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Using near-infrared spectroscopy (NIRS) and multichannel probes, we studied hemoglobin (Hb) concentration changes when single-pulse transcranial magnetic stimulation (TMS) was applied over the left hemisphere primary motor cortex (M1). Seventeen measurement probes were centered over left M1. Subjects were studied in both active and relaxed conditions, with TMS intensity set at 100%, 120%, and 140% of the active motor threshold. The magnetic coils were placed so as to induce anteromedially directed currents in the brain. Hb concentration changes were more prominent at channels over M1 and posterior to it. Importantly, Hb concentration changes at M1 after TMS differed depending on whether the target muscle was in an active or relaxed condition. In the relaxed condition, Hb concentration increased up to 3-6 s after TMS, peaking at ∼6 s, and returned to the baseline. In the active condition, a smaller increase in Hb concentrations continued up to 3-6 s after TMS (early activation), followed by a decrease in Hb concentration from 9 to 12 s after TMS (delayed deactivation). Hb concentration changes in the active condition at higher stimulus intensities were more pronounced at locations posterior to M1 than at M1. We conclude that early activation occurs when M1 is activated transsynaptically. The relatively late deactivation may result from the prolonged inhibition of the cerebral cortex after activation. The posterior-dominant activation at higher intensities in the active condition may result from an additional activation of the sensory cortex due to afferent inputs from muscle contraction evoked by the TMS.

Background: Imaging studies investigating repetitive transcranial magnetic stimulation (rTMS) mediated hemodynamic consequences revealed inconsistent results, mainly due to differences in rTMS parameters and technical difficulties with simultaneous recordings during rTMS., Objective/hypothesis: Quadri-pulse rTMS (QPS) induces bidirectional long-term plasticity of the human primary motor cortex (M1). To evaluate its on-line effects, near infrared spectroscopy (NIRS) recordings were performed during QPS. We hypothesized that on-line effects during QPS are different from long-term aftereffects., Methods: Using a novel TMS - on-line multi-channel NIRS setup we recorded hemoglobin concentration [Hb] changes at the stimulated M1 and adjacent sensory-motor areas during QPS protocols inducing oppositely directed aftereffects (QPS-5: interstimulus interval (ISI) 5 ms, potentiation; QPS-50: ISI 50 ms, depression). In two experiments we studied NIRS changes during either single or repeated QPS bursts., Results: The repetitive QPS-5 bursts significantly decreased oxyhemoglobin concentration ([oxy-Hb]) in the ipsilateral M1. A single QPS-5 burst decreased [oxy-Hb] in the M1 and premotor cortex. QPS-50 induced no significant NIRS changes at any sites., Conclusions: QPS can significantly alter cortical hemodynamics depending on the stimulation frequency. While bidirectional long-term aftereffects of QPS reflect synaptic efficacy changes, unidirectional on-line effects during QPS may represent pure electrophysiological property changes within the cell membrane or synapse. Since neuronal postexcitatory inhibitory postsynaptic potentials typically peak within the first 10-20 ms, only pulses delivered at higher frequencies may lead to summation of the inhibitory effects, resulting in [oxy-Hb] decrease only after QPS-5. Our new TMS-NIRS setup may be valuable to investigate TMS induced neurovascular coupling mechanisms in humans., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objective: Quadripulse transcranial magnetic stimulation (QPS) is a newly designed patterned repetitive transcranial magnetic stimulation (TMS). Previous studies of QPS showed bidirectional effects on the primary motor cortex (M1), which depended on its inter-stimulus interval (ISI): motor evoked potentials (MEPs) were potentiated at short ISIs and depressed at long ISIs (homotopic effects). These physiological characters were compatible with synaptic plasticity. In this research, we studied effects of QPS on the primary sensory cortex (S1)., Methods: One burst consisted of four monophasic TMS pulses at an intensity of 90% active motor threshold. The ISI of four pulses was set at 5 ms (QPS-5) or at 50 ms (QPS-50). Same bursts were given every 5s for 30 min. QPS-5 and QPS-50 were performed over three areas (M1, S1 and dorsal premotor cortex (dPMC)). One sham stimulation session was also performed. Excitability changes of S1 were evaluated by timeline of somatosensory evoked potentials (SEPs)., Results: QPS-5 over M1 or dPMC enhanced the P25-N33 component of SEP, and QPS-50 over M1 depressed it. By contrast, QPSs over S1 had no effects on SEPs., Conclusions: QPSs over motor cortices modulated the S1 cortical excitability (heterotopic effects). Mutual connections between dPMC or M1 and S1 might be responsible for these modulations., Significance: QPSs induced heterotopic LTP or LTD-like cortical excitability changes., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: To measure the conduction time from the motor cortex to the conus medullaris (cortico-conus motor conduction time, CCCT) for leg muscles using magnetic stimulation., Methods: Motor evoked potentials (MEPs) were recorded from tibialis anterior muscles in 51 healthy volunteers. To activate spinal nerves at the most proximal cauda equina level or at the conus medullaris level, magnetic stimulation was performed using a MATS coil. Transcranial magnetic stimulation of the motor cortex was also conducted to measure the cortical latency for the target muscle. To obtain the CCCT, the latency of MEPs to conus stimulation (conus latency) was subtracted from the cortical latency., Results: MATS coil stimulation evoked reproducible MEPs in all subjects, yielding CCCT data for all studied tibialis anterior muscles., Conclusions: MATS coil stimulation provides CCCT data for healthy subjects., Significance: This novel method is useful for evaluation of corticospinal tract function for leg muscles because no peripheral component affects the CCCT., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Using the paired-pulse paradigm, transcranial magnetic stimulation (TMS) has revealed much about the human primary motor cortex (M1). A preceding subthreshold conditioning stimulus (CS) inhibits the excitability of the motor cortex, which is named short-interval intracortical inhibition (SICI). In contrast, facilitation is observed when the first pulse (S1) is followed by a second one at threshold (S2), named short-interval intracortical facilitation (SICF). SICI and SICF have been considered to be mediated by different neural circuits within M1, but more recent studies reported relations between them. In this study, we performed triple-pulse stimulation consisting of CS-S1-S2 to further explore putative interactions between these two effects. Three intensities of CS (80-120% of active motor threshold: AMT) and two intensities of S2 (120 and 140% AMT) were combined. The SICF in the paired-pulse paradigm exhibited clear facilitatory peaks at ISIs of 1.5 and 3 ms. The second peak at 3 ms was significantly suppressed by triple-pulse stimulation using 120% AMT CS, although the first peak was almost unaffected. Our present results obtained using triple-pulse stimulation suggest that each peak of SICF is differently modulated by different intensities of CS. The suppression of the second peak might be ascribed to the findings in the paired-pulse paradigm that CS mediates SICI by inhibiting later I waves such as I3 waves and that the second peak of SICF is most probably related to I3 waves. We propose that CS might inhibit the second peak of SICF at the interneurons responsible for I3 waves.

