Download Context Dependency in the Globus Pallidus Internal Segment

RAPID COMMUNICATION
Context Dependency in the Globus Pallidus Internal Segment
During Targeted Arm Movements
MARTHA J. GDOWSKI,1,3 LEE E. MILLER,1 TODD PARRISH,2 EMMANUEL K. NENONENE,3
AND JAMES C. HOUK1
1
Department of Physiology and 2Department of Radiology, Northwestern University Medical School, Chicago 60611; and
3
Department of Neurology, Evanston Hospital, Evanston, Illinois 60201
Received 24 July 2000; accepted in final form 10 October 2000
Differing theories of globus pallidus (GP) function have
emerged from previous studies of behaviorally associated GP
neuronal activity. Some studies have indicated that these neurons carry information related to movement kinematics (Georgopoulos et al. 1983; Mitchell et al. 1987; Turner and Anderson 1997). Others have provided evidence that the GP (internal
and external segments) may mediate cognitive aspects of
movement such as multiple-segment movement sequencing
(Mushiake and Strick 1995) or movement preparation
(Brotchie et al. 1991a; Georgopoulos et al. 1983; Jaeger et al.
1993). All of these studies provide evidence for the great
diversity of discharge patterns exhibited by GP neurons in
different behavioral conditions.
The variety in task-related discharge properties is consistent
with evidence supporting the presence of anatomical projections from multiple cortical areas (Alexander et al. 1986; Strick
et al. 1995) that carry information through the basal ganglia.
The degree of convergence of cortical inputs within the striatum has not yet been definitively demonstrated. Strick’s findings support a theory in which discrete cortical areas project to
topographically distinct regions of the striatum and GP (Strick
et al. 1995). Yet, other anatomical studies have provided evidence for convergence of functionally related cortical inputs
within the striatum (Flaherty and Graybiel 1993; McFarland
and Haber 2000; Parthasarathy et al. 1992; Yeterian and Van
Hoesen 1978). Nonetheless, there is general agreement that
neighboring striatopallidal efferent populations project to functionally specific populations of pallidal neurons with adjacent
terminal arborizations that do not intermix (Parent et al. 1997).
Likewise, globus pallidus internal segment (GPi) efferents
project to thalamic neuron populations that, in turn, project to
single cortical neuron populations, as demonstrated by thalamic labeling following cortical injection of transneuronal
virus (Middleton and Strick 1997).
In addition to the task-related properties that may be a
consequence of their cortical inputs, GP neuronal responses
may potentially be influenced by another variable. Substantia
nigra pars compacta (SNpc) neurons release dopamine onto
frontal cortical neurons and striatal medium spiny neurons
which has been reported to modulate the activity of striatal
spiny neurons (Akaike et al. 1987; Kiyatkin and Rebec 1996).
These SNpc neurons have been demonstrated to provide signals during behavior that may be related to the prediction of
future events, progress through a behavioral task, or the likelihood of reward (Hollerman et al. 1998; Kawagoe et al. 1998;
Schultz 1998).
Owing to the fact that they receive cortical and dopaminergic afferents, striatal neurons may convey information to the
pallidum that reflects the processing of both types of influences. Consequently, the activity of a given pallidal output
neuron may be related to motor or associative aspects of
behavior, but could also convey information about progression
Address for reprint requests: L. E. Miller, Northwestern University Medical
School, Dept. of Physiology, 303 E. Chicago Ave., Chicago, IL 60611 (E-mail:
[email protected]).
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.
INTRODUCTION
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0022-3077/01 $5.00 Copyright © 2001 The American Physiological Society
www.jn.physiology.org
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Gdowski, Martha J., Lee E. Miller, Todd Parrish, Emmanuel
K. Nenonene, and James C. Houk. Context dependency in the
globus pallidus internal segment during targeted arm movements.
