Department of Surgery (Otolaryngology) and Anatomy, University of Mississippi Medical Center, Jackson, Mississippi 39216-4505; and Department of Otolaryngology and Anatomy, University of Texas Medical Branch, Galveston, Texas 77550
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ABSTRACT |
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Angelaki, Dora E., M. Quinn McHenry, J. David Dickman, and Adrian A. Perachio. Primate Translational Vestibuloocular Reflexes. III. Effects of Bilateral Labyrinthine Electrical Stimulation. J. Neurophysiol. 83: 1662-1676, 2000. The effects of functional, reversible ablation and potential recruitment of the most irregular otolith afferents on the dynamics and sensitivity of the translational vestibuloocular reflexes (trVORs) were investigated in rhesus monkeys trained to fixate near and far targets. Translational motion stimuli consisted of either steady-state lateral and fore-aft sinusoidal oscillations or short-lasting transient lateral head displacements. Short-duration (usually <2 s) anodal (inhibitory) and cathodal (excitatory) currents (50-100 µA) were delivered bilaterally during motion. In the presence of anodal labyrinthine stimulation, trVOR sensitivity and its dependence on viewing distance were significantly decreased. In addition, anodal currents significantly increased phase lags. During transient motion, anodal stimulation resulted in significantly lower initial eye acceleration and more sluggish responses. Cathodal currents tended to have opposite effects. The main characteristics of these results were simulated by a simple model where both regularly and irregularly discharging afferents contribute to the trVORs. Anodal labyrinthine currents also were found to decrease eye velocity during long-duration, constant velocity rotations, although results were generally more variable compared with those during translational motion.
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INTRODUCTION |
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A common characteristic of all vertebrate
vestibular systems is the existence of primary afferents with different
response dynamics. At the two extremes, the most regularly firing
primary otolith afferents are characterized by purely tonic response
properties (i.e., they encode linear acceleration), whereas the most
irregularly firing afferents have phasic or phasic-tonic response
dynamics (i.e., they encode a signal related to a fractional derivative of linear acceleration) (Fernández and Goldberg
1976a,b
; Goldberg et al. 1990
). These vestibular
afferents also differ in their excitability to electrical stimulation
of the labyrinths. Irregular (phasic) afferents have a lower threshold
and a higher sensitivity to electrical stimulation of the ear compared
with regular (tonic) firing cells (Chen-Huang et al.
1997
; Goldberg et al. 1984
; Minor and
Goldberg 1991
). In fact, when anodal (inhibitory) labyrinthine currents are delivered, a selective, reversible ablation (silencing) of
neural firing is produced in the most irregular afferents that lasts
for the duration of the electrical stimulation. Regularly firing
afferents, on the other hand, are little affected by even the largest
current levels used (Dickman and Angelaki 1993
;
Goldberg et al. 1984
). Even though constant anodal or
cathodal currents elicit horizontal and torsional nystagmus in both
eyes when only a single labyrinth is stimulated, bilateral anodal
stimulation results in the selective silencing of the most irregularly
firing neurons with no nystagmus being generated. Bilateral constant anodal stimulation has, thus, become a useful tool to study the contribution of irregular vestibular afferents to the production of the VORs.
Using this technique, it was demonstrated that irregular vestibular
afferents do not contribute to the rotational VOR in the dark at
frequencies between 0.5 and 4 Hz (Minor and Goldberg
1991). There has been some evidence, however, that irregular
vestibular afferents might contribute to the VOR during long-duration
rotations (Angelaki and Perachio 1993
; Angelaki
et al. 1992
) and the viewing distance-dependent changes in the
rotational VOR during near target fixation (Chen-Huang and
McCrea 1998
). Despite the modest effects of irregular
vestibular afferent ablation on the rotational VOR, vestibular nuclei
neurons have been shown to receive inputs from the whole continuum of
afferents (Boyle et al. 1992
; Chen-Huang et al.
1997
; Goldberg et al. 1987
; Highstein et
al. 1987
). The goal of the present study was to characterize
the effects of bilateral labyrinthine currents on the translational
VORs (trVORs). Several lines of evidence support the hypothesis that
the most irregularly firing otolith afferents could contribute to the
trVORs. First, trVORs are tuned to much higher frequencies compared
with the rotational VOR and are characterized by response sensitivities that increase with frequency (Angelaki 1998
;
Angelaki et al. 2000
; Paige and Tomko
1991
; Telford et al. 1997
). In essence, the
high-pass filtered properties of the translational VORs could partly
reflect the contribution from the high-pass filtered properties of
irregular otolith afferents. Second, as mentioned in the preceding
text, a contribution of irregular otolith afferents to the trVORs would explain, at least in part, the extensive irregular vestibular afferent
inputs to second-order vestibuloocular neurons (e.g., Boyle et
al. 1992
). Preliminary results of this work have been presented
elsewhere (Angelaki et al. 1998
, 1999b
)
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METHODS |
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Animal preparation and eye movement recording
Five juvenile rhesus monkeys were chronically implanted with a
circular molded, light-weight dental acrylic ring that was anchored by
stainless steel screws, placed as inverted T-bolts under the skull and
then secured to the ring. For single-unit recordings from the
vestibular nerve in three of the animals, a platform (3 cm × 3 cm, 5 mm height) constructed of machinable plastic-delrin was secured
stereotaxically to the skull and fitted inside the head ring (e.g.,
Correia et al. 1992). The platform had staggered rows of
holes (spaced 0.8 mm apart) that extended from the midline to the area
overlying the vestibular nerves bilaterally.
