Effect of Adaptation to Telescopic Spectacles on the Initial Human Horizontal Vestibuloocular Reflex

Benjamin T. Crane and Joseph L. Demer

Departments of Ophthalmology and Neurology, University of California, Los Angeles, California 90095-7002


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Crane, Benjamin T. and Joseph L. Demer. Effect of Adaptation to Telescopic Spectacles on the Initial Human Horizontal Vestibuloocular Reflex. J. Neurophysiol. 83: 38-49, 2000. Gain of the vestibuloocular reflex (VOR) not only varies with target distance and rotational axis, but can be chronically modified in response to prolonged wearing of head-mounted magnifiers. This study examined the effect of adaptation to telescopic spectacles on the variation of the VOR with changes in target distance and yaw rotational axis for head velocity transients having peak accelerations of 2,800 and 1,000°/s2. Eye and head movements were recorded with search coils in 10 subjects who underwent whole body rotations around vertical axes that were 10 cm anterior to the eyes, centered between the eyes, between the otoliths, or 20 cm posterior to the eyes. Immediately before each rotation, subjects viewed a target 15 or 500 cm distant. Lighting was extinguished immediately before and was restored after completion of each rotation. After initial rotations, subjects wore 1.9× magnification binocular telescopic spectacles during their daily activities for at least 6 h. Test spectacles were removed and measurement rotations were repeated. Of the eight subjects tolerant of adaptation to the telescopes, six demonstrated VOR gain enhancement after adaptation, while gain in two subjects was not increased. For all subjects, the earliest VOR began 7-10 ms after onset of head rotation regardless of axis eccentricity or target distance. Regardless of adaptation, VOR gain for the proximate target exceeded that for the distant target beginning at 20 ms after onset of head rotation. Adaptation increased VOR gain as measured 90-100 ms after head rotation onset by an average of 0.12 ± 0.02 (SE) for the higher head acceleration and 0.19 ± 0.02 for the lower head acceleration. After adaptation, four subjects exhibited significant increases in the canal VOR gain only, whereas two subjects exhibited significant increases in both angular and linear VOR gains. The latencies of linear and early angular target distance effects on VOR gain were unaffected by adaptation. The earliest significant change in angular VOR gain in response to adaptation occurred 50 and 68 ms after onset of the 2,800 and 1,000°/s2 peak head accelerations, respectively. The latency of the adaptive increase in linear VOR gain was ~50 ms for the peak head acceleration of 2,800°/s2, and 100 ms for the peak head acceleration of 1,000°/s2. Thus VOR gain changes and latency were consistent with modification in the angular VOR in most subjects, and additionally in the linear VOR in a minority of subjects.


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Key to vestibuloocular reflex (VOR) function is its ability to fine tune performance to reduce retinal image motion during head movement. The magnification of telescopic spectacles requires increased gain, the ratio of compensatory eye velocity to head velocity. Without any learning period, visual pursuit tracking acts synergistically with the VOR to minimize retinal image motion produced by head motion with telescopic spectacles (Crane and Demer 1997; Demer et al. 1990). Further, the VOR is subject to long-term adaptation to telescopic spectacles. After they are worn for as little as five minutes, VOR gain in darkness is increased (Collewijn et al. 1983; Demer et al. 1989). Continued visual-vestibular mismatch further modifies VOR gain over hours (Paige 1991a; Paige and Sargent 1991; Shelhamer and Young 1994) and days of adaptation (Cannon et al. 1985; Istl-Lenz et al. 1985).

Adaptive VOR gain change has been extensively investigated in animals. Such changes in the monkey are evident at a minimum latency of 19 ms after onset of head rotation (Lisberger 1984; Lisberger and Pavelko 1988), although latency varies slightly with the magnitude of head acceleration (Lasker et al. 1997). Although the minimum latency of adaptive VOR gain change in cat is 13 ms, after prolonged training with telescopes a second component of gain enhancement occurs at 68 ms (Khater et al. 1993). Adaptive VOR gain changes have a latency of 18-20 ms in goldfish (Pastor et al. 1994). Although previous human studies of VOR gain adaptation have investigated the steady state VOR, no transient studies have been conducted in humans and the transient dynamics of VOR adaptation in humans are unknown.

Although a magnified target may appear identical to a near one on the retina, the oculomotor system compensates for proximal and magnified targets differently (Crane and Demer 1997). Magnifying spectacles create the illusion of proximity caused by increased object size and parallax with head motion. Although vergence and accommodation could also provide cues of target distance under unmagnified conditions (Busettini et al. 1994), telescope spectacles interfere with both these systems. During angular head rotation centered at an orbit, the ocular rotation required to fixate an unmagnified target is independent of target distance. However, with spectacle magnification the eye movement required to fixate a target during head rotation is multiplied by the optical magnification. During head translation, the fixation of near targets requires larger ocular rotations than far targets. When vision is magnified, targets appear and move as if their distance were reduced by the inverse of spectacle magnification. Thus wearing telescopic spectacles should induce a gain change in the angular (semicircular canal) VOR, but adaptation in the linear (otolith) VOR could be achieved by either a gain change or a simple change in target distance estimate. Adaptation of the angular VOR was not found to have any consistent effect on the translational VOR during off-vertical axis rotation (Koizuka et al. 1997). However, adaptation in the translational VOR was demonstrated during horizontal axis rotation after training in which the vestibular stimulus and optokinetic nystagmus stimulus were mismatched during vertical axis rotation (Wall et al. 1992). The translational VOR has been shown to depend strongly on target distance (Crane et al. 1997; Paige 1991b; Snyder and King 1992; Viirre et al. 1986), a factor not systematically varied in any of these studies of translational VOR adaptation. Furthermore, its not clear if the linear stimulation delivered in these experiments was interpreted by the brain as translation because such stimulation could result from changes in the relative gravity vector caused by a pure roll rotation. Consideration of these issues is needed to clarify the role of the otoliths in VOR adaptation. If modification were introduced in the translational VOR pathway, postadaptation gain change would depend on the axis of rotation and target distance.