A single pulse of transcranial magnetic stimulation (TMS) can reset the 15- to 30-Hz beta-band oscillations in the motor cortex. These oscillations are known to influence the amplitude of corticospinal activity evoked by TMS. To garner further evidence for this resetting, we tested how electromyographic responses to motor cortex TMS were modulated by a preceding series of TMS pulses. We used a triad of conditioning TMS pulses at various interstimulus intervals (ISIs) in an attempt to drive cortical activity at the corresponding frequency. We then analyzed how the amplitude of motor-evoked potentials (MEPs) to a test pulse varied at different intervals after the conditioning triad. When conditioning pulses were given at an ISI of 25 ms, responses to the fourth (test) pulse were facilitated 25 ms later. Neither a single conditioning pulse nor triad of conditioning pulses separated by other ISIs enhanced responses to the test pulse at the expected timings. Triads of pulses at an ISI of 25 ms did not enhance subsequent MEPs to brainstem stimulation. Based on the intensity of the conditioning stimuli necessary to produce this effect and on the effective interval, we conclude that the facilitation at 25 ms differs from intracortical facilitation at 7-10 ms seen in the paired-pulse experiment originally reported by Kujirai et al. These results suggest that a triad of TMS pulses can enhance an intrinsic oscillatory rhythm of the motor cortex (40 Hz) and facilitate cortical activity at an ISI corresponding to the frequency of that rhythm.

Intracortical circuit excitability of the human motor cortex has been studied by measuring effects of some conditioning TMS stimulus on the succeeding test TMS stimulus in the motor cortex, such as short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF). A single-pulse TMS was used as a conditioning stimulus (CS) in these techniques, but a train of several TMS pulses might induce some intracortical changes in the motor cortex more effectively. For nine healthy volunteers, we compared the SICI and ICF induced by a single conditioning biphasic TMS pulse with those induced by a train of 10 biphasic TMS pulses of the same intensity. As a conditioning stimulus, we delivered a subthreshold single biphasic pulse (CS1) or 10, 10-Hz biphasic pulses (CS10) before a suprathreshold monophasic test stimulus at several interstimulus intervals (ISIs) of 3-40 ms over the hand motor area. The CS intensity was 50-100% of the active motor threshold (AMT). We compared the motor cortical excitability after the conditioning stimulus (single pulse or a train of ten pulses) at the intervals for SICI and ICF. A train of ten 10-Hz pulses elicited greater inhibition at short ISIs than a single conditioning pulse did. The facilitation at ISIs around 10 ms corresponding to the ICF was evoked by CS1 only at an intensity of 80% AMT; CS10 evoked no ICF. Furthermore, CS10 evoked MEP inhibition at longer intervals. Results show that a train of high-frequency, low-intensity, biphasic TMS pulses can have a strong inhibitory effect on the motor cortex.

Motor cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS) sometimes depends on the prior history of neuronal activity. These effects of preceding stimulation on subsequent rTMS-induced plasticity have been suggested to share a similar mechanism to that of metaplasticity, a homeostatic regulation of synaptic plasticity. To explore metaplasticity in humans, many investigations have used designs in which both priming and conditioning are applied over the primary motor cortex (M1), but the effects of priming stimulation over other motor-related cortical areas have not been well documented. Since the supplementary motor area (SMA) has anatomical and functional cortico-cortical connections with M1, here we studied the homeostatic effects of priming stimulation over the SMA on subsequent rTMS-induced plasticity of M1. For priming and subsequent conditioning, we employed a new rTMS protocol, quadripulse stimulation (QPS), which produces a broad range of motor cortical plasticity depending on the interval of the pulses within a burst. The plastic changes induced by QPS at various intervals were altered by priming stimulation over the SMA, which did not change motor-evoked potential sizes on its own but specifically modulated the excitatory I-wave circuits. The data support the view that the homeostatic changes are mediated via mechanisms of metaplasticity and highlight an important interplay between M1 and SMA regarding homeostatic plasticity in humans.

Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising tool to induce plastic changes that are thought in some cases to reflect N-methyl-d-aspartate-sensitive changes in synaptic efficacy. As in animal experiments, there is some evidence that the sign of rTMS-induced plasticity depends on the prior history of cortical activity, conforming to the Bienenstock-Cooper-Munro (BCM) theory. However, experiments exploring these plastic changes have only examined priming-induced effects on a limited number of rTMS protocols, often using designs in which the priming alone had a larger effect than the principle conditioning protocol. The aim of this study was to introduce a new rTMS protocol that gives a broad range of after-effects from suppression to facilitation and then test how each of these is affected by a priming protocol that on its own has no effect on motor cortical excitability, as indexed by motor-evoked potential (MEP). Repeated trains of four monophasic TMS pulses (quadripulse stimulation: QPS) separated by interstimulus intervals of 1.5-1250 ms produced a range of after-effects that were compatible with changes in synaptic plasticity. Thus, QPS at short intervals facilitated MEPs for more than 75 min, whereas QPS at long intervals suppressed MEPs for more than 75 min. Paired-pulse TMS experiments exploring intracortical inhibition and facilitation after QPS revealed effects on excitatory but not inhibitory circuits of the primary motor cortex. Finally, the effect of priming protocols on QPS-induced plasticity was consistent with a BCM-like model of priming that shifts the crossover point at which synaptic plasticity reverses from depression to potentiation. The broad range of after-effects produced by the new rTMS protocol opens up new possibilities for detailed examination of theories of metaplasticity in humans.