Subsequent to the eye coil surgeries and after animals had been trained sufficiently to fixate visual targets, labyrinthine stimulating electrodes were implanted in both ears. An incision was made on the rear side of the pinna and the temporal bone exposed. The soft tissue of the external ear canal was displaced gently and the bony meatus enlarged using a dental drill until the long process of the malleus and the chorda tympani (facial nerve) were visualized. A platinized Teflon-insulated silver wire (250 µm diam and insulated to within 1 mm of its tip) then was press fit into a small hole drilled into the promontorium between the round and oval windows. The electrode penetrated into the perilymphatic space but was sealed against perilymphatic leak by the Teflon insulation. A second, reference electrode was placed into a hole drilled close to the entrance of the bony meatus. The two wires were led under the skin to the top of the skull and mated to a connector. The incision in the temporal muscle and the skin was sutured closed. When animals were in their cages, the implanted delrin ring was covered with a cap to protect the recording platform and prohibit the animals from touching the leads of the eye coils and stimulating electrodes.
Binocular three-dimensional (3-D) eye movements were recorded in a
16-in side-length two-magnetic field system (CNC Engineering). For
this, dual eye coils were implanted (Hess 1990) in each
eye. Eye movements were calibrated in two stages. First, before
implantation using a calibration jig. Second, daily calibrations were
performed before experimental protocols by requiring the animals to
perform a visual fixation task. Details for surgical procedures, eye
movement calibration, and experimental testing have been reported in
the preceding papers (Angelaki et al. 2000
;
McHenry and Angelaki 2000
). All surgical procedures were
performed under sterile conditions in accordance to National Institutes
of Health guidelines.
Experimental setup and protocols
During experimental testing, the monkeys were seated in a
primate chair with their heads statically positioned such that the horizontal head plane was tilted 18° nose down. The animal's body was secured with shoulder and lap belts, while the extremities were
loosely tied to the chair. The primate chair then was secured inside
the inner frame of a vestibular turntable consisting of a 3-D rotator
on top of a 2-m linear sled (Acutronics). Constant currents, typically
2-s duration (5 s for frequencies 0.5 Hz), were delivered to each ear
by stimulus isolators (BAK Electronics, model BSI-1) and monitored with
in-series digital ammeters. Currents were designated as cathodal
(excitatory, negative) or anodal (inhibitory, positive) to indicate the
polarity of the perilymphatic electrode.
All animals participating in these experiments were pretrained using
juice rewards to fixate visual targets paired with auditory cues for
variable time periods (300-1,000 ms), then to maintain fixation for as
long as the auditory tone was sustained (1 s). During all fixations,
the room was illuminated (through small red lights) such that the
animals easily could establish relative distance estimates of the
targets. Adequate fixation was defined when both eyes were within
behavioral windows (separate for each eye) of less than ±1.0°.
As soon as animals were implanted and satisfactorily trained, the effectiveness of the stimulating electrodes was established in each animal by measuring the amplitude of the eye movements generated during unilateral ear stimulation (25-100 µA or 200 µA, 1- to 2-s duration). Once electrode effectiveness was established, the main experimental protocols consisted of an array of translational and rotational stimulus profiles, as follows.
LATERAL MOTION. 1) Three animals were sinusoidally laterally translated in complete darkness at several frequencies ranging between 0.3 and 12 Hz. At the lowest frequencies (0.3 and 0.37 Hz), the stimulus amplitude was 0.2 and 0.3 g, respectively. At higher frequencies, the amplitude was 0.3-0.4 g. To examine if the effects of the currents differed for different stimulus amplitudes, peak linear acceleration for 5-Hz oscillations was varied between 0.1 and 0.4 g in two animals.
2) Four animals were oscillated laterally at different frequencies between 4 and 12 Hz (0.3-0.4 g) while fixating on a centered (i.e., approximately zero horizontal eccentricity relative to a point midway between the two eyes) head-fixed target LED located 40, 30, 20, 15, or 10 cm from the eyes (in an otherwise dark laboratory room). 3) Four animals were translated laterally using 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; Fig. 8) while fixating on a centered space-fixed target LED located 87 and 10 cm (animals E, C, and P) or 15 cm (animal G) from the eyes.FORE-AFT MOTION. Three animals (C, P and G) were oscillated at 4 and 10 Hz (0.3-0.4 g peak acceleration) while fixating on one of two targets at a distance of 20 cm: ~6 cm to the left and to the right (relative to the right eye; eye positions of ~17°).
