Stimulus strength related effect of transcranial magnetic stimulation on maximal voluntary contraction force of human quadriceps femoris muscle

It is well accepted that transcranial magnetic stimulation (TMS) can modulate motor cortex excitability long after application. Furthermore, a positive TMS effect on the ability to perform a maximal voluntary contraction (MVC) of the quadriceps femoris muscle has been described. However, stimulus strength dependence and duration of this effect are currently unknown. In the present study these parameters of the TMS-induced MVC enhancement were investigated in seven healthy subjects. Initially, three repetitive transcranial magnetic stimuli of varying stimulus strength were applied every 4 s either during MVC or relaxation. Thereafter, MVC and the ability to activate the quadriceps muscle voluntarily (voluntary activation) were determined using a sensitive twitch interpolation technique. In a second experiment we investigated the effect of three transcranial magnetic stimuli applied either during MVC or during relaxation on MVC over a time period of 30 min. There was a small but significant and stimulus strength related positive effect of TMS on MVC. The effect of TMS on voluntary activation was not significant. TMS had to be given during MVC to be effective and the positive effect of TMS when applied during MVC was still present after 30 min. These results indicate that TMS acts differently on the motor cortex depending on its activation status. TMS might have potential therapeutic applications in diseases associated with diminished cortical motor drive and subsequent muscle weakness.     

Fearful faces selectively increase corticospinal motor tract excitability: a transcranial magnetic stimulation study

Fearful facial expressions are danger signals that rapidly trigger a cascade of neurobiological processes defensibly associated with action preparation. However, direct evidence for the activating effects of fearful facial expressions on the motor system is absent. The current transcranial magnetic stimulation (TMS) study investigated whether fearful facial expressions selectively increase corticospinal motor tract (CST) excitability. Focal TMS was applied over the left primary motor cortex during the exposure of fearful, happy, and neutral facial expressions in 12 healthy right-handed volunteers. Changes in CST excitability using the motor evoked potential (MEP) were recorded. Results showed significant selective increases in MEP to fearful facial expressions. These findings provide the first direct evidence for selective increases in CST excitability to threat and contribute to evolutionary views on emotion and action preparedness.     

Modulation of intracortical inhibition induced by low- and high-frequency repetitive transcranial magnetic stimulation

We studied the changes of duration of subsequent silent periods (SPs) during repetitive magnetic stimulation (rTMS) trains of ten stimuli delivered at low (1 Hz) and high (7 Hz) frequencies. The effects at different intensities of stimulation (motor threshold, MT, 115% and 130% above the MT) were also evaluated. rTMS was performed in eight healthy subjects with a figure-of-eight coil placed over the hand motor area. The SP was recorded from abductor pollicis brevis (APB) muscle during a voluntary contraction of 30% of maximum effort. rTMS at 1-Hz frequency progressively decreased the duration of SP, whereas an alternating pattern of smaller and larger values was observed during trains at 7-Hz frequency and higher stimulus intensity. The findings show that rTMS changes the duration of cortical SPs; the effect is probably due to the modulation of intracortical inhibitory interneurons depending on the frequency and intensity of stimulation.     

Postexercise depression of motor evoked potentials: a measure of central nervous system fatigue

Fatigue of voluntary muscular effort is a complex and multifaceted phenomenon. Fatigue of peripheral nervous system components, including the contractile apparatus and the neuromuscular junction, has been well studied. Central nervous system components also fatigue, but studies have lagged for want of objective methods. Transcranial magnetic stimulation is a relatively new technique that can be used to assess central nervous system excitability from the motor cortex to the alpha-motoneuron. In six normal volunteers, including four of the investigators, the amplitudes of motor evoked potentials elicited by transcranial magnetic stimulation were transiently decreased after exercise, indicating fatigue of motor pathways in the central nervous system. The decrease in amplitude was associated with a feeling of fatigue. The mechanism of this phenomenon is apparently decreased efficiency in the generation of the motor command in the motor cortex.     

