 |
 Previous Article | Next Article 
The Journal of Neuroscience, April 1, 2002, 22(7):2855-2861
Synchronized Neuronal Discharge in the Basal Ganglia of
Parkinsonian Patients Is Limited to Oscillatory Activity
Ron
Levy1,
William D.
Hutchison1, 2, 3,
Andres M.
Lozano2, 3, and
Jonathan O.
Dostrovsky1, 3
1 Department of Physiology, Faculty of Medicine,
University of Toronto, Toronto, Ontario, Canada M5S 1A8,
2 Division of Neurosurgery, Department of Surgery,
University of Toronto, The Toronto Western Hospital, Toronto, Ontario,
Canada M5T 2S8, and 3 The Toronto Western Research
Institute, The Toronto Western Hospital, Toronto, Ontario, Canada M5T
2S8
 |
ABSTRACT |
It has been proposed that an increase in synchronization between
neurons in the basal ganglia contributes to the clinical features of
Parkinson's disease (PD). To examine this hypothesis, we looked for
correlations in the discharge activity of pairs of neurons in the
globus pallidus internus (GPi), globus pallidus externus (GPe), and the
substantia nigra pars reticulata (SNr). Recordings were performed in PD
patients undergoing functional stereotactic mapping for pallidotomy
(eight patients) or subthalamic nucleus deep brain stimulation
(four patients). A double-microelectrode setup was used to
simultaneously record from neurons separated by distances as small as
250 µm. In the five pallidotomy patients without limb tremor during
the procedure, none of the 73 GPi pairs and 15 GPe pairs displayed
synchronous activity. In the three pallidotomy patients with limb
tremor, 6 of 21 GPi pairs and 5 of 29 GPe pairs displayed oscillatory
synchronization in the frequency range of the ongoing limb tremor (3-6
Hz) or at higher frequencies (15-30 Hz). Synchronized activity was not
observed in the SNr (10 pairs). The findings indicate that oscillatory
synchronization between pairs of GPi or GPe neurons is found in
patients with limb tremor. These results also suggest that overt
neuronal synchronization, which may be attributable to an
increase in direct synaptic connections or common collateral afferent
inputs, is not present in the basal ganglia of patients with PD.
Key words:
Parkinson's disease; globus pallidus; subthalamic
nucleus; substantia nigra pars reticulata; synchronization; limb
tremor
| |
INTRODUCTION |
Akinesia, limb tremor, and rigidity
are the main motor symptoms of Parkinson's disease (PD) (Lang and
Lozano, 1998 ) and have been associated with an excessive inhibition of
thalamic motor and brainstem nuclei by the globus pallidus internus
(GPi), the major output nucleus of the basal ganglia (Crossman et al.,
1985; Miller and DeLong, 1987; Albin et al., 1989; DeLong, 1990;
Eidelberg et al., 1997). In addition to an augmentation of GPi firing
rates, monkeys rendered parkinsonian with
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) display an increase
in the bursting activity of GPi, globus pallidus externus (GPe), and
substantia nigra pars reticulata (SNr) neurons (Miller and DeLong,
1987; Filion and Tremblay, 1991; Boraud et al., 1998) that may be
partially explained by the presence of tremor-related activity (Bergman
et al., 1994; Wichmann et al., 1999).
It has been proposed that a breakdown of the functional segregation
between parallel re-entrant subcircuits of the basal
ganglia-thalamocortical system (Alexander and Crutcher, 1990;
Alexander et al., 1990; Hoover and Strick, 1993) might underlie
parkinsonian pathophysiology (Filion et al., 1994; Nini et al., 1995;
Bergman et al., 1998a). Consistent with this hypothesis, simultaneous
microelectrode recording techniques have demonstrated that periodic or
"oscillatory" bursting in GPi neurons of tremulous MPTP-treated
monkeys and patients with PD is synchronized (Nini et al., 1995;
Bergman et al., 1998b; Hurtado et al., 1999; Raz et al., 2000). We
recently reported similar findings in the subthalamic nucleus (STN) of
tremulous patients with PD (Levy et al., 2000). These observations
support the hypothesis that synchronized oscillations are related to
the pathogenesis of limb tremor (Bergman et al., 1998a; Deuschl et al.,
2000). It is unclear, however, whether synchronized oscillatory activity is attributable to "direct" synaptic connection or common collateral afferent input within the basal ganglia or simply
attributable to synchronized activity occurring elsewhere (such as
proprioceptive input or motor cortex-related activity). If
synchronization is caused by changes in synaptic efficacy within the
basal ganglia, it is possible that the synchronization of neuronal
activity is present in patients without limb tremor. To test this
hypothesis, we assessed the degree of correlation between the discharge
of pairs of neurons in the GPi, GPe, and SNr in tremulous and
nontremulous patients with Parkinson's disease.
| |
MATERIALS AND METHODS |
Neurons were recorded during microelectrode-guided placement of
a unilateral pallidotomy (eight patients) or bilateral deep brain
stimulation (DBS) electrodes in the STN (four patients). The
indications for pallidotomy were akinetic-rigid parkinsonian syndromes
with fluctuating on-off periods and drug-induced dyskinesias (Lozano
et al., 1996). Similarly, the indications for STN DBS were bilateral
limb and axial manifestations of PD, medication-refractory motor
fluctuations, and drug-induced dyskinesias (Kumar et al., 1998). All
patients were studied during the stereotaxic surgery 12-14 hr after
the last dose of anti-parkinsonian medication, and all were typically
akinetic/rigid, with some patients displaying limb tremor (see
Results). The patients had a mean age of 59 years (range, 49-69
years), and the average duration of the disease was 14 years (range,
7-20 years) at the time of operation. All patients gave free and
informed consent, and procedures conformed to guidelines set down by
Canadian Institute of Health Research policy on Ethical Conduct for
Research Involving Humans and approved by the University of Toronto
Ethics Review Board.
