Precise motor rhythmicity relies on motor network responsivity.

Rhythmic movements are the building blocks of human behavior. However, given that rhythmic movements are achieved through complex interactions between neural modules, it remains difficult to clarify how the central nervous system controls motor rhythmicity. Here, using a novel tempo-precision trade-off paradigm, we first modeled interindividual behavioral differences in tempo-dependent rhythmicity for various external tempi. We identified 2 behavioral extremes: conventional and paradoxical tempo-precision trade-off types. We then explored the neural substrates of these behavioral differences using task and resting-state functional magnetic resonance imaging. We found that the responsibility of interhemispheric motor network connectivity to tempi was a key to the behavioral repertoire. In the paradoxical trade-off type, interhemispheric connectivity was low at baseline but increased in response to increasing tempo; in the conventional trade-off type, strong baseline connectivity was coupled with low responsivity. These findings suggest that tunable interhemispheric connectivity underlies tempo-dependent rhythmicity control.

Brain network flexibility as a predictor of skilled musical performance.

Interactions between the body and the environment are dynamically modulated by upcoming sensory information and motor execution. To adapt to this behavioral state-shift, brain activity must also be flexible and possess a large repertoire of brain networks so as to switch them flexibly. Recently, flexible internal brain communications, i.e. brain network flexibility, have come to be recognized as playing a vital role in integrating various sensorimotor information. Therefore, brain network flexibility is one of the key factors that define sensorimotor skill. However, little is known about how flexible communications within the brain characterize the interindividual variation of sensorimotor skill and trial-by-trial variability within individuals. To address this, we recruited skilled musical performers and used a novel approach that combined multichannel-scalp electroencephalography, behavioral measurements of musical performance, and mathematical approaches to extract brain network flexibility. We found that brain network flexibility immediately before initiating the musical performance predicted interindividual differences in the precision of tone timbre when required for feedback control, but not for feedforward control. Furthermore, brain network flexibility in broad cortical regions predicted skilled musical performance. Our results provide novel evidence that brain network flexibility plays an important role in building skilled sensorimotor performance.

Modulation of cortical beta oscillations influences motor vigor: A rhythmic TMS-EEG study.

Previous electro- or magnetoencephalography (Electro/Magneto EncephaloGraphic; E/MEG) studies using a correlative approach have shown that ß (13-30 Hz) oscillations emerging in the primary motor cortex (M1) are implicated in regulating motor response vigor and associated with an anti-kinetic role, that is, slowness of movement. However, the functional role of M1 ß oscillations in regulation of motor responses remains unclear. To address this gap, we combined EEG with rhythmic TMS (rhTMS) delivered to M1 at the ß (20 Hz) frequency shortly before subjects performed an isometric ramp-and-hold finger force production task at three force levels. rhTMS is a novel approach that can modulate rhythmic patterns of neural activity. ß-rhTMS over M1 induced a modulation of neural oscillations to ß frequency in the sensorimotor area and reduced peak force rate during the ramp-up period relative to sham and catch trials. Interestingly, this rhTMS effect occurred only in the large force production condition. To distinguish whether the effects of rhTMS on EEG and behavior stemmed from phase-resetting by each magnetic pulse or neural entrainment by the periodicity of rhTMS, we performed a control experiment using arrhythmic TMS (arTMS). arTMS did not induce changes in EEG oscillations nor peak force rate during the rump-up period. Our results provide novel evidence that ß neural oscillations emerging the sensorimotor area influence the regulation of motor response vigor. Furthermore, our findings further demonstrate that rhTMS is a promising tool for tuning neural oscillations to the target frequency.

Distinct roles of brain activity and somatotopic representation in pathophysiology of focal dystonia.

Two main neural mechanisms including loss of cortical inhibition and maladaptive plasticity have been thought to be involved in the pathophysiology of focal task-specific dystonia. Such loss of inhibition and maladaptive plasticity likely correspond to cortical overactivity and disorganized somatotopy, respectively. However, the most plausible mechanism of focal task-specific dystonia remains unclear. To address this question, we assessed brain activity and somatotopic representations of motor-related brain areas using functional MRI and behavioral measurement in healthy instrumentalists and patients with embouchure dystonia as an example of focal task-specific dystonia. Dystonic symptoms were measured as variability of fundamental frequency during long tone playing. We found no significant differences in brain activity between the embouchure dystonia and healthy wind instrumentalists in the motor-related areas. Assessment of somatotopy, however, revealed significant differences in the somatotopic representations of the mouth area for the right somatosensory cortex between the two groups. Multiple-regression analysis revealed brain activity in the primary motor and somatosensory cortices, cerebellum, and putamen was significantly associated with variability of fundamental frequency signals representing dystonic symptoms. Conversely, somatotopic representations in motor-related brain areas were not associated with variability of fundamental frequency signals in embouchure dystonia. The present findings suggest that abnormal motor-related network activity and aberrant somatotopy correlate with different aspects of mechanisms underlying focal task-specific dystonia.

