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-
Figure 1. ParadigmsofTBSandTheirEffects
(A) Graphical illustration of the three stimula-
tion paradigms used. Each paradigm uses a
theta burst stimulation pattern (TBS) in which
3 pulses of stimulation are given at 50 Hz,
repeated every 200 ms. In the intermittent
theta burst stimulation pattern (iTBS), a 2 s
train of TBS is repeated every 10 s for a total
burst stimulation paradigm (imTBS), a 5 s
train of TBS is repeated every 15 s for a total
of 110 s (600 pulses). In the continuous theta
burst stimulation paradigm (cTBS), a 40 s
train of uninterrupted TBS is given (600
(B) Timecourse of changes inMEP amplitude
following conditioning with iTBS (closed up
triangle), cTBS (closed down triangle), or
imTBS (open circle). There was a significant
effect of pattern of stimulation on change in
MEP size following stimulation [F(2,16) ?
20.32, p ? 0.001], with significant post hoc
differences between each pattern of stimulation. There was a significant facilitation of MEP size following iTBS lasting for about 15 min, and
a significant reduction of MEP size following cTBS lasting for nearly 60 min. imTBS produced no significant changes in MEP size.
(C) Comparison of the effects of cTBS given for 20 s (300 pulses; cTBS300 [open circle]) with the same paradigm given for 40 s (600 pulses;
cTBS600 [closed down triangle]). There was a significant effect of duration of cTBS conditioning on the time course of the effect (significant
TIME ? DURATION interaction [F(14,112) ? 2.24, p ? 0.05]) with the effect of cTBS300 lasting about 20 min compared to the effect of cTBS600,
which lasted about 60 min.
(D) Effects of cTBS600 on a longer timescale in order to confirm the return to baseline levels after 1 hr. Data are from 6 subjects and show
suppression at 25 and 45 min but no effect at 61 and 65 min.
(E) Comparison of the effect of continuous 15 Hz stimulation for 20 s (open square) (300 pulses) with cTBS given for 20 s (open circle) (300
pulses). Only the cTBS paradigm had any effect on MEP size following stimulation, and there was a significant interaction between TIME and
PATTERN [F(14,84) ? 2.55, p ? 0.005]. This graph also shows more clearly than (C) that the effect of cTBS300 had returned to baseline by
Results and Discussion
this data revealed a significant effect to TIME [F(3,15) ?
4.36, p ? 0.05], with post hoc tests showing significant
suppression of MEPs at 25 and 45 min but not at 61
and 65 min.
In order to understand which features of TBS patterns
are critical to the observed after effects, we compared
the results of applying 300 TMS pulses continuously at
15 Hz with the same number of pulses in the cTBS
pattern. Although it took 20 s to apply each type of
conditioning, only the cTBS pattern had any after effect
on the responses to TMS (Figure 1E) (significant interac-
tion between TIME and PATTERN [F(14,84) ? 2.55, p ?
burst component of TBS for producing long-lasting
A second experiment compared the effect of applying
a single train of TBS for either 2 s (i.e., the individual
component of the iTBS pattern) or 5 s (the component
from the small total number of pulses applied, these
short trains produced after effects that lasted only 15 s
or so. However, a 2 s train had a purely facilitatory effect
on MEPs (Figure 2A), whereas MEPs were initially facili-
tated aftera 5s train,but thensuppressed at10 sbefore
returning to baseline at 15 s (Figure 2B). Given that
a 20 s train of TBS (i.e., the cTBS pattern) is purely
suppressive, this suggests that a single train of TBS can
lead to a mixture of suppressive and facilitatory effects
on MEPs, with facilitation building up faster than sup-
pression, but with suppression being more powerful in
the long term.
Inthe firstexperiment, threepatterns ofTBS (Figure1A),
each consisting of a total of 600 pulses at an intensity of
80% active motor threshold, were given on different
days to the primary motor cortex of the same group of
subjects. The basic element of all of these patterns was
a burst of 3 stimuli at 50 Hz (i.e., 20 ms between each
stimulus), which was repeated at intervals of 200 ms
(i.e., 5 Hz). We refer to these patterns as continuous
TBS (cTBS), intermittent TBS (iTBS), and intermediate
before and after TBS was measured using single pulse
MEPs) in a small hand muscle. Figure 1B shows that
after cTBS, MEPs were suppressed for more than 20
min, whereas they were unaffected after imTBS and
facilitated after iTBS (ANOVA: significant effect of PAT-
TERN [i.e., iTBS, imTBS, or cTBS] [F(2,16) ? 20.32, p ?
0.001] with significant post hoc differences between
each pair of TBS patterns). Figure 1C shows that the
duration of the after effects was shorter when fewer
TMS pulses were applied in the cTBS pattern. MEPs
were suppressed for 60 min after a total of 600 pulses
(i.e., 40 s cTBS), whereas they were suppressed for
only 20 min after 300 pulses (i.e., 20 s cTBS) (ANOVA:
significant TIME ? DURATION interaction [F(14,112) ?
