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Marchiafava-Bignami disease (MBD) is a rare complication of chronic alcoholism that typically causes demyelination and necrosis of the corpus callosum. Here, we report a man with probable MBD with callosal and right medial paracentral lesions who presented with abnormal reaching behavior and ideomotor apraxia of the left hand. He exhibited difficulty in reaching with the left hand when a target object was placed on his right-hand side, and he exhibited rightward bias when using his right hand in a line bisection task. These disturbances in reaching suggest disruption of the top-down control of motor intention and spatial attention at the corpus callosum., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

A 83-year-old woman complained of muscular weakness in the left leg and trembling in all extremities. She was apathetic and had left leg paresis and asterixis in all extremities. Magnetic resonance imaging revealed acute cerebral infarctions in the bilateral frontal lobes perfused by the anterior cerebral artery (ACA). Anticoagulant treatments improved ischemia-induced damage of the frontal lobes, and then her neurological symptoms including asterixis gradually disappeared. A unique point of this case is that acute stroke in the bilateral ACA territory induced bilateral asterixis resembling metabolic encephalopathy. Occurrence of the bilateral ACA territory infarction is extremely rare, but it should be considered in patients presenting with bilateral asterixis., (Copyright © 2021. Published by Elsevier B.V.)

A 86-year-old woman with left hemiparesis was admitted to our hospital. When visiting to our hospital, hemichorea appeared on her left extremities in an ambulance. She also had mild disturbance of consciousness, spatial disorientation, and sensory disturbance. Blood biochemical studies revealed mild renal failure. DWI MRI showed hyperintensities in the postcentral gyrus and a posterior part of the insula in the right hemisphere, but no signal changes in FLAIR. No lesions were detected in the basal ganglia. The DWI-FLAIR mismatch suggested acute cerebral infarction, and we performed intravenous thrombolysis therapy. Her neurological symptoms including hemichorea gradually improved, and she was finally discharged on foot. Two conspicuous points of the present patient are the sensory cortical infarction and an association with renal failure. In this patient, the sensory cortical infarction must produce chorea even though sensory cortical lesions rarely caused chorea. The associated renal dysfunction may play some role in the production of chorea. The double-crash of cerebral infarction and metabolic abnormality (renal dysfunction) may cause hemichorea which is rarely seen in patients with cerebral infarction of the sensory cortex and insula with no metabolic abnormalities.

The decisions we make are sometimes influenced by interactions with other agents. Previous studies have suggested that the prefrontal cortex plays an important role in decision-making and that the dopamine system underlies processes of motivation, motor preparation, and reinforcement learning. However, the physiological mechanisms underlying how the prefrontal cortex and the dopaminergic system are involved in decision-making remain largely unclear. The present study aimed to determine how decision strategies influence event-related potentials (ERPs). We also tested the effect of levodopa, a dopamine precursor, on decision-making and ERPs in a randomized double-blind placebo-controlled investigation. The subjects performed a matching-pennies task against an opposing virtual computer player by choosing between right and left targets while their ERPs were recorded. According to the rules of the matching-pennies task, the subject won the trial when they chose the same side as the opponent, and lost otherwise. We set three different task rules: (1) with the alternation (ALT) rule, the computer opponent made alternating choices of right and left in sequential trials; (2) with the random (RAND) rule, the opponent randomly chose between right and left; and (3) with the GAME rule, the opponent analyzed the subject's past choices to predict the subject's next choice, and then chose the opposite side. A sustained medial ERP became more negative toward the time of the subject's target choice. A biphasic potential appeared when the opponent's choice was revealed after the subject's response. The ERPs around the subject's choice were greater in RAND and GAME than in ALT, and the negative peak was enhanced by levodopa. In addition to these medial ERPs, we observed lateral frontal ERPs tuned to the choice direction. The signals emerged around the choice period selectively in RAND and GAME when levodopa was administered. These results suggest that decision processes are modulated by the dopamine system when a complex and strategic decision is required, which may reflect decision updating with dopaminergic prediction error signals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chang, Wiratman, Ugawa and Kobayashi.)

