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Transcranial Magnetic Stimulation of the Cerebellum in Essential Tremor
A Controlled Study
Alexandre Gironell, MD;
Jaime Kulisevsky, MD;
José Lorenzo, MD;
Manel Barbanoj, MD;
Berta Pascual-Sedano, MD;
Pilar Otermin, MD
Arch Neurol. 2002;59:413-417.
ABSTRACT
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Background Growing evidence implicates an overactivity of the cerebellum in the
pathophysiology of essential tremor. In a small series of patients, we explored
the acute effects and therapeutic possibilities of low-frequency repetitive
transcranial magnetic stimulation (rTMS) of the cerebellum in patients with
essential tremor in a double-blind, crossover, placebo-controlled design.
Methods Ten patients with essential tremor underwent an active and a sham rTMS
session, at a 1-week interval. The rTMS was performed with a focal double
70-mm butterfly coil (maximum peak field of 2.2 T) applied 2 cm below the
inion. Each session consisted of 30 trains of 10-second duration separated
by 30-second pauses, at 100% of the maximum output intensity and at 1-Hz frequency.
Major evaluation outcomes were the score on the Tremor Clinical Rating Scale
and accelerometric recordings obtained before (-5 minutes), immediately
after (+5 minutes), and 1 hour after (+60 minutes) each rTMS session. Both
clinical and accelerometric measurements were obtained by a blinded neurologist.
Results On the +5-minute assessment, active rTMS produced a notable tremor improvement
compared with sham rTMS, as evidenced by a significant reduction in scores
on the clinical rating scale and accelerometric values. At +60 minutes, no
clinical or accelerometric benefit was evidenced. No adverse effects of rTMS
were observed.
Conclusions This exploratory study of the potential therapeutic properties of rTMS
on essential tremor showed an acute antitremor effect. Further investigation
in search of a more lasting benefit is warranted.
INTRODUCTION
REPETITIVE transcranial magnetic stimulation (rTMS) has become a useful
noninvasive tool to study the physiology of the human cortex.1
In healthy control subjects, fast rTMS at a frequency of 5 Hz and higher induces
an increase in cortical excitability beyond the time of stimulation, whereas
low-frequency rTMS at 1 Hz gives rise to a lasting decrease in cortical excitability.1-2 Several recent reports have suggested
that this modulation of cortical excitability by rTMS might have therapeutic
potential in patients with major depression, Parkinson disease, or focal dystonia.3
Essential tremor (ET), characterized by tremor during the maintenance
of posture and active movement, is one of the most common movement disorders.4 Pharmacologic treatment is poor and often unsatisfactory,
usually failing to achieve adequate tremor control.4-5
There is a clear need for new therapies for ET.4
Evidence of the overactivity of deep nuclei and cerebellar cortex in
the pathophysiology of ET is growing.6-13
In this preliminary exploratory study, we evaluated the acute effects and
therapeutic possibilities of low-frequency rTMS over the cerebellum in patients
with ET with a double-blind, crossover, placebo-controlled design.
PATIENTS AND METHODS
Ten outpatients (7 men and 3 women; mean age, 67.9 years; range, 57-77
years; mean tremor duration, 12.2 years; range, 5-25 years) attending the
Movement Disorders Section of the Sant Pau Neurology Department, Barcelona,
Spain, with moderate (sufficient to cause mechanical or social disability)
to severe ET were included in the study between June 1, 1999, and June 30,
2000, according to a previous sample size calculation. All 10 patients completed
the study. Diagnosis was established on the basis of chronic (ie, longer than
5 years), persistent (although the amplitude could fluctuate), bilateral (although
it could be asymmetric) postural tremor with or without kinetic tremor involving
hands or forearms (although tremor of other body parts could be present in
addition to upper limb tremor), with no other neurologic abnormalities related
to systemic or other neurologic disease (with the exception of the presence
of tremor, cogwheeling, and Froment sign) and no other explanation for tremor
(eg, the presence of known causes of enhanced physiologic tremor, concurrent
or recent exposure to drugs known to cause tremor, or the presence of drug
withdrawal state).14
The study protocol was approved by the hospital ethics committee and
was performed in accordance with international ethical regulations.15 The study was proposed to 42 patients. Twenty-eight
patients refused to participate, mainly because of the nature of the procedure,
and 4 patients were excluded from the trial for one of the following exclusionary
criteria: seizures (n = 1), cardiac pacemakers (n = 2), and tremor-active
drugs (n = 1). Tremor-active drugs included central cholinergic drugs (acetylcholine
chloride, muscarinic and nicotinic agonists, anticholinesterases, and aminopropranolols),
central monoaminergic drugs (neuroleptics, phenylethylamines, and indoles),
peripheral adrenergic drugs (lithium carbonate, amphetamine sulfate, adrenocorticosteroids,
and thyroid hormone supplements), and others such as anticonvulsants (valproic
acid), bronchodilators (theophylline and terbutaline sulfate), or antidepressants
(amitriptyline hydrochloride). Patients with dystonia were also excluded.
