Quantitative Evaluation of Cerebellar Function in Multiple System Atrophy with Transcranial Magnetic Stimulation.

Objective evaluation of cerebellar dysfunction in neurodegenerative disorders is often difficult because of other overlapping symptoms. Cerebellar inhibition (CBI) tested by dual-coil transcranial magnetic stimulation (TMS) is anticipated as a promising measure to estimate cerebellar function. Cerebellar TMS inhibits the primary motor cortex (M1), which can be measured as the decrease of motor evoked potential (MEP) elicited by a single-pulse TMS over the M1. This study was conducted to quantify cerebellar dysfunction using CBI in cerebellar type multiple system atrophy (MSA-C) patients. First, CBI was measured using MEP elicited from a hand muscle by stimulating the hand motor area of M1. The amount of CBI was defined as the degree of decrease in the MEP amplitude in the presence of cerebellar stimulation compared with the condition of M1 stimulation alone. Results of the MSA-C patients were compared with those of healthy volunteers. Correlation between amounts of CBI and a clinical scale of ataxia, the International Cooperative Ataxia Scale Rating (ICARS), was assessed. Healthy volunteers showed more inhibition than MSA-C patients. Moreover, ICARS showed that the CBI amount in the patients is correlated with the degree of ataxia significantly. Results suggest that CBI can be a good marker of disease progression in MSA-C patients.

Expanded clinical spectrum of oculopharyngodistal myopathy type 1.

INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.

Effect of caffeine on long-term potentiation-like effects induced by quadripulse transcranial magnetic stimulation.

Caffeine, an adenosine receptor antagonist, is known to affect sleep-awake cycles, the stress response, and learning and memory. It has been suggested that caffeine influences synaptic plasticity, but the effects of caffeine on synaptic plasticity in the human brain remain unexplored. The present study aimed to investigate the effects of caffeine on long-term potentiation (LTP)-like effects in the primary motor cortex of healthy humans. Twelve healthy participants (six women and six men; mean age: 44.8 ± 1.5 years) underwent quadripulse magnetic stimulation with an inter-stimulus interval of 5 ms (QPS5) to induce LTP-like effects, 2 h after administration of either a caffeine (200 mg) or placebo tablet in a double-blind crossover design. We recorded motor-evoked potentials (MEPs) before and after QPS5. The degree of MEP enhancement was compared between the placebo and caffeine conditions. Neither active nor resting motor thresholds were influenced by caffeine administration. Following caffeine administration, the degree of potentiation significantly decreased in "significant responders", whose average MEP ratios were greater than 1.24 in the placebo condition. The observed reduction in potentiation following caffeine administration is consistent with the A2A receptor antagonistic effect of caffeine. This is the first report of an effect of caffeine on neural synaptic plasticity in the human brain, which is consistent with the caffeine-induced plasticity reduction observed in primate studies. Because we studied only a small number of subjects, we cannot firmly conclude that caffeine reduces LTP in humans. The present results will, however, be helpful when considering further or new clinical uses of caffeine.

Case of 78-Year-Old Male with Cerebral Gas Embolism Associated with Combined Pulmonary Fibrosis and Emphysema.

Cerebral gas embolism (CGE) from the thoracic cavity is commonly associated with invasive procedures, and cases of spontaneous CGE are rare. A 78-year-old man presented with severe spontaneous CGE associated with combined pulmonary fibrosis and emphysema (CPFE). To the best of our knowledge, the comorbidity of CGE in a CPFE patient has not been documented until now. The patient became unconscious with left hemiparesis at approximately 2 a.m. Computed tomography scan revealed minute air densities scattered in the deep white matter of the right frontal lobe. The patient died on the sixth day of hospitalization. We postulated that CGE can be classified as either arterial CGE or retrogradely infused venous CGE. To differentiate between these two, the distribution of air densities provided useful information in our case. We assumed that the air was infused through the pulmonary vein to the left atrium of the heart, resulting in arterial CGE. A review of the literature further suggests that an upright position at the time of a CGE attack might be related to the retrogradely infused venous origin of the air, whereas arterial CGE may more likely occur when the patient is lying down.

