1Department of OtolaryngologyHead and Neck
Surgery, 2Department of Biomedical Engineering,
and 3Department of Neuroscience, The Johns
Hopkins University, Baltimore, Maryland 21287-0910
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ABSTRACT |
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Lasker, David M., Timothy E. Hullar, and Lloyd B. Minor. Horizontal Vestibuloocular Reflex Evoked by High-Acceleration Rotations in the Squirrel Monkey. III. Responses After Labyrinthectomy. J. Neurophysiol. 83: 2482-2496, 2000. The horizontal angular vestibuloocular reflex (VOR) evoked by high-frequency, high-acceleration rotations was studied in four squirrel monkeys after unilateral labyrinthectomy. Spontaneous nystagmus was measured at the beginning and end of each testing session. During the period that animals were kept in darkness (4 days), the nystagmus at each of these times measured ~20°/s. Within 18-24 h after return to the light, the nystagmus (measured in darkness) decreased to 2.8 ± 1.5°/s (mean ± SD) when recorded at the beginning but was 20.3 ± 3.9°/s at the end of the testing session. The latency of the VOR measured from responses to steps of acceleration (3,000°/s2 reaching a velocity of 150°/s) was 8.4 ± 0.3 ms for responses to ipsilesional rotations and 7.7 ± 0.4 ms for contralesional rotations. During the period that animals were kept in darkness after the labyrinthectomy, the gain of the VOR measured during the steps of acceleration was 0.67 ± 0.12 for contralesional rotations and 0.39 ± 0.04 for ipsilesional rotations. Within 18-24 h after return to light, the VOR gain for contralesional rotations increased to 0.87 ± 0.08, whereas there was only a slight increase for ipsilesional rotations to 0.41 ± 0.06. A symmetrical increase in the gain measured at the plateau of head velocity was noted after the animals were returned to light. The VOR evoked by sinusoidal rotations of 2-15 Hz, ±20°/s, showed a better recovery of gain at lower (2-4 Hz) than at higher (6-15 Hz) frequencies. At 0.5 Hz, gain decreased symmetrically when the peak amplitude was increased from 20 to 100°/s. At 10 Hz, gain was decreased for ipsilesional half-cycles and increased for contralesional half-cycles when velocity was raised from 20 to 50°/s. A model incorporating linear and nonlinear pathways was used to simulate the data. Selective increases in the gain for the linear pathway accounted for the recovery in VOR gain for 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 contribution of the nonlinear pathway. This pathway was driven into cutoff and therefore did not affect responses for rotations toward the lesioned side.
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INTRODUCTION |
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Unilateral labyrinthectomy results in an
ablation of vestibular inputs from one labyrinth and leads to static
and dynamic signs of hypofunction in the angular vestibuloocular reflex
(VOR) (Baarsma and Collewijn 1975; Fetter and Zee
1988
; Maioli et al. 1983
; Vibert et al.
1993
). Spontaneous nystagmus is the static sign attributable to
semicircular canal dysfunction. The slow phase components of this
nystagmus in the horizontal plane are directed toward the lesioned
labyrinth. The dynamic signs differ according to the stimuli being used
to assess the function of the VOR. When lower frequency sinusoidal
stimuli are used, the performance of the VOR often recovers over time
and asymmetries (gain lower for rotations toward the lesioned side) are
only noted at higher rotational velocities (Fetter and Zee
1988
; Jenkins 1985
; Paige 1989
).
In contrast to the rather subtle changes in the VOR noted with less
dynamic stimuli, the responses to higher frequency and acceleration
rotations show an enduring response asymmetry. Rotations in the yaw
plane toward the lesioned side evoke a VOR with substantially lower
gain than those toward the intact side. These effects have been most
extensively documented in humans (Aw et al. 1996
;
Crane and Demer 1998
; Halmagyi et al. 1990
; Tabak et al. 1997
) but parallel findings
have been noted in guinea pigs after ablative vestibular lesions
(Gilchrist et al. 1998
).
Most previous studies have explored these asymmetries for responses to
rotations that have high peak velocity but relatively low frequency and
acceleration. Fetter and Zee (1988) identified asymmetries in the gain of the horizontal VOR evoked by steps of head
velocity after unilateral labyrinthectomy in rhesus monkeys. When
tested in darkness within 1 day after the lesion, gain was decreased by
~50% in comparison to preoperative values. As the peak velocity of
the stimulus was increased from 30 to 300°/s, the gain of the VOR for
ipsilesional rotations decreased progressively with increasing head
velocity. Similar findings also have been observed in cats
(Maioli et al. 1983
) and in humans (Paige
1989
; Tusa et al. 1989
) for responses to higher
velocity rotations. Asymmetries to analogous stimuli were noted in
squirrel monkeys after unilateral plugging of the horizontal canal
(Paige 1983b
). In each case, the findings have been
interpreted as a manifestation of Ewald's second law: lower gains to
ipsilesional rotations are thought to be due to inhibitory cutoff in
vestibular-nerve afferents and/or central vestibular neurons on the
contralateral side (Ewald 1892
).