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     

Long-lasting depression of motor-evoked potentials to transcranial magnetic stimulation following exercise

We used transcranial magnetic stimulation to study the modulation of motor cortex excitability after rapid repetitive movements. Eleven healthy subjects aged 24–32 years were evaluated. Serial motor-evoked potential (MEP) recordings were performed from the right thenar eminence every 5 min for a period of 20 min at rest and for a period of 35 min after repetitive abduction-adduction of the thumb at maximal frequency for 1 min. All subjects presented distinct changes in MEP amplitude after exercise with an approximately 55% mean maximal decrease compared with basal conditions and complete recovery 35 min after the end of the exercise. The time course of MEP amplitude changes presented the following trend: (1) a rapid decrease phase within the first 5 min; (2) a maximal depression phase of 10 min duration (from the 5th to the 15th min); and (3) a slow recovery phase. No significant modifications in post-exercise MEP amplitude were found in ipsilateral non-exercised muscles. In order to determine the level where these changes take place, we recorded the M and F waves induced by median nerve stimulation at the wrist (all subjects) and MEPs in response to transcranial electrical stimulation (five subjects) at rest and during the decrease and maximal depression phases. None of these tests were significantly affected by exercise, indicating that the motor cortex was the site of change. Evaluation of maps of cortical outputs to the target muscle, performed in four subjects, showed an approximately 40% spatial reduction in stimulation sites evoking a motor response during the maximal depression phase. These data prove that exercise induces a reversible, long-standing depression of cortical excitability, probably related to intracortical presynaptic modulation, which transitorily reduces the motor representation area.     

经颅磁刺激对部位相关癫癎患者运动皮质功能的评估

目的:采用经颅磁刺激技术(TMS)探讨症状性运动部位相关癫癎患者发作间期运动皮质的兴奋性.方法:对诊断明确的34例癫癎患者(分治疗组和未治疗组)及20例年龄、性别匹配的正常对照组进行单脉冲经颅磁刺激,刺激部位头颅相应的运动手区和颈7棘突外侧,并于对侧小指外展肌记录运动诱发电位(MEP),分析其阈强度(TI)、周围潜伏期(PL)及皮质潜伏期(CL)、中枢传导时间(CCT)和静息期(SP).结果:所有癫癎患者PL、CL及CCT均在正常范围内,但TI和SP明显低于正常对照组(P< 0.01).在癫癎患者中,未治疗组TI及SP明显低于治疗组(P< 0.01),致癎灶侧TI及SP低于非致癎灶侧(P< 0.05),但非致癎灶侧SP亦缩短.结论:单脉冲低频TMS能有效地反映中枢运动皮质的功能状态,用于症状性运动部位相关癫癎患者发作间期运动皮质兴奋性研究具有重要的实用价值.     

Antiepileptic drugs and cortical excitability: a study with repetitive transcranial stimulation

Repetitive transcranial magnetic stimulation (rTMS) delivered at various intensities and frequencies excites cortical motor areas. Trains of stimuli (at 5 Hz frequency, and suprathreshold intensity) progressively increase the size of muscle evoked potentials (MEPs) and the duration of the cortical silent period (CSP) in normal subjects. The aim of this study was to evaluate the effect of the antiepileptic drugs carbamazepine, gabapentin, and topiramate on cortical excitability variables tested with rTMS. We tested the changes in motor threshold, MEP size and CSP duration evoked by focal rTMS in 23 patients with neuropathic pain before and after a 1-week course of treatment with carbamazepine, gabapentin, topiramate and placebo. None of the three antiepileptic drugs changed the resting or active magnetic and electrical motor threshold. Antiepileptic treatment, but not placebo, abolished the normal rTMS-induced facilitation of MEPs, but left the progressive lengthening of the CSP during the rTMS train unchanged. Our results suggest that carbamazepine, gabapentin and topiramate modulate intracortical excitability by acting selectively on excitatory interneurons.     