Although animal studies and studies on Parkinson's disease (PD) suggest that dopamine deficiency slows the pace of the internal clock, which is corrected by dopaminergic medication, timing deficits in parkinsonism remain to be characterized with diverse findings. Here we studied patients with PD and progressive supranuclear palsy (PSP), 3-4 h after drug intake, and normal age-matched subjects. We contrasted perceptual (temporal bisection, duration comparison) and motor timing tasks (time production/reproduction) in supra- and sub-second time domains, and automatic versus cognitive/short-term memory-related tasks. Subjects were allowed to count during supra-second production and reproduction tasks. In the time production task, linearly correlating the produced time with the instructed time showed that the "subjective sense" of 1 s is slightly longer in PD and shorter in PSP than in normals. This was superposed on a prominent trend of underestimation of longer (supra-second) durations, common to all groups, suggesting that the pace of the internal clock changed from fast to slow as time went by. In the time reproduction task, PD and, more prominently, PSP patients over-reproduced shorter durations and under-reproduced longer durations at extremes of the time range studied, with intermediate durations reproduced veridically, with a shallower slope of linear correlation between the presented and produced time. In the duration comparison task, PD patients overestimated the second presented duration relative to the first with shorter but not longer standard durations. In the bisection task, PD and PSP patients estimated the bisection point (BP50) between the two supra-second but not sub-second standards to be longer than normal subjects. Thus, perceptual timing tasks showed changes in opposite directions to motor timing tasks: underestimating shorter durations and overestimating longer durations. In PD, correlation of the mini-mental state examination score with supra-second BP50 and the slope of linear correlation in the reproduction task suggested involvement of short-term memory in these tasks. Dopamine deficiency didn't correlate significantly with timing performances, suggesting that the slowed clock hypothesis cannot explain the entire results. Timing performance in PD may be determined by complex interactions among time scales on the motor and sensory sides, and by their distortion in memory., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Terao, Honma, Asahara, Tokushige, Furubayashi, Miyazaki, Inomata-Terada, Uchibori, Miyagawa, Ichikawa, Chiba, Ugawa and Suzuki.)