Patients were requested to avoid alcohol, caffeine, and smoking for 24 hours
before testing. Finally, 10 subjects gave written informed consent to participate
after the nature of the procedure had been fully explained.
Patients were systematically asked about family history of ET. Three
patients reported a history in first-degree relatives. In addition to hand
tremor, tremor was present in the head in 3 patients. Kinetic tremor of the
upper limbs was present in all patients in addition to postural tremor. Four
patients were newly diagnosed, and the rest had been treated with antitremor
medication (5 with propranolol hydrochloride [mean dosage, 135 mg daily] and
1 patient with diazepam [15 mg daily]). Antitremor medication and doses were
not changed after the end of the study.
The rTMS was performed with a high-speed stimulator (Magstim Rapid,
Carmarthenshire, England) by means of a focal double 70-mm butterfly coil
with a maximum peak field of 2.2 T. The electrical field induced by this coil
was maximal beneath the center of the figure of 8.16
Use of this type of coil stimulates a small area of the cortex of approximately
2 cm in diameter.16-17 We presumed
it was unlikely that the coil placed over the occiput would stimulate structures
much deeper than 2 cm; ie, the cerebellum (at least 1.5 cm deep) would be
preferentially stimulated rather than the brainstem (at least 3.0 cm deep).17-19 The inion was taken
as a landmark of the boundary between the posterior cerebellum and the occipital
cortex. We therefore stimulated the area caudal to the inion to stimulate
the posterior cerebellum. The coil was oriented vertically and the current
was directed upward with respect to the head. The coil was applied 2 cm below
the inion (placement was based on previous studies that demonstrated effective
stimulation of the cerebellum).20-22
At the beginning of each rTMS session, single stimulations were administered
at the theoretical stimulation point. Motor effects (activation of pyramidal
tract or upper cervical motor roots) were monitored at this point by means
of electromyographic recording of the right abductor pollicis brevis muscle.
If motor effects appeared, the stimulation point was repositioned 2 cm upward,
and if photopsias were observed, the stimulation point was repositioned 2
cm lower. Each session consisted of 30 trains of 10 seconds in duration separated
by 30-second pauses. Stimulation was applied at 1-Hz frequency, at maximal
(100%) stimulator output intensity. These stimulation variables were to some
extent outside of the safety guidelines developed for rTMS of the motor cortex
to avoid the risk of epilepsy.23 Nevertheless,
we assumed that the risk of producing epileptic crisis with cerebellar stimulation
would be low. To obtain a more homogeneous administration of the rTMS variables
and to ensure the cerebellum was reached, we decided on this protocol of stimulation.
Stimulation was applied either with the coil resting flat on the scalp,
as required to achieve induction of adequate cortical stimulation (active
rTMS), or with the coil angled at 90° and with only the edge of the coil
resting on the scalp (sham rTMS). The sham rTMS induces a mild contraction
of the scalp muscles and a subjective sensation similar to that achieved with
active rTMS, but fails to induce a significant cortical stimulation.16, 24 Each stimulation session lasted nearly
20 minutes, and each subject received a total of 300 stimuli per session.
Stimulation sessions were performed by a trained neurologist (A.G.) in a room
equipped with the necessary instruments and medications for the prompt treatment
of a possible seizure. All patients wore earplugs during the stimulation session.
The study design was double blind (both patient and examiner were blinded
to study arms, although the neurologist who administered active and sham rTMS
was obviously not), crossover, and placebo controlled. Active and sham rTMS
were administered in random order (Latin square design) with a 1-week period
between sessions.
If the patient was taking antitremor medication, this was stopped 72
hours before the rTMS session and restarted after study measurements were
completed at each rTMS session.
Main outcome measures consisted of the comparison of results of a Tremor
Clinical Rating Scale (TCRS) and accelerometric recordings evaluated at baseline
(5 minutes before) and at +5 minutes and +60 minutes after rTMS session. Adverse
events were carefully monitored throughout the trial, with patients being
questioned about common side effects of rTMS.