J Neurophysiol 85: 998 –1004, 2001. Extracellular discharges from
single neurons in the internal segment of the globus pallidus (GPi)
were recorded and analyzed for rate changes associated with visually
guided forearm rotations to four different targets. We sought to
examine how GPi neurons contribute to movement preparation and
execution. Unit discharge from 108 GPi neurons recorded in 35
electrode penetrations was aligned to the time of various behavioral
events, including the onset of cued and return movements. In total, 39
of 108 GPi neurons (36%) were task-modulated, demonstrating statistically significant changes in discharge rate at various times between the presentation of visual cues and movement generation. Most
often, strong modulation in discharge rate occurred selectively during
either the cued (n ⫽ 32) or return (n ⫽ 2) phases of the task, although
a few neurons (n ⫽ 5) were well-modulated during both movement
phases. Of the 34 neurons that were modulated exclusively during
cued or return movements, 50% (n ⫽ 17) were modulated similarly in
association with movements to any target. The remaining 17 neurons
exhibited considerable diversity in their discharge properties associated with movements to each target. Cued phases of behavior were
always rewarded if executed correctly, whereas return phases were
never rewarded. Overall, these data reveal that many GPi neurons
discharged in a context-dependent manner, being modulated during
cued, rewarded movements, but not during similar self-paced, unrewarded movements. When considered in the light of other observations, the context-dependence we have observed seems likely to be
influenced by the animal’s expectation of reward.
CONTEXT DEPENDENCY IN THE GLOBUS PALLIDUS
METHODS
Single unit extracellular recordings were obtained in the GPi of an
awake, behaving adult female macaque monkey in accordance with
guidelines established by the NIH and the Northwestern Institutional
Animal Care and Use Committee. Tungsten microelectrodes (FHC,
Bowdoinham, Maine) were inserted into a recording chamber oriented
45° from vertical in the coronal plane. Recording location was determined using published coordinates from other laboratories (DeLong
and Georgopoulos 1979; DeLong et al. 1985; Horak and Anderson
1984) that were adjusted for this monkey using fiducial markings in
preoperative MR images. For each penetration, single units were
discriminated and identified as putamen or external and internal
pallidal neurons (GPe and GPi, respectively) based on standard criteria [electrode depth, firing rate, incidence of pausing (Anderson
1977; DeLong 1971)].
The monkey faced a white screen containing five light emitting
diodes (LEDs) positioned at 35° increments about an arc (shown
schematically in Fig. 1, top) and grasped a handle that rotated ⫾100°
from vertical during forearm supination and pronation. A handlemounted laser projected onto the screen, providing continuous visual
feedback about handle position, both during cued and self-paced
movements. Trial onset was designated by briefly lighting all five
LEDs, after which only the 0° target remained lit. Once the animal
held the handle within ⫾8° of the lit 0° target for a fixed 500 ms
duration, one of the other LEDs was randomly selected and lit. After
a variable hold period (0 –1000 ms), a long duration (440 ms) tone
triggered the monkey to rotate the handle to the instructed LED. The
FIG. 1. Histograms of globus pallidus internal segment (GPi) neuronal responses from two units aligned
with respect to movement onset for all four targets (Binwidth ⫽ 20 ms). Instructional cues used by the subject
during each phase of the trial are indicated at the top.
Handle position traces for each trial are shown overlayed
below the histograms. Periods of time corresponding to
rewarded, cued movements as well as to unrewarded,
return movements are indicated by dashed lines. A: unit
B181 paused phasically in association with all cued
movements, regardless of direction or amplitude (P ⬍
0.0001, small sample test statistic t for the difference
between two means). Pauses were absent from all return
movements (P ⬎ 0.05). B: unit B251 burst concurrently
with all cued movements (P ⬍ 0.01), but did not burst
during return movements (P ⬎ 0.05). C: unit B121 burst
prior to the cued ⫺70° (P ⬍ 0.0001) and 35° (P ⬍ 0.010)
movements and paused during the execution of the ⫺70°
movement (P ⬍ 0.020). None of the other cued or return
movements were significantly modulated (P ⬎ 0.05). In
spite of this diversity in responsiveness to the cued and
rewarded movements, a consistent feature of the neurons
shown is that none responded in association with the
unrewarded return movements.
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through a task or potential for a reward. This reward relationship has been ascribed to striatal neurons having firing patterns
sensitive both to eye or to limb movements and reward schedule. For instance, some caudate neuron responses have been
described that appeared to be contingent on behavioral cues
that were predictive of the prospect of reward if targeted
saccadic eye movements were executed correctly (Kawagoe et
al. 1998). In another experiment, visual signals were presented
within a predictable trial sequence providing contextual cues
that could be used to determine the appropriate motor response
in a go, no-go arm movement task (Schultz et al. 1998).
