Eric M. Wassermann

Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996

Single-pulse transcranial magnetic stimulation (TMS) is a safe and useful tool for investigating various aspects of human neurophysiology, particularly corticospinal function, in health and disease. Repetitive TMS (rTMS), however, is a more powerful and potentially dangerous modality, capable of regionally blocking or facilitating cortical processes. Although there is evidence that rTMS is useful for treating clinical depression, and possibly other brain disorders, it had caused 7 known seizures by 1996 and could have other undesirable effects. In June 1996 a workshop was organized to review the available data on the safety of rTMS and to develop guidelines for its safe use. This article summarizes the workshops deliberations. In addition to issues of risk and safety, it also addresses the principles and applications of rTMS, nomenclature, and potential therapeutic effects of rTMS. The guidelines for the use of rTMS, which are summarized in an appendix, cover the ethical issues, recommended limits on stimulation parameters, monitoring of subjects (both physiologically and neuropsychologically), expertise and function of the rTMS team, medical and psychosocial management of induced seizures, and contra-indications to rTMS.

Depression of motor cortex excitability by low‐frequency transcranial magnetic stimulation

We studied the effects of low-frequency transcranial magnetic stimulation (TMS) on motor cortex excitability in humans. TMS at 0.1 Hz for 1 hour did not change cortical excitability. Stimulation at 0.9 Hz for 15 minutes (810 pulses), similar to the parameters used to induce long-term depression (LTD) in cortical slice preparations and in vivo animal studies, led to a mean decrease in motor evoked potential (MEP) amplitude of 19.5%. The decrease in cortical excitability lasted for at least 15 minutes after the end of the 0.9 Hz stimulation. The mechanism underlying this decrease in excitability may be similar to LTD. TMS-induced reduction of cortical excitability has potential clinical applications in diseases such as epilepsy and myoclonus. Spread of excitation, which may be a warning sign for seizures, occurred in one subject and was not accompanied by increased MEP amplitude, suggesting that spread of excitation and amplitude changes are different phenomena and also indicating the need for adequate monitoring even with stimulations at low frequencies.

Transcranial direct current stimulation: State of the art 2008

Effects of weak electrical currents on brain and neuronal function were first described decades ago. Recently, DC polarization of the brain was reintroduced as a noninvasive technique to alter cortical activity in humans. Beyond this, transcranial direct current stimulation (tDCS) of different cortical areas has been shown, in various studies, to result in modifications of perceptual, cognitive, and behavioral functions. Moreover, preliminary data suggest that it can induce beneficial effects in brain disorders. Brain stimulation with weak direct currents is a promising tool in human neuroscience and neurobehavioral research. To facilitate and standardize future tDCS studies, we offer this overview of the state of the art for tDCS.

Daily repetitive transcranial magnetic stimulation (rtms) improves mood in depression

Converging evidence points to hypofunction of the left prefrontal cortex in depression. Repetitive transcranial magnetic stimulation (rTMS) activates neurons near the surface of the brain. We questioned whether daily left prefrontal rTMS might improve mood in depressed subjects and report a pilot study of such treatment in six highly medication-resistant depressed inpatients. Depression scores significantly improved for the group as a whole (Hamilton Depression Scores decreased from 23.8 ± 4.2 (s.d.) at baseline to 17.5 ± 8.4 after treatment; t = 3.03, 5DF, p = 0.02, two-tailed paired t-test). Two subjects showed robust mood improvement which occurred progressively over the course of several weeks. In one subject, depression symptoms completely remitted for the first time in 3 years. Daily left prefrontal rTMS appears to be safe, well tolerated and may alleviate depression.

Safety and cognitive effect of frontal DC brain polarization in healthy individuals

Background: Data from the human motor cortex suggest that, depending on polarity, direct current (DC) brain polarization can depress or activate cortical neurons. Activating effects on the frontal lobe might be beneficial for patients with frontal lobe disorders. This phase 1 study tested the safety of frontal DC, including its effects on frontal and other brain functions. Methods: The authors applied 20 minutes of anodal, cathodal, or sham DC to the left prefrontal cortex in three groups of right-handed subjects and looked for effects on global measures of processing and psychomotor speed, emotion, and verbal fluency, a measure of local cortical function. In one experiment (n = 30), the authors tested before and after 1 mA DC and monitored EEG in 9 subjects. In two other experiments using 1 mA (n = 43) and 2 mA (n = 30), the authors tested before and then starting 5 minutes after the onset of DC. Results: All subjects tolerated DC well. There were no significant effects on performance with 1 mA DC. At 2 mA, verbal fluency improved significantly with anodal and decreased mildly with cathodal DC. There were no clinically significant effects on the other measures. Conclusions: Limited exposure to direct current polarization of the prefrontal cortex is safe and can enhance verbal fluency selectively in healthy subjects. As such, it deserves consideration as a procedure to improve frontal lobe function in patients.

Human motor evoked responses to paired transcranial magnetic stimuli

We studied the changes in motor pathway excitability induced by transcranial magnetic stimulation of the motor cortex, using paired stimuli (conditioning and test stimulus) and varying interstimulus interval (ISI). The effects induced depended on the stimulus intensity. At a low intensity, there was inhibition of the response to the test stimulus at ISIs of 5-40 msec, followed by facilitation at ISIs of 50-90 msec. At a high intensity, there was facilitation at ISIs of 25-50 msec, followed by inhibition at ISIs of 60-150 msec and, occasionally, by another phase of facilitation at ISIs of more than 200 msec. Only tentative explanations are currently possible for these effects: the inhibition observed at low intensities and short ISIs may be due to activation of cortical inhibitory mechanisms. The facilitation that follows may arise from the coincidence of various factors that transiently increase the excitability in alpha motoneurons. The early facilitation observed at high intensities seems to be a consequence of a rise in cortical excitability induced by the conditioning stimulus, causing an increase in the number or size, or both, of descending volleys from the test stimulus. The profound inhibition that follows probably results from a combination of both segmental and suprasegmental inhibitory mechanisms.