Detailed descriptions of the use of microelectrode recording to
localize the GPi or the STN have been given previously (Lozano et al.,
1996; Hutchison et al., 1998). Briefly, single-unit microelectrode recordings were used to identify cell types, and stimulation mapping allowed the localization of physiological landmarks (Fig.
1A). Single units were
recorded using Parylene-coated tungsten microelectrodes with an exposed
tip size of 15-25 µm. Microelectrode tips were plated with gold and
platinum to reduce the impedance to ~0.2 M at 1 kHz. The
simultaneous recording of neuron pairs was performed using a
double-electrode setup in which two microelectrodes were inserted
either as a glued pair separated by a distance of 250-300 µm or
independently, with the electrodes separated by 600 µm and each
electrode driven by a separate microdrive. All neurons were sampled
with the patients at rest. Signals were amplified and filtered using
the Guideline System GS3000 (Axon Instruments, Foster City, CA). The
two channels of neuronal data were recorded along with wrist
flexor/extensor electromyography and accelerometer signals on analog
videotape (VR-100 digital recorder; Instrutech Corp., Port Washington,
NY) to be analyzed off-line. Single-unit event times were discriminated
using template-matching, spike-sorting software (Spike2; Cambridge
Electronic Design, Cambridge, UK). In this study, the mean number of
action potentials recorded per cell was 6776 (± 530 SEM) over an
average sample time of 73 sec (± 4.3 SEM). Only well isolated single
neurons recorded from different electrodes were examined.
View larger version (67K):
[in this window]
[in a new window]
|
Figure 1.
Locations of recorded neurons and the
interpretations of the neuron pair cross-correlations.
A, Sagittal sections based on the Schaltenbrand and
Wahren (1977) stereotactic atlas (standardized to the patient's
anterior-posterior commissural distance) displaying the microelectrode
trajectories (dashed lines) and neuronal activity in the
12 patients (definitions of the symbols used are given
at the bottom). The distance from the midline is shown
in the upper right corner of each panel.
The horizontal distance separating neurons in pairs recorded in the
same trajectory has been slightly expanded for clarity (actually ~600
µm; see Materials and Methods). Optic tract
(OT) and internal capsule (IC)
responses were obtained using microstimulation. Simultaneously recorded
pairs of neurons are joined by lines. H2, Fields of
Forel. B, Schematic of functional connections between
neuron A and a pair of recorded neurons
(B, C) that may give rise to
synchronization. (Correlograms that would indicate various neuronal
connectivity are shown below, with neuron C as the
trigger and A as the presynaptic source.)
Top, Direct synaptic connection between a neuron pair.
Middle, Neurons can be synchronized if they receive
common collateral input from a presynaptic source. Bottom, Neurons can
display oscillatory synchronization if they receive a common rhythmic
drive (i.e., from A1 and
A2).
|
|
To compare neuronal activity in this patient group with other patient
groups in previous studies, both firing rate and pattern were
quantified. Firing pattern was quantified by using the Poisson surprise
method of burst detection as described by Legendy and Salcman (1985),
which defines a "burst" as an improbable epoch of elevated
discharge rate in a spike train. This method was used to detect burst
discharges with a Poisson surprise value of >5. The number of spikes
in burst discharges was compared with the total number of spikes
sampled in each cell, and the percentage of spikes in bursts was
calculated (Wichmann et al., 1999). This gave a measure of the
"burstiness" of each neuron, because irregularly discharging
neurons will have a greater proportion of spikes that participate in
bursts than regularly discharging neurons.
Autocorrelation and cross-correlation analysis was used to detect
oscillatory neuronal activity of single neurons (Karmon and Bergman,
1993) and synchronization between two neurons, respectively. Correlations between separate spike trains can arise from functional connections between pairs of neurons that include direct
synaptic connections (Fig. 1B, top) or
"indirect" connections, such as common collateral input from
presynaptic sources (Fig. 1B, middle). These functional connections can be detected from the presence of a
single asymmetrical or symmetrical peak or trough, respectively, in the
cross-correlogram (Moore et al., 1970). In addition, oscillatory synchronization (Fig. 1B, bottom), which
arises from synchronous periodic bursting, shows up as multiple peaks
and troughs in the cross-correlogram and need not arise from direct or
indirect connections between neurons.
Correlograms were calculated for ±1 sec offset (5 msec bin size) and
±100 msec offset (0.5 msec bin size) and were quantified to the units
of rate (spikes per second) (Abeles, 1982). To assess synchronization,
peaks or troughs in the cross-correlograms were considered significant
if they consisted of three or more consecutive bins with values outside
a 99% confidence interval about the mean firing rate (Abeles, 1982).