YAW ROTATION. As a control, three animals also were tested during yaw oscillations (0.5-2 Hz). These same animals also were rotated at constant velocity (±60°/s) in complete darkness. The axis of rotation was either earth-vertical (yaw VOR) or tilted 23.6° from the earth-vertical (i.e., off-vertical axis or yaw OVAR).
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. After successful fixation had been satisfied, the sled (or rotator) was commanded to deliver either 3-25 cycles or the transient motion profile. During motion, the target remained illuminated but the background lights were turned off. For transient motion stimuli, labyrinthine stimulation started ~1 s before the execution of the movement. For sinusoidal motion stimuli, labyrinthine stimulation started ~20 ms before the execution of the movement. Because the transient portion of the sinusoidal response was discarded, analysis only focused on cycles ~500 ms after labyrinthine current onset. An attempt was made to repeat each sinusoidal protocol three times and each transient protocol a minimum of five times. Experimental sessions did not usually exceed 2-3 h and runs with no ear simulation, anodal and cathodal currents always were intermingled. Other than the unilateral ear stimulations where currents as high as 200 µA were used to elicit eye movements in three of the animals, all other labyrinthine electrical stimulations never exceeded 100 µA. Between experimental sessions, a shorting plug was used for both ear electrodes. Neither the surgical intervention nor the use of electrical stimulation interfered with labyrinthine function as demonstrated by normal rotational and trVOR responses (as compared with controls before electrode implantation). In addition, no increase in the threshold for evoking nystagmus was observed throughout the duration of these experiments (~2 wk in animals E, G, and H and ~2 mo in animals C and P). There was no sign of vestibular neuropathy (i.e., increased spontaneous nystagmus or head tilt) observed at any time during these experiments, in contrast to problems often encountered in previous studies (Angelaki and Perachio 1993Data analyses
All data analyses were performed off-line using a combination of
computer software written to perform specific tasks. 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 smoothened 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. 2000
). For steady-state
sinusoidal responses in the dark, the fast phases of nystagmus were
removed using a semiautomated procedure based on time and amplitude
windows set for the second derivative of the eye velocity vector
amplitude. For behaviorally controlled runs, no fast phase removal was
usually necessary. Selected cycles during application of electrical
currents were averaged and compared with the averaged cycles selected
during interleaved periods without currents. Cycles that occurred
during the onset and offset of current application were excluded from the analysis. As a general rule, responses within 500 ms from current
onset were always excluded. Otherwise, average response cycles were
computed from steady-state response components (i.e., horizontal,
vertical, and torsional) for each eye. 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 or
tachometer velocity for rotation) using a nonlinear least squares
algorithm based on the Levenberg-Marquardt method. trVOR 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. On the basis of the sign definitions used, the phase
of the compensatory horizontal response during lateral motion should be
~0°. Primary afferent activity was expressed as instantaneous
frequency. Gain and phase of neural activity during translation were
determined by fitting sinusoidal functions similarly as in eye velocity
responses. Both gain and phase of primary otolith afferent responses
have been expressed relative to linear acceleration (similarly as in
Fernández and Goldberg 1976b
).
For transient response analyses, the Savitzky-Golay quadratic
polynomial filter was used with a 1 (rather than 15)-point forward and
backward window. For each individual run, initial eye acceleration was
estimated as the slope of a line fitted to the first 17 ms after
response onset. Response latencies were computed as the onset of eye
velocity relative to ideal velocity (3-SD method) (see Angelaki
and McHenry 1999).
To quantitatively evaluate the effects of anodal and cathodal
labyrinthine stimulation on yaw VOR during long-duration velocity steps, a straight line was fit to 2-s segments of horizontal slow phase
velocity both immediately before and ~300 ms after onset of 3- or 5-s
duration of bilateral anodal or cathodal currents. The effect of
labyrinthine electrical stimulation to slow phase eye velocity then was
computed as the percent change in the zero-intercept of the two
regression lines for each current presentation (Table 4). Because there
was no consistent change in the rate of decay of slow phase eye
velocity (see also Angelaki and Perachio 1993), the
slopes of the fitted lines are not reported here. For yaw OVAR, the
same analysis was used to quantify the effects of the currents.
Nevertheless, quantitative measurements were only possible in two of
the three animals tested (animal E for ±60°/s and
animal C for +60°/s), when the relative magnitude of the
sinusoidal modulation was small compared with the steady-state,
"bias" horizontal component. Otherwise, when steady-state eye
velocity was small and the sinusoidal modulations in eye velocity
large, the effects of the currents (always lasting
5s) could not be evaluated.
Because of the larger efficacy of the labyrinthine electrodes in
animal E, stimulation effects were generally larger in this animal. However, all effects observed in animal E also were
present (although often they were smaller) in all other tested animals. Not all protocols were tested in all animals. In general, testing a
minimum of three animals was used as a goal for each of the specific
questions addressed here. Statistical comparisons were based on
analyses of variance (ANOVA) with repeated measures. For sinusoidal
response gain and phase, independent variables were frequency, viewing
distance, and labyrinthine stimulation. For transient analysis,
independent variables were adduction/abduction, viewing distance and
labyrinthine stimulation. All F values reported are based on
comparisons where the labyrinthine stimulation factor had three levels:
no stimulation, anodal stimulation (+100 µA), and cathodal
stimulation (100 µA). The effects of anodal or cathodal stimulation
alone also were tested separately (2-level comparisons). Unless
otherwise stated, when the three-level labyrinthine stimulation factor
was significant, the same significance levels also held for the
separate comparisons of anodal or cathodal stimulation with control values.
