1Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110; 2Department of Otolaryngology, University of Texas Medical Branch, Galveston, Texas 77555; and 3Department of Research, Central Institute for the Deaf, St. Louis, Missouri 63110
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ABSTRACT |
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Angelaki, Dora E., Shawn D. Newlands, and J. David Dickman. Primate Translational Vestibuloocular Reflexes. IV. Changes After Unilateral Labyrinthectomy. J. Neurophysiol. 83: 3005-3018, 2000. The effects of unilateral labyrinthectomy on the properties of the translational vestibuloocular reflexes (trVORs) were investigated in rhesus monkeys trained to fixate near targets. Translational motion stimuli consisted of either steady-state lateral and fore-aft sinusoidal oscillations or short-lasting transient displacements. During small-amplitude, steady-state sinusoidal lateral oscillations, a small decrease in the horizontal trVOR sensitivity and its dependence on viewing distance was observed during the first week after labyrinthectomy. These deficits gradually recovered over time. In addition, the vertical response component increased, causing a tilt of the eye velocity vector toward the lesioned side. During large, transient lateral displacements, the deficits were larger and longer lasting. Responses after labyrinthectomy were asymmetric, with eye velocity during movements toward the side of the lesion being more compromised. The most profound effect of the lesions was observed during fore-aft motion. Whereas responses were kinematically appropriate for fixation away from the side of the lesion (e.g., to the left after right labyrinthectomy), horizontal responses were anticompensatory during fixation at targets located ipsilateral to the side of the lesion (e.g., for targets to the right after right labyrinthectomy). This deficit showed little recovery during the 3-mo post-labyrinthectomy testing period. These results suggest that inputs from both labyrinths are important for the proper function of the trVORs, although the details of how bilateral signals are processed and integrated remain unknown.
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INTRODUCTION |
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Translational vestibuloocular reflexes (trVORs)
are elicited in response to translational head displacements. Even
though trVOR responses are either absent or rudimental in lateral-eyed species (Baarsma and Collewijn 1975; Dickman and
Angelaki 1999
; Hess and Dieringer 1991
), they
constitute a robust pattern of highly specific and geometrically
complex eye movement responses in primates and humans (Angelaki
and McHenry 1999
; Angelaki et al. 2000b
;
McHenry and Angelaki 2000
; Paige and Tomko
19991a
,b
; Schwarz and Miles 1991
; Telford
et al. 1997
). Although the properties and performance of the
reflex have been extensively studied, our knowledge of the neural
mechanisms underlying the trVOR circuitry remains quite limited. Among
the complicating factors that have impeded our understanding of the
neural and computational organization of the trVORs is the highly
distributed arrangement of motion signals in the otolith maculae. For
example, during lateral motion while looking straight ahead,
appropriate afferent signals to generate the compensatory eye movements
could arise from multiple sources. First, there exists the bilateral
structure of the peripheral vestibular system and commissural inputs to
central neurons (Uchino et al. 1999
). Second, there also
exists the opposite spatial vector organization of hair cells on
opposing sides of the striola. Thus a potential redundancy in
directional signals appears to exist within a single labyrinth or in
restricted regions of both labyrinths that could provide the necessary
signals for a push-pull arrangement of otolithocular signals in the
trVORs. In fact, the problem of redundancy is even greater when one
considers that spatially appropriate vestibular signals could be
provided through either labyrinth, either side of the striola, and
either saccular or utricular macula.
Examination of the eye movement pattern after unilateral
labyrinthectomy represents one of the first steps needed to understand the bilateral neural organization of the trVORs. In primate studies examining the effects of labyrinthectomy on the horizontal rotational VOR, it has been demonstrated that static deficits (e.g., spontaneous nystagmus) are the first to recover, whereas dynamic reflex properties slowly follow (Fetter and Zee 1988; Takahashi et
al. 1977
; Wolfe and Kos 1977
). Acutely after
unilateral labyrinthectomy, rotational VOR gain is reduced, primarily
during rotation toward the injured side, resulting in a relatively
large asymmetry that is exaggerated during high-frequency or
-acceleration rotations (Allum et al. 1988
;
Fetter and Dichgans 1990
; Fetter and Zee
1988
; Maioli and Precht 1984
; Maioli et
al. 1983
; Vibert et al. 1993
). In the otolith system, it is possible that a single labyrinth might be sufficient to
generate the trVORs. In fact, despite a complete loss of the early
(<100 ms) transient responses in human subjects with bilateral vestibular loss, a "relatively normal," bidirectional trVOR has been reported in chronic patients with unilateral labyrinthectomy or
unilateral vestibular damage (Bronstein et al. 1991
). In
a group of unilaterally labyrinthectomized patients tested 1 wk after
surgery, a deficient trVOR was reported during transient motion toward
the operated ear (Lempert et al. 1998
). On the other hand, symmetric, roughly conjugate trVOR responses have been reported during steady-state linear motion in the dark after unilateral labyrinthectomy in squirrel monkeys (Paige et al. 1996
).
In preliminary results obtained after unilateral labyrinthectomy in two
canal-plugged rhesus monkeys, we observed a significant impairment in
the reflex dependence on target distance and eccentricity, as well as
in the dynamics of the trVORs (Angelaki et al. 1999b
).
The recovery from canal plugging, however, might cause adaptive changes
in the otolith system that would complicate interpretation of the effects of unilateral labyrinthectomy. In the present study, we have
extended these investigations by directly comparing trVOR properties in
labyrinthine-intact and unilaterally labyrinthectomized animals. The
two most conspicuous deficits are a disruption in the tuning of the
fore-aft VOR as a function of gaze eccentricity and a reduction in
sensitivity during large amplitude transient lateral displacements.
Both of these deficits persist in compensated animals.