Putamen neuron discharge was enhanced in both go and no-go
conditions if contextual cues were predictive of reward. Movement-associated modulation was completely absent if there
was no possibility of reward, suggesting that it was not exclusively the movement, but also the behavioral context that
determined the neuronal discharge pattern.
While many GPi studies have examined neuronal responses
from trial onset through movement completion and reward,
few have contrasted neuronal discharge during movements
executed in different behavioral contexts. Therefore the present
study compared cued, rewarded movements, and similar selfpaced, unrewarded movements to determine whether the associated discharge was context dependent.
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GDOWSKI, MILLER, PARRISH, NENONENE, AND HOUK
RESULTS
In total, 108 GPi neurons were isolated during 35 electrode
penetrations, of which 35% (39/108) were task-modulated,
exhibiting statistically significant changes in discharge rate at
any time between the presentation of visual cues and end of
movement. Representative responses from three well-modulated GPi neurons during the execution of the task are shown
in Fig. 1. Neuron B181 (Fig. 1A) paused phasically in association with cued movements to all four targets (all P ⬍ 0.0001,
small sample test statistic t for difference between two means).
The depths of modulation of each of the pauses were similar
despite differences in movement amplitude and direction, although the latency of the pauses relative to movement onset
differed with movement direction. These observations suggest
that discharges from this neuron were not strongly associated
with movement kinematics per se. Modulation, which was
clearly evident during cued movements in either direction, was
notably absent during both clockwise and counterclockwise
return movements (all P ⬎ 0.05). Behavioral context affected
the discharge pattern of neuron B251 in a similar fashion (Fig.
1B). In contrast to the pausing of neuron B181, however, this
unit burst phasically in association with cued movements (all
P ⬍ 0.01), but did not burst during the return movements (all
P ⬎ 0.05). Like many of the neurons in this study (n ⫽ 17),
neurons B181 and B251 were modulated similarly during cued
movements to all four targets (n ⫽ 17). In contrast, neuron
B121 is more representative of the task-modulated neurons that
exhibited considerable diversity in their discharge properties
associated with movements to different targets (n ⫽ 17). Unit
B121 (Fig. 1C) burst prior to the cued ⫺70° (P ⬍ 0.0001) and
35° (P ⬍ 0.010) movements and paused during the execution
of the ⫺70° movement (P ⬍ 0.020). It was unmodulated with
all other cued and return movements (P ⬎ 0.05).
Most of the task-related neurons were also modulated in a
manner that depended on the context, i.e., strong, phasic modulation occurred only in conjunction with rewarded, cued
movements (32/39) or in a few units, only with unrewarded,
return movements (2/39). A small fraction of GPi neurons
(5/39) were strongly modulated during both cued and return
portions of the task and were considered to have a contextindependent discharge pattern. Half of the context-dependent
neurons (17/34) were similarly modulated in association with
movements to all four targets as in Fig. 1, A and B. The
remaining context-dependent neurons (n ⫽ 17) were preferentially modulated in association with movements to specific
targets as in Fig. 1C.
The context-dependent discharge shown in Fig. 1 was derived from comparison of cued and return movements that
were in opposite directions. To eliminate this factor as an
explanation for the disparate neuronal discharge observed in
the two conditions, the discharge associated with cued and
return movements of the same amplitude and direction was
examined as shown in Fig. 2. This figure shows the discharge
patterns associated with cued and return movements to the
⫺70° target (A, B) and ⫹70° target (C, D) for four neurons.
Unit discharge during cued (left column in A, B, C, and D) and
return (middle column) movements is presented as in Fig. 1. In
addition, this figure includes return movements from a different target that were of the same amplitude and direction as the
cued movement (right column, kinematically similar). Al-
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animal was required to move to within ⫾8° of the target within 2 s of
the movement trigger. On target acquisition, both LEDs were turned
off. At the completion of a fixed 500 ms hold period in the instructed
target window, a liquid reward was delivered. Following reward
delivery, the animal usually returned the handle to the center target
with a self-paced movement prior to the lighting of five LEDs at the
onset of the next trial. Comparison of the two behavioral contexts in
which movements were generated shows that cued movements were
triggered by an auditory tone and directed to lit LED targets, while
return movements were not triggered by a tone and were directed to
unlit targets (Fig. 1, top). The cued movements always started from a
single, central location, while return movements were initiated from
any of the four off-center targets. Furthermore, correct movements to
the instructed target elicited a liquid reward, while return movements
to the fixation target were unrewarded. Data were collected continuously over 10 –12 min intervals.
