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The Journal of Neuroscience, February 1, 2001, 21(3):1033-1038
Dopamine Dependency of Oscillations between Subthalamic Nucleus
and Pallidum in Parkinson's Disease
Peter
Brown1,
Antonio
Oliviero2,
Paolo
Mazzone3,
Angelo
Insola3,
Pietro
Tonali2, and
Vincenzo
Di
Lazzaro2
1 Medical Research Council Human Movement and Balance
Unit, Institute of Neurology, London WCIN 3BG, United Kingdom,
2 Institute of Neurology, Università Cattolica, 00168 Rome, Italy, and 3 Operative Unit of Functional and
Stereotactic Neurosurgery, Centro Traumatologico Ortopedico, "A.
Alesini" Hospital, 00145 Rome, Italy
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ABSTRACT |
The extent of synchronization within and between the nuclei of the
basal ganglia is unknown in Parkinson's disease. The question is an
important one because synchronization will increase postsynaptic efficacy at subsequent projection targets. We simultaneously recorded local potentials (LPs) from the globus pallidus interna (GPi) and
subthalamic nucleus (STN) in four awake patients after neurosurgery for
Parkinson's disease. Nuclei from both sides were recorded in two
patients so that a total of six ipsilateral GPi-STN LP recordings were
made. Without medication, the power within and the coherence between
the GPi and STN was dominated by activity with a frequency <30 Hz.
Treatment with the dopamine precursor levodopa reduced the
low-frequency activity and resulted in a new peak at ~70 Hz. This was
evident in the power spectrum from STN and GPi and in the coherence
between these nuclei. The phase relationship between the nuclei varied
in a complex manner according to frequency band and the presence of
exogenous dopaminergic stimulation. Synchronization of activity does
occur between pallidum and STN, and its pattern is critically dependent
on the level of dopaminergic activity.
Key words:
globus pallidus interna; subthalamic nucleus; coherence; synchronization; Parkinson's disease; dopamine
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INTRODUCTION |
Studies in
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates
and in patients with Parkinson's disease have found an increase in
firing rate and a tendency toward bursting in the neurons of the globus
pallidus interna (GPi) and subthalamic nucleus (STN) (Filion and
Tremblay, 1991 ; Bergman et al., 1994; Sterio et al., 1994; Hutchison et
al., 1997a, 1998; Merello et al., 1999). These changes are
likely to influence the projection targets of the basal ganglia in the
thalamus and brainstem, although not as much as if the postsynaptic
efficacy of neuronal activity was increased through the synchronization
of discharges emanating from these nuclei. There is some evidence for
the synchronization of neuronal discharges within the GPi of
MPTP-treated primates (Nini et al., 1995), but, to date, there is no
evidence for significant synchronization in patients with Parkinson's disease.
Here we look for synchronization within and between the human GPi and
ipsilateral STN in the presence and relative absence of dopaminergic
stimulation, by recording from the basal ganglia in patients undergoing
functional neurosurgery for severe Parkinson's disease. Patients were
recorded after withdrawal and reinstitution of treatment with the
dopamine precursor levodopa, which elevates levels of dopamine and its
metabolites in the parkinsonian brain, without significant change in
noradrenaline or serotonin (Scatton et al., 1983). To avoid
surgery-related time constraints, we recorded local potentials (LPs)
postoperatively from the different contacts of macroelectrodes rather
than the action potentials of individual neurons using intraoperative
microelectrodes. The use of bipolar contacts increased the likelihood
that only local potentials were recorded because activity generated
near one contact in a contact pair is more likely to give a deflection
than activity generated at a distance and picked up by both contacts.
We further confirmed the local generation of recorded potentials by
demonstrating reversal in the polarity of the cumulant density
estimates between consecutive bipolar pairs of contacts.
The LP is the product of synchronous activity in a population of
neurons. In the cerebral cortex, the timing of neuronal discharge is
closely related to fluctuations in the local field potential (LFP) (Creutzfeldt et al., 1966; Frost, 1968), and, by analogy, we considered fluctuations in the LP within GPi and STN to be a
surrogate marker of the synchronization of neuronal discharge in these
nuclei. The validity of this marker was checked by looking for
coherence between GPi and STN, because the presence of the latter would
suggest that LFP oscillations in GPi were locked to postsynaptic
effects in STN and visa versa.