The mechanism of chronic VOR gain adaptation to visual magnification is uncertain, but probably involves synapses of vestibular afferents on secondary vestibular neurons (Lisberger and Pavelko 1988; Peterson et al. 1996) and requires cerebellar pathways becuase adaptation is eliminated by cerebellectomy (Ito et al. 1974; Lisberger et al. 1984; Michnovicz and Bennett 1987; Robinson 1976) or interruption of olivocerebellar climbing fibers (Demer and Robinson 1982; Luebke and Robinson 1994). Less is known about the mechanism of immediate VOR gain enhancement with proximate targets. The short latency (<20 ms) of target distance effects during transient head rotation is consistent with changes occurring in the most basic three-neuron arc (Crane and Demer 1998b). In monkeys, both position-vestibular-pause and eye-head-vestibular neurons in the VOR pathway are modulated with changes in target distance (Chen-Huang and McCrea 1998a). The cerebellum is probably involved in the target distance effect because patients with cerebellar dysfunction are unable to increase VOR gain normally for near targets during pure linear translation (Baloh et al. 1995) or during combined translational and angular movement (Demer and Crane 1998). Although there are intriguing similarities between immediate VOR gain enhancement with near targets and VOR gain enhancement induced by chronic visual-vestibular mismatch, the mechanisms may fundamentally differ because complete VOR adaptation to magnified vision takes many days (Istl-Lenz et al. 1985). By studying possible interactions of the effects of adaptation with target distance, we sought insight into the mechanisms of VOR modulation.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Subjects

Ten normal paid volunteers gave written consent to participate in these experiments according to a protocol approved by the UCLA Human Subject Protection Committee in conformity with the tenets of the Declaration of Helsinki. There were four women and six men of average age 31 ± 10 yr (mean ± SD, range 20-48). Subjects underwent ophthalmologic examination to verify that they were free of ocular disease and could converge and focus the targets clearly without corrective lenses. All subjects had prior experience in the wearing of magnetic search coils in oculomotor research and were monitored via infrared closed circuit television and intercom. Of the 10 subjects, two experienced motion discomfort sufficient to cause them to discontinue the experiment after undergoing the initial testing and wearing the telescopes for up to two hours.

Apparatus

Angular eye and head positions were measured with magnetic search coils, as employed by other investigators (Grossman et al. 1989; Grossman and Leigh 1990) and previously described in our laboratory (Crane and Demer 1997, 1998b). Reference magnetic fields were generated by three pairs of solenoid coils, each 2 m in diameter (C-N-C Engineering, Seattle, WA), and arranged to form the sides of a cube. This configuration placed the center of the cube near eye level for the subjects. The two vertically-oriented coil pairs were driven by 60 KHz sinusoidal currents in phase quadrature (Collewijn et al. 1975). The horizontally oriented coil pair was driven by a 120 KHz sinusoidal current (Robinson 1963). Single-winding scleral magnetic search coil annuli were placed on the right eyes of all subjects. Angular head position was measured with a search coil mounted on a bite bar that was custom molded to the upper teeth of each subject. The ocular coil was embedded in an annular suction contact lens (Skalar Medical, Delft, The Netherlands) that adhered to the eye under topical anesthesia with 0.5% proparacaine (Collewijn et al. 1975). Search coils were connected to external detectors (C-N-C Engineering) operating on a phase angle principle for the horizontal axis (the only axis for which data were recorded) and thus were linear to ±100° in yaw. Each detector contained a one-pole low-pass filter set to 160 Hz. Search coil gain calibration curves were constant to ±5% within a central cube 58 cm on each side, and ±1.6% within a central cube measuring 11 cm on each side. Measured peak-to-peak position noise of the search coil system at a bandwidth of 0-100 Hz was 2 min arc. The root mean square (RMS) horizontal velocity noise of the system in a bandwidth of 0-43 Hz was 30 min-arc/sec. Because of the filtering, there was a slight oscillation in the data traces at 43 Hz that did not have a significant effect on latency determination.

Experiment control and data acquisition were performed by a Macintosh compatible computer running the MacEyeball software package (Regents of the University of California). Search coil data (horizontal and vertical gaze and head positions) were displayed on a digital polygraph and low-pass filtered over a bandwidth (4-pole Butterworth) of 300 Hz before simultaneous digital sampling with 16 bit precision at 1.2 kHz.

Subjects were rotated by a 500 N·m stepper motor (Compumotor, Rohnert Park, CA) with a dedicated driver and position feedback digital controller as previously described (Crane and Demer 1998b). The presence of the motor did not have a detectable effect on search coil measurements.

Measurement conditions

During each trial, subjects sat in a hardwood chair fabricated with nonmetallic fasteners. The seat, back, and sides of the chair were fit with dense foam cushions. Subjects' bodies were secured by lap, chest, knee, leg, and ankle belts. Arm rests and hand grips on the chair enabled subjects to further stabilize themselves. Subjects' heads were held against stiff conforming foam within a nonmetallic head holder while their foreheads and chins were secured by straps.

During each 50 s trial, 20 directionally unpredictable transient rotations (10 in each direction) were administered in random order. Rotations of 200-1,000 ms duration had a periodicity varying randomly by up to 250 ms. The fluorescent room lights were extinguished at a random interval 20-70 ms before each rotation and restored only after return of the chair to the starting position. Thus subjects had no visual experience during rotation yet had an accurate memory of the target position at which they were instructed to gaze. Large, highly visible targets were centered directly in front of the right eye at distances of either 15 or 500 cm; this assured that initial position of the eye would be the same for both near and distant targets. The 15 cm distance was chosen because it was the nearest that could be comfortably viewed; the target at 15 cm consisted of a 4-cm black cross surrounded by radiating black lines at the center of a white background measuring 50 × 43 cm. The target at 500 cm approximated optical infinity and was larger to maintain high visibility; it was a 14-cm black cross flanked by radial black stripes on a 102 × 81 cm white background. The near target was smaller to avoid collision with the subject during rotation around anterior axes. A featureless gray screen 6 m distant formed the remote background to both the near and far targets.

