Departments of 1OtolaryngologyHead and
Neck Surgery, 2Biomedical Engineering, and
3Neuroscience, The Johns Hopkins University,
Baltimore, Maryland 21287-0910; and 4Department
of Anatomy, University of Illinois College of Medicine, Chicago,
Illinois 60612-7300
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ABSTRACT |
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Lasker, David M.,
Douglas D. Backous,
Anna Lysakowski,
Griffin L. Davis, and
Lloyd B. Minor.
Horizontal Vestibuloocular Reflex Evoked by High-Acceleration
Rotations in the Squirrel Monkey. II. Responses After Canal
Plugging.
J. Neurophysiol. 82: 1271-1285, 1999.
The horizontal angular vestibuloocular reflex (VOR) evoked by
high-frequency, high-acceleration rotations was studied in four squirrel monkeys after unilateral plugging of the three semicircular canals. During the period (1-4 days) that animals were kept in darkness after plugging, the gain during steps of
acceleration (3,000°/s2, peak velocity = 150°/s)
was 0.61 ± 0.14 (mean ± SD) for contralesional rotations
and 0.33 ± 0.03 for ipsilesional rotations. Within 18-24 h after
animals were returned to light, the VOR gain for contralesional rotations increased to 0.88 ± 0.05, whereas there was only a
slight increase in the gain for ipsilesional rotations to 0.37 ± 0.07. A symmetrical increase in the gain measured at the plateau of head velocity was noted after animals were returned to light. The
latency of the VOR was 8.2 ± 0.4 ms for ipsilesional and 7.1 ± 0.3 ms for contralesional rotations. The VOR evoked by sinusoidal rotations of 0.5-15 Hz, ±20°/s had no significant half-cycle
asymmetries. The recovery of gain for these responses after plugging
was greater at lower than at higher frequencies. Responses to rotations
at higher velocities for frequencies 4 Hz showed an increase in contralesional half-cycle gain, whereas ipsilesional half-cycle gain
was unchanged. A residual response that appeared to be canal and not
otolith mediated was noted after plugging of all six semicircular canals. This response increased with frequency to reach a gain of
0.23 ± 0.03 at 15 Hz, resembling that predicted based on a reduction of the dominant time constant of the canal to 32 ms after
plugging. A model incorporating linear and nonlinear pathways was used
to simulate the data. The coefficients of this model were determined
from data in animals with intact vestibular function. Selective
increases in the gain for the linear and nonlinear pathways predicted
the changes in recovery observed after canal plugging. An increase in
gain of the linear pathway accounted for the recovery in VOR gain for
both responses at the velocity plateau of the steps of acceleration and
for the sinusoidal rotations at lower peak velocities. The increase in
gain for contralesional responses to steps of acceleration and
sinusoidal rotations at higher frequencies and velocities was due to an
increase in the gain of the nonlinear pathway. This pathway was driven
into inhibitory cutoff at low velocities and therefore made no
contribution for rotations toward the ipsilesional side.
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INTRODUCTION |
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Disruption of vestibular signals from one labyrinth results in
asymmetries in angular vestibuloocular reflexes (see Curthoys and Halmagyi 1995 for review). These asymmetries are subtle for less dynamic rotations (lower frequency, velocity, and acceleration) and may resolve as the gain of the VOR recovers through processes of
vestibular compensation (Fetter and Zee 1988
;
Paige 1983
). Entirely different findings are noted for
responses to more dynamic stimuli.
Halmagyi et al. (1990) observed a marked asymmetry in
vestibuloocular responses to manually delivered, high-frequency,
high-acceleration head movements in humans after unilateral ablative
vestibular lesions. For the horizontal angular VOR, rotations toward
the intact labyrinth resulted in a VOR with a gain that was slightly reduced in comparison with prelesion values (0.85-0.95). In contrast, rotations toward the lesioned side elicited a VOR with a gain that was
markedly lower (0.25-0.45). This asymmetry changed little during the
course of time that the responses were studied after the lesion.
Similar findings were noted when these high-acceleration, rotatory
stimuli were given in guinea pigs after unilateral labyrinthectomy or
vestibular neurectomy (Gilchrist et al. 1998
). These
effects have been studied most extensively for the horizontal VOR
evoked by rotations in the yaw plane, but analogous asymmetries in the magnitude and alignment of the VOR have been noted when responses from
humans were analyzed in three dimensions (Aw et al.
1996
). Rotations produced with a reactive torque helmet
revealed similar asymmetries after unilateral ablative vestibular
lesions and also indicated a longer delay in the initiation of the
reflex (Tabak et al. 1997
).
Asymmetries in the gain of the VOR, lower for ipsilesional in
comparison with contralesional rotations, also have been noted for
lower acceleration and frequency rotations that reach a higher peak
velocity in studies performed in monkeys. For sinusoidal rotations,
these asymmetries are manifested as a diminished gain for half-cycles
of the rotation toward the lesioned side and a bias velocity (slow
phase components directed toward the lesioned ear) during the rotation
(Paige 1989). For velocity-step rotations, the asymmetry
is observed as a diminished gain for rotations toward the lesioned ear
noted immediately after reaching the peak head velocity (Fetter
and Zee 1988
; Fetter et al. 1988
).