Effects of rTMS of pre-supplementary motor area on fronto basal ganglia network activity during stop-signal task.

Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre-SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans.

Cerebellar dysfunction in essential tremor.

OBJECTIVES: Few neurophysiological studies have investigated cerebellar function in patients with essential tremor, even though the cerebellum may contribute to tremor generation. Here, we studied cerebellar function in patients with essential tremor using 2 physiological methods. METHODS: Participants were 20 patients with essential tremor and 30 age-matched healthy volunteers, and the results were compared across the groups. We studied motor cortical inhibition using cerebellar magnetic stimulation and prism adaptation. RESULTS: Both cerebellar inhibition and prism adaptation were affected in patients with essential tremor. The degree of tremor did not correlate with the degree of abnormality in either of the 2 experiments. CONCLUSIONS: The simplest explanation for the present results is that the cerebellum itself, including the Purkinje cells, is involved in essential tremor, which may reflect a primary pathogenic lesion or secondary compensatory physiological phenomenon to an original pathogenic lesion elsewhere. © 2016 International Parkinson and Movement Disorder Society.

Modulation of error-sensitivity during a prism adaptation task in people with cerebellar degeneration.

Cerebellar damage can profoundly impair human motor adaptation. For example, if reaching movements are perturbed abruptly, cerebellar damage impairs the ability to learn from the perturbation-induced errors. Interestingly, if the perturbation is imposed gradually over many trials, people with cerebellar damage may exhibit improved adaptation. However, this result is controversial, since the differential effects of gradual vs. abrupt protocols have not been observed in all studies. To examine this question, we recruited patients with pure cerebellar ataxia due to cerebellar cortical atrophy (n = 13) and asked them to reach to a target while viewing the scene through wedge prisms. The prisms were computer controlled, making it possible to impose the full perturbation abruptly in one trial, or build up the perturbation gradually over many trials. To control visual feedback, we employed shutter glasses that removed visual feedback during the reach, allowing us to measure trial-by-trial learning from error (termed error-sensitivity), and trial-by-trial decay of motor memory (termed forgetting). We found that the patients benefited significantly from the gradual protocol, improving their performance with respect to the abrupt protocol by exhibiting smaller errors during the exposure block, and producing larger aftereffects during the postexposure block. Trial-by-trial analysis suggested that this improvement was due to increased error-sensitivity in the gradual protocol. Therefore, cerebellar patients exhibited an improved ability to learn from error if they experienced those errors gradually. This improvement coincided with increased error-sensitivity and was present in both groups of subjects, suggesting that control of error-sensitivity may be spared despite cerebellar damage.

Effects of the motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral motor cortex and interhemispheric interactions.

Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Using the paired-pulse transcranial magnetic stimulation (TMS) paradigm, we can measure interhemispheric inhibition (IHI) and interhemispheric facilitation (IHF) as indexes of the interhemispheric interactions in humans. We investigated how quadripulse transcranial magnetic stimulation (QPS), one form of repetitive TMS (rTMS), on M1 affects the contralateral M1 and the interhemispheric interactions. QPS is able to induce bidirectional plastic changes in M1 depending on the interstimulus intervals (ISIs) of TMS pulses: long-term potentiation (LTP)-like effect by QPS-5 protocol, and long-term depression-like effect by QPS-50, whose numbers indicate the ISI (ms). Twelve healthy subjects were enrolled. We applied QPS over the left M1 and recorded several parameters before and 30 min after QPS. QPS-5, which increased motor-evoked potentials (MEPs) induced by left M1 activation, also increased MEPs induced by right M1 activation. Meanwhile, QPS-50, which decreased MEPs elicited by left M1 activation, did not induce any significant changes in MEPs elicited by right M1 activation. None of the resting motor threshold, active motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, intracortical facilitation, and short-interval intracortical inhibition in right M1 were affected by QPS. IHI and IHF from left to right M1 significantly increased after left M1 QPS-5. The degree of left first dorsal interosseous MEP amplitude change by QPS-5 significantly correlated with the degree of IHF change. We suppose that the LTP-like effect on the contralateral M1 may be produced by some interhemispheric interactions through the corpus callosum.

