Paired-pulse repetitive transcranial magnetic stimulation of the human motor cortex

In nine healthy humans we modulated corticospinal excitability by using conditioning-test paired-pulse transcranial magnetic stimulation in a repetitive mode (rTMS), and we compared its effect to conventional single-pulse rTMS. We applied 80 single pulses or 80 paired pulses to the motor cortex at frequencies ranging from 0.17 to 5 Hz. The conditioning-test intervals were 2, 5, or 10 ms. Motor evoked potential (MEP) amplitudes from the abductor digiti minimi (ADM) as target muscle and extensor carpi radialis (ECR) indicated the excitability changes during and after rTMS. During paired-pulse rTMS at a facilitatory conditioning-test interval of 10 ms, we observed a facilitation of MEPs at 1, 2, and 5 Hz. A similar facilitation was found during single-pulse rTMS, when stimulus intensity was adjusted to evoke MEPs of comparable size. Using an inhibitory conditioning-test interval of 2 ms, paired-pulse rTMS at frequencies of 1 and 2 Hz caused no change in MEP size during the train. However, paired-pulse rTMS at 5 Hz caused a strong enhancement of MEP size, indicating a loss of paired-pulse inhibition during the rTMS train. Since no facilitatory effect was observed during single-pulse rTMS with an adjusted stimulus intensity, the MEP enhancement during 5 Hz rTMS was specific for "inhibitory" paired-pulse rTMS. After 5 Hz rTMS MEPs were facilitated for 1 min, and this effect was not substantially different between paired-pulse rTMS and single-pulse rTMS. The correlation between ADM and ECR was most pronounced at 5 Hz rTMS. We conclude that paired-pulse rTMS is a suitable tool to study changes in corticospinal excitability during the course of rTMS. In addition, our data suggest that short trains of paired-pulse rTMS are not superior to single-pulse rTMS in inducing lasting inhibition or facilitation. Electronic Publication     

Interactions between pairs of transcranial magnetic stimuli over the human left dorsal premotor cortex differ from those seen in primary motor cortex

A single TMS pulse (110% resting motor threshold, RMT) to the left dorsal premotor cortex (PMd) (CS2) suppresses the amplitude of motor evoked potentials (MEPs) from a test pulse (TS) over the right motor cortex (M1), and facilitates MEPs from the left motor cortex. We probed how this interaction was changed by a prior conditioning pulse over PMd (CS1) using a paired pulse TMS design. In the main experiments, the intensity of CS1 was 80% RMT. Basal suppression of right M1 was removed when CS1–CS2 was 1 ms or 5 ms with a similar tendency at 15 ms. Basal facilitation of left M1 was suppressed at CS1–CS2 of 5 ms. A similar time course was seen if CS2 was increased to 100% RMT, but there was no significant effect if CS1 was 70% RMT. Preconditioning PMd with continuous or intermittent theta burst repetitive TMS (cTBS, iTBS) abolished the basal CS2–TS interaction between premotor and motor cortices. Finally, if very short interstimulus intervals between CS1 and CS2 were explored to detect interactions similar to I-wave facilitation in M1, we found that the basal suppression of right M1 was abolished at CS1–CS2 intervals of 1.8 and 2.8 ms. We suggest that paired pulse TMS may be capable of investigating properties of intrinsic circuits in PMd and that their properties differ from those in the nearby M1. Paired TMS may be a useful method of studying the excitability of intrinsic circuits in non-primary areas of the motor system.     

Modulating neural networks with transcranial magnetic stimulation applied over the dorsal premotor and primary motor cortices

Our study uses the combined transcranial magnetic stimulation/positron emission tomography (TMS/PET) method for elucidating neural connectivity of the human motor system. We first altered motor excitability by applying low-frequency repetitive TMS over two cortical motor regions in separate experiments: the dorsal premotor and primary motor cortices. We then assessed the consequences of modulating motor excitability by applying single-pulse TMS over the primary motor cortex and measuring: 1) muscle responses with electromyography and 2) cerebral blood flow with PET. Low-frequency repetitive stimulation reduced muscle responses to a similar degree in both experiments. To map networks of brain regions in which activity changes reflected modulation of motor excitability, we generated t-statistical maps of correlations between reductions in muscle response and differences in cerebral blood flow. Low-frequency repetitive stimulation altered neural activity differently in both experiments. Neural modulation occurred in multiple brain regions after dorsal premotor cortex stimulation; these included motor regions in the frontal cortex as well as more associational regions in the parietal and prefrontal cortices. In contrast, neural modulation occurred in a smaller number of brain regions after primary motor cortex stimulation, many of these confined to the motor system. These findings are consistent with the known differences between the dorsal premotor and primary motor cortices in the extent of cortico-cortical anatomical connectivity in the monkey.     