We sought to determine the interaction of frequency, velocity, and acceleration in producing asymmetries of the horizontal VOR after disruption of vestibular function from one labyrinth. The lesion used for this study was unilateral plugging of the three semicircular canals. Evidence is presented indicating that canal plugging in squirrel monkeys results in a reduction in the dominant time constant of the canal and attenuation in the response gain while preserving both the spontaneous activity of the afferents and otolith function. The findings indicate that there is a frequency- and velocity-dependent asymmetry in the horizontal VOR evoked by rotations in the yaw plane after plugging. For more dynamic stimuli, rotations toward the lesioned labyrinth resulted in a VOR with a lower gain. The findings were interpreted in terms of a mathematical model of the VOR with inputs from linear and nonlinear pathways the parameters of which were derived from data in squirrel monkeys with normal vestibular function. The responses from steps of acceleration and sinusoidal rotations after plugging were accounted for by a selective increase in gain of the nonlinear pathway which, because of its dynamics at higher rotational frequencies and velocities, was prone to inhibitory cutoff.
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METHODS |
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Surgical procedures
The methods for implantation of the head restraining bolt and
eye coils were described in the companion paper (Minor et al. 1999).
The postauricular mastoid bone was removed with an otologic drill and curettes to expose the horizontal and posterior semicircular canals. The petrous bone was further removed anteriorly and superiorly to visualize the superior canal near its union with the common crus. This surgical exposure required gentle retraction of the petrosal lobe of the cerebellum during the procedure. The dura overlying the petrosal lobe remained intact and there was no evidence of hemorrhage or injury to this structure after the retraction had been released.
A fenestra was made in the osseous portion of each canal at a point that was approximately the maximal distance from its ampulla. The membranous canal remained intact and was compressed against the walls of the osseous canal by packing the osseous canal with bone dust and fascia.
Animals showed a slight (5-10°) head tilt and minimal gait ataxia during the initial 2 days after the plugging procedure. Their head orientation and gait were relatively normal thereafter. Two animals underwent plugging of the three canals on the opposite side 3-4 mo later. These animals had a head tilt toward the side on which the plugging procedure had been performed most recently that was of similar magnitude and resolved over a similar time course to that noted after the initial plugging procedure. Their gait returned close to normal within 1 wk after the remaining three canals had been plugged although their heads would occasionally oscillate for 2-3 s after rapid movements.
When testing was completed, animals were anesthetized deeply with sodium pentobarbital and perfused transcardially with 10% formalin. For three of the four animals in the study (M20, M314, and M330), the right and left temporal bones were removed, decalcified, embedded in celloidin, and cut in horizontal sections (80 µm). The sections were stained with cresyl violet.
Examination of the histological sections indicated that the lumen of each plugged canal was occluded. The sensory epithelia of the cristae and the otoliths as well as the afferent nerve fibers and cells in Scarpa's ganglion were intact and normal in histological appearance. Figure 1 shows a representative temporal bone specimen demonstrating intact sensory epithelia and plugged canals.
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Eye-movement responses
The experimental procedures used for recording eye movements were identical to those described for the animals before plugging. Animals typically were tested 8 h after the plugging procedure, 18-24 h after return to light, and on days 10 and 30 after plugging.
Rotational testing and data analysis
The testing paradigms and analysis procedures used for calculating gain and phase parameters were identical to those described in the companion paper. For steps of acceleration, responses to 10-15 stimulus repetitions in the ipsilesional and contralesional directions were studied. The acceleration gain of the VOR, GA, was measured for each trial as the ratio of the slope of a line through the eye velocity points to the slope of a line through the head velocity points during the latter portion of the step of acceleration. For the steps of acceleration that reached a maximum velocity of 150°/s, this period was 20-40 ms after the onset of the stimulus when head velocity was increasing from 60 to 120°/s. The velocity gain of the VOR, GV, was measured from the ratio of the mean eye and head velocity evaluated at 100-300 ms after the plateau head velocity had been reached for each trial. Responses to steps of acceleration that reached a lower peak velocity (3,000°/s2, 60°/s) were studied to define the transition between acceleration and velocity gains independent of fast phases. For these briefer rotational steps, the gain during the period of acceleration was measured as the ratio of the peaks of eye and head velocity, whereas the gain during the velocity plateau was defined as the ratio of eye and head velocity from 200 ms after the onset of the stimulus to the occurrence of the first fast phase.
Distinctly different responses, requiring different analytic fits, were
noted for contra- and ipsilesional steps of acceleration after the
plugging procedure. We analyzed the ipsilesional and contralesional
responses separately. To compare the contralesional and ipsilesional
responses with the data obtained from animals with normal vestibular
function, we inverted the eye- and head-velocity signals for the
averaged response to rotations in each direction and concatenated this
signal with the corresponding noninverted trace. Polynomial fits were
made for the contralesional responses, and the ipsilesional responses
were fit with a hyperbolic tangent function. For example, in Fig. 6 the
responses to rightward (contralesional) rotations are shown as positive
values for eye and head velocity. These signals were inverted to form
the head velocity responses that would have been expected if the lesion
had been on the right instead of the left side. These two responses
then were concatenated at the origin. The best fit to the
contralesional data will be with an odd-order polynomial, without
contribution from even-order terms, because the method for forming the
signal insured that the responses were symmetric about the origin. All
full description of these techniques for polynomial fits is given in
Minor et al. (1999).
Correction for response arising from plugged canals
As shown in Fig. 13, a response rising in amplitude and declining in phase lead re velocity with increased rotational frequency was noted in animals after plugging of the six semicircular canals. We wished to correct for the contribution that this response was making to the gains and phases measured with sinusoidal rotations. We assumed that the responses measured in animals after all canals had been plugged were due to equal contributions from excitation and inhibition of the respective canals. The gain at each frequency from the gain and phase plot of the six-canal-plugged animals was divided by two to obtain an estimate of the contribution from the plugged canals of a single labyrinth. Vector subtraction was used to calculate the difference between the measured response and the response assumed to arise from the plugged canals. This difference gave us a measure of gain and phase attributable to the intact labyrinth.
