Gaze-Stabilizing Deficits and Latent Nystagmus in Monkeys With Brief, Early-Onset Visual Deprivation: Eye Movement Recordings

Ronald J. Tusa,1 Michael J. Mustari,1 Andrew F. Burrows,2 and Albert F. Fuchs3

 1Yerkes Regional Primate Research Center and Department of Neurology, Emory University, Atlanta, Georgia 30322;  2Department of Anatomy and Neuroscience, University of Texas Medical Branch, Galveston, Texas 77555; and  3Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Tusa, Ronald J., Michael J. Mustari, Andrew F. Burrows, and Albert F. Fuchs. Gaze-Stabilizing Deficits and Latent Nystagmus in Monkeys With Brief, Early-Onset Visual Deprivation: Eye Movement Recordings. J. Neurophysiol. 86: 651-661, 2001. The normal development and the capacity to calibrate gaze-stabilizing systems may depend on normal vision during infancy. At the end of 1 yr of dark rearing, cats have gaze-stabilizing deficits similar to that of the newborn human infant including decreased monocular optokinetic nystagmus (OKN) in the nasal to temporal (N-T) direction and decreased velocity storage in the vestibuloocular reflex (VOR). The purpose of this study is to determine to what extent restricted vision during the first 2 mo of life in monkeys affects the development of gaze-stabilizing systems. The eyelids of both eyes were sutured closed in three rhesus monkeys (Macaca mulatta) at birth. Eyelids were opened at 25 days in one monkey and 40 and 55 days in the other two animals. Eye movements were recorded from each eye using scleral search coils. The VOR, OKN, and fixation were examined at 6 and 12 mo of age. We also examined ocular alignment, refraction, and visual acuity in these animals. At 1 yr of age, visual acuity ranged from 0.3 to 0.6 LogMAR (20/40-20/80). All animals showed a defect in monocular OKN in the N-T direction. The velocity-storage component of OKN (i.e., OKAN) was the most impaired. All animals had a mild reduction in VOR gain but had a normal time constant. The animals deprived for 40 and 55 days had a persistent strabismus. All animals showed a nystagmus similar to latent nystagmus (LN) in human subjects. The amount of LN and OKN defect correlated positively with the duration of deprivation. In addition, the animal deprived for 55 days demonstrated a pattern of nystagmus similar to congenital nystagmus in human subjects. We found that restricted visual input during the first 2 mo of life impairs certain gaze-stabilizing systems and causes LN in primates.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The human infant has limited gaze-stabilizing abilities at birth, but rapidly develops better control over the next 6 mo (Aslin 1987; Naegele and Held 1982; Shupert and Fuchs 1988). Normal development and the capacity to calibrate these gaze-stabilizing systems may depend on normal vision during infancy. Monocular deprivation of pattern vision from lid suture for the first 2 wk of life or artificial induction of esotropia induced during early infancy in monkeys results in decreased monocular optokinetic nystagmus (OKN) in the nasal to temporal (N-T) direction (Kiorpes et al. 1996; Sparks et al. 1986; Tychsen et al. 1996). In addition, strabismic humans with infantile esotropia syndrome and infant monkeys with surgical strabismus often show latent nystagmus (LN) when viewing monocularly (Kiorpes et al. 1996; Kommerell and Mehdorn 1982; Schor 1983; Tychsen et al. 1996). This immature pattern of OKN is found when cortical binocularity is disrupted early in simian or human development (see Schor 1983 for review). These types of deprivation result in significant competition between the two eyes. Psychophysical and physiological studies in visual cortex in monkeys show that sensory deficits caused by abnormal early visual experience as a result of monocular form deprivation in monkeys is much more severe than those associated with bilateral form deprivation (Crawford et al. 1993; Harwerth et al. 1991). The differences in the severity of visual deficits have been attributed to the consequences of binocular competition associated with unilateral form deprivation. There is no information on ocular motor behavior in monkeys with early binocular deprivation where there is no competition between the two eyes. Based on a study in cats, we believe that gaze-holding deficits can occur even with binocular deprivation. At the end of 1 yr of dark rearing, cats have gaze-stabilizing deficits similar to those of the newborn human infant including decreased monocular OKN in the N-T direction and decreased velocity storage in the vestibuloocular reflex (VOR) (Cynader 1985).