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MATERIALS AND METHODS |
Patients and surgery. All four patients (mean age of
59 years; range of 49-64 years; two females; mean duration of disease, 17 years; range of 9-27 years) participated with informed consent. Their mean United Parkinson's Disease Rating Scale (UPDRS) motor scores were 66 (range of 48-80) and 20 (range of 11-38) off and on
medication, respectively. Patients took a mean daily dosage of 770 mg
of levodopa (range of 400-1500 mg) and a single dose of 200 mg during
the recording session. UPDRS scores on and off treatment and the
efficacy of stimulation at different macroelectrode contacts were
assessed independently of the experiment and blind to any of the results.
The operative procedure and beneficial clinical effects of stimulation
have been described previously (Siegfried and Lippitz, 1994; Limousin
et al., 1995; Starr et al., 1998). Macroelectrodes were inserted after
GPi and STN had been identified by nontelemetric ventriculography and
localized using microelectrode recording and microstimulation while the
subject was awake. The coordinates at the tip of contact 0 were 19-24
mm from the midline of the patient, 2 mm in front of the midcommissural
point, and 6 mm below the anterior commissure (AC)-posterior
commissure (PC) line for Gpi, and 12 mm from the midline, 0 mm from the
midcommissural point, and 4-5 mm below the AC-PC line for STN.
Macroelectrode position was confirmed postoperatively using magnetic
resonance imaging (MRI). The macroelectrodes in the pallidum and STN
were models 3387 and 3389 (Medtronic Neurological Division,
Minneapolis, MN) with four platinum-iridium cylindrical surfaces (1.27 mm diameter and 1.5 mm length) and center-to-center separations of 3 and 2 mm, respectively. Contact 0 was the most caudal, and contact 3 was the most rostral. It was estimated that contacts 0-2 of the pallidal electrode were potentially in GPi, whereas only contacts 0 and/or 1 of the STN electrode were in the STN. However, the exact
position of the macroelectrode contacts cannot be determined antemortem. Postoperative stimulation of the macroelectrodes at clinically effective frequencies and intensities led to neither visual
or somaesthetic responses nor muscle activation.
Recordings. Subjects were supine and were recorded at
rest and while they performed isometric contraction of the wrist
extensors, so as to maintain the wrist dorsiflexed by ~30° from the
primary position. The forearm was supported in pronation, and wrist
extension was unconstrained. During each task, LPs from the GPi and STN macroelectrodes were recorded simultaneously with contralateral wrist
extensor EMG. EMG was picked up with bipolar 9-mm-diameter Ag-AgCl
electrodes. The degree of EMG activity was monitored on-line with
verbal feedback being given so that activity was matched on and off
medication. Deep brain activity was recorded from the adjacent four
contacts of each macroelectrode (0-1, 1-2, and 2-3). EMG was
band-pass filtered at 10-300 Hz and amplified (1000×). LPs and EEG
were filtered at 1-300 Hz and amplified (100-500,000×). Signals were
sampled at 1 kHz and recorded and monitored on-line using a
custom-written program.
Analysis. A fast Fourier transform was performed on
nonoverlapping sections of equal length (Halliday et al., 1995).
Results were averaged across sections, and the autospectra,
cross-spectra, and from this coherence were determined over 0-200
Hz. A total of 1027 segments (mean of 178 per pair of nuclei
from each subject) were averaged for each of the four conditions (rest
and tonic voluntary contraction on and off levodopa). The segment
length used was 1024 points, giving a frequency resolution of 0.98 Hz. The variances of autospectra were stabilized using a logarithmic (log10) transform. The variance of the coherence was normalized by
transforming the square root of the coherence (a complex valued function termed coherency) at each frequency using the Fisher transform. This results in values of constant variance for each record
given by 1/2L, where L is the number of
segment lengths used to calculate the coherence. A
 2 test was then used to test the
hypothesis of equal coherence values in the original records at each
frequency (Amjad et al., 1997). As multiple comparisons were performed,
the confidence limits (CL) for autospectra, coherence, and
2 spectra were calculated after a
Bonferroni correction. Phase was only analyzed over those frequencies
showing significant coherence between STN and GPi. The constant time
lag between the two signals was calculated from the slope of the phase
estimate after a line had been fitted by linear regression. The time
lag was only calculated from the gradient if the number of contiguous
data points included in the segment was equal to or more than eight,
and a linear relationship accounted for >80% of the variance. There
often appeared to be more than one component of differing slope. The
limits of individual components were defined by the turning points of
the best-fit second- or third-order polynomial fitted to all contiguous
plotted points. The polynomials accounted for >80% of the variance
and had the same or more than eight data points per model order. The results of phase analysis are useful in suggesting which nucleus is
active first over a particular frequency band. However, 95% CL were
generally large so that inferences about the precise temporal differences between structures could not be made, especially because bipolar electrodes may degrade phase information (Mima and Hallett, 1999). It should also not be assumed that the lags and leads reported here only reflect conduction delays.