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METHODS |
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Animal preparation, eye movement recording, and behavioral training
Five juvenile rhesus monkeys were chronically implanted with a
circular delrin ring that was anchored to the skull by inverted stainless T-bolts and dental acrylic. In addition, animals were also
implanted with a dual eye coil on one or both eyes (Hess 1990). Once animals were satisfactorily trained to fixate far and near targets for juice reward and after control responses were
obtained (see following text), animals were subjected to unilateral
labyrinthectomy. In two of the animals (B and E),
the left labyrinth was destroyed. The other three animals (H,
P, and R) underwent right labyrinthectomy.
Animals B and R were labyrinthectomized 3-4 mo
after all semicircular canals were inactivated as part of a different
study (Angelaki et al. 1999a
). In animals E,
H, and P, the semicircular canals were intact at the
time of unilateral labyrinthectomy.
Binocular three-dimensional (3-D) eye movements were recorded in a
16-in side-length two-magnetic field system (CNC Engineering). During
experimental testing, the monkeys were seated in a primate chair with
their heads statically positioned such that the horizontal semicircular
canals were tilted 18° nose-down relative to an earth-horizontal plane. All animals participating in these experiments were pretrained using juice rewards to fixate targets paired with auditory cues, then
to maintain fixation in the presence of the auditory tone (1 s).
Details for surgical procedures, eye movement calibration, experimental
testing, and training have been reported previously (Angelaki
and McHenry 1999
; Angelaki et al. 2000b
;
McHenry and Angelaki 2000
). All surgical procedures were
performed under sterile conditions in accordance to National Institutes
of Health guidelines.
Experimental protocols
The goal of the present study was to investigate changes in the
trVORs after unilateral labyrinthectomy. For this, 3-D eye movements
were recorded during both lateral and fore-aft motions. The following
experimental protocols were tested before (control responses) as well
as at different times after unilateral labyrinthectomy: 1)
All animals were oscillated at different frequencies between 4 and 12 Hz (0.3-0.4 g) while fixating on one of several target light-emitting
diodes (LEDs). These stimuli were characterized by small peak head
displacement and velocity (<18 cm/s; see Table 1 in Angelaki et
al. 2000b) and were thus used to study the effects of
unilateral labyrinthectomy on the small-signal range of the trVORs.
2) Four animals (B, E, P, and R) were
also tested with a transient stimulus consisting of a step-like linear
acceleration profile, followed by a short period of constant velocity
(peak linear acceleration: 0.5 g; peak linear velocity: ±22
cm/s). To determine the frequency content of these transient stimuli,
we used 1,000-order finite-impulse-response filters (as in Minor et al. 1999
). The frequency response characteristics of three such filters with corner frequencies of 15, 25 and 40 Hz are plotted in
the inset of Fig. 1 (plots of
gain vs. frequency). The head acceleration signal was then digitally
processed through each of these filters (Matlab, Mathworks), and the
result was compared with the raw head acceleration signal in Fig. 1. As
seen from the large differences between the filtered and raw signals,
the frequency content of the transient linear acceleration stimulus used in these studies was much higher than the 4- to 12-Hz frequency bandwidth that was used for sinusoidal testing (but most of the power
was <50 Hz). These large transient stimuli were primarily used to
examine the labyrinthectomy effects on the large-amplitude range of the
trVORs. These large transient stimuli evoke viewing distance-dependent
nonlinearities in animals with intact labyrinths. In addition, the
transient responses were also used to examine changes in response
asymmetry for the two directions of motion.
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For lateral motion stimuli, animals fixated an approximately centered target LED located 40, 30, 20, 15, and 10 cm from the eyes. For fore-aft motion, animals fixated one of several targets on a flat screen at a distance of 20 cm: centered approximately in between the two eyes, ~6 cm to the left/right, as well as ~6 cm up/down (relative to the right eye, i.e., eye positions of ~17°).
After unilateral labyrinthectomy, animals were characterized by the
well-described postural and eye movement static syndromes, including a
static head tilt toward the side of the lesion and a spontaneous
nystagmus with the slow phase directed toward the side of the lesion
(e.g., Fetter and Zee 1988). Animals were first tested
between 3 and 7 days after unilateral labyrinthectomy. The strong
spontaneous nystagmus prevented satisfactory fixation on the targets
for the first 2 days after the operation. On the third day after the
operation, the spontaneous nystagmus had decreased significantly and
some animals were able to fixate the presented LED targets. Animals
were subsequently tested at different times,
3 mo after the
labyrinthectomy. Because of differences in the eye-movement deficits
during lateral motion stimuli for the two animals whose canals were
plugged before the unilateral labyrinthectomy compared with the other
three animals (without canal plugging), data presented here have
primarily focused on lateral motion responses from the three animals
whose canals were intact prior to the labyrinthectomy (animals E,
H, and P). Results in the two animals that had
undergone prior plugging of all semicircular canals have been presented in detail elsewhere (Angelaki et al. 1999b
). Here, these
data are primarily presented and discussed for comparison. The deficits observed during fore-aft motion were similar for the two groups of
animals, thus canal-intact and canal-plugged data are presented together.
