SUMMARY1. In ten normal volunteers, a transcranial magnetic or electric stimulus that was subthreshold for evoking an EMG response in relaxed muscles was used to condition responses evoked by a later, suprathreshold magnetic or electric test shock. In most experiments the test stimulus was given to the lateral part of the motor strip in order to evoke EMG responses in the first dorsal interosseous muscle (FDI).2. A magnetic conditioning stimulus over the hand area of cortex could suppress responses produced in the relaxed FDI by a suprathreshold magnetic test stimulus at interstimulus intervals of 1-6 ms. At interstimulus intervals of 10 and 15 ms, the test response was facilitated.3. Using a focal magnetic stimulus we explored the effects of moving the conditioning stimulus to different scalp locations while maintaining the magnetic test coil at one site. If the conditioning coil was moved anterior or posterior to the motor strip there was less suppression of test responses in the FDI. In contrast, stimulation at the vertex could suppress FDI responses by an amount comparable to that seen with stimulation over the hand area. With the positions of the two coils reversed, conditioning stimuli over the hand area suppressed responses evoked in leg muscles by vertex test shocks.4. The intensity of both conditioning and test shocks influenced the amount of suppression. Small test responses were more readily suppressed than large responses. The best suppression was seen with small conditioning stimuli (0 7-0 9 times motor threshold in relaxed muscle); increasing the intensity to motor threshold or above resulted in less suppression or even facilitation.5. Two experiments suggested that the suppression was produced by an action * Present address: Third Department of Internal Medicine, Division of Neurology, Yamagata University, School of Medicine, 2-2-2 Iida-Nishi, Yamagata City 990-23, Yamagata, Japan.

SUMMARY1. Using two magnetic stimulators, we investigated the effect of a conditioning magnetic stimulus over the motor cortex of one hemisphere on the size of EMG responses evoked in the first dorsal interosseous (FDI) muscle by a magnetic test stimulus given over the opposite hemisphere.2. A single conditioning shock to one hemisphere produced inhibition of the test response evoked from the opposite hemisphere when the conditioning-test interval was 5-6 ms or longer. We shall refer to this as interhemispheric inhibition. However, the minimum latency of inhibition observed using surface EMG responses may have underestimated the true interhemispheric conduction time. Single motor unit studies suggested values 4-7 ms longer than the minimum interval observed with surface EMG.3. Interhemispheric inhibition was seen when the test muscle was active or relaxed. Increasing the intensity of the conditioning stimulus increased the duration of inhibition: increasing the intensity of the test stimulus reduced the depth of inhibition.4. The conditioning coil had to be placed on the appropriate area of scalp for inhibition to occur. The effect of the conditioning stimulus was maximal when it was applied over the hand area of motor cortex, and decreased when the stimulus was moved medial or lateral to that point. A. FERBERT AND OTHERS 6. When the test muscle was relaxed, the amount of interhemispheric inhibition could be increased slightly by voluntary contraction of the muscles in the hand contralateral to the conditioning hemisphere. This effect disappeared if the test muscle was held active throughout the experiment.7. Magnetic conditioning stimuli over one hemisphere were also capable of affecting on-going voluntary EMG activity in the ipsilateral FDI. Inhibition began 10-15 ms after the minimum corticospinal conduction time to the muscle, and lasted for about 30 ms. The depth of inhibition was approximately proportional to the level of on-going EMG. A similar period of inhibition was also observed in the forearm flexor muscles, but in biceps it was less clear and sometimes preceded by excitation.8. The interhemispheric inhibition described in these experiments is probably produced via a transcallosal pathway.