Recruitment of extensor-carpi-radialis motor units by transcranial magnetic stimulation and radial-nerve stimulation in human subjects

The responses of 34 extensor-carpi-radialis motor units to graded transcranial magnetic stimulation (TMS) and electrical stimulation of the radial nerve were investigated in six human subjects. Simultaneously with the recording of the single motor-unit discharges, motor-evoked potentials (MEPs) and H-reflexes evoked by the two types of stimulation were recorded by surface electrodes and expressed as a percentage of the maximal motor response (Mmax). Ten motor units were activated in the H-reflex when it was less than 5% of Mmax, but not in the MEP even when it was 15% of Mmax. The opposite was observed for three motor units. Eleven motor units were recruited by both stimuli, but with significantly different recruitment thresholds. Only ten motor units had a threshold similar to TMS and radial nerve stimulation. From these observations, we suggest that caution should be taken when making conclusions regarding motor cortical excitability based on changes in the size of MEPs, even when it is ensured that there are no similar changes in background EMG-activity or H-reflexes. Received: 20 November 1998 / Accepted: 4 June 1999     

Direct demonstration of reduction of the output of the human motor cortex induced by a fatiguing muscle contraction

A brief period of strong muscle contraction suppresses the amplitude of EMG responses evoked in relaxed muscle by transcranial magnetic stimulation (TMS) of the contralateral motor cortex. Here we investigate this phenomenon in more detail by recording the descending motor volleys evoked by TMS from electrodes in the cervical epidural space of three conscious patients implanted with chronic electrical stimulators for control of pain. We confirm that fatigue suppresses I waves evoked by TMS. In addition, D waves were suppressed in two of the patients, suggesting that axonal excitability might also be compromised by a period of intense muscle contraction. Electronic Publication     

The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation

Descending corticospinal volleys were recorded from a bipolar electrode inserted into the cervical epidural space of four conscious human subjects after monophasic transcranial magnetic stimulation over the motor cortex with a figure-of-eight coil. We examined the effect of reversing the direction of the induced current in the brain from the usual posterior-anterior (PA) direction to an anterior-posterior (AP) direction. The volleys were compared with D waves evoked by anodal electrical stimulation (two subjects) or medio-lateral magnetic stimulation (two subjects). As reported previously, PA stimulation preferentially recruited I1 waves, with later I waves appearing at higher stimulus intensities. AP stimulation tended to recruit later I waves (I3 waves) in one of the subjects, but, in the other three, I1 or D waves were seen. Unexpectedly, the descending volleys evoked by AP stimulation often had slightly different peak latencies and/or longer duration than those seen after PA stimulation. In addition the relationship between the size of the descending volleys and the subsequent EMG response was often different for AP and PA stimulation. These findings suggest that AP stimulation does not simply activate a subset of the sites activated by PA stimulation. Some sites or neurones that are relatively inaccessible to PA stimulation may be the low-threshold targets of AP stimulation.     

Effect of contraction strength on responses in biceps brachii and adductor pollicis to transcranial magnetic stimulation

The sizes of the motor-evoked potentials (MEPs) and the durations of the silent periods after transcranial magnetic stimulation were examined in biceps brachii, brachioradialis and adductor pollicis in human subjects. Stimuli of a wide range of intensities were given during voluntary contractions producing 0–75% of maximal force (maximal voluntary contraction, MVC). In adductor pollicis, MEPs increased in size with stimulus intensity and with weak voluntary contractions (5% MVC), but did not grow larger with stronger contractions. In the elbow flexors, MEPs grew little with stimulus intensity, but increased in size with contractions of up to 50% of maximal. In contrast, the duration of the silent period showed similar changes in the three muscles. In each muscle it increased with stimulus intensity but was unaffected by changes in contraction strength. Comparison of the responses evoked in biceps brachii by focal stimulation over the contralateral motor cortex with those evoked by stimulation with a round magnetic coil over the vertex suggests an excitatory contribution from the ipsilateral cortex during strong voluntary contractions. Received: 12 August 1996 / Accepted: 14 May 1997     