The confidence interval was calculated using correlogram estimates
located in the first and last 250 or 25 msec for correlograms
constructed with 5 or 0.5 msec bin size, respectively. Oscillatory
synchronization was also analyzed using coherence analysis and has been
described in detail previously (Levy et al., 2000). Coherence is a
function of frequency and is calculated from the cross-spectral density
between the two waveforms normalized by the power spectral density of
each waveform. Coherence values can range from 0 if the spike trains
are not linearly related to a value of 1 if the spike trains have a
perfectly linear relationship.
| |
RESULTS |
There were 148 pairs of neurons recorded. Figure
1A displays digitized parasagittal plates
(Schaltenbrand and Wahren, 1977) of the GP (Fig. 1A,
top two rows) and the SNr (Fig. 1A,
bottom row) to show the location of the microelectrode
trajectories and to provide information about the neuronal activity and
the locations of the simultaneously recorded neuron pairs in each
patient. Three of eight pallidotomy patients and three of four STN DBS
patients had limb tremor at the time of the recordings, and oscillatory neuronal activity was limited to these patients (Fig.
1A, asterisk). Examples of raw spike
trains simultaneously recorded from pairs of GPi neurons are shown in
Figure 2A. In the
bottom pair, it can be observed that the bursts of spikes are periodic
(~5 Hz) and that the neurons display oscillatory synchronization. The mean firing rate and percentage of spikes in bursts of single neurons
in each nucleus are given in Figure 2B. The mean
firing rates of neurons in these nuclei were similar to those reported in other patient groups (Hutchison et al., 1994, 1998). The percentage of spikes in bursts in the GPi was also similar to that reported in
another patient group (Levy et al., 2001) and was significantly lower
than the percentage of spikes in bursts found in the GPe.
View larger version (76K):
[in this window]
[in a new window]
|
Figure 2.
Raw spike trains, neuronal firing rates, and
patterns in each nucleus and an example of cross-correlograms in a
nontremulous patient. A, Examples of spike trains from
two pairs of GPi neurons. In both examples, neurons were separated by
600 µm. Note that the lower pair of neurons displays oscillatory
synchronization at ~5 Hz. B, Mean firing rate and
percentage of spikes in bursts (*p < 0.05; ANOVA
on ranks) in the GPi, GPe, and SNr. C, Example of
cross-correlograms from 20 GPi pairs recorded in a nontremulous patient
[All correlograms were constructed using 5 msec bins, normalized to
baseline firing rate and scaled to the 99% confidence interval
(CI).]
|
|
Neuronal activity in nontremulous patients or SNr is
not correlated
In the five nontremulous pallidotomy patients, single GP neurons
did not display oscillatory activity, and all of the cross-correlograms in the GPe (15 pairs) and GPi (73 pairs) were flat. An example of
cross-correlograms from 20 pairs of GPi neurons recorded from a single
nontremulous patient is displayed in Figure 2C. (This is the
patient whose electrode tracks are shown at the top right of
Fig. 1A; the cross correlograms are scaled to their
confidence intervals.) None of the single SNr neurons (which were
recorded in four patients) displayed oscillations, and synchronized
activity was not observed in any of the 10 pairs of SNr neurons
examined. As indicated in Figure 1A, three of the
four STN/SNr patients had limb tremor during the stereotactic
procedure, and many STN neurons displayed oscillatory activity at
tremor frequency or in the range of 15-30 Hz. As reported in a
previous study, oscillatory activity in the STN occurring in either
frequency range was synchronized, but only 15-30 Hz oscillations were
consistently in phase (Levy et al., 2000).
Synchronized tremor-frequency oscillations in
tremulous patients
In the three pallidotomy patients with limb tremor during the
microelectrode recordings, some pairs of neurons revealed nonflat cross-correlograms, although the majority of the cross-correlograms (23 of 29 pairs in the GPe and 15 of 21 pairs in GPi) were also flat.
Twelve of 41 GPi and 2 of 47 GPe single neurons (that were sampled from
pairs) displayed oscillations in the tremor frequency range (3-7 Hz).
An example of a single GPi neuron that showed a strong coherence with
resting tremor of the hand (as measured with an accelerometer) is shown
in Figure 3A. Coherence
between the GPi neuron firing and the limb movement was limited to the period of time with limb tremor. All nonflat cross-correlograms between
GP neuron pairs in tremulous patients were oscillatory (with the
exception of one pair; see below). Coherence analysis revealed that
five of six pairs of GPi tremor cells (TCs) displayed synchronization in the tremor frequency range. Neurons in each of these
pairs were located 250-1000 µm from one another. Two examples of
tremor-related coherence are displayed in Figure 3B. (These
are from the patient whose electrode tracks are shown at the top
left of Fig. 1A.) Variable phase relationships
(i.e., 0-180°) were observed between neurons with tremor frequency
synchronization.
View larger version (35K):
[in this window]
[in a new window]
|
Figure 3.
Synchronized activities between pairs of neurons
in tremulous patients. A, Example of coherence between
contralateral hand tremor [measured with an accelerometer
(Acc)] and GPi cell activity. Left,
Coherence during 30 sec with no tremor. Right, Coherence
during a subsequent 30 sec with limb tremor (0.98 Hz resolution; the
number beside the peak is the phase difference in
degrees, and the dashed horizontal line is
p < 0.01). B, Example of power
spectra (insets) and coherence of two pairs of GPi TCs
from a single patient (0.49 Hz resolution, calculated using 30 sec of
data for each pair; the number beside the peak is the
phase difference in degrees, and the dashed horizontal
line is p < 0.01 for coherence). These
plots demonstrate tremor-related synchronization and phase variability
in the GPi of a tremulous patient. Neurons in each pair were separated
by 250 µm, and pairs were located ~200 µm from one another.