The VOR in response to steps of acceleration
(2,000-4,000°/s2 for 40-70 ms) becomes
profoundly asymmetric after unilateral vestibular lesions. These
findings are evident at stimulus velocities that are lower than those
required to produce asymmetries to rotations of lower frequency and
acceleration. In a recent study of the horizontal VOR evoked by
high-frequency, high-acceleration rotations in squirrel monkeys,
Minor et al. (1999) showed that the reflex has inputs
from linear and nonlinear pathways. The nonlinear pathway is
responsible for a rise in the gain of the VOR with increasing frequencies and velocities of rotation. This pathway is rectified such
that there is inhibitory cutoff in its responses to stimuli >30°/s
for rotational frequencies
4 Hz. The gain of the nonlinear pathway is
selectively modifiable and accounts for the return of the
contralesional responses to normal levels after unilateral plugging of
the three semicircular canals (Lasker et al. 1999
). Recovery of gain for ipsilesional responses does not occur because the
nonlinear pathway on the intact side is driven into inhibitory cutoff
for these more dynamic stimuli.
The goal of this study was to define the dynamics of the horizontal VOR evoked by high-acceleration, high-frequency rotations in the yaw plane after unilateral labyrinthectomy. Our findings demonstrate asymmetries in the reflex similar to those we have reported after unilateral plugging of the three semicircular canals. In contrast to canal plugging, a large spontaneous nystagmus was noted after labyrinthectomy. This spontaneous nystagmus led to an offset in the eye-velocity responses and a bias velocity noted during the stimuli.
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METHODS |
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Surgical preparation
Surgery was done under sterile conditions in four adult squirrel
monkeys anesthetized with inhalation of halothane/nitrous oxide/oxygen. The techniques for implantation of the head
restraining bolt and eye coils have been described (Minor et al.
1999).
Labyrinthectomy was performed by making a postauricular incision and removing the mastoid bone with an otologic drill and curettes to expose the horizontal and posterior semicircular canals. The petrous bone was removed further anteriorly and superiorly to visualize the superior canal near its union with the common crus. Each of the semicircular canals then was obliterated with removal of the ampulla. The vestibule was entered, and the utriculus and sacculus were removed. The internal auditory canal was opened next, and the distal ends of the ampullary nerve branches were removed. The space created by the labyrinthectomy was packed with muscle and fascia and the postauricular incision was closed.
Eye-movement recordings
The experimental procedures used for recording eye movements
were identical to those that have previously been described for this
laboratory (Minor et al. 1999). Each animal was seated
in a plastic chair with its head restrained by securing the implanted bolt to a chair-mounted clamp. The chair was connected to a
superstructure that was mounted to the top surface of a
servo-controlled rotation table capable of generating a peak torque of
125 N-m (Acutronic, Pittsburgh, PA). The horizontal VOR was tested with
the animal seated in the upright position in the superstructure and
aligned such that the horizontal canals were in the earth-horizontal
plane of rotation.
Two pairs of field coils, each with a side length of 45 cm, were
rigidly attached to the superstructure and moved with the animal.
Voltages induced in the scleral search coils were monitored by a
detection circuit (Remmel Labs) that extracted signals proportional to
horizontal and vertical eye position. The peak-to-peak noise at the
output of the circuit was equivalent to an eye movement of 0.02°. All
signals transducing motion of the head or the eye were passed through
eight-pole Butterworth anti-aliasing filters with a corner frequency of
100 Hz. These signals then were digitized with a sampling rate of 1,000 Hz for acceleration steps and sinusoidal rotations at frequencies 2
Hz. A sampling rate of 200 Hz was used for sinusoidal rotations <2 Hz.
The eye-coil system was calibrated in two ways. A search coil identical
to the one implanted about each eye was placed in a gimbal located
where the animal's head was positioned in the field coil. This search
coil then was moved to angles of 5, 10, and 15° right-left and
up-down with respect to center and calibration factors relating volts
to degrees were determined. The second method involved sinusoidal
rotation of the animal in light at 0.5 Hz, ±60°/s, a stimulus in
which the gain of the visual-vestibuloocular reflex has been shown to
be 1.0 (Minor and Goldberg 1990; Paige 1983a
). Calibration factors obtained from these methods
typically agreed to within 5%. The center of the oculomotor range that
corresponded to straight-ahead horizontal eye position was determined
from the midposition of the responses to the sinusoidal rotations in light. These calibrations initially were made in the animals before labyrinthectomy and were shown to be constant from one experimental session to the next.
Measurement of spontaneous nystagmus
The animals were kept in darkness for 4 days after
labyrinthectomy. There were no restrictions on their movement at any
time after the procedure. The spontaneous nystagmus was measured in five testing sessions after the labyrinthectomy: 8-18 h and 3 days
(while animals were still in darkness), 1 day after animals had been
returned to normal light-dark cycles, and days 10 and 21 after the procedure. Spontaneous nystagmus was evaluated
at two points during each recording session. The first measurement was
before delivery of any motion stimuli after the animals had been seated
in a primate chair with their heads stationary for 15-20 min. The
second measurement was at the end of the recording session after a
30-min period of motion stimuli consisting of sinusoidal rotations and
steps of acceleration. The assessment of the spontaneous nystagmus at
the end of the recording session was 1 min after the delivery of the
previous rotational stimulus. The room lights had been off for
15 s
before the recording of the spontaneous nystagmus in darkness.
Rotational testing
Responses to steps of acceleration (3,000°/s2 acceleration to a peak velocity of 150°/s followed by a plateau of head velocity lasting 0.9-1.1 s and then deceleration to rest) were recorded with animals in darkness. The acceleration magnitude, direction, duration, and interstimulus interval were varied randomly from one trial to the next.
Sinusoidal head rotations (0.5-15 Hz, peak velocity 20-150°/s) were given with animals in darkness. Each stimulus frequency was given for 60 s. The order in which different frequencies and velocities were tested was varied.
