Departments of Neurology and Biophysics and Physiology, Mount Sinai School of Medicine, New York 10029; and Computer and Information Sciences, Brooklyn College of the City University of New York, Brooklyn, New York 11210
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ABSTRACT |
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Wearne, Susan, Theodore Raphan, and Bernard Cohen. Control of spatial orientation of the angular vestibuloocular reflex by the nodulus and uvula. J. Neurophysiol. 79: 2690-2715, 1998. Spatial orientation of the angular vestibuloocular reflex (aVOR) was studied in rhesus monkeys after complete and partial ablation of the nodulus and ventral uvula. Horizontal, vertical, and torsional components of slow phases of nystagmus were analyzed to determine the axes of eye rotation, the time constants (Tcs) of velocity storage, and its orientation vectors. The gravito-inertial acceleration vector (GIA) was tilted relative to the head during optokinetic afternystagmus (OKAN), centrifugation, and reorientation of the head during postrotatory nystagmus. When the GIA was tilted relative to the head in normal animals, horizontal Tcs decreased, vertical and/or roll time constants (Tcvert/roll) lengthened according to the orientation of the GIA, and vertical and/or roll eye velocity components appeared (cross-coupling). This shifted the axis of eye rotation toward alignment with the tilted GIA. Horizontal and vertical/roll Tcs varied inversely, with Tchor being longest and Tcvert/roll shortest when monkeys were upright, and the reverse when stimuli were around the vertical or roll axes. Vertical or roll Tcs were longest when the axes of eye rotation were aligned with the spatial vertical, respectively. After complete nodulo-uvulectomy, Tchor became longer, and periodic alternating nystagmus (PAN) developed in darkness. Tchor could not be shortened in any of paradigms tested. In addition, yaw-to-vertical/roll cross-coupling was lost, and the axes of eye rotation remained fixed during nystagmus, regardless of the tilt of the GIA with respect to the head. After central portions of the nodulus and uvula were ablated, leaving lateral portions of the nodulus intact, yaw-to-vertical/roll cross-coupling and control of Tcvert/roll was lost or greatly reduced. However, control of Tchor was maintained, and Tchor continued to vary as a function of the tilted GIA. Despite this, the eye velocity vector remained aligned with the head during yaw axis stimulation after partial nodulo-uvulectomy, regardless of GIA orientation to the head. The data were related to a three-dimensional model of the aVOR, which simulated the experimental results. The model provides a basis for understanding how the nodulus and uvula control processing within the vestibular nuclei responsible for spatial orientation of the aVOR. We conclude that the three-dimensional dynamics of the velocity storage system are determined in the nodulus and ventral uvula. We propose that the horizontal and vertical/roll Tcs are separately controlled in the nodulus and uvula with the dynamic characteristics of vertical/roll components modulated in central portions and the horizontal components laterally, presumably in a semicircular canal-based coordinate frame.
The angular vestibuloocular reflex (aVOR) exhibits the property of spatial orientation. During nystagmus induced by rotation of the subject or surround, the yaw axis component of slow-phase velocity tends to align with gravity or with the gravito-inertial acceleration vector (GIA) (Angelaki and Hess 1994a
Juvenile rhesus monkeys (Macaca mulatta; weight 3-4 kg) were used in these studies. Quantitative data came largely from two animals with representative complete and partial lesions (M9312 and M9303), but relevant results from five other monkeys with complete (M1107, M1152, and M1153) and partial lesions (M1173 and M1175) from previous studies (Cohen et al. 1992 Surgical procedures
Animals were prepared initially under anesthesia with a frontal plane coil to record horizontal and vertical eye position (Judge et al. 1980 Stimulation apparatus
Testing began ~1 wk after operation and continued for 12-36 mo. Eye movements were induced by optokinetic stimulation, by angular acceleration about an earth vertical axis with the animal either centered or at a 25-cm radius from the axis of rotation, or by rapidly reorienting the animal during postrotatory vestibular nystagmus. The stimulator (Neurokinetics, Pittsburgh, PA), has been described previously (Wearne et al. 1996 Coordinates and notation
The three-dimensional components of the vestibular stimuli and oculomotor responses were referenced to the right-handed Cartesian coordinate system shown in Fig. 1A. The X-, Y-, and Z-axes denote the interaural (positive left), nasooccipital (positive backward), and dorsoventral (positive up) axes of the head, respectively. Three-dimensional eye orientation is represented as Euler angles using the Fick rotation convention.2 The symbols, Calibration of eye position
Eye orientation was measured using the implanted scleral search coils. The normal to the frontal coil on the implanted eye was aligned with the visual axis. Portions of the frontal coil voltages were subtracted from the roll coil voltages to remove cross-talk as the upright animal was rotated around a spatial vertical axis. To calibrate eye position in untrained monkeys, we made use of the fact that Listing's plane is aligned approximately with the coronal head plane and is independent of the initial reference position from which eye position axes are calculated (Helmholtz 1866 Experimental protocol
The order of testing was independently randomized for each monkey, and repeated measures were performed on each experimental condition. Amphetamine sulfate (0.3 mg/kg) was given 30 min before testing to maintain alertness. Monkeys were rotated in yaw to habituate the time constant of velocity storage to some stable value. This ensured that effects of habituation during the experiments would not significantly influence the experimental results (Cohen et al. 1992
Data acquisition and processing
Eye position and photocell data were sampled at a rate of 600 Hz per channel. Before sampling, the eye position data were prefiltered by an 8-pole Butterworth filter with a cutoff corner frequency of 30 Hz. Slow-phase eye velocity was obtained by calculating the vector of eye velocity in head coordinates and removing saccades, using an order statistic filter (Engelken and Stevens 1990 Description of nodulo-uvular lesions
Sagittal sections in monkey M9312, in whom the entire nodulus and most of the uvula were removed are shown in Fig. 2, A and B. The lesion was also reconstructed on sagittal sections from a normal rhesus cerebellum (Fig. 2C) (Madigan and Carpenter 1971
Complete nodulo-uvulectomy and the time constants of velocity storage
Time constants of the velocity storage component of the aVOR are dependent on orientation of the head relative to gravity in normal monkeys, and the horizontal and vertical/roll components vary inversely. In each case, the time constants are maximal when animals are positioned so that the axis of the angular stimulus is coincident with the spatial vertical (Angelaki and Hess 1994a
Complete nodulo-uvulectomy and spatial orientation of the aVOR
During eccentric rotation (centrifugation) in the normal animal, the GIA vector tilts relative to the upright head. This has two consequences: the horizontal velocity storage time constant is reduced, and vertical cross-coupled components of eye velocity appear, tending to align the eye velocity axis with the GIA (Raphan et al. 1996
Partial nodulo-uvulectomy and time constants of velocity storage
After partial lesions that involved the central portions of the nodulus and uvula, animals retained control of the horizontal time constants, but lost control of the vertical and roll time constants. Thus the pitch and roll aVOR time constants were reduced for stimulation about a spatial vertical axis, as in the completely lesioned animals. Examples of reduction in the pitch aVOR time constant before and 1 wk after surgery are shown in Fig. 5, E and F; there was no recovery 4 mo later. The central (velocity storage) time constants of the vertical aVOR, recorded on-side in M9303, were reduced from 10.9 s to 1.7 ± 0.6 (SD) s for upward and from 8.6 s to 2.6 ± 0.4 s for downward slow phase velocities (Table 3). During velocity steps of 60°/s, either nose down (prone) or nose up (supine), the time constant of the roll VOR for both directions of rotation was reduced from an average 7.4 s before surgery to 2.2 s after surgery (Table 3).