2.24, p ? 0.05]). In a subset of 6 subjects, we extended
the period of measurement beyond 60 min in order to
confirm that the effects of 40 s cTBS had returned to
baseline after 1 hr (Figure 1D). The one-way ANOVA on
Theta Burst Stimulation of the Human Motor Cortex
Figure 3. The Effect of iTBS and cTBS on Short Intracortical Inhibi-
tion and Facilitation
(A and B) SICI was significantly increased (A) following iTBS
[F(4,24) ? 5.01, p ? 0.005], but was reduced (B) following cTBS
[F(5,30) ? 3.75, p ? 0.01].
(C and D) ICF was not significantly altered (C) following iTBS, but
was significantly reduced (D) at 10 min following cTBS [F(2,12) ?
7.40, p ? 0.01].
Figure 2. The Effect on MEP Size of a Short Burst of TBS
MEP size was measured at baseline and then at 1, 5, 10, and 15 s
following the end of stimulation. Following a 2 s train of TBS (A),
there was a significant facilitation of MEP size [F(4,16) ? 6.99, p ?
facilitation of MEP size at 1 s after the end of stimulation (p ? 0.05)
followed by a significant suppression of MEP size at 10 s (p ? 0.05).
that cTBS300 had a different effect on the reaction
times of the two hands. One-factor analyses showed
that there was a significant effect of time in both hands
tioned hand: [F(2,16) ? 7.82, p ? 0.005]). However, in
the unconditioned hand this was due to a decrease in
reaction times 30 min after cTBS300, whereas in the
conditioned hand it was due to an increase in reaction
time 10 min after cTBS300. The accuracy of the force
with which subjects pressed the button was not
changed in either hand following conditioning (condi-
tioned hand: [F(2,16) ? 0.18, ns]; unconditioned hand:
[F(2,16) ? 1.14, ns]).
Thesedata confirm that veryshort periods of low-inten-
sity TBS over motor cortex can have powerful effects on
physiology and behavior that outlast the conditioning by
up to 1 hr. Since spinal H-reflexes were unaffected
whereas two sets of intracortical circuitry tested by SICI
(a probable GABAa-ergic pathway [Chen et al., 1998;
Given the very low intensity of the individual pulses
used in the conditioning trains (80% AMT), it is unlikely
that TBS produced any activity in descending cortico-
spinal fibers, and therefore that there were any direct
effects of TBS on the excitability of circuits in the spinal
observed. Consistent with this, we found that cTBS with
significant interaction between TIME and RESPONSE
TYPE [F(1,7) ? 6.05, p ? 0.05]).
To confirm that TBS has an effect on the excitability
of circuits intrinsic to the motor cortex, we measured
short intervalintracortical inhibition (SICI)and intracorti-
cal facilitation (ICF) before and after iTBS and cTBS300
using a paired pulse paradigm. In these experiments,
the intensity of the second, test, stimulus was adjusted
so that it evoked the same size of baseline MEP before
and after TBS. Figures 3A and 3B shows that SICI was
significantly facilitated following iTBS (ANOVA on the
timecourse: [F(4,24)? 5.01,p ?0.005]) andsuppressed
after cTBS [F(5,30) ? 3.75, p ? 0.01]. In contrast, ICF
was unaffected by iTBS and slightly reduced 10 min
after cTBS300 [F(2,12) ? 7.40, p ? 0.01] (Figures 3C
Unlike most other methods of conditioning the motor
with 300 pulses in total produced clear changes in sim-
ple reaction times. In this experiment, cTBS300 was
applied to the left motor cortex and reaction times mea-
sured in the right (conditioned) and left (unconditioned)
hands (Figure 4). A two-factor ANOVA revealed a sig-
nificant interaction between time (before and after
cTBS300) and hand [F(2,16) ? 4.30, p ? 0.05], indicating
Figure 4. Changes in Simple Reaction Time following cTBS
There was a significant lengthening of reaction time in the condi-
tioned hand 10 min (A) after cTBS [F(2,16) ? 4.30, p ? 0.05] and a
significant shortening of reaction time in the unconditioned hand
30 min (B) after cTBS [F(2,16) ? 7.82, p ? 0.005].
Hanajima et al., 1998; Reis et al., 2002; Ziemann et al.,
1998]) and ICF (pathway unknown) were clearly modu-
lated, it seems likely that TBS was exerting its main
Given that there is now good evidence that other forms
of TMS conditioning produce their after effects by
changing the effectiveness of synaptic interactions (Lee
et al., 2003; Siebner et al., 2000, 2003), we believe that
At first sight, the opposite effects of different patterns
of TBS are surprising. However, a similar dissociation
pocchi et al., 1992; Hess and Donoghue, 1996; Heynen
used longer trains of TBS-like paradigms to produce
suppression (Heusler et al., 2000; Takita et al., 1999).