Data analysis
The data were analyzed off-line using software that we wrote in
the Matlab (The Math Works) programming environment. The methods of
analysis are similar to those that we have described previously (Lasker et al. 1999; Minor et al. 1999
).
ACCELERATION STEPS. The eye-position data first were passed through a 50-point, finite-impulse-response filter with a corner frequency of 100 Hz (to calculate latency) or 40 Hz (to assess dynamics of the response). Eye velocity was obtained from a seven-point central difference algorithm. The data from 10 to 30 trials in each direction were averaged to obtain a representation of the response. All data were taken before the first fast phase of the eye-velocity response.
Response latency was measured by a method that determined the onset of head and eye movements as the points at which the velocity signals deviated from the mean value measured before the onset of the stimulus for head and eye velocity, respectively, by >3 SD. The difference in these two onset points measured for each trial was defined as response latency (Minor et al. 1999SINUSOIDAL ROTATIONS.
Eye-position data were differentiated with a four-point central
difference algorithm to obtain eye velocity. Saccades were removed from
responses at frequencies <4 Hz, and an average cycle was obtained
based on the data representing slow phase eye velocity at each point in
time. Responses at frequencies 4 Hz were not desaccaded, and only
cycles without saccades were included in the analysis. Successive
cycles (5-10 at 0.5 Hz, 10-35 at 2-6 Hz, and 25-75 at 8-15 Hz)
were averaged. The amplitude and phase of the response fundamental were
obtained from a Fourier analysis as were the corresponding values for
the head-velocity signal. Gains and phases for eye with regard to head
velocity were expressed with the convention that a unity gain and zero
phase imply a perfectly compensatory VOR. A negative phase indicates
that eye movements lag head movements.
Modeling of the VOR
Mathematical models of the VOR were formulated in Simulink (The Math Works). The Dormand-Prince method with a fixed step size of 0.0001 s was used for simulation of the ordinary differential equations. Fourier analysis was used to calculate gain and phase of the simulated responses to sinusoidal inputs.
Statistical analysis
Results were described as means ± SD. Data from two groups were compared with an unpaired t-test. ANOVA was used to compare data from more than two groups.
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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 labyrinthectomy. The labyrinthectomy was performed on the right in two animals (M798 and M1308) and on the left in the other two animals (M243 and C86). The animals were kept in darkness for 4 days after the labyrinthectomy and were tested 8-18 h after the procedure and again on day 3. They then were brought into the light and tested on day 1 after being in the light as well as days 10 and 21 after the labyrinthectomy. Unless otherwise noted, all responses were measured in darkness.
Spontaneous nystagmus
A spontaneous nystagmus with slow phase components directed toward the side of the lesion was noted in each of the animals after labyrinthectomy. When evaluated 8-18 h after the labyrinthectomy (day 1 dark), the velocity of the horizontal spontaneous nystagmus (measured as the average velocity during the slow phases) was 17.3 ± 7.8°/s at the beginning of the testing session and 17.6 ± 8.6°/s (P > 0.90) at the end. The nystagmus at the beginning and end of the testing session at day 3 after labyrinthectomy (day 3 dark) was 16.7 ± 11.0 and 23.2 ± 17.4°/s, respectively (P > 0.64). After animals were returned to light, the amplitude of the spontaneous nystagmus at the beginning of the recording session was decreased substantially. On the first day after return to light (day 1 light), the spontaneous nystagmus at the beginning of the recording session was 2.8 ± 1.5°/s (P < 0.01 with respect to measurements made when animals had been kept in darkness). In contrast, the spontaneous nystagmus at the end of this recording session was 20.3 ± 3.9°/s, significantly larger than that measured at the beginning of the session (P < 0.01) and not different from that recorded before the animal was returned to light (P > 0.80). This difference in the slow-phase velocity of the nystagmus measured at the beginning and end of the recording session also was present at day 10 after the labyrinthectomy (4.7 ± 2.2°/s beginning, 17.2 ± 7.6°/s end, P < 0.02).
In three of the four animals (M798, M1308, and M243) the slow-phase components of the spontaneous nystagmus evaluated 8-18 h after labyrinthectomy showed an increase in eye velocity during the course of each slow-phase component (Fig. 1, A and B). The acceleration of the eye during the slow phase in these three animals measured 294.9 ± 168.1°/s2 when evaluated 8-18 h after labyrinthectomy. Eye velocity did not vary during the course of the slow-phase components in C86. Although there was considerable variability in the trajectory of the slow phases of the spontaneous nystagmus after the first testing session, the trend was for acceleration component of the slow phases to decrease with time. When data from the three animals were pooled across all days after the first testing session, the acceleration of the eye during the spontaneous nystagmus measured 109.9 ± 86.8°/s2 (P < 0.02, with respect to values obtained 8-18 h after labyrinthectomy).
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Steps of acceleration
The gain of the VOR measured during the period of the acceleration and at the velocity plateau of the stimulus was decreased after labyrinthectomy. Responses measured during the period of the acceleration had a lower gain for ipsilesional in comparison to contralesional rotations (Fig. 2).
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GA for ipsilesional rotations (GA-ipsi) when measured 3 days after labyrinthectomy, while animals were still being kept in darkness, was 0.39 ± 0.04. GA for contralesional rotations (GA-contra) measured at the same time was 0.67 ± 0.12 (P < 0.02). In contrast, GV measured at the velocity plateau of these same stimuli was symmetric for ipsilesional (GV-ipsi) and contralesional (GV-contra) rotations: 0.38 ± 0.02 and 0.44 ± 0.08, respectively (P > 0.3).
