Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois 60637
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ABSTRACT |
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Belton, Timothy and
Robert A. McCrea.
Role of the Cerebellar Flocculus Region in the Coordination of
Eye and Head Movements During Gaze Pursuit.
J. Neurophysiol. 84: 1614-1626, 2000.
The contribution of the
flocculus region of the cerebellum to horizontal gaze pursuit was
studied in squirrel monkeys. When the head was free to move, the
monkeys pursued targets with a combination of smooth eye and head
movements; with the majority of the gaze velocity produced by smooth
tracking head movements. In the accompanying study we reported that the
flocculus region was necessary for cancellation of the vestibuloocular
reflex (VOR) evoked by passive whole body rotation. The question
addressed in this study was whether the flocculus region of the
cerebellum also plays a role in canceling the VOR produced by active
head movements during gaze pursuit. The firing behavior of 121 Purkinje (Pk) cells that were sensitive to horizontal smooth pursuit eye movements was studied. The sample included 66 eye velocity Pk cells and
55 gaze velocity Pk cells. All of the cells remained sensitive to
smooth pursuit eye movements during combined eye and head tracking. Eye
velocity Pk cells were insensitive to smooth pursuit head movements.
Gaze velocity Pk cells were nearly as sensitive to active smooth
pursuit head movements as they were passive whole body rotation; but
they were less than half as sensitive (43%) to smooth pursuit head
movements as they were to smooth pursuit eye movements. Considered as a
whole, the Pk cells in the flocculus region of the cerebellar cortex
were <20% as sensitive to smooth pursuit head movements as they were
to smooth pursuit eye movements, which suggests that this region does
not produce signals sufficient to cancel the VOR during smooth head
tracking. The comparative effect of injections of muscimol into the
flocculus region on smooth pursuit eye and head movements was studied
in two monkeys. Muscimol inactivation of the flocculus region
profoundly affected smooth pursuit eye movements but had little effect
on smooth pursuit head movements or on smooth tracking of visual targets when the head was free to move. We conclude that the signals produced by flocculus region Pk cells are neither necessary nor sufficient to cancel the VOR during gaze pursuit.
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INTRODUCTION |
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The vestibuloocular reflex (VOR)
smoothly rotates the eyes in the opposite direction of head movements
so that images are stabilized on the retina when the head is perturbed.
The pathways that produce the VOR are also utilized to produce smooth
pursuit and optokinetic eye movements that track images moving in space with respect to the head (Collewijn et al. 1982;
McCrea and Cullen 1992
; Precht et al.
1985
; Robinson 1981
; Waespe and Henn
1985
). Smooth tracking head movements can also be used to
pursue moving images. When both eye and head movements are utilized to
stabilize images on the retina, the VOR must be suppressed or canceled
in order for image stability to be maintained.
Several ideas have been advanced for how the VOR might be canceled
during active voluntary head movements. One idea is that the brain
produces a common gaze velocity command utilized by both oculomotor and
head movement circuits, with the VOR functioning to coordinate the
movements of the eyes and the head by canceling the gaze motor command
at the level of the extraocular motoneuron (Lanman et al.
1978). A second idea is that the central pattern generators
that produce smooth visual following eye movements carry signals that
are gaze velocity commands. These gaze velocity commands add with
vestibular reafferent signals in the vestibular nuclei so that the
oculomotor signals carried by central VOR pathways are, on balance,
canceled (Barnes 1993
; Barnes and Eason
1988
; Lisberger and Fuchs 1978a
). A third idea
is that the central pattern generators that produce smooth eye
movements and smooth head movements are controlled by separate central
motor programs and that the VOR is canceled by the addition of an
internal estimate of the active head movement (Cullen et al.
1991
; Robinson 1982
; Tomlinson and
Robinson 1981
).
One way to assess which of these mechanisms is involved in coordinating
eye and head movements when both are used to stabilize images on the
retina is to examine the activity in neural circuits that are involved
in producing visuomotor reflexes and in modifying the VOR during smooth
eye and head movements. The cerebellar flocculus region (FLR, flocculus
and ventral paraflocculus) is an essential part of the neural substrate
for producing visual ocular following reflexes, and for modifying the
VOR (Büttner and Waespe 1984; Lisberger and
Fuchs 1978a
; Lisberger et al. 1994a
,b
;
Miles et al. 1980
; Noda and Suzuki 1979
).
In the accompanying paper (Belton and McCrea 2000
) we
showed that the firing behavior of Purkinje cells in the squirrel
monkey FLR was strongly modulated during smooth pursuit eye movements
and during cancellation of the VOR when a visual target moved with the
head during passive whole body rotation (WBR). One class of FLR
Purkinje (Pk) cells, the so-called gaze-velocity Pk cells (Gv Pk cells)
were modulated in phase with eye velocity during smooth ocular pursuit
and with head velocity when the VOR was canceled by fixation of a
visual target that moved with the head during passive WBR
(Büttner and Waespe 1984
; Lisberger and
Fuchs 1978a
; Miles et al. 1980
). The other major
class of FLR Pk cells, the eye velocity Pk cells (Ev Pk), was strongly
modulated during smooth ocular pursuit but was insensitive to passive
head movements during VOR cancellation. The signals produced by these
Pk cells were apparently essential for producing smooth ocular pursuit
eye movements and for VOR cancellation during passive head rotation,
since inactivation of the FLR using injections of muscimol profoundly
disrupted both behaviors. Similar observations have been made in other
primates (Takemori and Cohen 1974
; Waespe et al.