The responses attributable to the intact canals were fit with a transfer function with a single pole and zero, the values of which were determined from a least squares regression that minimized error between the fit and the observed values of gain and phase.
Eccentric rotations
The two animals that had undergone plugging of all six semicircular canals were tested with eccentric rotations to verify that their linear VOR (LVOR) was intact. The superstructure to which the animal was secured was placed 58 cm eccentric to the rotational axis. Rotations at 4 Hz, ±20°/s were given with animals facing toward and away from the axis of rotation. The peak tangential force for this stimulus was 5.0 m/s2 which is equivalent to 0.51g. Animals were tested in darkness and cycles with a vergence of <1 meter angle (MA) were used in the averages.
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RESULTS |
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The horizontal VOR evoked by steps of head acceleration and by sinusoidal rotations was examined in four squirrel monkeys after unilateral plugging of the three semicircular canals. Semicircular canals were plugged on the right in three animals and on the left in one. Unless otherwise noted, all responses were measured in darkness.
Spontaneous nystagmus
These four animals were kept in darkness after the plugging procedure. There were no restrictions on movement within their cages at any time after the procedure. When evaluated 8 h after plugging while animals were still in darkness, there was a spontaneous nystagmus with slow phase components directed toward the plugged side in three of these animals (M314, M20, and M51). The horizontal slow-phase eye velocity of this nystagmus was 9.0 ± 6.4°/s. On the first day after plugging (while the animal was still being kept in darkness) the slow- phase eye velocity had fallen to 5.4 ± 3.4°/s. This nystagmus increased in amplitude to 15.3 ± 3.2°/s (P < 0.02 with respect to slow phase velocities before animals were brought into light) when tested in darkness 8 h after they had been returned to light. The slow-phase velocity of the spontaneous nystagmus decreased to 3.8 ± 2.8°/s after the animals had been in light for 18-24 h. At 10 and 30 days after plugging, the spontaneous nystagmus measured 2.9 ± 3.0 and 3.1 ± 2.0°/s, respectively.
One animal (M330) had a spontaneous nystagmus with slow-phase components toward the intact labyrinth when measured while the animal was being kept in darkness 8 h after the plugging procedure. The slow-phase velocity was 6.9 ± 3.2°/s. The spontaneous nystagmus in this animal reversed in direction on the first day after surgery when the animal was still in darkness and had a slow phase velocity of 6.4 ± 1.8°/s. The nystagmus continued to beat toward the intact ear and had a slow-phase velocity of 5.2 ± 1.7°/s after the animal had been in light for 18-24 h. It measured 3.5 ± 1.6 and 4.1 ± 1.6°/s at 10 and 30 days, respectively, after the plugging procedure.
Steps of acceleration
The VOR evoked by steps of acceleration showed a reduction in gain after plugging with responses to ipsilesional rotations having a lower gain than those for contralesional rotations. These changes were noted on the first testing session conducted 8 h after the plugging procedure. Comparisons of GA and GV for specific times after plugging in the four animals are shown in Fig. 2.
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To account for the possible effects of small differences in the values of GA and GV between animals before the plugging procedure, these gains measured after plugging were normalized in each animal to that of the comparable parameter before the procedure. GA for ipsilesional rotations when measured 8 h after plugging (while animals were still in darkness) was 0.33 ± 0.03 and 0.61 ± 0.14 for contralesional rotations (P < 0.05). GV for ipsilesional rotations was also reduced in comparison with that for contralesional rotations at the time of this initial evaluation after plugging: 0.40 ± 0.05 and 0.52 ± 0.05, respectively (P < 0.01).
When tested 18-24 h after return to light, the asymmetry in GA had increased: GA for ipsilesional rotations (GA-ipsi) = 0.37 ± 0.07 and GA for contralesional rotations (GA-contra) = 0.88 ± 0.05 (P < 0.001). This increased asymmetry was due to a large rise in GA-contra after animals were returned to light (P < 0.02), whereas GA-ipsi was unchanged (P > 0.11). The rise in GA-contra after animals were returned to light brought this parameter close to its value before the plugging procedure. GV remained asymmetric when initially evaluated after return to light: GV for ipsilesional rotations (GV-ipsi) = 0.49 ± 0.07 and GV for contralesional rotations (GV-contra) = 0.62 ± 0.04 (P < 0.03). In contrast to GA, return to light resulted in increases in GV-ipsi and GV-contra that were significant for each direction (P < 0.04 for GV-ipsi; P < 0.01 for GV-contra).
One animal, M51, was kept in darkness for 4 days after the plugging procedure. The findings in this animal provided further support for the notion that return of the animal to light, and not simply the elapse of time after the procedure, provided the stimulus required for an increase in GA-contra. There was a small increase in GA-contra from 0.60 ± 0.04 measured 8 h after the plugging procedure to 0.68 ± 0.09 measured on day 4 after plugging but before return of the animal to light (P < 0.05). A large increase in GA-contra to 0.86 ± 0.04 occurred within the first 8 h after the animal was returned to light on day 4 (P < 0.00001). In contrast, GA-ipsi showed no change during this time period: 0.28 ± 0.03 at 8 h after plugging and 0.27 ± 0.06 on day 4 at 8 h after return to light (P > 0.4).
The asymmetry between values of
GA-ipsi in comparison with
GA-contra persisted throughout the 30 days after the plugging procedure (P < 0.003).
