Neuron, Vol. 45, 201–206, January 20, 2005, Copyright ©2005 by Elsevier Inc.DOI 10.1016/j.neuron.2004.12.033
ReportTheta Burst Stimulation
of the Human Motor Cortex
the motor cortex since it is possible to use the size of
the electromyographic (EMG) response to a single TMS
pulse as an objective measure of cortical excitability.
Here, results are often weak, highly variable from one
individual to another (Maeda et al., 2000), and rarely last
longer than half an hour. Behaviorally, the experiments
on the motor system produce no obvious effects on
basic motor parameters such as strength or speed of
contraction (Muellbacher et al., 2000). However, small
changes can be seen in more complex paradigms. Simi-
larly, rTMS over other cortical areas can induce subtle
changes in cognitive functions (Evers et al., 2001; Had-
land et al., 2001; Sparing et al., 2001), but again these
are relatively modest. Clinically, rTMS has been used
to try to treat a variety of neurological and psychiatric
conditions from Parkinson’s disease to obsessive-com-
pulsive disorder. The largest number of trials has been
for depression, but again, the results have been equivo-
cal (Hausmann et al., 2004; Martin et al., 2003).
There are several possible reasons for the previous
disappointing results of rTMS: first, even in animal ex-
periments, LTP/LTD is difficult to demonstrate in the
cortex of awake and freely moving animals without the
use of extended or repeated sessions of stimulation
(Froc et al., 2000; Trepel and Racine, 1998). Second,
concerns over safety have limited many human studies
to relatively low frequencies of stimulation (usually ?10
Hz) (Wassermann, 1998), whereas animal studies often
use much higher frequencies such as the “theta burst”
paradigm (3–5 pulses at 100 Hz repeated at 5 Hz) (Hess
et al., 1996; Huemmeke et al., 2002; Larson and Lynch,
1986; Vickery et al., 1997). Third, TMS in humans is
relatively nonfocal, and therefore cannot be used to tar-
get spatially specific neural connections. In most in-
stances, this means that rTMS will activate a mixture of
systems that potentially could have interacting effects
that make the final outcome difficult to predict.
Other stimulation methods have been used to try to
induce plastic changes in human cortex, for example
paired associative stimulation (PAS) (Ridding and Uy,
2003; Stefan et al., 2000) or transcranial direct current
stimulation (Nitsche and Paulus, 2000). PAS can pro-
30 min, and peripheral stimulation is given at 2–3 times
sensory threshold, which may be uncomfortable for
some subjects. There is less experience with the use of
minutes typically are needed to produce any effect.
A recent pilot study has shown that a single short,
low-intensity burst of rTMS at 50 Hz is safe and can
target specific populations of neurons in the motor cor-
tex (Huang and Rothwell, 2004). In the present experi-
ments, we have aimed to produce clear after effects of
rTMS in the human motor cortex by employing repeated
Ying-Zu Huang,1,2Mark J. Edwards,1
Elisabeth Rounis,1Kailash P. Bhatia,1
and John C. Rothwell1,*
1Sobell Department of Motor Neuroscience
and Movement Disorders
Institute of Neurology
University College London
London WC1N 3BG
2Department of Neurology
Chang Gung Memorial Hospital
Taipei City 10507
It has been 30 years since the discovery that repeated
electrical stimulation of neural pathways can lead to
long-term potentiation in hippocampal slices. With its
relevance to processes such as learning and memory,
the technique has produced a vast literature on mech-
the most promising method for transferring these
stimulation (rTMS), a noninvasive method of stimulat-
ing neural pathways in the brain of conscious subjects
through the intact scalp. However, effects on synaptic
plasticity reported are often weak, highly variable be-
tween individuals, and rarely last longer than 30 min.
Here we describe a very rapid method of conditioning
the human motor cortex using rTMS that produces
a controllable, consistent, long-lasting, and powerful
effect on motor cortex physiology and behavior after
an application period of only 20–190 s.
and manipulate the efficacy of synaptic transmission
by repetitive electrical stimulation of central nervous
pathways. This leads to the well-studied phenomena of
long-term potentiation (LTP) and depression (LTD) of
synaptic connections. Repetitive transcranial magnetic
stimulation (rTMS), which is a noninvasive method of
stimulating the brain of conscious human subjects
through the intact scalp, has obvious potential for mim-
icking the effects that have been observed in animal
models. Yet despite the striking effects on synaptic
transmission that have been achieved in animals, trans-
lation to the human brain using rTMS has been rela-
Investigations have been carried out on three levels:
physiological, behavioral, and clinical. All are designed
of particular patterns of rTMS to selected areas of cor-
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