1983
; Zee et al. 1981
).
Since the FLR produces signals that are essential for smooth tracking
of visual targets during passive head movements, it might also be the
source of central gaze motor commands for coordinating eye and head
motor control systems (Bizzi 1981; Lanman et al. 1978
); or it could produce a gaze velocity signal that adds
with vestibular signals on VOR pathways to cancel vestibular reafferent inputs (Barnes 1993
). On the other hand, if the FLR
produces signals that are related primarily to smooth eye movements,
regardless of the contribution of active head movements to gaze
pursuit, then it is likely that smooth eye and head movements are
controlled by separate motor programs, and that an internal estimate of
active head movements is used to cancel the VOR (Chambers and
Gresty 1983
; Tomlinson and Robinson 1981
).
In this study we examined the firing behavior of Pk cells in the FLR in
squirrel monkeys that were free to pursue visual targets by generating
a combination of head and eye pursuit movements. We compare the signals
those Pk cells generate during active head pursuit movements to the
signals generated during smooth pursuit eye movements and passive WBR.
In addition the effects of muscimol inactivation of the FLR on the
monkeys ability to generate smooth pursuit head movements and to cancel
the VOR during active gaze pursuit are described. Although we found
that many FLR Pk cells were weakly sensitive to smooth active head
movements, we argue that these signals are neither necessary nor
sufficient to cancel the VOR generated during active head movements. We
conclude that the FLR does not produce gaze velocity signals that
function to coordinate gaze when both eye and head movements are used
to stabilize images on the retina. A preliminary report of these
results has been published (Belton and McCrea 1999).
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METHODS |
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The methods used for recording and analyzing eye movements and
single-unit activity in squirrel monkeys and for injecting muscimol
into the FLR were described in the accompanying paper (Belton
and McCrea 2000). They are briefly described here along with
the methods for recording from the head-free monkey.
Methods for recording combined eye and head movements
The experimental recording apparatus is illustrated in Fig. 1. Monkeys were seated in a Plexiglas chair with the C1-C2 axis concentric with the turntable's rotational axis. The torso was somewhat restrained by a plate abutting the chest, which restricted arm raising. The head was attached to a delrin rod that rotated within a double ball bearing assembly (Barden Precision Bearings; Fig. 1, b) mounted to the turntable. The rod's axis of rotation was coincident with the axis of turntable rotation and passed through the intersection of the midsagittal and interaural planes and within 5 mm of the C1-C2 axis. Head movements were permitted in the plane of the horizontal semicircular canal (±45°, 15° nose down from the stereotaxic plane). A universal joint (Fig. 1, e) was placed in-line with the vertical rod above the animal's head (~5 cm) to permit slight postural adjustments. A clamp (Fig. 1, a) attached to the chair-mounted end of the rod could be quickly tightened for restraining head movements, although the flexibility of the delrin rod permitted small head movements even when its rotation was prevented. Liquid reinforcement was delivered through a headset-like tube that moved with the head (Fig. 1, d).
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The position of the right eye with respect to the turntable was recorded with a magnetic search-coil system (40 cm diam, Neurodata Instruments). The animal's head position was determined using a second search coil (Fig. 1, c) placed on the vertical rod below the universal joint. Table velocity, gaze, head, and target position signals were low-pass filtered (Frequency Devices, 7 kHz, 7-pole Butterworth) and sampled at 200 or 500 Hz (Cambridge Electronics, model CED1401).
Single-unit activity was recorded using Epoxy-insulated Tungsten
microelectrodes (4-7 M impedance) that were stereotaxically inserted into the cerebellum through a guide tube (22G) using a
micromanipulator. After placement, the electrode and guide tube, attached to the slave cylinder of a hydraulic microdrive, were secured
to the skull. The electrode was then advanced within the cerebellum
using the hydraulic microdrive. The methods of searching for,
identifying, and mapping the location of Pk cells were described in the
accompanying paper (Belton and McCrea 2000
).
Experimental protocols
The responses of each Purkinje cell were studied using the
following four paradigms when the head was free to move in the yaw
plane.
1)
Sinusoidal smooth gaze pursuit (0.5 Hz, ±12.7°, 40°/s peak target velocity). Monkeys were rewarded for accurate smooth gaze tracking (angular gaze position maintained within 2° of the target for approximately 1 s). Although rewards were delivered regardless of whether eye or head movements were used to pursue the target, approximately 60-80% of gaze velocity was produced by active head movements.
2)
WBR during fixation of an earth stationary target (0.5 Hz, 40°/s peak table velocity). In this condition the vestibular stimulus produced by passive WBR often evoked a compensatory vestibulo-collic reflex or a smooth compensatory head movement that reduced head velocity in space.
3)
WBR evoked during fixation of a head stationary target (0.5 Hz, 40°/s peak velocity). In this condition active head movements were usually minimal (<1.5°), and the VOR produced by passive WBR was canceled.
These responses were compared with those recorded when the head was restrained from moving.
The following experiments were carried out in a fraction of the Pk
cells.
4)
WBR in the light without a target present (0.5 Hz, 40°/s turntable rotation)
5)
Procedures 1-3 above at 2.3 Hz, 20°/s peak stimulus velocity
6)
Combined passive and active head movements: Passive WBR at 2.3 Hz (20°/s) during head-free pursuit of a target moving sinusoidally at 0.5 Hz with respect to the turntable or moving at a constant velocity (40°/s).