The asymmetry in values of GA became larger when tested 18-24 h after return to light (day 1 light): GA-ipsi = 0.41 ± 0.06 and GA-contra = 0.87 ± 0.08 (P < 0.0001). This asymmetry continued to grow with time after labyrinthectomy due primarily to an increase in GA-contra. On day 10 after labyrinthectomy, GA-contra = 1.04 ± 0.07 and GA-ipsi = 0.44 ± 0.08 (P < 0.001). The values of GA-contra were larger on day 10 than on day 3 after labyrinthectomy (P < 0.01). In contrast, the values of GA-ipsi were unchanged on day 10 in comparison to day 3 after labyrinthectomy (P > 0.4). The asymmetry in GA-contra and GA-ipsi was still present at day 21 after labyrinthectomy: 1.01 ± 0.22 and 0.52 ± 0.03, respectively (P < 0.02). One animal, M243, was tested on day 66 after labyrinthectomy. In this testing session, GA-contra = 0.89 ± 0.20 and GA-ipsi = 0.48 ± 0.08 (P < 0.0001).
The values of GV increased acutely after animals were brought into light but remained relatively constant thereafter. There was no asymmetry in values of GV during any of the testing sessions after labyrinthectomy. When tested 8-18 h after the lesion, while animals were still in darkness, GV-contra = 0.44 ± 0.08 and GV-ipsi = 0.38 ± 0.03 (P > 0.25). On day 1 after animals had been returned to light, GV-contra = 0.53 ± 0.03 and GV-ipsi = 0.52 ± 0.11 (P > 0.85). At day 21, GV-contra = 0.57 ± 0.03, GV-ipsi = 0.59 ± 0.05 (P > 0.6).
There was an increase in values of GV
when animals were returned to light after labyrinthectomy. To evaluate
changes in GV over time after the
lesion, we pooled data for GV-ipsi and
GV-contra obtained at the same testing
session. GV for day 1 dark
and day 1 light was 0.41 ± 0.06 and 0.53 ± 0.07, respectively (P < 0.02). At day 21, GV was 0.58 ± 0.04 (P = 0.17 when compared with day 1 light).
Thus most of the recovery in GV
occurred within the first day after animals were brought into light.
The data for GA and
GV at intervals 21 days after
labyrinthectomy are shown in Fig. 3.
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Latency
Figure 4 shows the initial responses evoked by ipsilesional and contralesional rotations at day 10 after labyrinthectomy. Table 1 presents the values of VOR latency calculated from the steps of acceleration at various times after labyrinthectomy in the four animals. There were no differences between the measures at specific times after labyrinthectomy 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 7.7 ± 0.4 ms, and the ipsilesional latency measured 8.4 ± 0.3 ms (P < 0.05).
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Fits to steps of acceleration
CONTRALESIONAL. The gain of the VOR was noted to increase with head velocity after the labyrinthectomy. Responses to contralesional rotations were analyzed with linear and cubic fits as described in METHODS. Table 2 gives the values for the coefficients of the terms for each of these fits. Figure 5 shows a plot of these responses at day 10 in M1308.
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IPSILESIONAL. The responses to ipsilesional, in contrast to contralesional, rotations showed no increase in gain with velocity. In fact, for all of the testing sessions (day 1 in the dark; days 1, 10, and 21 in the light), there was a decrease in the gain with increasing stimulus velocity. To quantify these responses, we fit the ipsilesional data obtained from these 4 days with a hyperbolic tangent optimized to fit the trajectory of the relationship between eye and head velocity (Fig. 6). The coefficients of this equation varied in accord with the day on which the data were obtained (Table 3). These findings indicate that the ipsilesional response becomes more linear with time after labyrinthectomy.
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Responses to sinusoidal rotations
Figure 7 displays the gain and phase plots of responses to sinusoidal rotations (0.5-15 Hz, ±20°/s) measured while animals were in darkness 8-18 h after unilateral labyrinthectomy, day 1 after the return to light, and days 10 and 21 after the lesion.
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A bias velocity was noted in the responses to sinusoidal rotations. It was manifested as a DC shift in the eye-velocity record in the direction of the slow-phase components of the spontaneous nystagmus. There appeared to be an interaction between the bias component and the sinusoidal response for 2-Hz rotations. This interaction was most pronounced during the testing session performed 8-18 h after the labyrinthectomy, while animals were still in darkness (Fig. 8, A and B). Note that the fast phases in the eye-velocity record occur at a fixed location in the stimulus. Removal of these fast phases gave a record that was incomplete and distorted. For this reason, data from responses to the 2-Hz stimulus at 8-18 h after labyrinthectomy were not included in Fig. 7. Although the profile of the response was less distorted after the animals were returned to light, there appeared to be an interaction between the bias velocity and the gain of the response (Fig. 8, C and D). To test this hypothesis, we summed the spontaneous nystagmus (with slow- and fast-phase components) measured on the same day and in the same animal with a sinusoidal waveform (2 Hz, ±20°/s; Fig. 8, E and F). In this summed response, the gain for ipsilesional half cycles was 1.20 ± 0.25, whereas that for contralesional half cycles was 1.29 ± 0.29. Had there been no interaction between the spontaneous nystagmus and the stimulus, a sinusoidal response with a gain of 1.0 would have been expected from the addition of these signals. This was the only frequency where such interactions were noted.