In the current study, we have examined the VOR, optokinetic response, and fixation of three monkeys with binocular lid suture initiated within 1 day of birth. We also examined ocular alignment, refraction, and visual acuity in these animals. We examined monkeys deprived for 25, 40, and 55 days of life to determine the duration of deprivation critical for causing ocular motor defects. The overall objective of this study was to determine to what extent the development of gaze-stabilization in monkeys depends on normal visual input during infancy, and to what extent visual deprivation results in irreversible gaze-stabilizing deficits and spontaneous nystagmus. Brief reports of some of these results have been presented elsewhere (Tusa et al. 1992, 1994).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects and general rearing conditions

Three infant rhesus monkeys (Macaca mulatta, 1 male and 2 females) born on the Johns Hopkins Primate Farm were used. All of the experimental and animal care procedures were in strict adherence with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Eyelids were sutured closed similar to the method of Raviola and Wiesel (1985). The animals were sedated with tiletamine and zolazepam and ketamine, and then the epithelial margins of the upper and lower eyelid lateral to the lacrimal papilla were trimmed. The cut surfaces of the lids of both eyes were joined by 4-0 nylon mattress sutures from the lateral canthus to the lacrimal papilla. After 7-10 days the sutures were removed. After 25, 40, and 55 days, the eyelids were opened with sharp dissection. The ocular motor behavior of these three monkeys was compared with that of six normal control rhesus monkeys.

Ocular examination

These methods were previously described (Repka and Tusa 1995; Tusa et al. 1991). In brief, ocular alignment, refraction of the eyes, axial length of the eye, and clinical examination of spontaneous eye movements during binocular and monocular viewing were assessed in all animals on the first day of birth, and repeated at 3, 6, and 12 mo of age. Ocular alignment was measured using a cover test with the monkey fixating on a toy at 33 cm combined with a Krimsky corneal light reflex test. A photographic determination of ocular alignment was also performed. Refractive error was measured by retinoscopy with the pupils dilated with cyclopentolate and the animal sedated with ketamine. Visual spatial acuity was measured using Teller Acuity Cards (VisTech Consultants, Dayton, OH).

Eye movement recordings

Eye movement recordings using the magnetic-field search coil technique began at day 60. A 14-mm eye coil was implanted around each eye, and the end of each wire was soldered to a small electrical plug anchored onto the skull with a small inverted flat-head screw (Judge et al. 1980). The entire skull assembly including plug, cement, and screw weighed 5 g. For the first few months of life, the eye movement recording system was calibrated by rotating the magnetic field coils 20° in each horizontal direction around the stationary animal in the dark while measuring average eye position. Calibration was also checked by rotating the field coils at a fixed velocity (30°/s) around the animal in the dark. We were usually able to record eye movements for 20-30 min before the infants became drowsy, at which time they were returned to their cages. Eye movements were recorded while the monkey sat in a small adjustable, primate chair. During eye movement recordings, the head was held stationary by lightly padded braces and Velcro straps attached to the chair. By 6 mo of age, the skull sutures were fused, and the skull was thick enough to accept a light-weight, removable aluminum halo, of the type used on human beings, to fix the head to the chair. The halos were removed every 2 wk for at least 1 wk to prevent infection and skull erosion. By 6 mo of age, the monkeys stayed alert in the chair for 1-2 h and were easily trained to fixate and follow a small target light rear-projected onto a tangent screen located 75 cm in front of the animal. The animal's performance was reinforced with a sweetened liquid. Spontaneous eye movements, OKN, and VOR were measured at 90, 180, and 365 days of age.

SPONTANEOUS EYE MOVEMENTS. These were measured while the monkey viewed a stationary OKN drum or a Ganzfeld (1/2 of a clean Ping-Pong ball placed over the eye).

FIXATION. Fixation was measured while the monkey viewed a 0.5° target light that was located in the primary and eccentric positions of gaze. The target light was always surrounded by a full-field grating background. In addition, fixation was measured while the monkey viewed a blinking 0.5° target light (0.5 Hz, duration 50 ms) in an otherwise dark room. This test was done to avoid visual stabilization by retinal-slip mediated tracking eye movements.