Aberrant cortical excitability reflects the loss of hand dexterity in musician's dystonia.

KEY POINTS: Dystonia is a movement disorder characterized by abnormalities at multifaceted aspects of motor dexterity and neural functions. Evidence bridging between pathophysiology and movement abnormalities is limited. A novel finding was that in focal task-specific dystonia (FTSD), an aberrantly reduced inhibition at the motor cortex was related to the temporal imprecision of the dexterous finger movements, whereas an elevated facilitation was associated with an abnormally sluggish transition of finger movements from flexion to extension. We newly identified two sets of behavioural-physiological covariations as hallmarks of hand FTSD, which is clinically significant because these findings provide novel evidence connecting distinct types of malfunctions within the motor cortex at rest with distinct aspects of motor dexterity degradation in FTSD patients. ABSTRACT: Focal task-specific dystonia (FTSD) compromises dexterous movements. A proposed pathophysiological mechanism of FTSD involves malfunction of the motor cortex (M1). However, no evidence is yet available regarding whether and how malfunctions of M1 are responsible for the loss of motor dexterity. Here, we addressed this issue by assessing both M1 excitability and detailed movement parameters, as well as their relationships. Transcranial magnetic stimulation was applied over M1 in 20 pianists with FTSD, 20 healthy pianists and 20 non-musicians. The patients demonstrated both reduced short-interval intracortical inhibition (SICI) and elevated intracortical facilitation (ICF) compared with the healthy controls. This indicates that the abnormal cortical excitability reflects pathophysiology but not current skills. Hand motor dexterity was evaluated by position sensors during piano playing at two tempi. The patients showed delayed transition from finger flexion to extension at the fastest tempo and greater timing variability of the finger movements. Furthermore, multivariate analyses identified distinct sets of covariation between cortical excitability and dexterity measures. Namely, the SICI measure and ICF measure were associated with the temporal variability of the movements and the quickness of the transition from flexion to extension, respectively. Specifically, the reduced inhibition and elevated facilitation at M1 in pianists was related to the temporal imprecision and impairment of quick transitions in the sequential finger movements. The present study provides novel evidence associating M1 malfunctions with dexterity loss.

Functional difference in short- and long-latency interhemispheric inhibitions from active to resting hemisphere during a unilateral muscle contraction.

The aim of the present study was to investigate whether there is a functional difference in short-latency (SIHI) and long-latency (LIHI) interhemispheric inhibition from the active to the resting primary motor cortex (M1) with paired-pulse transcranial magnetic stimulation during a unilateral muscle contraction. In nine healthy right-handed participants, IHI was tested from the dominant to the nondominant M1 and vice versa under resting conditions or during performance of a sustained unilateral muscle contraction with the right or left first dorsal interosseous muscle at 10% and 30% maximum voluntary contraction. To obtain measurements of SIHI and LIHI, a conditioning stimulus (CS) was applied over the M1 contralateral to the muscle contraction, followed by a test stimulus over the M1 ipsilateral to the muscle contraction at short (10 ms) and long (40 ms) interstimulus intervals. We used four CS intensities to investigate SIHI and LIHI from the active to the resting M1 systematically. The amount of IHI during the unilateral muscle contractions showed a significant difference between SIHI and LIHI, but the amount of IHI during the resting condition did not. In particular, SIHI during the muscle contractions, but not LIHI, significantly increased with increase in CS intensity compared with the resting condition. Laterality of IHI was not detected in any of the experimental conditions. The present study provides novel evidence that a functional difference between SIHI and LIHI from the active to the resting M1 exists during unilateral muscle contractions.

Robustness and adaptability of sensorimotor skills in expert piano performance.