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RESULTS |
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3-D eye movements evoked by unilateral anodal and cathodal labyrinthine stimulation
Unilateral anodal or cathodal stimulation elicited conjugate eye movements with slow phase velocity that increased sharply to a peak. Nystagmus persisted throughout the duration of stimulation, although some decay in slow phase velocity was occasionally observed (Fig. 1). For all five animals, the nystagmus was primarily horizontal and torsional with small, inconsistent vertical components (primarily with upward slow phase). Slow phases were contralaterally directed for cathodal (excitatory) currents. Left ear cathodal stimulation, for example, rotated both eyes clockwise (i.e., extorsion of the right eye and intorsion of the left eye) and rightward (Fig. 1, left; positive torsional and negative horizontal components, respectively). Opposite-directed eye movements were observed during anodal (inhibitory) stimulation (Fig. 1). Peak responses in all five animals are illustrated in Fig. 2. Despite consistent horizontal and torsional responses, vertical eye movements were highly variable. In four of the animals, the direction of vertical slow phase velocity was upward (negative) and independent of the polarity of the stimulus. In the fifth animal, left cathodal stimulation and right anodal stimulation elicited downward (positive) slow phase eye movements (Fig. 2, bottom).
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The peak amplitudes of the horizontal and torsional components were similar, although a strong asymmetry between anodal and cathodal stimulation was always observed, particularly for large current amplitudes. The peak amplitude of slow phase eye velocity increased for larger current amplitudes and exhibited a clear saturation for anodal stimulation of similar magnitude (Fig. 2). This behavior was quantified through second-order linear regression fits (Table 1). Anodal currents of 100 µA resulted in a slow phase velocity of ~15-30°/s in four of the animals and ~40-50°/s in the fifth animal (E). For this reason, animal E was tested with 50 and 100 µA (the remaining animals were tested primarily with 100 µA currents).
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Bilateral labyrinthine currents resulted in negligible horizontal nystagmus. Torsional nystagmus, however, was sometimes not completely cancelled (e.g., Fig. 3 and 9). We have used such bilateral anodal labyrinthine electrical stimulation during both lateral and fore-aft motion to study the effects of functional ablation of the most irregularly firing afferents on the trVORs.
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Effects of labyrinthine currents on the viewing distance-dependent properties of the trVOR during steady-state lateral oscillations
Both anodal and cathodal stimulation had a profound effect on the
sensitivity of trVORs during near target fixation. As shown in Fig. 3
for a viewing distance of 10 cm, anodal stimuli resulted in decreased
trVOR responses. In contrast, cathodal stimuli increased trVOR
responses. In the absence of labyrinthine electrical stimulation and as
expected based on the kinematic requirements of the reflex, the
elicited horizontal eye movements depended on target distance, as it
was varied between 10 and 40 cm (Fig.
4A, ). Horizontal response
sensitivity increased approximately proportional to the inverse of
viewing distance, although the regression line slope was never as steep
as that required for ideal gaze stabilization (see also Telford
et al. 1997
). In addition to a less than ideal slope,
regression lines did not pass through zero, suggesting that there is a
nonzero response during viewing at infinity (see also Telford et
al. 1997
).
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The effects of viewing distance depended on current stimulation (Fig.
4A, ,
,
, and
; see also Table
2). In the presence of cathodal
labyrinthine stimulation, both the zero intercept and the regression
line slope increased in amplitude. The opposite was generally true for
anodal currents. These differences were statistically significant
[slope: F(2,18) = 11.5, P < 0.01, 0-intercept: F(2,18) = 9.97, P < 0.01]. The same significance levels also were obtained when anodal or
cathodal effects were considered alone (and compared with control
data).
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The effects of labyrinthine stimulation were observed in all eye velocity components, not just the horizontal. Specifically, labyrinthine stimulation affected the viewing distance-dependence of the torsional and vertical eye velocity components of the trVOR (e.g., Fig. 3). As shown in Fig. 4B, for example, the magnitude of the torsional response component increased in a viewing distance-dependent manner in the presence of cathodal labyrinthine currents.
Effects of labyrinthine currents on the dynamics of the trVOR during lateral motion
In addition to the large effects on the sensitivity amplitude and viewing distance dependence of eye velocity, cathodal and anodal stimulation consistently altered the high-frequency dynamics of the trVOR during near target fixation (Fig. 5). The most profound effect was the observed changes in response phase [F(2,26) = 19.4, P < 0.01]. Compared with control responses, anodal currents increased the phase lags, whereas cathodal currents decreased the phase lags (or equivalently, increased the phase leads). Response sensitivity was also significantly affected by the currents [F(2,26) = 29.8, P < 0.01].