The TCRS consisted of the scale proposed by Fahn et al25
with minimal modifications. To study acute effects of rTMS, we used parts
1, 2, and 4 of this scale. Specifically, clinical examination was performed
by visual inspection of postural and kinetic tremor of the hands (fingers),
legs, head, and trunk (part 1), according to the following scale: 0, none;
1, mild (amplitude, <0.5 cm); 2, moderate (amplitude, 0.5-1.0 cm); 3, marked
(amplitude, >1.0-2.0 cm); and 4, severe (amplitude, >2.0 cm) (maximum score,
40). Scores for face, tongue, and voice were not included. Postural tremor
was assessed with the patient's hands held prone in front of the nose and
with the arms abducted, whereas kinetic tremor was assessed in the middle
of the transit phase of the finger-to-nose test with the target object held
at arm's length from the patient. Measures of motor task performance (part
2), including handwriting, drawing spirals (2 sizes) and lines, and pouring
liquids from one cup to another, were scored as follows: 0, normal; 1, mildly
abnormal, tremulous; 2, moderately abnormal, considerable tremor; 3, markedly
abnormal; and 4, severely abnormal, unable to perform the task (maximum score,
36). Part 4 (subjective assessment by the patient compared with last visit)
was scored as follows: 0, without changes; +1, slight improvement; +2, moderate
improvement; +3, marked improvement; -1, slight worsening; -2,
moderate worsening; and -3, marked worsening. Part 3 was not included.
All clinical assessments were carried out by the same examiner (J.L.) blinded
to study arms.
Neurophysiologic recordings were assessed as objective tremor measures
by means of the previously described method.26
Briefly, a single-plane accelerometer transducer (Grass Instruments Division,
Astro-Med Inc, West Warwick, RI) oriented in the vertical plane was attached
to the dorsal surface of the index finger of the most affected hand. The patient
was comfortably seated upright in a chair. Three recordings of 60 seconds'
duration each were obtained in a postural position of arms outstretched in
front of the chest. The hands were allowed to rest for 40 seconds between
recordings. Tremor was quantified by a power spectra analysis to determine
the dominant frequency peak (hertz) and the magnitude of the accelerometer
signal (absolute power of the dominant frequency peak in microvolts squared).
Final data for each time point consisted of the mean of the 3 recordings.
Statistical analysis of rTMS effects over the main variables (TCRS scores
[parts 1 and 2] and absolute power of the dominant frequency peaks) was evaluated
with an analysis of variance using ordinary least squares. The model included
2 within-subject factors: treatment (2 levels: sham vs active) and time (3
levels: baseline, +5 minutes, and +60 minutes). The time course of intervention
effects after each treatment and intertreatment effects at each time point
were subsequently assessed in a descriptive perspective by means of the corresponding
1-way repeated-measures analyses of variance and paired t tests. The results of TCRS part 4 were analyzed by means of the nonparametric
Wilcoxon matched-pairs test. Any P<.05 was considered
significant. Data are presented as mean (SD) unless otherwise indicated.
RESULTS
CLINICAL EXAMINATION AND MOTOR TASK PERFORMANCE (TCRS PARTS 1 AND 2)
The analysis of variance showed significant time (P = .001) and interaction (treatment x time) (P = .007) effects. Treatment effect showed a tendency toward significance
(P = .09).
Although no significant differences in TCRS scores between the interventions
were observed at baseline (sham, 23.8 ± 13.2; active, 25.2 ±
11.8) and at +60 minutes (sham, 23.4 ± 13.9; active, 22.9 ±
11.1), the TCRS scores were significantly lower at +5 minutes after active
rTMS (20.7 ± 11.8) than after sham rTMS (23.4 ± 13.9) (t9 = 2.77; P = .02).
When the time course of intervention effects was assessed, no significant
differences were obtained when sham rTMS was applied. However, significant
effects were observed after active rTMS, with scores at +5 minutes (t9 = 4,70; P = .001)
being significantly lower than those at baseline (Figure 1 and Figure 2).
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Figure 1. Course of tremor activity assessed
with the Tremor Clinical Rating Scale (TCRS; parts 1 and 2) in patients receiving
repetitive transcranial magnetic stimulation or sham treatment. Effects are
shown by mean values of 10 patients.
