1University Laboratory of Physiology and 2Department of Experimental Psychology, University of Oxford, Oxford OX1 3PT, United Kingdom
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ABSTRACT |
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van Donkelaar, P., J. F. Stein, R. E. Passingham, and R. C. Miall. Neuronal Activity in the Primate Motor Thalamus During Visually Triggered and Internally Generated Limb Movements. J. Neurophysiol. 82: 934-945, 1999. Single-unit recordings were made from the basal-ganglia- and cerebellar-receiving areas of the thalamus in two monkeys trained to make arm movements that were either visually triggered (VT) or internally generated (IG). A total of 203 neurons displaying movement-related changes in activity were examined in detail. Most of these cells (69%) showed an increase in firing rate in relation to the onset of movement and could be categorized according to whether they fired in the VT task exclusively, in the IG task exclusively, or in both tasks. The proportion of cells in each category was found to vary between each of the cerebellar-receiving [oral portion of the ventral posterolateral nucleus (VPLo) and area X] and basal-ganglia-receiving [oral portion of the ventral lateral nucleus (VLo) and parvocellular portion of the ventral anterior nucleus (VApc)] nuclei that were examined. In particular, in area X the largest group of cells (52%) showed an increase in activity during the VT task only, whereas in VApc the largest group of cells (53%) fired in the IG task only. In contrast to this, relatively high degree of task specificity, in both VPLo and VLo the largest group of cells (~55%) burst in relation to both tasks. Of the cells that were active in both tasks, a higher proportion were preferentially active in the VT task in VPLo and area X, and the IG task in VLo and VApc. In addition, cells in all four nuclei became active earlier relative to movement onset in the IG task compared with the VT task. These results demonstrate that functional distinctions do exist in the cerebellar- and basal-ganglia-receiving portions of the primate motor thalamus in relation to the types of cues used to initiate and control movement. These distinctions are most clear in area X and VApc, and are much less apparent in VPLo and VLo.
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INTRODUCTION |
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The cerebellum and basal ganglia project via the
thalamus to widespread yet overlapping parts of the cortex including
areas involved with the control of movement. At the level of the
thalamus, the projections from the deep nuclei of the cerebellum and
the internal segment of the globus pallidus (GPi) remain largely
segregated (Roullier et al. 1994; Sakai et al.
1996
). This level of neuroanatomic segregation,
although not as complete at the level of the cortex as was once
believed, has led to the suggestion that the cerebellum and basal
ganglia and their ascending projections also may be differentiated on a
functional basis. The exact nature of this functional differentiation
has been the focus of numerous studies. For example, the cerebellum has
been shown to be preferentially involved in movements that are
initiated and/or guided by the presence of sensory cues
(Jueptner et al. 1996
; Mushiake and Strick 1993
; Stein and Glickstein 1992
; van
Donkelaar and Lee 1994
). In contrast, the basal ganglia have
been shown to be preferentially involved in movement selection
(Jueptner et al. 1997
), the inhibition of undesired
movements (Mink 1996
), the sequencing of a series of
movements (Boecker et al. 1998
; Brotchie et al.
1991
; Kermadi and Joseph 1995
), and the
production of memorized or internally generated movements
(Crawford et al. 1989
; Hikosaka and Wurtz 1985
; Mushiake and Strick 1995
). These functions
attributed to the basal ganglia are not necessarily mutually exclusive.
In fact, a feature that may be common to each is the selection of
responses based on internal cues. Thus it has been suggested that at a
very general level the cerebellum may be involved preferentially in triggering and guiding movements based on external sensory stimuli, whereas the basal ganglia may be involved preferentially in selecting movements based on internal cues. Having said this, it is important to
emphasize that this dissociation is not complete. In other words, the
cerebellum also appears to be involved to a certain extent in movements
based on internal cues and the basal ganglia in movements triggered and
guided by external stimuli (Passingham 1993
;
Stein 1986
). Indeed, there is evidence to suggest that
the functional specificity described above may be restricted to certain portions of the cerebello- and basal ganglio-thalamo-cortical systems
(see following text). Thus the important point is that different
anatomically segregated subcircuits arising from the basal ganglia and
cerebellum appear to be involved to varying degrees in the performance
of movements based on external versus internal cues.
The purpose of the present experiment was to examine the extent of this
functional specificity at the level of the thalamus. Previous thalamic
recording studies have shown clear limb-movement-related activity in
both cerebellar- and basal-ganglia-receiving nuclei (e.g.,
Anderson and Turner 1991; Butler et al. 1992
,
1996
; Forlano et al. 1993
). In the present
study, we recorded from cells in different portions of the primate
motor thalamus during movements that were either visually triggered or
internally generated. We looked in particular at activity in the
cerebellar-receiving nuclei VPLo (oral portion of the ventral
posterolateral nucleus) and area X and the basal-ganglia-receiving
nuclei VLo (oral portion of the ventral lateral nucleus) and VApc
(parvocellular portion of the ventral anterior nucleus). We predicted
that the degree of functional specificity observed for each of these
nuclei would be dependent on its pattern of connectivity within each
subcortico-thalamo-cortical pathway.
Some insight into this issue can be gained by examining how output
cells in the cerebellum and basal ganglia that project to specific
portions of the motor thalamus respond in different movement contexts.