Bilateral responses of upper limb muscles to transcranial magnetic stimulation in human subjects

Anatomical and behavioural work on primates has shown bilateral innervation of axial and proximal limb muscles, and contralateral control of distal limb muscles. The following study examined if a clear boundary exists between the distal and proximal upper limb muscles that are controlled contralaterally or bilaterally. The right motor cortical area representing the upper limb was stimulated, while surface EMG was recorded bilaterally from various upper limb muscles during rest and phasic voluntary contractions. Peak-to-peak amplitude of motor evoked potential (MEP) was measured for each muscle on both sides. The ratio R = (ipsilateral MEP: contralateral MEP) was calculated for seven pairs of muscles. For each of the seven pairs, R was less than 1.0, implying that for each muscle and subject, the contralateral control is stronger. The boundary where R changed from almost zero to a clearly measurable magnitude depended on the subject. Ipsilateral MEPs from trapezius and pectoralis could be recorded with a small background contraction from almost all subjects; on the other hand, in deltoid and biceps brachii, ipsilateral MEPs were observed only with bimanual phasic contractions. The forearm and hand muscles, in general, did not show any ipsilateral MEPs. Major differences between subjects lay in the presence or the absence of ipsilateral MEPs in biceps brachii and deltoid, without defining a sharp boundary between proximal and distal muscles.     

Transcranial magnetic stimulation of the primary motor cortex modulates response interference in a flanker task

In a typical flanker task, responses to a central target (“S” or “N”) are modulated by whether the flankers are compatible (“SSSSS”) or incompatible (“NNSNN”), with increased reaction times and decreased accuracy on incompatible trials. The role of the motor system in response interference under these conditions remains unclear, however. Here we show that transcranial magnetic stimulation (TMS) of the left primary motor cortex modulates the amount of flanker interference depending on the hand used for the response. Left motor TMS delivered at 200 ms after the onset of the array increased interference from incompatible flankers (“SSNSS”) when the target response was associated with the contralateral motor response (i.e. for “N” responses with the right hand), relative to when responses were to targets using the (left) hand ipsilateral to the site of TMS. Interestingly, under identical conditions, the degree of flanker interference was reduced when the TMS pulse was applied later in time. The analyses of the TMS-induced motor evoked potentials pointed to motor activity varying in the same conditions. We discuss the implications for understanding response interference and the role of the primary motor cortex in response selection.     

Motor cortex excitability following short trains of repetitive magnetic stimuli

Trains of repetitive transcranial magnetic stimuli (rTMS) appear to have effects on corticospinal excitability that outlast the duration of the train. In order to investigate the mechanism of this effect in more detail we applied short periods of rTMS consisting of up to 20 stimuli at 5 Hz, 10 Hz or 20 Hz (rTMS) to the motor cortex at an intensity equal to resting threshold in 11 healthy, relaxed subjects. Spinal excitability, as judged by effects on the H-reflex or on transcranial anodal facilitation of the H-reflex, was not affected by the rTMS. However, cortical excitability, as judged by the effect on the size of EMG responses evoked by a suprathreshold TMS pulse, was decreased for up to 1 s after the end of rTMS. Post-train suppression was more powerful following longer trains or higher frequencies of rTMS. The predominant suppression contrasts with previous reports of facilitation, particularly after high-frequency rTMS. A second set of experiments, however, showed that this could be converted into facilitation if the intensity of rTMS was increased. We conclude that the after-effects of rTMS depend on its frequency, intensity and duration. The results are consistent with a model in which inhibition and facilitation build up gradually during the course of a conditioning train. Inhibition reaches its maximum effect after only a small number of stimuli, whereas facilitation takes longer. The threshold for evoking inhibition is lower than that for facilitation. Thus if moderate intensities of conditioning train are applied, inhibition is predominant after short trains, whereas facilitation dominates after long trains.     