For all behaviorally controlled experiments, each trial was initiated
under computer control when the animal had satisfactorily fixated the
target light in a dimly-illuminated environment for a random period of
~300-1,000 ms. After successful fixation had been satisfied, the
sled was commanded to deliver either between 5 and 25 cycles (the first
and last cycles were excluded from analyses) or the transient motion
profile. During sinusoidal motion, which usually involved a recording
period of 1 s, the target remained illuminated. This was necessary to
maintain vergence (particularly after labyrinthectomy). Because of
technical restrictions, only head-fixed target presentation was
possible during motion. Even though visual effects are minimal at
frequencies higher than ~4 Hz, we cannot exclude the possibility that
the presence of the head-fixed targets reduced the amplitude of the
elicited eye movements. Since, however, the stimulus conditions were
identical for all experiments, any suppression effect due to the
presence of the head-fixed targets would not have influenced the
comparisons between the responses before and after unilateral
labyrinthectomy. For the transient stimuli, the target was extinguished
~20 ms prior to the onset of movement, such that animals were in
complete darkness during motion. Since our analyses only focus on the
very early part of the response after motion onset, illumination of the
target during motion was not necessary. Intermingled with these
protocols also were runs where no movement occurred even though
satisfactory fixation was obtained. Stimulus presentation and
behavioral control during motion have been described in detail in the
preceding papers (Angelaki et al. 2000b
; McHenry
and Angelaki 2000
).
For each recording session, the eight voltage signals of the two eye coil assemblies, the three output signals of a 3-D linear accelerometer (mounted on fiberglass members that firmly attach the animal's head ring to the inner gimbal of the rotator), as well as velocity and position feedback signals from the linear sled were low-pass filtered (200 Hz, 6-pole Bessel), digitized at a rate of 833.33 Hz (Cambridge Electronics Design, model 1401, 16-bit resolution), and stored on a PC for off-line analysis. The majority of the data reported were from binocular 3-D recordings. Because of broken torsion coils at the time of labyrinthectomy, only monocular data are presented for animals R and H.
Data Analyses
Calibrated 3-D eye positions were expressed as rotation vectors,
E (Haustein 1989; van Opstal
1993
, the reference position was straight ahead). The eye
angular velocity vector,
, was computed from
3-D eye position, as previously described (c.f. Angelaki and
Hess 1996a
,b
). Both eye-position and angular eye-velocity vectors were expressed relative to a head-fixed right-handed coordinate system, as defined in the 18° nose-down position. Torsional,
vertical, and horizontal eye position and velocity were the components
of the eye-position and eye-velocity vectors along the nasooccipital, interaural, and vertical head axes, respectively. Positive directions were clockwise (as viewed from the animal, i.e., rotation of the upper
pole of the eye toward the right ear), downward and leftward for the
torsional, vertical, and horizontal components, respectively.
The horizontal, vertical, and torsional components of the calibrated
eye position vectors were smoothed and differentiated with a
Savitzky-Golay quadratic polynomial filter with a 15-point forward and
backward window (Press et al. 1988; Savitzky and
Golay 1964
). For frequencies >6 Hz, response amplitudes have
been corrected for the gain attenuation of the filter (Angelaki
1998
; Angelaki et al. 2000b
). For steady-state
sinusoidal runs, no fast phase removal was usually necessary. For each
run (corrected for head movement) (see Angelaki et al.
2000b
), average response cycles were computed from the
respective steady-state horizontal, vertical, and torsional velocity
components (usually from 3-10 custom-selected saccade-free cycles).
Since the selected segment did not include fast eye movements, the
obtained slow phase eye velocity responses were not contaminated by
post-saccadic drift. Because of gaze-holding deficits that are commonly
present after labyrinthectomy, it has been previously pointed out that
a traditional slow phase analysis is problematic when post-saccadic
drift is not taken into account in the estimation of VOR time constants
(Cannon and Robinson 1987
; Fetter and Zee
1988
; Rey and Galiana 1993
). The slow phase eye velocity analysis performed here was not subject to this limitation.
Sensitivity and phase were determined by fitting a sine function (and a
DC offset) to both response and stimulus (output of the 3-D linear
accelerometer) using a nonlinear least-squares algorithm based on the
Levenberg-Marquardt method. Translational VOR sensitivity was expressed
as the ratio of peak eye velocity to peak linear velocity (computed as
the integral of linear acceleration). Phase was expressed as the
difference (in degrees) between peak eye velocity and peak stimulus
velocity. Positive head motion was defined as rightward and backward.
Based on these sign definitions, the phase of the compensatory
horizontal response during sinusoidal lateral motion should be ~0°
(Angelaki et al. 2000b). For fore-aft motion, a
compensatory horizontal response phase would be ~0° when looking to
the right and ~180° when looking to the left (McHenry and
Angelaki 2000
). The trVOR vector angle in the roll plane was defined as the arc tangent of vertical over horizontal response sensitivities. In animals with intact labyrinths, the phase difference between the horizontal and vertical modulations was close to 180° (e.g., Fig. 2A). That is, an
upward vertical accompanied generation of a leftward horizontal eye
movement. Based on the coordinate system used, this is defined as a
positive tilt angle. When the phase of the vertical modulation changed
more than 90° after (relative to the values before)
labyrinthectomy, the trVOR tilt angle was defined to be negative.
Otherwise it was computed as a positive angle.
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For transient responses, a grand-average was computed for each stimulus
and prior viewing condition in each animal. A semi-automated analysis
routine displayed each experimental run sequentially and allowed the
experimenter to select only saccade-free runs to be included for grand
averages and further analysis. In addition, this step allowed direct
inspection of vergence throughout the motion profile. If there was an
obvious loss of vergence (usually associated with a saccade), the run
was discarded and excluded from further analysis. The onset times of
stimulus (linear acceleration) and response (horizontal eye velocity)
were computed based on the 3-SD method, as previously described
(Angelaki and McHenry 1999). Only the first 239 ms after
stimulus onset and the last 50 ms prior to stimulus onset were
quantitatively analyzed. The actual binocular fixation and vergence
angles were measured from mean eye position during the 50 ms prior to
motion onset. To describe the response profiles across different
viewing conditions, the left and right eye velocity were computed at
different time intervals after stimulus onset.