For example, Mushiake and Strick (1993) have demonstrated that the majority of cells in the caudal portion of the
cerebellar dentate nucleus display a preference for movements based on
visual cues
firing to a greater extent when a visual target triggers
and guides the response compared with when the same movements are
generated from memory. This area of the dentate projects mainly to area
X (Strick et al. 1993
), implying that cells in area X
also may display a preference for visually triggered and guided
movements. By contrast, Mushiake and Strick (1993)
also
found that cells in the more rostral portion of the dentate did not
differentiate as clearly between visually guided and memory-guided arm
movements. The rostral dentate projects mainly to VPLo (Strick et al. 1993
), implying that cells in this part of the thalamus may not differentiate between these two modes of movement as clearly as
cells in area X.
Studies that have examined these functional distinctions in basal
ganglia output cells have produced less consistent results. Mink
and Thach (1991b) and Inase et al. (1996a)
found
that inactivation of the GPi caused similar deficits in both visually
triggered and memory-guided or self-paced movements: namely, a flexor
drift in the affected arm. This led these researchers to conclude
justly that the basal ganglia was involved in turning off or biasing muscle activity to allow a particular movement to occur regardless of
the context. Consistent with their infusion results, Mink and Thach (1991a)
found that the activity of cells in the GPi did not differentiate between several different modes of movement including
visually triggered and self-paced movements. A similar lack of task
specificity has been found in cells located in the putamen
(Kimura et al. 1992
) and the SNpr (Hikosaka and
Wurtz 1983a
,b
). By contrast, Brotchie and coworkers
(1991)
suggested from the results of their experiments that
activity in GPi cells provided an internal cue that contributed to the
switching from one movement to another within a predictable sequence.
Importantly, the magnitude of this activity dropped off considerably
when the sequence became unpredictable (and therefore driven by
external sensory cues).
How can these differing results be accounted for while still
maintaining that the basal ganglia may be involved in some way in
movement selection based on internal cues? One possible explanation is
with respect to the location within the GPi in particular at which the
inactivation or recording took place. Mink and Thach (1991b) and Inase and coworkers (1996a)
inactivated the mid- to ventral half of GPi and Mink and Thach
(1991a)
recorded from the same area. Kimura and
coworkers (1991)
recorded from the putamen which projects to
the ventral two-thirds of the globus pallidus (Smith and Parent
1986
). On the other hand, Brotchie and colleagues (1991)
sampled "from the full extent of the GP" (p.1671).
Thus it may be that some portions of the GPi contribute preferentially to internally cued actions and that the mid- to ventral half of the GPi
is not one of those areas. Mushiake and Strick (1995)
explicitly tested this possibility and found that a large proportion of
cells (65%) located in the dorsal part of the GPi fired preferentially during memory-guided arm movements, whereas cells located more ventrally did not differentiate between visually guided and
memory-guided arm movements.
How such functional neuroanatomic distinctions may be reflected in the
basal-ganglia-receiving portions of the thalamus is not clear. Cells
located more dorsally in the GPi project mainly to lateral and rostral
aspects of VLo and VApc. In contrast, cells located more ventrally in
the GPi project to the middle portion of VLo (DeVito and
Anderson 1982). These results and those of Mushiake and
Strick (1995)
imply that cells within VApc may be more likely
to display a preference for internally driven movements than cells
within VLo, although it is not clear how much of a difference there
would be because of the overlap in the pallidothalamic projections.
To provide further insight into these questions, we describe
experiments in which single-unit recordings were made in the cerebellar- and basal-ganglia-receiving portions of the primate motor
thalamus during visually triggered and internally generated limb
movements. A preliminary report of portions of the present data were
presented previously (van Donkelaar et al. 1997a).
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METHODS |
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Animals and apparatus
Two juvenile rhesus macaque monkeys (Macaca mulatta), weighing between 4.8 and 5.2 kg, served as subjects in the present experiment. All procedures for animal care and use were in accord with the "Guiding Principles in the Care and Use of Animals" (American Physiological Society 1991). Each monkey was trained to perform reaching movements with the right hand using a manipulandum that allowed multijoint responses in a two-dimensional workspace. The manipulandum was positioned underneath an angled semisilvered mirror onto which could be projected the virtual image of a target (1 cm2) from an overhead computer screen. The manipulandum was made visible through the mirror with diffuse illumination of the homogeneous background. The position of the manipulandum was measured in the anterior-posterior and medial-lateral dimensions with two precision potentiometers. The monkey was rewarded for making forward movements with the manipulandum starting just in front of its torso and ending ~15 cm away with the arm almost fully extended.
Behavioral tasks
Two behavioral tasks were used. In both, the monkey was required
to wait before initiating a response with his hand grasping the
manipulandum at the start position located ~5 cm directly in front
and at the midline of his torso. In the visually triggered task (VT),
the target then would appear after a variable length of time (2-3 s),
and the monkey was rewarded for accurately reaching it with the
manipulandum. In 80% of the trials, the target would appear at the
center of the screen directly in front of the monkey. In the remaining
20% of trials, the target would appear 5 cm to the left or right of
center. These trials were included to keep the monkey from producing
stereotyped movements to the central target. In the internally
generated task (IG), no target appeared, and the monkey was rewarded
simply for making a spontaneous movement of the same extent (i.e., 15 cm) as in the VT task. A minimum interval of 3 s between each
movement was required, and early movements were signaled by a warning
tone after which the monkey was required to return to the starting
position. Thus in VT trials the target provided a visual cue about when
and where to reach, whereas in IG trials, no such cue was present. In
both tasks, the monkey was allowed to return to the start position on
successful completion of the response (i.e., no "target hold time"
was required). The two tasks were presented in separate blocks of
trials each lasting ~2-5 min, depending on how long it took the
monkey to complete 20 successful trials.