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The bias velocity for the stimuli used in this study did not vary in relation to the stimulus frequency (P > 0.6), amplitude (P > 0.3) or to the time after labyrinthectomy (P > 0.14). When responses to different stimuli and velocities were pooled, the bias velocity measured 19.4 ± 11.0 (day 1 dark), 14.2 ± 13.7 (day 1 light), 18.0 ± 7.8 (day 10), and 12.8 ± 5.8°/s (day 21). The average bias velocity over these 4 days of testing was 16.1 ± 3.1°/s. The spontaneous nystagmus recorded at the end of the testing sessions on these dates measured 19.4 ± 1.2°/s, which was not different from the bias velocity (P > 0.10). The bias velocity showed changes similar to those observed for the spontaneous nystagmus during the course of the testing sessions after animals were returned to light. It was larger for stimuli delivered near the end in contrast to the beginning of the testing session for day 1 in the light and for days 10 and 21 after labyrinthectomy (P < 0.005).
The gain of the VOR increased over time after the labyrinthectomy. While animals were still in darkness 8-18 h after the lesion, the gain was 0.47 ± 0.03 for frequencies ranging from 4 to 15 Hz. These gains did not change with respect to individual frequency (P > 0.7). The reduction in gain compared with prelesion values was 44 ± 4%. Gain increases were noted after the animals were returned to light. A larger gain was measured at 2 and 4 Hz in comparison with higher frequencies for responses evaluated on days 10 and 21 after labyrinthectomy. We pooled the data from days 10 and 21 to evaluate the effect of frequency of stimulation on gain. The gain values for responses to 2 and 4 Hz rotations were 0.73 ± 0.09 and 0.75 ± 0.06, respectively (P > 0.7). The gain of the response decreased as frequency was increased: 0.67 ± 0.09 at 6 Hz and 0.59 ± 0.05 at 15 Hz (P < 0.05 with respect to gains at 2 and 4 Hz). There was no difference in gain over the range of 6-15 Hz (P > 0.55).
The phase of the VOR when animals were still in darkness showed a lag
that increased with frequency to reach 9.3 ± 3.6° at 15 Hz
(Fig. 7). This lag at higher frequencies increased after animals were
returned to light. At day 21 after the lesion, the phase at
15 Hz measured
20.2 ± 6.0°. There were no differences at any
frequency between the phase data at days 10 and
21 (P > 0.4). The data from these 2 days
were pooled to develop a comparison with data obtained in darkness. An
increase in lag was noted at frequencies of 6-15 Hz when the pooled
data from days 10 and 21 were compared with the
data obtained in darkness (P < 0.03).
The following first-order transfer function was derived from a
least-squares fit to the data pooled for days 10 and
21
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(1) |
Differences in gains for ipsi- and contralesional half-cycles were compared for each frequency and day after the lesion (Fig. 9). The differences reached significance at individual frequencies and testing sessions only for 12 Hz at day 1 after return to light (P < 0.009) and at 15 Hz at day 10 (P < 0.03). The asymmetry, defined as the difference between ipsi- and contralesional gains divided by the sum of these gains, did not change with time after labyrinthectomy at any frequency (P > 0.4). We compared the asymmetry at different frequencies and testing sessions after the data for different days had been pooled. Half-cycle asymmetry measured 0.08 ± 0.02 and did differ with respect to frequency for responses at 2-15 Hz (P > 0.12). In contrast, the half-cycle asymmetry measured 0.01 ± 0.01 at 0.5 Hz, which was lower than that measured over the range of 2-15 Hz (P < 0.03). These findings indicate that, even for the responses to 20°/s rotations, there is a small half-cycle asymmetry at higher frequencies that is not observed at lower ones.
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Half-cycle asymmetries were dependent on stimulus frequency and velocity (Fig. 10). These comparisons were made on data pooled from days 10 and 21. Larger half-cycle asymmetries were noted for responses to higher frequency and velocity stimuli. At 4 Hz, ±100°/s, contralesional gain was 0.69 ± 0.14 and ipsilesional gain was 0.53 ± 0.06 (P < 0.05). This half-cycle asymmetry was not significant at 4 Hz, ±20°/s. At this lower stimulus velocity, the gain of the contra- and ipsilesional half-cycles was 0.74 ± 0.07 and 0.69 ± 0.05 (P > 0.55), respectively. A similar pattern was noted for the responses to 10-Hz rotations. At 10 Hz, ±20°/s, contralesional half-cycle gain was 0.58 ± 0.11, whereas ipsilesional half-cycle gain was 0.55 ± 0.07 (P > 0.7). The half-cycle asymmetry rose with increasing stimulus amplitude at 10 Hz. At 10 Hz, ±50°/s, contra- and ipsilesional half-cycle gains were 0.76 ± 0.03 and 0.55 ± 0.07, respectively (P < 0.04).
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In contrast to these findings at higher frequencies, at 0.5 Hz there was a decline in both contra- and ipsilesional gain as stimulus velocity increased from 20 to 100°/s. At 0.5 Hz, ±20°/s, contralesional gain was 0.59 ± 0.07 and ipsilesional gain was 0.59 ± 0.10 (P > 0.9). At 0.5 Hz, ±100°/s, contralesional gain was 0.44 ± 0.02 and ipsilesional gain was 0.46 ± 0.04 (P > 0.3). The data for contra- and ipsilesional half-cycle gains for 20 and for 100°/s were pooled. Contralesional and ipsilesional gains were lower at 100°/s than at 20°/s (P < 0.001).
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DISCUSSION |
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Asymmetries after unilateral labyrinthectomy
There are many similarities in the changes we observed after
unilateral labyrinthectomy and those that we have reported after unilateral canal plugging (Lasker et al. 1999). The
asymmetry in values of GA for
ipsilesional in comparison with contralesional steps of acceleration is
similar, as is the slightly longer latency for ipsilesional responses.