Bidirectional effects on interhemispheric resting-state functional connectivity induced by excitatory and inhibitory repetitive transcranial magnetic stimulation.

Several recent studies using functional magnetic resonance imaging (fMRI) have shown that repetitive transcranial magnetic stimulation (rTMS) affects not only brain activity in stimulated regions but also resting-state functional connectivity (RSFC) between the stimulated region and other remote regions. However, these studies have only demonstrated an effect of either excitatory or inhibitory rTMS on RSFC, and have not clearly shown the bidirectional effects of both types of rTMS. Here, we addressed this issue by performing excitatory and inhibitory quadripulse TMS (QPS), which is considered to exert relatively large and long-lasting effects on cortical excitability. We found that excitatory rTMS (QPS with interstimulus intervals of 5 ms) decreased interhemispheric RSFC between bilateral primary motor cortices, whereas inhibitory rTMS (QPS with interstimulus intervals of 50 ms) increased interhemispheric RSFC. The magnitude of these effects on RSFC was significantly correlated with that of rTMS-induced effects on motor evoked potential from the corresponding muscle. The bidirectional effects of QPS were also observed in the stimulation over prefrontal and parietal association areas. These findings provide evidence for the robust bidirectional effects of excitatory and inhibitory rTMSs on RSFC, and raise a possibility that QPS can be a powerful tool to modulate RSFC.

Origin coordinate influence on performance of temporally extended signal space separation in magnetoencephalography.

OBJECTIVE: Temporally extended signal space separation (tSSS) is a powerful method for artifact suppression in magnetoencephalography (MEG). Because tSSS first separates MEG signals coming from inside and outside a certain sphere, definition of the sphere origin is important. For this study, we explored the influence of origin choice on tSSS performance in spontaneous and evoked activity from epilepsy patients. METHODS: Interictal epileptiform discharges (IEDs) and somatosensory evoked fields (SEFs) were processed with two tSSSs: one with the default origin of (0, 0, 40 mm) in the head coordinate, and the other with an individual origin estimated using each patient's anatomical magnetic resonance imaging (MRI). Equivalent current dipoles (ECDs) were calculated for the data. The ECD location and quality of estimation were compared across conditions. RESULTS: MEG data from 21 patients revealed marginal differences in ECD location, but the estimation quality inferred from goodness of fit (GOF) and confidence volume (CV) was better for the tSSS with individual origins. This choice affected IEDs more than it affected SEFs. CONCLUSIONS: Individual sphere model resulted in better GOF and CV. SIGNIFICANCE: Application of tSSS using an individual origin would be more desirable when available. This parameter might influence spontaneous activity more strongly.

Recovery after Prolonged Disturbance of Consciousness and Repeated Cerebral Perfusion Changes in Neuronal Intranuclear Inclusion Disease.

Encephalitic episodes are a clinical manifestation of neuronal intranuclear inclusion disease (NIID) and often show transient disturbance of consciousness. We herein report a genetically confirmed patient with NIID who initially presented progressive dementia and showed prolonged disturbance of consciousness preceded by an acute-onset headache. During that time, we performed N-isopropyl-p-[123I] iodoamphetamine single-photon-emission computed tomography twice and found that the blood flow increased in different regions. Prolonged disturbance of consciousness following an encephalitic episode may be associated with repeated hyperperfusion in various regions resulting from mitochondrial dysfunction. NIID patients presenting with encephalitic episodes can recover gradually and spontaneously even after prolonged disturbances of consciousness.