Surgical procedures
When each monkey was trained sufficiently on both tasks, it was anaesthetized [ketamine hydrochloride (10 mg/kg im) and alphaxalone/alphadolone acetate (5 mg/kg iv)], and a vertically oriented recording chamber was implanted stereotaxically over the left thalamus under aseptic conditions. In addition, two small stainless steel tubes were horizontally positioned in front of and behind the chamber and cemented to the skull using dental acrylic. These subsequently were used to stabilize the head during recording sessions. During the surgery, frontal and sagittal ventriculographs were obtained to aid in the determination of the location of the thalamus with respect to the recording chamber. Analgesics and antibiotics were given postoperatively as required.
Neuronal recording procedures
The activity of isolated single units was recorded with
glass-insulated tungsten microelectrodes (impedance 1-2 M) inserted through a stainless steel guide tube extended to within ~5 mm of the
dorsal surface of the thalamus. Isolated waveforms were passed through
a time-voltage template (CED Spike2) to discriminate and produce a
pulse for each spike with a temporal resolution of 0.1 ms. The
potential relation between neuronal activity and the experimental task
initially was assessed by inducing the monkey to reach toward food
rewards presented by the experimenter. If the cell activity was
modulated in this task, then further tests were completed to ensure
that it was due more specifically to arm movement and not to associated
postural adjustments of the axial musculature or the legs or to facial
movements associated with licking/chewing. Briefly, these tests
consisted of examining the cell's response to passive rotation of the
relevant joints and active movements of the lower limbs and face (in
response to unexpected touches or directly administered food rewards,
respectively). If the cell responded exclusively to lower limb or face
movement or appeared to be related to the postural component of the
reaching response, it was not tested in the experimental task. If on
the other hand the cell displayed arm-movement-related activity, its response to the two different tasks was examined in detail. Although we
did not systematically examine cells with presumed leg-, torso-, and
face-related activity, we did note that there was some somatotopy present especially in VPLo and, to a lesser extent in VLo. In particular, as we moved mediolaterally with our penetrations, we tended
to encounter face, then arm, then leg cells. This is consistent with
previous reports that have examined motor thalamic somatotopy in more
detail (Vitek et al. 1994
, 1996
). Finally, we also
qualitatively tested the response of cells to saccadic and smooth
pursuit eye movements by inducing the monkey to look at or visually
track food rewards beyond their reach. We encountered several cells
that appeared to have eye-movement-related activity and were likely
located in VAmc (magnocellular portion of the ventral anterior
nucleus). Such cells were not investigated further.
For the arm-movement-related cells, spike frequency histograms triggered on movement onset (determined using a velocity threshold) were constructed on-line to allow the experimenter to visually determine whether the isolated cell was modulated significantly by either of the experimental tasks. In addition, histograms triggered on target onset also were generated for the VT task. These were used to confirm that the activity was movement-related rather than a long-latency sensory response to the visual stimulus. In all cases, the changes in activity were brisker and of a greater magnitude when triggered on movement onset rather than target onset. The spike trains, perimovement time histograms, timing of target appearance (in the VT task) and reward delivery, and the movement trajectory all were saved to computer for subsequent quantitative analysis.
Data analysis
Perimovement time histograms were constructed for a 3-s period
starting 1.5 s before the onset of movement and ending 1.5 s
after the onset of movement (40-ms bins). The mean and SD for the
baseline activity was calculated for the 500-ms period from 1.5 to
1 s before movement onset. Movement-related changes in neuronal
firing rate were considered significant when the mean firing rate
increased or decreased by 2 SD from the baseline activity for at
least three consecutive bins. The onset time of neuronal activity (the
1st of these significant bins) was measured relative to the beginning
of movement. The depth of modulation also was calculated as the average
percentage change during the movement relative to the baseline firing
rate. It is possible that preparatory activity in the IG task may start
well before our baseline period (see e.g., Schultz and Romo
1992
), thereby biasing the analysis of movement-related
changes. We tested for this by comparing the magnitude of the baseline
activity in the VT and IG tasks for the population of cells in each of
the thalamic nuclei examined. In every case no significant differences
were found (t-test, P > 0.05), confirming
that the preparatory activity was confined to the period just before
the onset of movement.
Thalamic stimulation
In separate sessions, we used thalamic stimulation as an aid to
help us determine whether our recording sites were in cerebellar- or
basal-ganglia-receiving areas of the thalamus. Several recent microstimulation experiments have demonstrated that movement can be
elicited at low thresholds from VPLo and VLc (caudal portion of the
ventral lateral nucleus) but not any other thalamic nuclei (Buford et al. 1996; Miall et al. 1998
;
Vitek et al. 1996
). Brief (100-300 ms) trains of
biphasic stimulation (negative/positive, 0.2 ms per phase, 0.3-ms
interpulse interval) were applied at a rate of 200 Hz at selected sites
along the presumed borders between the cerebellar- and basal-ganglia
receiving areas. Motor responses were monitored by visual observation
and palpation of the arm and hand. Stimulus current started at 10 µA
and was raised incrementally to a maximum of 150 µA. When movements
were elicited by the stimulation, a threshold was determined by
reducing current until a consistent (3 trials in a row) but barely
detectable muscle contraction was observed visually or by palpation. In
addition, in the final sessions, small electrolytic marking lesions
were made along selected tracks by passing DC current (20 µA, 30 s) through a microelectrode.