Partial nodulo-uvulectomy and spatial orientation of the aVOR
Although partially lesioned animals maintained the ability to modify the horizontal time constant, they partially or completely lost the ability to orient the eye velocity axis to the tilted GIA. Thus, during centrifugation in M9303 the predominant nystagmus velocity was horizontal (
Model of control of spatial orientation
Neural implementation of spatial orientation of the aVOR was related to our general model of the aVOR and its extension to three dimensions (Raphan and Cohen 1996 Results of modeling responses before and after partial and complete nodulectomy
By altering the eigenvalues and cross-coupled components, the model simulated the responses in the normal, partially lesioned, and completely lesioned states during OKN and OKAN (Fig. 19). Simulations were performed in response to a surround velocity of 60°/s with the head upright and tilted 90° in side down and prone/supine positions. The stimulus states are shown by the insets on the side of Fig. 19, and correspond to each of the traces in that row. Normal responses are shown in the first column, and responses after partial and complete nodulo-uvulectomy in the second and third columns, respectively.
This study shows that by controlling the time constants and cross-coupling parameters of velocity storage, the nodulus and ventral uvula orient eye velocity toward the GIA. After removal of the nodulus and uvula, the horizontal aVOR and OKAN time constants were long, the vertical and roll time constants were short, and eye velocity induced by yaw axis stimulation remained fixed along the yaw axis of the head, irrespective of the manner in which the GIA tilt was induced. Thus the eye velocity vector was now independent of the direction of the GIA, and spatial orientation was fixed in a mode that corresponded to the upright position in a gravitational field.
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
,b
; Dai et al. 1991
; Harris 1987
; Harris and Barnes 1987
; Raphan and Cohen 1986
; Raphan et al. 1992
, 1996
; Raphan and Sturm 1991
; Wearne et al. 1996
, 1997a
,b
). Alignment of the eye velocity vector with the GIA has been modeled by three processes: a reduction in the time constant of the dominant horizontal component, an increase in the torsional and/or vertical time constants, and the appearance of orthogonal vertical or torsional "cross-coupled" eye velocity (Dai et al. 1991
; Raphan and Cohen 1996
; Raphan et al. 1992
; Raphan and Sturm 1991
).1 We have shown that the velocity storage mechanism in the vestibular system is responsible for spatial orientation of the aVOR, and that the direct visual and vestibular pathways do not orient eye velocity to the GIA (Wearne et al. 1997a
). The study of the spatial orientation of the aVOR is therefore essentially a study of the three-dimensional characteristics of velocity storage. Because velocity storage is activated by somatosensory input in both monkey (Solomon and Cohen 1992
) and humans (Bles et al. 1984
), this type of spatial orientation is likely to be important for postural and gaze stabilization during angular locomotion (Cohen 1998).
; Fetter et al. 1992
) and in monkeys (Angelaki and Hess 1994a
; Merfeld 1995
; Merfeld et al. 1993
; Raphan et al. 1981
; Solomon and Cohen 1994
; Waespe et al. 1985
). The horizontal time constant is also reduced when subjects view a relative stationary visual surround during vestibular nystagmus or optokinetic afternystagmus (OKAN; light dumping) (Cohen et al. 1977
, 1981
; Waespe et al. 1983
, 1985
). Electrical stimulation of the nodulus and lobule 9d of the ventral uvula reproduces this reduction (Solomon and Cohen 1994
). Both tilt dumping and light dumping are lost after ablation of the nodulus and uvula (Angelaki and Hess 1994a
, 1995
; Waespe et al. 1985
).
, 1969
; Voogd et al. 1996
; Voogd and Bigaré 1980
). There are both visual (optokinetic) and vestibular climbing fiber afferents to the nodulus of the rabbit, and their sensitivity axes are aligned approximately with the axis of one of the three semicircular canals (Barmack and Shojaku 1992
, 1995
; Kano et al. 1990
; Wylie et al. 1994
). (The sensitivity axis of a neuron is that axis around which rotation causes a maximal modulation of its firing rate.) These axes, derived from physiological studies in the rabbit, are shown projected onto a monkey head in Fig. 1B. Activity induced by yaw optokinetic stimulation and nystagmus (OKN) about a vertical axis [VA (Yaw) OKN] is processed in the caudal dorsal cap (cdc), whereas activity related to optokinetic stimulation about an axis parallel to that of the ipsilateral anterior canal [horizontal axis, HA (135°) OKN] reaches the cerebellar cortex through the rostral dorsal cap (rdc) and ventrolateral outgrowth (vlo) (Balaban and Henry 1988
; Barmack and Shojaku 1992
; Graf et al. 1988
; Kano et al. 1990
; Katayama and Nisimaru 1988
; Leonard et al. 1988
; Simpson et al. 1981
; Takeda and Maekawa 1984
). Vestibular signals aligned approximately with the anterior and posterior canal axes [AC and PC (135°) VOR signals] project from the beta nucleus of the inferior olive (Alley et al. 1975
; Balaban and Henry 1988
; Barmack et al. 1993a
; Barmack and Shojaku 1992
, 1995
; Katayama and Nisimaru 1988
; Shojaku et al. 1991
). Utricular signals project from the dorsomedial cell column (DMCC) (Barmack and Fagerson 1994
) and the beta nucleus (Barmack et al. 1989
, 1993b
). As yet, no lateral canal-related signals have been found in the inferior olive or in climbing fiber responses (Barmack and Shojaku 1992
, 1995
).
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FIG. 1.
A: right-handed coordinate frame to which components of the eye velocity vector are referred. Positive direction of rotation about each axis is defined according to the right hand rule, as leftward yaw (+ Z), downward pitch (+
X) and counterclockwise roll (+
Y), from the animal's point of view. B: relation between the head reference frame used to describe 3-dimensional eye movements and maximal sensitivity axes for visual modulation of neurons in the left nodulus and right inferior olive of the rabbit (modified from Simpson and Graf 1985
). The excitatory direction for visually and vestibularly induced complex spike responses of Purkinje cells in the left nodulus of the rabbit is indicated by the curved arrows about axes VA and HA (135°) (Barmack and Shojaku 1992
). C-E: paradigms used to tilt the gravito-inertial acceleration vector (GIA) relative to the head during optokinetic or vestibular nystagmus. C: continuous tilts of GIA induced during optokinetic afternystagmus (OKAN) with the head upright and tilted left ear down (LED). Ag is the equivalent acceleration due to gravity. The angular velocity of the surround, along the Z-axis of the head, is given by
OZ. D: reorientation of the head with respect to the GIA during postrotatory nystagmus with the GIA equivalent to the vector of gravitational acceleration (Ag). The angular velocity of the head along the Z-axis is given by
HZ. During postrotatory nystagmus, the animal is tilted in the roll plane by the angle
, shifting the GIA relative to the head. E: centrifugation facing motion, centered and back to motion. Centripetal acceleration is indicated as Ac. The vector sum of Ag and Ac is the GIA vector. The angle between Ag and the GIA in the roll plane is given as
R. For +
HZ rotation, the animal was oriented right ear out when facing motion, and left ear out (LEO) when back to motion. An analogous stimulus paradigm was given for
HZ rotation, with left ear out when facing motion and right ear out (REO) when back to motion.
). Four sagittal zones have been distinguished, based on four white matter compartments innervated by discrete subnuclei of the contralateral inferior olive. The most medial zone (Zone 1) extends from the midline to 0.8 mm lateral in the nodulus and uvula. It receives composite climbing fiber input from the beta nucleus medially and the lateral caudal dorsal cap. If it is assumed that the same canal-, otolith-, and OKN-related information is present in the inferior olive of the monkey as in the rabbit, Zone 1 has horizontal axis [vertical canal, HA (135°) VOR] and otolith (
) as well as yaw axis representation [cdc; VA (Yaw) OKN]. The second zone (Zone 2) extends from 0.8 to 2.4 mm in the nodulus and uvula, and forms the lateral limits of the vermis over the posterior surface of the cerebellum. Zone 2 was labeled from injections that included the ventrolateral outgrowth, rostral beta, and rostral medial accessory olive (rMAO) in rhesus monkey (Voogd et al. 1996
). Input to this zone from vlo and from rostral
is related in the rabbit to HA (135°) OKN, HA (135°) VOR, and the utricle. Zone 3, innervated by the caudal dorsal cap in the monkey, would receive information about yaw axis OKN [VA (Yaw) OKN]. It extends from 2.4 to 3.2 mm in the nodulus and is restricted to the nodulus. Zone 4 extends from 3.2 to 4 mm lateral. Its olivocerebellar afferents are currently unidentified in rhesus monkey, but by analogy with the lateral zone in rabbit, probably include the DMCC and rMAO (Balaban and Henry 1988
; Katayama and Nisimaru 1988
; Tan et al. 1995
). We have adopted the classification of Voogd et al. (1996)
for the animals in our series, and these four zones are represented in Figs. 4 and 18.