Statistical comparisons are based on ANOVAs. In addition, regressions
were used to quantify the dependence on viewing distance. Based on
previous findings, a first-order regression was sufficient to
approximate the viewing distance dependence of the sinusoidal responses
(Angelaki et al. 2000a,b
). However, a second-order
regression was necessary to describe the nonlinearities characterizing
the viewing distance dependence of the transient responses (see
RESULTS). Data points for each animal were obtained at
different times following labyrinthectomy. Thus statistical comparisons
(ANOVA and regressions) were performed only on data collected before,
within the first week and 2-3 mo following labyrinthectomy.
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RESULTS |
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Changes in the trVORs during lateral oscillations
Unilateral labyrinthectomy resulted in small but consistent
decreases in the horizontal response sensitivity of the trVORs during
lateral motion. Table 1 summarizes the
relevant statistical comparisons. An example of responses before and
after unilateral labyrinthectomy is illustrated in Fig. 2. In addition
to a decrease in the horizontal response, the vertical response
modulation was increased. The elicited eye movement during lateral
motion should be primarily horizontal for fixation on the target with a
small vertical elevation. In animals with intact labyrinths, the
vertical response component is small, resulting in a tilt of the eye
velocity vector that is <10° from a purely horizontal direction
(Angelaki et al. 2000b). As seen in Fig. 2, however, the
vertical component significantly increased after unilateral (right)
labyrinthectomy (see also Table 1). In fact, peak-to-peak vertical eye
velocity oscillations after the lesion could be almost as large as
those of the horizontal component (e.g., Fig. 2). Torsional response sensitivity did not significantly change after labyrinthectomy [F(1,81) = 0.6, P > 0.05].
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The decrease in the horizontal response sensitivity, as well as the
increase in vertical response sensitivity, were both viewing distance
dependent, as shown in Fig. 3,
A and B, respectively (Table 1, statistical
comparisons in second row). This dependence was characterized using
first-order regressions (Table 2) (see also Angelaki et al. 2000a). The horizontal and vertical
response components were characterized by similar viewing-distance
dependencies such that the tilt of the trVOR vector away from a purely
horizontal response was independent of viewing distance
[F(4,160) = 1.8, P > 0.05]. In both
canal-intact animals that underwent a right labyrinthectomy, the trVOR
response vector tilted further to the right (positive tilt angle). That
is, a negative (upward) vertical eye movement accompanied generation of
a positive (leftward) horizontal eye movement (e.g., Fig.
2B). In the third canal-intact animal whose left labyrinth
was destroyed, the trVOR response vector tilted to the left (negative
tilt angle). Specifically for the first week after the operation, the
vector tilt averaged
14.4 ± 3.5° for animal E
(left labyrinthectomy; mean ± SD) and 13.6 ± 1.7 and 29.1 ± 1.6° for animals H and P
(right labyrinthectomy). In all three cases, these values were
statistically significantly different from those in the intact animals,
which averaged 5.4 ± 3.7, 5.9 ± 0.6, and 5.5 ± 1.6°
for each of the three animals, respectively [F(1,160) = 23.0, P < 0.01]. These changes in trVOR vector tilt
exhibited some recovery over time [F(1,146) = 49.8, P < 0.01; Fig.
4B].
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The decrease in horizontal response sensitivity also tended to recover
over time (see statistical comparisons in Table 1). Figure
4A illustrates the changes in the horizontal sensitivity slope (i.e., the slopes of the regression lines as a function of
inverse viewing distance, as in Fig. 3A) as a function of
time after unilateral labyrinthectomy. In all three nonplugged animals, horizontal response sensitivity recovered significantly within 2 mo
after the operation (Fig. 4A, ,
,
, and Table 1).
Figure 4A also illustrates the respective responses from the
two animals whose semicircular canals were plugged several months prior
to the labyrinthectomy (Angelaki et al. 1999b
). The
effects of unilateral labyrinthectomy on horizontal trVOR sensitivity
tended to be larger in the two animals whose semicircular canals were
plugged 3-4 mo prior to the labyrinthectomy (Fig. 4A,
,
) (see also Angelaki et al. 1999b
). The effects of
unilateral labyrinthectomy on trVOR response dynamics were also
different between canal-plugged and canal-intact animals. Whereas
horizontal response dynamics were altered after labyrinthectomy in the
canal-plugged animals (Angelaki et al. 1999b
), no
systematic changes in trVOR dynamics were observed after unilateral
labyrinthectomy in the canal-intact animals.
Changes in the trVORs during transient lateral motion
During the high-acceleration transient lateral motion stimuli in labyrinthine-intact animals, eye velocity did not exhibit a linear dependence on viewing distance throughout the motion profile (Table 3). The smallest nonlinearities were observed early into the movement. Twenty-five milliseconds after motion onset (and while the movement of the two eyes was conjugate), the eye velocity dependence on inverse viewing distance was rather linear (linear regression coefficients: 0.75-0.97; see Table 3). The nonlinear dependence was strong for the adducting eye and became apparent as soon as the two eyes diverged from each other for the near target viewing conditions (>25 ms into the motion). 239 ms after motion onset, there was little dependence of eye velocity on the inverse of viewing distance (Table 3).
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The decrease in horizontal response sensitivity observed after unilateral labyrinthectomy during the small-amplitude, sinusoidal oscillations was also observed during transient lateral motion. As shown in Fig. 5, which compares responses before (top) with those 1 wk and 1 mo after right labyrinthectomy (bottom), the largest changes were observed in the responses during near target viewing and ipsilateral motion (i.e., toward the side of the lesion). That is, positive (leftward) horizontal eye velocity responses elicited during rightward (ipsilateral) motion were lower after unilateral labyrinthectomy compared with control responses. The differences between the lesioned and control data were generally the largest for the smallest viewing distances. During contralateral (leftward) motion, the early part of the response also decreased.