Noninvasive mapping of muscle representations in human motor cortex.

We used transcranial magnetic stimulation to map the cortical representations of 4 upper extremity muscles (abductor pollicis brevis, flexor carpi radialis, biceps, and deltoid) of 10 normal subjects. Three stimuli were delivered to scalp positions 1 cm apart, and the amplitude and latency of the motor evoked potentials (MEPs) were averaged for each position. Maps were described in terms of number of excitable scalp positions, amplitude of MEPs, scalp positions for evoking largest amplitude MEPs, and threshold for producing MEPs. We compared different muscles across subjects and the same muscles on the left and right sides in individual subjects. Distal muscles had larger representations with higher amplitude MEPs and lower thresholds. Biceps and deltoid on the left had larger representations and higher MEP amplitudes than on the right. Maps showed a somatotopic progression on the scalp of proximal to distal muscles along a posteromedial to anterolateral axis.

Therapeutic application of repetitive transcranial magnetic stimulation: a review.

Transcranial magnetic stimulation (TMS), a non-invasive means of electrically stimulating neurons in the human cerebral cortex, is able to modify neuronal activity locally and at distant sites when delivered in series or trains of pulses. Data from stimulation of the motor cortex suggest that the type of effect on the excitability of the cortical network depends on the frequency of stimulation. These data, as well as results from studies in rodents, have been generalized across brain areas and species to provide rationales for using repetitive TMS (rTMS) to treat various brain disorders, most notably depression. Research into clinical applications for TMS remains active and has the potential to provide useful data, but, to date, the results of blinded, sham-controlled trials do not provide clear evidence of beneficial effects that replace or even match the effectiveness of conventional treatments in any disorder. In this review, we discuss the clinical and scientific bases for using rTMS as treatment, and review the results of trials in psychiatric and neurological disorders to date.

Opposite effects of high and low frequency rTMS on regional brain activity in depressed patients

BACKGROUND High (10-20 Hz) and low frequency (1-5 Hz) repetitive transcranial magnetic stimulation (rTMS) have been explored for possible therapeutic effects in the treatment of neuropsychiatric disorders. As part of a double-blind, placebo-controlled, crossover study evaluating the antidepressant effect of daily rTMS over the left prefrontal cortex, we evaluated changes in absolute regional cerebral blood flow (rCBF) after treatment with 1- and 20-Hz rTMS. Based on preclinical data, we postulated that high frequency rTMS would increase and low frequency rTMS would decrease flow in frontal and related subcortical circuits. METHODS Ten medication-free, adult patients with major depression (eight unipolar and two bipolar) were serially imaged using (15)O water and positron emission tomography to measure rCBF. Each patient was scanned at baseline and 72 hours after 10 daily treatments with 20-Hz rTMS and 10 daily treatments with 1 Hz rTMS given in a randomized order. TMS was administered over the left prefrontal cortex at 100% of motor threshold (MT). Significant changes in rCBF from pretreatment baseline were determined by paired t test. RESULTS Twenty-hertz rTMS over the left prefrontal cortex was associated only with increases in rCBF. Significant increases in rCBF across the group of all 10 patients were located in the prefrontal cortex (L > R), the cingulate gyrus (L >> R), and the left amygdala, as well as bilateral insula, basal ganglia, uncus, hippocampus, parahippocampus, thalamus, and cerebellum. In contrast, 1-Hz rTMS was associated only with decreases in rCBF. Significant decreases in flow were noted in small areas of the right prefrontal cortex, left medial temporal cortex, left basal ganglia, and left amygdala. The changes in mood following the two rTMS frequencies were inversely related (r = -.78, p <.005, n = 10) such that individuals who improved with one frequency worsened with the other. CONCLUSIONS These data indicate that 2 weeks of daily 20-Hz rTMS over the left prefrontal cortex at 100% MT induce persistent increases in rCBF in bilateral frontal, limbic, and paralimbic regions implicated in depression, whereas 1-Hz rTMS produces more circumscribed decreases (including in the left amygdala). These data demonstrate frequency-dependent, opposite effects of high and low frequency rTMS on local and distant regional brain activity that may have important implications for clinical therapeutics in various neuropsychiatric disorders.

Safety of rapid-rate transcranial magnetic stimulation in normal volunteers

In 9 normal volunteers, we studied the safety of rapid-rate transcranial magnetic stimulation (rTMS) applied to different scalp positions at various frequencies and intensities. Pure tone threshold audiometry showed temporary threshold shifts in 3 subjects. In the subject stimulated at the highest intensity, rTMS induced a focal, secondarily generalized seizure despite the absence of definite risk factors for seizures. Rapid-rate TMS did not result in any important changes in the neurological examination findings, cognitive performance, electroencephalogram, electrocardiogram, and hormone levels (prolactin, adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, and follicle-stimulating hormone). In 10 additional subjects, the electromyographic activity in several contralateral muscles showed that trains of rTMS applied to the motor cortex induced a spread of cortical excitability. The spread of excitability depended on the intensity and frequency of the stimuli and probably constituted an early epileptogenic effect of rTMS. Guidelines for preventing the undesirable side effects of rTMS are offered.