Clinical Neurophysiology 115 (2004) 2530–2541
www.elsevier.com/locate/clinph
Improvement of motor performance and modulation of cortical
excitability by repetitive transcranial magnetic stimulation
of the motor cortex in Parkinson’s disease
Jean-Pascal Lefaucheura,b,*, Xavier Drouota,b, Florian Von Raisonc,
Isabelle Ménard-Lefaucheura, Pierre Cesaroc, Jean-Paul Nguyend
a
Service de Physiologie—Explorations Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de Paris,
51 avenue de Lattre de Tassigny, 94010 Créteil, France
b
INSERM U421, Faculté de Médecine de Créteil, Créteil, France
c
Service de Neurologie, Hôpital Henri Mondor, Créteil, France
d
Service de Neurochirurgie, Hôpital Henri Mondor, Créteil, France
Accepted 24 May 2004
Available online 17 July 2004
Abstract
Objective: To assess the effects of focal motor cortex stimulation on motor performance and cortical excitability in patients with
Parkinson’s disease (PD).
Methods: Repetitive transcranial magnetic stimulation (rTMS) was performed on the left motor cortical area corresponding to the right
hand in 12 ‘off-drug’ patients with PD. The effects of subthreshold rTMS applied at 0.5 Hz (600 pulses) or at 10 Hz (2000 pulses) using a
‘real’ or a ‘sham’ coil were compared to those obtained by a single dose of l-dopa. The assessment included a clinical evaluation by the
Unified Parkinson’s Disease Rating Scale and timed motor tasks, and a neurophysiological evaluation of cortical excitability by single- and
paired-pulse TMS techniques.
Results: ‘Real’ rTMS at 10 or 0.5 Hz, but not ‘sham’ stimulation, improved motor performance. High-frequency rTMS decreased rigidity
and bradykinesia in the upper limb contralateral to the stimulation, while low-frequency rTMS reduced upper limb rigidity bilaterally and
improved walking. Concomitantly, 10 Hz rTMS increased intracortical facilitation, while 0.5 Hz rTMS restored intracortical inhibition.
Conclusions: Low- and high-frequency rTMS of the primary motor cortex lead to significant but differential changes in patients with PD
both on clinical and electrophysiological grounds. The effects on cortical excitability were opposite to previous observations made in healthy
subjects, suggesting a reversed balance of cortical excitability in patients with PD compared to normals. However, the underlying
mechanisms of these changes remain to determine, as well as the relationship with clinical presentation and response to l-dopa therapy.
Significance: The present study gives some clues to appraise the role of the primary motor cortex in PD. Clinical improvement induced by
rTMS was too short-lasting to consider therapeutic application, but these results support the perspective of the primary motor cortex as a
possible target for neuromodulation in PD.
q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Cortical excitability; Intracortical facilitation; Intracortical inhibition; Motor evoked potentials; Silent period
1. Introduction
Progressive
degeneration
of
mesencephalic
dopaminergic nuclei leads to various motor disturbances
* Corresponding author. Address: Service de Physiologie—Explorations
Fonctionnelles, Hôpital Henri Mondor, Assistance Publique—Hôpitaux de
Paris, 51 avenue de Lattre de Tassigny, 94010 Créteil, France. Tel.: þ 33-14981-2694; fax: þ 33-1-4981-4660.
E-mail address: jean-pascal.lefaucheur@hmn.ap-hop-paris.fr
(J.-P. Lefaucheur).
in Parkinson’s disease (PD). Initially, drugs like l-dopa or
dopaminergic agonists are able to control these symptoms,
but with the progress of the disease, these drugs disclose
some shortcomings, i.e. insufficient efficacy or adverse
effects. Therefore new therapeutic strategies have been
developed, like chronic electrical stimulation of deep brain
structures, particularly the subthalamic nucleus (Limousin
et al., 1995, 1998). According to the basal ganglia –
thalamocortical circuit model (Alexander et al., 1990), the
degeneration of dopaminergic nigrostriatal pathways would
1388-2457/$30.00 q 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.clinph.2004.05.025
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
result in functional deafferentation of the frontal cortex,
including the primary motor cortex, that could contribute to
the pathophysiology of motor disturbances in patients with
PD. Therefore, the motor cortex is an appealing target for
neuromodulation therapy in PD.