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Since transient trVOR velocities are robust and exhibit a systematic
viewing distance-dependent behavior only during the early (~100 ms)
part of the response, quantitative analyses of the effects of
labyrinthectomy have primarily focused on eye velocity within 70 ms
after motion onset. The latter corresponded approximately to the time
that horizontal eye velocity reached its peak value. These eye velocity
values have been plotted in Fig. 6 as a
function of the inverse of viewing distance before and 1 wk and 1 mo
after right labyrinthectomy ( and
,
and
,
and
). Because of the nonlinear dependence of response amplitude on the inverse of
viewing distance during large transient displacements (Table 3), a
second-order linear regression has been fitted through the data from
each eye (Fig. 6, · · · ,
, and - - -). The
regression coefficients have been included in Table
4. Unilateral labyrinthectomy significantly decreased the 70-ms responses in all animals
[F(1,40) = 7.8, P < 0.01; Table 4].
The response decline after unilateral labyrinthectomy was larger for
ipsilateral (i.e., toward the side of the lesion) compared with
contralateral motion. These differences between ipsilateral versus
contralateral motion responses were statistically significant in three
of the animals [F(2,43) = 7.2, P < 0.01; animal E was not included in the comparison]. For the two animals with complete data at all viewing distances (P
and B), recovery was small and statistically insignificant
[F(1,17) = 2.4, P > 0.05]. Similar
to steady-state sinusoidal responses, the effects of unilateral
labyrinthectomy during these transient stimuli tended to be larger in
those animals that had undergone canal plugging in comparison with
those that had not.
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Changes in the trVORs during fore-aft motion
Unilateral labyrinthectomy resulted in a large and persistent
deficit in the tuning of fore-aft trVOR as a function of target (and
gaze) eccentricity. A typical example of responses before and after
labyrinthectomy during sinusoidal fore-aft translationat 10 Hz is
illustrated in Fig. 7 for fixations at
three different targets. In labyrinthine-intact animals, horizontal eye
velocity modulated sinusoidally and out of phase for the targets to the left and to the right. Even though the amplitude of modulation was
generally less than that required for binocular fixation at the target
(Fig. 7A, compare hor with Ideal),
responses were appropriately tuned to target eccentricity. For example,
in line with the kinematic requirements of the reflex, purely vergence responses were observed during fixation at the center target, whereas a
combination of vergence and version responses were seen during fixation
of targets to the left and to the right (Fig. 7A) (see also
McHenry and Angelaki 2000
; Paige and Tomko
1991b
).
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After unilateral labyrinthectomy, the elicited horizontal responses were qualitatively similar to controls (albeit generally larger) during fixation at targets located contralateral to the side of the lesion, i.e., to the left after right labyrinthectomy (Fig. 7B, left). In contrast, kinematically inappropriate horizontal binocular responses were elicited during fixation at ipsilateral targets, i.e., to the right after right labyrinthectomy (Fig. 7B, right). Compared with responses before labyrinthectomy, horizontal eye velocity during right target fixation was of reverse phase. That is, responses were anticompensatory for fixation at ipsilateral targets. A deficit was also seen during center target viewing. Rather than purely vergence responses where the modulation of the right and left eyes were out of phase, a combination of version and vergence responses were observed after unilateral labyrinthectomy (Fig. 7, A and B, middle).
The changes in the horizontal response phase during fixation at
ipsilateral targets are further illustrated in Fig.
8 where horizontal sensitivity and phase
of the right eye as a function of frequency are compared for nine
different targets located at different horizontal/vertical
eccentricities on a flat screen at a distance of 20 cm (see
METHODS). In this case, data 3 days after left
labyrinthectomy are compared with those prior to the operation (Fig. 8,
and
circles, respectively). The organization of the plot
reflects the positions of the fixation targets (relative to the
animal), with center, up/down, left/right in the plot corresponding to
the respective location of the targets on the screen. In the intact
animal, trVOR phase was ~0° for right target fixation (i.e., eye
velocity in phase with linear head velocity), with a consistent tendency for small lags at the highest frequencies (Fig. 8,
; right groups of plots). Based on the coordinate definitions
used here, a phase of zero corresponded to a positive (leftward) eye movement being elicited during backward (positive) motion. For left
target fixations, trVOR phase was about
180° (Fig. 8,
; left groups of plots). In this case, eye velocity was also
in phase with linear velocity, albeit the eye movement direction was
reversed (i.e., a rightward eye movement was elicited during backward
motion; see also Fig. 7A). For targets in the midsagittal plane (where right eye position is to the left), the response sensitivities of the right eye were small with phases about
180° (Fig. 8,
; middle groups of plots). After the lesion,
responses were compromised for ipsilateral targets: during fixation to
the left, response sensitivity decreased and response phase shifted 180°. During fixation to the right, responses were compensatory and
response sensitivity was consistently increased. Even though it was not
systematically investigated, no consistent changes in vertical response
sensitivity were observed in the one animal tested during fixation on
vertical targets in the midsagittal plane.
|
Little recovery of function was seen in the fore-aft VOR for as long as
2-3 mo post-lesion (Fig. 9). The phase
of the reflex shifted and remained shifted through 180° for left
target fixation after left labyrinthectomy (Fig. 9, left,
and
) and for right target fixation after right labyrinthectomy
(Fig. 9, right,
and
). These observations were common
to all animals; thus canal-plugged and canal-intact data were
considered together. A selective destruction of responses for gaze
eccentricities ipsilateral to the side of the lesion was also observed
during transient fore-aft displacements (Fig.
10). Three weeks after right
labyrinthectomy, for example, responses for gaze directions
contralateral to the lesion side remained indistinguishable from those
before the lesion (Fig. 10, left). For gaze directions
ipsilateral to the lesion, however, responses were severely
compromised, particularly during backward motion (Fig. 10,
right).