C, Examples of coherence plots showing high-frequency
oscillatory synchronization in the GPe (left) and GPi
(right) of a tremulous pallidotomy patient (calculated
from 30 sec of data, 0.98 Hz resolution; the number
beside the peak is the phase difference in degrees, and the
dashed horizontal line is p < 0.01). D, A nonflat cross-correlogram in a tremulous
pallidotomy patient that is indicative of an inhibitory connection
between a pair of GPe neurons (0.5 msec bins; 7010 × 9252 events;
horizontal dashed lines indicate the 99% confidence
interval about the mean).
|
|
Synchronized high-frequency oscillations in tremulous patients
High-frequency oscillatory activity was detected in two of the
pallidotomy patients with limb tremor. In one of these patients, these
neurons were recorded simultaneously, and their activity was
correlated. It was found that one pair of GPi neurons and five pairs of
GPe neurons displayed coherent high-frequency oscillatory activity. The
mean frequency of the oscillatory synchronization was 20.6 Hz (range
19-22), with a mean absolute phase difference of 16.0° (range
3-35°). Examples of high-frequency coherence in a pair of GPe and
GPi neurons are shown in Figure 3C. In the same patient, one
pair of GPe neurons displayed an asymmetrical trough in the
cross-correlogram that was centered at ~2 msec, most likely indicating a direct inhibitory connection from one neuron to the other
(Fig. 3D) (Perkel et al., 1967).
| |
DISCUSSION |
The loss-of-segregation hypothesis predicts that dopamine
depletion in PD results in a breakdown of the independent activity in
subcircuits of the basal ganglia (Filion et al., 1994; Nini et al.,
1995; Bergman et al., 1998a; Vitek and Giroux, 2000). This study and
our data from the STN (Levy et al., 2000) demonstrate that in
parkinsonian patients, discharge synchronization between pairs of
neurons in the GPi, GPe, and STN is limited to oscillatory activity in
patients with limb tremor and is indicative of common rhythmic drive to
neuron pairs rather than to direct interaction between pairs of
neurons. In all nontremulous patients examined, synchronization was not
observed, suggesting that neuron pair synchronization attributable to
direct synaptic connections or common input is not present in the
parkinsonian basal ganglia. These conclusions are consistent with the
findings of studies in monkeys that examined the simultaneous activity
of pairs of GPi, GPe, STN, and striatal tonically active neurons and
failed to find an increase in nonoscillatory synchronization after
MPTP-induced parkinsonism (Bergman et al., 1994; Nini et al., 1995; Raz
et al., 1996, 2000, 2001).
Evidence of a direct functional connection (inhibitory synaptic
connection) was only observed in 1 of 44 pairs of GPe neurons (Fig.
3D). This observation is consistent with a recent study by
Raz et al. (2000) in intact monkeys in which ~1% of the
cross-correlograms of GPe neurons displayed a significant trough. It
has been observed that (GABAergic) GPe neurons emit short, intranuclear
axon collaterals (Oertel et al., 1984; Smith et al., 1987; Sato et al.,
2000) and could account for the observed inhibition in the
cross-correlogram. We did not encounter SNr neurons with oscillatory
activity in this study, although three of four patients displayed limb
tremor and tremor-related oscillations were observed in the STN. This is consistent with the observation in MPTP-treated monkeys and parkinsonian patients that tremor-related activity is not as prominent in the SNr as it is in the GPi or STN (Wichmann et al., 1999; Rodriguez-Oroz et al., 2001). It is possible, however, that differences in sampling (i.e., motor-related neurons in the GPi vs
non-motor-related neurons in the SNr) in parkinsonian patients might
account for the lack of tremor-related oscillatory activity in the SNr.
The SNr neurons sampled in this study may not have been in the motor area of the SNr, because this region is believed to be in the more
intermediate and lateral portion of the nucleus (DeLong et al., 1983;
Schultz, 1986; Hutchison et al., 1998). It has also been suggested that
the GPi contains a greater proportion of neurons with motor-related
activity than the SNr; therefore, the changes in discharge activity
attributed to parkinsonism may be greater in the GPi than the SNr
(Wichmann et al., 1999).
