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The Journal of Neuroscience, October 15, 2000, 20(20):7766-7775
High-frequency Synchronization of Neuronal Activity in the
Subthalamic Nucleus of Parkinsonian Patients with Limb Tremor
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 Department of Surgery, University of Toronto, Division of
Neurosurgery, The Toronto Western Hospital, Ontario, Canada M5T 2S8,
and 3 The Toronto Western Research Institute, Toronto,
Ontario, Canada M5T 2S8
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ABSTRACT |
It has been hypothesized that in Parkinson's disease (PD) there is
increased synchronization of neuronal firing in the basal ganglia. This
study examines the discharge activity of 121 pairs of subthalamic
nucleus (STN) neurons in nine PD patients undergoing functional
stereotactic mapping. Four patients had a previous pallidotomy. A
double microelectrode setup was used to simultaneously record from two
neurons separated by distances as small as 250 µm. In the six
patients who had limb tremor during the recording session
(n = 76 pairs), the discharge pattern of 12 pairs
of tremor cells (TCs) was found to be coherent at the frequency of the
limb tremor. Both in-phase and out-of-phase relationships were observed between TCs. Interestingly, in these six patients, 63/129 single neurons displayed 15-30 Hz oscillations, whereas 36/76 pairs were coherent in this frequency range. Although the oscillatory frequencies were variable between patients, they were highly clustered within a
patient. The phase difference between these pairs was found to be close
to 0. High-frequency synchronization was observed during periods of
limb tremor as well as during intermittent periods with no apparent
limb tremor. In contrast, in the three patients without limb tremor
during the recording session, only 1/84 neurons had high-frequency
oscillatory activity, and no TCs or synchronous high-frequency
oscillatory activity was observed (n = 45 pairs). These findings demonstrate that in PD patients with limb tremor, many
STN neurons display high-frequency oscillations with a high degree of
in-phase synchrony. The results suggest that high-frequency synchronized oscillatory activity may be associated with the pathology that gives rise to tremor in PD patients.
Key words:
Parkinson's disease; limb tremor; synchronization; tremor cells; subthalamic nucleus; basal ganglia
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INTRODUCTION |
The role of the subthalamic nucleus
(STN) in the pathogenesis of Parkinsonian symptoms has gained
prominence since the demonstration of the anti-parkinsonian effect of
injections of fiber-sparing neurotoxins into the STN of
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated nonhuman
primates (Bergman et al., 1990 ). Deep brain stimulation (DBS) (Limousin
et al., 1995) or lesions (Gill and Heywood, 1997; Obeso et al., 1997)
of the STN in Parkinson's disease (PD) patients have been shown to be
an effective treatment for rigidity, akinesia, and especially tremor
(Krack et al., 1998; Kumar et al., 1998). In PD patients, the reduction
of tremor by STN DBS is comparable with the response obtained by
thalamic stimulation for tremor (Krack et al., 1997). As in the
thalamus (Lenz et al., 1988), groups of STN neurons display
tremor-related spontaneous activity that is periodic at limb tremor
frequency (Hutchison et al., 1998), and microstimulation in these
regions has been shown to reduce resting tremor (Rodriguez et al.,
1998).
In monkeys treated with MPTP, degeneration of the substantia nigra pars
compacta and subsequent depletion of striatal dopamine is related to
the emergence of periodic oscillatory neuronal activity in the STN
(Bergman et al., 1994). It has been hypothesized that in PD, a loss of
dopamine is characterized by a reduction in the independence between
functionally segregated parallel circuits (Bergman et al., 1998a). The
internal segment of the globus pallidus (GPi) is the major output
nucleus of the basal ganglia and receives substantial excitatory input
from the STN (Parent and Hazrati, 1995). After MPTP-induced
parkinsonism in monkeys, synchronized oscillatory neuronal activity
between pairs of neurons in the internal segment of the GPi (Nini et
al., 1995) and the striatum (Raz et al., 1996) is observed. In these
studies, all parkinsonian monkeys displayed signs of resting tremor
and/or action tremor. The synchronization of neuron pairs with
tremor-related activity has also been shown in the GPi of PD patients
(Hurtado et al., 1999). However, it is unclear whether synchronized
tremor activity in the basal ganglia contributes to tremor pathogenesis
or is simply the result of tremor activity occurring elsewhere. For instance, the synchronization of tremor cells [(TCs) neurons with low-frequency oscillatory activity that is highly correlated with limb
tremor] could be caused by common tremor-related afferent inputs to
those cells.
To assess whether synchronous activity between neurons in the STN
underlies differences in parkinsonian pathophysiology, this study
examined the discharge activity of pairs of neurons in PD patients with
and without limb tremor. We provide evidence that groups of STN neurons
oscillate in phase at high frequencies in PD patients with limb tremor
but are not found in those patients without limb tremor.