Cortical activity can be transiently modified by the
application of repetitive transcranial magnetic stimulation
(rTMS). Shortening of reaction time and movement time
during 5 Hz rTMS applied over the motor cortex was first
shown in patients with PD in 1994 (Pascual-Leone et al.,
1994). Since this first study, several rTMS trials have been
reported in PD, based on various experimental designs:
(i) focal stimulation using a figure-of-eight coil or non-focal
stimulation using a circular coil; (ii) low-frequency stimulation (from 0.2 to 1 Hz) or high-frequency stimulation (5, 10
or 20 Hz); (iii) subthreshold stimulation, i.e. at intensity
lower than motor threshold, or suprathreshold stimulation,
i.e. at intensity above motor threshold; (iv) clinical assessment by motor task speed measurement or by motor
performance scoring, e.g. using the Unified Parkinson’s
Disease Rating Scale (UPDRS). Then, the results of all the
previous rTMS studies performed in patients with PD are
puzzling owing to their methodological differences. Only one
study assessed the effects of focal primary motor cortex
stimulation on UPDRS score (Siebner et al., 2000b) and
showed a significant improvement of the UPDRS score after
a 20 min session of subthreshold 5 Hz rTMS.
Beside rTMS protocols, single- or paired-pulse TMS
paradigms allow to study some excitatory and inhibitory
nervous pathways involved in motor control, and provide
various parameters of cortical excitability, e.g. motor
threshold, silent period, intracortical inhibition or
facilitation. Studies of cortical excitability determinants in
PD disclosed mainly a reduction of motor inhibitory
control, which could be restored following various antiparkinsonian medication or neurosurgical therapies
(reviewed in Cantello et al. (2002)), whereas the influence
of rTMS remains unknown.
In the present series of 12 patients with PD, we have
tested the effects of motor cortex rTMS on motor
performance assessed by UPDRS scoring and timed
motor tasks, and on motor cortex excitability assessed by
single- and paired-pulse TMS techniques. Sessions of rTMS
were applied at two frequencies, 0.5 and 10 Hz, compared to
sham stimulation (negative control) and to l-dopa
administration (positive control).
2. Patients and methods
2.1. Patients
Twelve patients (5 women and 7 men) aged from 51 to 76
years (mean ^ SEM: 64 ^ 2) were included in this study.
All these patients fulfilled the UK Parkinson’s Disease
2531
Brain Bank criteria for idiopathic PD (Gibbs and Lees,
1988) and suffered from a bilateral akinetic-rigid syndrome.
Patients with permanent rest tremor were excluded from the
study because of their impossibility to maintain a complete
relaxation of hand muscles, precluding a reliable determination of the rest motor threshold. Other exclusion criteria
were the presence of implanted devices or a past personal
history of seizure. All patients gave their written informed
consent for the study, which was approved by the ethical
committee of Henri Mondor Hospital. The clinical features
of the patients are presented in Table 1, including the
modified Hoehn and Yahr staging scale and the Schwab and
England Activities of Daily Living scale.
2.2. General design
Patients were examined 12 h after an overnight withdrawal of anti-parkinsonian medication, i.e. in ‘off-drug’
condition (no patient was treated by long-acting dopaminergic agonists). First, motor performance was assessed
clinically and TMS parameters of motor cortex excitability
(see below) were measured (‘pre’ condition). Second, one of
the 4 interventions, i.e. l-dopa intake, 0.5 Hz rTMS, 10 Hz
rTMS or sham rTMS (see below) was performed. Twenty
minutes after the end of the rTMS session, both clinical
motor evaluation and cortical excitability measurement
were checked on again (‘post’ condition). Evaluation after
l-dopa intake was performed in the earliest best-on
condition according to the patients (usually 30 – 60 min
after drug administration). About 30 – 45 min were
requested to complete both clinical and electrophysiological
evaluations. The order of the 3 rTMS interventions was
randomised across patients, and each session were separated
Table 1
Clinical data for the 12 patients
Patient
(n)
Age
Sex Hoehn
(years)
and Yahr
classification
Schwab
Disease l-Dopa
and
duration equivalent
England (years) (mg)
scale (%)
1
2
3
4
5
6
7
8
9
10
11
12
67
51
66
67
60
76
69
57
58
73
74
51
4
4
4
4
4
3.5
3.5
3
3
2.5
2.5
2.5
60
70
70
70
80
70
50
80
80
80
90
90
22
13
10
10
11
12
18
11
9
7
7
4
3.4^0.2
74^3
11^1
Mean^SEM 64^2
F
M
M
M
F
M
M
M
F
M
F
F
850
900
900
950
750
900
1000
560
700
750
500
250
701^75
The l-dopa equivalent dose was calculated on the basis of drug
correspondences proposed by Lozano et al. (1995).
2532
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
by at least 3 weeks in order to minimize the effects of
practice.
2.3. Clinical motor performance
A well-trained neurologist (Dr Florian Von Raison)
performed the clinical examination before and after each
intervention. This examiner and the patients were blinded
for the type of rTMS intervention.
First, the patients were rated on the motor section
(items 18– 31) of the UPDRS III. Rigidity score for the right
and the left upper limbs was the item 22 of the UPDRS
motor score. Bradykinesia score for the right and the left
upper limbs was calculated as the sum of items 23– 25 of the
UPDRS motor score.