The main limitation of this study is the possibility that
cross-correlation between pairs of neurons cannot detect weak neuronal synchronization that might involve a larger population of neurons. For
example, Brown et al. (2001) demonstrated that a 15-30 Hz synchronization between the GPi and STN could be detected in
parkinsonian patients by recording local field potentials in these
nuclei. This synchronization is reduced by the administration of
3,4-dihydroxyphenylalanine (L-dopa) and most likely
plays a role in the pathophysiology of the akinesia and bradykinesia
(Marsden et al., 2001). It is also reasonable to suppose that a longer
sampling time may detect weaker synchronization between pairs of
neurons. It should be noted, however, that with similar sampling times,
a substantially greater amount of nonoscillatory synchronization has
been reported in the thalamus in humans (Levy et al., 1999) and in the
cortex in monkeys (Nini et al., 1995). Another drawback of
cross-correlation analysis is that it is less sensitive for inhibitory
than for excitatory functional connectivity (of comparable strength),
and therefore, it is possible that some neuron-to-neuron inhibition would have failed to be detected using this technique (Aertsen and
Gerstein, 1985). In addition, an obvious difference between studies
comparing synchronization in MPTP-treated monkeys and patients with PD
is that patients undergo chronic L-dopa therapy over a
number of years and develop drug-induced dyskinesias (excessive abnormal involuntary movements), whereas parkinsonian monkeys are not
similarly treated with dopaminergic medication. Therefore, it is
possible that the MPTP monkey model does not replicate the idiopathic
PD (observed after years of dopaminergic treatment) in all its
physiological underpinnings. Finally, it is feasible that overt
neuronal synchronization in parkinsonism is displayed during active or
passive movements. It has been shown that after MPTP treatment in
monkeys, there is an increase in the number of GPi neurons responding
to passive movement and neurons tend to display exaggerated responses
and multilimb receptive fields (Filion et al., 1988; Boraud et al.,
2000). The administration of apomorphine, a nonselective
D1/D2 receptor agonist,
decreases the proportion of neurons with multilimbed receptive fields
in parkinsonian patients (Levy et al., 2001). However, preliminary data
from our group that examine the simultaneous activity of pairs of
neurons during a reaching task do not demonstrate that neurons with
similar responses have correlated discharges indicative of underlying
synaptic connections.
Our results of GPi TC synchronization are consistent with a previous
report in a single tremulous parkinsonian patient and in studies in
MPTP-treated monkeys with resting tremor and/or postural/action tremor
(vervet vs rhesus monkeys) (Nini et al., 1995; Bergman et al., 1998b;
Hurtado et al., 1999; Raz et al., 2000). Similar to activity in the STN
(Levy et al., 2000), tremor frequency oscillations in the GPi can be
synchronized and have variable phase relationships. This study also
described the novel finding of in-phase 15-30 Hz
("high-frequency") neuronal oscillatory synchronization in the
pallidum of a patient with tremor and supports microelectrode findings
in MPTP-treated vervet monkeys (Bergman et al., 1998b) and field
potential analysis in parkinsonian patients (Brown et al., 2001). Our
observations in the GPe are consistent with the demonstration in
tremulous MPTP-treated monkeys that pairs of GPe cells exhibit
high-frequency oscillatory synchronization with phase differences that
are centered around 0° (Raz et al., 2000), similar to our initial
findings in the STN of tremulous parkinsonian patients (Levy et al.,
2000). It is likely that pallidal high-frequency oscillations are
secondary to high-frequency oscillations transmitted via the
cortico-STN pathway (Marsden et al., 2001). These observations suggest
that the GPe-STN network (Plenz and Kital, 1999; Magill et al., 2000)
might be involved in maintaining in-phase high-frequency oscillatory
synchronization in patients with limb tremor (Levy et al., 2000).
In summary, this study demonstrates that the synchronization of neuron
pairs in the GP is limited to oscillatory activity occurring in the
tremor frequency range and in the 15-30 Hz range. The lack of
correlated activity in patients without limb tremor suggests that
significant neuron pair synchronization caused by direct synaptic
connections or common input is not present in the parkinsonian basal ganglia.
| |
FOOTNOTES |
Received June 15, 2001; revised Dec. 26, 2001; accepted Jan. 3, 2002.
Funding was provided by the National Institutes of Health, the Canadian
Institute of Health Research, and the Parkinson's Foundation of
Canada. A.M.L. is a Canadian Institute of Health Research clinician scientist.
Correspondence should be addressed to Jonathan O. Dostrovsky, Department of Physiology, Room 3305, Medical Sciences
Building, 1 King's College Circle, University of Toronto, Toronto,
Ontario, Canada M5S 1A8. E-mail: j.dostrovsky{at}utoronto.ca.
| |
REFERENCES |
-
Abeles M
(1982)
Quantification, smoothing, and confidence limits for single-units' histograms.
J Neurosci Methods
5:317-325[ISI][Medline].
-
Aertsen AM,
Gerstein GL
(1985)
Evaluation of neuronal connectivity: sensitivity of cross-correlation.
Brain Res
340:341-354[ISI][Medline].
-
Albin RL,
Young AB,
Penney JB
(1989)
The functional anatomy of basal ganglia disorders.
Trends Neurosci
12:366-375[ISI][Medline].
-
Alexander GE,
Crutcher MD
(1990)
Functional architecture of basal ganglia circuits: neural substrates of parallel processing.
Trends Neurosci
13:266-271[ISI][Medline].
-
Alexander GE,
Crutcher MD,
DeLong MR
(1990)
Basal ganglia-thalamocortical circuits: parallel substrates for motor, oculomotor, "prefrontal" and "limbic" functions.
Prog Brain Res
85:119-146[Medline].
-
Bergman H,
Wichmann T,
Karmon B,
DeLong MR
(1994)
The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism.
J Neurophysiol
72:507-520[Abstract/Free Full Text].
-
Bergman H,
Feingold A,
Nini A,
Raz A,
Slovin H,
Abeles M,
Vaadia E
(1998a)
Physiological aspects of information processing in the basal ganglia of normal and parkinsonian primates.
Trends Neurosci
21:32-38[ISI][Medline].
-
Bergman H,
Raz A,
Feingold A,
Nini A,
Nelken I,
Hansel D,
Ben Pazi H,
Reches A
(1998b)
Physiology of MPTP tremor.
Mov Disord
13 [Suppl 3]:29-34.