The 1.9× binocular telescopic spectacles had a field diameter of 16.8° and were mounted in custom-made adjustable frames with rubber hoods to occlude peripheral vision. Lenses were added to the telescopes as necessary to correct refractive errors. Subjects could view proximal targets by manually adjusting telescope focal length. Telescopic spectacles were fitted to the subject immediately after the preadaptive trials that established baseline performance. To allow adaptation, telescopes were worn for a chaperoned period of 6-8 h during which all visual experience was magnified. Ambulation and significant head movement were encouraged during everyday activities, but potentially dangerous activities such as driving were prohibited. After the adaptation period, subjects' heads were stabilized to the rotator and the telescopes were removed immediately before repeated testing. Adapted subjects experienced no head rotation with unmagnified visual feedback before the final trials.

Eccentricity of the head relative to the axis of rotation was varied by shifting the head holder on the rotator chair and by positioning the chair relative to the motor hub (Crane and Demer 1998b). Eccentricity of the rotational axis was defined relative to the midpoint between the eyes, with more anterior positions described as negative. The eccentricity of 7 cm was designed as an otolith-centered rotation based on the estimated location of the otoliths relative to the external auditory meatus (Crane et al. 1997). Subjects were rotated at two peak accelerations. The higher acceleration was 2,800°/s2 to a velocity of 190°/s, rotating the head 40° in 250 ms. The smaller head acceleration of 1,000°/s2 had a peak velocity of 70°/s, rotating the head 14° in 250 ms.

Data analysis

Data were analyzed automatically using custom software written with the LabView package (National Instruments, Austin, TX). Trials where eye position varied by more than 12 arc sec in the 80 ms preceding head rotation were discarded as failures of fixation and not considered for further analysis. Events were also discarded when an inappropriate saccade occurred early in the response.

Differences in ocular responses with testing condition were compared in terms of angular VOR gain, the ratio of eye velocity to head velocity. After numeric differentiation, sampled eye and head data were filtered using a third order low-pass Butterworth filter (0-50 Hz). The filter characteristics were chosen because they reduced noise without significant effect on the physiological response. Gain was determined by dividing instantaneous compensatory eye velocity by head velocity. This approach normalizes the effect of small variation in the head stimulus. Variation in head movement was common for the highest stimulus acceleration where there was greater decoupling of the head from the rotator and where the motor approached torque limits for heavier subjects rotating around eccentric axes. Decoupling could not be physically eliminated because the skin slides independently of the skull despite tight placement of head straps. A bite bar was not used to couple subjects to the rotator to avert dental injury and because the search coil on the upper teeth faithfully indicated skull movement. Onset of head movement could be reliably determined by finding the time when the head position moved 1° from the center, then subtracting an interval depending on the strength of the stimulus as previously described (Crane and Demer 1998b).

Onset of eye movement relative to head movement was determined in the position domain by two separate methods: an automated cross-correlation technique and an automated threshold technique as previously described (Crane and Demer 1998b). Each technique has advantages and disadvantages, as discussed elsewhere (Crane and Demer 1998b). In the first technique, latency was determined by cross-correlating eye position in the head with head position in space during the period from 20 ms before to 30 ms after onset of head rotation. The time (between a 0 and 30 ms eye delay) giving the maximum cross-correlation was taken as the VOR latency. The second technique computed the standard deviation (SD) of eye and head position during a 50-ms period before motor rotation. Onset of eye or head motion was determined by finding the time at which values exceeded three times the SD during rest. Latency was determined by subtracting head movement onset time from eye movement onset time. Values more extreme than a 10 ms eye lead or a 50 ms eye lag were not considered for further analysis. A similar technique has been used to determine the onset of the translational VOR in the monkey (Angelaki 1998).

We averaged responses to 10 rotations for each condition in each block of trials. Differences in gains between conditions were considered significant when the standard error of the mean (SE) did not overlap for the two conditions for a period of at least 25 ms. The onset of these gain differences was defined as the first time at which the SEs no longer overlapped. This conservative criterion tends to bias recognition of significant differences toward later times than the more liberal criteria employed by others (Khater et al. 1993; Lisberger 1990). Statistical analysis was performed using SuperANOVA (Gagnon et al. 1991).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

General features of the transient VOR

The vigorous transient head rotations employed here consistently evoked a robust VOR. Shortly after each head rotation began, the eye rotated in the opposite direction as appropriate to maintain gaze in space. This is seen for a representative subject in Fig. 1, A and B. Peak angular head acceleration was either 2,800 or 1,000°/s2. Linear acceleration experienced by the otoliths during rotation depended on the distance from the otoliths to the rotational axis, and at 2,800°/s2 varied between 0.6 g for the axis 20 cm posterior the eyes and 0.8 g (with the opposite phase) for the axis 10 cm anterior to the eyes. Despite efforts to tightly couple subjects to the rotator, the loose anatomic coupling of the skin to the skull made some decoupling unavoidable at these high accelerations. The amount and mode of decoupling were influenced by the location of the rotational axis and often differed slightly before and after adaptation for individual subjects. For reliability, the VOR response was quantified as gain (eye velocity/head velocity). The same trials plotted as velocities in Fig. 1, A and B, are plotted as gains in C and D. 