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To examine the effects of labyrinthine electrical stimulation on
the trVOR dynamics in a broader frequency range, three animals also
were tested in complete darkness (vergence angles of ~1 MA) (Angelaki 1998). Both anodal and cathodal stimulation
significantly altered the sensitivity [F(2,36) = 12.2, P < 0.01] and phase [F(2,36) = 39.2, P < 0.01] of the horizontal trVOR response, as tested at 0.3-12 Hz (Fig. 6). Labyrinthine
stimulation also significantly altered the frequency dependence of the
reflex [sensitivity: F(28,36) = 4.0, P < 0.01; phase: F(28,36) = 3.1, P < 0.01]; anodal currents decreased the slope of the sensitivity curves
and increased the phase lags. Cathodal stimulation had effects that
were opposite and usually larger. As a result of the change in slope,
trVOR sensitivity during cathodal labyrinthine stimulation was larger than control data at high frequencies but smaller than control data at
low frequencies. Between ~1 and 4 Hz, little effect of the current on
trVOR sensitivity actually was observed.
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The observed effects of labyrinthine currents were independent of peak acceleration (and consequently, velocity) amplitude. This was tested in two animals where the effects of the currents were studied for four different peak acceleration magnitudes at 5 Hz (Fig. 7). In both animals, the effects of the currents were independent of peak stimulus amplitude.
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Effects of labyrinthine currents on transient trVOR responses during lateral motion
The changes in the dynamics and sensitivity of the trVOR with anodal and cathodal labyrinthine currents that were observed during steady-state lateral oscillations were also apparent in the eye movements elicited during transient head displacements. Responses from four animals during fixation of a space-fixed target at a distance of 87 cm have been illustrated in Fig. 8. Similar to the data during sinusoidal oscillations (Fig. 6), current effects were largest in animal E (Fig. 8, top left). Despite variability in the magnitude of the changes (which reflected the different effectiveness of electrodes in the 4 animals; e.g., Fig. 2), anodal currents during transient motion elicited trVORs that had more sluggish dynamics as compared with control responses (Fig. 8, compare blue with green lines). Moreover, cathodal stimulation usually resulted in larger and more dynamic responses for the first ~60 ms following lateral motion onset (Fig. 8, red lines).
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Results from all four animals at both viewing distances (10 and 87 cm)
have been summarized in Table 3.
Labyrinthine stimulation had a significant effect on initial eye
acceleration [F(2,436) = 69.8, P < 0.01]. Initial eye acceleration significantly decreased during anodal
stimulation [F(1,322) = 127.2, P < 0.01]. Eye acceleration tended to increase in the presence of cathodal
currents, although the difference was not statistically significant.
During near target fixation, eye acceleration was larger for abducting
compared with adducting eye movements [F(1,229) = 23.0, P < 0.01] (see also Angelaki and McHenry
1999). These asymmetries were affected by the currents
[F(2,229) = 6.4, P < 0.01]. More
specifically, no significant asymmetry was observed in the presence of
anodal stimulation [F(1,174) = 0.03, P > 0.05]. Response latency was not significantly affected by the
currents and it ranged between 7 and 11 ms for all conditions (see also
Angelaki and McHenry 1999
).
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Effects of labyrinthine currents on fore-aft VOR
The effects of anodal and cathodal labyrinthine stimulation on the dynamics and sensitivity of the trVORs during fore-aft motion were tested in three animals (C, P and G) during 4 and 10 Hz oscillations while fixating targets to the left and to the right at a distance of 20 cm (vergence of ~10°). Results were similar to those during lateral oscillations. Accordingly, anodal labyrinthine stimulation decreased the sensitivity and the phase lags of the fore-aft VORs. Cathodal stimulation, on the other hand, increased the sensitivity and introduced larger phase leads. The current effects on both sensitivity and phase were statistically significant [F(2,64) = 35.6, P < 0.01 and F(2,64) = 6.63, P < 0.01, respectively]. The observed differences were similar for both 4 and 10 Hz.
Effects of labyrinthine currents on the rotational VOR
In contrast to the lack of any prominent changes in the rotational
VOR during 0.5-2 Hz sinusoidal oscillations, bilateral labyrinthine
stimulation resulted in changes in the rotational VOR during
long-duration velocity steps (see also Angelaki and Perachio
1993). In 2/3 animals tested, anodal currents consistently decreased slow phase eye velocity throughout the duration of per- or
postrotatory nystagmus (Fig. 9). In the
third animal (P), the effects were rather asymmetric for the
two directions of rotation. Percent changes in slow phase eye velocity
for all three animals have been included in Table
4A. Even though cathodal
currents tended to have the opposite effect and increase slow phase
velocity, results were more variable among animals. The effects of
current stimulation on the steady-state velocity during off-vertical
axis rotations (OVAR) could be evaluated using the 2-s straight line fit only when the relative magnitude of the horizontal slow phase velocity modulation was small compared with the steady-state
("bias") component. In the cases where the effects could be
assessed quantitatively, anodal currents decreased and cathodal
currents increased the steady-state horizontal eye velocity (Table
4B).
