brepetitive transcranial magnetic stimulation of different
Results: After 5 s of 10-Hz rTMS, the mean amplitude of MEP for the stimulated M1 cortex decreased for up to 90 min (P = 0.002) and
Repetitive transcranial magnetic stimulation (rTMS) is a
noninvasive method to modulate excitability of human
cerebral cortex. Depending on the stimulation paradigms
tory effects on cortical excitability can be varied. In
general, high-frequency (>5 Hz) rTMS is considered to
exert a facilitative effect on motor cortical excitability,
and low-frequency (61 Hz) rTMS has an inhibitory effect.
Based on this general view, rTMS has been therapeutically
applied in various neurological and psychiatric conditions
*
Corresponding author. Tel.: +82 31 787 7733; fax: +82 31 787 4056.
E-mail address: hyungik1@snu.ac.kr (H.-I. Shin).
Clinical Neurophysiologythat of the unstimulated M1 cortex decreased for up to 60 min (P = 0.008). Enhancement of ICI and suppression of ICF were observed
and sustained for more than 90 min in both stimulated (P = 0.001) and unstimulated (P = 0.003) M1 cortex after 5 s of 10-Hz rTMS.
After 1.5 s of 10-Hz rTMS, the mean amplitude of MEP increased in stimulated cortex for up to 120 min (P = 0.005).
Conclusions: With different stimulation durations, high-frequency subthreshold rTMS can produce different patterns of long-lasting
changes in corticospinal and intracortical excitability in stimulated and unstimulated motor cortex in healthy subjects.
Significance: The results have important implications for the selection of stimulation parameters other than the frequency of rTMS. The
clinical application of rTMS for the purpose of motor enhancement should be considered along with the mechanism of different
stimulation parameters.
 2007 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.
Keywords: Transcranial magnetic stimulation; Cortical excitability; Motor cortex; Motor-evoked potentials; Stimulation duration; Stimulation
parameter; Paired-pulse stimulation
1. Introduction such as frequency, stimulation intensity, regularity, stimu-
lation duration, and total number of pulses, the modula-stimulation durations
Se Hee Jung
a
, Jae Eun Shin
b
, Yong-Seol Jeong
c
, Hyung-Ik Shin
d,
*
a
Department of Rehabilitation Medicine, Seoul Metropolitan Boramae Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea
b
Department of Rehabilitation Medicine, National Rehabilitation Hospital, Seoul, Republic of Korea
c
Department of Rehabilitation Medicine, Kyung Hee East-west Neo Medical Center, Kyung Hee University College of Medicine, Seoul, Republic of Korea
d
Department of Rehabilitation Medicine, Seoul National University Bundang Hospital, 300 Gumi-dong, Bundang-gu, Seongnam-si,
Gyeonggi-do 463-707, Republic of Korea
Accepted 30 September 2007
Available online 26 November 2007
Abstract
Objective: To investigate the changes in cortical excitability of the human motor cortex induced by high-frequency repetitive transcranial
magnetic stimulation (rTMS) of different stimulation durations.
Methods: Twenty healthy subjects participated in the study. Subjects received 20 trains of 10-Hz rTMS at 80% of the resting motor
threshold (RMT) intensity with two different stimulation durations (5 and 1.5 s) over the motor hot spot for left first dorsal interosseous
(FDI) muscle. Electromyographic responses (motor-evoked potentials, MEPs) to single-pulse stimulation, and intracortical inhibition
(ICI) and intracortical facilitation (ICF) by paired-pulse stimulation were measured bilaterally in the relaxed FDI muscles before,
immediately after, and 30, 60, 90 and 120 min after rTMS.Changes in motor cortical excita1388-2457/$32.00  2007 International Federation of Clinical Neurophysiolo
doi:10.1016/j.clinph.2007.09.124ility induced by high-frequency
www.elsevier.com/locate/clinph
119 (2008) 71–79gy. Published by Elsevier Ireland Ltd. All rights reserved.

uropincluding stroke, Parkinson’s disease, and chronic pain.
For the stroke patients, rTMS has been used to modulate
the stroke-induced imbalance of cortical excitability
between hemispheres by reducing excitability of the unaf-
fected hemisphere, increasing excitability of the affected
hemisphere, or suppressing transcallosal inhibition from
the unaffected hemisphere (Lefaucheur et al., 2006). In Par-
kinson’s disease, in which the primary pathology is dopa-
minergic neurons in basal ganglia, altered motor cortical
excitability and intracortical excitability were observed.
Studies on rTMS over motor cortex showed improvement
in Parkinson’s disease symptoms (Siebner et al., 2000a;
Khedr et al., 2003; Lomarev et al., 2006). High-frequency
rTMS was suggested to have an analgesic effect in chronic
pain by restoring defective intracortical inhibitory mecha-
nisms and affecting structures involved in pain and sensory
processing (Lefaucheur et al., 2006).