-
Boraud T,
Bezard E,
Guehl D,
Bioulac B,
Gross C
(1998)
Effects of L-DOPA on neuronal activity of the globus pallidus externalis (GPe) and globus pallidus internalis (GPi) in the MPTP-treated monkey.
Brain Res
787:157-160[ISI][Medline].
-
Boraud T,
Bezard E,
Bioulac B,
Gross CE
(2000)
Ratio of inhibited-to-activated pallidal neurons decreases dramatically during passive limb movement in the MPTP-treated monkey.
J Neurophysiol
83:1760-1763[Abstract/Free Full Text].
-
Brown P,
Oliviero A,
Mazzone P,
Insola A,
Tonali P,
Di Lazzaro V
(2001)
Dopamine dependency of oscillations between subthalamic nucleus and pallidum in Parkinson's disease.
J Neurosci
21:1033-1038[Abstract/Free Full Text].
-
Crossman AR,
Mitchell IJ,
Sambrook MA
(1985)
Regional brain uptake of 2-deoxyglucose in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the macaque monkey.
Neuropharmacology
24:587-591[ISI][Medline].
-
DeLong MR
(1990)
Primate models of movement disorders of basal ganglia origin.
Trends Neurosci
13:281-285[ISI][Medline].
-
DeLong MR,
Crutcher MD,
Georgopoulos AP
(1983)
Relations between movement and single cell discharge in the substantia nigra of the behaving monkey.
J Neurosci
3:1599-1606[ISI][Medline].
-
Deuschl G,
Raethjen J,
Baron R,
Lindemann M,
Wilms H,
Krack P
(2000)
The pathophysiology of parkinsonian tremor: a review.
J Neurol
247 [Suppl 5]:V33-V48.
-
Eidelberg D,
Moeller JR,
Kazumata K,
Antonini A,
Sterio D,
Dhawan V,
Spetsieris P,
Alterman R,
Kelly PJ,
Dogali M,
Fazzini E,
Beric A
(1997)
Metabolic correlates of pallidal neuronal activity in Parkinson's disease.
Brain
120:1315-1324[Abstract/Free Full Text].
-
Filion M,
Tremblay L
(1991)
Abnormal spontaneous activity of globus pallidus neurons in monkeys with MPTP-induced parkinsonism.
Brain Res
547:142-151[ISI][Medline].
-
Filion M,
Tremblay L,
Bedard PJ
(1988)
Abnormal influences of passive limb movement on the activity of globus pallidus neurons in parkinsonian monkeys.
Brain Res
444:165-176[ISI][Medline].
-
Filion M,
Tremblay L,
Matsumura M,
Richard H
(1994)
Dynamic focusing of informational convergence in basal ganglia.
Rev Neurol (Paris)
150:627-633[Medline].
-
Hoover JE,
Strick PL
(1993)
Multiple output channels in the basal ganglia.
Science
259:819-821[Abstract/Free Full Text].
-
Hurtado JM,
Gray CM,
Tamas LB,
Sigvardt KA
(1999)
Dynamics of tremor-related oscillations in the human globus pallidus: a single case study.
Proc Natl Acad Sci USA
96:1674-1679[Abstract/Free Full Text].
-
Hutchison WD,
Lozano AM,
Davis KD,
Saint-Cyr JA,
Lang AE,
Dostrovsky JO
(1994)
Differential neuronal activity in segments of globus pallidus in Parkinson's disease patients.
NeuroReport
5:1533-1537[ISI][Medline].
-
Hutchison WD,
Allan RJ,
Opitz H,
Levy R,
Dostrovsky JO,
Lang AE,
Lozano AM
(1998)
Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease.
Ann Neurol
44:622-628[ISI][Medline].
-
Karmon B,
Bergman H
(1993)
Detection of neuronal periodic oscillations in the basal ganglia of normal and parkinsonian monkeys.
Isr J Med Sci
29:570-579[ISI][Medline].
-
Kumar R,
Lozano AM,
Kim YJ,
Hutchison WD,
Sime E,
Halket E,
Lang AE
(1998)
Double-blind evaluation of subthalamic nucleus deep brain stimulation in advanced Parkinson's disease.
Neurology
51:850-855[Abstract/Free Full Text].
-
Lang AE,
Lozano AM
(1998)
Parkinson's disease. First of two parts.
N Engl J Med
339:1044-1053[Free Full Text].
-
Legendy CR,
Salcman M
(1985)
Bursts and recurrences of bursts in the spike trains of spontaneously active striate cortex neurons.
J Neurophysiol
53:926-939[Abstract/Free Full Text].
-
Levy R,
Davis KD,
Hutchison WD,
Pahapill PA,
Lozano AM,
Tasker RR,
Dostrovsky JO
(1999)
Simultaneously recorded neuron pairs in the motor thalamus of patients with Parkinson's disease and essential tremor.
Soc Neurosci Abstr
25:1408.
-
Levy R,
Hutchison WD,
Lozano AM,
Dostrovsky JO
(2000)
High-frequency synchronization of neuronal activity in the subthalamic nucleus of parkinsonian patients with limb tremor.
J Neurosci
20:7766-7775[Abstract/Free Full Text].
-
Levy R,
Dostrovsky JO,
Lang AE,
Sime E,
Hutchison WD,
Lozano AM
(2001)
Effects of apomorphine on subthalamic nucleus and globus pallidus internus neurons in patients with Parkinson's disease.
J Neurophysiol
86:249-260[Abstract/Free Full Text].