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Figure 2. Representative example of one
patient's performance in drawing spirals before and after 1-Hz repetitive
transcranial magnetic stimulation (rTMS) of the cerebellum. A, Active rTMS.
B, Sham rTMS. At +5 minutes after active rTMS, the patient was better able
to draw the spiral with minimal line crossing.
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NEUROPHYSIOLOGIC DATA
The mean dominant frequency peak was 5.9 Hz (range, 4.4-7.8 Hz). Tremor
frequency was not altered by treatments and did not predict treatment response.
The analysis of variance showed significant time (P = .01) and treatment (P = .04) effects.
The interaction (treatment x time) effect showed a tendency toward significance
(P = .08).
Although no significant differences in accelerometry values between
the interventions were observed at baseline (sham, 4905 ± 7120 µV2; active, 3637 ± 4272 µV2) and at +60 minutes
(sham, 3687 ± 3959 µV2; active, 3497 ± 7017
µV2), the absolute power of the dominant frequency peak was
significantly lower at +5 minutes after active rTMS (1348 ± 1886 µV2) than after sham rTMS (4654 ± 7614 µV2) (t9 = 2.32; P = .05).
When the time course of intervention effects was assessed, no significant
differences were obtained when sham rTMS was applied. However, significant
effects were observed after active rTMS at +5 minutes (t9 = 2.79; P = .02). This decrement
reached a mean value of approximately 60% (Figure 3).
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Figure 3. Course of tremor activity assessed
with accelerometry in patients receiving repetitive transcranial magnetic
stimulation or sham treatment. Effects are shown by mean values of 10 patients.
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SUBJECTIVE ASSESSMENT BY PATIENT (TCRS PART 4) AND GLOBAL PATIENT APPRAISAL
A significant treatment effect (P = .03) was
observed in the analysis of subjective assessments by the patient; the score
after active rTMS (+0.8 ± 0.7) was higher (ie, better) than that after
sham rTMS (0.0 ± 0.0).
When patients were asked about the treatment course they preferred,
no patient indicated sham rTMS as the most effective treatment, 6 (60%) indicated
active rTMS, and 4 (40%) found both treatments similar.
ADVERSE EVENTS
Slight headache was mentioned by 1 patient after active rTMS; it disappeared
within 48 hours after the rTMS session without the need for analgesics. The
remaining patients did not report any adverse events during the study.
No motor effects were observed during stimulation in any patient or
in any stimulation condition. One patient experienced photopsias during active
rTMS stimulation at the theoretical stimulation point, and the coil was repositioned
2 cm downward.
COMMENT
The findings of this preliminary study showed that low-frequency rTMS
of the cerebellum can induce a moderate, transient, significant reduction
of tremor in patients with ET.
In addition to the small number of patients included as a result of
the exploratory nature of the study, 2 further limitations of the study should
be pointed out. The first of these is the intrinsic difficulty in assessing
tremor in clinical trials, especially with accelerometric assessments, which
may have great intrasubject variability. Nevertheless, this problem was minimized
with our crossover controlled design, and both accelerometry and clinical
data showed a consistent beneficial effect of rTMS, a pattern of changes sufficiently
reliable to ensure the significant active therapy effect obtained. Second,
there have been conflicting reports regarding whether it is possible to stimulate
the human cerebellum through the intact scalp by means of TMS.27
However, recent works have clearly demonstrated that the cerebellum is accessible
to TMS when butterfly coils that permit deeper stimulation are used and when
a stimulating coil is positioned on the inion area.20-22
A limitation of the present study is that we collected no direct evidence
to ensure that we had stimulated the cerebellum. Moreover, other structures
could also be affected by the stimulation strength used. However, placement
of the stimulating coil in accordance with previous studies, together with
the monitoring during rTMS sessions of brainstem or occipital adverse effects,
led us to suppose that cerebellar hemispheres were actively stimulated. We
did not compare cerebellar stimulation with stimulation of other brain regions.
However, the central pathways involved in the pathophysiology of tremor are
incompletely known and cortical regions might be implicated. Thus, to preserve
the singular stimulation of cerebellar areas, we used the coil placed on edge
to produce the sham stimulation.