GA-ipsi increased to 0.63 ± 0.11 at day 30 (P < 0.003 with respect to its initial value
after return to light), whereas GA-contra was unchanged when its value
on day 30 (0.98 ± 0.15) was compared with that after initially
returning to light (P > 0.20). The data for
GA and
GV at intervals of 30 days after
unilateral canal plugging are shown in Fig.
3.
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GV for rotations in each direction increased during the 30 days after the plugging procedure. When data from the four animals were pooled, the difference between values for GV-ipsi in comparison with GV-contra rotations ceased to be significant. At day 10 after the plugging procedure, GV-ipsi = 0.65 ± 0.07 and GV-contra = 0.71 ± 0.09 (P > 0.09). At day 30, GV-ipsi = 0.67 ± 0.09 and GV-contra = 0.79 ± 0.10 (P > 0.08). When data from each animal were considered separately, the difference between ipsilesional and contralesional values of GV was not significant at day 30 in three of the animals (P > 0.15). One animal, M51, had asymmetries in GV that persisted throughout the initial 30-day period of evaluation and even at day 63 after the plugging procedure: GV-ipsi = 0.73 ± 0.03 and GV-contra = 0.87 ± 0.03 (P < 0.0001).
Figure 4 shows the responses to steps of acceleration that reached a lower peak velocity (3,000°/s2, 60°/s). The contralesional gain values were 0.88 ± 0.10 for acceleration and 0.73 ± 0.06 for velocity (P < 0.002), whereas the ipsilesional gains were 0.52 ± 0.05 for acceleration and 0.70 ± 0.03 for velocity (P < 0.0001). Note that the contralesional acceleration gain is appreciably greater than that measured for ipsilesional rotations (P < 0.0001), whereas the velocity gains for ipsi- and contralesional rotations were indistinguishable (P > 0.43). These findings indicate that the decrease in gain that occurs at the end of the acceleration for contralesional rotations and the increase in gain that occurs at that point for ipsilesional rotations are both independent of fast phases.
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Latency
Whereas the latency calculated by the linear fit and 3-SD methods
(see Minor et al. 1999 for a description of these
methods) were identical before plugging, the diminished gain of the
ipsilesional responses after plugging resulted in a shorter latency
(4.0 ± 3.5 ms) with the linear fit method than that measured
prior to the lesion (Fig. 5A).
In contrast, the increasing gain with velocity noted for the
contralesional responses gave a longer estimate of latency (11.4 ± 1.0 ms) in comparison with prelesion values when the linear fit
method was used. The 3-SD method was less sensitive to such differences
in gain (Fig. 5B). The latency for ipsilesional responses on
day 10 after plugging for the four animals measured 8.4 ± 0.4 ms
and that for contralesional responses was 7.2 ± 0.1 (P < 0.01).
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Latency values calculated by the 3-SD method in the four monkeys are listed at various times after the plugging procedure in Table 1. There were no differences between the measures at specific times after plugging for contralesional (P > 0.5) or for ipsilesional (P > 0.9) rotations. The data for all of the measurement times in the animals were pooled to compare the responses in each direction. The contralesional latency measured 7.1 ± 0.3 ms and the ipsilesional latency measured 8.2 ± 0.4 ms (P < 0.0001).
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Fits to steps of acceleration
CONTRALESIONAL. The gain of the VOR was noted to increase with head velocity after plugging. Responses to contralesional rotations were analyzed with linear and polynomial fits to the data. Figure 6 shows a plot of these responses and the fits at day 10 after plugging in M51. Table 2 gives the values for the coefficients of the terms for each of these fits. As described in METHODS, the responses were symmetric about the head- and eye-velocity axes and the coefficient of the second-order term was zero in each case.
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IPSILESIONAL. The responses to ipsilesional rotations, in contrast to those for contralesional rotations, showed no increase in gain with velocity. In fact, for the initial two testing sessions (day 1 in the dark and day 1 in the light) there was a decrease in gain with increasing stimulus velocity. Therefore we fit the ipsilesional data obtained early after plugging with a hyperbolic tangent optimized to match the trajectory of the relationship between eye and head velocity (Fig. 7).
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Responses to sinusoidal rotations
Figure 8 displays the gain and phase plots of responses to sinusoidal rotations (0.5-15 Hz, ± 20°/s) measured while animals were in darkness 8-12 h after plugging, 18-24 h after return to light, and days 10 and 30 after plugging. The gain recovered across all frequencies over time after plugging. The gain measured in darkness after plugging was 0.49 ± 0.06 and did not change with respect to frequency (P > 0.9). The reduction in gain compared with prelesion values was 42 ± 4%. Gain increases were noted for each successive testing session after animals were returned to light. The recovery of gain evaluated at day 30 after plugging was largest over the frequency range of 0.5-6 Hz. The gain at these frequencies measured 0.70 ± 0.04 and did not differ between individual frequencies (P > 0.7). Less recovery of gain was noted for 8- to 15-Hz rotations. The gain at these frequencies was 0.61 ± 0.02 and did not differ for individual frequencies (P > 0.8). The difference in the mean gain values for these two frequency groups was significant (P < 0.01).
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The phase of the VOR when evaluated while animals were in darkness
8-12 h after plugging showed a lead that measured 2.2 ± 1.6°
and did not differ with respect to individual frequency
(P > 0.8). These phase leads represented a difference
from prelesion values at 10-15 Hz. At 10 Hz, the phase before plugging
was 2.4 ± 1.9°, whereas that immediately after plugging was
1.8 ± 2.0° (P < 0.03). At 12 Hz, the phase
before plugging was
2.5 ± 1.2° and after plugging was
5.3 ± 4.0° (P < 0.01). At 15 Hz, the phase before plugging was
4.8 ± 0.9° and after plugging was
0.6 ± 1.4° (P < 0.001). After animals were
returned to light, a phase lag at the higher frequencies was again noted.