Skillful sequential action requires the delicate balance of sensorimotor control, encompassing both robustness and adaptability. However, it remains unknown whether both motor and neural responses triggered by sensory perturbation undergo plastic adaptation as a consequence of extensive sensorimotor experience. We assessed the effects of transiently delayed tone production on the subsequent motor actions and event-related potentials (ERPs) during piano performance by comparing pianists and non-musicians. Following the perturbation, the inter-keystroke interval was abnormally prolonged in non-musicians but not in pianists. By contrast, the keystroke velocity following the perturbation was increased only in the pianists. A regression model demonstrated that the change in the inter-keystroke interval covaried with the ERPs, particularly at the frontal and parietal regions. The alteration in the keystroke velocity was associated with the P300 component of the temporal region. These findings suggest that different neural mechanisms underlie robust and adaptive sensorimotor skills across proficiency level.

Changes in interhemispheric inhibition from active to resting primary motor cortex during a fine-motor manipulation task.

The effect of performance of a sensorimotor task on the interhemispheric inhibition (IHI) induced from the active primary motor cortex (M1) to the resting M1 was examined in 10 right-handed subjects. Transcranial magnetic stimulation (TMS) was performed to produce motor evoked potentials (MEP) in the resting right (Rt)-first dorsal interosseous (FDI). For the paired-TMS paradigm, a conditioning stimulus (CS) was delivered to the Rt-M1, and its intensity was adjusted from 0.6 to 1.4 times the resting motor threshold of the MEP in the left (Lt)-FDI in 0.2 steps. The test stimulus was delivered to the Lt-M1, and its intensity was adjusted to evoke similar MEP amplitudes in the Rt-FDI among the task conditions. The interstimulus interval was fixed at 10 ms. As a sensorimotor task, a fine-motor manipulation (FM) task (using chopsticks to pick up, transport, and release glass balls) was adopted. In addition, an isometric abduction (IA) task was also performed as a control task. These tasks were carried out with the left hand. The IHI from the active to the resting M1 observed during the FM task was markedly increased compared with that induced during the IA task, and this effect was not dependent on the MEP amplitude evoked in the active Lt-FDI by the CS. The present findings suggest that the increased IHI from the active to the resting M1 observed during the FM task was linked to reductions in the activity of the ipsilateral intracortical inhibitory circuit, as we reported previously.

Alterations in human motor cortex during dual motor task by transcranial magnetic stimulation study.

The aim of this study was to determine how and whether changes in the primary motor cortex (M1) are affected by dual motor task. We further investigated how dual motor task is dependent on task properties measured using transcranial magnetic stimulation (TMS). TMS delivered to left M1 during the dual motor task and motor-evoked potential (MEP) were simultaneously evoked in the right FDI, thenar, FCR and ECR muscles. In experiment 1, subjects were asked to simultaneously walk on a treadmill and perform finger prehension. The gait conditions were employed 30, 50 and 80% of maximum walking speed (gait 30%, gait 50% and gait 80%). Conditions for finger prehension while following the visual tracking task varied with force outputs of 5 and 25% of maximum voluntary contraction (MVC). In experiment 2, the subjects were asked to perform optimal walking synchronized with the finger prehension task with an optimal walking rhythm (2-Hz dual motor task), as well as optimal walking desynchronized with the finger prehension task (0.7-Hz dual motor task). In experiment 1, MEPs were markedly decreased under the gait 50% condition compared with those under the gait 30 and 80% conditions at 5% MVC. In experiment 2, MEPs were markedly decreased with the 2-Hz dual motor task compared with those with the 0.7-Hz dual motor task. Our results suggest that the excitability changes in M1 during the dual motor task were dependent on changes in the gait speed, precision of prehension task and temporal movement.

Probing sensorimotor integration during musical performance.

An integration of afferent sensory information from the visual, auditory, and proprioceptive systems into execution and update of motor programs plays crucial roles in control and acquisition of skillful sequential movements in musical performance. However, conventional behavioral and neurophysiological techniques that have been applied to study simplistic motor behaviors limit elucidating online sensorimotor integration processes underlying skillful musical performance. Here, we propose two novel techniques that were developed to investigate the roles of auditory and proprioceptive feedback in piano performance. First, a closed-loop noninvasive brain stimulation system that consists of transcranial magnetic stimulation, a motion sensor, and a microcomputer enabled to assess time-varying cortical processes subserving auditory-motor integration during piano playing. Second, a force-field system capable of manipulating the weight of a piano key allowed for characterizing movement adaptation based on the feedback obtained, which can shed light on the formation of an internal representation of the piano. Results of neurophysiological and psychophysics experiments provided evidence validating these systems as effective means for disentangling computational and neural processes of sensorimotor integration in musical performance.