Objective: The short interval intracortical inhibition (SICI) of the motor cortex (M1) is reduced in both cortical myoclonus and focal hand dystonia. This reduction has been attributed to the dysfunction of GABAergic system within the motor cortex. However, the precise mechanisms underlying the reduction may not be entirely identical in these two disorders, being due to primary pathological involvement in M1 or secondary to functional changes outside M1. The aim of this study was to elucidate possible differences in intracortical inhibition between these two disorders., Methods: Subjects were 11 patients with benign myoclonus epilepsy, 7 with focal hand dystonia, and 11 normal volunteers. We studied SICI using anterior-posterior (AP) directed and posterior-anterior (PA) directed induced currents in the brain., Results: In both disorders, SICI with PA-directed currents was reduced as reported previously. In contrast, SICI studied with AP currents was normal in patients with focal hand dystonia, but reduced in patients with cortical myoclonus., Conclusions: The difference between the two disorders might reflect the underlying pathological difference. In cortical myoclonus, the inhibitory interneurons of the motor cortex are affected, whereas the same interneurons are intact in dystonia. The difference in SICI induced by AP and PA directed currents in dystonia may be explained by the following possibilities: the difference in composition of I-waves contributing to EMG generation and the difference in modulation of the interneuronal activity by voluntary contraction. These changes may be secondary to dysregulation of the motor cortex by the basal ganglia or related cortices in dystonia., Significance: The SICI using AP directed currents together with the conventional SICI using PA directed currents was able to demonstrate some difference in the intrinsic circuits of M1 between myoclonus and focal hand dystonia. SICI using AP directed currents can provide additional information about the motor cortical excitability changes over those obtained by the previously reported methods.

The aim of the present paper is to study effects of short and long duration transcranial direct current stimulation (tDCS) on the human motor cortex. In eight normal volunteers, motor evoked potentials (MEPs) induced by transcranial magnetic stimulation (TMS) were recorded from the right first dorsal interosseous muscle, and tDCS was given with electrodes over the left primary motor cortex (M1) and the contralateral orbit. We performed two experiments: one for short duration tDCS (100 ms, 1, 3 or 5 mA) and the other for long duration tDCS (10 min, 1 mA). The stimulus onset asynchrony (SOA) between the onset of tDCS and TMS were 1-7 and 10-120 ms for the former experiment. In the latter experiment, TMS was given 0-20 min after the end of 10 min tDCS. We evaluated the effect of tDCS on the motor cortex by comparing MEPs conditioned by tDCS with control MEPs. Cathodal short duration tDCS significantly reduced the size of responses to motor cortical stimulation at SOAs of 1-7 ms when the intensity was equal to or greater than 3 mA. Anodal short duration tDCS significantly increased MEPs when the intensity was 3 mA, but the enhancement did not occur when using 5 mA conditioning stimulus. Moreover, both anodal and cathodal short duration tDCS decreased responses to TMS significantly at SOAs of 20-50 ms and enhanced them at an SOA of 90 ms. Long duration cathodal tDCS decreased MEPs at 0 and 5 min after the offset of tDCS and anodal long duration tDCS increased them at 1 and 15 min. We conclude that the effect at SOAs less than 10 ms is mainly caused by acute changes in resting membrane potential induced by tDCS. The effect at SOAs of 20-100 ms is considered to be a nonspecific effect of a startle-like response produced by activation of skin sensation at the scalp. The effect provoked by long duration tDCS may be short-term potentiation or depression like effects.

Objective: Repetitive paired-pulse transcranial magnetic stimulation (TMS) at I-wave periodicity has been shown to induce a motor-evoked potential (MEP) facilitation. We hypothesized that a greater enhancement of motor cortical excitability is provoked by increasing the number of pulses per train beyond those by paired-pulse stimulation (PPS)., Methods: We explored motor cortical excitability changes induced by repetitive application of trains of four monophasic magnetic pulses (quadro-pulse stimulation: QPS) at 1.5-ms intervals, repeated every 5s over the motor cortex projecting to the hand muscles. The aftereffects of QPS were evaluated with MEPs to a single-pulse TMS, motor threshold (MT), and responses to brain-stem stimulation. These effects were compared to those after PPS. To evaluate the QPS safety, we also studied the spread of excitation and after discharge using surface electromyograms (EMGs) of hand and arm muscles., Results: Sizes of MEPs from the hand muscle were enhanced for longer than 75min after QPS; they reverted to the baseline at 90min. Responses to brain-stem stimulation from the hand muscle and cortical MEPs from the forearm muscle were unchanged after QPS over the hand motor area. MT was unaffected by QPS. No spreads of excitation were detected after QPS. The appearance rate of after discharges during QPS was not different from that during sham stimulation., Conclusions: Results show that QPS can safely induce long-lasting, topographically specific enhancement of motor cortical excitability., Significance: QPS is more effective than PPS for inducing motor cortical plasticity.

Objective: To study differences in the long-term after-effect between high-frequency, monophasic and biphasic repetitive transcranial magnetic stimulation (rTMS)., Methods: Ten hertz rTMS was delivered over the left primary motor cortex and motor evoked potentials (MEPs) were recorded from the right first dorsal interosseous muscle. To probe motor cortex excitability we recorded MEPs at several timings before, during and after several types of conditioning rTMSs. We also recorded F-waves to probe spinal excitability changes. Thousand pulses were given in total, with a train of 10 Hz, 100 pulses delivered every minute (ten trains for 10min). The intensity was fixed at 90% active motor threshold (AMT) or 90% resting motor threshold (RMT) for both monophasic and biphasic rTMS. In addition, we performed a monophasic rTMS experiment using a fixed intensity of 90% RMT for biphasic pulses., Results: At 90% AMT, MEPs were enhanced for a few minutes after both monophasic and biphasic rTMS. On the other hand, at 90% RMT, a larger and longer enhancement of MEPs was evoked after monophasic rTMS than after biphasic rTMS. Monophasic rTMS at an intensity adjusted to biphasic 90% RMT elicited a great enhancement similar to that after monophasic rTMS at monophasic 90% RMT. Neither F-wave amplitude nor its occurrence rate was significantly altered by 90% RMT monophasic rTMS., Conclusions: These results suggest that enhancement after rTMS occurs at the motor cortex. Monophasic rTMS has a stronger after-effect on motor cortical excitability than biphasic rTMS. This is probably because monophasic pulses preferentially activate a relatively uniform population of neurons oriented in the same direction and their effects summate more readily than biphasic rTMS activating differently oriented neurons at slight different timings altogether., Significance: The present results suggest that when using rTMS as a therapeutic tool or in research fields, the waveforms of magnetic pulses may affect the results profoundly.