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Fig. 1. Initial canal vestibuloocular reflex (VOR) of representative subject (5) before () and after () 8 h of adaptation to 1.9× telescopic spectacles. Responses to 10 leftward rotations were averaged. Thin dotted lines represent ±SE (n = 10), but are often too close to solid lines to be visible. The target was 500 cm away and the axis of rotation was otolith-centered at 7 cm posterior to the eyes. A: peak head acceleration 2,800°/s2. The adaptive eye velocity increase was first significant 50 ms after onset of head rotation (arrow). B: peak head acceleration 1,000°/s2. Note the later adaptive eye velocity increase, which becomes significant 80 ms after onset of head rotation (arrow). C: data in A plotted as VOR gain. Initial 20 ms of data not plotted because near zero head velocities made gain values indeterminate. D: data in B plotted as VOR gain.

The latencies of variations in the VOR caused by target distance, eccentricity, and adaptation to telescopes were determined by pairwise comparisons of conditions. The latency of the effect of changing a condition was defined by the time at which the SEs of gains for the two conditions no longer overlapped. For a gain difference to be detected using this method, it must be at least twice the SE. The SE of gain was greatest at the onset of motion when the signal-to-noise ratio (SNR) was poor, but decreased monotonically as head and eye velocity increased relative to measurement noise. To determine the earliest time at which differences could be detected, the average SE for the subjects who completed the experiment was determined as a function of time throughout the response. With the 2,800°/s2 peak head acceleration, the SE of gain diminished to <0.05 at 20 ms from onset of head rotation. With the 1,000°/s2 peak head acceleration, the SE of gain diminished to <0.09 at 25 ms and <0.05 at 40 ms from onset of head rotation. As will be indicated in Effects of target distance and axis eccentricity after adaptation, VOR gain changes caused by adaptation occurred well after the minimum times at which SNR considerations would have permitted detection of a significant effect. The SE of gain was independent of stimulus characteristics after 50 ms, after which SE averaged 0.035. The SE of gain did not depend significantly on peak head acceleration (P = 0.89) or rotational direction (P = 0.53) during the interval of the response when gain changes were induced by adaptation. After 50 ms, the SE of gain increased significantly by 0.009 after adaptation to telescopes (P = 0.02), and was 0.007 larger with the near than the distant target (P = 0.04). Both these differences were small enough that they are unlikely to have appreciably biased the results.

Tolerance of subjects for adaptation to telescopes

Although subjects were not required to perform specific tasks while wearing telescopic spectacles, they were encouraged to engage in activities, such as ambulation, entailing substantial head motion. Typical activities included walking between classes and errands on campus, playing billiards, or working in an office. All subjects had tolerated ocular magnetic search coil annuli readily in previous experiments in our laboratory and were informed of their freedom to discontinue the experiment at any time. There was substantial variation in tolerance to telescopic spectacles among the 10 subjects who attempted the protocol. Six of the subjects who completed the protocol did so easily. Of the remaining four, two males experienced nausea within the first hour of wearing the telescopes and discontinued the experiment. Two others (one male and one female) experienced nausea but persevered through the entire experiment. One of these subjects continued ambulating normally throughout the day; her data are shown in Fig. 1. The other subject who completed the protocol limited his head movement.

Effects of target distance and axis eccentricity before adaptation

It was necessary collect data in each subject on the effects of target distance and axis eccentricity on the unadapted VOR, although the findings qualitatively confirm those previously published (Crane and Demer 1998b). Latency of the VOR was calculated for the peak head acceleration of 2,800°/s2 using two independent methods. Using the cross-correlation method, VOR latency was 9.7 ± 0.7 ms (SE, n = 8 subjects); using the threshold technique the latency was slightly less at 7.8 ± 0.5 ms. Among individual subjects, VOR latency varied from 5 to 12 ms.

During the early VOR, target distance dominated gain irrespective of translation, whereas later the effect of translation was scaled by target distance. During the initial 50 ms of eye motion, mean gain was higher for near than far targets regardless of axis eccentricity for the 2,800°/s2 peak head acceleration, a presumably canal-mediated effect with a latency of 25-29 ms (Fig. 2, A and B; Table 1). This dominant effect of target distance on the angular VOR was not observed for the lower peak head acceleration of 1,000°/s2, where the earliest effect of target distance was significantly later at 65-71 ms. For the lower peak head acceleration, the effect of target distance always depended on rotational axis, suggesting that it was due to a linear VOR mediated by the otoliths (Table 1). Later in the response, the effect of target distance depended on the location of the rotational axis even at the higher acceleration. Relative to distant target, VOR gain with the near target increased when the axis was located posterior to the labyrinths (Fig. 2A) and decreased when the axis was located anterior to the labyrinths (Fig. 2B). The latency of the effect of translation (axis eccentricity) was determined for each angular acceleration during near target viewing by comparing the axis 10 cm anterior to the eyes (E = -10 cm) with the axis centered between the labyrinths (E = 7 cm; Fig. 2C; Table 1). These axes are informative because in the former case the translational VOR powerfully antagonizes the angular VOR to reduce gain, whereas in the latter case there is virtually no net input to the translational VOR. The two most extreme cases were not used because, as previously described, with the axis far posterior to the eyes (E = 20 cm), decoupling from the rotator occurred in the first 30 ms of the response, which confounded comparison with other axes (Crane and Demer 1998b). The time at which the linear component began to dominate the early angular target distance component was determined by finding the point when far target gain exceeded near target gain during a rotation around an axis anterior to the eyes. This time was slightly longer than the latency of axis eccentricity effects as determined with the near target (Table 1).



