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The Journal of Neuroscience, March 1, 2003, 23(5):1916
Stimulation of the Subthalamic Nucleus Changes the Firing Pattern
of Pallidal Neurons
Takao
Hashimoto1, 2,
Christopher M.
Elder1,
Michael S.
Okun1,
Susan K.
Patrick1, and
Jerrold L.
Vitek1
1 Department of Neurology, Emory University School of
Medicine, Atlanta, Georgia 30322, and 2 Third Department of
Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
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ABSTRACT |
To clarify the mechanism underlying improvement of parkinsonian
signs by high-frequency electrical stimulation (HFS) of the subthalamic
nucleus (STN), we investigated the effects of STN HFS on neuronal
activity of the internal and external segment of the globus pallidus
(GPi and GPe, respectively) in two rhesus monkeys rendered parkinsonian
by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. A
scaled-down version of the chronic stimulating electrode used in
humans, consisting of four metal contacts 0.50 mm in length each
separated by 0.50 mm, was implanted through a cephalic chamber targeting the STN. Histological reconstruction revealed that the cathode was located in the STN in both monkeys. Extracellular recordings from a total of 110 pallidal neurons during STN stimulation were performed. Poststimulus time histograms of single neurons triggered by 2 Hz STN stimulation pulses at 2.4-3.0 V revealed short-latency excitations at 2.5-4.5 and 5.5-7.0 msec after
stimulation onset and inhibitions at 1.0-2.5, 4.5-5.5, and 7.0-9.0
msec for both GPe and GPi neurons. These short-latency responses were
present with 136 Hz stimulation, at voltages effective for alleviation of parkinsonian signs, resulting in a significant increase in mean
discharge rate and a stimulus-synchronized regular firing pattern.
These results indicate that activation of the STN efferent fibers and
resultant changes in the temporal firing pattern of neurons in GPe and
GPi underlie the beneficial effect of HFS in the STN in Parkinson's
disease and further support the role of temporal firing patterns in the
basal ganglia in the development of Parkinson's disease and other
movement disorders.
Key words:
subthalamic nucleus; globus pallidus; Parkinson's
disease; MPTP; deep brain stimulation; motor circuit
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Introduction |
High-frequency electrical
stimulation (HFS) of the subthalamic nucleus (STN), internal segment of
the globus pallidus (GPi), and motor thalamus can improve motor signs
in patients with Parkinson's disease (PD) (Benabid et al., 1991 ;
Limousin et al., 1995; Davis et al., 1997; Krack et al., 1998; Kumar et
al., 1998); however, its mechanism of action remains unclear. In each
structure, ablation and stimulation produce similar effects on tremor
and other parkinsonian motor signs. These observations have lead to the
hypothesis that HFS acts to inhibit neuronal activity at the
stimulation site. Previous studies in anesthetized rats have
demonstrated decreased neuronal activity in the STN,
entopeduncular nucleus (EP), and substantia nigra pars
reticulata (SNr), and increased neuronal activity in the GP and
ventrolateral nucleus of the thalamus after 130 Hz STN stimulation
(Benazzouz et al., 1995). An in vitro study using isolated
slice preparations also revealed that high-frequency STN stimulation
induced strong suppression of STN neuronal activity secondary to
depression of intrinsic voltage-gated currents (Beurrier et al., 2001).
These results have led to the assumption that STN HFS improves
parkinsonian motor signs by suppressing STN excitatory output to its
target nuclei, i.e., the GPi and the SNr. On the other hand, an
intracerebral microdialysis study in rats demonstrated a significant
increase of extracellular glutamate levels in the EP and substantia
nigra (SN) by 130 Hz STN stimulation, consistent with activation of STN
neurons and axons (Windels et al., 2000). Because it has been
demonstrated in rats that STN neurons can discharge at a maximum
frequency of ~500 Hz (Kitai and Kita, 1987) and SN neurons can follow
STN stimulation at >100 Hz in rats (Hammond et al., 1978), it is
difficult to explain the discrepancy between the results of these
studies. To clarify the mechanism underlying the effects of STN HFS on
parkinsonian motor signs, we examined the effect of HFS in the STN on
the neuronal responses of pallidal neurons in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkey model of PD
using an experimental setting that was homologous to that used in humans.