Histological procedures and identification of thalamic nuclei
At the end of the experiments each monkey was killed with a lethal dose of pentobarbital sodium. They subsequently were perfused transcardially with saline, followed by 10% buffered Formalin. The brain was removed from the cranium and fixed, frozen, and sectioned in the sagittal plane at 50 µm. Every fifth section was stained with cresyl violet and mounted.
The thalamus was parcellated according to the nomenclature and
cytoarchitectonic criteria of Olszewski (1952) and
Matelli and colleagues (1989)
. Briefly, VPLo is located
in the ventrolateral part of the ventrolateral thalamus and is
separated anteriorally from VLc by VLo. VPLo possesses a heterogeneous
cellular population characterized by uniformly distributed large,
densely stained multipolar cells intermingled with cells of small
diameter. Area X is located medial to VPLo and VLo. It is composed of
lightly stained uniformly distributed large fusiform cells intermingled with small groups of lightly stained large multipolar cells. VLo is
located lateral to area X posteriorly and VApc more anteriorly. It is
characterized by darkly stained small round or oval cells densely
packed in clusters separated by poorly populated areas. Finally, VApc
is situated at the most rostral extent of the ventrolateral thalamus.
It borders on VAmc medially and the VLo laterally. It is composed of
medium-sized lightly stained irregularly distributed cells.
Nuclear borders and electrolytic marking lesions were identified for
each histological section. The nuclear borders were identified based on
the characteristic nuclear cell densities and sizes described in the
preceding text. Recording and stimulating positions were reconstructed
based on their microdrive coordinates and, where possible, gliosis
associated with the electrode tracks, relative to the marker lesions.
Several additional pieces of evidence were used to help confirm the
reconstructions. First, lateral and coronal X-rays taken after each
experiment with the electrode in place were compared with the
ventriculographs obtained during surgery to confirm the mediolateral
and anteroposterior position of the electrode with respect to the motor
thalamus. Second, the high-frequency discharge characteristic of the
reticular nucleus and the somatosensory responses characteristic of the
caudal portion of the ventral posterolateral nucleus (VPLc) aided in
the definition of the dorsoventral and posteriolateral borders,
respectively, of the motor thalamus. Third, the results from the
microstimulation sessions were used to confirm the location of
VPLo/VLc; previous studies have demonstrated that the threshold for
electrical stimulation of movement rises dramatically as one moves
rostrally from VPLo/VLc to VLo and VApc (Buford et al.
1996; Miall et al. 1998
; Vitek et al.
1996
). The reconstructed recording positions were mapped onto
specific thalamic nuclei based on the cytoarchetectonic criteria
described in the preceding text. These maps then were used to obtain
cell counts and task specific frequencies in each of the nuclei
examined. However, because of the difficulty in determining nuclear
borders in the thalamus, any cells estimated to be on or near the
borders were eliminated from subsequent analysis. Of the 224 cells from which recordings originally were made, 21 were discarded for this reason. Included in this group were several cells (n = 3) that fell near the border between VPLo and VLc. Other than these
cells we did not record any others within VLc.
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RESULTS |
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Movement characteristics
It was important to confirm that the VT and IG movements had similar temporal and kinematic characteristics. This would allow us to exclude the possibility that differences in neuronal activity between the two tasks were due simply to the fact that the movements themselves were different. Figure 1, A and B, provides the average peak velocity and movement time in the VT and IG tasks for each monkey. A 2 × 2 (task type × monkey) repeated-measures ANOVA (RM ANOVA) performed on each of these dependent variables revealed no significant effects. Thus movement time and peak velocity were similar for both tasks and for both monkeys.
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General patterns of neuronal activity
We recorded from a total of 203 cells (110 in monkey 1 and 93 in monkey 2) that displayed changes in activity in relation to at least one of the tasks. These cells fell into three general categories related to the nature and timing of their firing pattern. Examples of each of these categories are provided in Fig. 2. The first group of cells showed a significant increase in firing rate before and/or during the movement (Fig. 2B). The second group displayed a significant decrease in firing rate at this time (Fig. 2C). The third group showed an increase in firing rate exclusively at the end of the movement (Fig. 2D). These late onset cells could be coding the antagonist braking of the outward movement, the agonist activity of the return movement, or the delivery of the reward. This issue will be addressed in a subsequent publication. We never encountered cells that displayed a combination of these activity categories across task types (e.g., an increase in firing rate during the VT task and a decrease in firing rate during the IG task).
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Across the 203 cells examined, the majority displayed an increase in
firing rate before and/or during the movement (69%), with lower
percentages showing decreases around the movement (22%) or increases
exclusively at the end of the movement (9%). Moreover, as can be seen
in Fig. 3, A-D, the
percentage distributions of these three categories of cells appeared to
be similar in each of the four main thalamic nuclei (VPLo, area X, VLo,
VApc, respectively) from which we recorded. 2
analysis revealed a significant effect of activity category across the
four nuclei (
2 = 11.53, df = 2, P < 0.0003). Analytical comparisons demonstrated that
the significant effect of activity category was due to differences in
the percentage of cells showing an increase in activity before and/or
during the movement versus the percentage of cells in the other two
categories. Furthermore the differences between these latter two
categories were not significant. Thus in all four nuclei tested the
largest percentage of cells increased their activity before and/or
during the movement with significantly lower percentages of cells
showing decreases around the movement or increases only at the end of
movement. Thus the different cerebellar- and basal-ganglia-receiving nuclei could not be differentiated in terms of their general patterns of activity.