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FIG. 4.
Schematic diagram indicating complete and partial lesions of nodulus and uvula in the monkeys of this series, drawn on sagittal zones defined by Voogd et al. (1996) and J. Voogd (personal communication). Zones are based on AChE staining of margins of white matter compartments, which carry the climbing fibers to each zone. Numbers below represent mm from the midline.
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FIG. 18.
Model of 3-dimensional control of orientation and dynamics of velocity storage system by the canal related zones of the nodulus and ventral uvula. Above are shown the 4 zones of the rhesus monkey nodulus, based on inferior olive input (Voogd et al. 1996 ). Zone 1 receives input from the
nucleus and the caudal dorsal cap (cdc). Zone 2 receives input from the ventrolateral outgrowth (vlo), and Zone 3 from cdc. Inputs to Zone 4 are still unidentified in the monkey. The inputs to the various subnuclei of the inferior olive are shown above and on left. G0, gain matrix in integrator pathway; G1, direct vestibular pathway gain matrix; Tcan, matrix of head to canal coordinate transformation. See text for details.
). The same is likely true for the monkey. Accordingly, complete or partial nodulo-uvulectomy was reported to impair the dynamics of the low-frequency torsional aVOR in the monkey, leaving the vertical aVOR relatively unaffected (Angelaki and Hess 1994a
, 1995
). Preliminary results following similar nodulo-uvular lesions, however, suggest that the nodulus and uvula control aVOR dynamics in all dimensions (Wearne et al. 1996
).
).
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
; Waespe et al. 1985
) were reanalyzed to expand the database. The experiments conformed to the Principles of Laboratory Animal Care (NIH Publication 85-23, Revised 1985), and were approved by the Institutional Animal Care and Use Committee.
; Robinson 1963
). A roll coil was threaded around the superior rectus muscle on top of the eye to record roll eye position (Dai et al. 1994
; Yakushin et al. 1995
). Bolts implanted on the skull provided painless head stabilization during experiments. The animals were allowed to recover from anesthesia and received baseline testing. At a later date, they were reanesthetized, and a 25% solution of mannitol (250 mg/ml) was administered to a dose of 1 gm/kg to reduce brain vascularity and edema. Under gas inhalation anesthesia, the dura and pia mater were opened, and the cerebellum was exposed. The secondary fissure was identified, and a horizontal dissection plane was established below the secondary fissure, between lobules 9a and 9b. The rostral extension of this plane led to the fourth ventricle just caudal to the fastigial nucleus. Partial lesions were confined to the central vermis. The nodulus (lobule 10) and ventral uvula (sublobules 9c and 9d) were aspirated from the midline to the lateral margins of the uvula (approximately ±2 mm). Complete nodulo-uvulectomy was performed by extending the dissection laterally in its rostral portions to include the lateral 2 mm of the nodulus (Madigan and Carpenter 1971
; Snider and Lee 1961
). More of the dorsal uvula (sublobules 9a and 9b) was generally removed in the complete than the partially lesioned animals. Bleeding was generally slight and was controlled with cautery. Vomiting, which can occur postoperatively after nodulo-uvulectomy (Cohen et al. 1992
; Waespe et al. 1985
), was prevented by prophylactic administration of promethazine HCl(2 mg/kg). Animals also received analgesics and antibiotics postoperatively. The animals were initially posturally unstable, but this gradually disappeared over the next several weeks.
, 1997a
,b
). In brief, it had three independently controlled, gimbaled axes of rotation: an outer horizontal axis, a nested yaw axis, and a doubly nested inner pitch-roll axis. The yaw and pitch-roll axes were enclosed in a light-tight, optokinetic sphere, 109-cm diam, with 10° vertical black and white stripes on the inside. The axis of the OKN sphere, which was also independently controlled, was collinear with the yaw axis. When the OKN sphere rotated, it produced full field motion that induced OKN and OKAN.
; Yakushin et al. 1995
).
,
, and
, represent rotations about the Z-axis, the rotated X-axis, and the doubly rotated Y-axis (visual axis). These angular deviations from the reference position will be referred to as horizontal, vertical, and roll eye positions, respectively. The components of the eye velocity vector in head coordinates, symbolized by
= [
X,
Y,
Z] that denoted vertical, torsional, and horizontal components, were obtained directly from the Euler angles and their derivatives (Goldstein 1980
; Yakushin et al. 1995
). Positive directions for the rotations are in accordance with the right-hand rule (Fig. 1A).
; Barmack and Shojaku 1992
; Wylie et al. 1994
) has been superimposed on the coordinate frame utilized in this study on the monkey (Fig. 1B). The axes of the ipsilateral anterior and posterior canals (AC and PC), are oriented at ~45 and 135° from the nasooccipital axis of the head. The vertical axis (VA) is aligned with the +Z head axis, whereas the positive pole of the horizontal axis (HA) (135°) is rotated counterclockwise about the +Z-axis by 135° from the forward-pointing pole of the nasooccipital (
Y) axis. The VA and HA axes are those axes about which rotation of the head or visual surround maximally activates climbing fibers and complex spike responses of Purkinje cells (Barmack and Shojaku 1992
; Kano et al. 1990
; Simpson and Alley 1974
; Wylie et al. 1994
). Thus the VA axis aligns approximately with the axis of the lateral canals, and the HA (135°) axis aligns with the axis of the ipsilateral (left) anterior canal and contralateral (right) posterior canal.
; Tweed and Vilis 1990
). We assumed that the average coil voltages during spontaneous positions of fixation while the animal made saccades for 15-30 s in light correspond to the straight ahead eye position with zero roll. This assumption is consistent with data obtained in trained and calibrated monkeys for a large range of saccades in light and dark (van Opstal et al. 1995
). When the eye is in this orientation, the visual axis is aligned with the
eY axis of the head frame. To a good approximation, this aligns with the stereotaxic coordinate frame of the head, which we physically aligned with the axes of the horizontal and vertical field coils. More complete details of the calibration of eye orientation are presented in Yakushin et al. (1995)
.
). As a result the time constant and initial value of OKAN for the upright position remained approximately constant throughout the period of testing. The horizontal OKAN time constant in the upright position was ~15-25 s, depending on the monkey. Intrasubject variability remained low throughout the period of testing.
Z rotation, these conventions were reversed. For facing and back to motion centrifugation, Ac was directed along the interaural axis, and the GIA tilted dynamically in the roll plane of the head, through an angle (
) that increased with the angular velocity of the centrifuge. Animals were also rotated about a centered axis (Fig. 1E, middle).
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FIG. 11.
Two-dimensional phase plane trajectories of eye rotation axes during centrifugation in M9312, which tilted the GIA by 52° in the roll (A) or pitch plane (B). Each graph is composed of 4 trials, one for +Z and another for Z rotation before (
) and after operation (
). Circles start at the points farthest from the origin on the top and bottom halves of each graph and proceed toward zero. A: eye rotation axis during facing and back to motion centrifugation with right ear out (left panel), centered (middle panel), and left ear out (right panel). Preoperatively, the eye velocity axis gradually aligned with the GIA. Postoperatively, axis reorientation was abolished. B: eye rotation axis during centrifugation with nose out (left panel), centered, and nose in (right panel). Preoperatively, the axis tilted in the animal's pitch plane toward alignment with the GIA. Postoperatively, axis reorientation was abolished.