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Materials and Methods |
The experiments were conducted in two rhesus monkeys
(Macaca mulatta; R7160 and R370 weighing 5.2 and 6.9 kg,
respectively). The studies were performed in compliance with The
National Institutes of Health Guide for Care and Use of Laboratory
Animals (1996) and with the Emory University guidelines for
the use and care of laboratory animals in research.
MPTP treatment. The monkeys were treated with MPTP
via a single injection through the internal carotid artery (left side
in R7160, right side in R370). The total amounts of MPTP were 3.2 mg
(0.6 mg/kg) and 4.1 mg (0.6 mg/kg), respectively. Both monkeys developed a stable parkinsonian state characterized by contralateral rigidity and bradykinesia. Tremor was not present at rest or with action in either monkey.
Surgical procedure. A metal chamber was anchored over the
left cerebral hemisphere in monkey R7160 and the right cerebral hemisphere in monkey R370. The chamber was placed aseptically under
isofluorane anesthesia. A chronic stimulating electrode was implanted
through a recording chamber targeting the STN (Fig. 1), previously identified by
microelectrode mapping. The tips of the chronic stimulating electrode
were connected to a programmable pulse generator (Itrel II,
Medtronic Inc.) implanted subcutaneously in the monkey's
back. The stimulating lead was a scaled-down version of the chronic
stimulation electrode used in humans (Model 3387, Medtronic
Inc.) and consisted of four metal contacts (impedances of
100-150 M ) each with a diameter of 0.76 mm, thickness of
0.50 mm, and separation between contacts of 0.50 mm.
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Figure 1.
Location of the electrode contacts and neurons
recorded during 136 Hz at 1.8 V in monkey R7160 and at 3.0 V in monkey
R370, and changes in the firing rate. The cathode of the stimulation
electrode was located in the posteromedial portion of the STN in monkey
R7160 and on the posterior portion of the STN in monkey R370, 1 mm
lateral to that of monkey R7160. Scale bars, 5 mm. OT,
Optic tract; Ret, thalamic reticular nucleus;
SN, substantia nigra; STR, striatum;
TH, thalamus.
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Behavioral assessment. The amount of spontaneous movement
was assessed using a computer-assisted method of behavioral assessment to quantify the amount of movement (Bergman et al., 1990) while the
monkey was in a Plexiglas cage. Each session was videotaped for
subsequent rating by examiners blinded to the experimental condition.
During the videotape ratings the order of stimulation conditions was
randomized, and two scorers (blinded to the experimental condition)
counted the total movement time per 10 min for the arm and leg on the
right and left sides of the body from the video. A post hoc
analysis (Tukey's honestly significant difference) was used to
determine the significance of the difference in the amount of time of
limb movement. Muscle tone of the biceps brachii muscles evoked by
manual elbow extension contralateral to the HFS was assessed using
electromyography (EMG). The most effective pair of stimulating
electrode contacts was chosen for bipolar stimulation in each animal
after evaluation of the clinical effect and the adverse effects. The
threshold for adverse effects was determined by inspection of the
animal for capsular responses with the onset of stimulation. The effect
of STN stimulation on spontaneous movement and muscle tone was compared
under the different experimental conditions. Stimulation conditions
were 210 µsec pulse width, 20 and 136 Hz, and 1.4, 2.4, and 3.0 V in
R7160, and 90 µsec pulse width, 2, 136, and 185 Hz, and 2.0 and 3.5 V in R370. Maximal voltage for the behavioral assessment was set to just
below the threshold for corticospinal contraction at 136 or 185 Hz in
each monkey.