Topographic mapping of human motor cortex with transcranial magnetic stimulation: Homunculus revisited

Summany The purpose of this study was to non-invasively evaluate the homuncular organization of the motor cortex in man. We used transcranial magnetic stimulation to induce motor evoked potentials (MEP's) in Abductor Pollicis Brevis (APB) and Biceps Brachii (BB) muscles of 10 healthy volunteers. The practicality and accuracy of magnetic stimulation to scalp sites one cm apart was increased by the application to the scalp of a flexible nylon grid with grid size of 1×1 cm. Responsive scalp sites collectively contributed to distinct but overlapping muscle representational areas for the two muscles. The topography of these motor maps along and slightly anterior to the central fissure corresponds to the homuncular configuration as described by Penfield and Boldrey in 1937.     

Preconditioning repetitive transcranial magnetic stimulation of premotor cortex can reduce but not enhance short-term facilitation of primary motor cortex

Short trains of suprathreshold 5-Hz repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) evoke motor potentials (MEPs) in hand muscles that progressively increase in amplitude via a mechanism that is thought to be similar to short-term potentiation described in animal preparations. Long trains of subthreshold rTMS over dorsal premotor cortex (PMd) are known to affect the amplitude of single-pulse MEPs evoked from M1. We tested whether PMd-rTMS affects short-term facilitation in M1. We also explored the effect of PMd-rTMS on M1 responses evoked by single-pulse TMS of different polarities. We tested in 15 healthy subjects short-term facilitation in left M1 (10 suprathreshold TMS pulses at 5 Hz) after applying rTMS to left PMd (1,500 subthreshold pulses at 1 and 5 Hz). In a sample of subjects we delivered single-pulse TMS with different polarities and paired-pulse TMS at short intervals (SICI) after PMd-rTMS. Short-term facilitation in M1 was reduced after applying 1 Hz to PMd, but was unaffected after 5-Hz PMd-rTMS. PMd-rTMS with 1 Hz reduced the amplitude of MEPs evoked by monophasic posteroanterior (PA) or biphasic anteroposterior (AP)-PA but had little effect on MEPs by monophasic AP or biphasic PA-AP single-pulse TMS. PMd-rTMS left SICI unchanged. PMd-rTMS (1 Hz) reduces short-term facilitation in M1 induced by short 5-Hz trains. This effect is likely to be caused by reduced facilitation of I-wave inputs to corticospinal neurons.     

Synchronization of neuronal activity in the human primary motor cortex by transcranial magnetic stimulation: an EEG study

Using multichannel electroencephalography (EEG), we investigated temporal dynamics of the cortical response to transcranial magnetic stimulation (TMS). TMS was applied over the left primary motor cortex (M1) of healthy volunteers, intermixing single suprathreshold pulses with pairs of sub- and suprathreshold pulses and simultaneously recording EEG from 60 scalp electrodes. Averaging of EEG data time locked to the onset of TMS pulses yielded a waveform consisting of a positive peak (30 ms after the pulse P30), followed by two negative peaks [at 45 (N45) and 100 ms]. Peak-to-peak amplitude of the P30-N45 waveform was high, ranging from 12 to 70 microV; in most subjects, the N45 potential could be identified in single EEG traces. Spectral analysis revealed that single-pulse TMS induced a brief period of synchronized activity in the beta range (15-30 Hz) in the vicinity of the stimulation site; again, this oscillatory response was apparent not only in the EEG averages but also in single traces. Both the N45 and the oscillatory response were lower in amplitude in the 12-ms (but not 3-ms) paired-pulse trials, compared with the single-pulse trials. These findings are consistent with the possibility that TMS applied to M1 induces transient synchronization of spontaneous activity of cortical neurons within the 15- to 30-Hz frequency range. As such, they corroborate previous studies of cortical oscillations in the motor cortex and point to the potential of the combined TMS/EEG approach for further investigations of cortical rhythms in the human brain.     

