Effects of subthalamic nucleus stimulation and medication on resting and postural tremor in Parkinson’s disease
Molly M. Sturman,1 David E. Vaillancourt,1 Leo Verhagen Metman,4,5 Roy A. E. Bakay4,5 and Daniel M. Corcos1–4
Correspondence to: Molly M. Sturman, Department of
Movement Sciences (M/C 994), College of Applied Health
Sciences, University of Illinois at Chicago, 808 S. Wood
Street, 690 CME, Chicago, IL 60612, USA
E-mail: msturm3@uic.edu
Departments of 4Neurological Sciences and 5Neurosurgery,
Rush Presbyterian-St Luke’s Medical Center, Chicago,
IL, USA
(STN) and antiparkinsonian medication have proved to be
effective treatments for tremor in Parkinson’s disease. To
date it is not known how and to what extent STN DBS alone
and in combination with antiparkinsonian medication alters the pathophysiology of resting and postural tremor
in idiopathic Parkinson’s disease. The purpose of this study
was to examine the effects of STN DBS and antiparkinso-
nian medication on the neurophysiological characteristics
of resting and postural hand tremor in Parkinson’s disease.
Resting and postural hand tremor were recorded using
accelerometry and surface electromyography (EMG)
from 10 Parkinson’s disease patients and 10 matched con- trol subjects. The Parkinson’s disease subjects were exam-
ined under four treatment conditions: (i) off treatment;
(ii) STN DBS; (iii) medication; and (iv) medication plus
STN DBS. The amplitude, EMG frequency, regularity,
and 1–8 Hz tremor–EMG coherence were analysed.
Both STN DBS and medication reduced the amplitude,
regularity and tremor–EMG coherence, and increased the EMG frequency of resting and postural tremor in
Parkinson’s disease. STN DBS was more effective than
medication in reducing the amplitude and increasing the
frequency of resting and postural tremor to healthy phy-
siological levels. These findings provide strong evidence
that effective STN DBS normalizes the amplitude and fre-
quency of tremor. The findings suggest that neural activity
in the STN is an important modulator of the neural network(s) responsible for both resting and postural
tremor genesis in Parkinson’s disease.
Keywords: tremor; Parkinson’s disease; deep brain stimulation; subthalamic nucleus
Abbreviations: ANOVA = analysis of variance; ApEn = approximate entropy; DBS = deep-brain stimulation; RMS = root mean
square; STN = subthalamic nucleus; UPDRS = Unified Parkinson’s Disease Rating Scale; VIM = Ventral intermediate
Received March 31, 2004. Revised May 6, 2004. Accepted May 13, 2004. Advanced Access publication July 7, 2004
Introduction Tremor is one of three cardinal signs of idiopathic Parkinson’s
disease, and individuals with the disease often exhibit both
resting and postural tremor (Deuschl et al., 1998). Tremor in
either form can be a debilitating neurological symptom because
its presence severely disrupts activities of daily living, espe-
cially self-care tasks (Wasielewski et al., 1998). Deep brain
stimulation (DBS) of the subthalamic nucleus (STN) (Deep
Brain Stimulation for Parkinson’s Disease Study Group, 2001;
Benabid, 2003; Krack et al., 2003) and antiparkinsonian med-
ication (Cotzias et al., 1969; Yahr et al., 1969) are effective
treatments for Parkinson’s disease. The extent to which STN
DBS and medication change the neurophysiology of bradyki-
nesia (Vaillancourt et al., 2004), gait (Faist et al., 2001; Bastian
et al., 2003) and postural instability (Maurer et al., 2003) in
Parkinson’s disease to healthy levels have been established.
While STN DBS and medication reduce tremor rating scales
(Olanow et al., 1991; Friedman et al., 1997; Krack et al., 1998;
Rodriguez et al., 1998), it is not currently known how or to what
extent STN DBS alters the pathophysiology of resting and
postural tremor in Parkinson’s disease.
Previous research has used multiple dependent measures
to study the neurophysiological mechanisms of tremor in
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Parkinson’s disease. These measures include frequency
(Homberg et al., 1987), amplitude (Stiles and Pozos, 1976),
regularity (Vaillancourt and Newell, 2000) and tremor–
electromyogram (EMG) coherence (Brown et al., 1997;
Vaillancourt and Newell, 2000). In contrast to the 8–12 Hz
frequency of healthy physiological tremor (Halliday and
Redfearn, 1956; Lakie et al., 1986), the frequency of resting
and postural tremor inParkinson’sdisease is reduced to3–6 and
4–12 Hz, respectively (Findley et al., 1981; Elble and Koller,
1990;Deuschletal., 1998).There isanegativerelationbetween
the frequency and amplitude of tremor oscillations, such that if
the frequency decreases the amplitude increases (Stiles and
Pozos, 1976). The degree of rhythmicity in tremor, assessed
using approximate entropy (ApEn) (Pincus and Goldberger,
1994), is greater and more regular in patients with Parkinson’s
disease compared with healthy control subjects (Vaillancourt
and Newell, 2000). In addition, the amount of squared correla-
tion between the tremor and EMG signals (tremor–EMG coher-
ence) in patients with Parkinson’s disease is increased in the
low-frequency bands (Vaillancourt and Newell, 2000).
The purpose of this study was to examine the effects of
therapeutic doses of medication and STN DBS on the neuro-
physiological characteristics of resting and postural hand
tremor in patients with idiopathic Parkinson’s disease. The
study had three main objectives. First, we examined whether
STN DBS and medication reduced resting and postural tremor
amplitude, regularity and tremor–EMG coherence, and
whether the treatments increased resting and postural tremor
EMG frequency. Secondly, the study directly compared the
effects of STN DBS with those of medication on the neuro-
physiology of resting and postural tremor. The third objective
was to determine the extent to which STN DBS alone, medica-
tion alone, or the combination of STN DBS and medication
altered the neural control of resting and postural tremor to
healthy physiological levels. Ten individuals diagnosed with
Parkinson’s disease who received STN DBS participated in the
study. The patients’ hand tremor data were compared with data
fromneurologicallyhealthycontrolsubjectswhowerematched
according to age and gender. Patients were tested in four treat-
ment conditions: (i) off treatment; (ii) STN DBS; (iii) medica-
tion; and (iv) medication plus STN DBS. Each patient and
control subject was examined during resting and postural
hand tremor conditions. The findings from this study establish
neurophysiological correlates underlying the clinical efficacy
of medication and STN DBS in the treatment of resting and
postural hand tremor in Parkinson’s disease. Furthermore, the
first evidence is presented on whether STN DBS and/or
medication restore the neurophysiology of tremor to healthy
physiological levels.