As the field of noninvasive brain stimulation (NIBS) expands, there is a growing need for comprehensive guidelines on training practitioners in the safe and effective administration of NIBS techniques in their various research and clinical applications. This article provides recommendations on the structure and content of this training. Three different types of practitioners are considered (Technicians, Clinicians, and Scientists), to attempt to cover the range of education and responsibilities of practitioners in NIBS from the laboratory to the clinic. Basic or core competencies and more advanced knowledge and skills are discussed, and recommendations offered regarding didactic and practical curricular components. We encourage individual licensing and governing bodies to implement these guidelines., Competing Interests: Declaration of Competing Interest The content of this manuscript is solely theresponsibility of the authors and does not necessarily represent the official views of any of the institutions involved or any of the funding agencies and bodies. Peter J. Fried has nothing to disclose with regard to this manuscript. Emiliano Santarnecchi serves on the scientific advisory boards for Neuroelectrics, EBNeuro and Neurocare. He is listed as an inventor on several issued and pending patents on the application of noninvasive brain stimulation in patients with dementia and brain tumors. Andrea Antal serves as a paid consultant for NeuroConn, Ilmenau, Germany and Savir GmbH, Magdeburg, Germany. She is supported by the State of Lower Saxony, Germany (76251-12-7/19 (ZN 3456)). David Bartres-Faz has nothing to disclose with regard to this manuscript. Sven Bestmann has nothing to disclose with regard to this manuscript. Linda L. Carpenter is supportedby the National Institute of General Medical Sciencesof the National Institutes of Health under Award Number P20GM130452 (Core Resources of the Butler Hospital COBRE Center for Neuromodulation). She has received consulting income from Neuronetics, Nexstim, Janssen, AffectNeuro, and Sage Therapeutics. She has research support from Neuronetics, Neosync, AffectNeuro, and Nexstim. Pablo Celnik has nothing to disclose with regard to this manuscript. Dylan Edwards has nothing to disclose with regard to this manuscript. Faranak Farzan has nothing to disclose with regard to this manuscript. Shirley Fecteau is a deputy editor of Brain Stimulation and an editor of Scientific Reports.She is regular faculty of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education. Mark S. George is an unpaid consultant to Brainsway, Neuronetics, and Magstim. He has received loaned equipment or research grants from Mecta, Brainsway, Magstim, Magventure. He is a paid consultant to Neuralief. He does not own equity in any device company. He is the editor in chief of Brain Stimulation, with a stipend from Elsevier. Bin He has nothing to disclose with regard to this manuscript. Yun-Hee Kim has nothing to disclose with regard to this manuscript. Letizia Leocani is currently shortlisted for the European Commission expert panel on Medical Devices and in vitro diagnostic medical devices for Neurology. Sarah H. Lisanby is inventor on a patent for TMS technology, unrelated to the topic presented here, with no royalties.The opinions expressed in this article are the authors’ own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government. Colleen Loo has received competitive grant funding from the Australian National Health and Medical Research Council for brain stimulation research. Bruce Luber has nothing to disclose with regard to this manuscript. Michael A. Nitsche serves on the scientific advisory boards for Neuroelectrics and NeuroDevice. Walter Paulus serves as a member of the scientific advisory board of Precisis AG. Simone Rossi serves as a consultant for EB-Neuro and Neurocare Italy group. Paolo M. Rossini has nothing to disclose with regard to this manuscript. John Rothwell has nothing to disclose with regard to this manuscript. Alexander T. Sack serves as head of the scientific advisory board for AlphaSys Brain Technologies BV. He is founder of Neurowear Medical BV, and Director of the European Clinical TMS Certification Course (www.tmscourse.eu). Gregor Thut serves as a Section Editor for European Journal of Neuroscience and Brain Topography and as an Associate Editor for several Frontiers journals (Brain Imaging and Stimulation, Consciousness Research, Perception Science). Yoshikazu Ugawa has nothing to disclose with regard to this manuscript. Ulf Ziemann has received grants from European Research Council (ERC), German Research Foundation (DFG), German Federal Ministry of Education and Research (BMBF), Ministry of Research and Arts of the Federal State of Baden-Würrtemberg (MWK), Bristol Myers Squibb, Janssen Pharmaceutica NV, Servier, Biogen Idec GmbH, and personal fees from Bayer Vital GmbH, Pfizer GmbH, CorTec GmbH, all not related to this work. Mark Hallett was supported by the NINDS Intramural Program. He is an inventor of patents held by NIH for an immunotoxin for the treatment of focal movement disorders and the H-coil for magnetic stimulation; in relation to the latter, he has received license fee payments from the NIH (from Brainsway). He is on the Medical Advisory Boards of CALA Health and Brainsway. He has research grants from Allergan for studies of methods to inject botulinum toxins, Medtronic, Inc. for a study of DBS for dystonia, and CALA Health for studies of a device to suppress tremor. Alvaro Pascual-Leone serves on the scientific advisory boards for Starlab Neuroscience, Neuroelectrics, Magstim, Magventure, MedRhythms, and Cognito. He listed as an inventor on several issued and pending patents on the real-time integration of transcranial magnetic stimulation with electroencephalography and magnetic resonance imaging, and novel methods for transcranial electric stimulation. He is co-founder of Linus Health and TI Solutions A.G. He serves as associate editor for Annals of Neurology. He is co-director of yearly intensive mini-fellowships on TMS and tCS offered through Harvard Continuing Medical Education., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Premature saccades (PSs) are those made with latencies too short for the direction and amplitude to be specifically programmed. We sought to determine the minimum latency needed to establish accurate direction and amplitude, and observed what occurs when saccades are launched before this minimum latency., Methods: In Experiment 1, 249 normal subjects performed the gap saccade task with horizontal targets. In Experiment 2, 28 normal subjects performed the gap saccade task with the targets placed in eight directions. In Experiment 3, 38 normal subjects, 49 patients with Parkinson's disease (PD), and 10 patients with spinocerebellar degeneration (SCD) performed the gap saccade task with horizontal targets., Results: In Experiment 1, it took 100 ms to accurately establish saccade amplitudes and directions. In Experiment 2, however, the latencies needed for accurate amplitude and direction establishment were both approximately 150 ms. In Experiment 3, the frequencies of PSs in patients with PD and SCD were lower than those of normal subjects., Conclusions: The saccade amplitudes and directions are determined simultaneously, 100-150 ms after target presentation. PSs may result from prediction of the oncoming target direction or latent saccade activities in the superior colliculus., Significance: Saccade direction and amplitude are determined simultaneously., Competing Interests: Conflict of interest statement Dr. Tokushige was supported by a Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (19 K17046), and has received a speaker’s honoraria from Otsuka Pharmaceutical Co., Ltd. Dr. Hamada was supported by MEXT KAKENHI (Nos. 15 K19476, 15H01658, 16H01605, and 18 K07521). Dr. Ugawa received grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 25293206, 15H05881,16H05322, and 18 K10821), The Research Committee on the Medical Basis of Motor Ataxias, Health and Labor Science Research Grants, the Ministry of Health, Labor and Welfare of Japan, the Support Center for Advanced Telecommunications Technology Research, the Association of Radio Industries Businesses, and the Novartis Foundation (Japan) for the Promotion of Science, Nihon Kohden, Ltd., Takeda Pharmaceutical Company Limited, Nippon Boehringer Ingelheim Co.,Ltd., Mitsubishi Tanabe Pharma Corporation. Dr Ugawa received honoraria from the Taiwan Movement Disorders Society, Chinese Neurology Society, Astellas Pharma Inc., Eisai Co.,Ltd., FP Pharmaceutical Corporation, Otsuka Pharmaceutical Co.,Ltd., Elsevier Japan K.K., Kissei Pharmaceutical Co.,Ltd., Kyorin Pharmaceutical Co.,Ltd., Kyowa Hakko Kirin Co.,Ltd., GlaxoSmithKline K.K., Sanofi-Aventis K.K., Daiichi Sankyo Co.,Ltd., Dainippon Sumitomo Pharma Co.,Ltd., Takeda Pharmaceutical Co.,Ltd., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Ltd., Nippon Chemiphar Co.,Ltd., Nihon Pharmaceutical Co.,Ltd., Nippon Boehringer Ingelheim Co.,Ltd., Novartis Pharma K.K., Bayer Yakuhin, Ltd., and Mochida Pharmaceutical Co.,Ltd. and received royalties from Chugai-Igakusha, Igaku-Shoin Ltd., Medical View Co.Ltd., and Blackwell Publishing K. K. Dr. Terao was supported by a Research Project Grant-in-aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (18H05523)., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