As described in the following text, data from two animals that underwent subsequent plugging of the three remaining semicircular canals indicate that, at higher frequencies, responses do arise from the plugged canals. These residual responses after bilateral plugging of the six semicircular canals were subtracted at each frequency from that measured after unilateral canal plugging (see METHODS). This computation gave a representation of responses arising from the intact labyrinth.
Figure 9 displays gain and phase after correction for the response from the plugged canals for the following parameters: responses at day 30 after canal plugging, residual responses attributable to the plugged canals, the resultant responses arising from signals mediated by the intact canals, and the fit of a transfer function to these responses from the intact canals. Recovery of gain was greater at 0.5-4 Hz than it was at the higher frequencies. The gain at 0.5-4 Hz measured 0.70 ± 0.11 and did not differ between frequencies within this interval (P > 0.5). The gain at 6-15 Hz measured 0.54 ± 0.07 and did not differ with frequency (P > 0.5). The difference in mean gain values for these two frequency groups was significant (P < 0.01).
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The phase of the VOR evaluated on day 30 after plugging showed a slight
lead at 0.5 and 2 Hz (4.5 ± 4.7°) and did not differ between
these frequency values (P > 0.4). The phase declined
with frequency to have a lag that measured 11.7 ± 1.3° at 12 and 15 Hz and did not differ between these frequency values
(P > 0.4; Fig. 9). This difference in mean phase
values for these two groups was significant (P < 0.02). The phase lag at these highest frequencies was greater than that
observed at these frequencies before plugging (P < 0.0001).
Responses to sinusoidal rotations of 0.5-15 Hz, ± 20°/s also were analyzed in terms of half-cycle gains (Fig. 10). Although mean values of half-cycle gain for contralesional motion were typically higher than those for the corresponding ipsilesional half-cycle, these differences were not significant at any single frequency on each day tested (P > 0.05). There was also no difference in contra- or ipsilesional half-cycle gain across frequencies on any day tested (P > 0.10).
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M51 was tested at 4 Hz, ±100°/s after plugging, and considerably larger half-cycle gain asymmetries were noted (Fig. 11). At 0.5 Hz, there was no half-cycle asymmetry at any of the velocities that were tested (P > 0.6). At 4 Hz, the contralesional and ipsilesional half-cycle gains for 100°/s rotations measured 0.81 ± 0.05 and 0.53 ± 0.03 (P < 0.0001). An increased contralesional in comparison with ipsilesional half-cycle gain also was noted at 10 Hz, ±50°/s. This difference in half-cycle gain was due to an increase in the gain of the contralesional response at higher velocities. The ipsilesional half-cycle gain, in contrast, did not change as velocity was increased. Phase did not change as velocity was varied across these frequencies (P > 0.05). This asymmetry in half-cycle gains resulted in a harmonic distortion in the response that measured 8.8% at 4 Hz, ±100°/s.
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A bias velocity, defined as a DC shift in the response, was measured from the Fourier analysis of the data. The bias velocity was directed toward the plugged side and measured 2.8 ± 3.1°/s in responses to sinusoidal rotations of 2-15 Hz, ± 20°/s on day 1 in the dark, day 10, and day 21. The bias velocity was 9.5 ± 2.0°/s when measured 18-24 h after animals were brought into light. Responses to rotations at a peak velocity of 20°/s had a bias velocity that did not change with respect to frequency (P > 0.6) and that was indistinguishable from the spontaneous nystagmus measured for each testing session (P > 0.5). The bias velocity measured from data pooled at 2 and 4 Hz increased with head velocity, measuring 0.02 ± 4.5°/s and 10.9 ± 3.2°/s at peak velocities of 20 and 100°/s, respectively (P < 0.002).
The coefficients of polynomial fits to the contralesional half-cycles
for 4 Hz, ± 100°/s in M51 were similar to those
calculated from the contralesional steps of acceleration. At day 21 after plugging, the coefficient of the cubic term calculated from the fit to the contralesional steps of acceleration was 1.74 × 105, whereas that calculated from the
sinusoidal data was 1.77 × 10
5. As also
noted for the steps of acceleration, the responses to ipsilesional
half-cycles of rotations had a constant gain over the velocities tested.
Responses after bilateral plugging of the semicircular canals
Two monkeys underwent plugging of the three semicircular
canals of the left labyrinth at 137 days (M20) and 70 days
(M314) after the canals had been plugged on the right.
Responses to steps of acceleration (3,000°/s2
to 150°/s) recorded 2 wk after the left semicircular canals were plugged in M314 and M20 are shown in Fig.
12. The responses were symmetric for
rightward and leftward rotations. The following first-order transfer
function was derived from a least-squares fit to the data
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(1) |
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Responses to sinusoidal rotations at 0.5-15 Hz at 2 wk after the left semicircular canals had been plugged in M314 and M20 are shown in Fig. 13. The gain of the response grew with frequency to reach 0.23 ± 0.03 at 15 Hz. The response had a phase lead re head velocity of 52.4 ± 7.9° at 4 Hz and 16.0 ± 13.0° at 15 Hz. We also fit a first-order transfer function similar to Eq. 1 to the sinusoidal data. The best fit had a gain and time constant of 0.21 and 0.023 s, respectively. These values are quite similar to those noted in the fits to steps of acceleration. Figure 13 also shows the response that is predicted based on the coefficients of the first-order transfer functions derived from the responses to steps of acceleration and from the sinusoidal rotations.