Expertise-dependent motor somatotopy of music perception.

Precise mapping between sound and motion underlies successful communication and information transmission in speech and musical performance. Formation of the map typically undergoes plastic changes in the neuronal network between auditory and motor regions through training. However, to what extent the map is somatotopically-tuned so that auditory information can specifically modulate the corticospinal system responsible for the relevant motor action has not been elucidated. Here we addressed this issue by assessing the excitability of corticospinal system including the primary motor cortex (M1) innervating the hand intrinsic muscles by means of transcranial magnetic stimulation while trained pianists and musically-untrained individuals (non-musicians) were listening to either piano tones or noise. M1 excitability was evaluated at two anatomically-independent muscles of the hand. The results demonstrated elevation of M1 excitability at not all but one specific muscle while listening to piano tones in the pianists, but no excitability change in both of the muscles in the non-musicians. However, listening to noise did not elicit any changes of M1 excitability at both muscles in both the pianists and the non-musicians. These findings indicate that auditory information representing the trained motor action tunes M1 excitability in a non-uniform, somatotopically-specific manner, which is likely associated with multimodal experiences in musical training.

The contribution of interindividual factors to variability of response in transcranial direct current stimulation studies.

There has been an explosion of research using transcranial direct current stimulation (tDCS) for investigating and modulating human cognitive and motor function in healthy populations. It has also been used in many studies seeking to improve deficits in disease populations. With the slew of studies reporting "promising results" for everything from motor recovery after stroke to boosting memory function, one could be easily seduced by the idea of tDCS being the next panacea for all neurological ills. However, huge variability exists in the reported effects of tDCS, with great variability in the effect sizes and even contradictory results reported. In this review, we consider the interindividual factors that may contribute to this variability. In particular, we discuss the importance of baseline neuronal state and features, anatomy, age and the inherent variability in the injured brain. We additionally consider how interindividual variability affects the results of motor-evoked potential (MEP) testing with transcranial magnetic stimulation (TMS), which, in turn, can lead to apparent variability in response to tDCS in motor studies.

Transcranial direct current stimulation improves ipsilateral selective muscle activation in a frequency dependent manner.

Failure to suppress antagonist muscles can lead to movement dysfunction, such as the abnormal muscle synergies often seen in the upper limb after stroke. A neurophysiological surrogate of upper limb synergies, the selectivity ratio (SR), can be determined from the ratio of biceps brachii (BB) motor evoked potentials to transcranial magnetic stimulation prior to forearm pronation versus elbow flexion. Surprisingly, cathodal transcranial direct current stimulation (c-TDCS) over ipsilateral primary motor cortex (M1) reduces (i.e. improves) the SR in healthy adults, and chronic stroke patients. The ability to suppress antagonist muscles may be exacerbated at high movement rates. The aim of the present study was to investigate whether the selective muscle activation of the biceps brachii (BB) is dependent on altering frequency demands, and whether the c-tDCS improvement of SR is dependent on task frequency. Seventeen healthy participants performed repetitive isometric elbow flexion and forearm pronation at three rates, before and after c-tDCS or sham delivered to ipsilateral left M1. Ipsilateral c-tDCS improved the SR in a frequency dependent manner by selectively suppressing BB antagonist excitability. Our findings confirm that c-tDCS is an effective tool for improving selective muscle activation, and provide novel evidence for its efficacy at rates of movement where it is most likely to benefit task performance.

Patterned sensory nerve stimulation enhances the reactivity of spinal Ia inhibitory interneurons.