Clinical neurophysiology in the treatment of movement disorders: IFCN handbook chapter.

In this review, different aspects of the use of clinical neurophysiology techniques for the treatment of movement disorders are addressed. First of all, these techniques can be used to guide neuromodulation techniques or to perform therapeutic neuromodulation as such. Neuromodulation includes invasive techniques based on the surgical implantation of electrodes and a pulse generator, such as deep brain stimulation (DBS) or spinal cord stimulation (SCS) on the one hand, and non-invasive techniques aimed at modulating or even lesioning neural structures by transcranial application. Movement disorders are one of the main areas of indication for the various neuromodulation techniques. This review focuses on the following techniques: DBS, repetitive transcranial magnetic stimulation (rTMS), low-intensity transcranial electrical stimulation, including transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS), and focused ultrasound (FUS), including high-intensity magnetic resonance-guided FUS (MRgFUS), and pulsed mode low-intensity transcranial FUS stimulation (TUS). The main clinical conditions in which neuromodulation has proven its efficacy are Parkinson's disease, dystonia, and essential tremor, mainly using DBS or MRgFUS. There is also some evidence for Tourette syndrome (DBS), Huntington's disease (DBS), cerebellar ataxia (tDCS), and axial signs (SCS) and depression (rTMS) in PD. The development of non-invasive transcranial neuromodulation techniques is limited by the short-term clinical impact of these techniques, especially rTMS, in the context of very chronic diseases. However, at-home use (tDCS) or current advances in the design of closed-loop stimulation (tACS) may open new perspectives for the application of these techniques in patients, favored by their easier use and lower rate of adverse effects compared to invasive or lesioning methods. Finally, this review summarizes the evidence for keeping the use of electromyography to optimize the identification of muscles to be treated with botulinum toxin injection, which is indicated and widely performed for the treatment of various movement disorders.

Treatment of cryptogenic new-onset refractory status epilepticus (C-NORSE) with tocilizumab: A case report.

A 35-year-old woman with no prior history of epilepsy developed status epilepticus (SE), which was highly resistant to multiple antiseizure medications and sedatives. The etiology of SE was not identified despite extensive investigation, and the patient was diagnosed with cryptogenic new-onset refractory status epilepticus (C-NORSE). Although first-line immunotherapies such as high-dose corticosteroids and plasma exchange were ineffective, the patient manifested a resolution of SE after the administration of tocilizumab, which inhibits interleukin-6. Non-antibody-mediated inflammation has been hypothesized to be a probable pathophysiology of C-NORSE in recent studies, and tocilizumab may be a plausible second-line treatment.

Increased gene dosage of myelin protein zero causes Charcot-Marie-Tooth disease.

OBJECTIVE: On the basis of the hypothesis that copy number mutations of the genes encoding myelin compact proteins are responsible for myelin disorders in humans, we have explored the possibility of copy number mutations in patients with Charcot-Marie-Tooth disease (CMT) whose responsible genes remain undefined. METHODS: A family with 6 affected members in 3 consecutive generations, presenting with motor and sensory demyelinating polyneuropathy, was investigated. Characteristic clinical features in this pedigree include Adie pupils and substantial intrafamilial variability in the age at onset, electrophysiological findings, and clinical severity. Nucleotide sequence analyses of PMP22, MPZ, or GJB1 and gene dosage study of PMP22 did not reveal causative mutations. Hence, we applied a custom-designed array for comparative genomic hybridization (CGH) analysis to conduct a comprehensive screening of copy number mutations involving any of the known causative genes for CMT other than PMP22. RESULTS: The array CGH analyses revealed increased gene dosage involving the whole MPZ, and the flanking genes of SDHC and C1orf192. The gene dosage is estimated to be 5 copies. This mutation showed complete cosegregation with the disease phenotype in this pedigree. INTERPRETATION: The increased gene dosage of MPZ and increased expression level of MPZ mRNA emphasize the important role of the dosage of the MPZ protein in the functional integrity of peripheral nerve myelin in humans, and provide a new insight into the pathogenic mechanisms underlying CMT.