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Task-specific increases in activity
Because cells displaying an increase in activity around the
movement constituted the largest group encountered, we decided to
assess the response characteristics of this group in further detail. In
particular, we categorized these cells as to whether they fired in both
the VT and IG task, exclusively in the VT task, or exclusively in the
IG task. To be categorized as "exclusively" related to a particular
task type, a cell had to display a significant increase in firing rate
for that task and no significant increase above baseline levels in the
other task. This is a strict criterion that excludes cells that show a
"preference" for one task, that is, cells that fire with a greater
magnitude in one task than they do in the other (Mushiake and
Strick 1993, 1995
; Mushiake et al.
1991
). We included such cells in our first category (i.e., cells that fired in both tasks) and have analyzed their response characteristics in relation to each task within each of the nuclei examined (see in the following text).
Figure 4 provides examples of each type of response. The cell in Fig. 4A was located in VPLo and displayed significant increases in activity whenever an arm movement was made, regardless of whether the movement was visually triggered or internally generated. The cell in Fig. 4B was located in area X and fired only when an external target was presented to trigger and guide the movement. When no target was presented and the monkey was required to produce an internally generated response, the cell failed to fire above baseline levels. In contrast, Fig. 4C shows a cell located in VApc that displayed the opposite characteristics: it fired during internally generated movements, but not during visually triggered responses.
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The percentages of cells that fell into each of these categories were
calculated for each nucleus. As is clear from Fig.
5, A-D, there appeared to be
very different percentage distributions for each category within the
four nuclei. In VPLo (Fig. 5A) most cells (60%) were active
in both tasks, less were active exclusively in the VT task (29%) and
relatively few in the IG task only (11%). In area X (Fig.
5B), the largest group of cells were active exclusively in
the VT task (52%) with fewer active in both tasks (33%) and only a
small number active exclusively in the IG task (15%). In VLo (Fig.
5C), the largest group of cells were active in both tasks
(50%), less coded exclusively for the IG task (33%), and relatively
few for the VT task only (17%). Finally, in VApc (Fig. 5D),
most cells were active in the IG task only (53%), a smaller number in
both tasks (34%), and just a handful in the VT task only (13%).
2 analysis revealed a significant two-way
interaction between nucleus and activity category
(
2 = 31.53, df = 6, P < 0.0003). Analytical comparisons confirmed that the percentages of cells
in the largest group within each nucleus were significantly higher than
in the remaining two groups. In addition, the percentage differences
between these lower two groups were also significant for three of the
four nuclei (VPLo, area X, and VApc). Taken together, these results
demonstrate that functional distinctions do exist in certain parts of
the cerebellar- and basal-ganglia- receiving portions of the thalamus
in relation to the VT and IG tasks. In particular, these distinctions
clearly are observed in cells located in area X and VApc. By contrast, most cells in VPLo and VLo do not differentiate between the two types
of tasks. Because of the strict criterion in categorizing cells as
"exclusive", we decided to look in more detail at cells that were
active in both tasks to see whether they displayed preferences for the
VT or IG tasks.
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Response characteristics of cells active in both tasks
To assess whether cells that were active in both tasks nevertheless displayed some task-dependent response characteristics, we measured the depth of modulation in each cell and compared these across the two tasks within each nucleus. The depth of modulation was defined as the average percentage change during the movement period relative to the baseline firing rate. On the left side of Fig. 6, A-D, the percentage change in activity in the VT task is plotted against the percentage change in activity in the IG task for each cell that was active in both tasks. Those cells located above the line of unity were preferentially active in the VT task, whereas those falling below the line of unity were preferentially active in the IG task. On the basis of this simple categorization, there was a trend for more cells to be preferentially active during the VT task in area X (10/13-77%) and VPLo (13/20-65%) and more cells to be preferentially active during the IG task in VApc (9/13-69%) and VLo (9/15-60%). In Fig. 6, A-D, right, the average percentage change in activity is displayed for each task. The means for the individual cells for this variable were submitted to a 4 × 2 (nucleus × task type) RM ANOVA. The results revealed a significant interaction between nucleus and task type [F(3,122) = 2.76, P < 0.05]. Post hoc Tukey's tests showed that this was due to differences in the mean percentage activity change in each task in area X and VApc. On the other hand, the differences between task types in VPLo and VLo were not significant. Thus in addition to possessing many cells that were related exclusively to either the VT or IG task, respectively, area X and VApc also contained a large number of cells that were preferentially active in the VT or IG conditions, respectively. By contrast, although there was a tendency for a greater number of cells in VPLo and VLo to be preferentially excited in the VT and IG tasks, respectively, as a population the activity in these cells did not differentiate between the two conditions.