Recording procedure and data collection. Neuronal activity
was recorded extracellularly from the external globus pallidus (GPe)
and GPi. A glass-coated platinum-iridium microelectrode (impedances of
0.4-0.8 M at 2 kHz) was positioned within the chamber with the use
of an x-y coordinate microdrive (MO-95-lp, Narishige Scientific Instruments). Recording penetrations
were made in parasagittal planes moving in a rostral to caudal manner at an angle of 70° to the orbitomeatal line. Neurons in GPi
were examined for their response to passive manipulations of the limbs and orofacial structures. Spontaneous neuronal activity (with the
animal sitting still with head fixed) was recorded under the following
conditions: prestimulation, on-stimulation, and poststimulation. The
duration of the prestimulation and poststimulation periods was set at
15-25 sec, and the duration of the on-stimulation period was set at
25-35 sec for 136 Hz and at 100-110 sec for 2 Hz stimulation. The
change in neuronal activity was evaluated at 2 Hz stimulation with 2.4 V in R7160 and 3.0 V in R370, and at 136 Hz with 1.4 and 1.8 V in
R7160, and with 2.0 and 3.0 V in R370. The 136 Hz stimulation of 1.4 V
in R7160 and 2.0 V in R370 produced no apparent effect, but that of 1.8 V in R7160 and 3.0 V in R370 produced a consistent improvement in
rigidity and bradykinesia, on the basis of clinical examination of
animals in the primate chair. The effect of 5 min of extended 136 Hz,
3.0 V stimulation was studied in nine GP neurons in R370. The analog
neuronal signal was amplified, bandpass filtered at 300-10,000 Hz,
digitized, and sampled at 50 kHz with 4096-point vertical resolution
for off-line analysis.
Data analysis. The software for analysis of neural signals
during stimulation was developed using a C compiler running on DOS for
off-line analysis (Hashimoto et al., 2002). The template of the
stimulus artifact is constructed by averaging across all peristimulus
segments. During stimulation, the stimulus artifact template was
subtracted from the individual traces, and neuronal spikes were
detected. A peristimulus time histogram (PSTH) was constructed,
and mean discharge rates were determined. For comparison of the mean
frequency in the prestimulation, on-stimulation, and poststimulation
periods, Student's t test (two-tailed; p < 0.05) was used. A significant increase or decrease in firing
probability was accepted if a single bin in the PSTH was higher or
lower than the mean prestimulation firing probability ± 3.3 SDs
(p = 0.001), or when the p value of
two to four consecutive bins by the Wilcoxon signed rank test
was <0.01.
Histological analysis. After completion of the study the
monkeys were killed with an overdose of pentobarbital (100 mg/kg), and the brains were processed histologically. The brain was
sectioned in the frontal plane in R7160 and in the sagittal plane in
R370. Recording sites in the GPe and GPi were reconstructed by
identification of gliosis along the microelectrode and HFS electrode
tracks and electrophysiological landmarks (DeLong, 1971). The
stimulating lead was positioned in the STN 6 mm from the midline in
monkey R7160 and 7 mm from the midline in monkey R370 (Fig. 1). In both monkeys, tyrosine hydroxylase staining revealed a nearly complete loss
of dopaminergic cells in the substantia nigra pars compacta.
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Results |
Effects of STN HFS on parkinsonian signs
Stimulation at 136 Hz was associated with increased spontaneous
movement in both monkeys that was voltage and frequency dependent (Fig.
2A,B). The movement was
normal in nature (not dyskinetic), and although increased bilaterally,
the increase was significant only for the side contralateral to
stimulation. Muscle tone on the contralateral side was reduced with
high-frequency stimulation (Fig. 2C). The effect of
stimulation on spontaneous movement and rigidity appeared within the
seconds after onset of stimulation. The improvement of rigidity
disappeared within 10-20 sec and that of bradykinesia within seconds
to minutes after stimulation was discontinued.
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Figure 2.
Effect of STN stimulation on movement and
rigidity. The total movement time of the limbs was measured by raters
blinded to the experimental condition (S.P. and M.O.) from seven
recordings for each stimulation condition. Without stimulation, the
monkeys sat quietly with little movement of the extremities
(bradykinesia) on the side contralateral to the MPTP injection.
Stimulation at 136 Hz was associated with increased movement on both
sides in monkey R7160 (A) and monkey R370
(B). Increases in movement time were larger on
the side contralateral to STN stimulation in both monkeys (right side
in R7160, left side in R370). Asterisks indicate a
significant difference in the on versus off stimulation condition:
*p < 0.05, ***p < 0.001; a
post hoc analysis (Tukey's honestly significant
difference). C, Stimulation at 136 Hz, 3.0 V
(top, stimulation signals recorded from the chamber)
reduced biceps brachii EMGs (second trace, surface
EMGs) induced by manual elbow extension (bottom trace)
in monkey R370.
