL, Crawford MLJ, and von Noorden GK: Behavioral studies on the effect of abnormal early visual experience in monkeys: temporal modulation sensitivity. Vision Res 25:1511, von Noorden GK and Dowling JE: Experimental amblyopia in monkeys II. Behavioral studies of strabismus amblyopia. Arch Ophthalmol 84:215, Harwerth RS, Boltz RL, and Smith EL: Psychophysical evidence for sustained and transient channels in the monkey visual system. Vision Res 20:15, Campbell FW and Green DG: Optical and retinal factors affecting visual resolution. J Physiol 181:576, Harwerth RS and Levi DM: Increment-threshold spectral sensitivity in anisometropic amblyopia. Vision Res 17:585, King-Smith PE and Carden D: Luminance and color-opponent contributions to visual detection and adaptation to temporal and spatial integration. J Opt Soc Am 66:709, Thornton JE and Pugh EN: Red/green color oppenency at detection threshold. Science 219:191, Sperling HG and Harwerth RS: Red-green cone interactions in the increment-threshold spectral sensitivity of primates. Science 172:180, Harwerth RS and Sperling HG: Effects of intense visible radiation on the increment-threshold spectral sensitivity of the rhesus monkey eye. Vision Res 15:1193, Wyszecki G and Stiles WS: Color Science. New York, John Wiley &Sons, 1967, pp

9 254 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / February 1986 Vol Hess RF, Campbell FW, and Zimmern R: Differences in the neural basis of human amblyopes: the effects of mean luminance. Vision Res 20:295, Smith EL, Harwerth RS, and Crawford MLJ: Spatial contrast sensitivity deficits in monkeys produced by optically induced anisometropia. Invest Ophthalmol Vis Sci 26:330, Kratz KE and Lehmkuhie S: Spatial contrast sensitivity of monocularly deprived cats after removal of the non-deprived eye. Behav Brain Res 7:261, De Valois RL, Abramov I, and Jacobs GH: Analysis of response patterns of LGN cells. J Opt Soc Am 56:966, de Monasterio FM and Gouras P: Functional properties of ganglion cells of the rhesus monkey retina. J Physiol (Lond) 251: 167, Gouras P and Zrenner E: Color coding in primate retina. Vision Res 21:1591, Lepore FB, Cardus T, Rasmussen T, and Malino RB: Rod and cone sensitivity in destriate monkeys. Brain Res 93:203, Malmo RB: Effects of striate cortex ablation on intensity discrimination and spectral intensity distribution in the rhesus monkey. Neuropsychologia 4:9, Baker FA, Grigg P, and von Noorden GK: The effects of visual deprivation and strabismus on the response of neurons in the visual cortex of the monkey, including studies on the striate and prestriate cortex in the normal animal. Brain Res 66:185, Wong-Riley MTT: Changes in the visual system of monocularly sutured or enucleated cats demonstratable with cytochrome oxidase cytochemistry. Brain Res 171:11, Livingstone MS and Hubel DH: Anatomy and physiology of a color system in the primate visual cortex. J Neurosci 4:309, Livingstone MS and Hubel DH: Specificity of intrinsic connections in primate primary visual cortex. J Neurosci 4:2830, Zeki SM: Functional specialization in the visual cortex of the rhesus monkey. Nature 274:423, Harwerth RS, Smith EL, Duncan GC, Crawford MLJ, and von Noorden GK: A behavioral assessment of sensitive periods of visual development in monkeys. ARVO Abstracts. Invest Ophthalmol Vis Sci 26(Suppl):252, von Noorden GK: Mechanisms of amblyopia. Adv Ophthalmol 34:93, Jones KR, Berkley M, Spear P, and Tong L: Visual capacities of monocularly deprived cats after lid suture and enucleation of the nondeprived eye. Society for Neuroscience Abstracts 4:1516, 1978.