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.

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.

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.

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.

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.

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.

Neurophysiological differentiation of upper motor neuron damage in neurodegenerative disorders.

Objective: Using transcranial magnetic stimulation (TMS) to delineate upper motor neuron (UMN) signs of two neurodegenerative disorders: amyotrophic lateral sclerosis (ALS) and multiple system atrophy (MSA). Methods: Medical records including clinical signs for UMN damage and TMS results were reviewed retrospectively. The UMN signs were classified into none, mild, and severe based on neurological examination of various reflexes. Then TMS-elicited motor evoked potentials (MEPs) were recorded from a hand and a leg muscle to calculate the central motor conduction time (CMCT), which represents fast, mono-synaptic conduction along the corticospinal tract. Relations between the UMN signs and CMCT were analysed for the two diseases. Results: Prevalence and severity of the UMN signs for ALS and MSA were comparable for both upper and lower limbs. However, abnormality in CMCT was found more frequently in ALS: CMCT abnormalities were found in upper limbs for 44% in ALS patients but only for 7% in MSA patients; CMCT abnormalities in lower limbs were 55% in ALS and 20% in MSA. Some ALS patients showed abnormal CMCT in limbs without UMN signs, which was not true for most MSA patients. Conclusions: The abnormalities of CMCT were different in ALS and MSA, even for those who clinically had similar UMN signs. Sometimes, CMCT can reveal UMN damage in the absence of clinical UMN signs. Differences presumably derive from selective degeneration of different fibres in the motor descending pathways. Longitudinal studies must be conducted to accumulate neuroimaging and pathological findings. Significance: CMCT can be useful to differentiate ALS and MSA.

Asymptomatic myocardial infarction in a patient with myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) displays a wide range of cardiac manifestations, including conduction system disturbances, arrhythmias, and cardiomyopathy. As a result of progressive myocardial injury and fibrosis, patients with DM1 frequently show electrocardiogram (ECG) abnormalities which sometimes cannot be differentiated from myocardial ischemia. Even in DM1 cases with ECG findings indicative of coronary artery disease, coronary angiography and coronary computed tomography often demonstrate intact coronary arteries. In this article, we report a case of a 56-year-old DM1 patient with ST segment change on ECG, who was admitted to our hospital for further examination. Echocardiography revealed severe hypokinesis in the anteroseptal wall and left ventricular thrombus in the apex, suggesting the possibility of an old myocardial infarction in the left anterior descending artery (LAD) region. Coronary computed tomography angiography and coronary angiography demonstrated a severe stenosis suggestive of vulnerable plaque in the proximal part of LAD, although fractional flow reserve of the lesion did not indicate functional ischemia. A beta-blocker and a sodium-glucose cotransporter 2 inhibitor were introduced expecting a cardioprotective effect. One year after his discharge, the patient died of septic and cardiogenic shock triggered by aspiration pneumonia. Learning objective: Although the prevalent cardiac manifestations of patients with myotonic dystrophy type 1 are conduction abnormalities and cardiomyopathy, the possibility of having coronary artery disease should be considered because they often have some atherosclerotic risk factors with their tendency toward metabolic abnormalities such as diabetes mellitus due to insulin resistance and dyslipidemia and with diagnostic difficulty due to asymptomatic or non-specific manifestations.

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.

Age-related strengthening of cerebello-cortical motor circuits.

Effective connectivity between the cerebellum and primary motor cortex (M1) is critical for motor learning and motor control. Despite evidence of cerebellar atrophy and declines in motor learning and motor control with advanced age, recent behavioral studies indicate that cerebellar-dependent motor learning processes are preserved or even enhanced in older adults. However, physiological evidence of heightened cerebellar excitability leading to strengthened cerebellar-M1 connectivity with advanced age is lacking. Here, we used transcranial magnetic stimulation to assess age-related effects on cerebellar inhibition, a measure of cerebellar-M1 connectivity, in 20 young and 19 older adults. We observed stronger cerebellar inhibition in older compared with young adults. The behavioral implications of strengthened cerebellar inhibition with advanced age found in this study remain to be determined.

Outcomes of gastrointestinal cancer surgeries in Parkinson's disease patients: A nationwide study.

BACKGROUND: Parkinson's disease (PD) patients with comorbid cancers are increasing in aging populations. However, little is known about the impact of PD on the outcomes of surgeries to resect these cancers. We sought to clarify the association between PD and discharge status of patients who underwent surgery for gastrointestinal cancers, as the most prevalent malignant neoplasms worldwide. METHODS: We identified patients who underwent surgery for gastric and colorectal cancers between April 01, 2014 and March 31, 2018 using the Diagnosis Procedure Combination database, a nationwide administrative inpatient database in Japan. We then collected data on their sex, age, smoking status, body mass index, activities of daily living, cancer stage, and comorbidities. Multivariable Cox regression analyses were conducted to determine factors that influenced discharge to home. RESULTS: Compared with non-PD patients (n = 272,668), PD patients (n = 1341) were significantly older and less likely to receive laparoscopic surgery, and had lower body mass index, more advanced cancer stage, and lower activities of daily living. The proportions of PD and non-PD patients discharged to home were 80.3% and 96.2%, respectively. The adjusted hazard ratio for discharge to home for PD patients was 0.68 (95% confidence interval, 0.64-0.73; P < 0.001). CONCLUSIONS: Compared with non-PD patients, PD patients were less likely to be discharged to home after surgery for gastrointestinal cancers. The present results may indicate a necessity to improve perioperative care for patients with PD.