There was no asymmetry in GV measured at the plateau of the stimulus for either lesion. Responses to sinusoidal rotations at 2-15 Hz, ±20°/s showed a comparable
reduction in gain, but only a slight asymmetry, after each lesion.
Important differences in the effects of labyrinthectomy and canal
plugging on the horizontal VOR also were noted. Spontaneous nystagmus
was much greater after labyrinthectomy and resulted in a bias velocity
noted in the responses to sinusoidal rotations after this lesion. The
bias velocity altered dynamics of the response at 2 Hz after
labyrinthectomy. The time course of recovery for responses to steps of
acceleration toward the intact side was longer after labyrinthectomy
than after canal plugging. The ipsilesional responses had a trajectory
that was fit by a hyperbolic tangent function for 21 days after the
labyrinthectomy whereas this trajectory was only noted after return to
light in one of the four animals that underwent unilateral canal
plugging (Lasker et al. 1999
). Sinusoidal responses
to higher velocity rotations also differed for the two lesions. A
larger reduction in gain at higher velocities was noted after
labyrinthectomy in comparison to canal plugging.
These asymmetries for responses to steps of acceleration are similar to
those that have been observed in humans (Aw et al. 1996;
Halmagyi et al. 1990
) and in guinea pigs
(Gilchrist et al. 1998
) after ablative vestibular
lesions. The mechanism responsible for the asymmetry appears to be
fundamentally different from the inhibitory cutoff in responses of
vestibular-nerve afferents and/or central VOR interneurons (Ewald's
second law) that has been assumed to be the cause of the asymmetries at
lower frequencies and higher velocities (Fetter and Zee
1988
; Paige 1983b
, 1989
). For the responses in
our study, GA was significantly larger
for contralesional than for ipsilesional rotations yet there was no
asymmetry in GV measured once the
stimulus had reached a plateau of head velocity. If the asymmetry was
solely dependent on stimulus velocity, then
GV should have been more asymmetric
than GA because head velocity was
higher at the velocity plateau than during the period of acceleration.
Similar asymmetries for ipsi- and contralesional responses after
unilateral labyrinthectomy or plugging of the horizontal canal in cats
recently have been reported by Broussard et al. (1999a,b
). Their studies utilized steps of acceleration that
were lower in amplitude (50-750°/s2 reaching a
velocity plateau of 15-50°/s) than those we have used. Ipsi- and
contralesional half-cycle gains also were measured for sinusoidal
rotations
8 Hz with a peak velocity of 10°/s. The asymmetry between
contra- and ipsilesional responses to steps of acceleration was larger
than that observed at the plateau of head velocity. For responses to
sinusoidal rotations, the half-cycle asymmetry (due to a rise in
contralesional half-cycle gain) was noted to increase with frequency
while stimulus velocity was maintained constant. These findings in the
cat provide further support for the notion that a nonlinear component
of the reflex dynamics, present for excitation and absent for
inhibition, is responsible for the rise in contralesional gain after
labyrinthectomy or canal plugging.
Spontaneous nystagmus
A spontaneous nystagmus with slow-phase components directed toward
the side of the lesion was noted immediately after labyrinthectomy and
persisted throughout the time the animals were followed afterward. The
velocity of this nystagmus was somewhat lower than that observed in the
rhesus monkey after unilateral labyrinthectomy (44°/s) (Fetter
and Zee 1988). In the case of both species, it is clear that a
strong process that balances inputs from the two sides centrally must
be present from a very early time after the lesion. The following
considerations support this concept. Regularly discharging afferents
are known to provide the principal inputs to the VOR for stimuli of low
to mid frequencies and velocities (Minor and Goldberg
1991
). If the spontaneous nystagmus is due mainly to an
imbalance in activity from regular afferents between the two sides,
then the predicted velocity should be given by
EV = FR/RS, in which the
average rotational sensitivity (RS) of
regular afferents is ~0.3 spikes · s
1/deg · s
1 and the mean firing rate
(FR) is ~90 spikes/s
(Goldberg and Fernández 1971
; Lysakowski et
al. 1995
). Thus the predicted slow phase eye velocity
(EV) would be ~300°/s,
considerably greater than that observed in any species after such a lesion.
The trajectory of the slow phases of the nystagmus recorded while
animals were still in darkness after the lesion showed a rising
velocity profile. There are at least two possible explanations for this
finding. First, the static imbalance in vestibular activity brought
about by the labyrinthectomy may have resulted in an unstable velocity-to-position integrator (Cannon and Robinson
1987; Kramer et al. 1995
). Second, the slow
phase trajectories may have been influenced by the dynamics of the
inhibitory process that reduces the asymmetry in the resting rates of
central vestibular neurons immediately after the lesion.
The spontaneous nystagmus, tested in darkness, after animals were
returned to light was greater when measured at the end in comparison to
the beginning of each testing session. This effect indicates that the
asymmetry in resting rates between central vestibular neurons on the
contra- and ipsilateral sides after labyrinthectomy is enhanced after
rotational stimulation. Such a finding could occur because rotations
cause a reduction in the inhibition that is responsible for minimizing
the spontaneous nystagmus after the lesion (McCabe and Ryu
1969; Newlands and Perachio 1990
). The increase
in spontaneous nystagmus after head rotations is reminiscent of the
head-shaking induced nystagmus that has been reported in patients with
unilateral vestibular hypofunction (Hain et al. 1987
).