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MATERIALS AND METHODS |
Subjects. Nine patients underwent
microelectrode-guided placement of bilateral deep brain
stimulating electrodes for the treatment of the symptoms of PD.
These patients had a mean age of 51 years (±2.4 SE, range 34-66
years) at the time of operation. The average duration of the disease
was 12 years (±1.5 SE), and all patients had PD for at least 7 years.
Individual patient characteristics are listed in Table 1. All patients
were preoperatively assessed using the Unified Parkinson's Disease
Rating Scale (UPDRS). In both the preoperative assessment and during
surgery, patients were studied in the practically defined OFF
state, 12-14 hr after the last oral dose of levodopa. The mean motor
UPDRS score (motor subsection III) was 50 (±2 SE) (maximum possible
score is 108). UPDRS OFF period tremor score (maximum value is 28) was
calculated as the sum of UPDRS item 20 (resting tremor of right hand,
left hand, right leg, left leg, face) and item 21 (action tremor of right hand, left hand). Using the following criteria, patients were
divided into two groups. Those with any resting tremor of the limbs
during the microelectrode recording session were assigned to a
"tremor" group (n = 6). Patients without any
discernable resting tremor of the limbs during the microelectrode
recording session were assigned to a "non-tremor" group
(n = 3). Four patients had previously undergone a
unilateral pallidotomy (Table 1). In
these patients, pallidotomy was indicated for disabling drug-induced dyskinesia. Two of these patients were in the tremor group, and two were in the non-tremor group. In both of the tremor group patients
(patients A, F), pallidotomy led to a moderate decrease in
contralateral limb tremor at 6 months after surgery. However, the
tremor reduction was not maintained at the time of the STN recordings
(33 and 28 months after pallidotomy). One of the two non-tremor group
patients (patient I) did have mild facial tremor before and at 6 months
after pallidotomy, but this tremor was not present at the time of the
STN recordings. Because it is possible to induce or enhance
Parkinsonian resting limb tremor by having patients perform a cognitive
task that demands their attention, patients were periodically asked to
perform mental arithmetic during some of the microelectrode recordings.
Recording procedure and apparatus. The use of microelectrode
recording to localize DBS electrode placement in the STN has been
described previously (Hutchison et al., 1998). Briefly, single-unit microelectrode recordings and stimulation mapping allowed the identification of physiological landmarks and cell localization. Parasagittal trajectories at either 10.5 or 12 mm from the midline passed through the thalamic reticular nucleus and/or anterior thalamus,
zona incerta, STN, and the substantia nigra pars reticulata (SNr).
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. 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 electromyographic (EMG) and accelerometer signals on
analog videotape (VR-100 digital recorder, Instrutech Corp., Port
Washington, NY) to be analyzed off-line. 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, in which case the
electrodes were separated by 600 µm and each electrode was driven by
a separate microdrive. In most cases dual-electrode recordings were
obtained only on one side (usually the first). Recorded neurons were
included if they were well isolated and stable and were sampled for at
least 20 sec or at least 1000 action potentials. An example of a well
isolated neuron is displayed in Figure 1A. In this
study, the average number of action potentials recorded per cell was
2830 (±130 SE) over an average sample time of 62 sec (±3 SE).
Single-unit event times were discriminated off-line using two
dual-window discriminators (DDIS-1, BAK Electronics, Mount Airy, MD)
and storage oscilloscopes in spike-triggered mode or by
template-matching spike-sorting software (Spike2, Cambridge Electronic
Design, Cambridge, England).
Data analysis. Spontaneous ongoing discharge (tonic
activity) analyzed in this study was collected with the patient at rest and without any passive joint manipulation or voluntary movements. The
average neuronal firing rate (FR) and the median interspike interval
were calculated for each cell. Statistical analysis of group values was
performed using Student's t tests. In cases of non-normality, the Wilcoxon Signed Rank Test or Mann-Whitney Rank Sum
Test was used. Statistical significance was assigned at
p < 0.05 (i.e.,  = 0.05; two-tailed).
Autocorrelation analysis was used to detect and grade the rhythmic
neuronal activity of single neurons. Cross-correlation analysis was
used to detect coincident activity between pairs of neurons and detect
and grade the rhythmic neuronal activity within these pairs.
Correlation histograms of spike trains were plotted for delays of 1.0 sec (10 msec bin width) and 200 msec (2 msec bin width). Correlograms
were used to index the strength of the periodic activity. The strength
of the oscillation was graded according to standard examples given by
Karmon and Bergman (1993) for oscillating cells in MPTP-treated
monkeys, in which only cells with a strength of five or greater were
considered for further analysis. All correlation histograms were
quantified to the units of rate (spikes per second) (Abeles, 1982).