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To determine if the cells became active at different times relative to
the beginning of the movement in each task, we also measured the onset
time. This was defined as the time interval between the significant
increase in neuronal activity and the beginning of movement. Figure
7, A-D, displays the mean
onset times in the VT and IG tasks for the population of cells in each of the thalamic nuclei examined. The means for the individual cells
were submitted to a 4 × 2 (nucleus × task type) RM ANOVA. The results revealed a significant effect of task type only
[F(1,122) = 8.91, P < 0.05]. Thus
neuronal activity was initiated sooner before the onset of movement in
the IG task than in the VT task as has been shown previously for cells
in the striatum and SMA (Romo and Schultz 1992;
Schultz and Romo 1992
). Moreover the lack of a
significant interaction between nuclei and task type indicates that the
differences in onset times were similar across the four nuclei (see
also Anderson and Turner 1991
).
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Task-specific decreases in activity and late onset cells
We recorded from a total of 44 cells in the two monkeys that displayed decreases in activity at the onset of movement. There were approximately the same number of such cells in the cerebellar- (24/44; 55%) and basal-ganglia-receiving nuclei (20/44; 45%). In terms of the patterns of activity across the two tasks, just over half of the cells (23/44; 52%) decreased their activity in both the VT and IG conditions. A second large group of cells (18/44; 41%) decreased their activity exclusively in the IG task, and only three of the cells (7%) decreased their activity exclusively in the VT task. Although the numbers were not large, this pattern was similar across the four nuclei examined.
Cells that were active exclusively at the end of the movement constituted only 9% (18/203) of our sample. A much larger proportion of cells (84/203; 41%) displayed increases in activity during the movement that remained above baseline levels after the end of the movement (see for example, the cell depicted in Fig. 2B). As mentioned in the preceding text, the activity in these cells could be related to braking the outgoing movement, initiating the return movement to the starting position, or the delivery of the reward. Unfortunately, because of the manner in which the monkey performed the experimental task, it was difficult to separate out these possibilities. We are in the process of undertaking experiments designed to address this issue and will report the results in a subsequent publication.
Thalamic stimulation
In separate sessions after all recordings had been completed, we
applied microstimulation at selected sites to aid in the determination
of our recording locations. Several recent studies have demonstrated
that movements can be elicited at low thresholds by microstimulation
within VPLo and VLc but generally not within other thalamic nuclei
(Buford et al. 1996; Miall et al. 1998
; Vitek et al. 1996
). Thus this technique is useful in
determining the location of VPLo and VLc with respect to the other nuclei.
Because this study was first and foremost a recording study, we did not
complete an exhaustive series of microstimulation penetrations. Rather
our goal in performing the microstimulation was to help us confirm that
we had been recording from (at the very least) VPLo. Toward this end,
we made 11 penetrations in one monkey and 4 in the other at sites that
were presumably within one of the four nuclei examined in detail during
the recordings. Consistent with the other studies cited earlier, we
found that microstimulation at sites within VPLo elicited movement of
the arm, hand, face, or leg at thresholds as low as 20 µA. These
sites are shown in Figs. 8 and
9 (asterisks) along with the
reconstructed recording sites described in the following text. By
contrast, movements could either not be evoked or required currents as
high as 120 µA to be elicited within area X, VLo, and VApc. These
sites are depicted with dashes in Figs. 8 and 9. The one exception to this general finding was a low-threshold (30 µA) microexcitable zone
located at the lateral aspect of area X in the second monkey (Fig.
9D). A similar result was obtained by Buford et al.
(1996) and in fact may represent microexcitable areas at the
medial edge of VPLo. More importantly, however, movements were elicited
at the most anterior penetrations from which we recorded that we presumed to be within VPLo. This confirmed that our VPLo recording sites were behind the interdigitated border between this nucleus and
VLo.
|
|
Reconstruction of recording sites
Sagittal reconstructions of the recording sites for each monkey are shown in Figs. 8 and 9. These reconstructions were generated based on the coordinates of each recorded cell with respect to marker lesions and, when possible, the electrode tracks themselves. Each different type of symbol in Fig. 8 and 9 represents cells that displayed increases in activity in both tasks, in the VT task only, or in the IG task only. In general, there was no clear organization in which cells from the same activity category were grouped together. For example, on any single penetration we could find each type of activity category. For clarity, the reconstructed sites of cells that displayed decreases in activity around the movement or increases at the end of movement are not shown.
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DISCUSSION |
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Compared with the cerebellum and basal ganglia and their
respective cortical projection sites, there is a relative dearth of
single-unit recording studies aimed at understanding the processing occurring within the motor thalamus. One reason for this appears to be
that the motor thalamus traditionally is viewed simply as a "relay"
center through which subcortical structures send projections to
cortical targets. Thus the same neuronal information is assumed to be
present in the thalamus as in the cerebellum or basal ganglia. Although
not the focus of the current study, the presence of interneurons at
least within the cerebellar-receiving nuclei (Ilinsky et al. 1993) suggests that a significant amount of neuronal processing beyond a simple relay of information may be taking place within the
motor thalamus. In addition, other inputs particularly those arising
from corticothalamic projections also may modulate the activity of
cells in the cerebellar- and basal-ganglia- receiving thalamic nuclei
(see following text). These issues await further investigation.