To investigate the effects of repetitive transcranial magnetic stimulation (rTMS) on the central processing of motor preparation, we had subjects perform a precued-choice reaction time (RT) task. They had to press one of two buttons as quickly as possible after a go signal specifying both the hand to be used and the button to press. A precue preceding this signal conveyed full, partial, or no advance information (hand and/or button), such that RT shortened with increasing amount of information. We applied 1200 to 2400 pulses of 1-Hz rTMS over various cortical areas and compared the subjects' performances at various times before and after this intervention. rTMS delayed RT at two distinct phases after stimulation, one within 10 min and another with a peak at 20 to 30 min and lasting for 60 to 90 min, with no significant effects on error rates or movement time. The effect was significantly larger on left- than on right-hand responses. RT was prominently delayed over the premotor and motor cortices with similar effects across different conditions of advance information, suggesting that preparatory processes relatively close to the formation of motor output were influenced by rTMS. In contrast, the effect of rTMS over the supplementary motor area and the anterior parietal cortex varied with the amount of advance information, indicating specific roles played by these areas in integrating target and effector information. The primary motor area, especially of the left hemisphere, may take over this processing, implementing motor output based on the information processed in other areas.

Objective: Repetitive paired-pulse TMS (rPPS) given at an interstimulus interval (ISI) of 1.5 ms has been reported to induce a lasting motor evoked potential (MEP) facilitation. This after-effect was considered to be a cortical event because F-waves were not affected by the same rPPS. To confirm its cortical facilitation, we compared the after-effects of rPPS on MEPs to single pulse TMS over the motor cortex (motor cortical MEPs) with those to brainstem stimulation (brainstem MEPs)., Methods: Subjects were 10 healthy volunteers. Suprathreshold paired-pulse TMS at an ISI of 1.5 ms was applied to the motor cortex for 30 min at a rate of 0.2 Hz. After intervention, we measured motor cortical MEPs for 30 min. We also studied brainstem MEPs in five subjects., Results: Motor cortical MEPs were facilitated to about 190% of baseline (p<0.001) for 10 min post rPPS intervention and returned to the baseline at 10-15 min post intervention. Brainstem MEPs were not affected by the intervention., Conclusions: The facilitation of MEPs after rPPS at an interval of 1.5 ms occurs at the motor cortex., Significance: rPPS at an interval of 1.5 ms is an effective method for increasing motor cortical excitability.

Using near infrared spectroscopy and repetitive transcranial magnetic stimulation (rTMS), we studied interhemispheric interactions between bilateral motor and sensory cortices in humans. RTMS consisted of a triple-pulse burst (50 Hz) repeated every 200 m for 2 s (10 bursts, 30 pulses); one kind of theta burst TMS (TBS) (Huang et al. in Neuron 45:201-206, 2005). The hemoglobin concentration changes were recorded at the right prefrontal cortex, premotor area (PM), primary hand motor area (M1) and primary sensory area (S1) during and after TBS over the left PM, M1 and S1 or sham stimulation in eight normal volunteers. In addition, motor evoked potentials (MEPs) to TMS over the right M1 were recorded from the left first dorsal interosseous muscle after the conditioning TBS over left S1. TBS over PM induced a significant oxy-Hb decrease at the contralateral PM. TBS over M1 elicited a significant oxy-Hb decrease at the contralateral S1, and TBS over S1 significant oxy-Hb decreases at the contralateral M1 and S1. MEPs to TMS of the right M1 were significantly suppressed by the conditioning TBS over the left S1. These results suggest that there are mainly inhibitory interactions between bilateral PMs and bilateral sensorimotor cortices in humans. Those are partly compatible with the previous findings. In addition to between the primary motor cortices, bilateral connection is requisite for smooth bimanual coordination between the sensory cortices or premotor cortices.

Using transcranial magnetic stimulation (TMS), we addressed the contribution of both hemispheres to the visuomotor control of each hand. The subjects had to press one of two buttons as quickly as possible after the go-signal. A precue preceding this conveyed full, partial or no advance information (hand and/or button), such that reaction time (RT) shortened with increasing amount of information. We gave TMS over each hemisphere at various time intervals (100-350 ms) after the go-signal and before the expected onset of response, and measured its effect on RT, movement time (MT) and error rate. At short intervals (100-200 ms), left hemisphere TMS delayed RT and prolonged MT of both hands, while right hemisphere TMS delayed RT only of the right hand, without affecting error rates. At long intervals (250-350 ms), TMS produced slightly more pronounced RT delays of the contralateral hand. RT was delayed more if the precues were less informative. The results suggest the importance of interhemispheric transmission of visuomotor information for motor implementation. The right hemisphere may play a role mainly in calculating target and effector information, determining RT, while the left hemisphere may play a role in elaborating the motor program and determining MT.

Objective: To compare motor evoked potentials (MEPs) elicited by short train, monophasic, repetitive transcranial magnetic stimulations (rTMS) with those by short train, biphasic rTMS., Methods: Subjects were 13 healthy volunteers. Surface electromyographic (EMG) responses were recorded from the right first dorsal interosseous muscle (FDI) in several different stimulation conditions. We gave both monophasic and biphasic rTMS over the motor cortex at a frequency of 0.5, 1, 2 or 3Hz. To study excitability changes of the spinal cord, we also performed 3Hz rTMS at the foramen magnum level [Ugawa Y, Uesaka Y, Terao Y, Hanajima R, Kanazawa I. Magnetic stimulation of corticospinal pathways at the foramen magnum level in humans. Ann Neurol 1994;36:618-24]. We measured the size and latency of each of 20 MEPs recorded in the different stimulation conditions., Results: 2 or 3Hz stimulation with either monophasic or biphasic pulses evoked MEPs that gradually increased in amplitude with the later MEPs being significantly larger than the earlier ones. Monophasic rTMS showed much more facilitation than biphasic stimulation, particularly at 3Hz. Stimulation at the foramen magnum level at 3Hz elicited fairly constant MEPs., Conclusions: The enhancement of cortical MEPs with no changes of responses to foramen magnum level stimulation suggests that the facilitation occurred at the motor cortex. We hypothesize that monophasic TMS has a stronger short-term effect during repetitive stimulation than biphasic TMS because monophasic pulses preferentially activate one population of neurons oriented in the same direction so that their effects readily summate. Biphasic pulses in contrast may activate several different populations of neurons (both facilitatory and inhibitory) so that summation of the effects is not so clear as with monophasic pulses. When single stimuli are applied, however, biphasic TMS is thought to be more powerful than monophasic TMS because the peak-to-peak amplitude of stimulus pulse is higher and its duration is longer when the same intensity of stimulation (the same amount of current is stored by the stimulator) is used., Significance: This means that when using rTMS as a therapeutic tool or in research fields, the difference in waveforms of magnetic pulses (monophasic or biphasic) may affect the results.