Inactivation of flocculus region using muscimol
The methods of muscimol inactivation were described in the
accompanying paper (Belton and McCrea 2000). The
head-free experiments reported here were interleaved with experiments
reported in that paper that were carried out when the head was restrained.
Data analysis
ANALYSIS OF PURKINJE CELL SENSITIVITY TO HEAD POSITION. Sensitivity to static head position was assessed by multiple regression analysis of the mean firing rate recorded during 20 or more periods of stable gaze and stable head position in the absence of a target.
ANALYSIS OF DATA OBTAINED WITH SINUSOIDAL STIMULI.
The methods used for analyzing unit responses to sinusoidal stimuli are
described in the accompanying paper (Belton and McCrea 2000). Behavioral and unit responses to periodic sinusoidal
stimuli were analyzed by fitting desaccaded, averaged records with a
sinusoidal function whose frequency was fixed to that of the stimulus.
The desaccaded records excluded periods when gaze deviated from target position by more than 3° and periods that contained head and eye movements related to saccades.
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RESULTS |
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Smooth pursuit head movements in squirrel monkeys
When the head is free to move, squirrel monkeys pursue moving
targets with a combination of eye and head movements over a wide range
of stimulus frequencies and velocities (Cullen and McCrea
1990). Even though the target remained well within oculomotor range and could be pursued equally well with either eye or head movements, both of the squirrel monkeys used in this study chose to
pursue targets primarily with smooth head movements at 0.5 Hz, which
was the stimulus frequency that was most commonly used. Head movements
also contributed to smooth tracking at higher stimulus frequencies,
including the highest stimulus frequencies that were used (2.3 Hz).
The behavioral responses recorded concomitantly with single-unit recordings in three behavioral conditions at 0.5 Hz are summarized in Table 1. On average, smooth head movements contributed nearly three-quarters (74%) of the gaze velocity during sinusoidal gaze pursuit, and nearly two-thirds of the compensatory gaze shift evoked during WBR when the monkey fixated an earth stationary target. Head movement also contributed significantly to compensatory gaze velocity when no target was present during WBR. On the other hand, the head movements evoked by WBR when the monkey fixated a head stationary target were negligible or absent.
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Single-unit recordings from FLR Pk cells in head-free squirrel monkeys
Single-unit recordings were obtained from 121 FLR Pk cells that were sensitive to horizontal eye movements during combined eye and head smooth tracking. Most of the Pk cells were studied during passive WBR as well as during active smooth pursuit head movements. All of the units whose firing rate was modulated during active head movements or during passive WBR in the horizontal plane were also modulated during smooth pursuit eye movements. Consequently no Pk cells were found in the FLR whose firing behavior was related to head movements but not eye movements. A systematic effort was made to record from Pk cells in both the flocculus and the ventral paraflocculus, but no significant differences were found between the Pk cells located in the two regions; so the results obtained from cells in both regions will be combined. Many Pk cells were sensitive primarily to vertical eye movements or had firing behavior that was neither related to eye nor head movements, but these units were not systematically studied and are not included in the following discussion. The response gain during smooth pursuit of 6 of the 121 Pk cells was <0.2 spikes/s/deg/s. These signals were judged to be too small to allow accurate quantitative analysis and were dropped from further consideration.
The remaining 115 horizontal eye movement-related FLR Pk cells were
grouped into two categories based on their responses during ocular
pursuit and VOR cancellation (Belton and McCrea 2000). The majority of the cells (n = 66, 55% of the sample)
were sensitive to horizontal eye velocity during smooth pursuit eye
movements and to slow phase eye velocity during the VOR, but were
insensitive to head velocity during passive WBR. These were categorized
as eye velocity Pk cells (Ev Pk cells). When monkeys canceled their VOR
by fixating a head stationary target during passive WBR, the firing
rate of Ev Pk cells was related only to residual, unsuppressed eye
velocity. The remaining cells generated signals related both to eye
velocity during smooth ocular pursuit and to head velocity during
passive WBR, and were termed gaze velocity Pk cells (Gv Pk cells;
n = 55). A detailed description of the firing behavior of both classes of Pk cell in the squirrel monkey in the absence of
active head movements is available in the accompanying paper (Belton and McCrea 2000
).
Responses of Pk cells during head-free pursuit
During head-free gaze pursuit the firing rate of Ev Pk cells was related to pursuit eye movements but not to smooth pursuit head movements. Figure 2 illustrates the responses of an Ev Pk cell during smooth pursuit of a visual target when the head was restrained from moving (Fig. 2A) and when the head was free to move (Fig. 2B). Sample records of unit activity during smooth tracking are illustrated on the left side of the figure, and the averaged, desaccaded responses are illustrated on the right side. The dashed trace superimposed on the average firing rate histogram in B is the predicted response based on the cell's sensitivity to eye movements during ocular pursuit. The modulation of this Ev Pk cell, like every other Ev Pk cell examined, was dramatically reduced when head movements rather than only eye movements were used to pursue moving targets.
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The pursuit responses of most Gv Pk cells were also attenuated during combined eye and head pursuit. The Gv Pk cell illustrated in Fig. 3 was typical. When the monkey's head was restrained, the unit's firing rate was strongly modulated in phase with ipsilateral eye velocity during ocular pursuit (Fig. 3A). When the head was free to move, the monkey used primarily head movements to track the target (Fig. 3C), and the firing rate modulation was reduced. The green dashed trace superimposed on the average in C is the predicted response based on the cells sensitivities to eye velocity during ocular pursuit and passive head velocity during cancellation of the VOR (Fig. 3B).