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Fig. 2. Effect of adaptation to telescopes on the interaction of target distance and head translation (determined by axis eccentricity) in modulating VOR gain during 2,800°/s2 peak head acceleration. Data shown is for leftward rotation. A-C: preadaptation; D-F: postadaptation. In each case, adaptation shifted the response curves upward without changing the timing or qualitative effects of translation and target distance. A and D: axis was located 20 cm posterior to the eyes; effects of 15 and 500 cm targets are compared. The time at which gain with the near target exceeded gain with the far target is marked by up-arrow . Gain with the near target remained elevated throughout the response. B and E: axis was 10 cm anterior to the eyes; effects of 15 and 500 cm distances are compared. With the near target, gain was initially increased (first significant at up-arrow ) but later decreased (first significant at down-arrow ) so that gain for the near target was ultimately less than that for the far target. C and F: target was 15 cm distant. The effect of head translation was examined for the otolith-centered axis and an axis located 10 cm anterior to the eyes (17 cm anterior to the otoliths). The first significant change in VOR gain caused by head translation (Up-arrow  in C) occurred later than gain increasing effects of target distance (Up-arrow  in F). Thin dotted lines represent ±SE (n = 10).


                              
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Table 1. Latency of effects of target distance and translation on VOR gain

Change in VOR with adaptation

The earliest VOR response was unchanged after adaptation to telescopes in all eight subjects who completed the protocol, as illustrated for a representative in Fig. 1. After an initial unmodified period, however, VOR gain after adaptation increased in six subjects. This may be seen by comparing postadaptation gain tracings for a representative subject in Fig. 2, D-F, with preadaptation tracings in A-C; in this figure, all gains in the later part of each response are greater after adaptation. It is unclear why two subjects who completed the protocol exhibit no VOR gain increase. One of these subjects was nauseated while wearing telescopes and minimized head motion, but the other tolerated telescopes easily. Other subjects who experienced nausea nevertheless showed robust VOR gain increases.

Effects of target distance and axis eccentricity after adaptation

The dynamic time variation in VOR gain for multiple stimulus conditions is plotted on the same graphs before and after telescope adaptation for the representative subject in Fig. 3. All of the panels in Fig. 3 illustrate that for each condition where a gain increase ultimately occurred, it was preceded by an initial period during which gain was unmodified (Table 2). Comparison of the panels in Fig. 3 allows evaluation of the effects of target distance and axis eccentricity, which appear from the figure to be unchanged after adaptation to telescopes. This impression was confirmed by the quantitative analysis detailed in Table 1. Latency was determined by finding the point at which SE of gain no longer overlapped as described in METHODS. For the 2,800°/s2 peak head acceleration, near target gain exceeded far target gain early in the response regardless of axis location, and values represent the average of all four rotational axes. However, during 1,000°/s2 peak head acceleration, near target gain consistently exceeded far target gain only when the axis was located posterior to the eyes (eccentricities of 7 and 20 cm). For this reason, the value of early target distance effect at 1,000°/s2 reported in Table 1 is the average of data obtained during labyrinth-centered rotations only (E = 7 cm). The data in Table 1 were derived from the eight subjects who completed the entire experiment, and represents the average for both directions of rotation. Before telescope adaptation, gain with the near target was significantly greater than with the far target, beginning 25 ± 3 ms after onset of head rotation at the peak head rotation of 2,800°/s2, and 71 ± 6 ms after onset of head rotation at the peak head rotation of 1,000°/s2. These latencies were not significantly different after adaptation (Table 1).



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Fig. 3. Increase in VOR gain after adaptation was generally independent of translation and target distance effects, as illustrated for representative subject 5. In each case, VOR gain increased. Data represent average of 10 rotations to the left. Thin dotted lines represent ±SE. up-arrow  in A and E, onset of first significant differences between pre- and postadaptation responses. A-D: response to the 2,800°/s2 head acceleration. E-H: response to 1,000°/s2 peak head acceleration (note prolonged time scale). A and E: for axis 20 cm posterior to the eyes, gain with the near target was increased relative to the far target as early as 60 ms after onset of head rotation. B and F: same condition as in A and E except target was 500 cm away, where an initial VOR gain of about 1.0 is geometrically optimal. The greater gain increase late in the response for the 15 cm (A and E) than for the 500 cm (B and F) target distance reflects linear VOR adaptation. C and G: axis 10 cm anterior to eyes with target at 15 cm required a VOR gain decrease. Note in C and G the late gain increase caused by telescope adaptation was smaller than that in A and E, reflecting an adapted otolith response for the most anterior axis. D and H: same rotational axis as in C and G with the target 500 cm distant where geometry required VOR gain of ~1.0.


                              
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Table 2. Latency and magnitude of adaptive VOR gain change

When only the near (15 cm) target is considered, VOR gain varied systematically with the axis of rotation as geometrically required to stabilize images on the retina. The earliest difference caused by axis eccentricity was determined by comparing VOR gain for the labyrinth-centered axis (E = 7 cm) with gain for the axis anterior to the eyes (E = -10 cm) while subjects regarded the 15 cm target. The latency of the rotational axis effect before telescope adaptation was 54 ± 7 ms at the peak head rotation of 2,800°/s2 and 75 ± 4 ms at the peak head rotation of 1,000°/s2. These latencies were not significantly different after adaptation (Table 1).

The latency at which translation-dependent target distance effects first dominated the early target distance-dependent effect was determined by finding the time at which near target gain dropped below far target gain during rotation around an axis 10 cm anterior to the eyes (E = -10 cm). This latency before telescope adaptation was 89 ± 4 ms at the peak head rotation of 2,800°/s2 and 87 ± 5 ms at the peak head rotation of 1,000°/s2. These latencies were not significantly different after adaptation (Table 1).

Magnitude of adaptive VOR gain change

Further analysis of VOR gain adaptation is limited to the six subjects who demonstrated VOR gain increase after adaptation. Variation in the degree of adaptive VOR gain enhancement was quantified by determining the change in mean gain over the interval 90-100 ms after onset of head rotation. This interval was chosen because examination of individual trials demonstrated it to be sufficiently late to include adaptive gain changes, yet early enough to avoid confounding by saccades or the limit of the oculomotor range. Adaptive gain increases are illustrated in Fig. 4A for individual subjects.