) and was compared in the normal, completely lesioned and partially lesioned animals. These results are reported in Table 1 in which dumping was considered absent if the recovery velocity reached levels within 20% of those expected as a result of decline of eye velocity in darkness, plus losses due to visual feedback, determined from the rising time constant (Raphan et al. 1979
; Waespe et al. 1983
, 1985
). If the velocity profile was reduced by >20% from the expected level, then it was labeled as positive (+). For tilt dumping, the plus sign in Table 1 indicates that the horizontal velocity storage time constant was reduced by tilt dumps, and the minus sign indicates a lack of effect. Dumping was considered absent in response to tilt (
) if the time constant of decline in horizontal slow-phase velocity was consistently within 30% of the time constant recorded in the upright position.
View this table:
TABLE 1.
Horizontal and vertical VOR gains and time constants for nodulectomy animals
, 1991). Slow-phase velocities were analyzed from the onset of OKAN to the point where the yaw axis eye velocity decayed to zero. OKAN time constants were estimated by fitting a single exponential function to the decaying portion of eye velocity starting 2 s after the end of stimulation (Cohen et al. 1977
). During steps of angular velocity for M9312 and M9303, velocity storage time constants were estimated by fitting a sum of two exponential functions to the decaying portion of eye velocity (Raphan et al. 1979
). The cupula time constant was constrained to 4 s (Goldberg and Fernández 1971), and the initial integrator state was constrained to be zero. Whenever a single time constant is quoted for these animals, it is the central or velocity storage time constant. If secondary nystagmus appeared during measurement of aVOR time constants, the offset due to overshoot was subtracted before time constants were fitted. Time constants for the other animals were determined from paper records by dividing the area under the slow-phase velocity envelope by the initial jump in velocity (Raphan et al. 1979
). Animals in whom a single area time constant estimate was used are marked with double asterisks in Table 1. The direction of nystagmus is denoted in the figures and the text by the direction of the slow-phase velocity.
) by fitting the best tangent line to the three-dimensional eye velocity vector starting 10 s after reaching constant angular head velocity (Wearne et al. 1997a
,b
). Because the decay of the eye velocity trajectory approaches the yaw axis eigenvector in the limit (Raphan et al. 1992
; Raphan and Sturm 1991
), this tangent line is a close approximation to the eigenvector. The magnitude of axis shift in the head coordinate frame was computed as the angular difference between the yaw eigenvector and the Z-axis of the head. The three-dimensional tangent line was then projected into each cardinal head plane, and the angle made by this projection and the Z-axis was computed in each plane. Goodness of fit was verified in each data trace by plotting the fitted eigenvector over the components of desaccaded eye velocity trajectories in two and three dimensions (Wearne et al. 1996
, 1997a
,b
). In the text, single values are used when describing specific data traces to aid the reader in evaluating the figures. Whenever a data set was considered, means ± SD are given.
was used as an aid in plotting the location of the lesions. Roman numerals were used to denote the uvula (IX) and nodulus (X) for clarity. In other contexts, the numerals 9 and 10 refer to the uvula and nodulus, respectively.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
). The sections, ~0.5, 2.5, and 3.75 mm to the left (A) and right (B) of the midline, correspond to Zones 1, 3, and 4 of Voogd et al. (1996)
in the rhesus monkey. Medial portions of the nodulus and uvula were completely removed, and tissue was absent ventral to the secondary fissure (2°) [0.5 mm, Fig. 2, A, (1)B, (1) and C, Zone 1]. Laterally, the nodulus and uvula were completely ablated on the right (Fig. 2B, (3) R 2.5 mm; Fig. 2C, Zone 3, 2.5 mm), but a small portion of the dorsal uvula remained 2.5 mm from the midline on the left (Fig. 2A, (3), L 2.5 mm). The uvula was absent at 3.75 mm level, and the paramedian lobules (PML) were shifted toward the midline [Figs. 2A, (4) and B, (4), 3.75 mm]. Three other animals (M1107, M1152, and M1153) from an earlier study (Waespe et al. 1985
) had similarly complete lesions (Table 1).
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FIG. 2.
Sagittal sections through the cerebellum in M9312 in whom the nodulus and most of the uvula were removed. The drawings correspond to sections at ~0.5 mm, 2.5 mm, and 3.75 mm from the midline to the left (A) and right (B) of the midline. The numbers 1, 3, and 4 correspond to the rhesus monkey zones of Voogd et al. (1996) . The arrows point to the paramedian lobule in the lateral-most sections. C: normal rhesus monkey sagittal sections (Madigan and Carpenter 1971
) at 0.5 mm (Zone 1), 2.5 mm (Zone 3), and 3.75 mm (Zone 4) from the midline. The superimposed shaded regions indicate the extent of the lesion in M9312. Because the lesions were symmetric, only one side is shown in the reconstruction. FN, fastigial nucleus; AIN, anterior interposed nucleus; PIN, posterior interposed nucleus; PML, paramedian lobule. 1° and 2° refer to the primary and secondary fissures. IX and X refer to the nodulus and uvula, respectively. The uvula is further divided into sublobulesa-d.
). In each case the lesions were confined to the vermal portions of the nodulus and uvula, and the lateral portions of the nodulus were intact. The lesion was symmetric in M9303. Sections of the lesion 0.5, 2.5, and 3.75 mm from the midline in M9303 are drawn in Fig. 3, A and B, and the extent of the lesion was reconstructed on a normal cerebellum in Fig. 3C. The lesions in M1173 and M1175 are presented in Fig. 9 of Cohen et al. (1992)
, and a section is shown in Fig. 14B. In M9303, the central regions of lobules 9d and 10 of the caudal vermis were removed en bloc, extending to the lateral margins of the uvula [Fig. 3A, (1) B, (1) and C, Zone 1 (0.5 mm)]. The lateral-most 1.8 mm of the nodulus, corresponding to rhesus monkey zones 3 and 4 of Voogd et al. (1996)
, were left intact [Fig. 3, A-C (2.5 and 3.75 mm)]. Purkinje cells in this region had a normal appearance with intact nuclei and cytoplasm. Approximately 70% of the nodulus and rostral-ventral uvula (sublobule 9d) were destroyed in M1173 and M1175, also leaving lateral portions of the nodulus intact.
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FIG. 3.
Scheme as in Fig. 2. Sagittal sections through the partial lesion in M9303. Central portions of the nodulus and rostral-ventral uvula within 2 mm of the midline were removed. A and B: at 0.5 mm, only lobule 9a of the uvula was intact (arrows). At 2.5 and 3.5 mm, lateral portions of nodulus and lobule 9d of the uvula are visible. Arrows point to the residual nodulus. C: summary of the reconstruction showing the intact nodulus in Zones 3 and 4 (arrows).
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FIG. 14.
A: maximal cross-coupled vertical (upward) velocities during yaw axis OKAN with animals tilted at various angles between 0° (upright) and 90° (on-side) in M1175, before ( ) and after (
) the partial nodulo-uvulectomy shown in B (see Cohen et al. 1992
, for a more complete description of lesion). Before lesion, peak vertical velocities were close to the velocity of stimulation (60°/s). After lesion, they fell to ~14°/s.
. All of the nodulus and lobules 9c and 9d of the uvula were ablated in the complete lesions, whereas all or most of Zone 1 and most of Zone 2 of the nodulus and lobules 9c and 9d of the uvula were ablated in the partial lesions. This left a margin of intact nodulus and ventral uvula in Zone 2 and all of Zones 3 and 4 in the partial animals.
,b
, 1995
; Dai et al. 1991
, 1992
; Matsuo and Cohen 1984
; Raphan and Cohen 1986
, 1988
). Thus horizontal OKAN time constants are maximal in the upright position and decline as a function of tilt angle with animals side down, prone or supine (Dai et al. 1991
; Wearne et al. 1996
, 1997b
). Postrotatory vestibular horizontal time constants are similarly reduced in side-down positions (Angelaki and Hess 1994a
, 1995
; Benson 1974
; Guedry 1974
; Raphan et al. 1992
; Waespe et al. 1985
). In contrast, vertical and roll OKAN and vestibular time constants are maximal in side-down or prone and supine positions (Dai et al. 1992
), whereas the pitch and roll OKAN time constants become short when monkeys are upright (Matsuo and Cohen 1984
; Raphan and Cohen 1988
). This implies that the time constants of the velocity storage component of the pitch and roll aVOR are also short in the upright position.