VOR. The VOR was generated by rotating the monkey chair and the magnetic field coils en bloc at a constant velocity (60°/s and 240°/s) in the dark. Four trials were done to the left and four to the right at each speed. Velocity of the chair was measured by a tachometer. The VOR gain (eye velocity/chair velocity) for each trial was measured as the average of three consecutive peak slow-phase eye velocities, once maximum chair speed was obtained. The VOR time constant was measured as the time taken for the slow-phase eye velocity (SPEV) to decrease to one-third of its peak value.

OKN. OKN was generated by rotating a full-field drum around the animal. The drum contained a random pattern of black circles each subtending a visual angle of 8-16° on a white background. Optokinetic response gain (SPEV/drum velocity) under both monocular and binocular viewing conditions was measured. The drum moved at a constant velocity ranging from 5 to 180°/s for 60 s or until eye velocity reached a steady-state value based on a chart-recorder printout. OKN gain was measured during its initial rapid rise in slow-phase velocity (peak SPEV during the 1st second the light was turned on), and during steady state (the average velocity of the last 5 slow phases before the light was turned off). The initial value OKAN (optokinetic after nystagmus) was also examined (the average velocity of the 1st 3 slow phases beginning 1 s after the light was turned off).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Ocular examination

Table 1 summarizes the ocular findings for the three rhesus monkeys that had binocular eyelid suture (BD) for the first 25, 40, and 55 days of life and the six controls. Visual acuity was measured in cycles per degree and was displayed in both LogMAR (Log10 [1/decimal]) and its snellen equivalent. Visual acuity was measured with both eyes open. Visual acuity was better at 12 mo compared with 6 mo of age in each animal, but less than normal controls. The visual acuity for the animal with the longest deprivation was not as good as that of the animal with the shortest deprivation. The 25-day monkey had an esotropia of 10 prism diopters when the eyelids were opened, but it resolved 35 days later (2 mo of age). The 40- and 55-day monkeys developed a persistent exotropia. The 55-day animal also developed a persistent hyperopia in both eyes. The refractions of each eye of the controls were combined.


                              
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Table 1. Summary of ocular examinations for binocularly deprived (BD) and control monkeys

LN

GENERAL PROPERTIES. All animals had a jerk nystagmus, which persisted through the duration of the study (Fig. 1). When the right eye was covered there was a conjugate, left-beating nystagmus. The term left beating is used here based on the direction of the quick phases of the nystagmus. When the left eye was covered, there was a right-beating nystagmus. When both eyes were open, all animals had a low-amplitude, horizontal nystagmus. This combination of a low-amplitude horizontal nystagmus with both eyes viewing, and a strong horizontal nystagmus when only one eye was viewing (with slow phases always toward the nose in the viewing eye) resembles "manifest latent nystagmus" found in some human subjects (Dell'Osso et al. 1979). We will to refer to this as latent nystagmus (LN) throughout the paper. LN was not seen at birth in any of the animals, but LN was noted as soon as the eyes were opened after binocular deprivation.



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Fig. 1. Eye movement trace showing latent nystagmus (LN) in the 55-day monkey at 6 mo of age while viewing a stationary optokinetic nystagmus (OKN) drum. Viewing conditions were right eye covered, left eye covered, and both eyes viewing. With right eye covered, there was a conjugate left-beating nystagmus, with the left eye covered the nystagmus became right beating, and with both eyes viewing there was mild left-beating nystagmus. RHe, right eye horizontal eye position; RVe, right eye vertical eye position; LHe, left eye horizontal eye position; LVe, left eye vertical eye position. One-second tick mark is shown above the trace. Upward deflections of traces indicate rightward (or upward) eye motion. This convention will be used throughout the paper.

SPEV of LN are plotted in Fig. 2. In the 55-day monkey, when the left eye was covered, SPEV increased over the course of 60 s to plateau at ~90°/s (Fig. 2A). When the patch was switched to the right eye, SPEV increased over a period of ~40 s to plateau at ~40°/s. For the 40-day animal, the plateaus were ~40°/s with either eye viewing. The SPEV of LN in the 25-day animal was low and variable (Fig. 2B).