Nonrandom discharge, such as oscillatory activity of individual neurons (autocorrelation) or between pairs of neurons (cross-correlation), was
assessed by calculating confidence lines at ±2 SDs (~95% confidence interval) of the 100-200 or 500-1000 msec time interval mean. Oscillatory modulation of ongoing discharge was initially detected by
locating at least two successive peaks within the first 100 or 500 msec
of the autocorrelation functions (constructed from 100 bins of 2 or 10 msec, respectively). Peaks were considered significant if they were
found outside the area defined by the confidence lines. The frequency
of oscillation was then determined by calculating the reciprocal of the
peak-to-peak time of two successive peaks. Phase shifts were determined
by calculating the time of the highest peak (typically the peak closest
to zero time) divided by the oscillation period.
Spectral analysis was used to further characterize the frequency
content of neurons with oscillatory activity. Spike trains were
transformed from a series of events (sampled at 1000 Hz) to a
continuous function representing the density of spikes in time (using
conversion software from Spike2, Cambridge Electronic Design) (see Fig.
1B legend for detail). The size of the transform used
in the fast Fourier transform (FFT) analysis was 512 points, thereby
yielding a frequency resolution of 1.95 Hz (i.e., waveform channel
sampling rate divided by the FFT block size). Only cells that yielded
at least 19 nonoverlapping power spectrum blocks were used to calculate
spectra (i.e., 10 sec of data  19 blocks × 512/1000
sec/block). In this study, the average number of FFT blocks per sample
time was 154 (±18 SE). Graphic displays of frequency versus time were
constructed by calculating the frequency content within consecutive 10 sec windows and were scaled to the ratio of signal to noise. Spectral
noise was taken as the average of all spectral estimates between 0 and
30 Hz.
The similarity in oscillatory frequency content of pairs of neurons was
calculated using coherence techniques. 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. Because coherence is a measure of linear
similarity, the phase shift must be constant, and the amplitudes of the
two waveforms must have a constant ratio to be completely coherent at a
particular frequency over a given time range. A statistically
significant coherence value between the discharge of two neurons was
used to indicate the presence of oscillatory synchronization. A 99%
confidence level was determined by calculating a coherence value given
by Coherence = 1  (1 )1/(L 1), where = 0.99 and
L = number of windows used (Rosenberg et al., 1989).
This value or greater was considered to indicate a significant
probability (p < 0.01) of a linear relationship
between two cells. Phase relations were also assessed for those pairs of neurons that had a significant coherence at some frequency fi using Phase
(fi) = arctan(Q(fi)/L(fi)),
where fi is the
ith spectral estimate, Q is the
real part, and L is the imaginary part of the cross-spectra
between a pair of neurons (Glaser and Ruchkin, 1976). Graphic displays
of coherence or phase versus time were constructed by calculating the
coherence or phase within consecutive 10 sec windows.
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RESULTS |
Oscillatory activity of single neurons in the STN
A total of 213 single neurons (from 121 pairs) was recorded from
the STN of the nine patients. Three types of rhythmic activities were
identified over the range of the rhythmic frequencies investigated: (1)
tremor cells (4% of total STN population, n = 8),
which displayed rhythmic activity at tremor frequency concurrently with
limb tremor (Fig. 1C), (2)
cells with high (>10 Hz) frequency oscillations (20% of total STN
population, n = 44) (Fig. 1D), and
(3) cells with both tremor frequency and high-frequency oscillation
components (6% of total STN population, n = 12) (Fig.
1E). The median FR of all STN neurons was 45.7 Hz
(25% = 34.7, 75% = 61.7). Cells with no oscillatory discharge had a
median FR of 43.1 Hz (25% = 32.4, 75% = 61.1), whereas cells that
displayed oscillatory activity had a median FR of 53.4 Hz (25% = 40.2, 75% = 64.4), which was significantly greater (p < 0.05, Mann-Whitney Rank Sum Test) (Fig. 1F).
There was no significant difference in the FRs of TCs and cells with
high-frequency oscillatory activity.
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Figure 1.
The oscillatory behavior of single neurons in the
STN of PD patients. A, Raw trace of a well isolated STN
neuron. B, Spike trains were transformed from a series
of events (sampled at 1000 Hz) to a continuous function by replacing
each spike with a raised cosine with unit area under the curve and a
width of 10 msec. This resulted in a smooth continuous function with a
sampling rate of 1000 Hz that was used in subsequent FFT analysis.
C-E, Examples of autocorrelograms
(left column; dashed line is mean
discharge rate) and frequency spectra (right column;
numbers above peaks are the signal-to-noise ratio of the
peak) for three types of oscillatory STN neurons. C,
Cell with only a tremor frequency component (from patient D; see
G). D, Cell with only a high-frequency
oscillatory component (from patient B). E, Cell with
both oscillatory components (from patient B, a raw trace of this cell
is displayed in Fig. 1A). F,
Distribution of firing rates of oscillatory and non-oscillatory STN
neurons (10 Hz bins, data normalized by total cell number in each
group). The mean spontaneous firing rate of cells with an oscillatory
component (n = 64) was significantly higher than
the firing rate of cells without any oscillatory components
(n = 149) (p < 0.05).