Second, timed motor tasks were performed, including a
ballistic task and a pegboard test. For the ballistic task,
the patients were asked to tap with the index finger two
targets drawn on a table and fixed 30 cm apart, as fast as
possible, the score being the time (in seconds) to achieve 20
go-and-back. For the pegboard test, the patients had to pick
the pegs from a well, one by one, using only one hand and to
insert consecutively them into the holes. The peg tray
consisted in two rows of 30 holes each (Purdue Pegboard).
The subjects were instructed to move as fast as possible in
attempting to place all pegs. The score was the number of
pegs arranged in 30 s. For these both tests, the patients sat
comfortably on a chair and they performed the task with the
right hand first, then with the left hand.
Third, gait performance was analysed using the walking
test of the Core Assessment Program for Surgical
Interventional Therapies (CAPSIT) in PD (Defer et al.,
1999). Briefly, patients were asked to walk as fast as
possible 7 m back and forth including turning. The time and
the number of steps were recorded.
was recorded from the right FDI muscle using surface
electrodes in a belly-tendon montage. After amplification
and bandpass (20 – 5000 Hz) filtering, raw signals were
recorded and stored on floppy disk for off-line analysis
(Phasis II, EBNeuro, Florence, Italy).
In order to evaluate motor cortex excitability, we
measured the motor threshold at rest (RMT), the MEP
size at 120% RMT intensity (MEP120), the duration of the
cortical silent period (CSP) and both the intracortical
inhibition (ICI) and facilitation (ICF).
RMT was defined as the minimum intensity of
stimulation, which was required in producing MEPs of
50 mV in amplitude at least, in 5 out of 10 trials while the
target muscle being relaxed (Rossini et al., 1994).
Thereafter, average peak-to-peak MEP size was determined
over 5 single trials performed at 120% RMT intensity
(MEP120). CSP was obtained by delivering a single TMS
pulse at suprathreshold intensity (140% RMT) during a
tonic FDI muscle contraction. The shortest CSP duration
was measured from the negative peak of the MEP until the
first reoccurrence of voluntary electromyographic activity in
a series of 5 consecutive trials (Ridding et al., 1995).
Paired-pulse paradigm was performed to assess
intracortical excitability according to the Kujirai’s
procedure (Kujirai et al., 1993), using a BiStim module
(Magstim Co., Whitland, Carmarthenshire, Wales) and a
figure-of-eight coil. The intensity was set at 80% RMT for
the conditioning stimulus and at 120% RMT for the test
stimulus. Short interstimuli intervals (ISIs of 2 – 4 ms) were
applied to assess ICI, whereas longer ISIs (10 – 15 ms)
allowed ICF measurement. Eight trials were recorded for
each condition and were averaged. The conditioned test
MEP120 amplitude was expressed as percentage of the
unconditioned test MEP120 amplitude. For each patient,
the maximal ICI and ICF values, whatever ISI, were
retained for analysis (Chen et al., 1998).
2.4. Motor cortex excitability
2.5. Interventions
Patients sat on a comfortable reclining chair. Magstim
200 magnetic stimulator (Magstim Co., Whitland,
Carmarthenshire, Wales) and a figure-of-eight stimulating
coil (70 mm Double Coil, 9925-00, Magstim Co., Whitland,
Carmarthenshire, Wales) were used to activate the left
motor cortical area corresponding to the right first dorsal
interosseus (FDI) muscle. The coil was held tangentially to
the patients’ head surface over the left motor cortex with the
handle of the coil pointing occipitally. Using this
orientation, the current induced in the brain flows
perpendicular to the line of the central sulcus, which leads
to predominately trans-synaptic activation of the
corticospinal system (Kaneko et al., 1996). The coil was
moved to determine the optimal position for eliciting MEPs
of maximal amplitude in the right FDI muscle, i.e. the
‘motor hot spot’. When the motor hot spot was found,
the stimulation coil was fixed with a device to maintain the
same location throughout the experiment. Electromyogram
The 4 interventions were: (i) l-dopa intake.
Corresponding to 150% of the usual morning dose
administered per os; (ii) 0.5 Hz rTMS. A 20 min stimulation
applied at 80% RMT intensity and 0.5 Hz frequency
(600 stimuli) over the left primary motor cortical area
corresponding to the right hand using a real TMS coil;
(iii) 10 Hz rTMS. A series of 20 trains of 10 s duration
(50 s intertrain intervals) applied at 80% RMT intensity and
10 Hz frequency (2000 stimuli) over the same target using a
real TMS coil; (iv) sham rTMS. The same protocol as for
10 Hz rTMS but using a sham 8-shaped coil (Magstim
Placebo Coil System 1730-23-00, Magstim Co., Whitland,
Carmarthenshire, Wales). A sham rTMS session was not
performed at 0.5 Hz to lighten the protocol.