The cumulant density, equivalent to the cross-correlation between
signals, was calculated from the inverse Fourier transform of the
cross-spectrum. Reversals in the polarity of the cumulant density
estimate between consecutive bipolar pairs of contacts were used to
determine the source of oscillatory activity. Only peaks in the
cumulant density that were above the Bonferroni corrected 95% CL were assessed.
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RESULTS |
GPi and STN LPs
Four patients with idiopathic Parkinson's disease were studied
3-8 d after the simultaneous surgical implantation of macroelectrodes in the basal ganglia, in the period between implantation and subsequent subcutaneous rerouting to an internal stimulator (Fig.
1). Two patients were recorded twice as
both sides were implanted over the course of the study. This resulted
in LPs being sampled from a total of six GPi and six STN. Each patient
was recorded at rest and during tonic voluntary contraction of the
extensor muscles of the contralateral forearm after the overnight
withdrawal of their antiparkinsonian medication and again 1.5 hr after
ingestion of levodopa. Figure 2 shows
representative examples of the raw LP signals picked up in GPi and STN
and variations in their frequency content over time. Off treatment, the
records from both nuclei are dominated by oscillatory activity with a
frequency below 30 Hz (Fig. 2a). These oscillations are
reduced after the ingestion of levodopa, when a sharply tuned band of
activity appears in STN at ~70 Hz (Fig. 2b). Similar
features were seen in all subjects. After treatment, two of the
patients also showed a smaller peak in STN at ~140 Hz, a harmonic of
the major activity at 70 Hz (Fig. 2c). One patient became
drowsy during recordings made after levodopa, whereupon the 70 Hz
oscillations became greatly diminished (Fig. 2d).
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Figure 1.
T1-weighted magnetic resonance axial view in a
patient with Parkinson's disease after implantation of the left then
right pallidum and STN. The sites of the deepest contacts (0) are shown
and lie in STN (white arrows) and GPi (black
arrows), bilaterally. The scale to the right is in
centimeters.
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Figure 2.
Raw LP signals picked up in GPi12 and STN12/01 at
rest and variations in their frequency content over time.
a, Off treatment, the records from both nuclei are
dominated by activity with a frequency below 30 Hz. b,
Same patient after the ingestion of levodopa. Low-frequency activity is
reduced, and a sharply tuned band of activity appears in STN at ~70
Hz (arrow). In both a and
b, a 1 sec segment of corresponding LP is shown under
the frequency sonograms. c, Another patient recorded on
treatment, showing activity in STN at ~70 and 140 Hz
(arrows). d, A patient who fell drowsy
during treatment with levodopa. The peak in activity at ~70 Hz
(arrow) is present when alert but not drowsy (denoted by
black bars and defined as eyes closed and low-voltage
slow activity and  dropout in EEG).
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STN-GPi coherence off levodopa
Figures 3 and 5 illustrate the
power, coherence, and phase spectra at rest and during tonic extension
of the contralateral wrist in the different treatment states for
activities recorded from macroelectrode contacts STN12 and GPi12,
pooled across all subjects. These contacts were chosen because they
included at least one contact from the pair yielding the best clinical
improvement upon high-frequency stimulation in each patient and also
demonstrated the highest coherence with one another. At rest, off
antiparkinsonian medication, the coherence between LPs recorded at
STN12 and GPi12 demonstrated two peaks (Fig. 3B). The first
was relatively small and centered at ~6 Hz. STN led GPi at this
frequency as shown by the net negative phase slope in Figure
3E. The second peak was much larger and centered at ~20
Hz. Up to 25% of the activity at this frequency was synchronized
between GPi and STN. GPi led STN over this  band, as shown by
the net positive slope in Figure 3E. Cumulant density
estimates showed polarity reversal at contact 1 in GPi and STN (Fig.
4A), suggesting that
oscillations arose at this contact and were not volume conducted from
elsewhere. In the case of GPi, which is big enough to accommodate
several macroelectrode contacts, this result implies some functional
somatotopy within the nucleus and is in accord with other evidence
suggesting somatotopy in the human GPi (Bejjani et al., 1997; Krack et
al., 1998).
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Figure 3.