Corticospinal excitability and sleep: a motor threshold assessment by transcranial magnetic stimulation after awakenings from REM and NREM sleep

Transcranial magnetic stimulation (TMS) is a recently established technique in the neurosciences that allows the non-invasive assessment, among other parameters, of the excitability of motor cortex. Up to now, its application to sleep research has been very scarce and because of technical problems it provided contrasting results. In fact delivering one single suprathreshold magnetic stimulus easily awakes subjects, or lightens their sleep. For this reason, in the present study we assessed motor thresholds (MTs) upon rapid eye movement (REM) and non-rapid eye movement (NREM) sleep awakenings, both in the first and in the last part of the night. Taking into account that a full re-establishment of wake regional brain activity patterns upon awakening from sleep needs up to 20-30 min, it is possible to make inferences about the neurophysiological characteristics of the different sleep stages by analyzing the variables of interest immediately after provoked awakenings. Ten female volunteers slept in the lab for four consecutive nights. During the first night the MTs were collected, following a standardized procedure: 5 min before lights off, upon stage 2 awakening (second NREM period), upon REM sleep awakening (second REM period), upon the final morning awakening (always from stage 2). Results showed that MTs increased linearly from presleep wakefulness to REM sleep awakenings, and from the latter to stage 2 awakenings. There was also a time-of-night effect on MTs upon awakening from stage 2, indicating that MTs decreased from the first to the second part of the night. The increase in corticospinal excitability across the night, which parallels the fulfillment of sleep need, is consistent with the linear decrease of auditory arousal thresholds during the night. The maximal reduction of corticospinal excitability during early NREM sleep can be related to the hyperpolarization of thalamocortical neurons, and is in line with the decreased metabolic activity of motor cortices during this sleep stage. On the contrary, the increase of MTs upon REM sleep awakenings should reflect peripheral factors. We conclude that our findings legitimate the introduction of the TMS technique as a new proper tool in sleep research.     

Potentiating and fatiguing cortical reactions in a voluntary fatigue test of a human hand muscle

Fatigue-associated changes in the excitability of central motor mechanisms were investigated using transcranial magnetic stimulation (TMS) of the motor cortex. Test stimuli were applied before, during and after a voluntary fatigue test of the first dorsal interosseus muscle (FDI). Subjects were required to maintain 50% of their maximum voluntary force (MVC) for at least 2 min (1/2-MVC test) and electromyographic (EMG) reactions of FDI were measured with surface electrodes. Prior to the test, TMS pulses of 70% maximum output (about 1.4 T) produced muscle-evoked potentials (MEPs) of widely different amplitudes in different subjects, ranging from 13% to 55% of the maximum compound action potential (M-wave) evoked by ulnar nerve stimulation. During the test, MEPs of all subjects showed a potentiation; this effect was markedly greater in subjects with a small initial MEP. After the test, the differential degrees of contraction-evoked potentiation still influenced the MEP amplitudes; small pre-test MEPs showed a post-test net potentiation and larger pre-test MEPs showed a net post-test depression. The results underline that the net outcome of motor activation on motor cortex excitability, as studied with TMS, depends on a complex balance of fatiguing and potentiating effects.     