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Single-unit recordings from primary vestibular afferents
Because all previous studies of the effects of labyrinthine
electrical stimulation on primary vestibular afferent activity have
been conducted in other species, the efficacy of this technique in
rhesus monkeys was verified by examining the effects of 1-2 s
ipsilateral labyrinthine electrical stimulation on the firing rate of
vestibular afferent fibers. Examples from four afferent fibers, two of
which are characterized by regular firing rates and two of which are
characterized by irregular firing rates, have been illustrated in Fig.
10. Results in 15 cells recorded from
the vestibular nerve of two rhesus monkeys were similar to what has
been reported previously in squirrel monkey (Minor and Goldberg
1991), gerbil (Kaufman and Perachio 1994
;
Marshburn et al. 1997
), and pigeon afferents
(Dickman and Angelaki 1993
). The most irregularly firing
cells were silenced completely by positive 100-µA currents, whereas
regularly firing cells were affected only slightly.
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Because the dynamics of primate otolith afferents have only been
examined at frequencies 2 Hz and to be able to simulate the effects
of labyrinthine currents on the dynamics of the trVOR, we recorded the
gain and phase from 21 primary otolith afferents during sinusoidal
oscillations similar to those used for the eye movement studies. Of
these 21 afferents tested, 6 were regularly discharging (CV* < 0.1)
(CV* computed as in Goldberg et al. 1984
) and 15 were
irregularly discharging (CV* > 0.1). Average data for each population
are compared with those reported in squirrel monkeys in Fig.
11 (
and
: present study;
and
: Fernández and Goldberg 1976b
). Both sets of
data were fitted with the following transfer functions
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(1b) |
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DISCUSSION |
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We have examined the effects of bilateral labyrinthine electrical stimulation on the sensitivity, phase and viewing distance-dependent properties of the trVORs by delivering 100 µA of anodal (inhibitory) and cathodal (excitatory) currents during translational motion. Functional ablation (anodal currents), as well as potential recruitment (cathodal currents), have been both shown to alter the sensitivity, dynamics and viewing distance-dependence of the trVORs.
Use of labyrinthine currents as a means to investigate the functional role of irregular vestibular afferents
The sensitivity of primary vestibular afferents to labyrinthine
electrical stimulation has been shown to be a function of discharge
regularity. The more irregularly firing an afferent, the higher its
sensitivity to electrical stimulation (Goldberg et al.
1984). This property has been demonstrated to be true in several species, including squirrel monkeys (Goldberg et al.
1984
; Lysakowski et al. 1995
; Minor and
Goldberg 1991
), rhesus monkeys (present study), chinchillas
(Goldberg et al. 1990
), and pigeons (Dickman and
Angelaki 1993
). Even though unilateral ear stimulation results
in significant nystagmus, bilateral labyrinthine stimulation largely
cancels most nystagmus while concurrently decreasing the spontaneous
activity of many vestibular afferents. The technique of bilateral,
constant labyrinthine stimulation often has been used as a means of
addressing the role of irregularly firing vestibular afferents to the
VOR (Angelaki and Perachio 1993
; Angelaki et al.
1992
; Chen-Huang and McCrea 1998
; Minor
and Goldberg 1991
) and central vestibular processing
(Chen-Huang et al. 1997
; Dickman and Angelaki
1993
).
Even though bilateral labyrinthine electrical stimulation is still the sole way of addressing the role of different afferent types, it presents several limitations that can be both practical and functional. Repeated electrical stimulation often has been a problem in previous studies. In the present experiments, special care was taken to avoid electrode polarization. First, the two electrodes in each ear remained shorted in between experimental sessions. Second, both anodal and cathodal stimuli were alternated during each experimental session. Third, the labyrinthine electrodes were platinized rather than silver-chlorided before implantation. These three measures were sufficient to eliminate any observable effects due to electrode polarization throughout these experiments.
The functional effectiveness of the labyrinthine electrical stimulation technique is more difficult to quantify. There are at least two problems in interpreting results from these ablation studies. First, there is the possibility that the decrease in primary afferent discharge during anodal stimulation (including both regular and irregular afferents) results in a global silencing or lowering of spontaneous activity of central neurons such that large peak-to-peak sinusoidal stimuli drive the cells into inhibitory saturation. Such a central mechanism would result in decreased VOR responses without necessarily a direct involvement of irregular vestibular afferents to reflex properties. The following results argue against such an interpretation. 1) The largest effects of the currents on trVOR dynamics were observed in response phase. The global inhibitory saturation mechanism would predict changes in sensitivity but not response phase. 2) The effects of the currents were present not only during steady-state sinusoidal oscillations but also very early in the response during transient head displacements. And 3) if the observed results were primarily due to central inhibitory saturation, the effects of the currents should increase as a function of peak stimulus acceleration amplitude. When we varied peak linear acceleration, there was no evidence of such a dependence (Fig. 7).