Methods Subjects Ten patients with Parkinson’s disease, aged 52.9 years (SD = 8.03),
and 10 age- and gender-matched control subjects, aged 52.7 years
(8.26), participated in the study. A paired t test confirmed that there
were no statistically significant differences in age between the patient
and control groups. All clinical and motor control evaluations for all of
the patients were performed an average of 6.7 months after surgery and
after optimization of DBS parameters had occurred. A priori inclusion
criteria were established for the study, and the first 10 Parkinson’s
disease patients who received STN DBS and met the criteria were
chosen for the study. Patients were examined by a movement disorders
neurologist and included in the study if they: (i) had idiopathic
Parkinson’s disease as outlined by the Parkinson’s Disease Society
Brain Bank diagnostic criteria (Hughes et al., 1992a, b); (ii) were
deemed to have resting and/or postural tremor which was consistent
with the Movement Disorders Consensus Statement on Tremor Type I
or Type II classification (Deuschl et al., 1998); (iii) had a resting and/or
postural tremor which both responded positively to levodopa therapy;
and (iv) had a positive clinical improvement [greater than a 15%
reduction in scores from the entire motor section of the Unified
Parkinson’s Disease Rating Scale (UPDRS)] from the off-treatment
condition compared with the on STN DBS condition. All subjects gave
informed consent to all experimental procedures, which were
approved by the local institutional review board at The University
of Illinois at Chicago, USA.
In all cases a quadripolar stimulation electrode was placed in the
STN opposite to the most severely affected body side. Surgery was
performed as part of clinical care according to standard procedures
(Deep Brain Stimulation for Parkinson’s Disease Study Group, 2001;
Starr et al., 1998). Briefly, the anatomical target was based on standard
stereotactic coordinates while the patient was in the MRI scanner with
a Leksell stereotactic head frame in place (Cohn et al., 1998). MRI
images were subsequently reformatted and coordinates refined using a
Stealth system. Intra-operatively, microelectrode penetrations were
made through a burr hole to verify the neurophysiological target (Starr
et al., 1998, 2000; Vitek et al., 1998). Responses to sensory stimuli
(passive movements of upper and lower limbs) were sought to identify
the sensorimotor portion of the STN, where the DBS lead was sub-
sequently placed. Postoperatively, MRI demonstrated appropriate
placement of the DBS lead.
The same movement disorders neurologist administered the entire
motor section of the UPDRS to each patient before (pre) and after
(post) surgery, and these scores are reported bilaterally. Following
surgery, stimulation parameters were optimized in order to reduce
presurgery scores on the motor section of the UPDRS. Optimization
took place during several visits over the ensuing months. At the time of
the experiments, ineach case the pulse width and frequency were 60ms
and 185 Hz, respectively. The stimulation intensity varied from 1.8 to
3.1 V (mean = 2.26 V, SD = 0.42), and stimulation was delivered in a
monopolar fashion (Table 1).
12.90) off medication. Average postsurgical UPDRS scores were
37.85 (11.88) off treatment, 14.2 (10.42) on medication, 24.17
(11.51) on STN DBS, and 10.75 (8.98) on medication plus STN
DBS. Presurgery UPDRS scores were significantly different from
postsurgery off-treatment scores using a Wilcoxon matched pairs
test (Z = 2.29, P < 0.05).
Experimental setup The experiments for the patients were performed on two consecutive
days in each of four treatment conditions: (i) off treatment; (ii) STN
DBS; (iii) medication; and (iv) medication plus STN DBS. Examina-
tion of Figs 1–6 does not show trends in the data, suggesting that test
order was not a limitation in the study. On day 1, testing of condition 1
took place between 9 and 11 a.m. and condition 2 occurred between 1
and 3 p.m. On day 2, the same testing schedule as day 1 was set for
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conditions 3 and 4, respectively. The control subjects were tested on
one day. To ensure that each Parkinson’s disease patient was in the
operationally defined off state, patients were always tested in the off
condition following 12 h without the specific treatment (Langston
et al., 1992). For instance, the night prior to day 1 both treatments
were withheld, and the night prior to day 2 only STN DBS was with-
held. Each patient stayed in a hotel close to the laboratory and was
examined using a Medtronic Console Programmer (Model 7432
Minneapolis, Minnisota, USA) on each night prior to days 1 and 2
to make certain that the stimulator was off.
To ensure that each patient was on STN DBS, the motor section of
the UPDRS was administered 90 min after activation of the stimulator.
All patients had reduced UPDRS values 90 min following reactivation
of the stimulator. The patients’ normal medication dose schedule was
restarted on day 1 after tremor testing was completed. For all patients,
resumption of optimal levodopa therapy began at 3 p.m. on day 1 and
continued through day 2 of testing. On day 2, all patients took medica-
tion between 6 and 7 a.m. and then again at 9 a.m. Forty-five minutes
after the 9 a.m. dose, the motor section of the UPDRS was adminis-
tered to ensure that medication efficacy was optimized. All patients
responded to levodopa therapy, so tremor testing proceeded 50 min
after administration of the 9 a.m. levodopa dose. For the afternoon
session on day 2, patients took medication at 12:30 p.m., and the same
protocol for the morning session was followed. For all patients in this
study, the afternoon tremor testing commenced 50 min later. At each
dose, patients took the medications listed in Table 1.
Tremor testing Subjects were positioned in a 42 cm high straight-back chair with an
arm that was 43 cm in length and 58 cm from the ground. The arm of
the chair supported the subject’s forearm, with the ulnar styloid
process aligned with the end of the chair. The elbow joint was flexed
to approximately 90, the shoulder joint was slightly abducted, and the
forearm was pronated. A small table was positioned 30 cm in front of
the subject. The height of the table was adjusted to be level with the tip
of the subject’s hand when the wrist and fingers were extended parallel
with the floor. The table served as the visual target to enable the subject
to maintain the wrist in a neutral position. The width of the table edge
was 0.5 inches.
A calibrated Coulbourn type V 94–41 (Allen town Pennsylvania,
USA) miniature solid-state piezoresistive accelerometer was taped
to the hand (2 cm proximal to the middle of the second meta-
carpophalangeal joint). A Coulbourn Lab Linc V System V72-25A
resistive bridge strain gauge transducer with an excitation voltage
of 65 V amplified the acceleration signal. The accelerometer’s
resolution was 0.01 m/s2, and a 12-bit analogue–digital converter
sampled the signal at 1000 samples per second. To remove the DC
effects of gravity, all accelerometry data were collected in AC
mode with a 1 Hz analogue high-pass filter (Elble and Koller,
1990).
Surface EMG was used to measure the neuromuscular activity in
the extensor digitorum and the flexor digitorum superficialis. Elec-
trode placement was determined by muscle palpation during active
finger extension and flexion with the wrist in a neutral, extended
position. The EMG signal was amplified (gain = 1000) and band-
pass-filtered between 20 and 450 Hz (Delsys, Boston, MA, USA).