G, Box plot of frequencies of high-frequency
oscillations (gray boxes, top) and
of tremor frequency oscillations (open boxes,
bottom) of patients in tremor group.
Arrows indicate the mean limb tremor frequency during
the stereotaxic procedure. Numbers above patient
letter designations indicate total number of single STN neurons
that were sampled in each patient. Numbers above
boxes show the number of single STN neurons in each
group. In the box plot, the box indicates the 25th, 50th
(median), and 75th percentiles, the error bars indicate
the 10th and 90th percentiles, and the dots represent
outliers.
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Almost all (63/64) of the neurons with tremor frequency activity (TCs)
or high-frequency oscillations, or both, were found in the six
patients of the tremor group (129 single neurons examined), including
the two patients (A, F) with a pallidotomy (ipsilateral to the
recordings). In the three patients of the non-tremor group, only 1/84
STN neurons was found to have a high-frequency oscillation. Figure
1G shows box plots of the frequency distributions of the high-frequency oscillatory neurons in the tremor group (frequency calculated from autocorrelograms). Each of the six patients had high-frequency oscillations that were tightly centered about one frequency in the range from 15 to 25 Hz (Fig. 1G). In one
patient, high-frequency oscillatory activity was recorded on both
sides, and the frequency was similar on the two sides. Three of the
patients in the tremor group had TCs; the distribution of TC
frequencies is also shown in Figure 1G. For cells that had
both a tremor frequency oscillation and a high-frequency oscillation
(n = 12), the ratio of the mean high-frequency
oscillatory component to the mean frequency of the tremor component was
4.0 (±0.1 SE).
Highly synchronous high-frequency oscillatory activity in the STN
of tremor group patients
A total of 121 neuron pairs was recorded in the STN. Single
short-latency peaks in the cross-correlogram that would indicate short-interval interactions between STN neurons were never observed. However, 44/76 pairs of neurons were found to have a significant cross-correlation at high frequencies (>10 Hz) in the tremor group. High-frequency oscillatory activity was more evident in
cross-correlograms than in autocorrelograms of single neurons (55/129
single STN neurons with high-frequency oscillatory activity in the
tremor group). The oscillation strength ratings were stronger for
cross-correlation [7.4 (±0.1 SE)] than for auto-correlation [6.9
(±0.1 SE)] (two-tailed t test, p < 0.01).
Figure 2A shows the
spontaneous ongoing discharge of two simultaneously recorded STN
neurons, and Figure 2B shows the corresponding
correlograms and spectra for this pair. Although the spectral
signal-to-noise ratio of the high-frequency oscillation of unit 2 is
lower than for unit 1, there is a statistically significant coherence
between the pair. Figure 2C shows examples of
cross-correlograms and coherence functions of neuron pairs with
synchronous high-frequency oscillatory activity from four patients in
the tremor group; these pairs all oscillated in phase but each patient
had a unique oscillation frequency. Furthermore, 36/76 pairs of STN
neurons were found to have a significant coherence at a high frequency
[mean sample time for the pairs of neurons was 79.3 sec (±9.3 SE)].
Coherence analysis revealed that fast oscillatory cells were also in
synchrony for long periods of time. For example, eight of these pairs
were seen to be coherent and in phase for >2 min.
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Figure 2.
Synchronization of STN neurons with high-frequency
oscillations. A, Traces 2 (Unit 1) and 3 (Unit 2) show the discharge activity of two
simultaneously recorded neurons during wrist tremor (patient E). The
top trace is the recording of rectified wrist extensor
electromyographic activity (EMG). Note that the two
neurons tend to fire in synchrony with each other. B,
Corresponding correlograms (top row) and spectra
(bottom row) of the traces shown in A
(the total sample time used to construct these plots was 29 sec). In
all correlograms, the lines indicate mean FR. In the
cross-correlogram (right panel of top
row), Unit 1 is used as the trigger. The
thick dashed line in the coherence function indicates
the level of significant coherence, and number by the
peak is the phase difference (right panel of
bottom row; see Materials and Methods).
C, Examples of cross-correlograms (left
column; the dashed lines indicate mean ± 2 SD) and coherence functions (right column) of pairs of
STN neurons with a high-frequency oscillatory component from four
separate patients (A, D,
B, F, respectively). D,
Linear regression analysis of percentage of pairs of STN neurons with a
high-frequency cross-correlation as a function of amount of total limb
tremor (UPDRS: sum of action tremor and rest tremor) measured
preoperatively. The triangles indicate those patients in
whom tremor cells were also found. E, Linear regression
analysis of the phase relationship between pairs of fast oscillatory
STN neurons as a function of the distance between the microelectrodes
(phase calculated from cross-correlograms).