Autospectra of LP power (A,
B), coherence spectra between STN12 and GPi12
(C, D), and respective phase spectra
(E, F) after withdrawal
(A, C, E) or reinstitution
(B, D, F) of
levodopa. Data pooled from all records at rest in four patients with
Parkinson's disease (over 6 experimental sessions). Off medication,
there is coherence between STN12 and GPi12 at ~6 and 20 Hz.
Regression analysis of phase suggested that STN led GPi by 50 ± 19 msec from 3.9 to 11.7 Hz (r2 = 0.853; p = 0.0004), whereas GPi led STN by
20 ± 5 msec from 11.7 to 27.3 Hz
(r2 = 0.851;
p < 0.0001). It should be noted that the 95%
confidence limits for these and ensuing temporal differences were
broad, although they never encompassed zero. The low-frequency activity
is reduced on treatment when a peak appears at ~70 Hz in the
autospectrum of STN12 (B) and coherence spectrum
(D). STN led GPi by 31 ± 6 msec
(r2 = 0.928;
p < 0.0001). In this and Figure 5, phase is shown
in black (rather than gray) when it met
criteria for measurement as defined in Materials and Methods, bin size
is 0.98 Hz, and vertical bars and thin
lines are 95% CL in power spectra and in coherence and phase
spectra, respectively.
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Figure 4.
Cumulant density estimates after withdrawal
(A) and reinstitution of levodopa
(B) of levodopa recorded at rest.
Black and thick gray lines are calculated
from STN12-GPi12 and STN01-GPi12, respectively. STN01-GPi12 has been
inverted. The close superimposition of waves indicates polarity
reversal around contact 1 in STN for both the slow activity in
A and fast (70 Hz) activity evident in B.
The horizontal lines are the 95% CL.
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The picture was similar during tonic contractions made off levodopa
(Fig. 5C), except that
coherence between STN12 and GPi12 was not as high (Fig.
6C, confirmed by
2 test) and phase was indeterminate
(Fig. 5E). Cumulant density estimates again showed polarity
reversal at contact 1 in GPi and STN (data not shown).
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Figure 5.
Autospectra of LP power (A,
B), coherence spectra between STN12 and GPi12
(C, D), and respective phase spectra
(E, F) after withdrawal
(A, C, E) or reinstitution
(B, D, F) of
levodopa. Data pooled from all records in which the contralateral wrist
was tonically extended in four patients with Parkinson's disease (over
6 experimental sessions). Off medication, there is coherence between
STN12 and GPi12 at ~20 Hz. The temporal difference between STN and
GPi was indeterminate, with the best-fit line accounting for only 17%
of the variance. The low-frequency activity is reduced on treatment
when a peak appears at ~70 Hz in the autospectrum of STN12
(B) and coherence spectrum
(D). Regression analysis of phase suggested that
STN led GPi by 47 ± 9 msec from 69.3 to 82.0 Hz
(r2 = 0.910;
p < 0.0001).
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Figure 6.
A, Comparison of pooled coherence
at rest off and on levodopa. B, Comparison of pooled
coherence during tonic wrist extension off and on levodopa. In both
A and B, coherence was greater at ~20
and 70 Hz off and on levodopa, respectively. C,
Comparison of pooled coherence at rest and during tonic wrist extension
when off levodopa. Coherence was greater at rest at ~6 and 20 Hz.
D, Comparison of pooled coherence at rest and during
tonic wrist extension after treatment with levodopa. Coherence
was greater at rest at ~70 Hz.
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STN-GPi coherence after levodopa
The picture was very different after levodopa. The
latter was effective in improving parkinsonism (see Materials and
Methods). Both at rest and during tonic activity power in the STN12 and GPi12, LPs dropped at frequencies under 30 Hz and a new peak appeared in the LPs at ~70 Hz (Figs. 3B, 5B). This was
paralleled by a striking reduction in coherence between STN12 and GPi12
LPs at ~20 Hz and by an increase in coherence at ~70 Hz (Figs.
3B, 5B). There was no significant coherence
between STN12 and GPi12 above 90 Hz in the pooled or individual data.
The differences between coherence spectra on and off levodopa were
confirmed by a 2 test on the pooled
data (Fig. 6A,B). Thus, the
synchronization of activities in GPi and STN shifted to much
higher frequencies after treatment with levodopa. STN tended to
phase lead GPi over these higher frequencies, as shown by the net
negative gradients in Figures 3F and 5F. After
treatment, cumulant density estimates showed polarity reversal of the
70 Hz activity at contact 1 in GPi and STN, suggesting that the fast
oscillations arose within these nuclei (Fig. 4B),
although during tonic wrist extension, there was an additional slow
wave that did not phase reverse and probably represented volume
conduction from a more distant source (data not shown). The coherence
between STN12 and GPi12 LPs at ~70 Hz after levodopa tended to be
greater at rest than during tonic extension of the wrist (Fig.