The cerebellum is one of the regions within the central motor pathways
that demonstrates oscillatory behavior and is a main candidate for the origin
of any pathologic central tremor.11-12
The candidate role of the cerebellum in the genesis of ET is further supported
by the animal model of harmaline tremor, by regional blood flow studies, and
by functional imaging data that provide evidence that ET is associated with
abnormal bilateral overactivity not only of deep cerebellar nuclei but also
of the cerebellar cortex.6-10,13
Overall, these findings support the notion of a central oscillator inducing
bilateral overactivity of cerebellar connections in ET, even when subjects
are at rest.7-10
Furthermore, a recent study using single-pulse TMS over the cerebelum in ET
showed normal excitability of the cerebellothalamocortical pathways, suggesting
an abnormal firing pattern of the efferent pathway or abnormalities in the
cerebellar afferent input.28
The frequency of stimulation may be a critical factor in determining
the effect of rTMS. Studies in animals with electrical stimulation at frequencies
in the single-hertz range produced a long-term decrease in the efficiency
of synaptic neuronal transmission (long-term asssociative depression).29-30 In rats, seizure thresholds were
lowered with 1-Hz stimulation, a phenomenon that has been called quenching.31 In humans, rTMS may induce
transient changes in neocortical excitability. Specifically, long trains of
low-frequency rTMS (0.9 or 1.0 Hz) led to a reduction in motor cortex excitability
evidenced both by a decrease in motor evoked potential amplitudes and by a
decrease in the cerebral metabolic rate.2 The
physiologic mechanism of this phenomenon is unknown, but it is supposed to
be reminiscent of long-term associative depression. However, the extrapolation
of these effects, observed in animal studies and in human motor cortex, to
human cerebellum is plausible, but not yet demonstrated.
Similar mechanisms could be alleged to explain the transient antitremor
effect of rTMS of the cerebellum observed in our patients with ET. First,
rTMS may interfere with the synchronicity level of oscillatory cerebellar
neurons. It has been reported that synchronous oscillatory membrane activity
in a large population of olivary neurons is needed to create relevant oscillatory
activity on the motor system.32 Second, rTMS
stimulation can locally increase the level of  -aminobutyric acid (GABA)
in the cerebellum. It is known that the dentritic spines through which the
inferior olivary cells are electrotonically coupled receive GABAergic input
from the deep cerebellar nuclei.33 Changes
in the activity of these systems may also increase or decrease the population
of neurons that entrained at a particular frequency, thus increasing or decreasing
the amplitude of the tremor oscillation. Moreover, rTMS can provoke synaptic
changes that alter the neuronal function of the cerebellar structures. In
fact, TMS can create temporary functional changes, by activating cells and
removing them from participation in their normal function in a network.1-2
With the variables used in the present study, we found no long-lasting
antitremor effect. The absence of a durable effect with rTMS has also been
reported in similar studies on myoclonus, dystonia, and Parkinson disease.34-36 It seems that rTMS
may have a clinical effect on movement disorders when stimulation is ongoing,
but the effect disappears soon after stimulation is stopped. This would be
similar to results with electrical deep brain stimulation of basal ganglia,
a technique succesfully applied in Parkinson disease.37
AUTHOR INFORMATION
Accepted for publication October 8, 2001.
Author contributions: Concept
and design (Drs Gironell, Kulisevsky, and Lorenzo); acquisition of data (Drs Gironell, Lorenzo, Pascual-Sedano, and Otermin); analysis and interpretation of data (Drs Gironell, Kulisevsky,
and Barbanoj); drafting of the manuscript (Drs Gironell,
Kulisevsky, and Otermin); critical revision of the manuscript
for important intellectual content (Drs Gironell, Kulisevsky, Lorenzo,
Barbanoj, and Pascual-Sedano); statistical expertise
(Drs Barbanoj and Otermin); administrative, technical, or
material support (Drs Gironell and Lorenzo); study
supervision (Drs Gironell, Kulisevsky, Barbanoj, and Pascual-Sedano).
Presented in abstract form at the 52nd Annual Meeting of the American
Academy of Neurology, San Diego, Calif, May 2, 2000.
We thank Ignasi Gich, MD, Epidemiology Department, Sant Pau Hospital,
for his assistance with statistics.
Corresponding author and reprints: Alexandre Gironell, MD, Servei
de Neurologia, Hospital de Sant Pau, Av Sant Antoni Ma Claret 167,
08025 Barcelona, Catalonia, Spain (e-mail: agironell{at}cataloniamail.com).
From the Movement Disorders Section, Department of Neurology (Drs Gironell,
Kulisevsky, Pascual-Sedano, and Otermin), and Pharmacological Research Area
(Drs Lorenzo and Barbanoj), Research Institute, Sant Pau Hospital, Autonomous
University of Barcelona, Catalonia, Spain.
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