The goal of the present study was to examine whether any functional
segregation exists at the level of the thalamus in terms of the types
of cues used to trigger and guide movement. In particular, we were
interested in whether movements driven by external sensory stimuli as
opposed to internal cues were coded differentially by different
thalamic nuclei. The results demonstrated that cells in area X
preferentially contributed to movements triggered by visual stimuli (VT
task): just over half of the cells sampled in area X fired exclusively
in the VT task, 77% of area X cells that fired in both tasks did so to
a greater extent in the VT task, and as a population, the cells in area
X that were active in both tasks displayed a greater depth of
modulation in the VT task. By contrast, cells in VApc preferentially
contributed to movements that were generated based on an internal cue
(IG task): slightly more than half of the cells recorded from in VApc
fired exclusively in the IG task, 69% of VApc cells active in both
tasks fired to a greater extent in the IG task, and as a population, cells in VApc that fired in both tasks displayed a greater depth of
modulation in the IG task. Thus the evidence clearly supports a
functional distinction between area X and VApc in terms of the cues
used to trigger and guide movement. In contrast to this relatively high
degree of functional specificity, cells in VPLo and VLo did not show as
clear a preference for one condition or the other. Approximately 1/3 of
the cells in VPLo and VLo were exclusively related to the VT and IG
tasks, respectively. Moreover, of the cells that were active in both
tasks there was a categorical tendency for more of them to be
preferentially active in the VT task in VPLo and the IG task in VLo.
However, as a population these cells did not display a significant
difference in their depth of modulation across the two tasks. Thus
although there was a slight tendency for functional specificity related
to the tasks used in this study within VPLo and VLo, this tendency was
much weaker than that observed in area X and VApc. Instead, most of the
cells sampled in these two nuclei did not differentiate between the
conditions. The present results are consistent therefore with the idea
that different anatomically segregated portions of the motor thalamus
are involved to varying degrees in the control of visually triggered
versus internally generated movements. Preliminary evidence in which these nuclei were temporarily inactivated provides support for these
conclusions (van Donkelaar et al. 1997b). In particular, only VT movements were affected after inactivation of area X, infusion
of VApc caused specific deficits in the IG task, and both tasks were
influenced when either VPLo or VLo was inactivated. In what follows, we
discuss how these results can be interpreted in light of previous
functional and neuroanatomic studies within the cerebello- and
pallidothalamocortical systems.
Cerebellum and visually triggered movements
The cerebellum is intimately involved in the generation and
control of arm movements made toward visual targets. Subjects with
cerebellar damage have difficulty with such movements and show
improvements when vision of the target or their hand is removed (e.g.,
Beppu et al. 1987; van Donkelaar and Lee
1994
). Brain imaging studies have demonstrated significant
cerebellar activation during pointing movements made with visual
feedback of the hand (Inoue et al. 1998
) and when
movements are triggered and guided by external sensory cues
(Jueptner et al. 1996
). Mushiake and Strick
(1993)
have shown that this functional specificity for visually
guided action may be restricted at the level of the dentate to the most caudal portions of this nucleus: cells here display a preference for
visually guided movements, whereas cells located more rostrally in the
dentate do not differentiate as clearly between visually guided and
remembered movements. The caudal dentate projects mainly to area X
whereas the rostral dentate projects mainly to VPLo (Strick et
al. 1993
). Thus there is a clear association between the
functional specificity observed at the level of the dentate as shown by
Mushiake and Strick (1993)
and the functional
specificity in area X and VPLo within the thalamus in the present study.
Basal ganglia and internally generated movements
Evidence to support the idea that the basal ganglia are involved
preferentially in internally generated movements is less clear than
that supporting the role of the cerebellum in visually triggered
movements. Certainly, subjects with Parkinson's disease display
deficits in producing internally generated or remembered movements that
are ameliorated when external cues are provided (e.g., Crawford
et al. 1989; Morris et al. 1996
; Oliveira
et al. 1997
). Similarly, subjects with Huntington's disease
have difficulty generating predictive saccadic eye movements
(Tian et al. 1991
). Many recording and inactivation
studies in monkeys, however, have shown that the basal ganglia do not
clearly differentiate between visually triggered and internally
generated or remembered movements (e.g., Hikosaka and Wurtz
1983a
,b
; Inase et al. 1996a
;
Kimura et al. 1992
; Mink and Thach
1991a
,b
). The results of Mink and Thach
(1991a
,b
) and Inase and coworkers (1996a)
are
consistent instead with the idea that the basal ganglia are involved in
turning off or biasing muscle activity to allow a particular movement to occur regardless of the context. On the other hand, others have
demonstrated that the activity in basal ganglia output cells provides
an internal cue that contributes to the switching from one movement to
another within a predictable sequence (Brotchie et al.
1991
). Indeed, Mushiake and Strick (1995)
have
shown that this functional specificity may be localized to specific
portions of the internal segment of the globus pallidus (GPi). In
particular, they showed that the majority (65%) of cells located in
the dorsal part of the GPi fire preferentially during remembered
movements, whereas the majority of cells located more ventrally in the
GPi did not differentiate between visually triggered and remembered movements. The key issue with respect to these discrepant results appears to be the location at which the recording or inactivation took
place within the GPi. In the experiments by Mink and Thach (1991a
,b
) and Inase and colleagues (1996a)
the
mid to ventral half of the GPi was probed, whereas in the
Mushiake and Strick (1995)
study, a distinction between
the dorsal and ventral parts of the GPi was made. Taken together, these
results imply that the basal ganglia are involved in general in the
process of movement selection or inhibition regardless of the context
(Mink 1996
), but that the dorsal aspect of the GPi is
involved more specifically in the process of movement selection based
on internal cues.
The dorsal GPi projects mainly to the lateral and rostral aspects of
VLo and VApc, whereas the ventral GPi projects to the middle portion of
VLo (DeVito and Anderson 1982). Unlike the relatively segregated projections from the cerebellum to VPLo and area X, there
appears to be a substantial amount of overlap in the pallidal projections to VLo and VApc (DeVito and Anderson 1982
).