6D, see 2 test). Note
that the small peak in coherence at ~6 Hz at rest was greater off
medication than after levodopa (Fig. 6A) and greater off medication but at rest than during tonic wrist extension (Fig. 6C), in keeping with a tremor-related phenomenon.
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DISCUSSION |
Our results show a marked change in the nature of oscillatory
activity within and between GPi and STN in untreated and treated patients with Parkinson's disease. Off levodopa LPs in both nuclei were dominated by low-frequency activity with coherence between the two
signals at ~6 and 20 Hz. Conversely, after treatment with levodopa
doses sufficient to improve parkinsonism, this low-frequency synchronization was diminished and replaced by synchronization at ~70
Hz. Power changes were in the same direction as changes in coherence so
that the latter were not attributable to alterations in the
nonlinear components of the signals. These dramatic effects of levodopa
on pallidal-STN oscillations may have been exerted through the
projection of the substantia nigra pars compacta to the putamen and
thence to STN or directly via a dopaminergic substantia nigra pars
compacta-STN projection (Parent and Hazrati, 1995). In line with the
latter, the overall electrophysiological activity of the STN is known
to increase after the direct iontophoretic application of dopamine in
the rat (Cambell et al., 1985).
Origin of low- and high-frequency activities
Macroelectrode sites were deemed to be within GPi and STN on the
basis of their stereotactic coordinates, postoperative MRI, and the
antiparkinsonian effects of high-frequency stimulation at each site. In
addition, the phase reversal of the cumulant density estimates
indicated that the activities recorded by contacts GPi12 and STN12 were
generated locally rather than picked up through volume conduction from
more distant sources.
The networks subserving synchronized oscillations at above 15 Hz, which
represent the bulk of the activity recorded here, are obscure. To date,
there have been no reports of such oscillatory activity in
cross-correlations of single units within or between GPi and STN.
Nevertheless, recent investigations of organotypic cocultures suggest
that the STN-pallidal network can support rhythmic activity, albeit at
frequencies under 4 Hz (Plenz and Kital, 1999). Cortical (Magill et
al., 2000; Nambu et al., 2000) and subcortical influences, such as
those from the striatum (Ryan and Clark, 1992), thalamus (Bevan et al.,
1995; Smith et al., 1998), and pedunculopontine nucleus (Inglis and
Winn, 1995), may further modify this innate rhythmicity.
Phase relationships between GPi and STN
Phase relationships between GPi and STN are open to several
interpretations. However, we would choose to view them in the light of
current models of the basal ganglia (Albin et al., 1989; Alexander and
Crutcher, 1990; Parent and Hazrati, 1995; Chesselet and Delfs, 1996;
Smith et al., 1998). Off levodopa, activity in GPi led that in STN at
~20 Hz. This would be consistent with the common driving of STN and
GPi by globus pallidus externa (GPe) (with conduction and
neuronal delays to STN being longer than to GPi). Also off levodopa,
activity in STN at ~6 Hz led that in GPi and might contribute to the
postulated synchronization of output from GPi at low frequency in
untreated Parkinson's disease (Brown and Marsden, 1998).
Dopaminergic stimulation dramatically changed the pattern of functional
connectivity. Oscillatory interactions between STN and GPi were
dominated by activity at ~70 Hz in which STN led GPi, whereas those
below 30 Hz were greatly diminished. This would be consistent with the
driving of GPi by STN at high frequency when on treatment,
either through direct STN-GPi projections or via STN-GPe-GPi pathways.
The above may well not be the only interactions between GPi and STN;
some may involve asynchronous and nonoscillatory activity and escape
detection through frequency analysis of LPs. Nevertheless, the
connections identified above are likely to be quantitatively important because the postsynaptic effects of synchronized inputs are
greater than those of asynchronous ones.