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Figure 2D is a plot of the proportion of the pairs
that displayed high-frequency oscillatory cross-correlation in each
patient to each patient's presurgical UPDRS tremor rating score. There was a roughly linear relationship between the amount of high-frequency synchronous activity and the patients' tremor
(r2 = 0.67, p < 0.01). Data obtained from those patients in whom tremor cells were
encountered during the time of surgery are indicated by
triangles. Although all six of the tremor group patients had limb tremor during the procedure, the high-frequency rhythmic firing
was also present during some episodes when these patients did not have
any noticeable tremor. TCs were found in three of the six tremor group
patients. The TCs that were encountered appeared to be localized to
regions that also contained cells with a high-frequency oscillatory
component (see Fig. 5). There were nine instances of recording a TC on
one electrode and no discernible TC frequency component for the other
neuron; three of these pairs showed significant high-frequency
coherence. There were nine instances in which two TCs were recorded
simultaneously, and the tremor oscillation in eight of these pairs was
found to be coherent over the total amount of time sampled.
Figure 2E demonstrates that the phase relationship
between high-frequency oscillatory pairs (detected from the
cross-correlograms) was not dependent on the distance between the
recording sites. There were 61 pairs of STN neurons investigated that
were separated by 250 µm and 60 STN pairs that were separated by
distances of >600 µm. Figure 2E shows that
fast-frequency pairs were synchronous and in phase (absolute phase
difference) over distances up to 1.5 mm.
Temporal relationships between limb tremor and neural pair
synchronization are plotted in detail in Figure
3. Figure 3A displays individual power spectrums of two STN units (scaled to the
signal-to-noise ratio; see Materials and Methods) and the coherence
between them as a function of time during ongoing wrist tremor. Unit 1 was a STN TC with a high-frequency component, whereas unit 2 predominantly displayed high-frequency oscillatory activity. During a
period of limb tremor (40-70 sec), both cells were coherent at tremor frequency and at 20 Hz. When wrist tremor was suppressed by an examiner
holding the patient's wrist, the pair of units displayed an even
stronger high-frequency synchronization (as indicated by the value of
the coherence). In contrast to this type of modulation, high-frequency
synchronization in several pairs was observed by inducing or enhancing
resting tremor. Figure 3B shows the changes in coherence
between two cells in which, after a rest period and some repetitive
passive and voluntary movements [see accelerometer trace
(Acc)], resting tremor was induced by asking the patient to
mentally count backward. It can be seen that when no tremor was
present, there was no coherence between the two cells, but during ankle
tremor (~3.3 Hz), there was a strong high-frequency oscillatory
synchronization. Because of the limited time resolution, it is not
possible to ascertain whether coherence precisely coincides with the
limb tremor. However, at 83 sec, the ankle tremor was suppressed by
having an examiner hold the patient's ankle for ~5 sec and then
releasing, thereby letting tremor reappear. At this point (preceding
the high-frequency synchronization), the two cells were coherent at
tremor frequency. Note also that these cells were not coherent during
the passive arm movements but did show coherence at 26-28 Hz during
voluntary ankle movements. There was one other example in a different
patient in whom the high-frequency synchronization appeared during limb
tremor (data not shown). The issue of whether high-frequency
oscillatory synchronization occurred during activity other than tremor
was not fully explored. There were some neuron pairs that had ongoing
high-frequency oscillatory synchronization during repetitive voluntary
limb movements such as pointing with one hand and tapping with the
other hand. An example is shown in Figure
4A where the pair
displayed synchronization of their 24-28 Hz oscillation during passive
repetitive elbow movements. Synchronization within this frequency range
was absent during the voluntary pointing and tapping movements, but
synchronization at ~15 Hz remained or became even stronger. These
data indicate that high-frequency synchronization between STN neurons
is dynamic and depends on the state of limb tremor and/or passive and
voluntary movements.
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Figure 3.
Examples of the dynamic relationship between
high-frequency oscillatory synchronization and limb tremor.
A, Two STN neurons recorded from patient D. The
bottom two panels show the power spectrums for each
neuron, scaled to the ratio of signal to total noise (see Materials and
Methods). The top panel shows the coherence between the
two neurons. The top trace shows the electromyographic
activity (EMG) from the patient's wrist flexors
smoothed to give an estimate of the strength of the tremor (shown in
detail at the top right of this figure for the 60-64
sec period). Each unit displays both frequency components. However, the
power spectrum of Unit 1 shows that Unit
1 has a larger tremor component oscillation, whereas power
spectrum of Unit 2 shows that Unit 2 has
a larger high-frequency component oscillation. Note that high-frequency
coherence between Units 1 and 2 becomes maximal when the wrist is held.