The rTMS sessions were applied using the Super-Rapid
Magstim magnetic stimulator (Magstim Co., Whitland,
Carmarthenshire, Wales) and an 8-shaped coil (70 mm
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
2533
Double Coil, 9925-00, The Magstim Co., Whitland,
Carmarthenshire, Wales) held tangentially to the patients’
head surface over the left motor cortical hot spot
corresponding to the right FDI muscle with the handle of
the coil pointing occipitally. As aforementioned, using
this orientation, the induced current leads to
trans-synaptic activation of the corticospinal system over
the precentral gyrus.
The Magstim Placebo Coil System, which was designed
not to have a stimulating effect on the cortex, was preferred
to the method consisting in holding a real TMS coil angled
458 tangentially to the scalp, which do not meet the criteria
for an ideal sham, as previously shown (Loo et al., 2000).
Moreover, the patients were informed that the 3 rTMS
sessions were different but not that they included a placebo
condition. Therefore, even if the sham coil caused no
sensorimotor stimulation of trigeminal afferents or scalp
muscles, we assumed that the patients could not realize that
sham rTMS was ineffective.
and the rigidity subscore bilaterally, and improved walking;
10 Hz rTMS decreased the global UPDRS III motor score,
reduced rigidity and bradykinesia subscores and improved
the ballistic task for the right upper limb, without any effect
on gait; sham rTMS did not modify any parameter.
2.6. Statistical analysis
4. Discussion
The variations among the conditions were assessed for
the clinical scores of motor performance (rigidity and
bradykinesia subscores of UPDRS, ballistic task, pegboard
test and gait analysis) and for the various parameters of
motor cortex excitability (RMT, MEP120 amplitude,
CSP duration, ICI and ICF) using non-parametric repeated
measures ANOVA (Friedman test). Dunn’s post-tests were
applied to compare the results before and after each type of
intervention. A P value of less than 0.05 was considered as
significant.
The present study showed that primary motor cortex
stimulation could improve motor performance in patients
with PD, concomitantly with cortical excitability changes.
The mean reduction of UPDRS motor score resulting from
0.5 or 10 Hz rTMS (2 19.5 or 2 17.1%) was equal to
28 – 32% of the l-dopa effect (2 61.2%). Because it was not
ethical to keep patients unmedicated for several days, we
were not able to appraise the duration of rTMS effects, as it
was reported for patients with writer’s cramp (Siebner et al.,
1999a) or neurogenic pain (Lefaucheur et al., 2001).
However, a majority of patients indicated that the day
after the 10 Hz rTMS session was better than usual.
3.2. Motor cortex excitability
A significant variation among the conditions was found
for all the electrophysiological parameters (P , 0:05;
Friedman test), except for RMT ðP ¼ 0:94Þ: Dunn’s
post-tests disclosed various significant changes depending
on the type of intervention: MEP120 amplitude was reduced
by l-dopa; CSP duration was prolonged by l-dopa, 0.5 Hz
and 10 Hz rTMS; ICI was restored by l-dopa and 0.5 Hz
rTMS; ICF was improved only by 10 Hz rTMS. No other
significant modification was observed, particularly
following sham rTMS.
3. Results
4.1. Effects on motor performance
No adverse effect of rTMS was observed. The results of
the 4 interventions (l-dopa intake, 0.5 Hz rTMS, 10 Hz
rTMS or sham rTMS) are shown by Figs. 1 and 2 for clinical
scores and by Fig. 3 for motor cortex excitability
parameters. Due to the limited number of patients, it was
impossible to define subgroups and to determine statistically
the influence of the age of the patient, of the stage or the
duration of the disease, or of the dose of l-dopa intake on
these results.
3.1. Clinical motor performance
A significant variation among the conditions was found
for all the clinical parameters (P , 0:05; Friedman test in all
cases). Dunn’s post-tests disclosed various significant
effects for each type of intervention: l-dopa administration
decreased the global UPDRS III motor score, reduced
rigidity and bradykinesia subscores for both upper limbs,
and improved timed motor tasks and gait performance;
0.5 Hz rTMS reduced the global UPDRS III motor score
The present study compared the effects induced by highand low-frequency rTMS of the motor cortex in patients
with PD: 10 Hz rTMS improved bradykinesia and rigidity
subscores of the upper limb controlaterally to the stimulation, while 0.5 Hz rTMS improved upper limb rigidity
bilaterally, as well as walking. In fact, the two types of
stimulation differed for frequency but also for the
number of stimuli. The number of stimuli could act on the
duration of the after effects (Touge et al., 2001). In contrast,
the way of interhemispheric excitability changes was shown
to be associated with rTMS frequency (0.5 versus 5 Hz),
independent of pulse number (Gorsler et al., 2003).