-
Lozano A,
Hutchison W,
Kiss Z,
Tasker R,
Davis K,
Dostrovsky J
(1996)
Methods for microelectrode-guided posteroventral pallidotomy.
J Neurosurg
84:194-202[ISI][Medline].
-
Magill PJ,
Bolam JP,
Bevan MD
(2000)
Relationship of activity in the subthalamic nucleus-globus pallidus network to cortical electroencephalogram.
J Neurosci
20:820-833[Abstract/Free Full Text].
-
Marsden JF,
Limousin-Dowsey P,
Ashby P,
Pollak P,
Brown P
(2001)
Subthalamic nucleus, sensorimotor cortex and muscle interrelationships in Parkinson's disease.
Brain
124:378-388[Abstract/Free Full Text].
-
Miller WC,
DeLong MR
(1987)
Altered tonic activity of neurons in the globus pallidus and subthalamic nucleus in the primate MPTP model of parkinsonism.
In: The basal ganglia. II. Structure and function: current concepts (Carpenter MB,
Jayaraman A,
eds), pp 415-427. New York: Plenum.
-
Moore GP,
Segundo JP,
Perkel DH,
Levitan H
(1970)
Statistical signs of synaptic interaction in neurons.
Biophys J
10:876-900.
-
Nini A,
Feingold A,
Slovin H,
Bergman H
(1995)
Neurons in the globus pallidus do not show correlated activity in the normal monkey, but phase-locked oscillations appear in the MPTP model of parkinsonism.
J Neurophysiol
74:1800-1805[Abstract/Free Full Text].
-
Oertel WH,
Nitsch C,
Mugnaini E
(1984)
Immunocytochemical demonstration of the GABA-ergic neurons in rat globus pallidus and nucleus entopeduncularis and their GABA-ergic innervation.
Adv Neurol
40:91-98[Medline].
-
Perkel DH,
Gerstein GL,
Moore GP
(1967)
Neuronal spike trains and stochastic point processes. II. Simultaneous spike trains.
Biophys J
7:419-440.
-
Plenz D,
Kital ST
(1999)
A basal ganglia pacemaker formed by the subthalamic nucleus and external globus pallidus.
Nature
400:677-682[Medline].
-
Raz A,
Feingold A,
Zelanskaya V,
Vaadia E,
Bergman H
(1996)
Neuronal synchronization of tonically active neurons in the striatum of normal and parkinsonian primates.
J Neurophysiol
76:2083-2088[Abstract/Free Full Text].
-
Raz A,
Vaadia E,
Bergman H
(2000)
Firing patterns and correlations of spontaneous discharge of pallidal neurons in the normal and the tremulous 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine vervet model of parkinsonism.
J Neurosci
20:8559-8571[Abstract/Free Full Text].
-
Raz A,
Frechter-Mazar V,
Feingold A,
Abeles M,
Vaadia E,
Bergman H
(2001)
Activity of pallidal and striatal tonically active neurons is correlated in MPTP-treated monkeys but not in normal monkeys.
J Neurosci
21:RC128.
-
Rodriguez-Oroz MC,
Rodriguez M,
Guridi J,
Mewes K,
Chockkman V,
Vitek J,
DeLong MR,
Obeso JA
(2001)
The subthalamic nucleus in Parkinson's disease: somatotopic organization and physiological characteristics.
Brain
124:1777-1790[Abstract/Free Full Text].
-
Sato F,
Lavallee P,
Levesque M,
Parent A
(2000)
Single-axon tracing study of neurons of the external segment of the globus pallidus in primate.
J Comp Neurol
417:17-31[ISI][Medline].
-
Schaltenbrand G,
Wahren W
(1977)
In: Atlas for stereotaxy of the human brain. Stuttgart, Germany: Thieme.
-
Schultz W
(1986)
Activity of pars reticulata neurons of monkey substantia nigra in relation to motor, sensory, and complex events.
J Neurophysiol
55:660-677[Abstract/Free Full Text].
-
Smith Y,
Parent A,
Seguela P,
Descarries L
(1987)
Distribution of GABA-immunoreactive neurons in the basal ganglia of the squirrel monkey (Saimiri sciureus).
J Comp Neurol
259:50-64[ISI][Medline].
-
Vitek JL,
Giroux M
(2000)
Physiology of hypokinetic and hyperkinetic movement disorders: model for dyskinesia.
Ann Neurol
47:S131-S140[ISI][Medline].
-
Wichmann T,
Bergman H,
Starr PA,
Subramanian T,
Watts RL,
DeLong MR
(1999)
Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates.
Exp Brain Res
125:397-409[ISI][Medline].
Copyright © 2002 Society for Neuroscience 0270-6474/02/2272855-07$05.00/0
This article has been cited by other articles:
|
|
|
|
 
C. Dejean, B. Hyland, and G. Arbuthnott
Cortical Effects of Subthalamic Stimulation Correlate with Behavioral Recovery from Dopamine Antagonist Induced Akinesia
Cereb Cortex,
September 11, 2008;
(2008)
bhn149v1.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. A. Kuhn, F. Kempf, C. Brucke, L. Gaynor Doyle, I. Martinez-Torres, A. Pogosyan, T. Trottenberg, A. Kupsch, G.-H. Schneider, M. I. Hariz, et al.