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Fig. 2. Slow phase eye velocity (SPEV) of LN plotted against time in the 55-day (A) and 25-day (B) monkey at 1 yr of age. Data were collected on 2 separate days for each monkey. When either eye was covered in the 55-day monkey, the SPEV builds up in intensity until a plateau level was reached (mean and 1 SD listed during time when SPEV reached a steady-state value). The open eye was viewing a stationary OKN drum. When both eyes were viewing, the data illustrated came from the right eye, but eye movements were conjugate in all animals. When one eye was covered, the data illustrated came from the viewing eye. This convention of illustrating eye movements from the viewing eye will be used throughout the paper.

SENSORY CONDITIONS THAT INITIATE AND MAINTAIN LN. The stimulus that initiates LN does not appear to depend on retinal slip information in the viewing eye as the nystagmus could occur even when the monkeys viewed a Ganzfeld. Figure 3A shows the mean and 1 SD of SPEV recorded approximately every 10 s in the 55-day monkey when this animal viewed a stationary OKN drum (A) and a Ganzfeld (B). The average of the last five data points before the patch was moved to the other eye was determined for each condition (plateau). There was no significant difference (P > 0.01, t-test) between conditions A and B. The plateau velocity of LN partly depends on the luminance of the Ganzfeld stimulus (Fig. 4). As luminance was increased, velocity of LN increased until eye velocity saturated at ~110°/s.



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Fig. 3. Sensory conditions that initiate and maintain LN. SPEV of LN was plotted during different viewing condition of the open eye in the 55-day monkey at 1 yr of age. Data in both viewing conditions were collected on 2 separate days. The mean and 1 SD are shown of the plateau level (when SPEV reached a steady-state value). The open eye was viewing a stationary OKN drum (A) or a Ganzfeld (B). ANOVA revealed there was no significant difference in SPEV in conditions A and B (P > 0.01).



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Fig. 4. Effect of using neutral density filters to alter light intensity to the viewing eye on LN in the 55-day monkey. Maximum horizontal eye velocity (He) of LN was plotted against the luminance of a Ganzfeld stimulus. The nonviewing eye was covered with a black patch. Eye velocity increased as luminance was increased from 0.1 to 10 cd/m2.

ADAPTATION OF LN. The maximum velocity of LN decreased in the viewing eye if the animal wore a patch over the other eye continuously for at least 1 day. Figure 5 shows the mean and 1 SD of SPEV in the 55-day monkey during monocular viewing before and after 1 and 3 days of continuous occlusion of the left eye. Before occlusion, SPEV reached a plateau of 172°/s when the left eye was covered and 31°/s when the right eye was covered (Fig. 5A). The plateau was defined when there was no significant change in SPEV over a period of 10 s or more. After 1 day of occlusion of the left eye, SPEV was 94°/s when the left eye was covered and 110°/s when the right eye was covered, both of which represented significant changes from baseline (P < 0.001, t-test). After 3 days of occlusion (C), SPEV decreased further when the left was covered and increased when the right eye was covered compared with condition B (P < 0.001, t-test). In summary, a velocity bias of approximately 100°/s to the right developed when the left eye had been continuously occluded. Before occlusion, this animal fixated primarily from the left eye, which explains why SPEV was initially lowest when the right eye was covered during testing of LN. Thus the maximum SPEV of the habitually viewing eye decreases over the course of several days.



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Fig. 5. Adaptation of LN in the 55-day monkey induced by prolonged monocular occlusion. Mean and 1 SD of LN is plotted. SPEV is plotted 1st when the left eye was covered with a black patch and then when the right eye was covered. Values of mean and 1 SD are listed when SPEV reached a steady-state value. A: before occlusion, SPEV was much higher when the left eye was covered. B: after the left eye was occluded continuously for 1 day, steady-state SPEV decreased significantly by 78°/s during the left eye covered condition, and increased by 80°/s for the right eye covered condition (ANOVA, P < 0.001). C: after 3 days of occlusion, SPEV decreased further during the left eye covered condition and increased for the right eye condition (ANOVA, P < 0.005). This experiment was done twice on 2 consecutive months. The data were similar so were combined. Eye movements were conjugate, but only data from the viewing eye are illustrated.