Stability of maps of human motor cortex made with transcranial magnetic stimulation

Cortical representation maps derived by transcranial magnetic stimulation (TMS) are often used, inter alia, in studying the plasticity of the brain. Parameters such as map area, map volume, optimal stimulation site and centre of gravity are commonly used to quantify changes in the topography of the motor cortex. However, reports on the stability of these parameters over time has not been conclusive. In the present study, the areas of the scalp from which responses were evoked from corticospinal cells projecting to three intrinsic hand muscles were systematically mapped with TMS at intervals of 24 hours, one week and two weeks from eight normal subjects. The area, "volume" and centre of gravity of these maps did not change significantly over this period. It is concluded that mapping with TMS is suitable for studies which aim to study the effect of various interventions on the cortical representation of individual muscles in human subjects.     

Theta-burst repetitive transcranial magnetic stimulation suppresses specific excitatory circuits in the human motor cortex

In four conscious patients who had electrodes implanted in the cervical epidural space for the control of pain, we recorded corticospinal volleys evoked by single-pulse transcranial magnetic stimulation (TMS) over the motor cortex before and after a 20 s period of continuous theta-burst stimulation (cTBS). It has previously been reported that this form of repetitive TMS reduces the amplitude of motor-evoked potentials (MEPs), with the maximum effect occurring at 5–10 min after the end of stimulation. The present results show that cTBS preferentially decreases the amplitude of the corticospinal I1 wave, with approximately the same time course. This is consistent with a cortical origin of the effect on the MEP. However, other protocols that lead to MEP suppression, such as short-interval intracortical inhibition, are characterized by reduced excitability of late I waves (particularly I3), suggesting that cTBS suppresses MEPs through different mechanisms, such as long-term depression in excitatory synaptic connections.     

Interhemispheric interaction between human dorsal premotor and contralateral primary motor cortex

We used transcranial magnetic stimulation (TMS) in a paired pulse protocol to investigate interhemispheric interactions between the right dorsal premotor (dPM) and left primary motor cortex (M1) using interstimulus intervals of 4, 6, 8, 10, 12, 16 and 20 ms in ten healthy subjects. A conditioning stimulus over right dPM at an intensity of either 90 or 110% resting motor threshold (RMT) suppressed motor-evoked potentials (MEPs) evoked in the first dorsal interosseous (FDI) muscle by stimulation of left M1. Maximum effects occurred for interstimulus intervals (ISIs) of 8–10 ms. There was no effect if the conditioning stimulus was applied 2.5 cm lateral, anterior or medial to dPM. The effect differed from previously described M1 interhemispheric inhibition in that the threshold for the latter was greater than 90% RMT, whereas stimulation of the dPM at the same intensity led to significant inhibition. In addition, voluntary contraction of the left FDI (i.e. contralateral to the conditioning TMS) enhanced interhemispheric inhibition from right M1 but had no effect on the inhibition from right dPM. Finally, conditioning to right dPM at 90% RMT reduced short-interval intracortical inhibition (SICI; at ISI = 2 ms) in left M1 whilst there was no effect if the conditioning stimulus was applied to right M1. We conclude that conditioning TMS over dPM has effects that differ from the previous pattern of interhemispheric inhibition described between bilateral M1s. This may reflect the existence of commissural fibres between dPM and contralateral M1 that may play a role in bimanual coordination.     

Direct demonstration of interhemispheric inhibition of the human motor cortex produced by transcranial magnetic stimulation

 Electromyographic (EMG) responses evoked in hand muscles by a magnetic test stimulus over the motor cortex can be suppressed if a conditioning stimulus is applied to the opposite hemisphere 6–30 ms earlier. In order to define the mechanism and the site of action of this inhibitory phenomenon, we recorded descending volleys produced by the test stimulus through high cervical, epidural electrodes implanted for pain relief in three conscious subjects. These could be compared with simultaneously recorded EMG responses in hand muscles. When the test stimulus was given on its own it evoked three waves of activity (I-waves) in the spinal cord, and a small EMG response in the hand. A prior conditioning stimulus to the other hemisphere suppressed the size of both the descending spinal cord volleys and the EMG responses evoked by the test stimulus when the interstimulus interval was greater than 6 ms. In the spinal recordings, the effect was most marked for the last I-wave (I₃), whereas the second I₂-wave was only slightly inhibited, and the first I-wave (I₁) was not inhibited at all. We conclude that transcranial stimulation over the lateral part of the motor cortex of one hemisphere can suppress the excitability of the contralateral motor cortex. Received: 31 August 1998 / Accepted: 26 October 1998     

