Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS)
Section snippets
Principles
In 1831, Michael Faraday stated his law establishing that a time-varying current creates a magnetic field which, in turn, can induce an electric field and hence a secondary current within a nearby conducting medium. One hundred and fifty years later, Barker et al. (1985) proposed the first magnetic stimulator designed to stimulate the human brain transcranially, providing the prerequisite for subsequent clinical use of transcranial magnetic stimulation (TMS) (Barker, 1999). A number of TMS
Clinical applications of rTMS: methodology followed to derive the present guidelines
For each possible indication, bibliographic research was carried out independently by several experts, using keywords that will be specified at the beginning of each section. Each expert then proceeded to a critical reading of all selected publications in order to classify them according to the following criteria, used in a previous French version of the guidelines (Lefaucheur et al., 2011a) and derived from those proposed by the European Federation of Neurological Societies (Brainin et al.,
Pain
The present literature review and recommendations exclusively concern ongoing chronic pain and therefore exclude publications on the use of rTMS to relieve provoked acute or experimental pain, which has been reviewed elsewhere (Mylius et al., 2012b). Chronic pain can be neuropathic (originating from a lesion or disease of somatosensory systems, either peripheral or central), non-neuropathic (due to an excess of nociception secondary to inflammation or tissue lesion, or psychogenic), or without
Movement disorders
The bibliography on the use of rTMS in movement disorders is particularly extensive, with more than one hundred references, mainly concerning PD (Edwards et al., 2008). A number of these studies have, however, been discarded for this review due to various methodological limitations. First, the potential application of rTMS has not been considered in this work unless it was supported by at least 2 studies published by 2 independent research groups. Thus, despite the amount of published work, the
Stroke
The use of rTMS for therapeutic purposes or as part of a neurorehabilitation strategy for stroke recovery is relatively recent and the first clinical trials were begun in 2001 (see historical background in Hummel et al., 2008). Application of cortical stimulation in stroke is aimed at either correcting maladaptive brain plasticity induced by the cerebrovascular accident or enhancing adaptive brain plasticity during rehabilitation. This goal may be achieved by locally modifying cortical
Amyotrophic lateral sclerosis
The rationale for using rTMS as a therapeutic tool in amyotrophic lateral sclerosis (ALS) is based on the hypothesis that these protocols are capable of reducing motor cortex excitability and, thus, it would be theoretically possible to antagonize excitoxicity of an enhanced glutamate transmission in the motor corticospinal system. Moreover, it has been demonstrated that rTMS may modulate plasma levels of brain-derived neurotrophic factor (BDNF), a potent survival factor for motor neurons, in
Multiple sclerosis
A PubMed search (keywords: rTMS/TBS AND multiple sclerosis) identified 15 papers, but only 3 papers addressed therapeutic issues. In these 3 studies, performed by the same group, the effects of a 2-week protocol of 5 Hz rTMS delivered over the motor cortex were found to be beneficial for: (i) hand dexterity in a series of 8 multiple sclerosis patients with cerebellar symptoms (Koch et al., 2008c); (ii) lower limb spasticity in a series of 19 patients with relapsing-remitting multiple sclerosis (
Epilepsy
About 20% of patients with primary generalized epilepsy and up to 60% of patients with focal epilepsy do not respond adequately to antiepileptic drugs and develop drug-resistant epilepsy (Pati and Alexopoulos, 2010). Some of these patients may benefit from surgical treatment based on the resection of the epileptogenic zone. For the rest of the patients, it is important to develop alternative treatments, including neurostimulation techniques. Since rTMS modulates cortical excitability, which
Disorders of consciousness
An emerging, clinical application of rTMS focuses on chronic disorders of consciousness, a term currently used in the literature to indicate either a vegetative state (VS) or a minimally conscious state. A PubMed search (keywords: rTMS/TBS AND vegetative state OR disorders of consciousness) identified 9 papers, but no sham-controlled studies were found. Two case reports suggested the possibility that HF rTMS might produce some arousal in permanent VS patients, associated with an improvement of
Alzheimer’s disease
A PubMed search (keywords: rTMS/TBS AND Alzheimer’s disease) identified 48 papers. While several rTMS studies addressed the question of cortical excitability changes in patients with Alzheimer’s disease, only few data are available on the possible clinical impact of rTMS protocols in these patients. First, the effect of HF rTMS delivered to the right or left DLPFC on language abilities, especially naming accuracy, and sentence comprehension has been assessed, showing positive results (Cotelli