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Responses to eccentric rotations after plugging of the six semicircular canals
The sensitivity of the linear vestibuloocular reflex, LVOR,
at 4 Hz in M314 after all semicircular canals had been
plugged measured 18.4 ± 4.7° · s1 · g
1 with a
phase re head velocity of 168.5 ± 0.3° for rotations with the
animal facing the axis of rotation and 20.0 ± 5.1° · s
1 · g
1 with a
phase re head velocity of 14.3 ± 1.1° for rotations with the
animal facing away from the axis of rotation. For M20, the LVOR sensitivity with the animal facing the axis of rotation was 19.6 ± 5.5° · s
1 · g
1 and a phase re head velocity of 160.5 ± 0.6°. The LVOR sensitivity in M20 was 18.8 ± 5.5° · s
1 · g
1 with a phase of
6.2 ± 0.2° for
rotations with the animal facing away from the axis of rotation.
Although we did not measure the sensitivity of the LVOR in these
animals before plugging, these gain and phase values are comparable
with those measured with similar stimuli in animals with normal
vestibular function (Sargent and Paige 1991
).
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DISCUSSION |
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Asymmetries after unilateral plugging of the three semicircular canals
The asymmetry that we observed after unilateral canal plugging in
responses to ipsilesional in comparison with contralesional steps of
acceleration was comparable with that reported for similar stimuli
after ablative lesions of the vestibular periphery in humans (Aw
et al. 1996; Crane and Demer 1998
;
Halmagyi et al. 1990
). Because we have presented
evidence that spontaneous activity in the labyrinth is preserved after
canal plugging, this finding indicates that the asymmetry arises from
the dynamics of these responses and is not dependent on a static
imbalance in activity between the two vestibular nerves or nuclei.
This asymmetry was most prominent during the step of acceleration in comparison with the velocity plateau of the stimulus. The difference in GA between contralesional and ipsilesional responses was greater for steps of acceleration that had a longer duration and, as a consequence, reached a higher velocity. This observation indicates that acceleration is not the sole determinant of the asymmetry. There was only a small asymmetry in GV between contralesional and ipsilesional responses in contrast to the much larger asymmetry in the corresponding values for GA. The stimulus velocity was greater for the portion of the response during which GV was measured in contrast to the lower stimulus velocities over the interval used to measure GA. If stimulus velocity were the only parameter involved in the asymmetry, then a greater difference between ipsilesional and contralesional responses would have been expected for GV in comparison with GA. The findings indicate that the asymmetry increases with the velocity of the stimulus but only during the dynamic portion of the stimulus not at the plateau of head velocity. Thus a parameter other than acceleration and velocity also must be involved in the etiology of the asymmetry. The frequency content of the stimulus, in association with velocity, is an obvious suggestion for such a parameter.
The data from sinusoidal rotations at increasing stimulus velocities
support an interactive role of both frequency and velocity in the
origin of the asymmetry. Sinusoidal rotations at frequencies of 15 Hz
at a peak velocity of 20°/s showed only a slight, and often
insignificant, asymmetry between ipsilesional and contralesional responses. A prominent asymmetry was present at frequencies of
4 Hz
as the stimulus velocity was increased. The gain of responses to the
contralesional half-cycles of the rotation increased at higher stimulus
velocities, but the gain of ipsilesional responses stayed the same or
decreased slightly as peak stimulus velocity was raised. No change in
gain was seen as stimulus velocity was increased to
100°/s at 0.5 Hz.
GA measured from contralesional steps of acceleration showed a marked increase in gain within the initial day after animals were returned to light. The error signal driving this gain increase was most likely retinal slip resulting from a low-gain VOR. In contrast, there was only a slight increase in GA for ipsilesional responses. These findings support the existence of a highly modifiable, but rectified, signal that is more prominent for stimuli with a combination of both higher frequency and velocity components.
As will be shown later in this DISCUSSION, the model that
we developed for responses to steps of acceleration and sinusoidal rotations in monkeys with intact vestibular function (Minor et al. 1999) can be used to explain the findings after unilateral canal plugging. The asymmetries arise because of a greater increase in
the gain of the nonlinear, in comparison with the linear, pathway. A
more gradual rise with time after the lesion in the gain of the linear
pathway accounts for the relatively symmetric increase in gain of
responses to stimuli with lower frequency and velocity components.
Effects of plugging on transduction in the semicircular canals
Our findings indicate that plugging attenuates the responses of the affected canal to rotations while having little effect on the spontaneous activity of afferents innervating that labyrinth. The temporal bone histology showed that the plugging procedure obliterated the lumen of the canal while preserving the sensory epithelia of the semicircular canals and otoliths.
Four lines of evidence indicate that the plugs do not result in an ablation of spontaneous activity of afferents innervating the affected canals.
First, the spontaneous nystagmus recorded after plugging was
considerably lower than the horizontal slow-phase velocity of 43°/s
noted when monkeys were tested in darkness acutely after labyrinthectomy (Fetter and Zee 1988). This spontaneous
nystagmus after plugging was indicative of a decrease in activity from
the labyrinth on which plugging had been performed in three animals and
was excitatory with respect to the side of surgery in a fourth. An
alteration of endolymphatic pressures within the labyrinth or to a
transient inflammatory response resulting from the surgical procedure
are two potential explanations for the nystagmus.