Other forms of nystagmus

GAZE-EVOKED NYSTAGMUS. All monkeys had a conjugate, horizontal gaze-evoked nystagmus, which was quantified by having the animals fixate a blinking target (0.5 Hz, duration 50 ms) in a dark room to avoid reduction of the nystagmus from visual-tracking mechanisms. When the 25-day animal fixated targets to the left, slow phases of nystagmus moved the eyes back toward the right (Fig. 6A). This testing was performed during binocular viewing to evaluate gaze-evoked nystagmus without LN. Similarly, when the animal fixated targets to the right, slow phases of nystagmus were directed to the left. The SPEV decreased during each single slow phase as the fixation target was positioned closer to the center of gaze. Figure 6B shows the eye velocity of each slow phase while the animal fixated a small target located at different eccentricities. The estimates of SPEV decreased exponentially with decreases in the eccentricity of the fixation target. To determine the time constant (Tc) of the gaze-holding integrator, we fitted an exponential curve through the data. The Tc for the gaze-holding integrator in this animal was 15 s. A similar analysis in the 40-day animal revealed a Tc of 12 s. Eye velocity was frequently not symmetric across the midline due to a small amount of spontaneous nystagmus in primary gaze. Vertical gaze-evoked nystagmus was not present in any of the animals while they fixated targets that moved vertically. The waveform of the slow phases of LN was velocity decreasing in the 25- and 40-day animals, and SPEV varied with orbital eye position (Fig. 6C). Gaze-evoked nystagmus was not observed at birth and was observed immediately after the eyelids were opened, but it was not quantified in a dark room at these times.



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Fig. 6. Gaze-evoked nystagmus in the 25-day monkey at 1 yr of age. A: horizontal eye position traces during binocular viewing of a target at center of gaze and eccentrically. In all cases the direction of slow phases brings the eye back toward the center of gaze. B: plot showing the relationship of horizontal eye velocity and the fixation point. In this animal, eye velocity was higher for orbital positions to the left of center of gaze because of the spontaneous left-beating nystagmus when both eyes are open. C: LN while the monkey fixated target at center of gaze (right eye covered). Slow phases were velocity decreasing. This is best seen in the velocity trace. He, horizontal eye position; He, horizontal eye velocity.

VELOCITY-INCREASING JERK NYSTAGMUS. In contrast to both the 25- and 40-day animals, the eye velocity of the 55-day animal had velocity-increasing slow phases in eccentric gaze. This was most apparent in the light when the animal fixated a small target light (arrows in Fig. 7). This animal also had a spontaneous left-beating nystagmus in the dark, which primarily had linear or velocity-increasing slow phases.



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Fig. 7. Spontaneous, jerk nystagmus with velocity-increasing slow phases and pendular nystagmus in the 55-day monkey at 1 yr of age. Recordings were made while the monkey had both eyes open while sitting in the dark, or while viewing a 0.5° light. In the dark there was a left-beating nystagmus with linear and velocity-increasing slow phases. In the light, this animal had marked velocity-increasing slow phases in eccentric gaze (arrows). Transient bursts of pendular nystagmus were also present (horizontal bars). RHe, right eye horizontal eye position; RVe, right eye vertical eye position; LHe, left eye horizontal eye position; LVe, left eye vertical eye position. One-second tick mark is shown above the trace.

PENDULAR NYSTAGMUS. All monkeys had a low-amplitude, conjugate pendular nystagmus. This is illustrated in Fig. 7 (horizontal bars) for the 55-day monkey and Fig. 8 for the 25-day monkey. The peak-to-peak amplitude was 0.5-2.0°, and the frequency was 7-10 Hz. Pendular nystagmus was not readily apparent when the eyelids were first opened, but did become apparent by age 1 yr.



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Fig. 8. Low-amplitude, high-frequency pendular nystagmus in the 25-day monkey. He, horizontal eye position; Ve, vertical eye position; He, horizontal eye velocity; Ve, vertical eye velocity. One-second tick mark is shown above the trace.

VOR

All monkeys had mildly reduced VOR gains but normal time constants for 60 and 240°/s constant-velocity chair rotations compared with six normal monkeys tested at 1 yr of age (Table 2). The gain was measured as the average of the three consecutive peak slow-phase eye velocities once chair velocity reached peak velocity.