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Effects of STN stimulation on pallidal neurons
In the two monkeys, the activity of a total of 110 GP neurons was
studied. Eighty-two percent of GPi neurons showed somatosensory responses, indicating that most recorded GPi neurons were located in
the sensorimotor territory. GPe neurons analyzed were all
high-frequency-discharge type (DeLong, 1971); burst-type neurons
(DeLong, 1971) were not included. The responses of 29 GPe and 47 GPi
neurons were recorded during both ineffective and effective STN
stimulation at 136 Hz. The locations of these neurons are illustrated
in Figure 1. The effect of a range of stimulation frequencies (2, 136, and 157 Hz) at both ineffective and effective voltages (effect on
rigidity and bradykinesia) on neuronal activity were studied. STN
stimulation of 2 Hz at voltages and pulse widths effective in
ameliorating bradykinesia and rigidity at high frequency (2.4 V, 210 µsec in monkey R7160 and 3.0 V, 90 µsec in monkey R370) produced a
pattern of short-latency responses that consisted of five consecutive components of inhibition and excitation
(Fig. 3, Table 1). The sequence of
inhibition and excitation after 2 Hz stimulation pulses was preserved
at stimulation frequencies of 136 and 157 Hz. At stimulation
frequencies of 136 and 157 Hz, the later components of these
short-latency responses were partially obscured by the next stimulation
pulse. Consequently, at higher frequencies of stimulation the
interstimulus period was occupied by four short-latency components
(inhibition-excitation-inhibition-excitation). The excitation
components of the short-latency responses were more tightly correlated
to the time of the stimulation pulse at higher stimulation frequencies
(Fig. 3).
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Figure 3.
Overlay of 50 sweeps of neuronal activity of a
GPi cell during 2 Hz (top), 136 Hz
(middle), and 157 Hz (bottom) stimulation
at 3.0 V (R370). Depolarization (negative potential) is shown as an
upward deflection. Each stimulation frequency is associated with
excitation peaks at 2.5-4.0 msec and 5.5-7.0 msec after the onset of
stimulation. Short-latency excitation was greater and more tightly
coupled to each stimulation pulse during higher-frequency stimulation.
Arrows indicate residual stimulation artifacts after
artifact template subtraction.
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The consistent pattern and precise latencies of the responses that
occurred during stimulation changed the spontaneous irregular firing of
GP neurons into a high-frequency regular pattern of discharge (Fig.
4). The interstimulus interval (ISI)
histograms of the prestimulation and poststimulation periods show
widely varying ISIs with a small peak at 4-5 msec. The ISI histogram of the 136 Hz stimulation period, on the other hand, revealed large
peaks at 4 and 8 msec, indicating a regular firing pattern with most
ISIs occurring at regular intervals after the stimulation pulse. The
increased mean firing rate reflected the dominant effect of the
short-latency excitatory responses after each stimulation pulse (Fig.
5A,B).
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Figure 4.
Rasters (A) and ISI histograms
(B) of GPi neuronal activity (R370). The firing
changed from an irregular pattern with varying ISIs into a
high-frequency regular pattern with most ISIs occurring at 4 or 8 msec
during 136 Hz, 3.0 V stimulation.
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Figure 5.
A, B, Examples of
neuronal responses occurring during STN stimulation in a GPi and GPe
cell, respectively. Top traces show analog signal
overlays of 100 sweeps made by triggering at 10 msec intervals in the
prestimulation (before start of stimulation) period and by triggering
on the stimulation pulse in the on-stimulation period.
Arrows indicate residual stimulation artifacts after
artifact template subtraction. Middle traces display
PSTHs reconstructed from successive 7.0 msec time periods in the
prestimulation period and from the interstimulus periods, in the
on-stimulation period. The first PSTH bin is omitted in the
on-stimulation period because of signal saturation and residual
stimulation artifacts. *Significant increase at p < 0.01;  significant decrease at p < 0.01; Wilcoxon signed rank test. Bottom plots
represent the mean firing rate calculated every 1 sec on the basis of
the PSTH illustrating the time course of the firing rate.