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Fig. 4. Individual variation in VOR gain increase and latency of changes induced by adaptation to telescopic spectacles. Data shown represent the average of both directions, all axes, and target distance conditions. Error bars represent ±SE. A: VOR gain increase after adaptation. Gain values used for difference calculation were determined by averaging during the period 90-100 ms after onset of head motion. B: latency of postadaptation gain increase for each subject in whom a gain increase occurred. Latency was shorter for the higher acceleration stimulus.

The latency of postadaptation VOR gain changes was determined in the six subjects who demonstrated adaptive gain increase (Fig. 4B). Latency was defined by the time at which the gains ± SE no longer overlapped for similar testing conditions before and after adaptation. In each subject, the latency of the adaptive VOR gain increase was shorter for the higher than the lower peak head acceleration. Although the amount of induced gain change varied among the six subjects, the latency of adaptation-related gain changes was similar among subjects, averaging 50 ± 2 ms at 2,800°/s2 and 68 ± 2 ms at 1,000°/s2.

Adaptation of linear VOR

To determine if translation influenced the dynamic time course of VOR gain, instantaneous adaptive gain change was calculated by subtracting the preadaptation gain from the postadaptation gain at each sampled time point (Fig. 5). When such plots were compared, differences in the axis of rotation generally had no effect on the amount of gain increase. However, for the near target, two of the six subjects (subjects 4 and 5) had a larger gain increase when the axis was posterior to the head than for anterior axes. Because this posterior axis provides a strong otolithic stimulus tending to augment VOR gain that would be heavily weighted during near target viewing, the larger increase after adaptation suggests an increase in gain of the linear VOR. Data from one subject demonstrating this effect is shown in Fig. 5.



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Fig. 5. Time course of adaptive VOR gain change (gain postadaptation - gain preadaptation) for subject 5, one of two subjects exhibiting both angular and linear VOR gain modification. Leftward rotations are shown at four axis eccentricities. Error bands omitted for clarity. A and B: response to 2,800°/s2 head acceleration. C and D: response to 1,000°/s2 head acceleration (note differing time scales). For the distant target (B and D), the gain increase was independent of axis eccentricity. For near target viewing where linear VOR responses were influential (A and C), gain increases were greater for more posterior rotational axes. This effect was most evident for the higher peak head acceleration (A).

To evaluate possible adaptation of the linear VOR in all subjects who exhibited adaptive angular VOR gain increase, we examined the effect of rotational axis and target distance on mean gain and mean gain increase during the interval 90-100 ms from onset of head rotation. As anticipated based on geometric considerations, gain before adaptation was insensitive to axis when the target was 500 cm distant (Fig. 6A). During the interval 90-100 ms from onset of head rotation, average VOR gain before adaptation was highest with the target 15 cm away and the rotational axis located most posterior to the labyrinths (20 cm). Average VOR gain was lowest with the near target and the rotational axis anterior to the head (-10 cm). The near target increases the geometric importance of translation to the required compensatory eye movement, whereas the extreme rotational axes deliver strong otolith stimulation either synergistic (20 cm) or antagonistic (-10 cm) to semicircular canal stimulation. The magnitude of postadaptation gain increase was calculated for each target distance and eccentricity over this same time interval for the six subjects who achieved a gain increase (Fig. 6B). Unlike absolute VOR gain, there were no significant trends in the amount of gain increase with either target distance or axis of rotation (P = 0.26). When data from all six subjects were pooled, there was no significant effect of target distance or axis on the mean amount of adaptation.



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Fig. 6. Mean preadaptation VOR gain and increase in gain postadaptation as measured in the initial 90-100 ms after onset of 2,800°/s2 peak head acceleration around multiple axes for both target distances and rotation directions. Data averaged (±SE) from 6 subjects who exhibited increases in VOR gain after telescope adaptation. A: baseline VOR gain preadaptation varied depending on location of the target and axis of rotation. B: an approximately constant increment was added to the baseline VOR gain after telescope adaptation independent of large changes in baseline gain. Error bars ±SE.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This experiment demonstrates that adaptive increase in human transient VOR gain occurs in response to prolonged wearing of telescopic spectacles. This VOR gain increase has a relatively long latency of at least 50 ms after onset of head rotation (Figs. 1 and 3). Adaptation to telescopic spectacles affects the angular VOR in most subjects and the linear VOR in some subjects. The first finding differs from shorter latencies of adaptive gain modification in the range of 13-20 ms reported in animals (Khater et al. 1993; Lasker et al. 1997; Lisberger 1984; Pastor et al. 1994). Some of this discrepancy may be attributed to methodological differences in determination of the onset of adaptive gain changes. Previous investigators defined the onset as the latest time at which pre- and postadaptation VOR gain curves cross (Lisberger 1984); this technique has the disadvantage that it may erroneously identify differences caused by noise before a significant difference actually exists. We preferred a more conservative criterion. Responses to 10 rotations for each condition were averaged, and the onset of a difference between conditions was defined as the time when the mean ± SE of gain for one condition no longer overlapped the mean ± SE for the other for an interval of at least 25 ms. This technique has the advantage of identifying the onset of events only when responses differ statistically. In our laboratory, the technique can identify differences at much shorter latency than that found for adaptive gain modification; for example, effects of target distance were detected within the first 20 ms of the response. Examination of the data (Fig. 3) shows that our technique and the latest crossover technique of Lisberger (1984) often identify the onset of events within 5 ms. A potential disadvantage of our technique for determining latency is that with smaller amounts of movement (i.e., with a lower acceleration stimulus) the instrumentation SNR is lower, potentially delaying identification of very early changes. To verify that our SNR was adequate to detect adaptation-related gain changes early in the response, we determined the SE of gain throughout the response. The average gain increases with adaptation were 0.19 and 0.12 for the peak head accelerations of 1,000 and 2,800°/s2, respectively. Our technique could have detected these differences as early as 25 and 17 ms for each of the stimuli, respectively, had the physiological latencies indeed been this short. It can be concluded that the relatively long latency of VOR adaptation found in the present study is not an artifact of a poor SNR.