The study examined two types of tremor. In the resting tremor
condition, subjects were instructed to relax their forearm and hand
muscles and allow the wrist to dangle unsupported over the edge of the
supportive surface for 30 s (Marsden et al., 1969; Burne et al., 1984;
Table 1 Profile of each subject
Subject Age (years)
Deep brain stimulation parameters Item 21
Anti-parkinsonian medications
1 43 F 3 3 2.8 Monopolar: 0 Cþ Carbidopa/levodopa 25/100 0.5 tab 2 49 F 0 1 2.6 Monopolar: 1 Cþ Carbidopa/levodopa 25/100 0.5 tab
Pergolide 2 mg 1 tab Amantadine 100 mg 1 tab
3 53 F 3 2 2.0 Monopolar: 1 Cþ Carbidopa/levodopa 25/100 1 tab 4 63 F 3 3 2.2 Monopolar: 0 Cþ Carbidopa/levodopa CR 50/200 1 tab
Carbidopa/levodopa 25/100 1 tab Amantadine 100 mg 1 tab
5 65 F 3 3 1.8 Monopolar: 2 Cþ Carbidopa/levodopa CR 25/100 1 tab Pramipexole 1.5 mg 1 tab
6 46 M 3 2 2.1 Monopolar: 1 Cþ Carbidopa/levodopa 25/100 3 tabs Pramipexole 1 mg 3 tabs
7 47 M 1 1 2.0 Monopolar: 1 Cþ Carbidopa/levodopa 25/100 1.5 tab 8 47 M 3 3 2.0 Monopolar: 1 Cþ Carbidopa/levodopa CR 50/200 1 tab
Carbidopa/levodopa 25/100 1 tab Pergolide 1 mg 1 tab Amantadine 100 mg 1 tab
9 53 M 0 1 2.0 Monopolar: 1 Cþ Carbidopa/levodopa 25/100 2 tabs Ropinirole 5 mg 2 tabs Amantadine 100 mg 1 tab Entacapone 200 mg 2 tabs
10 63 M 3 0 3.1 Monopolar: 0 Cþ Carbidopa/levodopa CR 50/200 1.5 tab Carbidopa/levodopa 25/100 1 tab Entacapone 200 mg 1 tab Pergolide 1 mg 1 tab
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Henderson et al., 1994; Raethjen et al., 2000). In the postural tremor
condition, subjects were asked to maintain their wrist and hand in a
neutral, extended position while keeping it level with the target for 30 s
(Elble and Randall, 1976; Homberg et al., 1987; Henderson et al.,
1994; Raethjen et al., 2000). Subjects performed three trials at each
respective condition and were explicitly instructed throughout each
trial not to suppress resting or postural tremor.
Data analysis Before performing all data analyses, the acceleration and EMG data
were conditioned by the following methods. The EMG data were
digitally rectified, and the acceleration and EMG data were
downsampled to 200 Hz (Vaillancourt and Newell, 2000). The accel-
eration and EMG data were digitally filtered using a fourth-order
Butterworth filter with a low-pass cutoff frequency of 60 Hz for
the EMG signals and 30 Hz for the acceleration signals. All data
analyses were performed on the entire 30 s data segment—the
same for each subject, trial, and condition. The dependent measures
were averaged across the three trials for each condition. All data
processing and subsequent time and frequency analyses were
performed using software written in Matlab (MathWorks, Natick,
MA, USA).
Amplitude and regularity of tremor The amplitude and regularity of hand tremor were quantified in the
same way as in our study of essential tremor (Vaillancourt et al., 2003).
The amplitude of tremor was calculated using a method in which
spectral analysis is used to extract the root mean square (RMS) tremor
displacement from the dominant frequency of tremor (Stiles, 1976).
The RMS displacement is obtained as if it had resulted from a single-
frequency, periodic oscillation. This assumption is reasonable when
examining hand tremor because the 5–10 Hz peak dominates the
spectrum (Elble and Koller, 1990). First, the spectrum of the tremor
acceleration is calculated. Secondly, the sum of the central three
spectral values of the principal band from the spectrum is taken as
the variance of the tremor oscillations at the dominant frequency ( f ).
Thirdly, the RMS acceleration at this frequency ( f ) was obtained as
the square root of this sum and then converted to units of displacement
by dividing by the square of v (v = 2f ). The RMS displacement value
is reported in centimetres.
The degree of rhythmicity or regularity of hand tremor was
calculated using approximate entropy (ApEn), a measure of the
time-dependent structure of the signal (Pincus, 1991). ApEn returns
a value in the approximate range of 0–2, and it reflects the
predictability of future values in a time series based on previous
values. For example, a sine wave has accurate short- and long-term
predictability, and this corresponds to an ApEn value near 0.
If varying amplitudes of white Gaussian noise are added to a
sine wave, then the ApEn value will increase. This increases
the uncertainty of making future time series predictions when ran-
dom elements are added. For a completely random signal (viz.,
white Gaussian noise), each future value in the time series is
independent and unpredictable from previous values, and the
ApEn value tends towards 2. Because ApEn is influenced by filter-
ing characteristics, data length, and other factors (Pincus and
Goldberger, 1994), the same algorithm and parameter settings
(m = 2; r = 0.2 SD of the signal) were used to be consistent
with previous work (Pincus and Goldberger, 1994; Vaillancourt
et al., 2003).
Coherence between acceleration and extensor EMG activity The coherence between the acceleration and EMG signals estimates
the degree of motor unit entrainment affecting the acceleration signal
(Elble and Randall, 1976). The cross-spectrum was calculated using
Welch’s averaged periodogram method (bin width = 0.7813 Hz).
Coherence between the acceleration and extensor EMG signals
(tremor–EMG coherence) was calculated, and a 95% confidence
interval was determined based on the number of disjoint sections
from the sample record (Rosenberg et al., 1989; Farmer et al.,
1993). This method revealed a broad band of significant coherence.
Next, we determined the peak coherence value in the coherence spec-
trum in the 1–8, 9–15, 15–30 and 35–50 Hz bins.
Frequency The dominant frequency in the EMG spectrum recorded during
resting and postural hand tremor was examined using autospectral
analysis of the extensor EMG signal between 3 and 15 Hz.
Statistical analysis The dependent variables described in the preceding sections were
evaluated by analysis of variance (ANOVA). First the effects of med-
ication and STN DBS on tremor were evaluated using a three-way
ANOVA: medication (off versus on) STN DBS (off versus on) tremor type (resting versus postural). Secondly, a direct comparison
between medication and STN DBS was performed using a one-way
ANOVA: treatment (on medication versus on STN DBS). Thirdly, a
comparison of each treatment alone and the combination of both
treatments with healthy tremor was performed using a two-way
ANOVA: group (Parkinson’s disease versus control) by tremor
type (resting versus postural).
using a non-parametric Wilcoxon matched pairs test. Postsurgical,
off-treatment, unilateral UPDRS hand tremor scores (Table 1) were
compared with scores on medication, STN DBS, and medication plus
STN DBS. UPDRS hand tremor scores were considered unilaterally
because patients received unilateral STN DBS, and the dependent
measures quantified hand tremor unilaterally. All statistical analyses
were interpreted as significant when there was no more than a 5%
chance of making a type I error. For important statistical comparisons,
we wanted to protect against making a type II error. Therefore, addi-
tional power analyses were conducted for non-significant findings
when comparing between medication and STN DBS, and comparing
between each treatment and control subjects. The results from this
power analysis are reported after the F values in two ways. Both the
percentage of power in the current study with the current sample size
and the sample size required to achieve 90% power are reported. All
statistical analyses were completed using Statistica (StatSoft, Tulsa,
OK, USA).
Results Clinical effects All 10 patients demonstrated positive clinical benefits from
either medication or STN DBS. Postsurgical, unilateral
UPDRS resting hand tremor scores (item 20) averaged
across subjects were 2.2 (SD = 1.32) off treatment, 1.4
(1.26) on medication, 0.80 (0.92) on STN DBS, and 0 (0)
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on medication plus STN DBS. Compared with off treatment,
medication (Z = 2.2, P < 0.05), STN DBS (Z = 2.37, P <
0.01) and medication plus STN DBS (Z = 2.52, P < 0.01)
reduced unilateral hand tremor UPDRS scores for item 20.