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The sensitivity of Ev and Gv Pk cells to gaze velocity in the head-restrained and head-free conditions is compared in Figs. 4 and 5. Since most Pk cells were less sensitive to head velocity than to eye velocity, the firing rate modulations during head-free pursuit were significantly smaller than those recorded during ocular pursuit, although the response phase in the two conditions was comparable (Fig. 4, A2 and B2). In Fig. 5A Ev and Gv Pk unit sensitivity to gaze velocity in the head-free condition during 0.5-Hz, 40°/s pursuit is plotted as a function of their sensitivity to gaze velocity during ocular pursuit in the head-restrained condition. Most units were significantly less sensitive to gaze velocity during head-free pursuit than during ocular pursuit, although a few Gv Pk cells generated comparable responses in both conditions. On average, Pk cells were about half as sensitive to gaze velocity during 0.5-Hz pursuit when the head was free to move as compared with when the head was restrained.
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Pk unit responses during head-free pursuit were predictable from the responses measured during ocular pursuit and VOR cancellation. The reduction in Ev Pk cell responses was roughly proportional to the reduction in the contribution of eye velocity to gaze pursuit (mean reduction in modulation of 58% compared with a mean concomitant reduction in peak eye velocity of 66%), which suggests that the signals generated by Ev Pk cells were related primarily to eye movements during both head-restrained and head-free pursuit. A prediction of Gv Pk unit responses during head-free pursuit was made by decomposing the averaged, desaccaded gaze velocity record into eye and head movement components, and modeling each unit's expected response by summation of its sensitivity to eye movements during ocular pursuit and to head velocity during cancellation of the VOR. In Fig. 5B the predicted Gv Pk response during head-free pursuit is plotted as a function of the observed response. The mean predicted modulation of Gv Pk cells during head-free pursuit was 23.8 spikes/s, or 0.78 spikes/s/deg/s re gaze velocity, compared with a mean observed modulation of 21.5 spikes/s, or 0.71 spikes/s/deg/s re gaze velocity.
The sensitivity of Gv Pk cells to head velocity during smooth head
pursuit was estimated by vector subtraction of the estimated ocular
pursuit component from each unit's head-free pursuit response. Figure
6 plots this estimated active head
movement sensitivity versus sensitivity to passive head velocity as
measured during VOR cancellation. Since the VOR was usually not
entirely suppressed in the VOR cancellation paradigm (see Table 1), the
estimate of passive head velocity sensitivity was obtained with the
algorithm described in the accompanying paper (Belton and McCrea
2000), which corrected for the influence of residual eye
velocity on unit firing behavior. Although most Gv Pk cells were less
sensitive to head velocity during active gaze pursuit than to passive
head velocity during VOR cancellation, some units were more sensitive to active pursuit head movements than to VOR cancellation. On average,
Gv Pk cells were less sensitive to head velocity during active gaze
pursuit than to passive head velocity during VOR cancellation. The
slope of a linear regression fit to the data in Fig. 6 was 0.76.
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In sum, only a few FLR Pk cells were as sensitive to gaze velocity during gaze pursuit as they were during ocular pursuit. The unequal modulation of FLR Pk cells during comparable types of smooth pursuit suggests that this region of the cerebellar cortex does not contribute as much to the control of gaze velocity during combined eye-head pursuit as it does to eye velocity during ocular pursuit.
Responses of Pk cells during passive WBR with the head free
In head-restrained squirrel monkeys, passive WBR evokes eye
movements that compensate for head movement in space both in the presence and absence of visual targets. Most FLR Pk cells are sensitive
to the eye velocity evoked by passive WBR, although the sensitivity is
significantly enhanced by the presence of an earth stationary visual
target (Belton and McCrea 2000). With their head free to
move, the monkeys generated smooth compensatory head movements as well
as eye movements during passive WBR. The combined gaze velocity
produced by eye and head movements was nearly sufficient to stabilize
gaze in space (Table 1). Since most Pk cells were more sensitive to eye
velocity than to head velocity, the firing rate modulation observed
during passive WBR when the head was free was typically smaller than
that observed when the head was restrained. Examples of the responses
of typical Ev and Gv Pk cells are illustrated in Fig.
7A. The traces at the top of Fig. 7A show averaged, desaccaded
responses evoked by 0.5 Hz WBR when the head was restrained (Fig.
7A, left) and when the head was free to move
(right). In both cases the monkey fixated an earth
stationary target and maintained relatively stable gaze (Gv traces).
When the head was restrained, gaze stability was maintained by smooth
compensatory eye movements (Ev) alone. However, when the head was free,
stability was maintained with a combination of smooth eye movements and
head on trunk, or neck movements (Nv). The neck movements reduced the
head-in-space movement (Hv) that would otherwise have been induced by
the stimulus.