Therefore we assumed that the differential effects obtained
in this study following 0.5 or 10 Hz rTMS sessions were
likely to result from the difference in stimulation frequency
rather than in pulse number.
The various studies including rTMS protocols applied
over the primary motor cortex and performed in
patients with PD are listed in Table 2. The first trial of
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J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
Fig. 1. Total UPDRS III score and subscores for rigidity and bradykinesia of the right (R) and the left (L) upper limb, before (black bars) and after (white bars)
each type of intervention (l-dopa intake or rTMS session). Values are presented as means þ s.e.m. Variation among the conditions was significant for all the
scores (P # 0:0001 (a –e), Friedman test). Significant differences between before and after intervention are indicated (*: P , 0:05; **: P , 0:01; ***:
P , 0:001; Dunn’s post-tests).
high-frequency rTMS of the primary motor cortex was
characterized by positive effects on reaction time and
movement time in patients with PD compared to controls:
performance on the pegboard test was significantly
improved during subthreshold 5 Hz rTMS (Pascual-Leone
et al., 1994). However, this result was not confirmed in a
larger replicative study compared to sham stimulation,
some patients performing faster during rTMS, others
showing the opposite effect (Ghabra et al., 1999). Using a
ballistic task, Siebner et al. (1999b) reported that
bradykinesia could be reduced in patients with PD beyond
the time of magnetic stimulation, i.e. after subthreshold
5 Hz rTMS applied over the cortical area corresponding to
the moving arm. In the present study, we confirmed
that subthreshold high-frequency rTMS over the left
motor cortex was able to improve the performance of the
right upper limb in a timed ballistic task, without any
significant change in the pegboard score. This discrepancy
probably reflects the distinct effect that rTMS exerted on
brain networks engaged by the two tests, which disclose
different abnormalities of motor control resulting in
bradykinesia.
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
2535
Fig. 2. Results for timed motor tasks (ballistic task: hand-arm movement (time in seconds) and pegboard score (number of pegs) for the right (R) and the left (L)
upper limb; gait: walking time and number of steps), before (black bars) and after (white bars) each type of intervention (l-dopa intake or rTMS session).
Values are presented as means þ SEM. Variation among the conditions was significant for all the parameters (P ¼ 0:0011 (a), 0.0319 (b), 0.0107 (c), 0.0221
(d), 0.0001 (e), 0.0005 (f), Friedman test). Significant differences between before and after intervention are indicated (*: P , 0:05; **: P , 0:01; Dunn’s
post-tests).
Improvement of UPDRS motor score after motor cortex
stimulation was previously reported in only one paper,
which tested one session of 5 Hz rTMS compared to
midfrontal sham rTMS (Siebner et al., 2000b). The reduction
in UPDRS score was mainly due to alleviation of
bradykinesia and rigidity in the upper limb contralaterally
to the stimulated cortex. Similar results were obtained in
the present study following one session of 10 Hz
rTMS. Another study assessed clinical motor effects of
high-frequency rTMS (5, 10 or 20 Hz) in a series of 7
unmedicated patients with PD, but did not report any
significant change in UPDRS score, walking speed or motor
reaction time (Tergau et al., 1999). Unfortunately, this latter
study was performed with a large circular coil centred over
the vertex. The possibility of stimulating various cortical
areas other than the primary motor cortex limits
considerably the value of non-focal stimulation of frontal
areas using a circular coil in PD. For example, stimulation
of the motor supplementary area, which is located only
2 –4 cm anterior to the vertex, adjacent to the leg area of the
primary motor cortex, was consistently shown to worsen
motor performance in patients with PD (Boylan et al., 2001;
Cunnington et al., 1996).
Positive effects of low-frequency rTMS on motor
performance of patients with PD were also previously
reported, even by means of repeated sessions (Ikeguchi
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J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
Fig. 3. Rest motor threshold, motor evoked potential (MEP) size at 120% suprathreshold intensity, silent period duration to cortical stimulation, intracortical
inhibition and intracortical facilitation (expressed as % of conditioned MEP amplitude), before (black bars) and after (white bars) each type of intervention
(l-dopa intake or rTMS session). Values are presented as means þ SEM. Variation among the conditions was significant for all the parameters (P ¼ 0:0333
(b), 0.0003 (c), 0.0001 (d), 0.0070 (e), Friedman test), except for the motor threshold (P ¼ 0:9416 (a), Friedman test). Significant differences between before
and after intervention are indicated (*: P , 0:05; **: P , 0:01; Dunn’s post-tests).
et al., 2003; Mally and Stone, 1999a,b; Shimamoto et al.,
2001). However, these results remained controversial
(Okabe et al., 2003) and were also obtained with a large
circular coil applied to frontal areas, raising the same
problems of specificity as discussed above. The present
study used a focal coil and showed that bilateral effects
on upper limb rigidity could result from unilateral,
low-frequency stimulation of the hand motor cortical area.