                              
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Table 2. VOR gain and time constant for BD and control monkeys

OKN

A robust OKN response was elicited in all three animals when both eyes were viewing, but the response was severely impaired in the N-T direction during monocular viewing. The rapid rise, steady-state OKN and OKAN for the 25-day monkey is plotted in Fig. 9. For both eyes viewing there was a good response to constant velocity steps (Fig. 9A). During monocular viewing, OKN was reduced in the N-T direction, especially for OKAN (Fig. 9, C and D). Table 3 compares the OKN responses in both the 25- and 55-day monkeys to six normal controls tested at 1 yr of age. For the 25-day monkey, steady-state OKN was slightly reduced in the N-T direction, and OKAN was significantly reduced in the N-T direction compared with controls. It is likely that the LN present during monocular viewing contributed to this reduced response in the N-T direction. The OKN response for the 55-day monkey was more severely impaired (Table 3). For both eyes viewing, steady-state OKN and OKAN was reduced at high target velocities. During monocular viewing, OKN was severely impaired for all drum velocities in the N-T direction for all three components of OKN. In the T-N direction, OKN was impaired for high drum velocities.



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Fig. 9. Plots of SPEV plotted against OKN drum velocity in the 25-day monkey at 1 yr of age. A: mean and 1 SD of steady-state OKN during a stimulus that increased in small velocity steps with both eyes open (the fine dashed line represents perfect tracking). B: mean OKN to constant-velocity drum rotations at 15, 30, 60, and 90°/s rotations. The rapid rise (RR), steady-state OKN (SS), and optokinetic afternystagmus (OKAN) components are illustrated. These OKN components are shown for left eye viewing (C) and for right eye viewing (D). For each plot, data were collected on 3 separate days and combined. Because spontaneous nystagmus occurred whenever one eye was covered (LN), monocular viewing OKN was measured in the following way. The animal faced a stationary OKN drum in the light with both eyes open. The lights were turned off, the drum was rotated at constant velocity, one eye was patched, and then the lights were turned on. This technique reduced the spontaneous nystagmus of LN during the rapid rise portion of OKN.


                              
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Table 3. Optokinetic nystagmus in monkeys tested at 12 mo of age

When OKN is tested to constant velocity steps, a high retinal-slip velocity is delivered. To determine whether the reduced OKN response of the 55-day monkey to N-T velocity steps was due to an impairment in the processing of high retinal-slip velocities, we measured steady-state OKN to a stimulus that started out at a velocity slightly greater than the animal's LN velocity and then decremented in 5°/s steps at 15-s intervals (Fig. 10). The mean and 1 SD of SPEV of LN every 50 s is plotted during right eye view (A) and left eye view (B). The staircase line represents the velocity of the OKN drum. There was small trend in SPEV in response to the stimulus (eye velocity = 0.07 times target velocity in A and 0.06 times target velocity in B), but there was no significant change in SPEV (t > 0.01, Pearson correlation). This helped confirm that there was no significant monocular OKN response in the N-T direction in the 55-day monkey.



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Fig. 10. Inability of monocular OKN in the N-T direction to suppress LN in the 55-day monkey. Means and 1 SD of the velocity of LN (circles) are plotted during right eye view (A) and left eye view conditions (B). The staircase line represents the velocity of the OKN drum. At time 0, the drum was rotating near the same speed as the slow phases of LN to create little retinal slip. The drum was then slowly decelerated by 5°/s steps every 15 s. For each figure, data were collected on 2 separate days and combined.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Images are stabilized on the retina by several gaze-stabilizing systems, including the VOR, OKN, and fixation (Leigh et al. 1988). Table 4 summarizes our findings on gaze-stabilizing systems and fixation instability in the BD monkeys tested at 12 mo of age. The most significant defect was the impaired monocular OKN response in the N-T direction and the presence of nystagmus.