C, An example of the time course of the change in firing
rate of a GPi neuron during prolonged 136 Hz STN stimulation. Increased
mean discharge rates in this neuron were sustained during the 5 min
stimulation period. The thick bars indicate the
stimulation period.
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During HFS at 136 and 157 Hz, the discharge rate quickly attained its
maximum and then gradually decreased in approximately half of GPe and
GPi neurons in which a change was noted. Although the discharge rate
gradually decreased during stimulation, it remained higher than the
prestimulation period (Fig. 5A,B). During periods of
prolonged stimulation lasting >5 min, a sustained increase in mean
discharge rate occurred in seven of seven GPi neurons and two of two
GPe neurons (Fig. 5C).
Changes in the shape of action potentials were observed during HFS in
more than half of recorded neurons in which the firing rate increased.
During HFS there was a decrement in the amplitude of both the negative
and positive phases (Figs. 3, 5A,B). The degree of amplitude
decrement was <20% in most neurons, but a few neurons showed changes
of nearly 50%. Action potential amplitude began to change with a time
lag of several seconds after the start of stimulation and returned to
normal within several seconds after termination of stimulation.
On the basis of the fixed latency of response with no jitter, it
appeared that some GPe neurons were antidromically activated. Some of
these antidromic responses may have been obscured by the stimulation
artifact. Given the interference of the stimulation artifact with
antidromic potentials, no attempts were made in the present study to
confirm their presence in GPe by paired-pulse stimulation or collision testing.
Changes in the average firing rate of GPe and GPi neurons with 136 Hz
stimulation at 1.4 and 1.8 V in monkey
R7160 and 2.0 and 3.0 V in monkey R370
are shown in Figure 6. In monkey R7160 at 1.4 V stimulation at
136 Hz (ineffective in improving bradykinesia or rigidity), the overall
firing rate of GPe and GPi neurons was not changed significantly (Fig.
6A). At 1.8 V stimulation (effective for alleviation
of parkinsonian signs), however, there was a shift in the proportion of
neurons in both GPe and GPi that showed a significant increase in the
average firing rate. The overall firing rate in GPe increased from
50.4 ± 9.9 (mean, SD) to 65.4 ± 28.5 spikes per second and
in GPi from 63.2 ± 17.2 to 81.7 ± 37.0 spikes per second,
respectively (Fig. 6B). At the effective voltage, 53% of GPe neurons (8 of 15) and 61% of GPi neurons (14 of 23) showed
a significant increase in mean discharge rate (Fig. 6C). Similar to monkey R7160, in monkey R370, stimulation at 136 Hz at a
voltage ineffective in improving bradykinesia or rigidity (2.0 V) did
not produce a significant change in the average firing rate or
discharge pattern of neurons in GPe or GPi (Fig. 6D). At a voltage effective for alleviation of parkinsonian motor signs (3.0 V stimulation at 136 Hz), however, the overall firing rate in GPe
increased from 40.5 ± 17.4 to 102.9 ± 54.0 spikes per
second and in GPi from 70.4 ± 27.6 to 112.0 ± 36.8 spike
per second, respectively (Fig. 6E). During effective
stimulation, 86% of GPe neurons (12 of 14) and 88% of GPi neurons (21 of 24) showed a significant increase in the average firing
rate and developed a more regular pattern of discharge (Fig.
6F).
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Figure 6.
Change in the mean firing rate of GPe and GPi
neurons during 136 Hz STN stimulation in the two monkeys.
A-C, Monkey R7160. During 1.4 V stimulation, the firing
rates did not change significantly in either GPe or GPi, but during 1.8 V stimulation, the mean discharge rate increased significantly, and the
percentage of neurons displaying a change in the firing rate showed a
strong shift to excitation in both GPe and GPi. D-F,
Monkey R370. Stimulation of 2.0 V did not induce a significant change
in the firing rate, but 3.0 V stimulation increased the firing rate
significantly and shifted the percentage of neurons to excitation in
both GPe and GPi. Asterisks indicate a significant
difference in on versus off stimulation conditions. Significant
differences: *p < 0.01, **p < 0.001, ***p < 0.001; t test.