Such a bilateral improvement resulting from unilateral rTMS
could be explained at a cortical level, as discussed later.
To resume the clinical results of the present study, rTMS
at both high and low frequencies improved motor
performance, but on different parameters and to a lesser
extent than l-dopa. Concomitant changes in cortical
excitability could account for these clinical effects, as we
will see below.
4.2. Effects on cortical excitability
In the present study, various cortical excitability changes
were induced by l-dopa intake or by motor cortex rTMS,
depending on stimulation frequency. The physiological
significance of these excitability parameters is now
understood. RMT measures the membrane-related aspects
of pyramidal cell excitability (Ziemann et al., 1996), while
MEP size reflects global excitability of the corticospinal
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
2537
Table 2
Studies including clinical or electrophysiological assessment of repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex in patients
with Parkinson’s disease
Patients (n)
Stimulus
frequency
(Hz)
Pulses (n)
8-shaped coil, assessment during rTMS session
Pascual-Leone et al. (1994a)
6
5
Ghabra et al. (1999)
Gilio et al. (2002)**
5
5
40
10
2000
750
2250
750
11
15
8-shaped coil, assessment after rTMS session
The present study
12
Siebner et al. (1999b)
Siebner et al. (2000a)
Siebner et al. (2000b)
12
10
10
5
5
5
Sommer et al. (2002)**
The present study
11
12
1
0.5
900
600
Circular coil, assessment after rTMS session
Tergau et al. (1999)
7
20, 10, 5, 1
1000
Mally and Stone (1999a, b)
Shimamoto et al. (2001)
Ikeguchi et al. (2003)
Okabe et al. (2003)*
1
0.2
0.2
0.2
30 £ 2/day, (7–10 days)
30 £ 2/week (2 months)
30 £ 2/2 day (2 weeks)
50 £ 2/week (2 months)
10, 49
9
12
85
Results
Shortening of reaction time
and movement time
No significant effect on movement time
Normal increase in CSP duration,
absence of rest MEP size increase
Increase in CSP duration and
intracortical facilitation
UPDRS improvement (rigidity and
bradykinesia contralaterally to rTMS)
Shortening of movement time
Increase in CSP duration
UPDRS improvement (rigidity and
bradykinesia contralaterally to rTMS)
Increase in finger tapping frequency
Increase in CSP duration and
intracortical inhibition
UPDRS improvement (rigidity ipsi-and
contralaterally to rTMS)
No significant effect on UPDRS
or reaction time
UPDRS, H&Y and ADL improvement
UPDRS, H&Y and ADL improvement
UPDRS and ADL improvement
No significant effect on UPDRS
Stimulus intensity was lower than the rest motor threshold in most of the studies, but higher than the active motor threshold in one case (*) or than the rest
motor threshold in two cases (**). UPDRS, unified Parkinson’s disease rating scale; H&Y, Hoehn and Yahr score; ADL, activities of daily living score; MEP,
motor evoked potential; CSP, cortical silent period.
pathway (Devanne et al., 1997). ICF results from highthreshold interneuronal excitatory input to the pyramidal
cells (Ilic et al., 2002). ICI is mediated by a low-threshold
GABA A receptor-dependent inhibitory pathway (Ilic et al.,
2002). CSP and ICI are produced through activation of
different cortical GABAergic circuits (Sanger et al., 2001).
RMT was found to be similar in patients with PD and in
normals (Ridding et al., 1995; Valls-Sole et al., 1994).
However, at a given intensity above RMT, MEP size could
be larger in patients than in normals (Cantello et al., 1991;
Valls-Sole et al., 1994). Then, it was suggested that
excitability of the corticospinal motor output was enhanced
in PD, at least at rest and during both premovement and
post-movement periods (Chen et al., 2001). This excessive
tonic corticospinal activity at rest is coupled with a relative
failure of volitional recruitment, as shown by the
reduction of MEP facilitation during voluntary contraction
(Valls-Sole et al., 1994). Regarding ICF, the earliest
descriptions did not report any significant differences
between patients and controls (Hanajima et al., 1996;
Marchese et al., 2000; Ridding et al., 1995). A slight
reduction of ICF was first noted in PD by Strafella et al.
(2000). The present series disclosed more clearly a defective
ICF in patients with PD. However, recruitment bias in
patients’ selection and the criterion to retain maximal ICF
for analysis may have concurred to find defective ICF,
as well as a reduced excitability of the high-threshold
circuits responsible for ICF. In summary, excitability
changes in PD are characterized by an overactive
corticospinal output at rest, coupled with a reduction of
the facilitatory inputs involved in ICF or voluntary
contraction.