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The histograms at the bottom of Fig. 7A illustrate the averaged responses of an Ev and Gv Pk cell in both conditions. Both cell types were sensitive to WBR in the head-restrained condition, but the modulation in the Gv Pk cell's firing rate was less due to the oppositely directed eye and head velocity-related signals being out of phase and thus canceling in this paradigm. When the head was free to move, the modulation in firing rate of both Pk types was reduced. Figure 7B summarizes the relative sensitivity of both cell types to the stimulus velocity during WBR in the presence of an earth stationary target in the head-restrained and head-free conditions. On average, the modulation of FLR Pk cells was reduced by more than half (i.e., the slope of a linear fit to the data illustrated in Fig. 7B was 0.43), which corresponded well to the reduction in VOR eye velocity observed in the head-free condition (i.e., a 58% reduction). Thus FLR Pk cells are preferentially sensitive to eye velocity during a task that requires stable gaze to be maintained during passive WBR as well as during smooth gaze pursuit.
Responses of Pk cells during simultaneous gaze pursuit and passive WBR
One question that arises is whether the head movement sensitivity of FLR Purkinje cells during VOR cancellation and head-free pursuit is due to vestibular sensory inputs or to active pursuit motor commands. Interactions of active and passive head movements were studied by rotating the turntable at one frequency (2.3 Hz) while the monkey pursued a target in the head-free condition that was moved at a second, nonharmonic frequency (0.5 Hz). The responses of an Ev and a Gv Pk cell during combined active and passive head movements are illustrated in Fig. 8. The target was projected from a turntable-mounted laser, so that the passive oscillation of the turntable did not perturb the 0.5-Hz target motion with respect to the monkey's head (dashed trace, Tgv, in Fig. 8B). Thus the movement of the target in space (dashed trace in Fig. 8A) was a combination of the 2.3-Hz turntable motion and the 0.5-Hz movement of the target with respect to the head and eyes.
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The passive head oscillation induced by higher frequency turntable rotation was reduced by compensatory vestibulocollic reflex head movements, but the residual passive head movement (blue traces in Fig. 8C) did drive gaze off the target when the VOR was not completely suppressed. The responses of Pk cells to this combination of active and passive head rotation were analyzed by averaging cycles at the frequency of target movement (B1 and B2) and turntable movement (C1 and C2).
The modulation in the firing rate of both Pk cell types with respect to target velocity and with respect to passive head velocity were similar to responses predicted from their firing behavior during ocular pursuit and VOR cancellation (dotted traces superimposed on the averaged, desaccaded histograms in Fig. 8, B and C). Ev Pk cells were nearly equally sensitive to eye velocity related to ocular following movements evoked at 0.5 Hz as they were to the compensatory (but retinal slip producing) eye movements evoked by turntable rotation at 2.3 Hz. Their responses were similar to those predicted from their sensitivity to ocular pursuit in the absence of active or passive head movements (dotted trace superimposed on unit firing rate in Fig. 8, B1 and C1). The firing behavior of Gv Pk cells during combined head-free pursuit and WBR were also predictable from the responses recorded in the head-restrained condition during ocular pursuit and VOR cancellation (dotted traces in Fig. 8, B2 and C2).
The eye and head velocity-related signals observed during 0.5-Hz
ocular pursuit and VOR cancellation were evident at a similar gain and
phase both in the firing rate modulation associated with active
head-driven pursuit and also with the smaller modulation (or lack of
modulation) related to passive WBR. The equivalent sensitivity of both
types of Pk cells to eye and head movements that both aided and
inhibited target tracking suggest that the head movement signals they
produce in response to head rotation are more likely related to
vestibular, or to neck reafferent (Wilson et al. 1976)
signals during head-free pursuit than to an internal estimate or
prediction of target motion.
Effects of muscimol inactivation of the flocculus region on combined eye-head pursuit
The effect of unilateral inactivation of the flocculus region on
gaze pursuit was studied in two animals. In each animal the injection
of muscimol was into an area of the FLR where the majority of Gv Pk
cells were encountered in preceding single-unit recording sessions (see
Belton and McCrea 2000 for details). A comparison of the
effects of muscimol injection on smooth pursuit when the head was
restrained and when the head was free to move are shown in Fig.
9. Prior to muscimol injection, pursuit
gaze velocity (red traces in Fig. 9, A1 and A2)
was comparable in the head-free and head-restrained conditions, despite
the fact that pursuit was accomplished primarily by eye movements in
the head-restrained condition and by head movements in the head-free
condition. On injection of 1.25 µL of 2% muscimol into the FLR,
ocular pursuit was greatly compromised (Fig. 9B1). Head-free
pursuit was relatively unaffected, although the frequency of ocular
saccades during pursuit ipsilateral to the lesion increased markedly
(Fig. 9B2). The preserved ability of the monkey to pursue
targets with smooth head movements compensated for the loss of the
ability to generate smooth eye movements. Both monkeys were able to
suppress VOR eye movements during head-driven target pursuit (Fig. 9,
B2 and C2) and were able to match gaze to target
velocity well enough to be consistently rewarded in this paradigm
during the period of muscimol inactivation of the FLR. Multiple cycles
of desaccaded 0.5-Hz pursuit were averaged to quantify the effects of
inactivating the FLR (Fig. 9C). Prior to muscimol injection
the mean gain of ocular pursuit (solid red filled trace in Fig.
9C1) was approximately 0.84 in one monkey and 0.79 for the
other monkey. Following muscimol injection the gain of smooth pursuit
eye movements in both directions was reduced by half to approximately
0.4. Ipsilateral ocular pursuit was more affected in one monkey
(illustrated in Fig. 9), while in the other monkey contralateral ocular
pursuit was more affected. In each monkey the pursuit deficits were
superimposed on a spontaneous nystagmus that was present both in the
dark and in the light. In one the muscimol injection produced a weak
(
3°/s) ipsilateral spontaneous nystagmus, while in the other it
produced a weak contralateral spontaneous nystagmus. The quick phase of
the nystagmus was to the direction in which pursuit was most affected.