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DISCUSSION |
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We have studied the changes in the translational VORs after
unilateral labyrinthectomy. Based on the redundant representation of
motion direction in the peripheral vestibular organs (Flock 1964; Lindeman 1969
), it could be possible that
destruction of one labyrinth did not significantly alter the reflex
properties. We found this not to be true. During high-frequency lateral
oscillations, a small decrease in the trVOR sensitivity and its
dependence on viewing distance was observed when animals were tested
3-7 days after the lesion. These deficits of the trVOR tended to
gradually recover over the next 2-3 mo. In addition, a misalignment in
the eye velocity vector was revealed after unilateral labyrinthectomy. The vertical response component was increased such that the eye velocity vector tilted in the roll plane away from a purely horizontal direction toward the side of the lesion. This misalignment exhibited some recovery over the time period tested. A tilt in the eye velocity response during lateral motion has been observed after unilateral labyrinthectomy in squirrel monkeys but reported to be in the opposite
direction (Paige et al. 1996
).
The decrease in horizontal eye velocity after labyrinthectomy was also present during transient motion stimuli. Responses were also asymmetric for the two motion directions. During translation toward the lesioned labyrinth, eye velocity was smaller than that during motion toward the intact labyrinth. The closer the target, the larger the decrease in horizontal sensitivity. Even though these responses recovered over time, severe deficits and large asymmetries were still present 2-3 mo after the operation. Interestingly, no systematic difference in deficits was seen for the ipsilateral versus the contralateral eye, suggesting that each labyrinth contributes to a binocular trVOR organization.
The most profound effect of the lesions was observed during fore-aft motion. In this case, the effects of unilateral labyrinthectomy were asymmetric not to the direction of motion, as was the case for lateral motion, but to the direction of gaze. Whereas responses were kinematically appropriate for fixation away from the side of the lesion (e.g., to the left after right labyrinthectomy), horizontal responses were anticompensatory during fixation at targets located ipsilateral to the side of the lesion (e.g., for targets to the right after right labyrinthectomy). In other words, the single remaining labyrinth could only generate the same horizontal eye movement direction, independently of horizontal gaze eccentricity. This deficit showed little recovery in the 3 mo post-labyrinthectomy. In contrast to these changes in horizontal eye movements, vertical response sensitivities during fixation at up/down targets remained qualitatively the same.
Unilateral labyrinthectomy and vestibular compensation
Based on previous work regarding the rotational VOR, it appears
that there are two phases in compensation (Curthoys and Halmagyi 1995; Fetter and Zee 1988
; Ris et al.
1995
; Smith and Curthoys 1989
). Within
approximately the first week, recovery is fast and involves mainly
compensation of the static imbalance and recovery of central vestibular
neuron discharge. The VOR reflex gain recovery observed during this
first week could be at least partly due to the restoration of
spontaneous activity in central vestibular neurons. The dynamic
compensation is slower and takes place within several weeks or months
after unilateral labyrinthectomy.
Because of the confounding problems associated with the strong
spontaneous nystagmus and difficulties in fixation, the present work
has not examined the changes in the trVORs during the first couple of
days after unilateral labyrinthectomy. Rotational VOR gains, which have
been reported to decrease to ~0.5 immediately after labyrinthectomy,
exhibited a fast recovery within the first 2-3 days after exposure to
light. For low-velocity stimuli, in particular, rotational VOR gain
tested after 2-3 days increased to ~80-90% of the value that was
eventually reached after 3 mo (Fetter and Zee 1988).
After unilateral deafferentation of the otolith organs in squirrel
monkeys, the VOR gain enhancement during eccentric rotations was
compromised acutely after the lesion but compensated to relatively
normal values 6-8 wk after the operation (Takeda et al.
1990
). It is possible that had we tested trVOR responses
acutely (i.e., within hours) after unilateral labyrinthectomy, the
deficits would be greater. The goal of this study, however, was not the
early deficits that could be at least partly due to the loss of
spontaneous activity in the deafferented side but rather the prevailing
deficits in the trVORs once static vestibular imbalance had been mostly
restored. For this reason (and because animals could not consistently
fixate acutely after labyrinthectomy), our earliest quantitative data
presented here were obtained 3-7 days after the operation.
Response asymmetry
Several studies of the rotational VOR in humans and monkeys have
clearly demonstrated that the observed recovery in the gain of the
reflex varies depending on the stimuli used. First, it depends on peak
head acceleration. The higher the peak acceleration, the smaller the
recovery and the larger the asymmetry to ipsilateral and contralateral
rotation responses (Gilchrist et al. 1998;
Halmagyi et al. 1990
; Tabak et al. 1997
;
Vibert et al. 1993
). For low-acceleration sinusoidal
rotations, in particular, a nearly complete recovery of the horizontal
VOR has been shown in both humans and monkeys (Allum et al.
1988
; Baloh et al. 1984
; Fetter and
Dichgans 1990
; Fetter and Zee 1988
;
Takahashi et al. 1977
, 1984
; Wolfe and Kos 1977
). Second, horizontal VOR recovery and symmetry has also
been shown to be smaller for impulsive rotations that had the same peak
head acceleration compared with sinusoidal oscillations (Crane and Demer 1998
; Gilchrist et al. 1998
).
Differences between the ipsilesional and contralesion movement
directions have also been reported during center and eccentric
rotations in subjects with unilateral vestibular deafferentation
(Crane and Demer 1998
). Ewald's second law
(Ewald 1892
) has been often proposed as an explanation
for such response asymmetries in the horizontal canal system
(Crane and Demer 1998
; Curthoys et al.