Our data would be compatible with similar mechanisms
in which cTBS might reducethe efficacy of transmission
through the synaptic connections that are recruited
when evoking an MEP (i.e., the I wave circuits), whereas
iTBS would have the opposite effect. Similar arguments
can account for the changes in SICI and ICF that we
observed. Thus, we suggest that cTBS decreased the
effectiveness of synaptic connections that are recruited
in circuits involved in both SICI and ICF. This would
reduce SICI, resulting in less MEP inhibition probed by
SICI, and also reduce MEP facilitation probed with ICF.
Conversely, iTBS, which facilitated MEPs, might also
increase the effectiveness of connections involved in
SICI and increase MEP suppression probed by SICI.
There was no corresponding facilitation of the SICF cir-
cuit in the present data after iTBS. The reason for this
is unclear, but it may be related to the fact that more
or that we simply did not have sufficient subjects to
demonstrate statistically significant facilitation. If so,
then a simplified conclusion would be that cTBS had an
inhibitory effect on the circuits underlying MEP produc-
tion (I wave circuits), SICI, and ICF, while iTBS had an
opposite effect on these circuits.
We found our different TBS paradigms to have large
effect sizes and acceptable interindividual variability
compared with traditional rTMS paradigms. Thus, the
mean percentage change of MEP size in the period
where the maximum effect occurred (i.e., 7–14 min after
was ?45.0% (SD ? 8.9%), ?42.2% (SD ? 24.0%), and
75.7% (SD ? 40.9%), respectively. These effect sizes
and variability compare well with traditional rTMS para-
digms, such as those explored by Maeda et al. (2000),
where a much larger number of rTMS pulses (1600) pro-
duced mean effects of ?34.03% (SD ? 37.87%) after 1
Hz and 37.87% (SD ? 53.59%) after 10 Hz.
The effectiveness of these paradigms raises ethical
issues about the use of these methods in normal human
subjects, who have nothing to gain from modulation of
synaptic plasticity, in contrast to patients with particular
neurological disorders. We were aware of these ethical
issues, so in addition to putting our proposed experi-
tution and gaining consent from subjects, we pursued
the experiments in an incremental fashion starting with
smaller intensities and lower frequencies of stimulation
than those reported here. We found in all experiments
that cortical excitability eventually returned to baseline,
and no subject reported any side effects from experi-
mentation. However, as methods for inducing plastic
changes in human cortex become more powerful, such
issues will require constant scrutiny and vigilance on
the part of experimenters.
The results of the experiments with single trains of
TBS suggest that in humans, TBS produces a mixture
of facilitatory and inhibitory effects on synaptic trans-
mission, with facilitation building up faster than inhibi-
tion. If we assume that both facilitation and inhibition
saturate at some level, then it is possible to explain the
to dominate in the long run. Thus, a short, intermittent
protocol such as iTBS would favor rapid build-up of
facilitation. In contrast, a longer lasting continuous pro-
tocol such as cTBS would initially produce facilitation,
but eventually this would saturate, and inhibitory effects
(which build up slower but saturate at a higher level)
would dominate. An intermediate protocol such as
imTBS might have no net effect by achieving a balance
between the build-up of inhibitory and facilitatory ef-
fects. This model is speculative at this stage but would
in which a mixture of opposing effects on LTP and LTD
has been induced by the same protocol. For example,
blocking some of the pathways that are needed for LTD
induction, e.g., inositol triphosphate receptors (Nishi-
yama et al., 2000), can result in LTP after a protocol that
usually produces LTD, whereas blocking LTP-depen-
dent receptors, e.g., NMDA subunit 2A (Liu et al., 2004),
that on occasion, a single protocol can cause LTP in
and Crepel, 1990; Shen et al., 2003).
In conclusion, we have developed novel methods of
delivering rTMS based on patterns of theta burst stimu-
lation. We have found these stimulation paradigms to
be safe in normal subjects and capable of producing
consistent, rapid, and controllable electrophysiological
and behavioral changes in the function of the human
motor system that outlast the period of stimulation by
more than 60 min. In particular, we have found that the
pattern of delivery of TBS (continuous versus intermit-
tent) is crucial in determining the direction of change in
synaptic efficiency. The method may prove useful not
only in the motor cortex but also in other regions of the
brain for both the study of normal human physiology
and for therapeutic manipulation of brain plasticity.