Changes in the dynamics of the horizontal VOR after unilateral labyrinthectomy
LATENCY.
Our findings after unilateral labyrinthectomy are similar to those
reported after unilateral plugging of the three semicircular canals
(Lasker et al. 1999). The striking observation is that the VOR latency, which measures 7.3 ± 1.5 ms for animals with intact vestibular function, changes little after unilateral
labyrinthectomy. Thus loss of half of the total population of inputs to
this push-pull system has little effect on the initiation of the
reflex. The VOR latency was slightly longer for ipsi- than for
contralesional rotations. This difference could be related to the lower
gain of the VOR for rotations toward the lesioned side. The overall similarity in the VOR latency before and after unilateral
labyrinthectomy means that the initiation of the reflex is sensitive to
inhibitory as well as excitatory modulation. Unlike the VOR gain and
phase, the latency did not change with time after the lesion. This
finding suggests that vestibular compensation occurs independently from signals conveying the onset of head rotation.
RESPONSES TO STEPS OF ACCELERATION. Many aspects of the responses after unilateral labyrinthectomy were similar to those observed after unilateral canal plugging. The overall decrease in GA and GV immediately after each lesion was ~50%. A similar asymmetry for both lesions in the values of acceleration gain (GA-contra was 30-40% > GA-ipsi) was noted after animals were returned to light. Polynomial fits to the data showed that the gain enhancement of GA-contra after return to light was caused by a nonlinear increase in gain with head velocity. There was no evidence for this nonlinear increase in gain in GA-ipsi after either lesion. GA-ipsi showed a profile of saturation for head velocities >30°/s for day 1 in the dark. This saturation decreased over the course of time after animals were returned to light. There was effectively no asymmetry between values of GV-contra and GV-ipsi at any day tested after either canal plugging or labyrinthectomy.
The most striking difference between unilateral labyrinthectomy and unilateral canal plugging for responses to steps of acceleration was the time course for recovery of gain. The first term for the cubic fit to GA-contra after labyrinthectomy was smaller [(1.40 ± 0.61) × 10RESPONSES TO SINUSOIDAL ROTATIONS.
A bias velocity, manifested during the stimulus as a DC shift in the
eye-velocity record in the direction of the slow-phase components of
the spontaneous nystagmus, was noted in the responses after
labyrinthectomy. This bias velocity could vary considerably in
amplitude between trials but did not differ from the spontaneous nystagmus measured near the end of each testing session. Unlike the
spontaneous nystagmus, bias velocity did not change during the course
of a testing session. For rotations at 2 Hz on day 1 in the
dark, the bias velocity with associated slow- and fast-phase components
appeared to distort the response to the rotation in that there were
fast phases of nystagmus that were phase locked to the frequency of the
stimulus. There appeared to be an interaction between the gain of
responses to 2-Hz rotations and the bias velocity at this frequency
when examined on other testing sessions. This interaction increased the
apparent overall gain of the response at that frequency and was evident
when a comparison was made between responses that were simulated (by
the addition of a spontaneous nystagmus with slow- and fast-phase
components to a sinusoidal input) and those that were recorded at 2 Hz
(see Fig. 8). The factors that may have influenced this interaction
include the temporal sequencing of the fast phases relative to the
stimulus and the influence of fast phases on the dynamics of slow
phases (Galiana 1991).
RELATIONSHIP TO STUDIES OF SINGLE-UNIT PHYSIOLOGY.
Recordings of single-unit activity in the vestibular nuclei after
unilateral labyrinthectomy provide some useful insights into the
changes in neuronal activity that may underlie these effects on the
VOR. The resting rate of Type I, horizontal canal-related central
vestibular neurons decreases from ~40 spikes/s before the lesion to
<10 spikes/s immediately afterwards in gerbils (Newlands and
Perachio 1990) and in guinea pigs (Ris et al.
1995
). There is a reciprocal rise in resting rate of Type I
neurons contralateral to the side of the lesion (Ris and Godaux
1998
). Resting rates in the ipsilateral and contralateral
vestibular nuclei return to control values within 1 wk after the
lesion. In contrast, the sensitivity to head velocity of Type I neurons
in the ipsi- and contralateral vestibular nuclei decreases after
unilateral labyrinthectomy with a gradual, although incomplete,
recovery over 1 wk (Ris and Godaux 1998
; Ris et
al. 1995
). These changes parallel the resolution of the
spontaneous nystagmus and the gradual recovery in responses mediated by
the linear pathway. Sinusoidal rotational stimuli of relatively low
frequency and velocity (0.1-1.3 Hz, peak velocity = 20-50°/s)
were used in these previous studies. Effects of the nonlinear pathway
were not observed
probably because the stimuli were not of sufficient
frequency, acceleration, and velocity.