In the present study, the increase in angular VOR gain averaged 0.16 ± 0.02 when measured 90-100 ms after onset of head rotation (Fig. 4A). Paige and Sargent (1991) found that human sinusoidal VOR gain increased by 0.09-0.29, depending on frequency and amplitude of head rotation, after 8 h of wearing 2× telescopic spectacles. The magnitude of the VOR gain increase observed here is consistent with Paige and Sargent's findings. The present study confirms earlier findings that the adaptive VOR gain increase induced by telescopic spectacles varies appreciably among individual humans (Demer et al. 1989; Paige and Sargent 1991). Only six of eight subjects tested here exhibited significant VOR gain increase in response to the wearing of telescopes.

Implications for adaptation on semicircular canal and otolith pathways

The effect of adaptation on angular VOR gain is clear because gain enhancement occurred even when otolith translation was minimized by rotating around an otolith-centered axis. Since no purely translational stimulus was used, determination of the effect of adaptation on the translational VOR requires some analysis. The gain increase caused by adaptation was calculated by subtracting the gain before adaptation for a given condition from the gain after adaptation under similar conditions. The effect of adaptation to telescopic spectacles on the translational VOR was assessed by comparing sets of trials in which only the amount of translation was altered by varying the axis of rotation (Fig. 5). Variation in the amount of near target gain increase with rotational axis was taken as evidence that adaptation directly influenced the linear VOR with the near target (Fig. 5, A and C). Two subjects exhibited gain increases for near targets that were modulated by rotational axis (Fig. 5) for the near target with the greatest effect for the most posterior rotational axis (20 cm) when otolith stimulation augmented the angular VOR. We interpret this data as indicating that adaptive gain increase occurred in both the angular and linear VOR pathways in these two subjects. Lack of effect of rotational axis on far target gain increase was taken as evidence that adaptation had no effect on the linear VOR with the far target (Fig. 5, B and D). None of the subjects exhibited an effect of rotational axis on far target VOR gain, a finding that was anticipated because translational VOR gain should ideally always be zero for remote targets.

In four of the six subjects who demonstrated VOR gain increase after adaptation to telescopic spectacles, the gain increase was also independent of rotational axis for near targets, suggesting that the linear VOR had not been adapted in these subjects. It is not entirely surprising that adaptive changes in the linear VOR were not demonstrable in all subjects because adaptation in the canal VOR typically cannot be demonstrated in all normal humans (Demer et al. 1989). In the two subjects in whom translation influenced the VOR gain change, the latency of adaptive change in the translational VOR was indistinguishable from that of adaptive change in the angular VOR of ~50 ms (Fig. 5, A and B), and also similar to the typical latency of 25-90 ms of the human linear VOR itself, as determined during eccentric axis rotation (Crane and Demer 1998b).

It has been recently found that target distance influences the responses of secondary vestibular neurons in behaving monkeys (Chen-Huang and McCrea 1998b). These neurons, which receive both monosynaptic canal and otolith input, have responses to steady state angular head movement that are scaled in roughly the same proportion to target distance as the behavioral VOR of the monkey. If similar secondary vestibular neurons exist in humans, they could form the direct substrate for the early target distance-dependent angular VOR that is not influenced by adaptation to telescopic spectacles, and also the later target distance-dependent angular and translational VOR responses that are enhanced by adaptation to telescopic spectacles. The former responses might be caused by enhancement of net synaptic weighting of canal inputs to secondary vestibular neurons, whereas the latter responses would presumably reflect summation of the former with longer-latency polysynaptic pathways carrying both canal and otolith signals modulated by target distance. The present data suggest that human angular and linear VOR adaptation are mediated only by longer-latency polysynaptic pathways. The current data imply that adaptation to telescopic spectacles induces an increase in gain for the later angular VOR. The mechanism is clearly distinct from that subserving short (~10 ms) latency VOR gain enhancement in response to target proximity because the latency of the later effect was 50 ms.

This study confirms the finding (Crane and Demer 1998b) that the earliest effect of target proximity is an increase in canal VOR gain at a latency (~10 ms) not distinguishable from that of the earliest VOR itself. The short latency of the target distance effect is thus consistent with target distance modification of the behavior of the primitive disynaptic VOR. The early target distance-mediated effect was always to increase VOR gain for proximate targets, even for rotations around axes for which the resulting otolith stimulation later decreased gain in a geometrically appropriate manner. In the present study, there was no effect of adaptation to telescopes on the early target distance-related gain increase that is presumably mediated by the semicircular canals. The later (90-100 ms after rotation onset) adaptive VOR gain increase observed for the otolith-centered axis of rotation (eccentricity 7 cm, Fig. 6B) was similar for both the near and the far targets. Since net otolith stimulation was negligible for the otolith-centered axis, it is concluded that the adaptive gain increment caused by the semicircular canals after telescope wearing was independent of target distance.

Plausibility of current VOR learning models

In animals, the latency of canal VOR gain adaptation has been reported to be earlier than in the current human data: 19 ms in the monkey (Lisberger 1984), 18-20 ms in the fish (Pastor et al. 1994), and 13 ms in the cat (Khater et al. 1993). Thus in these animals, the adapted VOR response diverges from the control within a few ms of the earliest eye movement evoked by head rotation. This short latency has motivated the proposal that VOR adaptation affects the basic three-neuron arc (Broussard and Lisberger 1992; Lisberger et al. 1994). The cellular mechanism of VOR adaptation at this level is not well understood. In vitro studies of the rat VOR have suggested two possible mechanisms (Peterson et al. 1996) involving gaze-velocity Purkinje (GVP) cells projecting to the vestibular nuclei. The first mechanism involves GABAergic GVPs modifying the strength of second-order vestibuloocular relay neurons via GABAB-induced long-term depression. The second mechanism, proposed by Peterson et al. (1996), involves GVPs adjusting signal transmission between the vestibular afferents and second-order neurons via N-methyl-D-aspartate-mediated long-term potentiation. However, in humans, the 50 ms minimal latency of adaptive VOR gain change is so much longer than the 7-10 ms latency (Crane and Demer 1998b; Maas et al. 1989; Tabak and Collewijn 1994) of the earliest unadapted VOR that it is difficult to hypothesize these changes within the human three-neuron arc. On the other hand, the short latency of the target distance-dependent modulation of the human canal VOR has suggested that this latter function might reside within the three-neuron arc (Crane and Demer 1998b).