B, Two STN neurons recorded from patient B. Power
spectrums (bottom two panels) and coherence plot between
two STN neurons during periods of ankle tremor, voluntary and passive
ankle movements, and rest are shown. The two cells are synchronized at
15 Hz during resting limb tremor of ~3.3 Hz. Because of the time
resolution of the coherence plot, it is unclear whether this
synchronization precedes or follows limb tremor. After the ankle is
released, tremor amplitude increases, and the neuron pair
resynchronizes at the same oscillation frequency. The top
trace shows foot accelerometer (Acc) output.
Coherence and autospectra plots were constructed by analyzing
consecutive 10 sec sections of nonoverlapping data.
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Figure 4.
Changes in phase relationship between oscillatory
STN neurons over time. A, Power spectrums, coherence,
and phase (at ~17 Hz; see Materials and Methods) between two STN
neurons during a long sampling period containing passive and voluntary
movements of elbow and arm (patient B). Note that the phase remains
constant over the 3 min sampling period. Coherence during passive
repetitive elbow movements was at ~17 Hz and 24-28 Hz. Coherence
during voluntary pointing and tapping with the opposite hand was
limited to ~17 Hz. The top trace shows hand
accelerometer (Acc) output. Same legend as in Figure 3.
B, Same plots as in A showing that the
phase relationship between two STN TCs varies over time (patient D).
The top left trace shows the smoothed EMG from the
patient's wrist extensors. Phase at ~5 Hz was calculated for time
periods in which the pair of TCs displayed significantly coherent
activity at this frequency.
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Phase relationships of pairs of STN oscillatory neurons
Figure 4A also demonstrates that the pair of STN
neurons with a high-frequency coherence had a stable phase relationship
for a long period of time (>3 min). This is in contrast to pairs of STN TCs. An example of the phase variability of two TCs is shown in
Figure 4B. These cells go from being in phase at
50-60 sec to nearly out of phase at 70-80 sec. It is conceivable that
lower coherence values were obtained in the tremor activity frequency range versus the high-frequency activity range because of differences in phase variability between TC activity and high-frequency oscillatory activity (i.e., a high coherence value is related to a stable phase
relationship; see Materials and Methods).
The tremor oscillations in pairs of tremor cells within the same
patients were also observed to have variable phase relationships. Figure 5 shows the spatial distribution
of oscillatory activity in a single patient in which two independent
electrodes were used. During these recordings the patient had a robust
4-5 Hz resting tremor in both the contralateral hand and foot. The
first STN cell was encountered at 3.2 mm, whereas the last STN cell (a
TC) was found at 1.0 mm. The schematic illustrates the oscillatory behavior of single units and the distances between the pairs of neurons. As indicated by the cross-correlograms and the corresponding coherence function, some pairs of TCs were in phase (e.g., pair 0.6 × 1.1), whereas others were out of phase (e.g., pair 0.2 × 0.0). It can also be seen that the phase relationships between neighboring TCs could be out of phase even at distances as small as 200 µm between neurons (e.g., cells in track 2 at 0.9 and 1.1 mm vs cell
at 0.6 mm in track 1). Furthermore, not all pairs of TCs studied in
this patient were coherent (e.g., pair 1.3 × 1.7). Synchronization between neurons with high-frequency oscillations, in
contrast to TC activity, was always close to 0. The mean phase difference between the high-frequency oscillatory pairs in the two
microelectrode tracks was only 8.7° (±4.4 SE; maximum value is 31 degrees). Differences in coherence values between TCs and high-frequency oscillatory neurons observed in Figure 5 could also be
attributable to differences in sampling time. That is, over a long
sampling time (i.e., pair 1.3 × 1.7 was sampled for 130 sec),
lower coherence values might be obtained for pairs of TCs with a
variable phase relationship. Close inspection of Figure 5 also reveals
that it was possible to detect oscillatory synchrony from the
cross-correlograms even if there was no significant oscillation in the
autocorrelogram of one of the pair of neurons (e.g., pair 1.6 × 1.8, and pair 0.6 × 0.9).
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Figure 5.
The central box shows a
reconstruction of simultaneously recorded neuron pairs from two
microelectrode tracks in a single patient (patient D). Pairs of neurons
are denoted by their location along each track (track
1 × track 2). The meanings of the symbol
shape and shading are indicated at the bottom. The
strength of the high-frequency component is as follows: none = <6, weak = 6-7, strong = 8-10 (see Materials and Methods).