View this table:
TABLE 2.
Complete nodulo-uvulectomy (M9312); OKAN and aVOR time constants about a vertical axis
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FIG. 5.
Vertical (A, B, E, and F) and roll (C and D) angular vestibuloocular reflex (aVOR) time constants before and after complete (A-D) and partial (E and F) nodulectomy. As shown in the insets, animals were rotated left ear down or prone about a spatial vertical axis. Top trace in each part is yaw axis position, recorded with a potentiometer that resent every 360°. This gives the "sawtooth" appearance during constant velocity rotation. The 2nd trace is desaccaded vertical ( X) or roll (
Y) eye velocity. The central (velocity storage) time constant is listed over each trace. It was obtained by a double exponential fit with the cupula time constant constrained to 4 s. Note the up-down asymmetry in the preoperative vertical eye velocity. Postoperatively, the time constants for upward and downward velocities were similarly short. The central time constant of roll after lesion fell to between 1 and 3 s.
; Waespe et al. 1985
). The change in the sensitivity of the vertical time constant to gravity is shown in Fig. 6. Before lesion, M9312 had strong upward OKN and OKAN in the left ear down position (
X; Fig. 6A), with an OKAN time constant of 13.3 s. Postoperatively, upward OKN was equally vigorous, but the on-side time constant of upward OKAN was now 2.5 s (
X; Fig. 6B). This is close to the mean upward OKAN time constant recorded in four cynomolgus monkeys when sitting erect (3.5 s) (see Fig. 6A of Dai et al. 1991
).
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FIG. 6.
Vertical optokinetic nystagmus (OKN) and OKAN before (A) and after (B) complete nodulo-uvulectomy. The animal was on its side, 90° right ear down (RED), and received upward optokinetic stimulation in pitch about a vertical axis (see inset). Preoperatively, there was strong upward OKAN, which decayed with a time constant of 13.3 s. Postoperatively, OKAN decayed rapidly with a time constant of 2.5 s.
). The PAN was somewhat asymmetric in M9312, being shorter to the left than to the right, with a mean period of 170 s (Fig. 7). The velocity vector of the nystagmus was predominantly horizontal (
Z), but there was a small torsional component (
Y) that tipped the vector back in the head, as well as nonperiodic spontaneous downward nystagmus. Horizontal PAN was also present in each of the other three animals with complete lesions (Table 1). It developed spontaneously if animals were in darkness, but was also elicited by low-amplitude vestibular or optokinetic stimuli. The periods ranged from 150 to 250 s. PAN was suppressed in light. It disappeared with parenteral administration of small doses of baclofen (0.5-1 mg/kg) (Halmagyi et al. 1980
), a
-aminobutyric acid-B (GABAB) agonist that shortens the dominant horizontal time constant of velocity storage (Cohen et al. 1987
). This is consistent with the postulate of Leigh et al. (1981)
that the oscillation of PAN is produced by large increases in the time constant of brain stem integrators, unchecked by inhibition.
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FIG. 7.
Periodic alternating nystagms (PAN) following complete nodulo-uvulectomy in M9312. Nystagmus was initiated by a step of velocity of 60°/s in yaw around a yaw axis. Continuous oscillations developed in horizontal ( Z) and roll (
Y) eye velocity with a period of ~150 s. A sustained downward vertical nystagmus (
X) was also present.
) (Table 1). In the example shown in Fig. 8A, horizontal eye velocity (
Z) rapidly dropped by ~70% during the visual exposure, presumably due to activation of direct visual-oculomotor pathways that suppressed the nystagmus. Eye velocity returned to close to preexposure levels after the animal was once again in darkness and decayed with the same long time constant as the response in darkness. A small loss of stored velocity in Fig. 8A is expected, due to visual feedback from the eyes moving over the stationary surround during the period of suppression, rather than to activation of the dump mechanism (Waespe et al. 1985
). Loss of control of the horizontal time constant in tilt- and light-dumping paradigms after nodulo-uvulectomy was present in each of the completely lesioned animals (Table 1).
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FIG. 8.
Postoperative light-dumping in complete (A; M9312) and partially lesioned (B; M9303) animals during per-rotatory nystagmus. The animals and the surround were rotated at 60°/s in the same direction in darkness. The light was switched on (top trace, light on) for 4 s, exposing a self-stationary visual surround. There was little loss of stored eye velocity in the completely lesioned animal (A), whereas eye velocity had almost disappeared in the partially lesioned animal (B). Note the long horizontal time constant in the completely lesioned animal.
; Wearne et al. 1996
, 1997b
). The completely lesioned animal lost both of these features. In the example shown in Fig. 9, the horizontal time constant for centered rotation was 13.5 s (Fig. 9B). Horizontal time constants for facing and back to motion centrifugation, which tilted the GIA by 51° about the nasooccipital axis, were the same whether facing motion (13.1 s, Fig. 9A) or back to motion (12.6 s, Fig. 9C). In addition, spatial orientation was lost, and there was no vertical (
X) or torsional (
Y) cross-coupling (Fig. 9, A and C). A small downward vertical component, present to the same extent during centered rotation (Fig. 9B, arrow A) as during facing and back to motion centrifugation (B and C), was probably spontaneous nystagmus. Ocular counter-rolling in response to the tilt of the GIA about the nasooccipital axis was preserved (Fig. 9, A and C; arrows B,
). It should be noted that the horizontal time constant was ~13 s in response to rotation at 400°/s during centered and off-center rotation (Fig. 9). This was substantially less than the average aVOR time constants of this animal when rotated at 60°/s (Table 2). The difference is due to the reduction in horizontal time constant as rotational velocity increases. This relationship originally described in normal animals (Raphan et al. 1979
), was present after both partial (Cohen et al. 1992
) and complete nodulo-uvulectomy. Thus it does not depend on the integrity of the nodulus and uvula.
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FIG. 9.
Postoperative responses of M9312 to Z yaw axis centrifugation. Eye position and eye velocity responses during centrifugation (A and C) and centered rotation (B) in yaw with an angular acceleration of 40°/s2 up to a peak angular velocity of 400°/s. Three-dimensional eye position is represented using Euler angles in the Fick rotation convention, with (
,
,
) designating rotations about the yaw axis, the rotated pitch axis, and the optic (roll) axis in that order. Pitch (
X), roll (
Y), and yaw (
Z) components of the eye velocity vector are displayed in head coordinates. Top panel shows the angular and linear stimulus profiles over time: the angular velocity of the centrifuge (ANG VEL) is indicated with a light line and ranges from 0 to 400°/s; the corresponding tilt angle of the GIA is indicated with a heavier line. For centered rotation, the GIA tilt remains at 0°. A-C: time constant of horizontal eye velocity (
Z) was the same when facing or back to motion (A and C) as in centered rotation (B). Therefore it was unaffected by the tilted GIA. No cross-coupling from horizontal to vertical was present (compare arrows A in A and C with arrow A in B). During centrifugation, torsional eye position (
), shifted in the direction of theGIA tilt, indicating normal counter-rolling (arrows B).
Y; Fig. 10A, arrowheads). In accordance with the backward tilt of the GIA, the roll component reversed during clockwise and counterclockwise rotation in the nose-out orientation. The time constant of the roll component was long and was approximately equal to the time constant of the horizontal component (
Z). A small vertical component (
X) was also present during acceleration. The peak horizontal eye velocity was 140°/s, less than would be expected given the acceleration and peak velocity of the stimulus. This lower value was likely due to the reduction in the horizontal time constant produced by the tilted GIA.After lesion, the peak horizontal eye velocity reached 200°/s.This higher peak velocity was consistent with the loss of sensitivity of the horizontal time constant to the tilted GIA (
Z; Fig. 10C). There was a transient increase in roll eye velocity during the angular acceleration, concurrent with activation of the semicircular canals, but it decayed to zero when constant angular velocity was reached; in the constant angular velocity phase, there was no cross-coupling to roll.
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FIG. 10.