For postural tremor (item 21), the average postsurgical uni-
lateral hand tremor UPDRS scores were 1.90 (1.10) off
treatment, 1.1 (1.10) on medication, 1.1 (0.99) on STN
DBS, and 0.2 (0.42) on medication plus STN DBS.
Compared with off treatment, medication (Z = 2.37,
P < 0.01), STN DBS (Z = 2.03, P < 0.05) and the combina-
tion of medication plus STN DBS (Z = 2.52, P < 0.01)
reduced postsurgical unilateral postural hand tremor
UPDRS scores. Furthermore, patient reports concurred
with UPDRS scores that both treatments reduced the amount
of tremor experienced by the patients.
Characterization of resting and postural tremor in individual subjects Figure 1 depicts acceleration, extensor EMG and flexor EMG
signals from a patient with Parkinson’s disease (Case 6,
Table 1) and a control subject during the resting tremor con-
dition. Off treatment (Fig. 1A), the Parkinson’s disease subject
had a high-amplitude tremor (RMS = 11.05 cm) with a high
degree of regularity, which corresponded to a low ApEn value
equal to 0.50. The EMG revealed the pattern characteristic of
Parkinson’s disease resting tremor—alternating bursts of
flexor and extensor EMG activity. In Fig. 1B, medication
decreased the amplitude of tremor to 1.33 cm and increased
ApEn to 0.52. On STN DBS (Fig. 1C), the amplitude of the
tremor also decreased to 0.03 cm and ApEn increased to 0.60.
Resting physiological tremor data collected from a represen-
tative control subject (Fig. 1D) had a minute amplitude of
0.008 cm and ApEn equal to 0.66. In contrast to the bursting
Fig. 1 Resting tremor acceleration, extensor EMG and flexor EMG of a patient with Parkinson’s disease off treatment, on medication and on STN DBS, and a control subject. (A) The Parkinson’s disease subject off treatment. (B) The same subject on medication. (C) The same subject on STN DBS. (D) The control subject. The time series shows a 2 s recording during the same time period from the 30 s trial. The units for the y axis of the extensor EMG are in millivolts (mV) and the units for the acceleration y axis are in m/s2.
Fig. 2 Acceleration, extensor EMG and flexor EMG during postural tremor of a patient with Parkinson’s disease off treatment, on medication, on STN DBS, and a control subject. The recording status in A–D is the same as in Fig. 1A–D.
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EMG pattern in Fig. 1A, the EMGs depicted in Fig. 1B–D show
a small, evenly dispersed amount of EMG activity consistent
with a resting limb state.
Figure 2 shows time series data from the postural tremor
condition. Off treatment (Fig. 2A), the Parkinson’s disease
patient (Case 3, Table 1) had a high-amplitude tremor of
18.95 cm with ApEn equal to 0.46. Similar to resting
tremor, postural tremor for the Parkinson’s disease patient
off treatment presented with alternating bursts of flexor and
extensor EMG activity. Medication (Fig. 2B) reduced the
amplitude of postural tremor to 1.32 cm and increased
ApEn to 0.58. STN DBS (Fig. 2C) reduced the amplitude of
Fig. 3 Resting and postural tremor amplitude of the Parkinson’s disease patients (n = 10) off medication (closed hexagons), patients on medication (open triangles) and control subjects (n = 10) (closed squares). Each value was averaged across subjects (mean 6 SE) under each treatment condition during resting and postural tremor. (A) RMS displacement amplitude (cm) measured from the acceleration signal and converted to displacement units (Stiles, 1976) for resting tremor. (B) RMS displacement for postural tremor. Refer to text for significant differences.
Fig. 4 Resting and postural tremor regularity of the Parkinson’s disease patients (n = 10) off medication (closed hexagons), patients on medication (open triangles) and control subjects (n = 10) (closed squares). Each value was averaged across subjects (mean 6 SE) under each treatment condition during resting and postural tremor. (A) Regularity of the acceleration signal quantified with ApEn for resting tremor. (B) Regularity (ApEn) for postural tremor. Refer to text for significant differences.
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postural tremor to 0.18 cm and increased ApEn to 0.63. Both
treatments reduced the prominent alternating bursts of EMG
activity that occurred off treatment. In Fig. 2D
the representative control subject’s postural tremor had an
amplitude of 0.03 cm. The control subject’s physiological
postural tremor had an ApEn value of 0.76, which was higher
than the value for the Parkinson’s disease patient on each
treatment independently or in combination.
Fig. 5 Resting and postural tremor EMG frequency for Parkinson’s disease patients (n = 10) and control subjects (n = 10), off medication (closed hexagons), on medication (open triangles) and control subjects (closed squares). (A) EMG spectrum for resting tremor from a Parkinson’s disease patient off treatment. (B) EMG spectrum for postural tremor from the Parkinson’s disease patient shown in A off treatment. (C) EMG spectrum for resting tremor from the Parkinson’s disease patient shown in A on STN DBS. (D) EMG spectrum for postural tremor from the Parkinson’s disease patient shown in A on STN DBS. (E) Resting tremor EMG frequency averaged across subjects (mean 6 SE). (F) Postural tremor EMG frequency averaged across subjects (mean 6 SE). Refer to text for significant differences.
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Amplitude of tremor Effects of medication and STN DBS Figure 3A and B depict across-subject average RMS displace-
ments for resting and postural tremor from Parkinson’s disease
patients and control subjects. The within-subject ANOVA
revealed that postural tremor displacement was greater than
resting tremor displacement for the Parkinson’s disease sub-
jects [F(1,9) = 5.76, P < 0.05]. There was no interaction
between medication and/or STN DBS and tremor type. How-
ever, there was a significant interaction between medication
and STN DBS [F(1,9) = 9.59, P < 0.01]. Because of the inter-
action, one-way ANOVAs were conducted on the medication
and STN DBS data separately. Medication significantly
reduced displacement when patients were off STN DBS
[F(1,9) = 10.80, P < 0.01]. Medication did not affect displace-
ment when patients were on STN DBS [F(1,9) = 1.42, P = 0.26,
10%, n = 168]. STN DBS reduced displacement when patients
were either off medication [F(1,9) = 13.02, P < 0.01] or on
medication [F(1,9) = 7.15, P < 0.05].
In order to determine directly which of the two treatments
was more efficacious, tremor amplitude of Parkinson’s disease
patients on medication was compared with amplitude on STN
DBS. STN DBS reduced tremor amplitude below that of med-
ication [F(1,9) = 6.71, P < 0.05]. These results show that each
treatment reduces tremor, but that STN DBS is more effective
than medication for tremor amplitude reduction.
Fig. 6 Resting and postural 1-8 Hz tremor-EMG coherence between the acceleration and extensor EMG of Parkinson’s disease patients (n = 10) and control subjects (n = 10), patients off medication (closed hexagons), patients on medication (open triangles) and control subjects (closed squares). (A) Resting tremor–EMG coherence from a Parkinson’s disease patient off treatment (dotted line) and on STN DBS (solid line). (B) Postural tremor–EMG coherence from the same Parkinson’s disease patient shown in A off treatment and on STN DBS. (C) Resting tremor–EMG coherence averaged across subjects (mean 6 SE). (D) Postural tremor–EMG coherence averaged across subjects (mean 6 SE). The thick dotted line in A and B is the 95% confidence line for significant coherence. Refer to text for significant differences.