Patterned sensory nerve stimulation has been shown to induce plastic changes in the reciprocal Ia inhibitory circuit. However, the mechanisms underlying these changes have not yet been elucidated in detail. The aim of the present study was to determine whether the reactivity of Ia inhibitory interneurons could be altered by patterned sensory nerve stimulation. The degree of reciprocal Ia inhibition, the conditioning effects of transcranial magnetic stimulation (TMS) on the soleus (SOL) muscle H-reflex, and the ratio of the maximum H-reflex amplitude versus maximum M-wave (H(max)/M(max)) were examined in 10 healthy individuals. Patterned electrical nerve stimulation was applied to the common peroneal nerve every 1 s (100 Hz-5 train) at the motor threshold intensity of tibialis anterior muscle to induce activity changes in the reciprocal Ia inhibitory circuit. Reciprocal Ia inhibition, the TMS-conditioned H-reflex amplitude, and H(max)/M(max) were recorded before, immediately after, and 15 min after the electrical stimulation. The patterned electrical nerve stimulation significantly increased the degree of reciprocal Ia inhibition and decreased the amplitude of the TMS-conditioned H-reflex in the short-latency inhibition phase, which was presumably mediated by Ia inhibitory interneurons. However, it had no effect on H(max)/M(max). Our results indicated that patterned sensory nerve stimulation could modulate the activity of Ia inhibitory interneurons, and this change may have been caused by the synaptic modification of Ia inhibitory interneuron terminals. These results may lead to a clearer understanding of the spinal cord synaptic plasticity produced by repetitive sensory inputs.

Effect of tactile stimulation on primary motor cortex excitability during action observation combined with motor imagery.

We aimed to investigate the effects of the tactile stimulation to an observer's fingertips at the moment that they saw an object being pinched by another person on the excitability of observer's primary motor cortex (M1) using transcranial magnetic stimulation (TMS). In addition, the above effects were also examined during action observation combined with the motor imagery. Motor evoked potentials (MEP) were evoked from the subjects' right first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles. Electrical stimulation (ES) inducing tactile sensation was delivered to the subjects' first and second fingertips at the moment of pinching action performed by another person. Although neither the ES nor action observation alone had significant effects on the MEP amplitude of the FDI or ADM, the FDI MEP amplitude which acts as the prime mover during pinching was reduced when ES and action observation were combined; however, no such changes were seen in the ADM. Conversely, that reduced FDI MEP amplitude was increased during the motor imagery. These results indicated that the M1 excitability during the action observation of pinching action combined with motor imagery could be enhanced by the tactile stimulation delivered to the observer's fingertips at the moment corresponding to the pinching being observed.

Excitability changes in the left primary motor cortex innervating the hand muscles induced during speech about hand or leg movements.

In the present study, we used transcranial magnetic stimulation (TMS) to investigate the changes in the excitability of the left primary motor cortex (M1) innervating the hand muscles and in short-interval intracortical inhibition (SICI) during speech describing hand or leg movements. In experiment 1, we investigated the effects of the contents of speech on the amplitude of the motor evoked potentials (MEPs) induced during reading aloud and silent reading. In experiment 2, we repeated experiment 1 with an additional condition, the non-vocal oral movement (No-Voc OM) condition, and investigated the change in SICI induced in each condition using the paired TMS paradigm. The MEP observed in the reading aloud and No-Voc OM conditions exhibited significantly greater amplitudes than those seen in the silent reading conditions, irrespective of the content of the sentences spoken by the subjects or the timing of the TMS. There were no significant differences in SICI between the experimental conditions. Our findings suggest that the increased excitability of the left M1 hand area detected during speech was mainly caused by speech-related oral movements and the activation of language processing-related brain functions. The increased left M1 excitability was probably also mediated by neural mechanisms other than reduced SICI; i.e., disinhibition.

Inter-individual variation in reciprocal Ia inhibition is dependent on the descending volleys delivered from corticospinal neurons to Ia interneurons.

INTRODUCTION: We investigated the extent to which the corticospinal inputs delivered to Ia inhibitory interneurons influence the strength of disynaptic reciprocal Ia inhibition. METHODS: Seventeen healthy subjects participated in this study. The degree of reciprocal Ia inhibition was determined via short-latency (condition-test interval: 1-3ms) suppression of Sol H-reflex by conditioning stimulation of common peroneal nerve. The effect of corticospinal descending inputs on Ia inhibitory interneurons was assessed by evaluating the conditioning effect of transcranial magnetic stimulation (TMS) on the Sol H-reflex. Then, we determined the relationship between the degree of reciprocal Ia inhibition and the conditioning effect of TMS on the Sol H-reflex. RESULT: We found that the degree of reciprocal Ia inhibition and the extent of change in the amplitude of the TMS-conditioned H-reflex, which was measured from short latency facilitation to inhibition, displayed a strong correlation (r=0.76, p<0.01) in the resting conditions. CONCLUSION: The extent of reciprocal Ia inhibition is affected by the corticospinal descending inputs delivered to Ia inhibitory interneurons, which might explain the inter-individual variations in reciprocal Ia inhibition.