Pre- (A) and postoperative (B) centrifugation in M9312 in the radial orientation with the nose out. A: horizontal, vertical, and roll eye velocities for both directions of rotation. Centrifugation induced a positive cross-coupled roll component during Z rotation and a negative roll component during +Z rotation (arrowheads). B: eye velocity axis plotted in 3 dimensions (
) with superimposed fitted eigenvector (heavy black line). Each graph is composed of 2 trials, one for +Z and another for
Z rotation. Circles start at the points farthest from the origin on the top and bottom halves of each graph and proceed toward zero. The eye rotation axis and the eigenvector both tilted back in the head by ~35-40°, slightly underestimating the tilt of the GIA (indicated on inset showing monkey's head). The components of the fitted eigenvectors for +Z and
Z horizontal eye velocity are shown in the inset to the far right of the 3-D graph. C: after nodulo-uvulectomy, eye velocity reached a higher peak due to the longer horizontal time constant. A roll component developed during angular acceleration in the direction opposite to that required to align the eye velocity with the GIA. This component decayed quickly and did not affect the final eye velocity trajectory. D: in 3 dimensions, the fitted eigenvector remained close to alignment with the Z-axis.
). The components of the fitted eigenvectors for the +
Z and
Z eye velocities to the right of the three-dimensional graph demonstrate the alignment of the eigenvector with the GIA. It tilted back in the head by 38° for +
Z eye velocities and 36° for
Z eye velocities. This underestimated the 51° backward tilt of the GIA. Postoperatively, the eye velocity axis remained aligned with the Z-axis of the head (Fig. 10D,
). The fitted eigenvector (heavy line) reflected this alignment. The X and Y components of the eigenvector were close to zero for both directions of rotation (+
Z: X,
0.06; Y, 0.07;
Z: X, 0.02; Y, 0.01) and the Z component was close to 1 (0.99 and
0.99), producing negligible tilt of the eigenvector.
). Axis shifts in the roll plane were asymmetric, producing larger shifts during upward (
X) than downward (+X) cross-coupling. With right ear out, the axis tilted by 50 and 45° for upward and downward cross-coupling. With left ear out, it tilted by 32 and 25° for upward and downward coupling. Nose out in the radial orientation, the eye velocity axis tilted by 38° for +
Z and by 36° for
Z eye velocities, and when nose in, by 70° for +
Z and by 34° for
Z eye velocities (Fig. 10, bottom row,
). After lesion (Fig. 11,
), the eye velocity axis remained aligned with the head Z-axis during eccentric rotation, irrespective of the direction of GIA tilt, and there were only negligible tilts of the fitted eigenvector in both roll (A) and pitch (B) planes, similar to the alignment during centered rotation.
). This corroborates the loss of spatial orientation after complete nodulo-uvulectomy in these animals.
View this table:
TABLE 3.
Partial nodulo-uvulectomy (M9303); aVOR time constants about a vertical axis
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FIG. 12.
Pre- and postoperative horizontal OKAN time constants in M9303 as a function of head tilts, 0, 45, and 90° to LED and RED. Slope parameters were obtained from 1st-order linear regressions. Each data point is the average of 2 measurements. A: rightward OKAN eye velocities. Preoperatively ( ), the time constant was ~14 s in the upright position, and fell with a slope of
0.09 s/deg. Postoperatively (
), the upright time constant was several seconds longer, but the slope was not reduced by the partial lesion (
0.1 s/deg). B: leftward OKAN eye velocities. Preoperatively (
), the slope was
0.6 s/deg. Postoperatively (
), the upright time constant was similar to preoperative values, whereas the slope (
0.03) was slightly reduced from the preoperative value.
0.09 s/deg of tilt (Fig. 12A). Postoperatively, the upright time constant was slightly longer (2.5 s), but the slope was the same (
0.1 s/deg vs. 0.09 s/deg). For leftward eye velocities (Fig. 12B), the preoperative slope was
0.06s/deg. Postoperatively, the slope was slightly less (
0.03s/deg). The ability to discharge velocity storage in response to rapid reorientation of the head during postrotatory nystagmus was also present in the other partially lesioned monkeys (Table 1).
Z) throughout stimulation, and there was no cross-coupling from yaw to vertical (Fig. 13, A and C;
Y, arrows A). Despite this, the horizontal time constant fell from 12.9 s when rotated on-center to 6.6 s when facing motion and 4.7 s when back to motion during centrifugation. Ocular counter-rolling was also normal after operation (Fig. 13, A and C;
, arrows B).
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FIG. 13.
Postoperative responses of M9303 to Z yaw axis, facing (A) and back to motion (C) centrifugation and centered rotation (B) in yaw with angular acceleration of 40°/s2 up to a peak angular velocity of 400°/s. Scheme as in Fig. 9. A-C: the time constant of horizontal eye velocity (
Z) was shorter when facing and back to motion (A and C) than when centered (B). Therefore sensitivity to the tilted GIA was unaffected from preoperative levels. No cross-coupling from horizontal to vertical was present (cf. arrow A in A and C with arrow A in B). During centrifugation, torsional eye position (Y) shifted in the direction of the GIA tilt, indicating normal counter-rolling (arrows B).
). After partial nodulectomy (Cohen et al. 1992
) (Fig. 14B), peak vertical cross-coupled OKAN was only ~11°/s (11.4 ± 1.8°) with the animal tilted in the same range (Fig. 14A,
).
, left; Fig. 16A). With the left ear down, upward coupling produced a 69° roll plane tilt, and downward coupling a 50° tilt (Fig. 15A,
, right). Thus the animal demonstrated the same up-down asymmetry found in other normal monkeys when tilted in the roll plane (Dai et al. 1991
; Matsuo and Cohen 1984
; Matsuo et al. 1979
; Wearne et al. 1997b
). In the pitch plane, the fitted eigenvector tilted by 32° for +
Z and 38° for
Z when nose down, and when nose up, it tilted by 77° for +
Z and by 66° for
Z (Fig. 15B,
). Postoperatively, cross-coupling was reduced but not abolished during GIA tilts in the roll plane. In the right ear down position, upward coupling produced a roll plane tilt of 39° and downward coupling a tilt of 16° (Fig. 15A,
, left; Fig. 16B). For left ear down, upward coupling produced a tilt of 40° and downward coupling a tilt of 35° (Fig. 15A,
, right). Three-dimensional analysis of this residual cross-coupling (Fig. 16B) demonstrated that both vertical and torsional cross-coupled components were present postoperatively, but neither the magnitude nor direction correctly estimated the GIA tilt. Cross-coupling was abolished postoperatively for tilts in the pitch plane (Fig. 15B,
).
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FIG. 15.
Two-dimensional phase plane trajectories of eye rotation axes during OKAN in M9303 with the head tilted the GIA left and right ear down (A) or prone and supine (B). Scheme as in Fig. 11. Preoperatively ( ), the eye rotation axis was tilted more for upward than for downward cross-coupled components. Postoperatively, cross-coupling was markedly reduced but not abolished in the roll plane (A). B: preoperatively, the eye rotation axis tended to align with the GIA when the animal was supine (
, right panel), but tilted by less than 1/2 the angle when the animal was prone (
, left panel). Postoperatively, axis reorientation was abolished in the pitch plane.
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FIG. 16.
Pre- (A) and postoperative (B) OKAN with head tilted right ear down in partially lesioned monkey M9303. The axis of eye velocity is plotted in 3 dimensions ( ) with superimposed fitted eigenvector (heavy black line). Scheme as in Fig. 11B. A: for +Z eye velocity, a downward cross-coupled vertical component appeared that tilted the eye rotation axis and the fitted eigenvector by 58° in the roll plane. For
Z eye velocity, a stronger upward cross-coupled component was present, tilting the eye velocity and fitted eigenvector by 85.3° in the roll plane. B: after operation, cross-coupling in both directions was reduced, and the fitted eigenvector was no longer confined to the animal's roll plane. For +Z eye velocities, the fitted eigenvector tilted by 16.3° in the roll plane and by 32.8° in the pitch plane. For
Z eye velocities, the eigenvector tilted by 39.6° in the roll plane and by 15.6° in the pitch plane.