That is, the asymmetry in the effect of muscimol injection on pursuit
in both the head-restrained and head-free conditions was probably due to a concomitantly produced spontaneous nystagmus.
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DISCUSSION |
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The Purkinje cells in the flocculus region of the cerebellum are essential for producing and coordinating gaze velocity when eye movements alone are used to track a target. Most FLR Pk cells are strongly modulated during smooth pursuit eye movements, and inactivation or removal of the FLR compromises both the ability to produce smooth pursuit eye movements and the ability to suppress the VOR when the head is passively perturbed. However, the FLR is less influential in the control of gaze when smooth head movements are used to track a moving target. Half of the cells in the FLR, the Ev Pk cells, were completely insensitive to active, smooth pursuit head movements. Gv Pk cells, which constitute the other half of the output of the FLR, were less sensitive to smooth pursuit head movements than to smooth pursuit eye movements. When the FLR was inactivated using muscimol, there was no effect on pursuit head movements and little effect on the ability to cancel the VOR during smooth head tracking. The signals produced by FLR Pk cells are thus neither sufficient nor necessary for producing smooth pursuit head movements or for canceling the VOR during gaze pursuit.
We conclude that, while the flocculus region of the cerebellum is essential for the production of smooth pursuit eye movements, it is probably not an essential part of the neural substrate for controlling gaze velocity. The implication is that pursuit eye and head movements may not be coordinated by a common gaze velocity command that summates with vestibular reafferent signals in the FLR, the vestibular nuclei, or extraocular motoneurons. We suggest that pursuit eye and head movements are separately programmable and controllable and that they are coordinated by summation of a central estimate of active head movements with vestibular reafferent signal on VOR pathways (Fig. 10).
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Absence of gaze velocity signals in the squirrel monkey FLR
The output of the squirrel monkey flocculus and ventral
paraflocculus is rarely, if ever, related to gaze velocity. In
the accompanying paper we reported that half of the Pk cells in the FLR
(the Ev Pk cells) were not sensitive to gaze velocity during VOR
cancellation, and that only a few of the FLR Gv Pk cells that were sensitive to passive head movements were equally sensitive to gaze velocity during ocular pursuit and VOR cancellation
(Belton and McCrea 2000). We also found that the signals
produced by Gv Pk cells were not strictly related to head and eye
velocity during passive head movements, since the amplitude of their
response was usually dependent on the presence of a target. In this
study we found not one Gv Pk cell that was equally sensitive to gaze velocity during ocular pursuit and gaze pursuit. The lack of
correlation of Gv Pk cell firing rate and gaze velocity was even more
evident during other types of gaze shifts. No FLR Pk cell coded gaze
velocity during saccadic gaze shifts (Belton and McCrea
1999
) or during cervicoocular reflex eye movements (unpublished observations).
We referred to Gv Pk cells as gaze velocity Pk cells in our
studies primarily because cells with similar characteristics in the
rhesus monkey were labeled in this way. In those animals many Gv Pk
cells are, on average, equally sensitive to horizontal eye velocity
during smooth pursuit eye movements and to head velocity during VOR
cancellation (Fukushima et al. 1999; Lisberger
and Fuchs 1978a
; Miles et al. 1980
). Although
the choice of nomenclature of rhesus macaque FLR Gv Pk cells was
understandable at the time it was given, the appropriateness of the
nomenclature is questionable. FLR Pk cells have been reported to
produce signals that are related to head movements in many species, but
Pk cells that are equally sensitive to eye and head movements are
relatively rare in goldfish (Pastor et al.
1994
), rabbits (Ghelarducci et al.
1975
; Leonard and Simpson 1986
), cats
(Cheron et al. 1997
; Fukushima et al. 1996
) squirrel monkeys, and Japanese macaques (Fukushima
et al. 1999
).
One difference between squirrel monkeys and rhesus monkeys that could
be relevant is that squirrel monkeys have a more limited oculomotor
range and are presumably less inclined to rely entirely on ocular
pursuit to track moving targets. Suppression of the VOR must occur
frequently in such arboreal animals. In fact, squirrel monkeys prefer
to track moving targets with head movements when given the opportunity,
and it is likely that this strategy utilizes other, nonvisual
mechanisms for canceling the VOR (Cullen et al. 1991). A
second difference between squirrel monkeys and larger primates is that
they have a relatively small interocular distance that then requires a
smaller vergence angle to be maintained during fixation or pursuit of a
target that is located in a small laboratory. If, as seems likely, the
FLR were involved in modifying the VOR as a function of viewing
distance, the relatively low sensitivity of squirrel monkey FLR Pk
cells to head rotation could reflect the comparative absence of
required viewing distance-related modifications in the VOR in our experiments.
Recently Fukushima and colleagues (Fukushima et al.
1999) reported that most of the vertically responsive macaque
FLR Pk cells were less sensitive to head velocity during VOR
cancellation than to eye velocity during ocular pursuit. They referred
to FLR Pk cells whose head velocity signals were significantly weaker
than their pursuit eye velocity signals as eye-head-velocity Pk cells. In light of the poor correlation between Gv Pk cell firing behavior with gaze velocity in so many behavioral contexts, it would probably be
better to refer to all Pk cells in the FLR in every species that are
sensitive to head velocity as eye-head-velocity Pk cells in the future.