Effects of pathological synchronization below 30 Hz
In the presence of deficient dopaminergic input, as in untreated
Parkinson's disease, subthalamo-pallidal networks seem to be favored
that oscillate at frequencies below 30 Hz. There appear to be two main
effects. First, there are oscillations at 4-10 Hz in which STN leads
GPi. These oscillations may be related to tremor as reported in
microelectrode single-unit studies in monkeys (Bergman et al., 1994,
1998) and parkinsonian patients (Hutchison et al., 1997b; Taha
et al., 1997; Magnin et al., 2000). Certainly, in one of our cases with
a florid rest tremor off medication, there was coherence between the
STN LP and EMG at tremor frequency. The second oscillatory activity
occurred in the range, with a peak centered at ~20 Hz. Here GPi
phase led STN. Both activities may disrupt normal motor function
(Wichmann and DeLong, 1996). Artificial driving of the pallidum in the
cat (Hassler and Dieckmann, 1967; Dieckmann, 1968) or of STN in humans
(Demeret et al., 1999) at low frequency brings on or exacerbates
parkinsonism, suggesting that the spontaneous synchronization at low
frequency may contribute to the abnormal pattern of movement in
Parkinson's disease (Brown and Marsden, 1998). This hypothesis
deserves further investigation, because it may help explain some of the
paradoxical effects of functional neurosurgery (see below).
Effects of synchronization at ~70 Hz
Our results imply that elements within the pallidum and STN
form a functional network that ordinarily, in the presence of a normal
dopaminergic drive, resonates at ~70 Hz. That such a rhythm is
important for the optimal organization of voluntary movement is
strongly suggested by the antiparkinsonian effects of stimulation of
the same nuclei at frequencies likely to cause resonance within this
network, at or near the base frequency of 70 Hz or its second harmonic
(Siegfried and Lippitz, 1994; Limousin et al., 1995; Starr et al.,
1998). However, the oscillations occurring after the reinstitution of
dopaminergic stimulation are unlikely to be directly related to the
execution of voluntary movement because they occur at rest as well as
during motor activity. As such, they could be related to attentional
processes operating in the executive domain, acting through the
thalamus to favor cortico-cortical interactions in the gamma band
(Hassler, 1980; Brown and Marsden, 1998). In support of this is the
disappearance of the 70 Hz activity with drowsiness in one patient,
although one might have expected the same activity to be increased
rather than reduced during tonic voluntary contraction. Alternatively, the 70 Hz activity could act as a carrier rhythm for motor commands. The narrow band nature of the high-frequency activity evident in
individual power and coherence spectra would be particularly suited to
a carrier function.
Implications for functional neurosurgery
The present findings could help explain the paradoxical
results of functional neurosurgery for Parkinson's disease. Hitherto, the efficacy of this treatment has been difficult to explain in terms
of the known physiology of the basal ganglia. There are two surgical
techniques, lesioning of GPi or STN and stimulation of the same sites
at high frequency through implanted macroelectrodes (Siegfried and
Lippitz, 1994; Limousin et al., 1995; Gill and Heywood, 1997; Starr et
al., 1998). Focal lesions of GPi should destroy the major output of the
basal ganglia to the motor cortex and abolish their contributions to
normal voluntary movement. Lesions would therefore be expected to
impair motor performance, but the reverse is seen in Parkinson's
disease. On the other hand, the similarity between the effects of
stimulation at frequencies in excess of 50 Hz and focal lesioning might
imply that the former works through the induction of a virtual lesion
by depolarization block (Limousin et al., 1995). However, human GPi
neurons discharge at frequencies of ~85-140 Hz in Parkinson's
disease, suggesting that neural elements are more likely to be driven
than blocked by high-frequency stimulation (Hutchison et al.,
1997a; Merello et al., 1999; Magnin et al., 2000).
These paradoxical observations could be reconciled by the present
findings if we are correct in hypothesizing that the low- and
high-frequency modes of the subthalamic-pallidal circuit impair and
promote motor function, respectively. In this case, the low-frequency activity could be blocked with beneficial effect by either exogenous dopaminergic stimulation or the focal destruction of GPi or STN. At the
same time, therapeutic stimulation of either nucleus at high frequency
might artificially drive a circuit that normally requires dopaminergic
stimulation to resonate in its optimal mode.
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FOOTNOTES |
Received July 11, 2000; revised Oct. 19, 2000; accepted Nov. 13, 2000.
This work was supported by the Medical Research Council. We thank
J. C. Rothwell for his assistance in recording one of the patients
and D. H. Halliday and D. Buckwell for computer programs.
Correspondence should be addressed to Dr. P. Brown, Medical Research
Council Human Movement and Balance Unit, Institute of Neurology, Queen
Square, London WCIN 3BG, UK. E-mail: p.brown{at}ion.ucl.ac.uk.
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TOP
ABSTRACT
INTRODUCTION