2138 M. M. Sturman et al.
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ic.oup.com /brain/article-abstract/127/9/2131/313153 by guest on 14 April 2019
Comparison of each treatment with controls Figure 3A and B also illustrate that resting and postural tremor
amplitude for control subjects was similar to Parkinson’s dis-
ease patients when on STN DBS [F(1,18) = 1.51, P = 0.23, 9%,
n = 272] alone, and under the combination of medication plus
STN DBS [F(1,18) = 3.37, P = 0.08, 11%, n = 108]. However,
patients in the medication-alone condition had greater tremor
amplitude compared with control subjects [F(1,18) = 7.15, P <
0.01]. The results from the three between-group ANOVAs
showed non-significant interactions between group and tremor
type, and non-significant main effects for tremor type. These
findings demonstrate that only STN DBS normalized the
amplitude of tremor.
Approximate entropy of tremor Effects of medication and STN DBS Figure 4A and B and statistical analysis revealed that medica-
tion [F(1,9) = 15.45, P < 0.01] and STN DBS [F(1,9) = 15.04,
P < 0.01] increased ApEn (reduced regularity) during resting
and postural tremor conditions. There were no differences in
ApEn between resting and postural tremor, and no significant
interactions with the treatment conditions. Furthermore, there
was no difference between the medication alone and STN DBS
alone conditions [F(1,9) = 0.00, P = 0.99, 9%, n = 250]. These
findings show that medication and STN DBS equally reduce
the regularity of tremor.
Comparison of each treatment with controls When comparing Parkinson’s disease patients under each
treatment condition with control subjects, Parkinson’s disease
patients always had lower ApEn values (Fig. 4A and B)
[medication alone, F(1,18) = 9.29, P < 0.01; STN DBS
alone, F(1,18) = 11.53, P < 0.01; medicationþ STN DBS,
F(1,18) = 6.52, P < 0.01]. For each of the three between
group comparisons, there was a main effect of tremor type
(P values < 0.05), with ApEn values greater for postural tremor
than for resting tremor. These analyses show that the tremor of
Parkinson’s disease patients is still more regular than that of
control subjects regardless of treatment interventions.
Frequency of tremor Effects of medication and STN DBS Figure 5A and C depict the EMG spectrum during resting
tremor from a representative Parkinson’s disease patient
(Case 8, Table 1) off treatment and on STN DBS. Figure 5B
and D show the EMG spectrum during postural tremor from the
same Parkinson’s disease patient off treatment and on STN
DBS. In the off-treatment condition (Fig. 5A and B), the peak
frequency in the EMG spectrums is below 10 Hz, and there is
high peak power in the spectrum in the low peak frequency
range. In the on STN DBS condition, the peak frequency in the
EMG spectrum is at a greater frequency (10 Hz), and the
amount of power in the spectrum is reduced for both resting
(Fig. 5C) and postural (Fig. 5D) tremor.
The statistical analysis resulted in a main effect for medica-
tion [F(1,9) = 10.48, P < 0.01] and STN DBS [F(1,9) = 19.17,
P < 0.01] on resting and postural tremor EMG frequency
(Fig. 5E and F). There was also a main effect of tremor type
[F(1,9) = 14.05, P < 0.01]. Figure 5E and F present group data,
which show that postural tremor EMG frequency is greater than
resting tremor EMG frequency. There were no significant inter-
actions between treatment condition and tremor type. When
directly comparing the two treatments, Fig. 5E and F and the
statistical analysis show that Parkinson’s disease patients
on STN DBS had greater EMG frequencies compared with
the on-medication condition [F(1,9) = 9.28, P < 0.01]. Thus,
both medication and STN DBS increased tremor frequency, yet
STN DBS had a greater effect on frequency than medication.
Comparison of each treatment with healthy controls Figure 5E and F present mean EMG frequencies from healthy
subjects for resting tremor and postural tremor. Patients on
medication alone had lower EMG frequencies than healthy
subjects [F(1,18) = 23.65, P < 0.01]. However, EMG frequen-
cies of Parkinson’s disease patients on STN DBS alone
[F(1,18) = 2.72, P = 0.12, 12%, n = 102] and the combination
of medication plus STN DBS [F(1,18) = 2.81, P = 0.11, 12%,
n = 105] were statistically indistinguishable from those of
control subjects. For each of the three between-group compar-
isons there was a main effect of tremor type (P values < 0.01),
such that postural tremor EMG frequency was greater than
resting tremor EMG frequency. In summary, STN DBS was
the only treatment that normalized tremor EMG frequency.
Tremor–EMG coherence Effects of medication and STN DBS Figure 6A depicts resting tremor from a Parkinson’s disease
patient (Case 4, Table 1) showing a reduction in 1–8 Hz resting
tremor–EMG coherence from 0.70 to 0.32 as a result of STN
DBS. Similarly, in the same patient during postural tremor,
STN DBS (Fig. 6B) decreased tremor–EMG coherence in the
1–8 Hz bin from 0.75 to 0.42. We also examined resting and
postural tremor–EMG coherence between 9 and 15 Hz, 15 and
30 Hz, and 35 and 50 Hz using exactly the same methods as
described for the 1–8 Hz bin (see Method’s section: Coherence
between acceleration and extension EMG activity). However,
we did not find statistically significant differences between
treatment conditions in these higher frequency bins.
Figure 6C and D depict across subject average resting and
postural tremor–EMG coherence for Parkinson’s disease
patients and control subjects. From the within-subject
ANOVA, there was no effect of tremor type on tremor–
EMG coherence, and no interactions between the treatments
and tremor type. Conversely, there was a significant interaction
between medication and STN DBS [F(1,9) = 5.12, P < 0.05].
Due to this interaction, one-way ANOVAs were conducted on
the medication and STN DBS data separately. STN DBS
reduced tremor–EMG coherence both when patients were
Effects of STN DBS/medication on tremor in PD 2139
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off medication [F(1,9) = 23.42, P < 0.01] and when they were
on medication [F(1,9) = 6.42, P < 0.05]. Medication also sig-
nificantly reduced tremor–EMG coherence when patients were
off STN DBS [F(1,9) = 10.48, P < 0.01]. However, when
patients were on STN DBS the addition of medication did
not affect tremor–EMG coherence [F(1,9) = 0.87, P = 0.37,
9%, n = 150]. Finally, when medication and STN DBS were
compared directly, tremor–EMG coherence for the STN DBS
condition was lower than for the medication condition, yet the
analysis did not reach statistical significance [F(1,9) = 3.61, P =
0.09, 29%, n = 41]. In summary, medication and STN DBS
reduced tremor–EMG coherence compared with off treatment,
but only STN DBS provided additional reductions in coherence
when on medication.
Comparison of each treatment with healthy controls Mean resting (Fig. 6C) and postural (Fig. 6D) tremor–EMG
coherence for control subjects was lower than tremor–EMG
coherence for patients in each treatment condition. The statis-
tical analysis confirmed the observation from Fig. 6C and D.
Medication [F(1,18) = 15.10, P < 0.01], STN DBS [F(1,18) =
5.80, P < 0.05] and the combination of medication plus STN
DBS [F(1,18) = 7.85, P < 0.01] did not reduce tremor–EMG
coherence in Parkinson’s disease patients to healthy physio-
logical levels. The results from the three between-group
ANOVAs also showed non-significant interactions between
group and tremor type, and non-significant main effects for
tremor type. These analyses demonstrate that the treatment
interventions did not normalize tremor–EMG coherence.