Electrical stimulation over the cerebellum is known to transiently suppress the contralateral motor cortex in humans. However, projections from the cerebellar nuclei to the primary motor cortex are disynaptic excitatory pathways through the ventral thalamus. In the present investigation we studied facilitatory effects on the motor cortical excitability elicited by electrical stimulation over the cerebellum by recording surface electromyographic (EMG) responses from the first dorsal interosseous (FDI) muscle in nine normal volunteers. For primary motor cortical activation magnetic stimuli were given over the contralateral hand motor area with a figure-of-eight shaped coil with a current to preferentially elicit I3-waves (test stimulus). For cerebellar stimulation high-voltage electric stimuli were given with an anode on the ipsilateral mastoid process and a cathode over the contralateral process as previously described (conditioning stimulus). The effect of conditioning-test interstimulus intervals was investigated. Anodal cerebellar stimuli increased the size of EMG responses to magnetic cortical stimulation at an interstimulus interval of 3 ms. Reversing the current of conditioning stimulus abolished the facilitation. The same (anodal) conditioning stimuli did not affect electrically evoked cortical responses. Based on the effective polarity of the conditioning stimulus and the time course of facilitation we consider that this effect is due to motor cortical facilitation elicited by activation of the excitatory dentatothalamocortical pathway at the deep cerebellar nuclei or superior cerebellar peduncle. We conclude that the motor cortical facilitation is evoked by cerebellar stimulation in humans.

Single pulses of transcranial magnetic stimulation (TMS) were applied to the right hemisphere over either the hand sensory area, the hand motor area (M1), ventral premotor area (vPM), dorsolateral prefrontal cortex, or 10 cm away from head (sham stimulation) in order to test the effect on motor evoked potentials (MEPs) elicited by single pulse TMS or transcranial electrical stimulus (TES) over the left M1 or the somatosensory evoked potential (SEP) elicited by an electrical stimulus to the right median nerve. The interstimulus intervals (ISIs) for MEP experiments were 50, 100, 150, 200, 300 and 400 ms, with those for SEP experiments being adjusted for the impulse conduction time from the wrist to the cortex. TMS over the right M1 reduced MEPs elicited by TMS of the left motor cortex at ISIs of 50-150 ms, whereas MEPs produced by TES were unaffected. TMS over M1 and vPM facilitated the contralateral cortical median nerve SEPs at an ISI of 100-200 ms, whereas it had no effect on tibial nerve SEPs or paired median nerve stimulation SEP. Based on these results, we conclude that at around 150-ms intervals, TMS over the motor areas (M1 and vPM) reduces the excitability of the contralateral motor area. This has a secondary effect of enhancing the responsiveness of the sensory cortex through cortico-cortical connections.

Paired-pulse magnetic stimulation has been widely used to study intracortical inhibition of the motor cortex. Inhibition at interstimulus intervals (ISIs) of 1-5 ms is ascribed to a GABAergic inhibitory system in the motor cortex. However, Fisher et al. have proposed that different mechanisms are operating at an ISI of 1 ms and 2.5 ms. In order to confirm their concept and clarify whether inhibition at all these intervals is produced by a single mechanism, we compared effects of paired-pulse stimulation at ISIs of 1 ms, 2 ms, and 3-5 ms. We evaluated how intracortical inhibition affected the I3-wave, I1-wave, magnetic D-wave, and anodal D-wave components of electromyographic (EMG) responses using previously reported methods. The data suggest that three separate effects occur within these ISIs. At ISIs of 3-5 ms, inhibition was evoked only in responses to I3-waves, whereas no inhibition was elicited in responses to I1-waves or magnetic D-waves. In contrast, at an ISI of 1 ms, responses to I3-waves and I1-waves were moderately suppressed. Moreover, even magnetic D-waves were slightly suppressed, whereas anodal D-waves were unaffected. At an ISI of 2 ms, none of the descending volleys were inhibited. We propose that we should use ISIs of 3-5 ms for estimating function of the GABAergic inhibitory system of the motor cortex by paired-pulse transcranial magnetic stimulation (TMS). Our results support the idea of Fisher et al. that the mechanism responsible for the inhibition at an ISI of 1 ms is not the same as that responsible for suppression at ISIs of 3-5 ms (GABAergic inhibitory circuits in the motor cortex). At an ISI of 2 ms, we suggest that the inhibitory influence evoked by the first stimulus (S1) should collide with or be occluded by the second stimulus (S2), which leads to the lack of inhibition when the subjects make a voluntary contraction of the target muscle.

Objective: In the present study, we studied effects of 1 Hz repetitive transcranial magnetic stimulation (rTMS) over the left primary motor cortex (M1) on regional cerebral blood flow (rCBF) using single-photon emission computed tomography (SPECT)., Methods: SPECT measurements were carried out under two experimental conditions: real and sham stimulation. In sham stimulation, to exclude other components besides currents in the brain in rTMS, we applied sound and electrical stimulation to the skin of the head. 99mTc-ethyl cysteinate dimer was injected during the real or sham stimulation. Images were analyzed with the statistical parametric mapping software (SPM99). Relative differences in adjusted rCBF between two conditions were determined by a voxel-by-voxel paired t test., Results: 1 Hz rTMS at an intensity of 1.1 x active motor threshold evoked increase of rCBF in the contralateral (right) cerebellar hemisphere. Reduction of rCBF was observed in the contralateral M1, superior parietal lobule (most probably corresponding to PE area in the monkey) (Rizzolatti G, Luppino G, Matelli M. Electroenceph clin Neurophysiol 1998;106:283-296), inferior parietal lobule (PF area in the monkey (Rizzolatti et al., 1998)), dorsal and ventral premotor areas (dPM, vPM) and supplementary motor area (SMA)., Conclusions: Increase of rCBF in the contralateral cerebellum must reflect facilitatory connection between the motor cortex and contralateral cerebellum. Reduced rCBF in the contralateral M1 may be produced by transcallosal inhibitory effect of the left motor cortical activation. CBF decrease in the right PM, SMA and parietal cortex may reflect some secondary effects. Low frequency rTMS at an intensity of around threshold for active muscles can evoke rCBF changes., Significance: We demonstrated that rCBF changes could be elicited even by low frequency rTMS at such a low intensity as the threshold for an active muscle. Combination of rTMS and SPECT is one of powerful tools to study interareal connection within the human brain.