For each neuron, data from successful trials were grouped according to the instructed target. Rasters and cumulative histograms were
generated by aligning neuronal discharge with respect to the time of
a variety of behavioral events (trial onset, target on, tone on, target off,
and reward) and to the onset of both cued and return movements.
Movement onset was defined as the point at which the derivative of
the handle position signal (velocity) exceeded a fixed threshold of
three times the standard deviation of the noise floor of the velocity
trace. The maximum rate change (burst or pause, or both in the case
of biphasic responses) within 500 ms of the trigger event was determined for each histogram. The mean discharge was determined in a
250-ms window around these time points. Modulation in discharge
rate during the bursts or pauses associated with the cued movement
was compared to the mean rate in the period 1000 –750 ms before
cued movement onset. Modulation in discharge rate during the return
movements was compared to the mean rate in the period 750 –1000
ms after return movement onset. Neurons were included in subsequent
analyses if the event-related discharge differed significantly from
baseline (small-sample test statistic t for the difference between two
means, P ⬍ 0.05). In some cases (8/39), the change in discharge
occurred after the presentation of the visual cue, but before movement
onset, and could not be definitively attributed to either behavioral
event. Neurons were subsequently classified according to the magnitude of phasic modulation in conjunction with cued and return movements. If phasic modulation with similar statistical significance were
detected during both the cued and return movements, the neuron was
classified as “context-independent.” Alternatively, strong phasic modulation associated exclusively with either cued or return movements
led us to categorize the neuron as “context-dependent.”
Surface electromyograms (EMGs) were collected during some of
the final GPi recording sessions from triceps, biceps, brachioradialis,
pronator teres, and flexor carpi radialis muscles. Skin surfaces were
shaved and cleaned with alcohol prior to application of bipolar,
surface EMG electrodes whose contacts were lightly coated with
conductive gel. EMG signals were amplified and high-pass filtered at
75 Hz. During most experiments, behavioral signals were all sampled
at 200 Hz; however, when EMGs were collected, all signals were
sampled at 1000 Hz. EMG signals were subsequently rectified and
smoothed.
During the final recording session, histological lesions (50 ␮A for
20 –30 s) were placed in several locations within the recording chamber using stainless steel microelectrodes (FHC). After lesioning, the
monkey received a lethal dose of sodium pentobarbital and was
perfused with physiological saline followed by 4% paraformaldehyde
and 1% potassium ferrocyanide. The brain was removed, blocked,
cryoprotected, and sectioned at 50 ␮m. Sections were mounted and
stained with thionin and neutral red. Electrode penetrations were
reconstructed and the distribution of neurons in anterior-posterior,
medial-lateral, and dorsal-ventral dimensions was plotted. To summarize this distribution, the extent of the nucleus along each dimension
was divided in half, and the cell was assigned to one half or the other.
CONTEXT DEPENDENCY IN THE GLOBUS PALLIDUS
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FIG. 2. Averaged GPi responses from four neurons and corresponding handle position signals are shown aligned with respect to the onset of ⫺70° (A, B) and ⫹70° (C, D) movements.
Time periods are indicated as in Fig. 1. Note that all four
neurons were well-modulated with the rewarded, cued movements (P ⬍ 0.002), while none were strongly modulated during
unrewarded, return movements [all P ⬎ 0.20, except D (P ⫽
0.044)], even when the return movements were kinematically
similar to the cued movements [all P ⬎ 0.30, except B (P ⫽
0.010)].
parison of EMG activity during the cued movements and
kinematically similar return movements (e.g., ⫺70° cued
movement compared with the return from the ⫹70° target as
shown in Fig. 3) illustrates that muscle activation patterns were
quite similar.
Reconstruction of lesions and recording positions indicated
that neurons were sampled from the full extent of GPi, with the
exception of the ventralposteriomedial region of the nucleus.