Investigating the technical feasibility of magnetoencephalography during transcranial direct current stimulation.

Introduction: Magnetoencephalography (MEG) can measure weak magnetic fields produced by electrical brain activity. Transcranial direct current stimulation (tDCS) can affect such brain activities. The concurrent application of both, however, is challenging because tDCS presents artifacts on the MEG signal. If brain activity during tDCS can be elucidated by MEG, mechanisms of plasticity-inducing and other effects of tDCS would be more comprehensively understood. We tested the technical feasibility of MEG during tDCS using a phantom that produces an artificial current dipole simulating focal brain activity. An earlier study investigated estimation of a single oscillating phantom dipole during tDCS, and we systematically tested multiple dipole locations with a different MEG device. Methods: A phantom provided by the manufacturer was used to produce current dipoles from 32 locations. For the 32 dipoles, MEG was recorded with and without tDCS. Temporally extended signal space separation (tSSS) was applied for artifact rejection. Current dipole sources were estimated as equivalent current dipoles (ECDs). The ECD modeling quality was assessed using localization error, amplitude error, and goodness of fit (GOF). The ECD modeling performance with and without tDCS, and with and without tSSS was assessed. Results: Mean localization errors of the 32 dipoles were 1.70 ± 0.72 mm (tDCS off, tSSS off, mean ± standard deviation), 6.13 ± 3.32 mm (tDCS on, tSSS off), 1.78 ± 0.83 mm (tDCS off, tSSS on), and 5.73 ± 1.60 mm (tDCS on, tSSS on). Mean GOF findings were, respectively, 92.3, 87.4, 97.5, and 96.7%. Modeling was affected by tDCS and restored by tSSS, but improvement of the localization error was marginal, even with tSSS. Also, the quality was dependent on the dipole location. Discussion: Concurrent tDCS-MEG recording is feasible, especially when tSSS is applied for artifact rejection and when the assumed location of the source of activity is favorable for modeling. More technical studies must be conducted to confirm its feasibility with different source modeling methods and stimulation protocols. Recovery of single-trial activity under tDCS warrants further research.

Perioperative Use of Intravenous Levodopa as an Anti-Parkinsonian Drug: A Propensity Score Analysis.

Background: Perioperative discontinuation of oral anti-parkinsonian medication can negatively impact the prognosis of abdominal surgery in patients with Parkinson's disease. Although intravenous levodopa may be an alternative, its efficacy has not yet been investigated. Objectives: To determine the efficacy of intravenous levodopa as an alternative to oral anti-Parkinsonian drugs during gastric or colorectal cancer surgery. Methods: We identified patients with Parkinson's disease who underwent surgery for gastric or colorectal cancer between April 2010 and March 2020, using the Diagnosis Procedure Combination database, a nationwide inpatient database in Japan. Patients were divided into two groups: those who received intravenous levodopa during the perioperative period and those who did not. We compared in-hospital mortalities, major complications, and postoperative length of stay between the groups after adjusting for background characteristics with overlap weights based on propensity scores. Results: We identified 648 patients who received intravenous levodopa and 1207 who did not receive levodopa during the perioperative period. In the adjusted cohort, the mean postoperative length of stay was 24.7 and 29.0 days (percent difference, -7.7%; 95% confidence interval, -13.1 to -1.5); in-hospital death was 3.2% and 3.3% (adjusted odds ratio, 0.95; 95% CI: 0.54-1.67); and incidence of major complications were 21.4% and 19.3% (adjusted odds ratio, 0.89; 95% confidence interval, 0.70-1.13) in those with and without intravenous levodopa, respectively. Conclusions: Intravenous levodopa was associated with a shorter postoperative length of stay, but not with mortality or morbidity. Intravenous levodopa may improve perioperative care in patients with Parkinson's disease.