Tinnitus
The use of rTMS in the treatment of tinnitus stems from the development of models of central generation and maintenance of disabling subjective tinnitus (Langguth et al., 2003, Plewnia et al., 2003). Tinnitus usually follows acute or chronic cochlear injury or disease (acoustic trauma, drug toxicity, presbyacusis) and its neural correlates reflect central changes induced by auditory deafferentation (neural plasticity with hypersynchrony or hyperactivity of cortical and subcortical auditory and
rTMS and psychiatry: general considerations
For 20 years, many studies have suggested that rTMS could be efficacious in the treatment of major depression and other psychiatric indications. This literature has gradually expanded and the methodological quality of work has improved along with the changes in stimulation protocols. Given its potential efficacy and its ease-of-use, the place of this technique in the therapeutic armamentarium at our disposal is an important issue, especially since several countries outside Europe (USA, Canada,
Depression
According to studies conducted in the general population, depression is a common mental condition with an annual prevalence ranging between 5% and 15%. Unfortunately, not all patients respond to the available pharmacological treatment algorithms (Fava, 2003, Nemeroff, 2007). The French Agency for Sanitary Safety of Health Products (AFSSAPS) indicated that about one-third of patients do not respond to an initial antidepressant treatment after 4–8 weeks of treatment (”On the good use of
Anxiety disorders
Anxiety disorders such as posttraumatic stress disorder (PTSD) and panic disorder (PaD) are currently treated by antidepressant drugs or psychotherapy, including cognitive behavioral therapies that have proven their efficacy. However, in some patients, these treatments are insufficient to control symptoms. Thus, rTMS could, on theoretical grounds, be a potential second-line technique to treat residual anxiety symptoms.
Obsessive compulsive disorder
Several therapeutic studies have been conducted in this indication. Published studies to date employed very heterogeneous methodologies, reflecting the various hypotheses on the underlying pathophysiological mechanisms. A PubMed search (keywords: rTMS/TBS AND obsessive-compulsive disorder) identified 48 papers, including 9 original placebo-controlled studies with at least 10 patients who received active rTMS of the DLPFC (Table 11). The analyzed results cover 215 patients.
The results of these
Auditory hallucinations
During auditory hallucinations, brain areas involved in the perception of speech (primary auditory cortex and associative areas of language in the left hemisphere) show pathological hyperactivity, as determined by neuroimaging studies (Silbersweig et al., 1995, Shergill et al., 2000). Decreasing the excitability of the TPC by LF rTMS became therefore an interesting line of research for the treatment of drug-resistant auditory hallucinations (Hoffman et al., 1999).
A PubMed search (keywords:
Substance abuse, addiction and craving
Abuse and addiction to substances, such as alcohol, nicotine, cocaine, or other drugs, are major health issues. These disorders are difficult to treat and the relapse rate is high, even following detoxification, pharmacological and psychological interventions (Fant et al., 2009, Heinz et al., 2009). The rationale to use rTMS as a treatment for substance addiction and craving is that the DLPFC, which plays a major role in top-down inhibitory control mechanisms and reward mechanisms, is
Conversion
Regarding functional neurological symptoms such as motor conversion disorder, a PubMed search (keywords: rTMS/TBS AND conversion) identified 23 papers, but no blinded or placebo-controlled study. There were mostly case reports following the pioneering work of Schönfeldt-Lecuona et al., 2003, Schönfeldt-Lecuona et al., 2006, and less than 10 studies have been published to date (reviewed in Pollak et al., 2014). Stimulation sites were essentially the motor cortex and the vertex, targeted using a
Summary of recommendations
This work presents for the first time an extensive evidence-based synthesis of established and potential therapeutic applications of rTMS in the neurological, ENT, and psychiatric domains. According to this synthesis, there is a sufficient level of evidence to recommend specific rTMS protocols in clinical practice for several indications, as summarized in Table 15.
It should be emphasized that a Level A recommendation has only been achieved so far for the beneficial effect of HF rTMS on
Acknowledgments
Massimo Cincotta and Simone Rossi have received grants from EBNeuro S.p.A, Florence, Italy. Hartwig Siebner and Simone Rossi have received travel support from MagVenture, Farum, Denmark and Magstim Co., Whitland, Carmarthenshire, UK, respectively. The other authors have no conflicting interests related to this article to declare.
Sasa Filipovic was supported by the Project Grant (OI 175012) from the Ministry for Education, Science, and Technological Development of the Republic of Serbia. Josep
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