Invited reviewA comprehensive review of the effects of rTMS on motor cortical excitability and inhibition
Introduction
Transcranial magnetic stimulation (TMS) is a non-invasive means of stimulating nerve cells in superficial areas of the brain (Barker, 1991). Repetitive stimulation of the brain with TMS (rTMS) has been shown to alter aspects of cortical excitability and cortical inhibition (Chen and Seitz, 2001). Over the last decade, numerous studies have been conducted exploring the therapeutic potential of rTMS in the treatment of a variety of psychiatric diseases including, but not limited to, major depressive disorder, schizophrenia, obsessive compulsive disorder, post-traumatic stress disorder, bipolar disorder, epilepsy and Parkinson’s disease (Wassermann and Lisanby, 2001, Fitzgerald et al., 2002a, Fitzgerald et al., 2002b, George et al., 2003). The development of rTMS methods in clinical practice has progressed considerably in its application in major depressive disorder and there are ongoing investigative efforts in a number of these other illness states.
Despite the large amount of research that has gone into investigating the efficacy of rTMS, considerable uncertainties remain about the way in which it may alter cortical activity and how this relates to therapeutic effects. The most well-established aspect of our understanding in regards to the effects of rTMS is that different stimulation settings produce differing direct effects on cortical excitability. In general, it is widely believed that high-frequency stimulation produces a local increase in cortical excitability in contrast to low-frequency stimulation which produces the opposite effect (Chen and Seitz, 2001). These notions are supported by a considerable number of physiological studies that have been conducted in recent years exploring the effects of rTMS stimulation. These studies fall into two broad categories: those exploring effects on cortical excitability and those exploring effects on cortical inhibition.
Cortical excitability is traditionally measured as either the resting motor threshold (RMT) or motor evoked potential (MEP) size (Pascual-Leone et al., 1998, Fitzgerald et al., 2002a, Fitzgerald et al., 2002b). RMT is typically defined as the minimal stimulator intensity that is required to produce a reliable twitch in a peripheral muscle. MEP size is usually measured as the averaged response to a series of pulses applied at a consistent stimulator intensity or measured as the increasing MEP size produced with the increasing stimulator intensity (referred to as a response curve) (Wassermann et al., 1998). There are several methods of measuring cortical inhibition with TMS measures. The most common of these include measurement of the cortical silent period (CSP) (Chen et al., 1999) and cortical inhibition measured with paired pulse TMS (Kujirai et al., 1993). CSP duration is a period of suppression of tonic EMG activity produced by cortical stimulation; this period is likely related to GABAB receptor mediated inhibitory mechanisms (Werhahn et al., 1999). On the contrary, evidence suggests cortical inhibition measured with paired pulse TMS is linked to GABAA receptor mediated inhibitory mechanisms (Sanger et al., 2001).
In addition, several novel stimulation paradigms have recently been evaluated. However, the vast majority of therapeutic studies that have been conducted or appear to be underway have utilised traditional high and low-frequency stimulation chiefly based on the original studies conducted with rTMS in the mid-1990s. Due to the proliferation of these studies, a review of experiments evaluating the potential neurophysiological effects of rTMS is timely. The purpose of this review, therefore, was to comprehensively characterize the effects of differing rTMS paradigms on cortical excitability and inhibition to provide information that will be useful in guiding the choice of stimulation parameter settings in therapeutic and investigative protocols. A review of the effects of rTMS on functional imaging was not included as it was felt to be outside the focus of this paper. We originally planned to conduct quantitative meta-analyses of the various rTMS effects. However, we found the marked study heterogeneity, including the lack of consistently applied ‘outcomes’ (for example the methods for measuring MEP size), precluded this approach.
Section snippets
Methods
Articles were collected using the journal search Medline database with the terms “repetitive transcranial magnetic stimulation”, “transcranial magnetic stimulation”, “TMS”, “rTMS”, “motor”, “motor cortex”, resting motor threshold” and “motor evoked potential”. In addition, references in the articles were inspected to identify additional studies. Only those articles investigating healthy participants either as a control group or as the focus of the experiment were included. Where we identified
Effects on cortical excitability: Low frequency stimulation
Studies investigating the effects of low frequency (0.1–1.0 Hz) stimulation on the ipsilateral and contralateral motor cortex are summarized in Table 1. Most of these focused on post-train effects although studies have reported an absence of effects on resting and active MEP size within train (Fierro et al., 2001, Inghilleri et al., 2006), a progressive increase in MEP size (Siebner et al., 1999a, Siebner et al., 1999b) and a fluctuation of MEP amplitude (Pascual-Leone et al., 1994). Of 19
Discussion
A considerable body of research has been invested into understanding the effects of rTMS on motor cortical excitability and inhibition. These studies have explored a range of stimulation parameters and as a corollary have produced a range of results, that are often contradictory. In regards to low frequency stimulation, this appears to produce a decrease in motor cortical excitability, most consistently assessed by decreased MEP size, that is measurable post stimulation train, but these effects
Acknowledgements
PF was supported by a Practitioner Fellowship grant from National Health and Medical Research Council (NHMRC) and a NARSAD Young Investigator award. ZJD was supported by the Canadian Institutes of Health Research (CIHR) Clinician Scientist award, by the Ontario Mental Health Foundation (OMHF) and by Constance and Stephen Lieber through a National Alliance for Research on Schizophrenia and Depression (NARSAD) Lieber Young Investigator award.
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