Conditioning intensity-dependent interaction between short-latency interhemispheric inhibition and short-latency afferent inhibition.

The relationship between sensory and transcallosal inputs into the motor cortex may be important in motor performance, but it has not been well studied, especially in humans. The aim of this study was to reveal this relationship by investigating the interaction between short-latency interhemispheric inhibition (SIHI) and short-latency afferent inhibition (SAI) in humans with transcranial magnetic stimulation. SIHI is the inhibition of the primary motor cortex (M1) elicited by contralateral M1 stimulation given ∼10 ms before, and it reflects transcallosal inhibition. SAI is the inhibition of M1 elicited by contralateral median nerve stimulation preceding M1 stimulation by ∼20 ms. In this investigation, we studied the intensity dependence of SIHI and SAI and the interaction between SIHI and SAI in various conditioning intensities. Subjects were 11 normal volunteers. The degree of effects was evaluated by comparing motor evoked potential sizes recorded from the first dorsal interosseous muscle between a certain condition and control condition. Both SIHI and SAI were potentiated by increment of the conditioning stimulus intensity and saturated at 1.4 times resting motor threshold for SIHI and 3 times sensory threshold for SAI. No significant interaction was observed when either of their intensities was subthreshold for the inhibition on its own. Only when both intensities were strong enough for their inhibition did the presence of one inhibition lessen the other one. On the basis of these findings, we conclude that interneurons mediating SIHI and SAI have mutual, direct, and inhibitory interaction in a conditioning intensity-dependent manner.

Aging influences central motor conduction less than peripheral motor conduction: a transcranial magnetic stimulation study.

INTRODUCTION: In this study we investigated the effects of aging on corticospinal tract conduction by measuring the corticoconus motor conduction time (CCCT). METHODS: Motor evoked potentials were recorded from the right tibialis anterior muscle in 100 healthy volunteers. To activate the most proximal part of the cauda equina, magnetic stimulation was performed using a MATS coil over the L1 spinous process (L1-level latency). Transcranial magnetic stimulation of the motor cortex was also conducted (cortical latency). To obtain the CCCT, the L1-level latency was subtracted from the cortical latency. RESULTS: Age was significantly correlated with L1-level latency, but it was not significantly correlated with CCCT. CONCLUSIONS: CCCT is the most direct indicator of corticospinal tract conduction, whereas L1-level latency reflects whole peripheral motor conduction. Central motor conduction was found to be relatively less affected by aging compared with peripheral motor conduction.

Increased primary motor cortical excitability by a single-pulse transcranial magnetic stimulation over the supplementary motor area.

The supplementary motor area (SMA) is a secondary motor area that is involved in various complex hand movements. In animal studies, short latency and probably direct excitatory inputs from SMA to the primary motor cortex (M1) have been established. Although human imaging studies revealed functional connectivity between SMA and M1, its electrophysiological nature has been less studied. This study explored the connection between SMA and M1 in humans using a single-pulse transcranial magnetic stimulation (TMS) over SMA. First, TMS over SMA did not alter the corticospinal tract excitability measured by the size of motor evoked potential elicited by single-pulse TMS over M1. Next, we measured short-interval intracortical facilitation (SICF), which reflects the function of a facilitatory circuit within M1, with or without a single-pulse TMS over SMA. When the intensity of the second pulse in the SICF paradigm (S2) was as weak as 1.0 active motor threshold for a hand muscle, SMA stimulation significantly enhanced the SICF. Furthermore, this enhancement by SMA stimulation was spatially confined and had a limited time window. On the other hand, SMA stimulation did not alter short-interval intracortical inhibition or contralateral silent period duration, which reflects the function of an inhibitory circuit mediated by gamma-aminobutyric acid A (GABA(A)) or GABA(B) receptors, respectively. We conclude that a single-pulse TMS over SMA modulates a facilitatory circuit within M1.