Short-term reduction of intracortical inhibition in the human motor cortex induced by repetitive transcranial magnetic stimulation

Ten healthy subjects and two patients who had an electrode implanted into the cervical epidural space underwent repetitive transcranial magnetic stimulation (rTMS; 50 stimuli at 5 Hz at active motor threshold intensity) of the hand motor area. We evaluated intracortical inhibition before and after rTMS. In healthy subjects, we also evaluated threshold and amplitude of motor evoked potentials (MEPs), duration of cortical silent period and short-latency intracortical facilitation. rTMS led to a short-lasting reduction in the amount of intracortical inhibition in control subjects with a high interindividual variability. There was no significant effect on other measures of motor cortex excitability. Direct recordings of descending corticospinal volleys from the patients were consistent with the idea that the effect of rTMS on intracortical inhibition occurred at the cortical level. Since the level of intracortical inhibition can be influenced by drugs that act on GABAergic systems, this may mean that low-intensity repetitive magnetic stimulation at 5 Hz can selectively modify the excitability of GABAergic networks in the human motor cortex. Electronic Publication     

Two different effects of transcranial magnetic stimulation to the human motor cortex during the pre-movement period

A single-pulse TMS to the human motor cortex (M1) influences reaction time (RT). We may summarize from previous studies where different groups of subjects participated in various types of RT tasks that TMS above motor threshold (MT) delays RT, whereas TMS below MT shortens RT and that these RT changes depends on TMS timings during RT period. However, these effects have never been systematically investigated in a single study where an identical group of subjects participated. The purpose of this study is to test previous TMS effects in a study of simple RT task. Seven subjects isometrically abducted their right index fingers as quickly as possible when a visual stimulus appeared. A single-pulse TMS was randomly delivered over the left M1 at various timings during RT period in a single trial (at 0, 40, 60, 80 or 100 ms after the visual stimulus). Motor-evoked potential (MEP) and EMG activity for response were recorded from the right finger muscles. Only the TMS above MT delivered at 80 or 100 ms, which increased MEP amplitude, significantly delayed RT and increased the size of response EMG activities that may reflect contents of central motor commands. The TMS below MT at these timings, which occasionally evoked MEP, exclusively shortened RT despite the fact that the response EMG size was unchanged. A single-pulse TMS has different effects on the ongoing neuronal processes in M1 during the pre-movement period: TMS above MT may temporally retard the processes and also affect contents of central motor commands, whereas TMS below MT may simply facilitate its processes without affecting motor commands.     

Unconscious modulation of motor cortex excitability revealed with transcranial magnetic stimulation

The neuronal effects of sensory events that do not enter conscious awareness have been reported in numerous pathological conditions and in normal subjects. In the present study, unconscious modulation of corticospinal excitability was probed in healthy volunteers with transcranial magnetic stimulation (TMS). TMS-induced motor evoked potentials (MEPs) were collected from the first dorsal interosseus muscle while subjects performed a masked semantic priming task that has been shown to elicit covert motor cortex activations. Our data show that the amplitude of the MEPs is modulated by an unseen prime, in line with temporal patterns revealed with event related potentials. These data confirm previous reports showing specific motor neural responses associated with an unseen visual stimulus and establish TMS as a valuable tool in the study of the neural correlates of consciousness.     

Prefrontal [correction of Prefontal] cortex in long-term memory: an "interference" approach using magnetic stimulation

Neuroimaging has consistently shown engagement of the prefrontal cortex during episodic memory tasks, but the functional relevance of this metabolic/hemodynamic activation in memory processing is still to be determined. We used repetitive transcranial magnetic stimulation (rTMS) to transiently interfere with either left or right prefrontal brain activity during the encoding or retrieval of pictures showing complex scenes. We found that the right dorsolateral prefrontal cortex (DLPFC) was crucial for the retrieval of the encoded pictorial information, whereas the left DLPFC was involved in encoding operations. This 'interference' approach allowed us to establish whether a cortical area activated by a memory task actually contributes to behavioral performance.     