To our knowledge, modification of RMT, ICF or MEP
size by anti-parkinsonian treatment was not previously
reported, except a reduction in MEP size for 5 patients after
pallidotomy (Young et al., 1997). The present study
disclosed that l-dopa intake did not change RMT or ICF
but reduced MEP amplitude. Enhanced MEP size at rest is
related to an excessive tonic activity in the whole
cortico-motoneuron system (including the spinal level),
and seems to be specifically associated with rigidity in PD
(Cantello et al., 1991). Therefore, the decrease in MEP size
following l-dopa intake could more particularly reflect the
decrease in rigidity induced by this drug.
2538
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
Changes in the excitability of inhibitory drive seem also
involved in the pathophysiology of PD and in the
mechanisms of action of anti-parkinsonian treatment. CSP
duration was found to be shorter and/or ICI to be reduced in
patients with PD compared to normals (Cantello et al., 1991;
Hanajima et al., 1996; Haug et al., 1992; Marchese et al.,
2000; Nakashima et al., 1995; Priori et al., 1994; Ridding
et al., 1995; Strafella et al., 2000; Valls-Sole et al., 1994).
These results suggested an imbalance of the corticospinal
excitability in PD towards a state of disinhibition or a
decrease in the excitability of inhibitory circuits. Moreover,
CSP duration is normalized and/or ICI is restored by acute
or chronic treatment with l-dopa or apomorphine (Manfredi
et al., 1998; Marchese et al., 2000; Nakashima et al., 1995;
Pierantozzi et al., 2001; Priori et al., 1994; Ridding et al.,
1995; Strafella et al., 2000), as well as by pallidotomy
(Young et al., 1997) or subthalamic nucleus stimulation
(Cunic et al., 2002; Dauper et al., 2002; Pierantozzi et al.,
2002). The present results confirmed that l-dopa intake was
able to prolong CSP duration and to restore ICI in patients
with PD.
Regarding rTMS influence, published data were lacking
in PD, in contrast to normals. In normals, low-frequency
subthreshold rTMS was found to reduce global excitability
(MEP size) and/or facilitatory input (ICF) (Gangitano et al.,
2002; Maeda et al., 2000; Romero et al., 2002; Touge et al.,
2001), but not to increase inhibition (Fitzgerald et al., 2002;
Romero et al., 2002). This was evoking a phenomenon of
disfacilitation. In the present series of patients with PD, the
opposite was observed, since an increase in inhibitory drive
(CSP duration and ICI) was observed rather than a decrease
in corticospinal output. The present patients were older
(mean age 64 years) than most of the healthy volunteers in
whom rTMS effects have been previously studied, but age
differences should probably not explain opposite results.
Moreover, younger patients with focal dystonia (mean age
41 years) presented a pattern of response to low-frequency
motor cortex rTMS similar to that observed in the patients
of the present study (Siebner et al., 1999a).
Effects of high-frequency rTMS on cortical
excitability are more complex. In healthy subjects,
subthreshold high-frequency stimulation is sufficient to
increase MEP size (Gangitano et al., 2002; Maeda et al.,
2000) and to reduce ICI (Peinemann et al., 2000),
corresponding to a state of disinhibition, while suprathreshold intensity is required to increase ICF (Wu et al.,
2000) and prolong CSP duration (Romeo et al., 2000),
corresponding to a facilitation of both excitatory and
inhibitory drive or to an action on the excitatory
mechanisms alone. In the present series, ICF increase
and CSP lengthening were observed following subthreshold 10 Hz TMS, without any change in MEP size or
ICI. This strongly evoked a reversed balance of cortical
excitability in patients with PD compared to normals. A
prolonged CSP duration following subthreshold highfrequency rTMS applied over the motor cortex was
already reported in 10 patients with PD (Siebner et al.,
2000a). The effects on ICF, which were not observed
after l-dopa intake, suggested a non-dopaminergic effect
induced by high-frequency rTMS for this variable.
To resume the cortical excitability changes observed in
the present study, motor cortex rTMS could restore
inhibitory mechanisms at low frequency and both excitatory
and inhibitory mechanisms at high frequency.