The second problem in the interpretation of results from ablation
studies is related to the fact that primary vestibular afferents are
known to constitute a continuum, such that absolute segregation into
regular and irregular afferents is problematic. Electrical stimulation
of the labyrinth results in changes in the mean firing rates of both
regularly and irregularly firing vestibular afferents (e.g., Fig. 10),
although irregularly firing afferents are much more sensitive. In fact,
our experience in both rhesus monkeys and pigeons suggests that it is
essentially impossible to silence regularly firing afferents even with
very large currents (500 µA) that we were able to deliver in acute
bird preparations (Dickman and Angelaki 1993
).
Significant changes in a VOR response parameter in the presence of
anodal labyrinthine stimulation could suggest that irregularly firing
afferents contribute to the normal function of the reflex. Quantitative
conclusions regarding more specific afferent contributions are,
however, difficult. Keeping these functional limitations in mind, the
following paragraphs summarize the main experimental results in the
context of previous knowledge as well as attempt to speculate on the
functional implications of the present findings by simulating a simple
model for the trVOR.
Effects of labyrinthine electrical stimulation on the dynamics and viewing distance dependence of the trVORs
Significant effects of anodal and cathodal labyrinthine stimulation on the dynamics of the translational VORs were observed in the present studies. Anodal stimulation decreased trVOR sensitivity and increased phase lags. Cathodal stimulation had the opposite effects and resulted in more high-pass filter properties (i.e., it increased both the phase leads and the slope of the sensitivity changes as a function of frequency). Changes in reflex sensitivity and phase were common to both fore-aft and lateral responses.
The effects of the currents on the trVOR dynamics were also significant
during transient head displacements. Anodal stimulation significantly
decreased initial eye acceleration compared with control values. As
also shown in our previous study (Angelaki and McHenry
1999), initial eye acceleration during near target viewing was
larger for abduction compared with adduction responses. Anodal
stimulation eliminated this asymmetry, suggesting that there might be a
differential irregular afferent input to the otolith-abducens compared
with the otolith-medial rectus pathways.
The significant effects of labyrinthine stimulation on the dynamics of
the trVORs observed here might seem in contrast to recent results
during eccentric rotation in squirrel monkeys (Chen-Huang and
McCrea 1998). Using comparisons between the VOR elicited during centered and eccentric rotations, the authors concluded that there was
no effect of the currents on the translational VOR. The difference in
the two sets of observations could be due to the different stimuli used
in the two studies. Chen-Huang and McCrea (1998)
used
relatively low frequencies (0.5-4 Hz). As shown here, labyrinthine stimulation alters the slope of the sensitivity increase over frequency
such that the largest changes are seen for frequencies >5 Hz (Figs. 5
and 6). Coactivation of both semicircular canal and otolith-ocular
pathways during eccentric rotation might also constitute another
difference. For example, nonlinear interactions between semicircular
canal and otolith signals have been shown recently to be fundamental in
the detection of head translation (Angelaki et al.
1999a
).
Irregularly firing vestibular afferents are characterized by more
phasic response properties compared with regularly firing cells (Fig.
11) (see also Fernández and Goldberg 1976b;
Goldberg et al. 1990
). Thus the reduced initial eye
acceleration, the increase in phase lag and the decrease in the
high-pass filtered properties of the reflex in the presence of anodal
stimulation could then be a direct consequence of the functional
ablation of the most phasic afferents. This hypothesis has been
investigated further here by simulating a simple model considering both
regular and irregular otolith afferents (see following text). The
opposite effects of cathodal stimulation in the dynamics of the trVORs are more puzzling. To explain these results, one would have to consider
a "functional recruitment" during cathodal stimulation that
operates in a similar fashion as the postulated "functional ablation" due to silencing of the background discharge of a
population of vestibular afferents during anodal stimulation. For
example, cathodal currents could increase the background discharge of
low-firing irregular vestibular afferents that normally would rectify
during high-frequency stimuli. By increasing the peak-to-peak
modulation of these units, their contribution to the central pathways
mediating the reflex also increases. Hence addition of the dynamics
from a larger number of phasic, higher-lead afferents could augment the
high-pass filtered properties and increase the phase leads of the
trVORs (see following text).
Anodal and cathodal labyrinthine stimulation also resulted in
significant but opposite changes in the reflex sensitivity as a
function of viewing distance. Anodal stimulation did not simply induce
a parallel-shift in the linear regression lines describing response
sensitivity as a function of the inverse of viewing distance, but also
decreased their slopes (Fig. 4; Table 2). In fact, it was both the zero
crossing (viewing distance-independent component) and the regression
line slope (viewing distance-dependent component) (see Angelaki
et al. 2000) that decreased with anodal stimulation. The
opposite effects of cathodal labyrinthine stimulation whereby both the
zero crossing and slope of the lines increased might represent an
effect of functional recruitment, as outlined in the preceding text.
Response dynamics-model simulations
The dynamic properties of the translational VORs have been
simulated here using the following transfer function (Fig.