Modeling of asymmetries in the VOR after labyrinthectomy
Figure 11 shows a bilateral model
of the VOR that we used to simulate the asymmetries in ipsi- and
contralesional responses after labyrinthectomy. This model is similar
to the one we described in our previous study of asymmetries after
unilateral plugging of the three semicircular canals (Lasker et
al. 1999). We propose that inputs to the reflex come from
linear and nonlinear pathways. The linear pathway confers the dynamics
of the reflex responses to sinusoidal rotations over the frequency
range of 0.5-15 Hz at 20°/s peak stimulus velocity. This pathway is
also responsible for the linear component of the polynomial fit to the
responses for steps of acceleration. The nonlinear pathway confers the
frequency- and velocity-dependent increase in gain noted in the
sinusoidal responses and manifested in the coefficients for the
higher-order polynomial fits.
|
The larger asymmetry between ipsi- and contralateral values of GA in comparison with GV can be understood in terms of the contributions of the linear and nonlinear pathways to the responses. The higher values of GA-contra in comparison with GA-ipsi are due to inhibitory cutoff of the nonlinear pathway on the intact side in response to rotations toward the lesioned side. The nonlinear pathway is inherent in the dynamics of the horizontal VOR for responses to high-frequency, high-acceleration rotations (such as during the 3,000°/s2 acceleration). The nonlinear pathway makes up ~20-30% of the response during this step of acceleration. Values of GA-contra are higher than those for GA-ipsi because the nonlinear pathway on the intact side is responding in an excitatory direction for rotations toward the intact side. The nonlinear pathway makes little contribution to the response at the velocity plateau of the stimulus. Values of GV are almost exclusively determined by dynamics of the linear pathway. Responses of the linear pathway from the intact side are relatively symmetric for excitation and inhibition. Thus GV-ipsi and GV-contra show little asymmetry.
There are two main differences in the model of the linear pathway after
labyrinthectomy in comparison with that used to describe the data after
canal plugging. First, a transfer function was fit (Fig. 11) to the
sinusoidal data at 20°/s and placed in the linear pathway to model
the changes noted with time and frequency of rotation after animals
were returned to light (i.e., frequencies at 2-4 Hz recover better
than 6-15 Hz). Second, a least-squares fit analysis was used to fit a
sigmoidal function to the data at 0.5 Hz, ±20 and ±100°/s. This
function provides a representation of the saturation noted for
rotations at higher velocities. This equation was of the following
form:
![]() |
(2) |
Because we were concerned mainly in modeling asymmetries that persist
after a unilateral vestibular lesion, we used data from 10 days after
labyrinthectomy to determine the coefficients of this equation. To
simulate the effects of the lesion, we removed the inputs from one side
and decreased the spontaneous rate of central vestibular neurons on the
lesioned side from 90 to 80 spikes/s. This asymmetry in spontaneous
rate between the ipsi- and contralesional vestibular nuclei will lead
to a spontaneous nystagmus that is close to the value we measured
(20°/s). We could account for the increases observed in responses
over time after labyrinthectomy by adjusting the central gain elements
in the linear and nonlinear pathways
(kl and
kn).
Because there was no manifestation of the nonlinear pathway for
ipsilesional rotations after labyrinthectomy, we propose that this
pathway was driven into inhibitory cutoff for velocities of ~30°/s.
This cutoff point is predicted based on the sensitivity of units in the
nonlinear pathway (pn1 = 3.0 spikes · s1/deg · s
1). On the basis of this premise of inhibitory
cutoff for the nonlinear pathway, the gains for the ipsilesional
responses were used to specify kl, the
central gain element for the linear pathway. The data support the
conclusion that the gain of the linear pathway (kl) is symmetric for rotations in
each direction. The gain of the nonlinear pathway
(kn) then was calculated from the
third-order coefficient of the fits to the contralesional responses.
The gain and phase plot of the simulated responses at day 10 after labyrinthectomy is shown in Fig.
12A. The increase in gain for contralesional responses was accounted for by an increase in
kn from 1.0 × 105 before to 2.5 × 10
5 after labyrinthectomy. The value of
kl was raised from 1.0 before to 1.20 after labyrinthectomy. The increase in
kl occurred more gradually and was
responsible for the increase in gain at lower frequencies and
velocities that occurred with time after the lesion.
|
Figure 12, B and C, shows a comparison of the data and simulations at 4 Hz, ±100°/s plotted as eye versus head velocity at day 10 after unilateral canal plugging and labyrinthectomy, respectively. After canal plugging, there was an increase of gain with rising head velocity in the contralesional direction that was not as apparent after labyrinthectomy. We propose that, at least at 4 Hz, this rise in gain with stimulus velocity for contralesional half-cycles after canal plugging is effectively canceled by saturation of the linear pathway.
The response of the model to steps of acceleration at 3,000°/s with the same coefficients developed from the sinusoidal data are shown in Fig. 13. Although the contralesional gain (0.78) is higher than the ipsilesional gain (0.45), it is not as high as predicted by the data (0.9-1.0). This finding suggests that the nonlinearity is more sensitive to transient than steady-state motion. There are two possible ways that this behavior could be manifested. First, the saturation that is seen during the sinusoidal rotations might not be as prominent during the responses to steps of acceleration. Second, the steps of acceleration may be more effective for eliciting the nonlinearity than are the sinusoidal rotations.
|
Properties of the stimuli or the nonlinearities in the neuronal
responses to the stimuli we have used may be responsible for these
differences in responses to steps of acceleration and sinusoidal rotations. The frequencies encompassed by the steps of acceleration include 8-12 Hz with peak velocities in the range of 100-150°/s (Minor et al. 1999). These peak velocities are higher
than those that our rotation system is capable of delivering at these
high frequencies. Vestibular-nerve afferents and/or central vestibular neurons may be more sensitive to steps of acceleration than to sinusoidal rotations. More information is needed about the response dynamics of these neurons to the stimuli that we have shown to be
important in eliciting the asymmetries.
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ACKNOWLEDGMENTS |
---|
We thank P. D. Cremer 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 and T32 DC-00027, 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 |
---|
Address for reprint requests: L. B. Minor, Dept. of
OtolaryngologyHead and Neck Surgery, Johns Hopkins University School
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 18 October 1999; accepted in final form 27 December 1999.
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REFERENCES |
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