Discussion The purpose of this study was to examine the effects of ther-
apeutic doses of medication and STN DBS on the neurophy-
siological characteristics of resting and postural hand tremor in
patients with Parkinson’s disease. Consistent with previous
work on essential tremor (Vaillancourt et al., 2003), the tremor
amplitude, regularity, tremor–EMG coherence and EMG fre-
quency were quantified. There were three important findings
from this study. First, medication and STN DBS reduced rest-
ing and postural tremor amplitude, regularity and tremor–
EMG coherence while increasing tremor frequency. Secondly,
STN DBS was more effective than medication in reducing the
amplitude and increasing the frequency of resting and postural
tremor. Thirdly, STN DBS caused resting and postural tremor
amplitude and frequency to approximate healthy physiological
tremor, but medication did not. This is similar to the normal-
izing effect of STN DBS on gait stride length and gait velocity
during treadmill walking in Parkinson’s disease patients (Faist
et al., 2001). In contrast, STN DBS did not normalize tremor
regularity and 1–8 Hz tremor–EMG coherence, which is com-
parable to the effects of STN DBS on self-paced, overground
walking (Bastian et al., 2003), postural control (Maurer et al.,
2003) and bradykinesia (Vaillancourt et al., 2004). These
differences are important because they suggest that STN
DBS operates with different magnitudes of clinical efficacy
based on the task and/or the specific motor deficit. Our results
are discussed in terms of the clinical significance and insight
they provide for the central oscillator(s) of resting and postural
tremor in Parkinson’s disease.
Tremor amplitude The finding that medication (Koller, 1986; Koller et al., 1989;
Henderson et al., 1994) and STN DBS (Krack et al., 1998;
Rodriguez et al., 1998) reduced the amplitude of resting and
postural hand tremor in patients with Parkinson’s disease is
consistent with previous literature. However, the results from
this study are the first to determine the extent to which STN
DBS normalizes resting and postural tremor to healthy levels.
Specifically, we found that the resting and postural tremor
amplitude of Parkinson’s disease patients on STN DBS
alone were both similar to the tremor amplitude of control
subjects. In contrast, medication alone did not reduce tremor
amplitude to the level of control subjects. While it is possible
that suprathreshold doses of medication could have further
reduced tremor, such doses would also cause dyskinesias,
thereby compromising the clinical benefits of medical therapy.
Previous reports demonstrate that DBS of the ventral inter-
mediate (VIM) thalamic nucleus reduces postural tremor
amplitude in patients with Parkinson’s disease (O’Suilleabhain
et al., 2003), but the extent to which VIM DBS restores tremor
to control levels remains unclear. Nevertheless, clinical reports
indicate that STN DBS also reduces rigidity, bradykinesia, and
postural instability in patients with Parkinson’s disease (Deep-
Brain Stimulation for Parkinson’s Disease Study Group, 2001;
Benabid, 2003), supporting the current view that the STN
rather than the VIM thalamic nucleus may be the preferred
neurosurgical target for the treatment of parkinsonian patients
exhibiting the classic triad of abnormal motor signs.
Tremor regularity, frequency and coherence Increased regularity from physiological output is considered a
biomarker for ageing and disease in the cardiovascular, endo-
crine and nervous systems (Lipsitz and Goldberger, 1992;
Vaillancourt and Newell, 2002). Previous research has
shown that Parkinson’s disease patients have more regular
tremor compared with control subjects during resting and pos-
tural tremor (Vaillancourt and Newell, 2000). Our findings of
reduced tremor regularity following STN DBS and medication
are consistent with the effects that DBS of the VIM thalamic
nucleus has on the regularity of essential tremor (Vaillancourt
et al., 2003). The decrease in regularity demonstrates that STN
DBS and medication actually change the time-dependent
structure of tremor in patients with Parkinson’s disease rather
than merely suppressing the amplitude of the pathological
oscillations. It is important to note that neither treatment
alone or in combination decreased resting and postural tremor
regularity to control levels.
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1–8 Hz tremor–EMG coherence in Parkinson’s disease
patients. Due to the established relation between tremor–
EMG coherence and motor unit synchronization (Halliday
et al., 1999), the reduction in tremor–EMG coherence
suggests that either treatment reduced motor unit synchro-
nization. Primate electrophysiology has shown that STN
lesions can desynchronize oscillatory neural activity in
the STN while simultaneously reducing the amount of
limb tremor (Wichmann et al., 1994). Similarly, dopamine
and dopamine receptor agonists have been shown to reduce
the 3–8 Hz oscillatory activity (Levy et al., 2001), and the
coherence between these oscillatory neurons in the STN
(Brown et al., 2001). This suggests that when previously
synchronized basal ganglia oscillations become desynchro-
nized, motor units are allowed to fire more independently
rather than in synchrony. Since STN DBS and medication
reduced tremor–EMG coherence, we postulate that motor
units fired more independently, which also reduced tremor
regularity and tremor amplitude.
An important finding from this study was that STN DBS
and medication altered the EMG frequency of resting and
postural tremor. In addition, STN DBS operated with
sufficient efficacy such that resting and postural tremor
EMG frequency in Parkinson’s disease patients was similar
to that in control subjects. While previous studies have
found that medication did not affect the frequency of
tremor in Parkinson’s disease (Koller et al., 1989; Hender-
son et al., 1994), we found that medication did alter the
frequency of tremor. These earlier studies determined the
frequency of tremor by analysing the acceleration signal,
which includes contributions from both the mechanical and
the central oscillator(s). In contrast, the present study
examined the EMG spectrum to determine the frequency
of tremor, thereby focusing on the effect of treatment on
the pathological central oscillator(s). Differences in disease
severity and medication dosage between the Parkinson’s
disease patients in our study and the Parkinson’s disease
patients in previous studies may also explain the null effect
medication had on tremor frequency in the preceding
literature.
postural tremor EMG frequencies are unclear. One possible
mechanism is that the treatments directly changed the fre-
quency of the central oscillator(s). While this explanation is
plausible, we prefer the hypothesis that STN DBS and medica-
tion suppressed the pathological central oscillator(s), which
would allow input from other oscillators (mechanical-reflex)
to become more dominant in the system. The fact that the EMG
frequency of tremor following STN DBS was similar to that in
control subjects strengthens the argument that STN DBS
unmasked oscillations which are characteristic of physiologi-
cal tremor. Further study is necessary to determine if STN DBS
resets or suppresses the central oscillator(s) frequency, thus
allowing mechanical-reflex factors to play a larger role in the
genesis of tremor.
Physiology of tremor reduction Circuit models of the basal ganglia suggest that the STN is
involved in the genesis of parkinsonian tremor (Bergman et al.,
1994; Rodriguez et al., 1998; Liu et al., 2002). In primates the
administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyri-
dine (MPTP) causes dopamine depletion, which increases
the neuronal firing rate in the STN and the internal segment
of the globus pallidus (Bergman et al., 1990; DeLong, 1990).
When neuronal activity was examined in the primate STN
following administration of MPTP, 4 Hz oscillatory activity
was prominent and was correlated with limb tremor (Bergman
et al., 1994). Single-unit recordings in Parkinson’s disease
patients also implicate the STN as a site for oscillatory neuronal
activity that may be tremor-related (Krack et al., 1998;
Rodriguez et al., 1998; Levy et al., 2000; Liu et al., 2002).
