An estimate of placebo effect of repetitive transcranial magnetic stimulation
Erica Hyunji Bae
, William H. Theodore
, Felipe Fregni
, Roberto Cantello
, Alexander Rotenberg
Department of Neurology, Children's Hospital, Harvard Medical School, Boston, MA, USA
Berenson–Allen Center for Noninvasive Brain Stimulation, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
National Institutes for Health (NIH), Bethesda, MD, USA
Laboratory of Neuromodulation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, MA, USA
Department of Clinical and Experimental Medicine, Section of Neurology, Amedeo Avogadro University, Novara, Italy
Received 9 August 2010
Revised 30 November 2010
Accepted 1 December 2010
Available online 7 January 2011
Repetitive transcranial magnetic stimulation
Objective: Low-frequency repetitive transcranial magnetic stimulation (rTMS) is emerging as a therapeutic
tool in epilepsy. In recent years, several open-label trials have shown an encouraging reduction in seizure
frequency in patients with epilepsy. However, the data from controlled trials are mixed with respect to
antiepileptic rTMS efﬁcacy, and the ﬁeld would beneﬁt from further carefully controlled trials. Prior to
initiating new trials, it is important assess the magnitude of the placebo effect of presently used sham rTMS
Methods: We systematically analyzed individual subject data from three placebo-controlled trials and
measured the placebo effect at follow-up intervals of 2, 4, and 8 weeks after sham rTMS treatment. Given the
relatively small subgroup sample size, placebo condition data were pooled for analysis.
Results: Three methods for sham rTMS were employed in the reviewed studies: (1) coil positioning
orthogonal to the scalp, (2) a spring-loaded sham coil, and (3) a double active-sham coil. The placebo
response overall was consistently low across follow-up intervals, both for median change in seizure frequency
(Kruskal–Wallis, P N0.4, df= 2) and for responder (deﬁned as ≥50% seizure frequency reduction) rate
(Fisher's exact rest, P N0.9, df =2). The aggregate effect of the placebo condition was a 0–2% median seizure
reduction rate and a responder rate of 16–20%.
Conclusion: We anticipate that these data will contribute to future power analysis as well as selection and
design of sham rTMS methods for controlled rTMS trials.
© 2010 Elsevier Inc. All rights reserved.
Transcranial magnetic stimulation (TMS) is a noninvasive method
for focal electrical brain stimulation whereby small intracranial
electrical currents are generated by a rapidly changing extracranial
magnetic ﬁeld . Low-frequency (0.3–1 Hz) repetitive TMS (rTMS)
can induce a lasting reduction in cortical excitability and has plausible
therapeutic potential for epilepsy . In recent years, several open-
label trials have shown that low-frequency rTMS may reduce seizure
frequency in patients with refractory epilepsy [3–8]. However, there
are only three published placebo-controlled trials, each employing
distinct rTMS protocols and subject selection, with inconsistent
conclusions. The ﬁrst found that the clinical effect of rTMS was mild
and short-lived . The second showed signiﬁcant seizure reduction
and improvement of the interictal EEG in the treated group, relative to
sham . The third concluded that active rTMS was no better
than placebo for seizure reduction, but that it signiﬁcantly reduced
interictal EEG epileptiform abnormalities . These inconsistent
ﬁndings with respect to seizure suppression in the controlled trials, as
well as the discrepancy between the open-label and controlled data,
suggest that further placebo-controlled trials of rTMS in epilepsy are
necessary to fully characterize its antiepileptic potential.
Estimation of the placebo effect of rTMS is necessary for future trial
design, particularly for power analyses and sample size calculations.
In addition, because of the limitations of available sham rTMS
methods, it is important to investigate whether there are differences
in placebo effect among the sham methods used in published trials.
Accordingly, we conducted a meta-analysis of individual data from
placebo-controlled rTMS trials to estimate the rTMS placebo effect.
Using PubMed we identiﬁed three English-language publications
describing placebo-controlled rTMS trials in epilepsy published from
Epilepsy & Behavior 20 (2011) 355–359
⁎ Corresponding author. Department of Neurology, Harvard Medical School,
Children's Hospital, Boston, MA 02115, USA. Fax: +1 617 730 0463.
E-mail address: email@example.com (A. Rotenberg).
1525-5050/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
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