                              
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Table 4. Summary of gaze-stabilizing ability and nystagmus in BD monkeys tested at 12 mo of age

OKN

In human infants, OKN is depressed in the N-T direction compared with the T-N direction during monocular viewing at birth and becomes symmetric by 6 mo of age (Naegele and Held 1982). If normal visual development is disrupted by unequal visual inputs from the two eyes due to strabismus, anisometropia, or a congenital cataract in one eye, then monocular OKN asymmetry persists (Maurer et al. 1983; Schor and Levi 1980; Shawkat et al. 1995; Westall and Schor 1985). This monocular OKN asymmetry has also been found in monkeys following 14 days of monocular eyelid suture starting at 7-14 days of age (Sparks et al. 1986). Our study has extended these findings. We have examined both the rapid rise and the velocity storage components of OKN (OKAN). Our results suggest that the velocity-storage component of OKN in the N-T direction is the component most impaired by binocular deprivation in monkeys. When the duration of deprivation increases, the rapid rise component of OKN is also impaired in the N-T direction and eventually, OKN deficits may start to occur in the T-N direction at high target velocities, as was found in the 55-day monkey. It is likely that the reduced OKN in the N-T direction is partially due to the presence of LN. We chose not to subtract the LN from OKN, as these visual tracking systems may be nonlinear. Our testing using a moving OKN drum that changed speeds in small steps indicates that these deficits in OKN were not simply due to an inability to process high retinal-slip velocities, but represented a true deficit in generating an OKN response.

A schematic diagram illustrating the possible basis for a decreased monocular OKAN response in the nasal-to-temporal direction is shown in Fig. 11. Neural activation of the nucleus of the optic tract (NOT) evokes ipsiversive eye movements (dashed lines above NOT) (Mustari and Fuchs 1990; Schiff et al. 1988). NOT neurons are activated by ipsilaterally directed retinal slip. Normally, NOT receives inputs directly from the contralateral eye (T-N motion) and indirectly (via cerebral cortex) from the ipsilateral eye (Mustari and Fuchs 1990). In the BD monkey, NOT loses its input from the ipsilateral eye (cortical input) and responds only to T-N motion viewed from the contralateral eye. Consequently, the BD monkey cannot generate OKN to N-T stimuli during monocular viewing. This loss of visual input to NOT from the ipsilateral eye may be due to a defect in any number of sites indicated by the "X" marks.



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Fig. 11. Schematic diagram of the proposed disruption within the circuit mediating the velocity-storage component of OKN. Dashed lines indicate target motion and slow-phase eye movement (SPEM) directions. Continuous lines indicate anatomical projections. A cortical afferent system includes a projection from the dorsolateral geniculate nucleus (dLGN) to striate cortex (V1) to the middle temporal area (MT). This system processes information about target motion from each eye. The cortical efferent system includes a projection from the medial superior temporal (MST) area to the nucleus of the optic tract (NOT). NOT also receives a direct retinal projection from the contralateral eye. Each NOT generates ipsilateral slow-phase eye movements via a projection to the medial vestibular nucleus (MVN), 6th nerve nucleus (6th) and 3rd nerve nucleus (3rd). In the schematic, black and open arrows indicate the visual pathways from the left and right eyes, respectively. Gray arrows indicate pathways downstream from NOT. Most neurons in NOT are normally activated only by target motion toward the ipsilateral side (indicated by the 3 small dashed lines above NOT).

VOR gain

Human infants have VOR gains similar to adults (Ornitz et al. 1985; Weissman et al. 1989). In contrast, VOR velocity storage is poorly developed at birth, although it improves rapidly over the course of 2 mo and then slowly reaches adult values over the course of 2 yr (Ornitz et al. 1985; Weissman et al. 1989). In cats reared for 1 yr in the dark, VOR gain is reduced, and the VOR velocity-storage is poor (Cynader 1985; Harris and Cynader 1981). These deficits endure despite subsequent exposure to a normal visual environment. VOR gain has not been previously examined in visually deprived monkeys. In our study, 25-55 days of binocular derivation beginning at birth resulted in a small decrease in VOR gain and no change in the velocity storage system compared with normally reared monkeys. These results suggest that the vestibular system still received adequate retinal-slip information to be maintained and calibrated in these animals despite the presence of the monocular OKN deficits.

Nystagmus

CRITICAL PERIOD. Based on our study along with others, it appears that deprivation-induced nystagmus in monkeys only occurs if deprivation is initiated during the first few weeks of life. Furthermore, nystagmus may persist even with as little as 25 days of deprivation. Nystagmus resembling LN occurs in monkey following artificial induction of esotropia within the first 2 wk of life (Kiorpes et al. 1996), and nystagmus resembling congenital nystagmus occurs following monocular lid suture initiated within 1 day of life as long as the fellow eye is suture closed within 3 wk (Tusa et al. 1991). Spontaneous nystagmus has not been reported in monkeys reared with monocular or bilateral eyelid suture starting 30 days or later after birth for up to 4-18 mo of deprivation (Crawford et al. 1993; Harwerth et al. 1991).