Intracortical inhibition of lower limb motor-evoked potentials after paired transcranial magnetic stimulation

The aim of the present study was to determine the characteristics of intracortical inhibition in the motor cortex areas representing lower limb muscles using paired transcranial magnetic (TMS) and transcranial electrical stimulation (TES) in healthy subjects. In the first paradigm (n=8), paired magnetic stimuli were delivered through a double cone coil and motor evoked potentials (MEPs) were recorded from quadriceps (Q) and tibialis anterior (TA) muscles during relaxation. The conditioning stimulus strength was 5% of the maximum stimulator output below the threshold MEP evoked during weak voluntary contraction of TA (33±5%). The test stimulus (67±2%) was 10% of the stimulator output above the MEP threshold in the relaxed TA. Interstimulus intervals (ISIs) from 1–15 ms were examined. Conditioned TA MEPs were significantly suppressed (P<0.01) at ISIs of less than 5 ms (relative amplitude from 20–50% of the control). TA MEPs tended to be only slightly facilitated at 9-ms and 10-ms ISIs. The degree of MEP suppression was not different between right and left TA muscles despite the significant difference in size of the control responses (P<0.001). Also, conditioned MEPs were not significantly different between Q and TA. The time course of TA MEP suppression, using electrical test stimuli, was similar to that found using TMS. In the second paradigm (n=2), the suppression of TA MEPs at 2, 3, and 4 ms ISIs was examined at three conditioning intensities with the test stimulation kept constant. For the pooled 2- to 4-ms ISI data, relative amplitudes were 34±6%, 61±5%, and 98±9% for conditioning intensities of 0.95, 0.90, and 0.85× active threshold, respectively (P<0.01). In conclusion, the suppression of lower limb MEPs following paired TMS showed similar characteristics to the intracortical inhibition previously described for the hand motor area. Received: 21 June 1996 / Accepted: 23 May 1997     

Motor cortex excitability in Alzheimer's disease: a transcranial magnetic stimulation follow-up study

Transient cognitive and behavioral stabilization of patients with Alzheimer's disease (AD) is the main goal of acetylcholinesterase inhibitor (AChEI) therapy. Response to treatment is variable and it is usually assessed clinically via neuropsychological scales. Functional neuroimaging could ideally permit the objective evaluation of the topographic correlates of therapy on brain functioning, but is expensive and little available on a large scale. On the other hand, neurophysiological methods such as transcranial magnetic stimulation (TMS) could offer an alternative, low-cost and risk free tool of assessing response to treatment in AD. Previous TMS studies have demonstrated hyperexcitability and asymptomatic motor cortex reorganization in the early stages of AD in patients with normal motor function. The aim of this study was to compare motor cortex functionality in 10 AD patients before and after long-term AchEIs therapy in order to monitor potential drug-related changes in cortical excitability and organization. Examined parameters of motor cortex physiology were found to be unchanged in patients with stabilized cognitive performance during the therapy. TMS, along with clinical, neuropsychological, and neuroimaging data, could be an inexpensive measure of biological progression in AD and it might supplement traditional methods to assess the effects of therapy.     

脑卒中患者经颅电刺激运动诱发电位的临床研究

目的：研究经颅电刺激运动诱发电位（MEP）与脑卒中患者运动功能状态的关系,评估MEP对脑卒中病人运动功能恢复的预测价值。方法：对54例有偏瘫的脑卒中患者在病后10天内行MEP检查,同时作肌力和临床神经功能评分测定,并于10周后对其中的28例复查,正常对照组为30例健康者。结果：脑卒中病人急笥期MEP的异常率为89％,主要表现为MEP缺失,潜伏期延长,波幅降低或波形异常,中枢运动传志时间（CMCT）延长,患侧与健侧及与对照组比较,有显著差异（P＜0．01）,MEP缺乏者,瘫痪重,MEP可引出者,瘫痪程度轻,两者间差异亦显著（P＜0．01）。10周后复查时发现MEP有不同程度的改善。／这种改善与临床上的功能恢复相一致,早期MEP缺乏者,功能恢复差,早期MEP仅仅波幅低或CMCT延长者,其功能恢复好,两者间差异显著（P＜0．01）,结论：MEP可定量分析脑卒中病人运动功能的缺损情况,并可作为运动功能恢复的早期预测指标。