This patient had a 4-5 Hz resting tremor in the hand and foot during
these recordings. The first column of each pair of columns is the
cross-correlogram, and the second column is the corresponding coherence
function (resolution 1.95 Hz; dashed line indicates
significance level) between each pair of neurons. The
numbers at top left of each pair of plots
indicate the depth of the pair of neurons in tracks 1 and 2, respectively. The numbers in parentheses
indicate sampling time in seconds. The numbers beside
each significant peak in the coherence function indicate the phase
difference in degrees.
|
|
| |
DISCUSSION |
The existence of tremor-related activity in the STN in some of the
PD patients in this study supports previous findings by our group and
others (Hutchison et al., 1998; Krack et al., 1998; Rodriguez et al.,
1998). This study provides the first demonstration of neurons with
high-frequency oscillatory activity in the STN of PD patients and
associates the synchronization of these neurons with TC activity and
limb tremor. High-frequency oscillatory activity was better detected
from cross-correlograms or coherence functions than from
autocorrelograms or autospectra, suggesting that high-frequency oscillatory behavior of the STN reflects population synchronization rather than individual neuron behavior. Our study found that the median
discharge rate of cells with no rhythmic discharge was lower (43 Hz)
than that for neurons with rhythmic discharge (53 Hz). This differs
from the findings of Rodriguez et al. (1998), who reported that the
mean firing rate for TCs was 25 and 49 Hz for other neurons. However,
data from the present study are consistent with findings from MPTP
monkeys that indicate that there are differences in the spontaneous
discharge rate of oscillatory versus non-oscillatory STN cells (Bergman
et al., 1994). After MPTP treatment in African green monkeys, there was
an increase in the overall spontaneous discharge of STN neurons from 19 to 26 Hz, whereas tremor-related neurons showed an even more prominent
increase in FR to 35 Hz. In addition, the mean firing rates of
oscillatory neurons was greater than the firing rates of other neurons
in all three parkinsonian monkeys. Our observations support the
hypothesis that the STN is hyperactive in PD patients, especially those
patients with significant limb tremor.
The relationship between oscillatory neural activity and limb tremor
has been explored in various monkey species in which limb tremor is
differentially present after MPTP treatment. In a study by Bergman et
al. (1998b), neuronal oscillations in the GPi were synchronized and
more in phase in tremulous MPTP-treated vervet (African green) monkeys
than in non-tremulous parkinsonian rhesus monkeys (i.e., MPTP-treated
rhesus monkeys display short episodes of 10-16 Hz action
tremor). Parkinsonian African green monkeys have a 3-5 Hz limb tremor
that closely resembles that found in patients with PD. It has also been
demonstrated that the induction of limb tremor in the MPTP African
green monkey model brings about not only low-frequency tremor-related
activity in the STN, but also high-frequency oscillations in the
frequency range of 8-20 Hz (Bergman et al., 1994). The present study
supports these observations and further demonstrates that TCs and cells with high-frequency oscillations in the STN of PD patients discharge in
oscillatory synchrony. One caveat to this study is that the precise
nature of the temporal relationship between limb tremor and
high-frequency synchronization was not ascertained. In some pairs of
STN neurons in the tremor group, the appearance of limb tremor
coincided with high-frequency synchronization, whereas others displayed
increases in oscillatory synchronization when limb tremor was
suppressed (Fig. 3). However, there was a paucity of single neurons
with oscillatory activity and no synchronous oscillations between pairs
of STN neurons in the three patients that did not have significant limb
tremor (45 neuron pairs examined). For the group of nine patients, the
proportion of high-frequency synchronized neuron pairs encountered
during the stereotaxic mapping was correlated to the preoperative UPDRS
tremor score. Together these findings indicate that limb tremor and TC
activity are associated with synchronized high-frequency oscillations.
These results also imply that in those patients with rigidity or
akinesia but little tremor, oscillatory synchronization is not an
underlying factor. That is, different neuronal activity patterns at the
level of the STN are present in PD patients expressing different
clinical features. The present study also demonstrated that in each
patient not all STN TCs were coherent with each other and therefore
supports the hypothesis that there are independent
"tremor-generating" circuits in the basal ganglia (Alberts et al.,
1965; Hurtado et al., 1999; Raethjen et al., 2000). Pairs of TCs were
found to be coherent and out of phase at distances as small as ~250
µm, suggesting that each tremor-generating circuit could occupy a relatively small volume of the STN. Our finding of variability in phase
differences over time between pairs of STN TCs is also consistent with
the hypothesis that parkinsonian tremor is nonstationary (Bergman et
al., 1998b; Hurtado et al., 1999).
The STN plays a central role in basal ganglia circuitry (Alexander and
Crutcher, 1990). In this study, no neuron pairs were found that
displayed a single short-latency peak in the cross-correlogram. This
indicates that oscillatory synchronization is likely not caused by
intranuclear interactions as a result of recurrent collaterals (Kita et
al., 1983) or possible interneurons (Rafols and Fox, 1976), although
the existence of interneurons in the STN remains unclear (Yelnik and
Percheron, 1979; Van Der Kooy and Hattori, 1980; Ryan et al., 1992).