Based on these studies the critical period in which visual deprivation causes gaze instability may be over by the first few weeks of life in monkeys. This brief duration for motor deficits from visual deprivation is in striking contrast to purely visual perceptual problems from visual deprivation. Based on monocular deprivation studies in monkeys, the development of scotopic threshold spectral sensitivity has a critical period of 3 mo, the critical period for development of photopic threshold sensitivity is complete by 6 mo of age, and binocular visual function is complete by 2-3 yr of age (Crawford et al. 1993; Harwerth et al. 1986).

All of the BD monkeys had strabismus when the eyelids were opened. It is possible that ocular motor function of our monkeys may have deteriorated further after the eyelids were opened due to visual deprivation from strabismus and amblyopia. It is even possible that some ocular motor deficits may have occurred due to competition between the two eyes behind closed eye lids. The hairless eyelids of macaque monkeys allow transmission of 10% of light in the adult, perhaps more in the infant (Crawford and Marc 1976; Robinson et al. 1991). Competition between the two eyes from strabismus during the first few weeks of life may be the cause of LN in both lid-sutured monkeys and induction of artificial esotropia.

CHARACTERISTICS OF LN IN BD MONKEYS. Certain features of LN in monkeys are similar to LN in human subjects. First is the presence of horizontal nystagmus elicited by closing one eye whose direction depends on which eye is closed (slow phases are directed toward the closed eye). Second, the maximum velocity of LN decreases in the viewing eye if the animal wears a patch over the other eye continuously for a few days, similar to that reported by patients with LN (Simonsz 1989). This reduction of SPEV by patching one eye continuously appears to be due to the development of a constant velocity bias whose slow phases are directed toward the habitually viewing eye. The direction of this bias can be reversed after patching the eye for 1 day. Remarkably, this reduction in SPEV occurred even in the 55-day monkey, which suggests that this animal can still decrease SPEV of LN even without any monocular OKN in the N-T direction. Thus this type of adaptation may not rely solely on retinal-slip in the viewing eye.

We found three additional features of LN in monkeys that we believe help elucidate potential neural mechanisms. First, when one eye is patched, the slow phases of LN build up slowly over the course of 30-60 s. Second, LN occurs even when the open eye is viewing a Ganzfeld. Thus the stimulus that evokes LN when one eye is closed does not appear to require retinal slip. The stimulus may in part be due to a difference in light intensity in the two eyes. Third, the peak SPEV of LN varied in each monkey, but was correlated inversely with the amount of monocular OKN in the N-T direction. Thus retinal slip in the viewing eye may not be inducing LN, but it may activate OKN that, in turn, decreases LN. Consider the 25-day monkey that had a partial monocular OKN response in the N-T direction. When one eye was closed, LN was induced such that retinal slip occurred opposite to the direction of the slow phases N-T. This retinal slip should stimulate the OKN system to generate slow phases opposite to the LN. When the monocular OKN response is completely normal, no LN may be seen, whereas when the monocular OKN response in the temporal direction is completely absent, maximum LN may be seen. These three properties of LN suggest that the NOT may be involved in LN. When the NOT is electrically stimulated on one side, horizontal nystagmus is elicited whose SPEV builds up over 60 s or less (Mustari and Fuchs 1990; Schiff et al. 1988). Cells in NOT respond to both retinal slip and transient light changes, and NOT is involved in the generation of OKN.

In the companion paper we examine specifically the physiological properties of the NOT neurons in two of these monkeys (Mustari et al. 2001).


    ACKNOWLEDGMENTS

We are grateful for the technical assistance of J. R. Economides.


    FOOTNOTES

Address for reprint requests: R. J. Tusa, Yerkes Research Center, 954 Gatewood Rd. NE, Emory University, Atlanta, GA 30322 (E-mail: rtusa{at}rmy.emory.edu).

Received 3 November 2000; accepted in final form 10 April 2001.


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ABSTRACT
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0022-3077/01 $5.00 Copyright © 2001 The American Physiological Society