4.3. Pathophysiological significance regarding primary
motor cortex involvement in PD
Thus, the present study showed that the stimulation of the
primary motor cortex improved motor performance in
patients with PD, concomitantly with well-characterized
cortical excitability changes. In particular, a bilateral
clinical improvement was observed after low-frequency
rTMS. A bilateral modulation of motor cortex activity
induced by unilaterally applied low-frequency rTMS was
already described in functional brain imaging studies of
healthy subjects (Fox et al., 1997; Lee et al., 2003) or on the
basis of cortical excitability changes (Plewnia et al., 2003;
Wassermann et al., 1998). Specifically, subthreshold rTMS
applied unilaterally at a frequency of 0.5 Hz with a figureof-eight coil was shown to modify cortical excitability of the
unstimulated primary motor cortex (Gorsler et al., 2003) or
to modulate oscillatory activity of the primary sensory
cortex (Ogawa et al., 2004). High-frequency motor cortex
rTMS was also associated in healthy subjects with bilateral
cortical activation persisting beyond the time stimulation
(Siebner et al., 2000c), but such effects in patients with PD
were not supported by the present results. The changes
induced by rTMS in the complex patterns of interregional
coupling within the motor system may well differ between
high- and low-frequency rTMS, as it was shown for the
transcallosal cross-talk between the right and left primary
motor cortices (Gorsler et al., 2003).
In addition, apart from the cortical changes, an influence
of cortical stimulation on subcortical structures cannot be
ruled out. For instance, primary motor cortex rTMS was
shown to increase dopamine release in the nigrostriatal
system (Strafella et al., 2003). However, rTMS effects
did not overlap the effects of l-dopa (cf. effects of
high-frequency rTMS on ICF), and the mechanisms of
action of rTMS were supposed to take place, at least partly,
at the cortical level in the present study. Thus, these results
support the interest of modulating motor cortex activity to
act on motor performance in patients with PD.
A dysfunction in the primary motor cortex, related to the
impaired nigriostriato-thalamic network, could contribute
to motor disturbances in patients with PD, as suggested by
various neurophysiological or imaging data. For instance,
an abnormal synchronization between cortical and
subcortical (basal ganglia) oscillatory activities has been
demonstrated at the origin of akinesia (Cassidy et al.,
2002). In particular, bradykinesia was associated with a
J.-P. Lefaucheur et al. / Clinical Neurophysiology 115 (2004) 2530–2541
movement-related decrease in desynchronization of the mu
rhythm over the primary motor cortex (Devos et al., 2004).
A bilateral overactivation of the primary motor cortex was
observed in imaging studies of patients with PD (using
functional magnetic resonance imaging, single-photon or
positron emission tomography) (Haslinger et al., 2001;
Sabatini et al., 2000; Samuel et al., 1997; Thobois et al.,
2000). This hyperactivity, either primary or secondary to
the development of compensatory mechanisms (Buhmann
et al., 2003), was shown reduced after dopaminergic
treatment (Feigin et al., 2001; Haslinger et al., 2001) or
deep brain stimulation (Ceballos-Baumann et al., 1999;
Limousin et al., 1997; Thobois et al., 2002). However,
imaging studies did not allow the distinction between
excitatory and inhibitory synaptic changes.
Results obtained by TMS techniques in patients with PD
suggested an imbalance of the corticospinal excitability
towards a state of reduced inhibition at rest, especially in
rigid patients, and towards a defective activation when a
voluntary output was to be produced, especially in akinetic
patients (Cantello et al., 2002). In the present study,
low-frequency rTMS increased inhibitory mechanisms and
decreased rigidity whereas high-frequency rTMS increased
both inhibitory and excitatory mechanisms and improved
both rigidity and bradykinesia. Thus, the restoration of
inhibitory inputs may relieve rigidity by reducing the
excessive corticospinal motor output at rest, whereas
the restoration of excitatory inputs may relieve bradykinesia
by improving a defective cortical activation during
voluntary movement. However, such correlations between
excitability changes and the relief of specific parkinsonian
symptoms are purely speculative, and future studies,
based on larger series of patients, might test these
hypotheses properly.
4.4. Clinical perspectives for motor cortex stimulation
in PD
The present study provided original data that could open
perspectives to act on motor performance in patients with
PD by stimulating the primary motor cortex. As assessed
on UPDRS motor score, the clinical improvement obtained
by unilateral motor cortex stimulation in the present study
was significant (17 – 19.5% reduction) and not far from the
results, which were reported for unilateral subthalamic
nucleus stimulation (23% reduction) (Kumar et al., 1999).
This improvement was clearly transient, inconsistent with a
therapeutic goal, but resulted just from one session of
stimulation. By repeating rTMS sessions, the clinical
effects could be enhanced or prolonged, as it was shown
for the treatment of depression (George et al., 2000).
Nevertheless, the best way to stimulate a targeted cortical
area remains to implant electrodes. Recently, promising
clinical effects were obtained by chronic, unilateral
stimulation of the motor cortex using implanted extradural
electrodes in patients with PD (Canavero et al., 2002) and
2539
in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)lesioned monkeys, the primate model of PD (Drouot et al.,
2002). Even if rTMS effects are not necessarily predictive
of a good outcome of an implanted cortical procedure,
the present results gave some clues to guide the
development of original therapeutic strategies using
cortical stimulation to control motor disability in PD.
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