Z traces) were similar before and after lesion (15.1 s before, Fig. 17A; 14.2 s after, Fig. 17B) and fell rapidly when the head was reoriented both before [Fig. 17A, time constant (Tc) = 3.2 s] and after lesion (Fig. 17B, Tc = 4.3 s). Before lesion, a vertical component slowly developed with the head in the side down position (
X, arrow, Fig. 17A), shifting the axis of eye velocity by 90°, from alignment with the body yaw axis toward alignment with the spatial vertical axis. This is shown in the three-dimensional graph to the right of Fig. 17A. The fitted eigenvector (heavy line), computed as [
0.99,
0.05,
0.09], produced a roll plane tilt of 84.8°, which was close to the 90° tilt of the GIA. After lesion, cross-coupling during tilt dumping was lost. There was a 7° tilt in both the pitch and roll planes (computed eigenvector [0.12, 0.12, 0.99]), but eye velocity remained closely aligned with the body yaw, not with the spatial vertical axis (Fig. 17B, heavy line, 3-D graph). Thus the reduction in cross-coupling for the population of partially lesioned animals in whom it was measured (M1175 and M9303) was
80% in all orientations in all paradigms.
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FIG. 17.
Pre- (A) and postoperative (B) tilt dumping to left ear down (top inset) in partially lesioned monkey M9303. The direction of the GIA with the head tilted is represented by the arrow out of the right ear (top right inset). A: preoperatively the horizontal time constant was reduced (dumped) to 3.2 s as a result of head reorientation, and an upward cross-coupled vertical component appeared (arrow). The eye velocity trajectory is plotted in 3 dimensions in the graph on the right. The fitted eigenvector (black line) tilted by 84.8°, approximately aligning with the tilted GIA (inset). The eigenvector components, to the far right of the 3-D graph, reflect this tilt. B: postoperatively, the tilt dump following head reorientation was retained [time constant (Tc) = 4.3 s], but cross-coupling to vertical was lost (trace X). As a result, the eye velocity axis and fitted eigenvector remained aligned with the head Z-axis (3-D graph on right, and eigenvector components).
; Raphan et al. 1979
; Raphan and Sturm 1991
). The model, shown in Fig. 18, has a direct vestibular pathway with gain matrix, (G1), which is independent of gravity (Wearne et al. 1997a
). The nodulus and uvula do not control the direct pathway, but rather the parameters of velocity storage. While all central processing is performed in semicircular canal coordinates, the velocity storage system matrix, [H], has been transformed into head coordinates by the similarity transformation [T
1can][H][Tcan], where the matrix Tcan represents the transformation from head ([X,Y,Z]) coordinates to semicircular canal coordinates, and T
1can the inverse transformation from canal to head coordinates (Robinson 1982
; Yakushin et al. 1995
).3 In accordance with previous behavioral results (Dai et al. 1991
), this structure shows that the time constants of horizontal, vertical, and roll are determined by the diagonal vertical elements. Cross-coupling, given by the nonzero off-diagonal terms, only occurs from horizontal to vertical and horizontal to roll. All other cross coupling terms are zero.
; Reisine and Raphan 1992
; Yokota et al. 1992
). The aVOR integrator pathway, whose response characteristics are determined by the matrix H, is under parametric control by the nodulus and uvula, which adjusts the values of the time constants and the cross-coupled components. The arrows through the matrix entries indicate this. According to the results of this study, the vertical and roll time constants (1/h11 and 1/h22) and cross-coupled components (h13 and h23) are modulated by central portions of the nodulus and uvula (Zones 1 and 2), whereas lateral portions of the nodulus (Zone 3) control the horizontal time constant (1/h33). Control of the horizontal time constant is independent of cross-coupling between axes. Because there is no cross-coupling from the pitch or roll to other axes (Dai et al. 1991
; Raphan and Sturm 1991
), activity responsible for cross-coupling flows from the yaw axis to the other axes, not the reverse.
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FIG. 19.
Model simulations of the roll, pitch, and yaw slow-phase velocities induced by roll, pitch, and yaw stimulation with the animal upright (A), on-side (B), and prone/supine (C). The 1st column are normal responses, the 2nd and 3rd columns are responses after partial and complete nodulo-uvulectomy. The direction of gravity is denoted by g. The large upward arrows in B and C refer to cross-coupled vertical and roll velocities, respectively. See text for further details.
4 s; h11 = 0.25/s). The normal roll response (Fig. 19A, Normal, Roll) induced pure torsional OKN and OKAN of
20°/s, which had a time constant of 2 s (h22 = 0.5/s). There was no direct pathway response for roll OKN. After partial nodulectomy, these response characteristics were unaltered (Fig. 18A, 2nd column, Partial).
40°/s), and the OKAN time constant was longer (Tc = 9 s; h11 = 0.11 s). The steady-state value and time constant of roll OKN and OKAN (not shown) were the same in the side-down and upright positions (Fig. 19A, Normal, Roll).
40°/s), and the OKAN time constant was longer (Tc = 9 s; h22 = 0.11 s). The steady-state value and time constant of pitch OKN and OKAN (not shown) were unchanged from the upright condition (Fig. 19A, Normal, Pitch). Partial nodulectomy decreased the time constant of yaw OKAN to 9 s with the animal prone/supine (Fig. 19C, Partial, Yaw). The roll OKAN time constant, in response to roll stimulation, was unaltered from the upright condition and remained at 2 s (Fig. 19C, Partial, Roll). The yaw and roll time responses were unaffected in the prone/supine condition after complete nodulectomy and were similar to responses from the upright condition (Fig. 19C, Complete).
; Raphan et al. 1992
; Raphan and Sturm 1991
) shows how the nodulus and uvula could control the spatial orientation and temporal aspects of the response to both optokinetic stimulation and centrifugation.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
; Raphan et al. 1992
, 1996
; Raphan and Sturm 1991
; Wearne et al. 1996
, 1997a
,b
). A fundamental finding of this study was that complete lesions resulted in an inability to modulate both the horizontal and vertical time constants, but that control of the horizontal time constant was retained in each of the animals with partial lesions. This is sufficient to show that parts of the nodulus that were left in the partial animals were responsible for control of the horizontal time constant. It also strongly suggests that the parts of the nodulus that were removed in the partial animal M9303 were responsible for the loss of control of the vertical time constant. This was supported by findings in both M1173 and M1175, in which yaw to vertical cross-coupling was greatly diminished. From this, we hypothesize that the function of medial regions of the nodulus (Zones 1 and 2) and ventral uvula is related to control of vertical and torsional time constants and to cross-coupling. These regions produce gravitational dependence of vertical and roll time constants when animals are in side-down or supine/prone positions, and adjust these time constants when the GIA tilts with regard to the head. In contrast, lateral portions of the nodulus (Zone 3) appear to exert tonic control of the horizontal aVOR time constant and mediate its dependence on relative tilts of the GIA.
, 1995)
have also implicated the nodulus and ventral uvula in the control of spatial orientation. They found a similar reduction of orientation to the GIA after nodulo-uvulectomy, but dynamic control of time constants was lost only for torsional eye velocities. From this, they inferred that the nodulus and uvula predominantly control roll eye velocity. In our study, however, vertical and roll time constants were concurrently reduced for vestibular and optokinetic stimulation whenever the nodulus and uvula were damaged (Figs. 5 and 6; Tables 1-3). There was some residual vertical cross-coupling during OKAN in tilted positions in M9303 (Figs. 15A and 16B). However, the three-dimensional plots show that the magnitude of the cross-coupled components was inappropriate postoperatively, and an additional orthogonal component was present that caused misalignment of the eye velocity axis with the GIA. Moreover, vertical and torsional cross-coupled components were lost in this animal during facing and back-to-motion centrifugation (Fig. 13), during OKAN with the animal prone or supine (Figs. 14 and 15B), and during rapid reorientation in the roll plane during postrotatory nystagmus (Fig. 17). Presumably, the residual cross-coupling was produced by portions of Zone 2 of the nodulus that remained in M9303 (Fig. 4). A similar explanation may account for the discrepancy between the two studies, i.e., the differences may be related to differences in portions of the nodulus or uvula that were ablated or spared.