There is evidence suggesting multiple mechanisms of VOR adaptation outside the fast three-neuron arc. In cats, an initial VOR gain change induced by short-term training was observed at 13 ms latency; after a longer training period, a second adaptive effect was found at 68 ms latency (Khater et al. 1993). In monkeys, Raymond and Lisberger found that transient (or high-frequency) stimuli produce changes in VOR amplitude without a change in dynamics. However, sustained (or low-frequency) stimuli change both VOR dynamics and amplitude (Raymond and Lisberger 1996).

It is possible that the short-latency motor learning in the three-neuron arc may be an atavistic phenomenon limited to animals and that human VOR gain adjustment occurs via another mechanism. With only behavioral data available in humans, it is impossible to implicate a specific mechanism with any certainty. One possibility would be for adaptive changes to occur within the cerebellar cortex without altering the dynamics of the three-neuron arc. A computational model of VOR learning (Lisberger 1994; Lisberger and Sejnowski 1992) suggests that learning at only one site could not change the gain of the VOR without changing its dynamics. However, the predicted changes in the dynamics of the human VOR did not accompany changes in gain in other human studies of VOR adaptation (Istl-Lenz et al. 1985; Paige 1991a; Paige and Sargent 1991), and dynamic changes were not evident here.

In goldfish, the cerebellum is required for VOR adaptation to visual-vestibular mismatch, and gain is elevated after cerebellectomy, which is consistent with cerebellar involvement in changing the weighting of synapses in the three-neuron arc (Pastor et al. 1994). Nevertheless, Pastor et al. (1994) found that the constant-velocity VOR could be modified even after cerebellectomy. Anatomic evidence suggests at least two sites of VOR adaptation: vestibular connections in the cerebellum and neurons in the brain stem targeted by the flocculus. There is evidence for dual mechanisms of adaptation in rabbits (Dufosse et al. 1978), cats (Luebke and Robinson 1994), and monkeys (Lisberger and Pavelko 1988; Miles et al. 1980; Partsalis et al. 1995; Watanabe 1984) .

We found no evidence for short-latency VOR motor learning in humans. Such a mechanism might potentially exist but was not induced by the adapting paradigm, or perhaps was not evoked by the chosen stimulus. Neither possibility seems likely. Probably no more than six hours of training are required to induce an adaptive change in the three-neuron arc because such changes are readily observed in animals with equal or shorter training periods (Khater et al. 1993; Pastor et al. 1994). Furthermore, wearing of telescopic spectacles during natural ambulation provides both rich visual experience and head movement with significant frequency components to at least 2 Hz (Crane and Demer 1997). Any VOR adaptation that cannot be induced in such a paradigm may not be physiologically relevant. The head accelerations used (1,000 and 2,800°/s2) were similar to (Lasker et al. 1997) or exceeded (Lisberger 1984) those used in animal studies.

Dependence of latency on stimulus acceleration

The latency of adaptive VOR gain change was shorter with the higher peak head acceleration of 2,800°/s2 (50 ± 2 ms) than with the lower acceleration of 1,000°/s2 (68 ± 2 ms) as shown in Fig. 3 and Table 2. An effect of stimulus intensity on latency of adaptive VOR gain change has also been observed in monkey (Lasker et al. 1997). In the present study, after 50 ms of head acceleration that peaked at 2,800°/s2, the head had moved 1.8° and reached a velocity of 72°/s. After 68 ms of head acceleration at 1,000°/s2, the head had moved 1.0° and reached a velocity of 28°/s. Because adaptive gain change was detected at a head velocity of only 28°/s for the lower peak head acceleration but was not evident until the head reached 72°/s for the higher peak acceleration, it seems doubtful that a head velocity nonlinearity determines the onset of adaptive VOR gain change. This nonlinear effect might more plausibly be related to a displacement threshold of 1-2° required to manifest the modified VOR gain. Voluntary VOR cancellation occurs in humans only after the head has rotated to a threshold angle of approximately 1.5° over a broad range of head accelerations from 500 to 2,800°/s2 (Crane and Demer 1998a). If VOR gain adaptation does exhibit a displacement threshold nonlinearity, it must be more variable with head acceleration than during cancellation. This behavioral difference is further evidence that the neural mechanism mediating VOR cancellation differs from that mediating VOR gain adaptation.


    ACKNOWLEDGMENTS

The authors thank L. Fleischman for technical assistance and for chaperoning subjects while they wore telescopes. N. De Salles scheduled the subjects, chaperoned them while they wore telescopes, and assisted with the experiments. J. Tian also chaperoned subjects and assisted with the experiments.

This research was supported by National Institutes of Health Grant DC-02952. B. T. Crane was supported by an NIH Medical Scientist Training Program grant and NIH Training Grant EY-07026. J. L. Demer was recipient of the Research to Prevent Blindness Lew R. Wasserman Merit Award and is Laraine and David Gerber Professor of Ophthalmology.


    FOOTNOTES

Present address and address for reprint requests: J. L. Demer, Jules Stein Eye Institute, 100 Stein Plaza, University of California, Los Angeles, CA 90095-7002.

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11 January 1999; accepted in final form 30 September 1999.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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