12A)
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(2) |
|
The following simulations were performed with
Ho(s) = s/(s + 1),
= 0.318s
(corresponding to a frequency of 0.5 Hz),1
Greg = 0.148 and
Girreg = 0.0148 (Fig. 12B,
). Anodal and cathodal stimulation was assumed to decrease and
increase the irregular afferent contribution by 1/2 (Fig.
12B,
and
, respectively). Within the constraints
related to the fact that Fig. 12A is only a very rough
approximation of the trVOR processing, simulations agree qualitatively
with experimental results. Anodal stimulation that is assumed to
decrease the contribution of irregular afferents decreases trVOR
sensitivity and increases the phase lags. Cathodal stimulation that is
assumed to increase the contribution from irregular afferents increases
trVOR sensitivity and decreases the phase lags. The simple block
diagram summarized in Fig. 12A could predict the viewing
distance effects of the currents only if it is assumed that the
irregular afferent signals are selectively scaled by the inverse of
viewing distance (Fig. 12C). When this scaling was applied
to all afferent signals, the simulated effects of the currents were to
change the trVOR sensitivity without affecting the slope of the
dependence on 1/D. Because of the crudity of the simplified
model of Fig. 12A, no attempt was made to simulate quantitative aspects of the trVORs (e.g., the nonzero sensitivity during viewing at infinity).
It should be added that multiple computational schemes could be
implemented to account for the effects of the currents in the viewing
distance dependence of the trVORs. The exact details of each plausible
scheme would depend fundamentally on how the viewing distance-dependent
properties are implemented in the VORs. In the simplified block diagram
of Fig. 12A (proposed by Paige and colleagues, e.g.,
Telford et al. 1997), vergence has been assumed to
directly modulate trVOR interneurons based on simple multiplicative
interactions. Alternatively the viewing distance-dependent properties
of the trVORs could be implemented through distributed networks where
the linear scaling of response sensitivity as a function of the inverse
of viewing distance emerges as a network property and the neuronal
implementation of this scaling is more complex than the simple
multiplication scheme. For example, one such network could be
postulated to modulate the background (mean) firing rates of the
constituent neurons as a function of vergence angle. That is, the
closer the target and the higher the vergence angle, the larger the
firing rates and the larger the number of neurons that are recruited to
participate in the trVORs. In fact, such a mechanism could easily be
made to account for the nonzero sensitivity during viewing at infinity.
According to such a hypothetical scheme, labyrinthine currents would
"mimic" larger or lower vergence angles by affecting the background
firing rates of the network neurons.
Effects of labyrinthine electrical stimulation on the rotational VOR
Even though there is universal agreement that labyrinthine
electrical stimulation has no effect on the midfrequency (~0.5-4 Hz)
rotational VOR in darkness, this is not the case for other aspects of
the VOR during head rotation. Chen-Huang and McCrea (1998), for example, reported that the small viewing distance dependent increases in the gain of the rotational VOR were abolished during anodal labyrinthine stimulation. In addition, Angelaki and Perachio (1993)
reported that anodal labyrinthine
stimulation seemed to decrease slow phase eye velocity during long
duration rotation steps in squirrel monkeys. Similar results to those
previously reported in squirrel monkeys also were made here (Fig. 9;
Table 4).
It should be noted also that the effects of bilateral labyrinthine electrical stimulation on the rotational VOR have not yet been tested at high frequencies (i.e., >4 Hz). It is possible that the current effects on the rotational VOR parallel those seen in the translational VOR at a corresponding frequency and viewing distance range. Taken together, the present and previous results suggest that labyrinthine electrical stimulation seems to alter specific aspects of the VORs, primarily at low and high frequencies. Even though the details of such a processing await investigation, these behavioral observations do provide some preliminary conclusions regarding the differential role of the vestibular afferent continuum in the sensorimotor transformations of the vestibuloocular system.
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ACKNOWLEDGMENTS |
---|
The authors thank A. Haque for contributions to single-unit recordings. The authors also acknowledge 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-12814 and EY-10851) and the Air Force Office of Scientific Research (F-49620) and a National Aeronautics and Space Administration Presidential Young Investigator Award.
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FOOTNOTES |
---|
Present address and address for reprint requests: D. Angelaki, Dept. of Anatomy and Neurobiology, Washington University School of Medicine, Box 8108, 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.
1
Function
Ho(s) consists of an
integrator (which can be either neural or contributed by the eye plant)
(e.g., Green and Galiana 1998) and a high-pass filter.
Even though this simple function cannot accurately describe the phase
of the reflex, it has been used here for simplicity (see also
Telford et al. 1997
). To precisely describe the gain and
phase dependence of the trVORs a much more complex transfer function is
required (e.g., Angelaki 1998
). Even though we strongly
believe that a lumped block diagram that does not incorporate the
bilateral organization of the system is inappropriate to capture the
intricate properties of the trVORs, the simulations of the diagram of
Fig. 12A are presented here merely to demonstrate that
the main effects of the currents could be predicted through a
functional ablation and recruitment of irregular otolith afferents.
Received 5 February 1999; accepted in final form 16 November 1999.
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REFERENCES |
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