Thus it is not clear how the results of the present study on the
ventral thalamus and those by Mushiake and Strick (1995)
on the GPi are to be integrated. The fact that cells in VApc displayed
a strong preference for internally generated movements but cells in VLo did not despite receiving inputs from the dorsal GPi suggests that
other inputs may be modulating the activity in the motor thalamus in a
task-specific fashion. One such input may be that arising from motor
cortical projections back down to the thalamus. Therefore the
interactions between the thalamus and the motor areas of the cortex
will be considered next.
Thalamocortical and corticothalamic projections
The projections from the cerebellar- and pallidal-receiving
portions of the thalamus overlap considerably at the level of the
cortex (e.g., Holsapple et al. 1991; Hoover and
Strick 1993
, 1999
; Inase and Tanji 1995
;
Inase et al. 1996b
; Matelli and Luppino 1996
). For example, VPLo sends projections to the motor cortex, the dorsal and ventral premotor cortex, and the supplementary motor
area. VLo also sends projections to each of these areas as well as to
the presupplementary motor area. In terms of function, the finding from
the present study implies that the majority of cells in VPLo and VLo
contribute similar signals to each of these areas during movements
based on external visual cues versus internal cues.
The projections from both area X and VApc terminate in the ventral
premotor cortex, the presupplementary motor area, and the frontal and
supplementary eye fields. The degree to which area X and VApc
projections overlap categorically at the cortical level is difficult to
reconcile with our results showing functional segregation between these
nuclei in terms of the cues used to trigger and guide movement. When
the strength of the projection is taken into account, however, the
relationship between activity in area X and VApc and their cortical
projection sites becomes somewhat more tractable. Area X projects more
heavily to the ventral premotor cortex than does VApc (Mattelli
and Luppino 1996; Mattelli et al. 1989
). The
ventral premotor cortex has been shown to integrate oculomotor and hand
movement signals during responses triggered and guided by external
sensory cues (Fujii et al. 1998
; Mushiake et al.
1997
). In addition, the number of cells in the ventral premotor
cortex that are related to visually triggered movements is two to three
times greater than the number of cells related to internally guided
movements (Mushiake et al. 1991
). This is very similar
to our own finding that the activity in the majority of cells in area X
is related to visually triggered movements.
Relative to area X, VApc sends a somewhat stronger projection to the
presupplementary motor area (Matelli and Luppino 1996). Brain-imaging studies have demonstrated that this area participates in
the selection of motor responses based on memorized information (Petit et al. 1998
; Picard and Strick
1996
) but does not contribute to visually triggered pointing
movements (Inoue et al. 1998
). The results from
recording and inactivation studies in primates are consistent with
these findings. Cells in the presupplementary motor area participate in
the acquisition and control of memorized sequences of movements
(Clower and Alexander 1998
; Nakamura et al.
1998
). Similarly, temporary inactivation of the
presupplementary motor area disrupts the ability to produce memorized
but not visually triggered sequences of movements (Shima and
Tanji 1998
). These results are similar to our own showing a
preference for movements based on internal cues within VApc.
The projections from the motor thalamus to the motor areas of the
cortex are to a certain extent reciprocal. Both the motor cortex and
supplementary motor area project to VPLo and VLo but not area X or VApc
(Jurgens 1984; Kunzle 1976
). By contrast,
the ventral premotor cortex and the anterior portion of the
supplementary motor area (i.e., the presupplementary motor area)
project to area X and VApc but not VPLo or VLo (Kunzle
1978
). The projection from the motor cortex to VPLo and VLo
could help to explain the lack of clear task specificity observed in
these nuclei in the present study. The motor cortex codes for the basic
parameters of movement like force and direction (Georgopoulos
1991
) and does not differentiate between movements based on
external cues versus internal cues (Mushiake et al.
1991
). If the input from the motor cortex modulates or even
dominates the activity in VPLo and VLo, then it follows that they too
will not differentiate between the tasks used in the present study.
Conclusions
The present experiment was designed to test whether the neuronal processing in the cerebellar- and basal-ganglia-receiving nuclei of the motor thalamus was consistent with the functional specificity previously suggested for these subcortical structures during visually triggered and internally generated limb movements. We have demonstrated that cells located in area X showed a strong preference for visually triggered movements; whereas cells located in VApc displayed a strong preference for internally generated movements. In each case, more than half of the cells recorded in these areas coded exclusively for their preferred movement condition. By contrast, cells located in VPLo and VLo did not as clearly differentiate between the two movement tasks. Taken together, these results are consistent with the hypothesis that specific subcircuits within the cerebello-thalamo-cortical and basal ganglio-thalamo-cortical pathways clearly differentiate between visually triggered and internally generated movements, respectively.
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ACKNOWLEDGMENTS |
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The authors thank Dr. Xuguang Liu for performing the implantation surgery, J. Winter for technical assistance, and the staff at the University Laboratory of Physiology Animal House for expert care.
This research was funded by grants from the Wellcome Trust and the Medical Research Council.
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FOOTNOTES |
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Present address and address for reprint requests: P. van Donkelaar, Dept. of Exercise and Movement Science, 2C Esslinger Hall, University of Oregon, Eugene, Oregon 97403-1240.
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 26 February 1998; accepted in final form 21 April 1999.
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REFERENCES |
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