Electrical and magnetic repetitive transcranial stimulation of the primary motor cortex in healthy subjects

Repetitive transcranial magnetic stimulation (rTMS) delivered in short trains at 5 Hz frequency and suprathreshold intensity over the primary motor cortex (M1) in healthy subjects facilitates the motor-evoked potential (MEP) amplitude by increasing cortical excitability through mechanisms resembling short-term synaptic plasticity. In this study, to investigate whether rTES acts through similar mechanisms we compared the effects of rTMS and repetitive transcranial electrical stimulation (rTES) (10 stimuli-trains, 5 Hz frequency, suprathreshold intensity) delivered over the M1 on the MEP amplitude. Four healthy subjects were studied in two separate sessions in a relaxed condition. rTMS and anodal rTES were delivered in trains to the left M1 over the motor area for evoking a MEP in the right first dorsal interosseous muscle. Changes in MEP size and latency during the course of the rTMS and rTES trains were compared. The possible effects of muscle activation on MEP amplitude were evaluated, and the possible effects of cutaneous trigeminal fibre activation on corticospinal excitability were excluded in a control experiment testing the MEP amplitude before and after supraorbital nerve repetitive electrical stimulation. Repeated measures analysis of variance (ANOVA) showed that rTES and rTMS trains elicited similar amplitude first MEPs and a similar magnitude MEP amplitude facilitation during the trains. rTES elicited a first MEP with a shorter latency than rTMS, without significant changes during the course of the train of stimuli. The MEP elicited by single-pulse TES delivered during muscle contraction had a smaller amplitude than the last MEP in the rTES trains. Repetitive supraorbital nerve stimulation left the conditioned MEP unchanged. Our results suggest that 5 Hz-rTES delivered in short trains increases cortical excitability and does so by acting on the excitatory interneurones probably through mechanisms similar to those underlying the rTMS-induced MEP facilitation.     

The neural response to transcranial magnetic stimulation of the human motor cortex. II. Thalamocortical contributions

Beta oscillations (15–30 Hz) constitute an important electrophysiological signal recorded in the resting state over the human precentral gyrus. The brain circuitry involved in generating the beta oscillations is not well understood but appears to involve both cortical and subcortical structures. We have shown that single pulses of transcranial magnetic stimulation (TMS) applied over the primary motor cortex consistently elicit a brief beta oscillation. Reducing the local cortical excitability using low-frequency repetitive TMS does not change the amplitude of the induced beta oscillation (Van Der Werf and Paus in Exp Brain Res DOI 10.1007/s00221-006-0551-2). Here, we investigated the possible involvement of the thalamus in the cortically expressed beta response to single-pulse TMS. We included eight patients with Parkinson’s disease who had undergone unilateral surgical lesioning of the ventrolateral nucleus of the thalamus. We administered 50 single pulses of TMS, at an intensity of 120% of resting motor threshold, over the left and right primary motor cortex and, at the same time, recorded the electroencephalogram (EEG) using a 60-electrode cap. We were able to perform analyses on seven EEG data sets and found that stimulation of the unoperated hemisphere (with thalamus) resulted in higher amplitudes of the single-trial induced beta oscillations than in the operated hemisphere (with thalamotomy). The beta oscillation obtained in response to pulses applied over the unoperated hemisphere was also higher than that obtained in healthy controls. We suggest that (1) the beta oscillatory response to pulses of TMS applied over the primary motor cortex is higher in Parkinson’s disease patients, (2) thalamotomy serves to reduce the abnormally high TMS-induced beta oscillations, and (3) the motor thalamus facilitates the cortically generated oscillation, through cortico-subcortico-cortical feedback loops.The first author was funded by a fellowship from the Canadian Institute of Health Research (CIHR).     

Simultaneous recording of slow brain potentials and transcranial magnetic stimulation of hand area in human motor cortex

Recording of slow brain potentials (SPs) and transcranial magnetic stimulation (TCMS) of the human motor cortex were combined to probe the relationship between SP level and excitability of cortical neurons. In experiment 1, TCMS was applied during and shortly after the warning interval in a forewarned reaction time task. Electromyographic (EMG) responses to TCMS increased only slightly during the warning interval and were significantly elevated 150 ms after the imperative stimulus. In experiment 2, TCMS was applied during biofeedback-induced cortical positivity and negativity. In this non-motor task a dependence of TCMS response on SP amplitude was not significant. Results indicate higher local excitability of motor cortex during cortical negativity when a preparatory motor task in required. TCMS may better be suited to probe processes involved in motor tasks rather than non-motor and cognitive conditions.