The distribution of neurons that were modulated and those that
were not modulated is shown in Table 1. While most taskmodulated neurons were encountered in the anterior half of the
nucleus (31/39), they were evenly distributed along the dorsalventral (18 dorsal, 21 ventral) and medial-lateral (19 medial, 20
lateral) axes. There was no apparent clustering of neurons
along any axis with respect to context-dependence. However,
the context-dependent neurons that exhibited modulation primarily in association with presentation of visual cues (8/39)
tended to be clustered in the medial and anterior portion of the
nucleus.
DISCUSSION
In this study, neuronal discharge during cued and return
phases of a movement task was compared. Most task-modulated GPi neurons exhibited strong, phasic changes in discharge rate in association with cued, but not return movements.
Cued movements were instructed by lit targets, triggered by a
tone, and always rewarded if executed correctly. Return movements were usually executed while targets were off, were
self-paced, and were never rewarded. Thus, many GPi neurons
seemed to be selectively modulated during movements generated in a specific behavioral context. While small differences in
the EMG patterns during cued and return movements were
observed as shown in Fig. 3, these were unlikely to provide an
explanation for such dramatic differences in neuronal activity
during the two phases of movement. Although we were unable
to exclude the influence of the other contextual cues on neu-
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though all neurons shown were well-modulated during the
cued movements (P ⬍ 0.002), none were strongly modulated
with any of the return movements (P ⬎ 0.20), except D (P ⫽
0.044) or kinematically similar return movements (P ⬎ 0.30),
except B (P ⫽ 0.010). Although these neurons were modulated
in association with both cued and return movements to some
targets (P ⬍ 0.05), the differences in the magnitude of the
significance during these movements led us to characterize
them as context-dependent. One would expect that the cued
and kinematically similar movements might have elicited similar responses; however, the lack of modulation during either
the actual return, or the kinematically similar return movements clearly excludes directional preference as an explanation
for the differences in modulation for any given neuron with
context-dependent discharge properties. Thus even when kinematically similar movements were compared, most (34/39)
task-modulated neurons responded selectively during the cued
or return movement but not both. Consequently, these data
support the hypothesis that most GPi neurons are selectively
modulated within specific contextual settings.
Figure 3 shows the discharge of a GPi neuron during cued
and kinematically similar counterclockwise 70° movements
along with position, velocity, and EMG signals which were
aligned with respect to the onset of movement and ensemble
averaged. This neuron was strongly modulated in association
with the cued counterclockwise movements of both 35° and
70° amplitudes (P ⬍ 0.0001); however, only the 70° movement is shown for simplicity. Similar to the neurons in Fig. 2,
this neuron was modulated at a level that exceeds the statistical
threshold to be considered task-modulated (P ⬍ 0.05). However, the magnitude of the modulation during the return movements (P ⬎ 0.03) was considerably smaller than that during the
cued movements. Comparison of the cued and return movements from the ⫾70° targets revealed some small differences
in muscle activation patterns that likely reflect differences in
agonist/antagonist muscle activation during execution of these
two opposing movements (data not shown). However, com-
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GDOWSKI, MILLER, PARRISH, NENONENE, AND HOUK
FIG. 3. Responses of a neuron are aligned with respect to the onset of
counterclockwise cued (left) and return (right) 70° movements. This neuron
was strongly modulated in association with cued, counterclockwise movements to the 35° and 70° targets (P ⬍ 0.0001). However, only the 70°
movement and its kinematically similar counterclockwise 70° movement are
shown for simplicity. In addition to rasters, cumulative histograms of the
neuronal discharge and ensemble averages of position, velocity, and electromyogram (EMG; triceps, biceps, brachioradialis, and pronator teres/flexor
carpi radialis) are shown. The neuron paused in association with the cued
movement, but was not strongly modulated during the return movements (P ⬎
0.03). Time periods are indicated as Fig. 1. A comparison of EMG activity
during these cued and kinematically similar movements reveals that the muscle
activation patterns were nearly the same.