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.

Alanine transaminase is predominantly increased in the active phase of anti-HMGCR myopathy.

Autoantibodies against 3­hydroxy-3-methylglutaryl-CoA reductase (HMGCR) and the signal recognition particle (SRP) are representative antibodies causing immune-mediated necrotizing myopathies (IMNM), called as anti-HMGCR and anti-SRP myopathies, respectively. Here, we analyzed the differences in routine blood test results between 56 anti-HMGCR and 77 anti-SRP myopathy patients. A higher alanine transaminase (ALT) level and a lower aspartate transaminase (AST)/ALT ratio were observed in anti-HMGCR myopathy patients [ALT, 265.7 ±â€¯213.3 U/L (mean ± standard deviation); AST/ALT ratio, 0.88 ±â€¯0.32] than in anti-SRP-myopathy patients (ALT, 179.3 ±â€¯111.2 U/L, p < 0.05; AST/ALT ratio, 1.28 ±â€¯0.40, p < 0.01). In the active phase, anti-HMGCR myopathy often showed ALT predominance, whereas anti-SRP myopathy often showed AST predominance. In addition, there were differences in erythrocyte sedimentation rate (ESR), total cholesterol (TChol) level, and high-density lipoprotein (HDL) level between anti-HMGCR and anti-SRP myopathies (ESR: HMGCR, 24.4 ±â€¯20.8 mm/1 h; SRP, 35.7 ±â€¯26.7 mm/1 h, p = 0.0334; TChol: HMGCR, 226.7 ±â€¯36.6 mg/dL; SRP, 207.6 ±â€¯40.8 mg/dL, p = 0.0163; HDL: HMGCR, 58.4 ±â€¯13.9 mg/dL; SRP, 46.2 ±â€¯17.3 mg/dL, p < 0.01). Additional studies on the differences in routine blood test results may further reveal the pathomechanisms of IMNM.

Cranial Nerve Involvement and Dysautonomia in Post-COVID-19 Guillain-Barré Syndrome.

The clinical characteristics of Guillain-Barré syndrome (GBS) after coronavirus disease 2019 (COVID-19) remain unclear due to the small number of cases. We herein report a case of a Japanese patient with post-COVID-19 GBS who presented with facial and limb muscle weakness, sensory deficits, and autonomic dysfunction. Nerve conduction studies revealed demyelination. Head magnetic resonance imaging showed contrast enhancement in the bilateral facial nerves. Systemic management, including intubation, intravenous immunoglobulin therapy, and rehabilitation, improved the patient's condition. This was the first Japanese case of acute inflammatory demyelinating polyneuropathy after COVID-19 and was characterized by autonomic dysfunction and facial nerve enhancement.

Plasticity induction in the pre-supplementary motor area (pre-SMA) and SMA-proper differentially affects visuomotor sequence learning.

BACKGROUND: Both pre-supplementary motor area (pre-SMA) and SMA-proper (SMA) must play important roles in visuomotor sequence learning. However, functional differences between the pre-SMA and SMA have not been well studied in humans. OBJECTIVE: To elucidate the functional differences between the pre-SMA and SMA in sequence learning in humans. METHODS: To induce LTP/LTD, we administered quadripulse transcranial magnetic stimulation (QPS) with an inter-stimulus interval of 5 or 50 ms (QPS-5/50) over the pre-SMA or SMA in healthy volunteers. The sham stimulation was also done as a control. We studied the effects of LTP/LTD in the pre-SMA/SMA on a new sequence learning and the performance of well-learned sequence by using sequence learning task called the "2 × 10 task". Effects on the simple choice reaction time task were also studied for comparison. RESULTS: QPS-5 over the pre-SMA increased the error rate without any changes in movement speed. When administered over the SMA, QPS-5 decreased, and QPS-50 increased the rate of reaction time reduction across trials without changes in the error rate. QPS over neither the pre-SMA nor SMA affected the performances of a well-learned sequence or a simple choice reaction time task. CONCLUSIONS: Our findings that QPS over the pre-SMA correlated with sequence learning performance and that over the SMA with execution speed are consistent with the previous results in animals and humans. Our results lend further support to the utility of QPS for modulating motor learning in humans.

Rituximab improves not only back stiffness but also "stiff eyes" in stiff person syndrome: Implications for immune-mediated treatment.