Second, the postural signs after canal plugging were more subtle and
transient than the head tilt and ataxia noted in animals after
labyrinthectomy (Fetter and Zee 1988; Precht
1986
). In particular, the two animals in our companion study
that had undergone bilateral labyrinthectomy (Minor et al.
1999
) had significantly impaired movement and ataxia in
contrast to the relatively subtle behavioral changes noted in the
animals in which all six canals had been plugged.
Third, a small response to higher-frequency rotations was noted after all six canals were plugged in contrast to animals after bilateral labyrinthectomy in which responses to these same stimuli were completely absent.
Fourth, the linear VOR as evaluated by eccentric rotations was intact
after all six canals had been plugged. The LVOR sensitivity for these
4-Hz rotations measured 19° · s1
· g
1 comparable with that reported in animals
with no prior surgical manipulation of the labyrinth (Paige and
Tomko 1991
; Sargent and Paige 1991
). As
expected, the phase of the LVOR response shifted by ~180° when the
animal was moved from a position facing toward to a position facing
away from the axis of rotation indicating that the response was of
otolith and not canal origin.
Our data on the residual responses after plugging of all canals are
similar to those recently reported in cynomolgus monkeys by
Yakushin et al. (1998). They showed a persistent
response in the plane of the plugged canal that increased with
rotational frequency. The monkeys in our study that had undergone
plugging of the six semicircular canals also showed small VOR gains
that increased in magnitude as rotational frequency was increased. The
phase of this residual VOR led head velocity by 60-80° at 2 Hz and
returned to being more in phase with velocity as the rotational
frequency was increased to 15 Hz.
Yakushin et al. (1998) suggested that the effect of
canal plugging was to alter the low-frequency 3-dB roll-off and
corresponding dominant time constant of the canals. Our data are
consistent with this interpretation. The principal difference between
the parameters of the model used for the data in cynomolgus monkeys and
our findings in squirrel monkeys was a shorter dominant time constant
(32 ms) in the latter in comparison with the former (70 ms). The gain
of the responses after plugging (0.25) in squirrel monkeys was also
lower than that observed after plugging (0.8) in cynomolgus. We could
predict the responses to steps of acceleration based on the change in
time constant and gain calculated from the sinusoidal responses.
The lower dominant time constant and gain noted in squirrel monkeys
after plugging of all canals in comparison with the findings in
cynomolgus monkeys provides an explanation for the substantially lower
responses that we noted at 4 Hz in comparison with those observed by
Yakushin et al. The reduced time constant in squirrel monkeys can be
understood in terms of the effects of plugging on the mechanics of the
semicircular canal (Rabbitt et al. 1999). The greater
cross-sectional diameter of the semicircular canals in cynomolgus in
comparison with squirrel monkeys leads to the prediction that responses
after plugging should be greater in the former than in the latter.
Our findings on the VOR after six-canal plugging in squirrel monkeys
are also consistent with the single-unit recordings from afferents
presumed to innervate the crista of the plugged horizontal canal in the
study of Paige (1983). There was no observed response of
these afferents to rotations at <2 Hz; this is in accord with the VOR
data at these frequencies after all canals had been plugged.
Could the vestibuloocular responses we observed in the
six-canal-plugged animals when their heads were centered on the axis of
rotation be of otolith origin? Misalignment of the head with respect to
the rotational axis would result in tangential forces that could
produce an LVOR. The gain of this LVOR would be expected to increase
with frequency and have a phase closer to head acceleration for lower
frequencies and closer to head velocity for higher frequencies. Quantitative consideration of the measured gains, sensitivities, and
tangential forces indicate that this was not the case. Rotations at 4 Hz, ±50°/s with the animal's head centered on the axis of rotation
produced a vestibuloocular response with a peak eye velocity of 5°/s.
We estimate that the maximum misalignment of the animal's head with
respect to the axis of rotation was 1 cm, which would produce a
tangential force 0.02 g for this stimulus. The LVOR generated by such a force would need to have a sensitivity of 250° · s1 · g
1 to produce an eye movement of 5°/s at 4 Hz. This sensitivity is over an order of magnitude greater than the
sensitivity we measured in these animals in response to 4-Hz rotations
at an eccentricity of 58 cm; thus we conclude that the responses we measure to on-axis rotations were canal and not otolith mediated.
Changes in the VOR after unilateral canal plugging
LATENCY. The latency calculated from the linear fit and 3-SD methods in animals with intact vestibular function was identical. These methods did not produce equivalent findings when used on the data after canal plugging. The linear fit method led to an erroneously short estimate of VOR latency for ipsilesional responses because the gain decreased with increasing head velocity. This method also led to a longer estimate of latency for contralesional responses due to the nonlinear rise in eye velocity with head velocity over the interval of 20-40 ms after the onset of the stimulus.
The 3-SD method was less susceptible to these differences in VOR gain between contra- and ipsilesional responses. The latency measured by this method was identical for contralesional rotations in comparison with prelesion values. In contrast, the latency was 1 ms longer for ipsi- than for contralesional rotations after plugging. The reason for this slight asymmetry between latencies for ipsi- and contralesional responses after plugging is not clear. Ipsilesional responses do have a lower gain that could have affected the time at which an eye movement response could be discerned. The latency measured by the 3-SD method did not change with time after plugging. This finding indicates that the mechanisms responsible for changes in acceleration and velocity gain after plugging occurred independent of signals conveying the onset of the head rotations.RESPONSES TO STEPS OF ACCELERATION. GA and GV for ipsi- and contralesional rotations were reduced by ~43% when measured during the first testing session after plugging in comparison with prelesion values. The attenuation in responses to head velocity arising from the labyrinth with plugged canals provides the most obvious explanation for the initial reduction in VOR gain. We observed three effects that appeared to result from an inhibitory process during the period animals were kept in darkness after plugging.