STN DBS could be acting via ‘conduction block’, inhibition
(Benazzouz et al., 1995, 2000), or excitation (Hashimoto et al.,
2003; Hershey et al., 2003) to alter the output of STN neurons.
Although previous research in primates does not distinguish
between resting and postural tremor, behaviourally these two
types of oscillations have distinct characteristics. For instance,
in Parkinson’s disease the frequency of postural tremor has
been shown to be greater than the frequency of resting tremor
(Lance et al., 1963; Findley et al., 1981; Elble and Koller,
1990). Furthermore, according to the Consensus Statement
on Tremor (Deuschl et al., 1998), type II parkinsonian tremor
is characterized by the occurrence of both resting and postural
tremor, where the frequency of postural tremor is higher than
resting tremor. Although a re-emergent resting tremor can
occur during postural tasks (Deuschl et al., 1998; Jankovic
et al., 1999), the patients in this study did not demonstrate
this phenomenon. Evidence for this from our study is that
the frequency of postural tremor was higher than resting tre-
mor, further supporting the behavioural distinction between
these two types of oscillations. A single- or dual-circuit model
could account for the difference in frequency between resting
and postural tremor. The output from a single circuit could be
differentially modulated depending on a resting or an active
limb state. An alternative explanation is the existence of separ-
ate circuits oscillating at different frequencies. Nevertheless,
the important finding from this study was that medication
and STN DBS reduced both resting and postural tremor in
Parkinson’s disease. However, unlike medication, STN DBS
enabled resting and postural tremor amplitude and frequency to
approximate healthy physiological levels.
Acknowledgements We wish to thank Medtronic for donating the Medtronic
Console Programmer (Model 7432) for use in this study.
We also thank Jean Arzbaecher, Sue Leurgans and the staff
at the Section for Movement Disorders in the Department of
Neurological Sciences at Rush Presbyterian-St Luke’s
Medical Center. This research was supported in part by grants
from the National Institutes of Health (R01-AR-33189, R01-
NS-28127, R01-NS-40902 and F32-NS-044727).
D ow
References
Bastian AJ, Kelly VE, Revilla FJ, Perlmutter JS, Mink JW. Different effects of
unilateral versus bilateral subthalamic nucleus stimulation on walking and
reaching in Parkinson’s disease. Mov Disord 2003; 18: 1000–7.
Benabid AL. Deep brain stimulation for Parkinson’s disease. Curr Opin
Neurobiol 2003; 13: 696–706.
Benazzouz A, Piallat B, Pollak P, Benabid A. Responses of substantia nigra
pars reticulata and globus pallidus complex to high frequency stimulation of
the subthalamic nucleus in rats: electrophysiological data. Neurosci Lett
1995; 189: 77–80.
Benazzouz A, Gao DM, Ni Z, Piallat B, Bouali-Benazzouz R, Benabid AL.
Effect of high frequency stimulation of the subthalamic nucleus on the
neuronal activities of the substantia nigra pars reticulata and ventrolateral
nucleus of the thalamus in the rat. Neuroscience 2000; 99: 289–95.
Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinson-
ism by lesions of the subthalamic nucleus. Science 1990; 249: 1436–8.
Bergman H, Wichmann T, Karmon B, DeLong MR. The primate subthalamic
nucleus. II. Neuronal activity in the MPTP model of parkinsonism.
J Neurophysiol 1994; 72: 507–20.
Brown P, Corcos DM, Rothwell JC. Does parkinsonian action tremor
contribute to muscle weakness in Parkinson’s disease? Brain 1997; 120:
401–8.
Brown P, Oliviero A, Mazzone P, Insola A, Tonali P, Di Lazzaro V. Dopamine
dependency of oscillations between subthalamic nucleus and pallidum in
Parkinson’s disease. J Neurosci 2001; 21: 1033–8.
Burne JA, Lippold OC, Pryor M. Proprioceptors and normal tremor. J Physiol
1984; 348: 559–72.
Cohn MC, Hudgins PA, Sheppard SK, Starr PA, Bakay RA. Pre- and post-
operative MR evaluation of stereotactic pallidotomy. AJNR Am J Neuro-
radiol 1998; 19: 1075–80.
Cotzias GC, Papavasiliou PS, Gellene R. Modification of parkinsonism—
chronic treatment with L-dopa. N Engl J Med 1969; 280: 337–45.
Deep-Brain Stimulation for Parkinson’s Disease Study Group. Deep-
brain stimulation of the subthalamic nucleus or the pars interna of the
globus pallidus in Parkinson’s disease. N Engl J Med 2001; 345:
956–63.
DeLong MR. Primate models of movement disorders of basal ganglia origin.
Trends Neurosci 1990; 13: 281–5.
Deuschl G, Bain P, Brin M. Consensus statement of the Movement Disorder
Society on Tremor. Ad Hoc Scientific Committee. Mov Disord 1998; 13
Suppl 3: 2–23.
Elble RJ, Koller WC. Tremor. Baltimore (MD): Johns Hopkins University
Press; 1990.
Elble RJ, Randall JE. Motor-unit activity responsible for 8- to 12-Hz compo-
nent of human physiological finger tremor. J Neurophysiol 1976; 39:
370–83.
Faist M, Xie J, Kurz D, Berger W, Maurer C, Pollak P, et al. Effect of bilateral
subthalamic nucleus stimulation on gait in Parkinson’s disease. Brain 2001;
124: 1590–600.
Farmer SF, Bremner FD, Halliday DM, Rosenberg JR, Stephens JA. The
frequency content of common synaptic inputs to motoneurones
studied during voluntary isometric contraction in man. J Physiol 1993;
470: 127–55.
Findley LJ, Gresty MA, Halmagyi GM. Tremor, the cogwheel phenomenon
and clonus in Parkinson’s disease. J Neurol Neurosurg Psychiatry 1981; 44:
534–46.
Friedman JH, Koller WC, Lannon MC, Busenbark K, Swanson-Hyland E,
Smith D. Benztropine versus clozapine for the treatment of tremor in
Parkinson’s disease. Neurology 1997; 48: 1077–81.
Halliday AM, Redfearn JW. An analysis of the frequencies of finger tremor in
healthy subjects. J Physiol 1956; 134: 600–11.
Halliday DM, Conway BA, Farmer SF, Rosenberg JR. Load-independent
contributions from motor-unit synchronization to human physiological
tremor. J Neurophysiol 1999; 82: 664–75.
Hashimoto T, Elder CM, Okun MS, Patrick SK, Vitek JL. Stimulation of the
subthalamic nucleus changes the firing pattern of pallidal neurons. J Neu-
rosci 2003; 23: 1916–23.
HendersonJM,YiannikasC,MorrisJG,EinsteinR,JacksonD,BythK.Postural
tremor of Parkinson’s disease. Clin Neuropharmacol 1994; 17: 277–85.
Hershey T, Revilla FJ, Wernle AR, McGee-Minnich L, Antenor JV,
Videen TO, et al. Cortical and subcortical blood flow effects of subthalamic
nucleus stimulation in PD. Neurology 2003; 61: 816–21.
Homberg V, Hefter H, Reiners K, Freund HJ. Differential effects of changes in
mechanical limb properties on physiological and pathological tremor. J
Neurol Neurosurg Psychiatry 1987; 50: 568–79.