Coordination of eye and head movements during smooth tracking of visual targets
The problem of coordinating eye and head movements during
smooth tracking of visual targets has been studied in both monkeys and
humans (Barnes 1993; Barnes and Eason
1988
; Grant et al. 1992
; Gresty and Leech
1977
; Kubo et al. 1981
; McKinley and
Peterson 1985
). One way the output of the two motor systems
could be coordinated is by subtraction of a vestibular reafferent
signal related to active head movement from a gaze velocity command,
produced from an internal estimate of target motion (Bizzi
1981
; Lanman et al. 1978
; Lisberger et
al. 1981
). The subtraction could occur on extraocular motoneurons or on central VOR pathways. The difference would be used to
produce a smooth pursuit eye movement that kept the image on the
retina. However, this scheme does not account for important features of
the eye and neck motor systems. The axes of rotation of the eye and the
head are usually different; which means that rotation of the head
produces translation as well as rotation of images on the retina. More
importantly, the VOR cannot be used to coordinate gaze during head
movements that require eye rotations larger than the range of the
oculomotor plant (±20° in squirrel monkeys). Presumably one of the
primary reasons why pursuit head movements are generated rather than
eye movements alone is the expectation that the target movement might
extend beyond the oculomotor range.
Head movements play a prominent role in gaze control, but they
also subserve other, equally important, functions (Fuller
1992). For example, it seems likely that head movements play an
important role in auditory, somatosensory, and olfactory tracking.
Retinal or oculomotor coordinates seem inappropriate for producing
accurate head tracking with those modalities. It may also be useful to separate eye and head control during visual tracking. In this study
only angular head movements in the horizontal plane were unrestricted.
When active gaze shifts are restricted in this manner, the central
programming of the angular rotation of the head and eyes is nearly
equivalent. However, the programming of eye and head movements is
inherently different in most circumstances. The head/neck motor plant
has many degrees of freedom and is capable of significant translation
as well as rotation. Eye movements are exclusively angular rotations
with three degrees of freedom. A separate computation of linear
translation to angular rotation must be carried out to produce
adjustments in the VOR related to linear translation of the head
(Chen-Huang and McCrea 1999b
). Not only are the
coordinates of eye and head movement control different, but the range
and axes of the two motor systems are significantly different. Thus it
is unlikely that the vestibular reafferent signals produced during
active head movements would be adequately canceled by a central
estimate of target velocity in space or gaze velocity. Even if the
brain constructed an internal estimate of gaze velocity in space based
on a summation of eye movements and vestibular reafference, the
estimate would have to be significantly transformed to take into
account the changing distance of the target and the posture of the head
and the eye before the signal could be used to program or update a
pursuit movement.
A simpler way to coordinate angular eye and head movements during
pursuit would be to subtract an efference copy of intended head
velocity from vestibular reafferent signals in central VOR pathways
(Fig. 10). Any errors in the computation could be corrected using
visual feedback. The flocculus region of the cerebellum could adjust
the output of central VOR pathways based on visual feedback or
unanticipated passive head movements. It would not play a primary role
in coordinating eye and head movements, but rather provide the
substrate for producing relatively small smooth pursuit eye movements
that compensate for both anticipated and unanticipated errors in
tracking a moving image. The results of our recent studies in the
vestibular nuclei suggest that the summation of active head movement
signals with passive vestibular reafferent signals occurs in the
vestibular nuclei on secondary vestibular neurons (Gdowski and
McCrea 1999; McCrea et al. 1996
,
1999
). The primary advantage of using an
internal estimate of head movement to cancel vestibular signals in VOR
pathways rather than a gaze velocity signal or a central estimate of
target velocity in space is that it allows eye and head movements to be
separately controlled.
Sensitivity of FLR Pk cells to passive and active head movements during pursuit
Summation of gaze pursuit commands with vestibular signals on VOR pathways may not always be appropriate for coordinating pursuit eye and head movements, but it is necessary for modifying signals in VOR pathways when a visual target moves with the head during passive rotation or translation of the whole body. For example, when the substrate on which a primate is standing (e.g., a tree limb or a commuter train) has objects of interest attached to it, the VOR must be canceled to maintain stable vision. In that circumstance, summation of sensory vestibular reafferent signals with ocular pursuit commands is the best way to maintain image stability. In the accompanying paper we reported that most of the Purkinje cells in the FLR were more sensitive to ocular pursuit eye movements than to passive head movements when the monkeys canceled their VOR by fixating a head stationary target. In spite of the relative insensitivity of most Pk cells to head velocity, inactivation of the flocculus compromised smooth pursuit eye movements and VOR cancellation approximately equally, which suggested that the output of flocculus region Pk cells were necessary for both functions. The implication is that the output of the FLR is used to cancel the VOR during passive, but not active head rotation.
Considered as a population, FLR Ev Pk cells were insensitive to head
velocity during both active and passive head movements. However, this
region of the cerebellum is apparently essential for canceling the VOR
when the head is passively moved and the VOR must be canceled
(Belton and McCrea 2000; Partsalis et al. 1995
; Takemori and Cohen 1974
; Waespe et
al. 1983
; Zee et al. 1981
; Zhang et al.