Long-term practice induced plasticity in the primary motor cortex innervating the ankle flexor in football juggling experts.

The aim of this study was to investigate the plasticity of M1 innervating the tibialis anterior muscle (TA) induced by the long-term practice of football juggling using a transcranial magnetic stimulation (TMS) technique. Ten football juggling experts and ten novices participated in this study. Motor evoked potentials (MEP) and the H-reflex were recorded from the right TA during isometric dorsiflexion at 10% of maximum voluntary contraction. The MEP input-output curve of the experts was steeper than that of the novices, and reduced short-interval intracortical inhibition and long-interval intracortical inhibition were observed in the experts. In contrast, the ratio of Hmax to Mmax did not differ between the groups. Our results show that football juggling experts displayed enhanced excitability in the M1 innervating the TA, which was induced by the long-term practice of the ankle movements required to perform football juggling well.

Neural mechanisms underlying the changes in ipsilateral primary motor cortex excitability during unilateral rhythmic muscle contraction.

The aim of this study was to investigate the neural mechanisms underlying the changes in the ipsilateral primary motor cortex (ipsi-M1) excitability induced during the unilateral rhythmic muscle contraction of the first dorsal interosseous (FDI) (rhythmic contraction) muscle with three different frequencies of auditory cues (1, 2, and 3 Hz). The effect of different frequencies of unilateral rhythmic contraction on changes in the ipsi-M1 excitability was assessed using a single-pulse transcranial magnetic stimulation (TMS) technique when subjects were performing the unilateral rhythmic contractions according to each auditory cue frequency. After that, the changes in short intracortical inhibition (SICI)/facilitation (ICF), long intracortical inhibition (LICI) within the ipsi-M1, and interhemispheric inhibition (IHI), as well as dorsal premotor cortex to M1 (PMd-M1), and dorsolateral prefrontal cortex to M1 (DLPFC-M1) connectivity from the contralateral hemisphere to the ipsi-M1 were assessed using paired-pulse TMS techniques. The motor evoked potentials (MEP) induced in the right FDI were recorded. In the results, the ipsi-M1 excitability induced in response to single-pulse TMS was significantly decreased in the 2 Hz conditions, compared with the 1Hz and 3Hz conditions. Furthermore, PMd-M1 connectivity and LICI were significantly modulated depending on the frequency of the unilateral rhythmic contraction. In contrast, the changes in the SICI, ICF, IHI, and DLPFC-M1 were not directly associated with the rhythm frequency. These results suggest that PMd-M1 connectivity and LICI within the ipsi-M1 are likely to preferentially operate to modulate ipsi-M1 excitability during the performance of unilateral rhythmic contraction with different frequencies.

Change in the ipsilateral motor cortex excitability is independent from a muscle contraction phase during unilateral repetitive isometric contractions.

The aim of this study was to investigate the difference in a muscle contraction phase dependence between ipsilateral (ipsi)- and contralateral (contra)-primary motor cortex (M1) excitability during repetitive isometric contractions of unilateral index finger abduction using a transcranial magnetic stimulation (TMS) technique. Ten healthy right-handed subjects participated in this study. We instructed them to perform repetitive isometric contractions of the left index finger abduction following auditory cues at 1 Hz. The force outputs were set at 10, 30, and 50% of maximal voluntary contraction (MVC). Motor evoked potentials (MEP) were obtained from the right and left first dorsal interosseous muscles (FDI). To examine the muscle contraction phase dependence, TMS of ipsi-M1 or contra-M1 was triggered at eight different intervals (0, 20, 40, 60, 80, 100, 300, or 500 ms) after electromyogram (EMG) onset when each interval had reached the setup triggering level. Furthermore, to demonstrate the relationships between the integrated EMG (iEMG) in the active left FDI and the ipsi-M1 excitability, we assessed the correlation between the iEMG in the left FDI for the 100 ms preceding TMS onset and the MEP amplitude in the resting/active FDI for each force output condition. Although contra-M1 excitability was significantly changed after the EMG onset that depends on the muscle contraction phase, the modulation of ipsi-M1 excitability did not differ in response to any muscle contraction phase at the 10% of MVC condition. Also, we found that contra-M1 excitability was significantly correlated with iEMG in all force output conditions, but ipsi-M1 excitability was not at force output levels of below 30% of MVC. Consequently, the modulation of ipsi-M1 excitability was independent from the contraction phase of unilateral repetitive isometric contractions at least low force output.