Subjects were nine healthy volunteers between the ages of 23 and
52 (mean age: 33.6 ? 7.8 years) who gave their informed consent
for the experiments. The project protocol was approved by the Joint
Ethics Committee of the National Hospital for Neurology and Neuro-
Stimulation and Recording
Subjects were seated and EMGs recorded with a gain of 1000 and
5000 using Ag-AgCl surface electrodes over the right first dorsal
Theta Burst Stimulation of the Human Motor Cortex
interosseous muscle (dominant hand in all subjects). Magnetic stim-
ulation was given over the hand area of the motor cortex using a
hand-held figure of eight coil (70 mm standard coil, Magstim Co.,
pointing posteriorly. Single and paired pulses were delivered by
Magstim 200 machines, and rTMS was delivered using a Magstim
Super Rapid stimulator. The stimulation intensity was defined in
relation to the active motor threshold (AMT) for each Magstim ma-
chine separately as the minimum single pulse intensity required to
produce an MEP of greater than 200 ?V on more than five out of
a voluntary contraction of about 20% of maximum using visual
measures ANOVA was used to compare variables before and after
TBS, and paired t tests were used to compare the effect of TBS on
H-reflexes and MEPs recorded from FCR and the effect of a single
imTBS, and cTBS were performed on normalized data, whereas the
statistical analysis of each time course separately was performed
on absolute values. The comparison of data between MEP and
H-reflex was performed on log-transformed values in order to nor-
malize the distribution of the amplitude data. All figures represent
group data. Error bars refer to the standard error of the measure-
The patterns of rTMS all consisted of bursts containing 3 pulses at
50 Hz and an intensity of 80% AMT repeated at 200 ms intervals
a 2 s train of TBS is repeated every 10 s for a total of 190 s (600
pulses). In the intermediate theta burst stimulation paradigm (imTBS),
a 5 s train of TBS is repeated every 15 s for a total of 110 s (600
pulses). In the continuous theta burst stimulation paradigm (cTBS),
a 40 s train of uninterrupted TBS is given (600 pulses) (Figure 1A).
An additional comparison was made in some subjects with regular
15 Hz stimulation at the same intensity.
Corticospinal excitability was assessed by measuring the peak-
to-peak amplitude of MEPs in the contralateral FDI muscle to single
pulse TMS in resting subjects. Before TBS, 30 pulses were given
every 4.5–5.5 s. After TBS, batches of MEPs to 12 single pulses
were measured at different intervals.
To better understand the mechanism of our different TBS para-
digms, we explored the effect of a single train of 10 and 25 bursts
given over the motor hand area. MEPs were accessed 4–5 s before
the train of bursts and at 1 s, 5 s, 10 s, and 15 s after the train in
one block of testing. The block was then repeated every 40–45 s
for 10 repeats. Two separate sessions using either a 10 burst or a
25 burst train were assessed in each subject. Five subjects (3 men,
2 women; mean age, 27 ? 5 years) were recruited in this part.
We assessed short interval intracortical inhibition (SICI) and facili-
tation (ICF) in the motor hand area of seven subjects before and
after TBS using the double-pulse method described by Kujirai et al.
(1993). SICI was evaluated at an interstimulus interval (ISI) of 2 ms
using a conditioning intensity of 80% AMT, and ICF at an ISI of 10
intermixed with controls. The RMT was increased from 49.0% ?
8.9% to 51.0% ? 9.7% of maximum output of the magnetic stimula-
tor (t ? ?3.24, p ? 0.05) by cTBS, while AMT stayed unchanged
(t ? 0.55, ns). We therefore adjusted the intensity of the test stimuli
while assessing SICI and ICF after TBS to maintain the amplitude
of test MEPs at approximately 1 mV, but left the conditioning inten-
We also tested the H-reflex and MEP in the contralateral flexor
One block mixing 12 trials of H-reflex and 12 trials of MEP was
recorded prior to conditioning, and another block was recorded at
10 min after cTBS.
In a separate experiment, we assessed reaction time before and
after cTBS in nine subjects. Subjects were seated in a comfortable
chair with each index finger placed on a button. An electrical stimu-
lus at an intensity of 3 times sensory threshold was delivered ran-
domly to the left or the right hand through Ag/Ag-Cl electrodes
attached over the hypothenar eminence. Subjects were instructed
that when they felt a stimulus on the right or the left hand, they were
to press the button under the corresponding finger as quickly as
possible. In addition, subjects were asked to press the button with a
given on a screen in front of them.
Two blocks of reaction time testing were performed, with 40 stim-
uli to each hand given at random intervals, ranging from 1.5 to 2.5 s,
and in a random pattern. cTBS was then given over the left motor
hand area, and the process was repeated at 10 and 30 min.
We would like to thank Mr. Peter Asselman for all his help in main-
taining and running the labs used to perform these experiments.
The work was funded by the Medical Research Council.
Received: June 21, 2004
Revised: October 12, 2004
Accepted: November 23, 2004
Published: January 19, 2005
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