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Discussion |
Our experimental setting closely reproduces the HFS system used in
humans, and the results demonstrated that STN stimulation produces
short-latency excitatory responses that tonically increase the average
firing rate in both GPi and GPe. The results are in stark contrast to
previous studies in anesthetized rats that showed a reduction of EP and
SNr activity consistent with suppression of STN neuronal output during
STN HFS (Benazzouz et al., 1995; Beurrier et al., 2001). We also
observed a decrease in the ratio of action potential amplitude to
duration in many neurons, similar to the change preceding
depolarization block as observed in spinal or nigral dopamine neurons
(Curtis et al., 1960; Hollerman et al., 1992). Although the increased
firing rate in GP neurons was sustained in the present study, it is
possible that STN neurons could enter a state of depolarization block
with inhibition of STN neuronal activity, as observed in previous
studies (Benazzouz et al., 1995; Beurrier et al., 2001). Although
activation of GPi neurons coincident with inhibition of STN during HFS
in the STN may appear paradoxical, it is consistent with previous
modeling studies suggesting that axons exiting the stimulated structure may be activated at stimulation parameters that inhibit neuronal activity (McIntyre and Grill, 1999). Our studies were also performed in
awake primates using a stimulating lead that is similar to that used in
humans. Thus, the difference in the experimental conditions could also
contribute to the different observations and may explain the
discrepancy between our results and that of the previous study.
Although we did not directly explore the mechanism(s) underlying the
short-latency excitation and inhibition observed in this study, it is
likely that the earliest excitatory response (peak, 3-4 msec after the
stimulation pulse) occurred as the result of orthodromic activation of
STN  GPe and STN GPi axons. The latency of monosynaptic EPSPs of
STN EP nucleus projections of 1.7 ± 0.5 msec (mean, SD)
reported in the rat (Nakanishi et al., 1991) and that of STN GPe,
GPi projections of 2-10 msec in the monkey (Nambu et al., 2000) would
be consistent with this assumption. The second facilitation (peak,
5.5-7.0 msec after the stimulation pulse) could occur as a result of
splitting the early excitation peak into two excitation periods by
interposition of the second inhibition. The second inhibition at
4.5-5.5 msec may have been elicited through disynaptic STN GPe and
GPe GPi pathways or by the refractory period of the earliest
excitation. The inhibition preceding the earliest excitation evoked by
STN stimulation in GPi could occur as the result of antidromic
activation of GPe STN collaterals to GPi, consistent with single
neuron staining studies in the rat (Kita and Kitai, 1994) and the
monkey (Shink et al., 1996; Sato et al., 2000). This would also be
consistent with previous observations in Japanese macaques of
antidromic activation of GPe at 1.0 ± 0.3 msec (mean, SD)
(Hasegawa and Hamada, 2000) after stimulation in the STN and may
provide physiological confirmation of the existence of axon collaterals
from GPe to GPi (Smith et al., 1994; Nambu and Llinás, 1997). In
addition to the above mechanisms, resetting of pallidal neuronal
activity after IPSPs has been reported (Kita, 2001), and this mechanism could also contribute to the induction of a more rhythmic discharge pattern, time-synchronized to inhibitory inputs.