1995
). In this circumstance the signals generated by FLR Pk
cells are altered in two ways. The eye velocity signals normally
present during when an earth stationary target moves relative to the
head are absent, and the Gv Pk cells generate a signal related to head
velocity in space. The removal of the eye velocity signal represents
the larger part of the change in firing behavior, both in individual Pk
cells and in the population as a whole. The two changes together
constitute a considerable change in the output of the FLR. Since
similar changes in FLR Pk cell output occur during head-free pursuit,
why was smooth head pursuit essentially unaltered when muscimol was
injected into the FLR?
One possible explanation is that two parallel mechanisms for VOR
cancellation coexist, and that one mechanism can replace the other when
the other is absent or compromised (Barnes 1993). We
suggested above that the VOR may be canceled during gaze pursuit by the
subtraction of an efference copy of active head movements from a
vestibular reafferent signal in the vestibular nuclei. A second
mechanism may also be available that relies on subtraction of an
internal estimate of target movement with respect to the head from
vestibular reafferent signals in the vestibular nuclei. FLR Pk cells
are essential for the second mechanism but not the first. The VOR
evoked by passive, unpredictable head movements in space could not be
suppressed by an efference copy mechanism, and the FLR is clearly
essential in that circumstance. During head-free pursuit the VOR is
canceled primarily with another, efference copy, mechanism, and the
flocculus is not essential for canceling the VOR. A second, related
explanation is that a large fraction of the eye movement-related
signals produced by FLR Pk cells are derived from inputs that are
modulated by the output of VOR pathways (Stone and Lisberger
1989
). These efference copy eye velocity signals would in
effect be canceled if head movement efference copy signals modified the
output of VOR pathways directly.
Implications for functional organization of the cerebellar cortex in motor control
The question of the role of the FLR in gaze control can be considered a test of the more general question of whether individual efferent modules in the cerebellar cortex are organized to coordinate the contribution of disparate muscle groups and motor pattern generators to the control of multiple movement fields, or whether each efferent module is organized to ensure the accurate control of a single central pattern generator with a more limited behavioral objective.
The cerebellar cortex is organized into a series of parasagittal
microzones containing Purkinje cells that receive a common climbing
fiber input from a group of cells in the inferior olive and which
project to a discrete region(s) of the cerebellar or vestibular nuclei
(Herrup and Knemerle 1997; Ito et al.
1977
; Oscarsson 1979
; Voogd et al.
1996
). Since the microzones often cross regions of the
cerebellar cortex that are involved in controlling movements of several
different parts of the body (Brooks and Thach 1981
;
Ito 1984
; Thach et al. 1992
), each zone
could be organized to modify the output of a set of central pattern
generators with a common motor function (e.g., pattern generators
related to the extensor phase of locomotion, eye blink, smooth eye
rotation). Alternatively, each zone could be organized to control
pattern generators that share a common behavioral goal (maintenance of balance during locomotion, prevention of corneal damage, prevention of
retinal image slip). In short, an individual efferent zone in the
cerebellar cortex could be designed to control central networks that
produce particular patterns of movements or it could be organized so
that it plays a more general role in coordinating behavior, regardless
of specific motor circuits involved in producing it.
There is anatomical and electrophysiological evidence that the
efferent zones in the FLR influence brain stem pattern generators that
produce smooth eye movements in a particular direction. The FLR is
spanned by several zones that each receive climbing fiber inputs
related to retinal image slip in a single plane that also corresponds
to the horizontal/vertical activation planes of the vestibular canals
(De Zeeuw et al. 1994; Sato and Kawasaki
1990
, 1991
; Tan et al.
1995
; Van der Steen et al. 1994
).
Microstimulation within each zone produces eye movements in one
direction, and the Pk cells in each zone tend to have signals related
to eye movements in the same direction (Balaban et al.
1984
; Belknap and Noda 1987
; Ito et al.
1977
; Nagao et al. 1985
).
The results of our studies suggest that the efferent zones that span the flocculus and ventral paraflocculus are not involved in coordinating the gaze velocity produced by simultaneous eye and head movements but rather are dedicated to regulating the speed of smooth eye movements as a function of behavioral context. The general implication of this result is that the output of one efferent zone in the cerebellar cortex is dedicated to modifying the output of one central motor pattern generator, rather than coordinating the activity of multiple disparate groups of muscles and joints in multiple reference frames.
Conclusion
The flocculus region of the cerebellum is an essential part of the neural substrate that the brain utilizes for modifying signals in VOR pathways and for producing smooth visual following eye movements. However, it does not appear to be either necessary or sufficient to coordinate gaze during smooth pursuit when head movements are used for tracking. Two implications of these observations are that the efferent zones in the FLR primarily function to regulate the speed of smooth eye movements rather than gaze, and that smooth pursuit eye movements are not used to cancel the VOR during smooth tracking.
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ACKNOWLEDGMENTS |
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This work was supported by National Institutes of Health Grants RO1-EY-08041 and P60-DC-02072.
Present address of T. Belton: Dept. of Physiology and Biophysics, New York University Medical Center, 550 First Ave., New York, NY 10016.
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FOOTNOTES |
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Address for reprint requests: R. A. McCrea, Dept. of Neurobiology, Pharmacology and Physiology, Abbott 07, University of Chicago, 5830 So. Ellis Ave., MC 0926, Chicago, IL 60637 (E-mail: ramccrea{at}midway.uchicago.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 3 January 2000; accepted in final form 23 May 2000.
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REFERENCES |
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