1991b
). Recent studies have recently further addressed this
issue during head rotations (Broussard et al. 1999
;
Lasker et al. 1999
; Minor et al. 1999
).
Similarly to the results during head rotations, asymmetric responses
were also observed here during large-amplitude transient lateral
movements. We have also found that the transient response asymmetry
does not totally recover within the 2-3 mo of post-lesion testing.
Asymmetric responses to ipsilateral/contralateral motion directions
have been also previously reported during transient linear motion in
darkness one week after unilateral labyrinthectomy (Lempert et
al. 1998). Responses regained symmetry when tested 6-10 wk
after the operation. In addition, a "relatively normal," bidirectional trVOR was reported in chronic patients with unilateral labyrinthectomy or unilateral vestibular damage (Bronstein et al. 1991
). The transient stimuli used here differ from those of Lempert et al. in two ways. First, the head displacement and peak head
acceleration, as well as the frequency content of the transient stimulus, were all higher in the present study. Second, animals in the
present study fixated near targets (at 10 cm, vergence angles were
14-18°). Most likely the lack of a large recovery in the transient
responses reported here is due at least in part to the large
acceleration and/or frequency content of the transient stimulus.
The deficits reported here are most likely due to the removal of
specific connections from the lesioned utricular/saccular macula to the
brain stem. It is unlikely that the observed asymmetries, particularly
those pertinent to long-lasting effects during fore-aft oscillations or
transient lateral motion, are due to a decrease in the spontaneous
activity of central neurons after unilateral labyrinthectomy. The
restoration of spontaneous activity in guinea pig central neurons is
complete within a week after unilateral labyrinthectomy (Ris et
al. 1995). The recovery of neural discharge in primates has not
yet been investigated, although behavioral data suggest that
spontaneous nystagmus in complete darkness decreases to less than half
within 10 days after operation (Fetter and Zee 1988
).
Differences between canal-intact and canal-plugged animals
The observation that the unilateral labyrinthectomy deficits
during lateral movements were larger in canal-plugged than in canal-intact animals suggests that otolith and semicircular canal signals are not independent in their central processing and adaptation. We have recently shown, for example, that a nonlinear interaction between semicircular canal and otolith signals is necessary for an
appropriate central decomposition of linear accelerations into translational and gravitational components (Angelaki et al.
1999a). The differences in adaptation between canal-intact and
canal-plugged animals constitute further evidence that otolith and
semicircular canal signals are subject to extensive central processing
and convergence.
Deficits for fore-aft motion stimuli
Perhaps the largest and most consistent effect of unilateral
labyrinthectomy in all five animals tested was the destruction in the
tuning of the fore-aft trVOR as a function of gaze eccentricity. Whereas responses were qualitatively unchanged during fixation of
contralateral targets, responses were anticompensatory during fixation
of targets ipsilateral to the lesion side. In contrast to fore-aft
responses in intact animals where the direction of the elicited eye
movement reverses for leftward and rightward eye positions
(McHenry and Angelaki 2000; Paige and Tomko
1991b
), forward motion elicited leftward eye movements for all
gaze directions following right labyrinthectomy. The opposite was true
after left labyrinthectomy. The absence of purely vergence eye
movements during center target fixation, as well as the gradual
decrease in the horizontal response modulation as the fixation position shifted toward the ipsilateral (lesioned) side (e.g., Fig. 7) are
suggestive of a shift of the zero-sensitivity direction in the lesioned
animals. In intact animals, sensitivity exhibits a V-shape dependence
on eye position with the gaze direction with zero sensitivity being
approximately straight ahead (even though some small but consistent
departures from ideal behavior are present) (see McHenry and
Angelaki 2000
). The results presented here would be consistent
with the zero sensitivity point being shifted toward the lesion side
after unilateral labyrinthectomy. For example, if the V-shape curve
shifted to the right following right labyrinthectomy by >20°,
horizontal response sensitivity during fore-aft motion would exhibit no
phase reversal and response amplitude should increase monotonically as
a function of gaze direction. In other words, the destruction of the
spatial tuning of the fore-aft responses reported here, if indeed due
to a shift in the V-shape curve toward the side of the lesion, might
suggest that the conjugate and disjunctive components of the trVOR are
tuned by the appropriate weighting of signals from the two labyrinths.
Implications for otolith-ocular connectivity
For the present results to be extrapolated in a simple conceptual
diagram that could be used to generate the trVORs, knowledge of the
main excitatory otolith-ocular connectivity is fundamental. For
example, depending on whether the main excitatory projections are to
the ipsilateral or contralateral abducens, either the medial or the
lateral side of the striola could elicit compensatory horizontal eye
movements during lateral motion. In fact, the observation that
ipsilateral translations (that cause excitation to utricular afferents
innervating the lateral side of the striola) were more severely
compromised following unilateral labyrinthectomy led Lempert et
al. (1998) to conclude that afferents in the trVOR originate
from the lateral side of the striola. However, an implicit assumption
for the conclusions of Lempert et al. (1998)
is the existence of a (semicircular canal-like) contralateral excitatory utriculoabducens pathway. Currently, there is no experimental evidence
regarding a short-latency excitatory contralateral utriculoabducens pathway. In fact, there is growing evidence that the main, excitatory utriculoocular pathway is ipsilateral, in sharp contrast to the horizontal canal-ocular pathway (Schwindt et al. 1973
;
Uchino et al. 1979
). Intracellular recordings from cat
motoneurons and internuclear neurons have demonstrated the existence of
di- (and mono-) synaptic excitatory postsynaptic potentials (EPSPs) in the ipsilateral abducens nucleus during stimulation of the utricular nerve (Uchino et al. 1994
, 1997
). In contrast, only
small hyperpolarizations with a longer latency were reported in some
cells in the contralateral abducens nucleus during utricular nerve
stimulation. Even though the existence of similar connections is yet to
be documented in primates, we consider it inappropriate to embrace the
conclusion of Lempert et al. (1998)
at this point.