We studied remote effects of teeth clenching on motor cortical and spinal cord excitability using transcranial magnetic stimulation (TMS), brainstem electrical stimulation (BES), and ulnar nerve stimulation (F-wave) in eight normal volunteers. The TMS, BES, and ulnar nerve stimulation at the wrist were given at different intervals (0-200 ms) after the onset of masseter contraction. Surface electromyographic responses were recorded from the first dorsal interosseous muscle. Responses at different intervals were compared with the response elicited when the subject made no teeth clenching (control response). In TMS, conditioned responses (during teeth clenching) were significantly larger than the control at all intervals. In contrast, in BES and F-waves, conditioned responses were not larger than the control at an early phase (intervals shorter than 50 ms), whereas they were larger than the control at later intervals (longer than 50 ms). These results suggest that facilitation occurs in the hand motor area at the early phase of teeth clenching, and spinal facilitation dominates at its late phase. This time course of facilitation may indicate that the motor cortex must regulate hand muscles finely at the early phase of teeth clenching, and spinal cord may stabilize them firmly at the late phase. The excitability changes of the hand motor area may be in parallel with that of the masseter motor area which reflects the pattern of masseter contraction when the subject activates the masseter muscle phasically at the early phase and sustains that contraction at the late phase.

Objectives: To study changes in the excitability of the sensory cortex by repetitive transcranial magnetic stimulation (rTMS) in humans., Methods: Somatosensory evoked potentials (SEPs) and antidromic sensory nerve action potentials (SNAPs) were elicited by right median nerve stimulation at the wrist before and after low frequency (1 Hz) rTMS over the left motor cortex, lateral premotor cortex, sensory cortex, and also after sham stimulation. The intensity of rTMS was fixed at 1.1 times the active motor threshold at the hand area of motor cortex., Results: N20 peak (N20p)-P25 and P25-N33 amplitudes were suppressed after rTMS over the motor cortex, whereas the N20 onset (N20o)-N20p and SNAP amplitudes were not affected. They recovered to the baseline about 100 min after the rTMS. rTMS over the premotor cortex or sensory cortex or sham stimulation had no suppressive effect on SEPs., Conclusions: The reduction of N20p-P25 and P25-N33 components without any changes of N20o-N20p amplitude suggests that the suppression occurs in the sensory cortex. rTMS (1 Hz) of the motor cortex induces a long-lasting suppression of the ipsilateral sensory cortex even at an intensity as low as 1.1 times the active motor threshold, probably via cortico-cortical pathways between motor and sensory cortex.

1. We investigated interhemispheric interactions between the human hand motor areas using transcranial cortical magnetic and electrical stimulation. 2. A magnetic test stimulus was applied over the motor cortex contralateral to the recorded muscle (test motor cortex), and an electrical or magnetic conditioning stimulus was applied over the ipsilateral hemisphere (conditioning motor cortex). We investigated the effects of the conditioning stimulus on responses to the test stimulus. 3. Two effects were elicited at different interstimulus intervals (ISIs): early facilitation (ISI = 4-5 ms) and late inhibition (ISI > or = 11 ms). 4. The early facilitation was evoked by a magnetic or anodal electrical conditioning stimulus over the motor point in the conditioning hemisphere, which suggests that the conditioning stimulus for early facilitation directly activates corticospinal neurones. 5. The ISIs for early facilitation taken together with the time required for activation of corticospinal neurones by I3-waves in the test hemisphere are compatible with the interhemispheric conduction time through the corpus callosum. Early facilitation was observed in responses to I3-waves, but not in responses to D-waves nor to I1-waves. Based on these results, we conclude that early facilitation is mediated through the corpus callosum. 6. If the magnetic conditioning stimulus induced posteriorly directed currents, or if an anodal electrical conditioning stimulus was applied over a point 2 cm anterior to the motor point, then we observed late inhibition with no early facilitation. 7. Late inhibition was evoked in responses to both I1- and I3-waves, but was not evoked in responses to D-waves. The stronger the conditioning stimulus was, the greater was the amount of inhibition. These results are compatible with surround inhibition at the motor cortex.

To investigate the cortical information processing during the preparation of vocalization, we performed transcranial magnetic stimulation (TMS) over the cortex while the subjects prepared to produce voice in response to a visual cue. The control reaction time (RT) of vocalization without TMS was 250-350 msec. TMS prolonged RT when it was delivered up to 150-200 msec before the expected onset of voice (EOV). The largest delay of RT was induced bilaterally over points 6 cm to the left and right of the vertex (the left and right motor areas), resulting in 10-20% prolongation of RT. During the early phase of prevocalization period (50-100 msec before EOV), the delay induced over the left motor area was slightly larger than that induced over the right motor area, whereas, during the late phase (0-50 msec before EOV), it was significantly larger over the right motor area. Bilateral and simultaneous TMS of the left and right motor areas induced delays not significantly different from that induced by unilateral TMS during the early phase, but induced a large delay well in excess of the latter during the late phase. Thus, during the cortical preparation for human vocalization, alternation of hemispheric lateralization takes place between the bilateral motor cortices near the facial motor representations, with mild left hemispheric predominance at the early phase switching over to robust right hemispheric predominance during the late phase. Our results also suggested involvement of the motor representation of respiratory muscles and also of supplementary motor cortex.

We performed transcranial magnetic stimulation (TMS) to elucidate the D- and I-wave components comprising the motor evoked potentials (MEPs) elicited from the leg motor area, especially at near-threshold intensity. Recordings were made from the tibialis anterior muscle using needle electrodes. A figure-of-eight coil was placed so as to induce current in the brain in eight different directions, starting from the posterior-to-anterior direction and rotating it in 45 degrees steps. The latencies were compared with those evoked by transcranial electrical stimulation (TES) and TMS using a double cone coil. Although the latencies of MEPs ranged from D to I3 waves, the most prominent component evoked by TMS at near-threshold intensity represented the I1 wave. With the double cone coil, the elicited peaks always represented I1 waves, and D waves were evoked only at very high stimulus intensities, suggesting a high effectiveness of this coil in inducing I1 waves. Using the figure-of-eight coil, current flowing anteriorly or toward the hemisphere contralateral to the recorded muscle was more effective in eliciting large responses than current flowing posteriorly or toward the ipsilateral hemisphere. The effective directions induced I1 waves with the lowest threshold, whereas the less effective directions elicited I1 and I2 waves with a similar frequency. Higher stimulus intensities resulted in concomitant activation of D through I3 waves with increasing amount of D waves, but still the predominance of I1 waves was apparent. The amount of I waves, especially of I1 waves, was greater than predicted by the hypothesis that TMS over the leg motor area activates the output cells directly, but rather suggests predominant transsynaptic activation. The results accord with those of recent human epidural recordings.