A leading hypothesis regarding the development of movement disorders of
basal ganglia origin suggests that hyperkinetic and hypokinetic
disorders occur as a result of changes in the mean discharge rate in
the GPi and SNr, which in turn suppress thalamocortical output (Albin
et al., 1989; DeLong, 1990). Metabolic studies using positron emission
tomography (Playford et al., 1992; Eidelberg et al., 1994) and
physiological recordings of neuronal activity in the basal ganglia
(Miller and DeLong, 1987; Filion and Tremblay, 1991) are consistent
with this hypothesis. In addition to changes in mean discharge rate,
however, altered firing patterns in the pallidum have also been
reported in MPTP-induced parkinsonian animals. Increases in bursting
activity (Filion and Tremblay, 1991; Bergman et al., 1994),
periodic oscillatory activity (Bergman et al., 1994; Nini et al., 1995;
Raz et al., 2000), and synchronization of GPi (Bergman et al., 1994;
Nini et al., 1995) or GPi and striatal neurons (Raz et al., 2001) have
all been reported to occur in this model. Increases in bursting and
oscillation patterns of STN neurons in parkinsonian animals have also
been observed (Bergman et al., 1994; Hassani et al., 1996; Plenz and
Kitai, 1999), suggesting that the altered STN output may contribute to
the observed changes in pattern in GPi neurons. Synchronized
oscillatory bursts of the GPe, GPi, or STN have been proposed to have a
causative relationship for the development of parkinsonian motor signs
(Bergman et al., 1994; Nini et al., 1995). Synchronous oscillation in
the basal ganglia may break down independent processing in the motor
circuit and disrupt signal processing at the cortical level (Raz et
al., 2000). The results from the present study indicate that the firing rate in these structures is not an absolute determinant for the development or relief of parkinsonian symptoms. Indeed, the change in
discharge pattern in GP neurons during STN HFS, from an irregular to a
stimulus-synchronized regular pattern of discharge in the face of a
further increase in mean discharge rate, suggests that temporal and
spatial patterns of neuronal activity in the basal ganglia may play a
more significant role than rate in the development of parkinsonian
motor signs.
The significance of changes in temporal and spatial firing patterns of
neurons in the basal ganglia in the pathophysiology of movement
disorders has been supported by observations in humans with PD and
dystonia undergoing microelectrode recording procedures. Decreased
firing rates in the GPi have been commonly observed in patients with
generalized dystonia (Lozano et al., 1997; Lenz et al., 1998; Vitek et
al., 1999) and hemiballism (Lozano et al., 1997; Suarez et al., 1997;
Vitek et al., 1999), both of which have been classified as hyperkinetic
disorders. Although inactivation of the GPi is expected to worsen
hyperkinetic disorders by increased disinhibition of the
thalamocortical projection, most patients with generalized dystonia and
hemiballism have shown significant improvement by posteroventral
pallidotomy (Lozano et al., 1997; Suarez et al., 1997; Ondo et al.,
1998; Vitek et al., 1999). Irregular firing and widened sensory
receptive fields in GPi cells were observed in generalized dystonia,
and a "burst and pause" firing pattern correlated to EMG activity
in the hemiballistic limb has been reported (Lenz et al., 1998; Vitek
et al., 1999). Abolition of dystonia and hemiballism after inactivation
of the GPi by pallidotomy suggests that the abnormal firing pattern is
more fundamental to the development of these movement disorders than
the mean firing rate.
The present study demonstrates that during STN stimulation the
interstimulus period is occupied by periodic sequences of neuronal activity in the pallidum that are time-locked to the stimulation pulse.
As a result, there may be little chance for a spike train conveying
normal or abnormal information to reach its targets intact. In a
functional sense, improvement of parkinsonian motor signs by STN HFS
may be achieved by blocking transmission of altered patterns of
neuronal activity in the basal ganglia to its target structures in the
thalamus and brainstem. Conceptually, high-frequency regular firing of
the pallidum resulting from STN HFS may itself represent a form of
abnormal activity. Thus, HFS may essentially replace one type of
subcortical noise with another that is less disruptive to cortical function.
In summary, the present results provide experimental evidence to
support the concept that HFS increases output from the
stimulated site and changes the firing pattern and mean
discharge rate of neurons at the projection sites. The results further
support the hypothesis that altered patterns of neuronal activity
in the basal ganglia play a significant role in the
pathophysiology of movement disorders and provide a physiological basis
for the improvement of parkinsonian motor signs during HFS in the STN.
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FOOTNOTES |
Received Aug. 15, 2002; revised Oct. 18, 2002; accepted Dec. 11, 2002.
This work was supported National Institutes of Health Grants
R-29NS30719 and RO1 NS 37019 and a grant from Medtronic Inc., Neurological Division. We thank M. R. DeLong, M. D. Crutcher, T. Wichmann, and G. Russo for discussions and for reviewing this manuscript.
Correspondence should be addressed to Dr. Jerrold L. Vitek, Department
of Neurology, Woodruff Memorial Building, Suite 6000, Emory
University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322. E-mail: jvitek{at}emory.edu.
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TOP
ABSTRACT
Introduction