) or midline section (Katz et al. 1991
; Wearne et al. 1997a
). Rather, the vertical and roll time constants (
2.5 s) were characteristic of the vertical and roll time OKAN time constants in the upright animal (Dai et al. 1991
). It is not possible to measure vertical and torsional VOR time constants with animals upright and rotating about a horizontal axis, because this induces concurrent otolith activation that also produces eye velocity. However, aVOR and OKAN time constants measure activation of the same velocity storage mechanism (Raphan et al. 1979
), and on-side vertical aVOR time constants were consistent with the on-side and upright vertical OKAN time constants (Table 2). Examples of short on-side vertical time constants, similar to those recorded in the upright position, are shown in Figs. 5 and 6B.
; Oscarsson 1969
, 1979
; Voogd and Bigaré 1980
; Voogd et al. 1996
). This modular organization suggests a physical basis for the separate control of horizontal and vertical/roll time constants and cross-coupling parameters found in this study. In rabbit, Wylie et al. (1994)
have correlated the climbing fiber zones of the ventral surface of the nodulus with Purkinje cell projections to the vestibular and deep cerebellar nuclei. In this and other species, nodular Purkinje cells target peripheral regions of SVN (Angaut and Brodal 1967
; Haines 1977
; Wylie et al. 1994
), caudal MVN (Brodal and Brodal 1985
; Haines 1977
; Shojaku et al. 1987
; Walberg and Dietrichs 1988
; Wylie et al. 1994
), and rostral MVN (Haines 1977
; R. McCrea 1995, personal communication). Neurons that are believed responsible for the production of velocity storage are located in the targeted portions of peripheral SVN and rostral MVN (Holstein et al. 1996
; Reisine and Raphan 1992
; Yokota et al. 1992
). On the basis of the results of our study, we suggest that parameters of velocity storage are controlled by the specific projections from separate zones in the nodulus to these neurons in SVN and MVN. More specifically, projections from the medial Zones 1 and 2 in the nodulus to SVN could control the vertical and torsional components of the cross-coupled responses and the vertical and roll time constants, whereas projections from lateral Zone 3 to MVN could control the horizontal (yaw) time constant.
), the partially lesioned animals, M1173 and M1175, lost all previous habituation of the horizontal time constant as well as the ability to habituate the horizontal time constant further on repeated rotational stimulation after medial lesions. This suggests that the medial nodulus may also have some function related to control of the horizontal time constant. Consistent with this, there is input from the caudal dorsal cap [VA (Yaw) OKN] to Zone 1 in the nodulus in the rabbit (Wylie et al. 1994
), and electrical stimulation of central portions of the nodulus and uvula in the monkey shortened the horizontal time constant (Solomon and Cohen 1994
). One possibility is that gravitational and plastic (habituative) control of the horizontal aVOR time constants may be organized separately, with dependence of the horizontal time constant on gravity being mediated in lateral portions of the nodulus and plastic control of the horizontal time constant (habituation) being dependent on medial or medial plus lateral portions of the nodulus and uvula. There are other aspects of orientation that are not directly linked to control of velocity storage, which may also depend on the nodulus and uvula. Control of autonomic function, for example, appears to be mediated by the lateral zones of the nodulus that project to caudal MVN (Precht et al. 1976
; Wylie et al. 1994
; Yates 1992
; Yates et al. 1993
). The close relation between spatial orientation and nausea could be realized through the lateral nodulus, thereby providing a link between disorientation and motion sickness.
; Brodal and Hoivik 1964
), and this input is likely to exist in the monkey. Both the nodulus and sublobule 9d have extensive interconnection with the vestibular nuclei, and with regions of the inferior olives that process optokinetic and vestibular information (Voogd et al. 1996
). This is in contrast to sublobules 9a-c of the uvula, which have different anatomic connections and are likely to have different functions. For example, stimulation of sublobule 9d generated slow changes in eye velocity that long outlasted the stimulus (Heinen et al. 1992
; Heinen and Keller 1996
). In addition, postrotatory and OKAN time constants were shortened by stimulation of 9d in a manner similar to the changes produced by stimulation of the nodulus (lobule 10) and to the effects of tilt and light dumping (Solomon and Cohen 1994
). In sublobules 9a-c, on the other hand, only rapid changes in eye velocity were induced by electrical stimulation, and storage was unaffected by stimulation or lesions (Heinen et al. 1992
; Heinen and Keller 1996
; Solomon and Cohen 1994
;). Taken together, it is likely that the nodulus and sublobule 9d of the uvula comprise a functional unit that is related to control of velocity storage and its spatial orientation.
) and the results of electric stimulation (Heinen et al. 1992
; Solomon and Cohen 1994
) suggest that it also is not functionally related to the nodulus and sublobule 9d.
). This limited distribution and the low firing rates of climbing fibers make it unlikely that they could mediate the information required for spatial orientation. On the other hand, primary otolith afferent input that comes through mossy fibers is widely distributed via granule cells through parallel fibers across the folia of the nodulus and lobule 9d (Barmack et al. 1993a
; Brodal and Hoivik 1964
; Marini et al. 1975
), and there is direct input to mossy fibers from the vestibular nuclei. Mossy fibers have a patchy distribution (Bower and Woolston 1983
), but they extend across several zones. Thus the critical information relating head position to the GIA is probably mediated by mossy fibers. The climbing fibers could mediate a signal related to image slip, similar to that in the flocculus (Stone and Lisberger 1989
). This image slip signal could trigger the postulated dump switch that initiates rapid loss of horizontal eye velocity during per- or postrotatory nystagmus or OKAN in monkeys when they are exposed to a self-stationary visual surround (Raphan et al. 1979
; Waespe et al. 1985
).
; Reisine and Raphan 1992
; Wearne et al. 1997a
; Yokota et al. 1992
), are likely to provide the activity that drives the vertical VO neurons during cross coupling. Thus the three-D H matrix of the velocity storage mechanism is probably realized by interconnections of horizontal and vertical VO neurons in the vestibular nuclei.
; Gizzi et al. 1994
; Schiff et al. 1988
; Yokota et al. 1992
).
), disinhibition is likely to be a fundamental excitatory process in controlling the spatial orientation properties of velocity storage. By contrast, control of the horizontal time constant is likely to be accomplished by an inhibitory projection from Purkinje cells in the nodulus and sublobule 9d to horizontal VO neurons.
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ACKNOWLEDGEMENTS |
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We thank Drs. Gay R. Holstein and Jean Büttner-Ennever for helping with anatomic sectioning and analysis. We thank Dr. Jan Voogd for providing anatomic data and measurements relating to the structural organization of the rhesus monkey nodulus and ventral uvula. We are grateful to Dr. Walter Waespe for providing some of the data used in this study. V. Rodriguez made an outstanding contribution assisting in the operations and in producing the figures.
This work was supported by National Institutes of Health Grants NS-00294, EY-11812, EY-04148, EY-01867, and DC-09284.
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FOOTNOTES |
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1 We define spatial orientation of the aVOR as alignment of the eye velocity vector with gravito-inertial acceleration (GIA). GIA is the vector sum of gravitational and inertial accelerations. Cross-coupling is the appearance of vertical and/or torsional eye velocities in response to tilts of the GIA during yaw axis stimulation.
2 The Fick rotation convention parameterizes any three-dimensional rotation as three sequential rotations about three nonorthogonal axes, Z, the rotated X, and the final Y (visual axis) in that order.
3 Showing the matrix in head coordinates simplifies the representation and demonstrates its upper triangular structure. This coordinate frame makes it clear which parameters of the system matrix are controlled by the various portions of the nodulus. In canal coordinates there would be no clear way to associate the parameters of velocity storage with the effects of partial and complete lesions.
Address for reprint requests: B. Cohen, Dept. of Neurology, Box 1135, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029.
Received 30 August 1997; accepted in final form 22 January 1998.
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REFERENCES |
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