The main difference between neural synchronization that occurred at the
tremor frequency compared with high-frequency synchronization was that
all high-frequency oscillatory activity was consistently in phase and
independent of the distance between recording sites. Pairs of neurons
with high-frequency oscillatory synchronization displayed constant
phase differences over long sampling periods, whereas pairs of TCs did
not. Also, the distribution of high-frequency oscillations was tightly
centered about a frequency that was unique to each patient. These
findings imply that the underlying mechanisms of the two types of
oscillatory synchrony are different. It is likely that the in-phase
high-frequency synchronization observed in the STN of PD patients is
caused by synchronous activity occurring in other areas. Two likely
candidates are the external segment of the globus pallidus (GPe) and
the cerebral cortex, both of which send massive input to the STN
(Carpenter et al., 1981; Canteras et al., 1990). These two areas are
integral to corticostriatal-GPe-STN-GPi ("indirect" pathway) and
cortico-STN-GPi-thalamic circuitry, respectively (Alexander and
Crutcher, 1990).
The STN sends excitatory output to the GPe and also receives GABAergic
input from the GPe, and thus the GPe may provide feedback inhibition to
the STN (Rouzaire-Dubois et al., 1980). It has been shown that the GPe
influences the firing rate and discharge pattern as well as the degree
of correlated firing of adjacent STN neurons in the rat (Ryan et al.,
1992). In a study by Plenz and Kital (1999), evidence from in
vitro rat organotypic brain slices of the STN and the GPe suggests
that together these nuclei form a central pacemaker capable of
sustained synchronous in-phase and out-of-phase oscillations. However,
synchronized oscillations between STN neurons occurred at frequencies
that were significantly lower (<4 Hz) than those reported in this
study, yet it was also demonstrated that a few GPe neurons have
considerable control over synchronized activity in the STN. It is
therefore possible that synchronization could occur in the GPe or the
striatum. It has also been shown that tonically active neurons
(cholinergic interneurons) in the striatum of monkeys display
synchronized high-frequency oscillatory activity (~15 Hz) after the
depletion of dopamine attributable to MPTP treatment (Raz et al.,
1996).
The STN receives a substantial excitatory glutamatergic input from the
cortex (Afsharpour, 1985; Rouzaire-Dubois and Scarnati, 1985), and it
has been shown that neighboring STN neurons share common cortical
inputs (Ryan et al., 1992). Furthermore, the increase in the firing
rates of the STN in 6-OHDA-treated rats is not solely dependent on GPe
(Hassani et al., 1996), suggesting that direct corticosubthalamic
connections could be involved in the pathology of the parkinsonian STN.
The response of the STN to cortical stimulation can be shaped by the
GPe (Ryan and Clark, 1991; Mouroux et al., 1995). The interaction
between the STN and GPe is intimately related to cortical activity, and
rhythmic oscillatory activity in STN-GPe may be driven by cortex
(Magill et al., 2000). Direct cortico-STN input can also modulate the
inhibitory influence of the direct striatonigral pathway on SNr neurons
(Maurice et al., 1999). It is therefore possible that the source of the
overt synchronization of high-frequency activity in the STN of PD
patients with limb tremor is caused by disturbances in cortical
synchrony. The involvement of the cortex in parkinsonian tremor has
been well documented (Parker et al., 1992). Duffau et al. (1996)
showed that during periods of limb tremor in PD patients, there were
increases in the normalized regional cerebral blood flow in areas that
were also modulated by voluntary repetitive arm movements. In patients with PD, cortical tremor-related network oscillations have been observed using magnetoencephalography (Volkmann et al., 1996) and
electroencephalography (Alberts et al., 1969). Disturbances in cortical
synchronization of parkinsonian patients at frequencies other than limb
tremor frequencies have also been reported (Makela et al., 1993;
Neufeld et al., 1994; Brown and Marsden, 1999). These disturbances are
hypothesized to result from the inability of the parkinsonian basal
ganglia to release cortical elements from low-frequency "idling"
rhythms, such as (~10 Hz) and  (15-30 Hz), and allow for
synchronization in the  range (30-50 Hz) (Brown and Marsden,
1998).
In summary, we have demonstrated that highly synchronous in-phase
oscillatory activity is present in the STN of PD patients with
tremor-predominant symptoms. Synchronized high-frequency activity in
the STN is likely involved in the pathophysiology of PD tremor and
might in itself contribute to the expression of limb tremor.
| |
FOOTNOTES |
Received March 24, 2000; revised Aug. 1, 2000; accepted Aug. 2, 2000.
This work was funded by National Institutes of Health and the
Parkinson's Foundation of Canada. We thank Dr. H. Kwan and Dr. W. Mackay for their helpful suggestions and comments. We gratefully acknowledge Axon Instruments for providing some of the
electrophysiological equipment used in this study.
Correspondence should be addressed to Jonathan O. Dostrovsky,
Department of Physiology, Room 3305, Medical Sciences Building, 1 Kings
College Circle, University of Toronto, Toronto, Ontario, Canada M5S
1A8. E-mail: j.dostrovsky{at}utoronto.ca.
| |
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TOP
ABSTRACT
INTRODUCTION