First, the spontaneous nystagmus present after plugging was noted to transiently increase when animals were returned to light and then rapidly declined during the course of 1 day to an amplitude of ~3°/s. Paige (1983)RESPONSES TO SINUSOIDAL ROTATIONS.
The data from rotations at 0.5-15 Hz, ±20°/s before animals were
brought into light after unilateral canal plugging showed a phase lead
at higher frequencies that was not present prior to the lesion. This
small phase lead may be due to greater inhibition for lower-frequency
responses and/or to the residual response arising from the plugged
canals. There was a return of the phase lag at higher frequencies and
an increase in gain at the lower frequencies noted after the animals
were returned to light. We derived the transfer function in Eq. 2 with a single pole and zero to fit the gain and phase data (see
Fig. 9) at day 30 after plugging
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(2) |
Modeling of asymmetries in the VOR after unilateral canal plugging
Figure 14 shows a bilateral model
of the VOR that we have used to simulate the asymmetries in ipsi- and
contralesional responses identified in our study. The inputs, arising
from linear and nonlinear pathways, and coefficients used in the model
are described in the companion paper (Minor et al.
1999). Because we were concerned mainly with modeling the
asymmetries that persist after a unilateral vestibular lesion, we used
data from
10 days after the plugging procedure (i.e., after the
inhibitory effects had resolved). To simulate the effect of the lesion,
we removed the inputs from the plugged side while maintaining the
spontaneous rate. We could account for the changes observed in
responses to the stimuli used in this study after canal plugging by
adjusting the central gain elements of the linear and nonlinear
pathways (kl and
kn). The other coefficients in this
model were calculated from data in the animals before plugging and were
not changed in the simulations of the findings after canal plugging.
|
Because there was no manifestation of the nonlinear pathway for
ipsilesional rotations after plugging, we propose that this pathway is
driven into inhibitory cutoff for velocities of ~30°/s. This cutoff
point is predicted based on the sensitivity of neurons in the nonlinear
pathway (pn1 = 3.0 spikes · s1/° · s
1). On
the basis of this premise, the gains for the ipsilesional responses
could be used to specify kl, the
central gain element for the linear pathway. The data support the
conclusion that the gain of the linear pathway is symmetric for
rotations in each direction. We therefore calculated this gain of the
linear pathway (kl) from the
ipsilesional responses. The gain of the nonlinear pathway
(kn) then was calculated from the
contralesional responses by subtracting the component of these
responses that arose from the linear pathway.
Figure 15 shows the gain and phase plot
of the simulated responses at day 10 after canal plugging. The increase
in gain for contralesional responses was accounted for by an increase
in kn from 1.0 × 105 before to 1.5 × 10
5 after plugging. The value of
kl was increased from 1.0 before to
1.25 after plugging. The increase in
kl occurred more gradually and was
responsible for the increase in gain at lower frequencies and lower
velocities seen with time after the lesion.
|
The inset in Fig. 15 shows the agreement between the simulation of the model and the data from 4 Hz, ±100°/s rotations plotted as eye versus head velocity at day 10 after plugging in M51. The differences between the ipsi- and contralesional responses are apparent on the plot. Note the contralesional response has a trajectory that is similar to that observed in the contralesional responses to steps of acceleration (see Fig. 6). The ipsilesional responses have a linear trajectory also similar to those noted for the steps of acceleration, at day 10 and longer, after plugging.
The coefficients determined for kl and kn at different days after plugging were used to fit the responses to steps of acceleration. Figure 16 shows the response asymmetries between ipsi- and contralesional rotations observed in the data and predicted by the model. The trajectories of the eye velocity during the period of the acceleration are predicted well by the model. The model predicts a lower gain at the velocity plateau than that observed in the data. Fast phases may be involved in increasing gain and in restoring linearity during the velocity plateau.
|
Concluding remarks
The physiological basis of asymmetries between ipsi- and contralesional responses for high-frequency, high-acceleration rotations after unilateral plugging of the three semicircular canals can be summarized as follows.
First, there is inhibitory cutoff at stimulus velocities of ~30°/s in the nonlinear pathway that is inherent in the dynamics of the normal VOR. The nonlinear pathway therefore makes no contribution to the ipsilesional responses after canal plugging.
Second, the gain of the nonlinear pathway is selectively increased when animals are returned to light, and experience retinal slip, after plugging. As a result, contralesional responses for more dynamic stimuli show a large increase in gain within 18-24 h after return to light.
Third, the gain of the linear pathway is increased more slowly after plugging and contributes to the symmetrical rise in responses to less dynamic stimuli with time after plugging.
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ACKNOWLEDGMENTS |
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We thank A. Saada for assistance with perfusion of the animals, S. Price for histological preparation of the temporal bones, and D. A. Robinson for helpful comments on an earlier version of the manuscript.
This work was supported by National Institute on Deafness and Other Communication Disorders Grants R01 DC-02390, P60 DC-00979, and T32 DC-00027; the National Aeronautics and Space Administration Cooperative Agreement NCC 9-58 with the National Space Biomedical Research Institute; and the Research Fund of the American Otological Society.
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FOOTNOTES |
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Address for reprint requests: L. B. Minor, Dept. of
OtolaryngologyHead and Neck Surgery, Johns Hopkins Univ. Sch. of
Medicine, 601 N. Caroline St., Rm. 6253, Baltimore, MD 21287-0910.
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 9 February 1999; accepted in final form 11 May 1999.
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REFERENCES |
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