OBJECTIVE: Stiff person syndrome (SPS) is usually characterized by truncal muscle rigidity and episodic painful spasms, but it sometimes appears with ocular symptoms called "stiff eyes". We recorded saccade movements in an SPS patient manifesting with "stiff eyes" conditions with slow saccade velocity and evaluated the effect of immunotherapy including rituximab on saccade parameters. METHODS: We repeatedly conducted saccade eye recordings using video-based eye tracking system on a 42-year-old male SPS patient with slow saccade. The velocity and onset latency of visual guided saccades (VGS) were measured at each recording. Because VGS velocity is affected by saccade amplitude, estimated peak velocity (Vmax) was also calculated by taking the relationship between the velocity and the amplitude of saccade into account. RESULTS: The mean VGS velocity improved significantly after two courses of rituximab administration compared with its lowest value. The estimated Vmax decreased as the clinical manifestations worsened, but it increased after rituximab administration. Other neurological symptoms in this patient such as muscle rigidity and gait instability also improved after the treatment. CONCLUSION: Slow saccade in a "stiff eyes" patient improved after rituximab administration. Our study also indicated that the saccade eye recording is useful for evaluating the clinical condition of SPS when it is complicated with ocular symptoms.

Multinodular and vacuolating neuronal tumor (MVNT): A presumably incidental and asymptomatic case in an intractable epilepsy patient.

INTRODUCTION: Multinodular and vacuolating neuronal tumor (MVNT) had been initially described as an epilepsy-related brain tumor, but recent studies demonstrated it could be found incidentally in non-epilepsy patients. CASE REPORT: A 33-year-old woman with intractable post-encephalitis epilepsy presented a cluster of multinodular T2 hyperintensity in the left temporal lobe, which was very similar to the characteristics of MVNT. Long-term video electroencephalogram demonstrated that the habitual seizures were originated from bilateral temporal area and the interictal epileptic discharges were seen multifocally, although the lesions with MVNT appearance were localized in the left temporal lobe. It was presumed that the epilepsy in this patient was due to encephalitis in the past, and the link between the lesions and the epilepsy in this patient seemed weak. CONCLUSION: Although MVNT had been considered as an epilepsy-related brain tumor, we suggest it is not necessarily preferable to perform surgical resection of MVNT even on patients with epilepsy, unless epileptic foci are highly related to MVNT.

Effects of L-DOPA on quadripulse magnetic stimulation-induced long-term potentiation in older adults.

Reduced cortical plasticity has been previously reported in older adult as compared with young adults. However, the effects of dopamine on this plasticity reduction remain unknown. Here, we assessed the effects of high-dose (200 mg) and medium-dose (100 mg) L-3,4-dihydroxyphenylalanine (L-DOPA) intake on the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS) in older adults (aged ∼65 years). The subjects were 32 (200 mg) and 20 (100 mg) healthy older adult volunteers. This study was designed as a double-blind, crossover and placebo-controlled trial on one dose of L-dopa. Two hours after taking L-DOPA or placebo-drug, QPS was applied over the motor cortex. Motor evoked potentials were recorded to evaluate the motor cortical excitability changes. We found that both doses of L-DOPA enhanced LTP after QPS in older adults as one group. We classified subjects into QPS responders and QPS nonresponders. Both L-DOPA doses produced significant LTP enhancement in QPS nonresponders, whereas either of doses did not produce significant LTP enhancement in QPS responders. Collectively, our findings suggest that the neural plasticity reductions observed in older adults could be partly improved by dopamine.

Increased facilitation of the primary motor cortex in de novo Parkinson's disease.

INTRODUCTION: Paired-pulse transcranial magnetic stimulation (TMS) is useful to estimate the balance between inhibitory and facilitatory circuits of the primary motor cortex (M1) in Parkinson's disease (PD). Results of earlier studies are, however, incongruent: some reports describe normal short-interval intracortical inhibition (SICI), but others describe reduced SICI. We hypothesize that exaggerated intracortical facilitation masks normal inhibition, and that a triple-pulse method can reveal masked inhibition in PD. METHODS: Ten PD patients who had not been exposed to dopaminergic medications were enrolled. Results were compared with those obtained from 10 age-matched healthy volunteers. We measured TMS-elicited motor evoked potential (MEP) as an index of M1 excitability. We tested SICI, intracortical facilitation (ICF), and short-interval intracortical facilitation (SICF), which has three distinct facilitatory peaks, using the paired-pulse TMS paradigm. A triple-pulse protocol, SICI + SICF, was investigated as described in our earlier study. This protocol examined SICF in the presence of SICI, thereby allowing our test of true inhibitory influence on a specific component of MEP-generating mechanism known as I3 wave. RESULTS: In PD patients, SICI estimated using the conventional method was decreased, whereas SICF was enhanced around its second peak out of the three. Results for SICI + SICF were comparable between PD patients and healthy controls, suggesting normal inhibition of I3 waves in PD patients. CONCLUSION: We confirmed the SICF enhancement in drug naïve PD patients. We propose that I3 wave inhibition by a subthreshold pulse shown by SICI paradigm is unaffected in PD. The triple-pulse method can reveal masked inhibition.