High-Frequency Stimulation of the Subthalamic Nucleus Suppresses Oscillatory {beta} Activity in Patients with Parkinson's Disease in Parallel with Improvement in Motor Performance
J. Neurosci.,
June 11, 2008;
28(24):
6165 - 6173.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P Plaha, S Khan, and S S Gill
Bilateral stimulation of the caudal zona incerta nucleus for tremor control
J. Neurol. Neurosurg. Psychiatry,
May 1, 2008;
79(5):
504 - 513.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P Plaha, S Filipovic, and S S Gill
Induction of parkinsonian resting tremor by stimulation of the caudal zona incerta nucleus: a clinical study
J. Neurol. Neurosurg. Psychiatry,
May 1, 2008;
79(5):
514 - 521.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Baufreton and M. D. Bevan
D2-like dopamine receptor-mediated modulation of activity-dependent plasticity at GABAergic synapses in the subthalamic nucleus
J. Physiol.,
April 15, 2008;
586(8):
2121 - 2142.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Ramanathan, T. Tkatch, J. F. Atherton, C. J. Wilson, and M. D. Bevan
D2-Like Dopamine Receptors Modulate SKCa Channel Function in Subthalamic Nucleus Neurons Through Inhibition of Cav2.2 Channels
J Neurophysiol,
February 1, 2008;
99(2):
442 - 459.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Nevet, G. Morris, G. Saban, D. Arkadir, and H. Bergman
Lack of Spike-Count and Spike-Time Correlations in the Substantia Nigra Reticulata Despite Overlap of Neural Responses
J Neurophysiol,
October 1, 2007;
98(4):
2232 - 2243.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. K. H. Tang, E. Moro, N. Mahant, W. D. Hutchison, A. E. Lang, A. M. Lozano, and J. O. Dostrovsky
Neuronal Firing Rates and Patterns in the Globus Pallidus Internus of Patients With Cervical Dystonia Differ From Those With Parkinson's Disease
J Neurophysiol,
August 1, 2007;
98(2):
720 - 729.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. E. DeCoteau, C. Thorn, D. J. Gibson, R. Courtemanche, P. Mitra, Y. Kubota, and A. M. Graybiel
Oscillations of Local Field Potentials in the Rat Dorsal Striatum During Spontaneous and Instructed Behaviors
J Neurophysiol,
May 1, 2007;
97(5):
3800 - 3805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Heimer, M. Rivlin-Etzion, I. Bar-Gad, J. A. Goldberg, S. N. Haber, and H. Bergman
Dopamine Replacement Therapy Does Not Restore the Full Spectrum of Normal Pallidal Activity in the 1-Methyl-4-Phenyl-1,2,3,6-Tetra-Hydropyridine Primate Model of Parkinsonism
J. Neurosci.,
August 2, 2006;
26(31):
8101 - 8114.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. Magill, A. Sharott, J. P. Bolam, and P. Brown
Delayed synchronization of activity in cortex and subthalamic nucleus following cortical stimulation in the rat
J. Physiol.,
August 1, 2006;
574(3):
929 - 946.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Alonso-Frech, I. Zamarbide, M. Alegre, M. C. Rodriguez-Oroz, J. Guridi, M. Manrique, M. Valencia, J. Artieda, and J. A. Obeso
Slow oscillatory activity and levodopa-induced dyskinesias in Parkinson's disease
Brain,
July 1, 2006;
129(7):
1748 - 1757.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Plaha, Y. Ben-Shlomo, N. K. Patel, and S. S. Gill
Stimulation of the caudal zona incerta is superior to stimulation of the subthalamic nucleus in improving contralateral parkinsonism
Brain,
July 1, 2006;
129(7):
1732 - 1747.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rivlin-Etzion, Y. Ritov, G. Heimer, H. Bergman, and I. Bar-Gad
Local Shuffling of Spike Trains Boosts the Accuracy of Spike Train Spectral Analysis
J Neurophysiol,
May 1, 2006;
95(5):
3245 - 3256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Marceglia, G. Foffani, A. M. Bianchi, G. Baselli, F. Tamma, M. Egidi, and A. Priori
Dopamine-dependent non-linear correlation between subthalamic rhythms in Parkinson's disease
J. Physiol.,
March 15, 2006;
571(3):
579 - 591.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Fogelson, D. Williams, M. Tijssen, G. van Bruggen, H. Speelman, and P. Brown
Different Functional Loops between Cerebral Cortex and the Subthalmic Area in Parkinson's Disease
Cereb Cortex,
January 1, 2006;
16(1):
64 - 75.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Garcia, G. D'Alessandro, P.-O. Fernagut, B. Bioulac, and C. Hammond
Impact of High-Frequency Stimulation Parameters on the Pattern of Discharge of Subthalamic Neurons
J Neurophysiol,
December 1, 2005;
94(6):
3662 - 3669.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Baufreton, Z.-T. Zhu, M. Garret, B. Bioulac, S. W. Johnson, and A. I. Taupignon
Dopamine receptors set the pattern of activity generated in subthalamic neurons
FASEB J,
November 1, 2005;
19(13):
1771 - 1777.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G Foffani, A. M Bianchi, G Baselli, and A Priori
Movement-related frequency modulation of beta oscillatory activity in the human subthalamic nucleus
J. Physiol.,
October 15, 2005;
568(2):
699 - 711.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. Meissner, A. Leblois, D. Hansel, B. Bioulac, C. E. Gross, A. Benazzouz, and T. Boraud
Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations
Brain,
October 1, 2005;
128(10):
2372 - 2382.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