If indeed the main excitatory horizontal trVOR pathway in primates is
ipsilateral (as is the case in cats) and to generate a compensatory eye
movement during lateral translation, cells in the excitatory horizontal
trVOR pathway should originate from the medial side of the striola. For
example, left utricular afferents originating from the medial side of
the striola would be excited during a rightward head acceleration. Left
utricular afferents would excite the left abducens nucleus, thus
eliciting a leftward (compensatory) eye movement. Such a connectivity,
however, would have predicted the opposite asymmetries from those seen
after unilateral labyrinthectomy. Following lesions of the left
labyrinth, for example, it should be rightward (contralateral) head
movements that should have been more severely compromised. The fact
that the electrophysiological and lesion data are not mutually
consistent with any such simplified scheme suggests that the actual
organization of the translational VORs is more complex. The extensive
convergence of the two sides of the striola, as well as the two
labyrinths, on single second-order neurons (Uchino et al.
1999) would also suggest that no simple connectivity scheme
would be the answer to the organization of the translational VORs.
Finally, it should be pointed out that no data are currently available
on changes in the neural coding of linear acceleration after unilateral
labyrinthectomy in any species that has been shown to exhibit
functionally-appropriate trVORs (i.e., horizontal/vertical eye
movements that are scaled by target distance and eccentricity). Even
though such data are available in nonprimate species (e.g., Chan
1997; Wadan and Dieringer 1994
), their relevance
to the neural organization of the trVORs is questionable since they
might reflect signal processing in the orienting otolith-ocular
reflexes (counter-rolling/counter-pitching). It is nevertheless
interesting to notice that, although ipsilateral ear-down responses
predominated, the best response orientations of vestibular nuclei
neurons in unilateral labyrinthectomized cats pointed in all directions
in the horizontal plane (Chan 1997
). Such a result
provides further evidence that both sides of the striola project
(either directly or indirectly) onto vestibular nuclei neurons. Indeed,
monosynaptic EPSPs were observed during electrical stimulation of both
sides of the striola in ~20% of secondary utricular neurons in the
cat (Uchino et al. 1999
). An additional 40% of
secondary utricular neurons exhibited monosynaptic EPSPs and disynaptic
inhibitory postsynaptic potentials, suggesting cross-striolar
inhibition (Uchino et al. 1999
).
Considering the present and previous results together, we are faced
with a serious limitation in our current understanding of the
neuroanatomy and functional connectivity of the system. The
labyrinthectomy results in both humans and monkeys are not easily
reconciled with what has been observed electrophysiologically in cats.
As mentioned above, this apparent discrepancy might be at least partly
due to extensive convergence of utricular afferents from both sides of
the striola. Nevertheless despite a remaining uncertainty in the
neuroanatomical architecture of the trVORs, the fact that the deficits
during lateral motion were small during small-amplitude sinusoidal
lateral oscillations suggest that a commissural pathway probably exist
in the trVORs. Earlier work had suggested that otolith-related
commissural projections to the lateral vestibular nucleus might have a
purely excitatory effect on second order neurons in the cat
(Shimazu and Smith 1971). However, more recent work in
the same species has suggested that approximately half of the secondary
utricular neurons receive commissural inhibition, whereas the remaining
do not receive commissural signals at all (Uchino et al.
1999
).
The neuroanatomical architecture seems to be less controversial for
other aspects of the otolith-ocular system. For example, there is
consistent experimental evidence that the main excitatory drive for the
orienting components of the otolith-ocular system (i.e.,
counter-rolling and counter-pitching) might arise from the medial side
of the striola. First, patients with unilateral vestibular neurectomies
have been shown to underestimate the magnitude of roll head tilt when
the resultant acceleration is directed toward their operated ear
(Curthoys et al. 1991a; Dai et al. 1989
). Second, patients with unilateral lesions have also been shown to elicit
smaller ocular counter-rolling for ipsilateral head roll tilts (albeit
with largely inconsistent results) (e.g., Diamond and Markham
1981
; Kanzaki and Ouchi 1978
; Krejcova et
al. 1971
; Nelson and House 1971
). Finally,
electrical stimulation of the utricle elicited torsional eye movements
appropriate to compensate for an ipsilateral roll tilt (Curthoys
1987
; Fluur and Mellström 1970
;
Suzuki et al. 1969
). These torsional and vertical eye
movements, albeit of small amplitude in primates and humans,
constitutes the primary otolith-ocular responses in lateral-eyed
species, including frogs (Hess et al. 1984
), rats
(Hess and Dieringer 1991
), rabbits (Baarsma and
Collewijn 1975
), and pigeons (Dickman and Angelaki
1999
).
If indeed there is extensive convergence from both sides of the striola in central vestibular neurons participating in the trVORs, the neuronal architecture of the trVORs will be harder to understand using tools and principles that have been proven very successful for the rotational VOR. At present, several pieces of the puzzle remain missing and so is also a basic neuroanatomical diagram that could be consistent with both the electrophysiological, lesion, and stimulation data regarding the trVORs.
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ACKNOWLEDGMENTS |
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The authors thank A. Haque and Q. McHenry for help with figures, J. Loya and B. Harris for technical help, and M. Phillips for ordering and secretarial assistance.
The work was supported by grants from the National Eye Institute (EY-2814 and EY-10851) and a Presidential Young Investigator Award for Scientists and Engineers (NASA).
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FOOTNOTES |
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Address for reprint requests: D. Angelaki, Dept. of Anatomy and Neurobiology, Box 8108, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110.
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 23 September 1999; accepted in final form 23 February 2000.
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REFERENCES |
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