However, the neurophysiological mechanisms of rTMS
that modulate cortical excitability are not well-established.
There are heterogeneous and contradictory results from
numerous studies on the effect of rTMS on corticospinal
excitability. Several studies reported no change (Di Lazz-
aro et al., 2002; Lang et al., 2004) or a decrease (Gangitano
et al., 2002) in corticospinal excitability after high-fre-
quency rTMS. There are differing results related to the
changes in intracortical excitability following high-fre-
quency rTMS (Modugno et al., 2003; Quartarone et al.,
2005; Daskalakis et al., 2006; Fitzgerald et al., 2006; Khedr
et al., 2007). Therefore, this treatment can cause unin-
tended after-effects and perhaps even harm if it is simply
applied based on the hypotheses that high-frequency rTMS
is facilitative and low-frequency rTMS is inhibitory. The
neurophysiological effects of various stimulation parame-
ters need to be established before rTMS is widely used
for therapeutic purposes.
We applied unilateral high-frequency rTMS to M1 cor-
tex with two different stimulation durations to determine:
(1) if high-frequency rTMS consistently enhanced or sup-
pressed corticospinal excitability; (2) if high-frequency
rTMS consistently enhanced or suppressed the intracortical
inhibition (ICI) and intracortical facilitation (ICF) in the
stimulated cortex; (3) if there was any change in corticospi-
nal excitability, ICI or ICF of unstimulated motor cortex;
and (4) if the modulatory effect of rTMS was long-lasting
enough to justify therapeutic applications of rTMS.
2. Methods
2.1. Subjects
Twenty healthy young volunteers (11 men and 9 women;
age 21–36 years, mean 27.2 years) with no history of neuro-
logical or psychiatric disorder participated in this study. All
participants were right handed, according to the Edinburgh
Handedness Inventory (Oldfield, 1971). Informed consent
72 S.H. Jung et al. / Clinical Newas obtained from all subjects prior to the study. The
experimental procedures were conducted according to theDeclaration of Helsinki and approved by the local Institu-
tional Review Board of Seoul National University Bund-
ang Hospital.
2.2. Preparation
Subjects sat in a comfortable chair and were asked to
relax. A recording electrode was placed on the first dorsal
interosseous (FDI) muscle at the proximal edge adjacent
to the first and second carpal–metacarpal joint using dis-
posable self-adhesive 19-mm diameter surface electrodes
(VIASYS Healthcare, Wisconsin, USA). A reference elec-
trode was placed on the second metacarpophalangeal joint.
Motor-evoked potential (MEP) signals were filtered
(bandpassed between 50 Hz and 2kHz), amplified, and dis-
played on a conventional electromyograph (EMG)
machine (Medelec Ltd., Surrey, UK). Audiovisual EMG
feedback was given to assist subjects in achieving complete
muscle relaxation.
rTMS on M1 cortex was delivered through a figure-of-
eight coil connected to a Magstim 200 magnetic stimulator
(Magstim Co., Whitland, Dyfed, UK). The external diam-
eter of each loop was 90 mm and the peak magnetic field
was 2.2 T. The coil was placed tangentially to the scalp
approximately 45 from the midline, and the handle of
the coil pointed 45 backwards and laterally. To avoid
uncontrolled coil displacement during the TMS session, a
combination of manual handling and mechanical fixation
of the coil was used.
We determined the ‘‘hot spot’’ for activation of the left
FDI muscle, where stimuli-evoked motor potentials with
maximal peak-to-peak amplitude. Stimuli at slightly supra-
threshold intensity were given over the right M1 cortex and
the coil was moved in 5-mm steps to determine the optimal
scalp position. We then determined resting motor threshold
(RMT), which was defined as the minimum stimulation
intensity required to evoke MEPs of more than 50 lVin
at least five of 10 trials, at rest to the nearest 1% stimulator
output.
2.3. Repetitive transcranial magnetic stimulation
This study consisted of three separate sessions, two real
rTMS sessions and one sham rTMS session, conducted
more than 1 week apart. In real rTMS sessions, the subjects
received 20 trains of 10-Hz stimuli delivered with either a
duration of 5 s (5-s session) or 1.5 s (1.5-s session). rTMS
was applied at 80% of RMT intensity with a 55-s intertrain
interval. The figure-of-eight coil was centered over the
scalp position previously determined. Throughout the
study, subjects wore a tightly fitting cap on which the
‘‘hot spot’’ was marked to ensure accurate stimulation
and consistent repositioning of the coil.
The procedure was identical for sham stimulation to the
real 5-s rTMS session, but the coil was placed perpendicu-
hysiology 119 (2008) 71–79lar to the scalp without direct contact. Subjects clearly
heard the clicks of the coil.