1 In seven normal subjects, subthreshold transcranial magnetic conditioning stimuli (using a figure-of-eight coil) were applied over the motor cortex in order to evoke activity in intracortical neuronal circuits. The net effect on cortical excitability was evaluated by measuring the effect on the size of EMG responses elicited in the abductor digiti minimi (ADM) muscle by a subsequent suprathreshold test stimulus. 2. A single conditioning stimulus suppressed the size of the test response at interstimulus intervals (ISIs) of 1-4 ms whereas the response was facilitated at ISIs of 6-20 ms. The facilitation could be augmented if pairs of conditioning stimuli were given. 3. Inhibition and facilitation appeared to have separate mechanisms. The threshold for inhibition (0 7 active motor threshold) was slightly lower than that for facilitation (0-8 active threshold). Similarly, the inhibitory effect was independent of the direction of current flow induced in the cortex by the conditioning shock, whereas facilitation was maximal with posterior-anterior currents and minimal with lateromedial current. 4. Direct corticospinal effects were probably not responsible for the results since facilitation of cortical test responses could be produced by conditioning stimuli which had no effect on the amplitude of H reflexes elicited in active ADM muscle. 5. Inhibition and facilitation appeared to interact in a roughly linear manner, consistent with separate inputs to a common neurone. 6. We suggest that subthreshold transcranial magnetic stimulation is capable of activating separate populations of excitatory and inhibitory interneurones in the motor cortex. Kujirai et al. (1993) reported that a single subthreshold magnetic stimulus over the motor cortex could suppress the response to a later suprathreshold test stimulus. They postulated that the first stimulus produced this effect by activation of a set of intracortical inhibitory neurones. They also noted a later phase of facilitation, but did not investigate the mechanism in any detail. The present paper addresses this question and shows that the later facilitation is probably caused by the activation of a separate set of facilitatory cortical neurones. The outputs of these two sets of neurones appear to interact independently at or before the final stage of pyramidal output. METHODSThe experiments were performed, with the approval of the joint ethical committee of the National Hospital for Neurology and Institute of Neurology, on seven normal healthy subjects (all men) aged 27-44 years. The subjects gave their informed consent and were seated in a comfortable reclining chair during the procedures.Surface electromyographic (EMG) recordings were made from the right abductor digiti minimi (ADM) muscle with the active electrode placed over the motor point and the reference electrode on the proximal interphalangeal joint of the small finger. The raw signal was amplified and filtered by Digitimer D150 amplifiers (Digitimer Ltd, Welwyn Garden City, Herts, UK) with a time constant of 10 ...

Low intensity transcranial electrical stimulation (TES) in humans, encompassing transcranial direct current (tDCS), transcutaneous spinal Direct Current Stimulation (tsDCS), transcranial alternating current (tACS), and transcranial random noise (tRNS) stimulation or their combinations, appears to be safe. No serious adverse events (SAEs) have been reported so far in over 18,000 sessions administered to healthy subjects, neurological and psychiatric patients, as summarized here. Moderate adverse events (AEs), as defined by the necessity to intervene, are rare, and include skin burns with tDCS due to suboptimal electrode-skin contact. Very rarely mania or hypomania was induced in patients with depression (11 documented cases), yet a causal relationship is difficult to prove because of the low incidence rate and limited numbers of subjects in controlled trials. Mild AEs (MAEs) include headache and fatigue following stimulation as well as prickling and burning sensations occurring during tDCS at peak-to-baseline intensities of 1–2 mA and during tACS at higher peak-to-peak intensities above 2 mA. The prevalence of published AEs is different in studies specifically assessing AEs vs. those not assessing them, being higher in the former. AEs are frequently reported by individuals receiving placebo stimulation. The profile of AEs in terms of frequency, magnitude and type is comparable in healthy and clinical populations, and this is also the case for more vulnerable populations, such as children, elderly persons, or pregnant women. Combined interventions (e.g., co-application of drugs, electrophysiological measurements, neuroimaging) were not associated with further safety issues. Safety is established for low-intensity ‘conventional’ TES defined as <4 mA, up to 60 min duration per day. Animal studies and modeling evidence indicate that brain injury could occur at predicted current densities in the brain of 6.3–13 A/m2 that are over an order of magnitude above those produced by tDCS in humans. Using AC stimulation fewer AEs were reported compared to DC. In specific paradigms with amplitudes of up to 10 mA, frequencies in the kHz range appear to be safe. In this paper we provide structured interviews and recommend their use in future controlled studies, in particular when trying to extend the parameters applied. We also discuss recent regulatory issues, reporting practices and ethical issues. These recommendations achieved consensus in a meeting, which took place in Göttingen, Germany, on September 6–7, 2016 and were refined thereafter by email correspondence.

Using the technique of transcranial magnetic stimulation over the motor areas of cortex and recording electromyographic (EMG) responses from the first dorsal interosseous muscle, we measured the excitability of corticocortical inhibitory circuits at rest using a double pulse paradigm, in 11 patients with Parkinson's disease (PD) studied both on (ON) and off (OFF) (after overnight withdrawal) their normal medication and in 10 age-matched control subjects. There was a significant decrease in the amount of corticocortical inhibition at short (1-5 msec) interstimulus intervals in patients relative to their controls, which improved after L-dopa intake. For comparison with previous reports using transcranial magnetic stimulation we also measured the duration of the EMG silent period when stimuli were given to voluntarily active muscle, and the threshold for evoking an EMG response in both the active and relaxed states. There was no change in the threshold for evoking EMG responses whether muscles were active or relaxed. However, the silent period was significantly prolonged when ON compared with OFF, although in neither state was the duration significantly different from that seen in normals. We suggest that there may be abnormalities of motor cortical inhibitory mechanisms in patients with Parkinson's disease that are not readily detected using threshold or silent period measurements alone.