TABLE
1. Summary of neuronal recordings
GPi Region
Modulated
Not Modulated
Total
AMD
AMV
ALD
ALV
PMD
PMV
PLD
PLV
Total
8 (7.41)
9 (8.33)
7 (6.48)
7 (6.48)
1 (0.93)
0 (0.00)
2 (1.85)
5 (4.63)
39 (36.11)
13 (12.04)
7 (6.48)
5 (4.63)
11 (10.19)
7 (6.48)
0 (0.00)
12 (11.11)
14 (12.96)
69 (63.89)
21 (19.44)
16 (14.81)
12 (11.11)
18 (16.67)
8 (7.41)
0 (0.00)
14 (12.96)
19 (17.59)
108
Values are number of neurons recorded with percentage of total in parentheses. A, anterior; P, posterior; M, medial; L, lateral; D, dorsal; V, ventral.
task-modulated striatal neurons seem to be influenced by the
expectation of reward (Hollerman et al. 1998), one might
expect many GPi neurons to be associated with reward-related
context detection as well. This may be especially true for GPi
neurons receiving input from neurons in the ventral striatum
that were shown to carry signals related to progression through
a task, or proximity to reward (Shidara et al. 1998). The fact
that the majority of task-modulated neurons responded to both
movement-related variables and behavioral context is one of
the most striking observations in the present study. This may
reflect convergence of movement and motivation-related signals at the striatal level, since neurons that appear to carry
information about movement preparation or initiation also appear to encode information about behavioral context. Alternatively, it may reflect the prominence of striatopallidal projections that are related to goal attainment, or even the importance
of reward in the areas of prefrontal cortex that provide inputs
to striatal and GPi neurons.
Other laboratories have observed context-dependent firing
behavior in pallidal neurons. GPi neurons have been described
that were modulated differently in association with sequential
wrist flexion and extension movements (Brotchie et al. 1991b)
depending on whether or not the next movement was predictable. These findings suggest that GPi neurons may indeed
participate in the process of behavioral context encoding. Since
the animal may have been more likely to prepare for and
successfully complete a predictable movement than an unpredictable one, this may further reflect reward expectation. Caudate and pallidal neurons were studied during flexion/extension
hand movements made either to an instructed target, or as
corrective movements following torque step perturbations (Aldridge et al. 1980). Analogous to the findings of Brotchie et al.,
neuronal responses for similar movements differed as a function of the behavioral context in which the movements were
generated, suggesting that both striatal and pallidal neurons
participate in this process of context encoding.
Context-dependent discharge patterns in GPi could possibly
be associated with other aspects of behavior. Some channels
through the basal ganglia, for example those receiving input
from prefrontal cortical neurons, are likely to participate in the
sequencing of multiple-segment movements. Prefrontal cortical neurons have been described (Barone and Joseph 1989;
Tanji et al. 1996) that were selectively modulated during
specific segments of a movement sequence. These neuronal
responses were sometimes specific to the order in which a
movement segment occurred within a sequence. Similarly,
Mushiake and Strick (1995) described pallidal neurons that
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ronal discharge using this behavioral paradigm, we speculate
that the monkey identified the context for each movement, and
that reward expectation was the most important variable influencing GPi neuronal activity. Previous reports of GPi neurons
have described a variety of response patterns that appeared to
be influenced by variables of target dependence (Mushiake and
Strick 1995), movement duration (Anderson and Turner 1991),
movement direction (Georgopoulos et al. 1983; Turner and
Anderson 1997), movement amplitude, or velocity preference
(Anderson and Turner 1991; Georgopoulos et al. 1983). Consistent with these previous reports, the task-modulated neurons
in this study also exhibited great diversity in their response
patterns that may reflect the influence of some of these variables. However, the neurons studied in this report appeared to
be influenced by an additional contextual variable that contributed to the discharge patterns by determining whether the unit
will be strongly modulated in association with cued movements, return movements, or both.
Hypothetically, GPi receives this contextual information via
striatal inputs and conveys it to thalamic neurons via specific
channels through the basal ganglia, thereby encoding information about motivation or the potential for reward. Since most
CONTEXT DEPENDENCY IN THE GLOBUS PALLIDUS
The authors thank A. Gruber for valuable discussions of this work and K.
Novak for assistance with behavioral software development.
This work was supported by the Ruggles Fellowship in Movement Disorders, Department of Neurology, Evanston Hospital, Evanston, IL, and by a
National Institute of Mental Health Center Grant (MH-48185-09), J. C. Houk,
Center Director.
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are generated, in particular, information about movement sequence or reward prediction. Experiments are in progress to
further characterize the salient aspects of the behavior which
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