Objective: To study the effect of a loud auditory stimulus on the excitability of the human motor cortex., Methods: Ten normal volunteers participated in this study. The size of responses to transcranial magnetic or electrical cortical stimulation (TMS or TES) given at different times (ISIs) after a loud sound were compared with those to TMS or TES alone (control response). Different intensities and durations of sound were used at several intertrial intervals (ITIs). In addition, we examined how the presence of a preceding click modulated the effect of a loud sound (prepulse inhibition). The incidence of startle response evoked by various stimuli was also studied., Results: A loud auditory stimulus suppressed EMG responses to TMS when it preceded the magnetic stimulus by 30-60 ms, whereas it did not affect responses to TES. This suggests that the suppression occurred at a cortical level. Significant suppression was evoked only when the sound was louder than 80 dB and longer than 50 ms in duration. Such stimuli frequently elicited a startle response when given alone. The effect was not evoked if the ITI was 5 s, but was evoked when it was longer than 20 s. A preceding click reduced the suppression elicited by loud sounds., Conclusions: Auditory stimuli that produced the greatest effect on responses to TMS had the same characteristics as those which yielded the most consistent auditory startle. We suggest that modulation of cortical excitability occurs in parallel with the auditory startle and both may arise from the same region of the brain-stem.

Air-puff stimulation applied to a fingertip is known to exert a location-specific facilitatory effect on the size of the motor evoked potentials elicited in hand muscles by transcranial magnetic stimulation. In order to clarify its nature and the pathway responsible for its generation, we studied 27 patients with discrete lesions in the brain (16, 9 and 2 patients with lesions in the cerebral cortex, thalamus and brainstem, respectively). Facilitation was absent in patients with lesions affecting the primary sensorimotor area, whereas it was preserved in patients with cortical lesions that spared this area. Facilitation was abolished with thalamic lesions that totally destroyed the nucleus ventralis posterolateralis (VPL), but was preserved with lesions that at least partly spared it. Lesions of the spinothalamic tract did not impair facilitation. The size of the N20-P25 component of the somatosensory evoked potential showed a mild correlation with the amount of facilitation. The facilitation is mainly mediated by sensory inputs that ascend the dorsal column and reach the cortex through VPL. These are fed into the primary motor area via the primary sensory area, especially its anterior portion, corresponding to Brodmann areas 3 and 1 (possibly also area 2), without involving other cortical regions. The spinothalamic tract and direct thalamic inputs into the motor cortex do not contribute much to this effect. Some patients could generate voluntary movements despite the absence of the facilitatory effect. The present method will enable us to investigate in humans the function of one of the somatotopically organized sensory feedback input pathways into the motor cortex, and will be useful in monitoring ongoing finger movements during object manipulation.

Objective: A well-organized input-output relation similar to that of the monkey motor cortex has been demonstrated in the human hand motor area (Terao Y, Ugawa Y, Uesaka Y, Hanajima R, Gemba-Shimizu K, Ohki Y, Kanazawa I. Input-output organization in the hand area of the human motor cortex, Electroenceph clin Neurophysiol 1995;97:375-381). The aim of this study is to investigate the input-output organization of the human foot motor area., Methods: We studied the effect of tactile stimuli given to the toe tip on the sizes of following responses; motor evoked potentials (MEPs) elicited by transcranial magnetic or electrical stimulation (TMS or TES) over the motor cortex and magnetic stimulation at the foramen magnum level., Results: Air stimuli applied to the toe tip facilitated magnetically evoked MEPs of mainly the muscle attached to that toe, although a less prominent facilitation was also noted in muscles attached to the adjacent toes. Neither responses evoked by TES, nor those by stimulation at the foramen magnum level, were affected by air stimuli. These results suggest that the observed facilitatory effect occurs at the cortical level., Conclusion: A fairly well-organized input-output relation is present also in the foot motor area in humans, although the facilitatory effect is not so topographically restricted as is noted for the hand motor area.

Intracortical inhibition of the motor cortex was investigated using a paired pulse magnetic stimulation method in 14 patients with chorea caused by various aetiologies (six patients with Huntington's disease, one with chorea acanthocytosis, a patient with systemic lupus erythematosus with a vascular lesion in the caudate, three with senile chorea and three with chorea of unknown aetiology). The time course and amount of inhibition was the same in the patients as in normal subjects, suggesting that the inhibitory mechanisms of the motor cortex studied with this method are intact in chorea. This is in striking contrast with the abnormal inhibition seen in patients with Parkinson's disease or focal hand dystonia, or those with a lesion in the putamen or globus pallidus. It is concluded that the pathophysiological mechanisms responsible for chorea are different from those producing other involuntary movements.

Objectives: To investigate whether the cortico-cortical inhibition originally reported for the human hand motor area is present in the motor cortex for sternocleidomastoid muscle (SCM) and to evaluate the amount of inhibition in spasmodic torticollis and essential tremor., Methods: Subjects were 14 normal healthy volunteers, 10 patients with spasmodic torticollis and 5 with essential tremor involving neck muscles. A paired-pulse magnetic stimulation was performed for the SCMs and first dorsal interosseous muscles (FDIs)., Results: In normal subjects, a subthreshold magnetic conditioning stimulus suppressed responses to a suprathreshold magnetic test stimulus when their interval was 1-5 ms in SCM. This indicates that the similar cortico-cortical inhibitory mechanism is present in the motor cortex for SCM as in the hand motor area. In the patients with spasmodic torticollis, the cortico-cortical inhibitory effect was reduced or absent in SCM, but normal in the FDI. In contrast, in patients with essential tremor, normal cortico-cortical inhibition was seen in both the SCM and FDI., Conclusions: The cortico-cortical inhibitory mechanisms of the motor cortex for SCM can be studied by a paired-pulse magnetic stimulation method. Our result of reduced cortico-cortical inhibition in torticollis patients suggests abnormal excitability (hyperexcitable or disinhibited) of the motor cortex for SCM in spasmodic torticollis.