Hughes AJ, Ben-Shlomo Y, Daniel SE, Lees AJ. What features improve the
accuracy of clinical diagnosis in Parkinson’s disease: a clinicopathologic
study. Neurology 1992a; 42: 1142–6.
Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of
idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases.
J Neurol Neurosurg Psychiatry 1992b; 55: 181–4.
Jankovic J, Schwartz KS, Ondo W. Re-emergent tremor of Parkinson’s disease.
J Neurol Neurosurg Psychiatry 1999; 67: 646–50.
Koller WC. Pharmacologic treatment of parkinsonian tremor. Arch Neurol
1986; 43: 126–7.
Koller WC, Vetere-Overfield B, Barter R. Tremors in early Parkinson’s
disease. Clin Neuropharmacol 1989; 12: 293–7.
Krack P, Benazzouz A, Pollak P, Limousin P, Piallat B, Hoffmann D, et al.
Treatment of tremor in Parkinson’s disease by subthalamic nucleus stimula-
tion. Mov Disord 1998; 13: 907–14.
Krack P, Batir A, Van Blercom N, Chabardes S, Fraix V, Ardouin C, et al.
Five-year follow-up of bilateral stimulation of the subthalamic nucleus in
advanced Parkinson’s disease. N Engl J Med 2003; 349: 1925–34.
Lakie M, Walsh EG, Wright GW. Passive mechanical properties of the wrist
and physiological tremor. J Neurol Neurosurg Psychiatry 1986; 49: 669–76.
Lance JW, Schwab RS, Peterson EA. Action tremor and the cogwheel phe-
nomenon in Parkinson’s disease. Brain 1963; 86: 95–110.
Langston JW, Widner H, Goetz CG, Brooks D, Fahn S, Freeman T, et al. Core
assessment program for intracerebral transplantations (CAPIT). Mov Disord
1992; 7: 2–13.
Levy R, Hutchison WD, Lozano AM, Dostrovsky JO. High-frequency syn-
chronization of neuronal activity in the subthalamic nucleus of parkinsonian
patients with limb tremor. J Neurosci 2000; 20: 7766–75.
Levy R, DostrovskyJO, Lang AE, Sime E, HutchisonWD, LozanoAM. Effects
of apomorphine on subthalamic nucleus and globus pallidus internus neu-
rons in patients with Parkinson’s disease. J Neurophysiol 2001; 86: 249–60.
Lipsitz LA, Goldberger AL. Loss of ‘complexity’ and aging. Potential applica-
tions of fractals and chaos theory to senescence. JAMA 1992; 267: 1806–9.
Liu X, Ford-Dunn HL, Hayward GN, Nandi D, Miall RC, Aziz TZ, et al. The
oscillatory activity in the parkinsonian subthalamic nucleus investigated
using the macro-electrodes for deep brain stimulation. Clin Neurophysiol
2002; 113: 1667–72.
Marsden CD, Meadows JC, Lange GW, Watson RS. The role of the ballisto-
cardiac impulse in the genesis of physiological tremor. Brain 1969; 92:
647–62.
Maurer C, Mergner T, Xie J, Faist M, Pollak P, Lucking CH. Effect of chronic
bilateral subthalamic nucleus (STN) stimulation on postural control in
Parkinson’s disease. Brain 2003; 126: 1146–63.
Olanow CW, Nakano K, Nausieda P, Tetrud JA, Manyam B, Last B, et al. An
open multicenter trial of Sinemet CR in levodopa-naive Parkinson’s disease
patients. Clin Neuropharmacol 1991; 14: 235–40.
O’Suilleabhain PE, Frawley W, Giller C, Dewey RB Jr. Tremor response to
polarity, voltage, pulsewidth and frequency of thalamic stimulation. Neuro-
logy 2003; 60: 786–90.
Pincus SM. Approximate entropy as a measure of system complexity. Proc Natl
Acad Sci USA 1991; 88: 2297–301.
Pincus SM, Goldberger AL. Physiological time-series analysis: what does
regularity quantify? Am J Physiol 1994; 266: H1643–56.
Raethjen J, Pawlas F, Lindemann M, Wenzelburger R, Deuschl G. Determi-
nants of physiologic tremor in a large normal population. Clin Neurophysiol
2000; 111: 1825–37.
Rodriguez MC, Guridi OJ, Alvarez L, Mewes K, Macias R, Vitek J, et al. The
subthalamic nucleus and tremor in Parkinson’s disease. Mov Disord 1998;
13 Suppl 3: 111–8.
2142 M. M. Sturman et al.
D ow
ic.oup.com /brain/article-abstract/127/9/2131/313153 by guest on 14 April 2019
Rosenberg JR, Amjad AM, Breeze P, Brillinger DR, Halliday DM. The Fourier
approach to the identification of functional coupling between neuronal spike
trains. Prog Biophys Mol Biol 1989; 53: 1–31.
Starr PA, Vitek JL, Bakay RA. Deep brain stimulation for movement disorders.
Neurosurg Clin N Am 1998; 9: 381–402.
Starr PA, Subramanian T, Bakay RA, Wichmann T. Electrophysiological
localization of the substantia nigra in the parkinsonian nonhuman primate.
J Neurosurg 2000; 93: 704–10.
Stiles RN. Frequency and displacement amplitude relations for normal hand
tremor. J Appl Physiol 1976; 40: 44–54.
Stiles RN, Pozos RS. A mechanical-reflex oscillator hypothesis for parkinso-
nian hand tremor. J Appl Physiol 1976; 40: 990–8.
Vaillancourt DE, Newell KM. The dynamics of resting and postural tremor in
Parkinson’s disease. Clin Neurophysiol 2000; 111: 2046–56.
Vaillancourt DE, Newell KM. Changing complexity in human behavior
and physiology through aging and disease. Neurobiol Aging 2002; 23:
1–11.
Vaillancourt DE, Sturman MM, Verhagen Metman L, Bakay RA, Corcos DM.
Deep brain stimulation of the VIM thalamic nucleus modifies several fea-
tures of essential tremor. Neurology 2003; 61: 919–25.
Vaillancourt DE, Prodoehl J, Verhagen Metman L, Bakay RA, Corcos DM.
Effects of deep brain stimulation and medication on bradykinesia and
muscle activation in Parkinson’s disease. Brain 2004; 127: 491–504.
Vitek JL, Bakay RA, Hashimoto T, Kaneoke Y, Mewes K, Zhang JY, et al.
Microelectrode-guided pallidotomy: technical approach and its application
inmedically intractableParkinson’sdisease. JNeurosurg1998;88:1027–43.
Wasielewski PG, Burns JM, Koller WC. Pharmacologic treatment of tremor.
Mov Disord 1998; 13 Suppl 3: 90–100.
Wichmann T, Bergman H, DeLong MR. The primate subthalamic nucleus. III.
Changes in motor behavior and neuronal activity in the internal pallidum
induced by subthalamic inactivation in the MPTP model of parkinsonism.
J Neurophysiol 1994; 72: 521–30.
Yahr MD, Duvoisin RC, Schear MJ, Barrett RE, Hoehn MM. Treatment of
parkinsonism with levodopa. Arch Neurol 1969; 21: 343–54.
Effects of STN DBS/medication on tremor in PD 2143
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