In order to locate the site of action of transcranial magnetic stimulation (TMS) within the human motor cortices, we investigated how the optimal positions for evoking motor responses over the scalp corresponded to the hand and leg primary-motor areas. TMS was delivered with a figure-8 shaped coil over each point of a grid system constructed on the skull surface, each separated by 1 cm, to find the optimal site for obtaining motor-evoked potentials (MEPs) in the contralateral first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. Magnetic resonance imaging scans of the brain were taken for each subject with markers placed over these sites, the positions of which were projected onto the cortical region just beneath. On the other hand, cortical areas where blood flow increased during finger tapping or leg movements were identified on functional magnetic resonance images (fMRI), which should include the hand and leg primary-motor areas. The optimal location for eliciting MEPs in FDI, regardless of their latency, lay just above the bank of the precentral gyrus, which coincided with the activated region during finger tapping in fMRI studies. The direction of induced current preferentially eliciting MEPs with the shortest latency in each subject was nearly perpendicular to the course of the precentral gyrus at this position. The optimal site for evoking motor responses in TA was also located just above the activated area during leg movements identified within the anterior portion of the paracentral lobule. The results suggest that, for magnetic stimulation, activation occurs in the primary hand and leg motor area (Brodmann area 4), which is closest in distance to the optimal scalp position for evoking motor responses.

1. In paired-pulse cortical stimulation experiments, conditioning subthreshold stimuli suppress the electromyographic (EMG) responses of relaxed muscles to suprathreshold magnetic test stimuli at short interstimulus intervals (ISIs) (1-5 ms) and facilitate them at long ISIs (8-15 ms). 2. We made paired-pulse magnetic stimulation studies on the response of the first dorsal interosseous muscle (FDI) produced by I1 or I3 waves using our previously reported method which preferentially elicits one group of I waves when subjects make a slight voluntary contraction. In some experiments the conditioning and test stimuli were oppositely directed, in the others they were oriented in the same direction. Single motor unit responses were recorded with a concentric needle electrode, and surface EMG responses with cup electrodes. 3. In post-stimulus time histograms (PSTHs) of the firing probability of motor units, the peaks produced by I3 waves were decreased by a subthreshold conditioning stimulus that preferentially elicited I1 or I3 waves at an ISI of 4 ms. The amount of decrement depended on the intensity of the conditioning stimulus. The stronger the conditioning stimulus, the greater the suppression. In contrast, the peaks produced by I1 waves were little affected by any type of subthreshold conditioning stimulus, given 4 ms prior to the test stimulus. At an ISI of 10 ms, a subthreshold conditioning stimulus slightly decreased the size of the peak produced by the I3 waves, but did not affect the peaks evoked by I1 waves. 4. Surface EMGs showed that a subthreshold conditioning stimulus suppressed the responses produced by I3 waves irrespective of its current direction (anterior or posterior). Both the amount and duration of suppression depended on the intensity of the conditioning stimulus, but not on its current direction. Both parameters increased when the intensity increased. At a high intensity conditioning stimulus, suppression was evoked at ISIs of 1-20 ms, compatible with the duration of GABA-mediated inhibition found in animal experiments. Responses produced by I1 waves were little affected by any type of subthreshold conditioning stimulus. 5. We conclude that a subthreshold conditioning stimulus given over the motor cortex moderately suppresses I3 waves but does not affect I1 waves. The duration of suppression of the I3 waves supports the idea that this is an effect of GABAergic inhibition within the motor cortex.

Transcranial magnetic stimulation (TMS) over the human primary motor cortex (MI) evokes motor responses in the contralateral limb muscles. The latencies and amplitudes of those responses depend on the direction of induced current in the brain by the stimuli (Mills et al. 1992, Werhahn et al. 1994). This observation suggests that different neural elements might be activated by the differently directed induced currents. Using a figure-of-eight-shaped coil, which induces current with a certain direction, we analyzed the effect of direction of stimulating current on the latencies of responses to TMS in normal subjects. The latencies were measured from surface electromyographic responses of the first dorsal interosseous muscles and the peaks in the peristimulus time histograms (PSTHs) of single motor units from the same muscles. The coil was placed over the MI, with eight different directions each separated by 45 degrees. Stimulus intensity was adjusted just above the motor threshold while subjects made a weak tonic voluntary contraction, so that we can analyse the most readily elicited descending volley in the pyramidal tracts. In most subjects, TMS with medially and anteriorly directed current in the brain produced responses or a peak that occurred some 1.5 ms later than those to anodal electrical stimulation. In contrast, TMS with laterally and posteriorly directed current produced responses or a peak that occurred about 4.5 ms later. There was a single peak in most of PSTHs under the above stimulation condition, whereas there were occasionally two peaks under the transitional current directions between the above two groups. These results suggest that TMS with medially and anteriorly directed current in the brain readily elicits I1 waves, whereas that with laterally and posteriorly directed current preferentially elicits I3 waves. Functional magnetic resonance imaging studies indicated that this direction was related to the course of the central sulcus. TMS with induced current flowing forward relative to the central sulcus preferentially elicited I1 waves and that flowing backward elicited I3 waves. Our finding of the dependence of preferentially activated I waves on the current direction in the brain suggests that different sets of cortical neurons are responsible for different I waves, and are contrarily oriented. The present method using a figure-of-eight-shaped coil must enable us to study physiological characteristics of each I wave separately and, possibly, analyse different neural elements in MI, since it activates a certain I wave selectively without D waves or other I waves.

Objective: To measure the conduction time from the motor cortex to the conus medullaris (cortico-conus motor conduction time, CCCT) for leg muscles using magnetic stimulation. Methods: Motor evoked potentials (MEPs) were recorded from right tibialis anterior muscle in 100 healthy volunteers. To activate spinal nerves at the most proximal cauda equina level or at the conus medullaris level, magnetic stimulation was performed using a MATS coil. Transcranial magnetic stimulation of the motor cortex was also conducted to measure the cortical latency for the target muscle. To obtain the CCCT, the latency of MEPs to conus stimulation (conus latency) was subtracted from the cortical latency. Results: MATS coil stimulation evoked reproducible MEPs in all subjects, yielding CCCT data for all studied tibialis anterior muscles. Conclusions: MATS coil stimulation provides CCCT data for healthy subjects. This novel method is useful for evaluation of corticospinal tract conduction for leg muscles because no peripheral component affects the CCCT. [Copyright &y& Elsevier]