The cortical silent period (CSP) induced by transcranial magnetic stimulation (TMS) has been reported to be prolonged in 2 Creutzfeldt-Jakob disease (CJD) patients who presented with periodic myoclonus. Herein, we will show a prominent prolongation of TMS-induced CSP in a patient with CJD who did not have periodic myoclonus. The patient was a 66-year-old woman who developed rapidly progressive dementia. No myoclonic jerks were observed. Brain magnetic resonance imaging showed high-intensity lesions in the cerebral cortex, basal ganglia, and thalamus on diffusion-weighted images. Electroencephalography (EEG) showed diffuse and continuous slow waves, but no periodic synchronous discharges (PSDs). A TMS study revealed that the duration of CSP was prominently prolonged: the duration of CSP (370 ms) equaled that of the mean + 6.5 SD of the normal value. One month after admission, the patient exhibited akinetic mutism and developed periodic myoclonus in her limbs. The clinical course was compatible with CJD. To date, CSP has been measured in only 2 CJD patients. The common findings in both cases were marked prolongation of CSP, periodic myoclonus, and PSD on EEG. In short, we demonstrated that TMS-induced CSP was prominently prolonged even at the early stage of CJD without periodic myoclonus or PSD. In other disorders, the CSP has not been reported to be comparably prolonged to that of CJD patients. Therefore, we conclude that TMS-induced CSP could be prominently prolonged even in the early stage of CJD. The marked prolongation of the CSP might be an early biomarker of CJD., Competing Interests: The authors have no disclosures. The authors have no potential conflicts of interest., (Copyright © 2020 by S. Karger AG, Basel.)

To study cortical excitability changes induced by external stimulation with a certain rhythm, we developed a new method using motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) over the primary motor cortex. In this method, three conditioning TMS with the intensity below the motor threshold are given prior to the supra-threshold test stimulus with the four TMSs were separated by a certain interval (triad-conditioning stimulation: TCS). In healthy volunteers, MEP facilitation was elicited at an interval of 25ms, whereas TCSs with other intervals induced no facilitation. This frequency-dependent facilitation may reflect some intrinsic rhythm of M1 (25ms, i.e. 40Hz). In cortical myoclonus, the facilitation at 25ms was gone whereas facilitation was elicited by triad-conditioning stimulus at 40ms (25Hz), which is consistent with a previously reported abnormal beta rhythm in cortical myoclonus reported previously. Facilitation at 25ms was evoked in neither Parkinson's disease nor in amyotrophic lateral sclerosis. With TCS, we were able to investigate the intrinsic rhythmic activity of M1 and its changes in neurological disorders.

Background: Theta burst stimulation (TBS) and quadripulse stimulation (QPS) are known to induce synaptic plasticity in humans. There have been no head-to-head comparisons of the efficacy and variability between TBS and QPS., Objective: To compare the efficacy and interindividual variability between the original TBS and QPS protocols. We hypothesized that QPS would be more effective and less variable than TBS., Methods: Forty-six healthy subjects participated in this study. Thirty subjects participated in the main comparison experiment, and the other sixteen subjects participated in the experiment to obtain natural variation in motor-evoked potentials. The facilitatory effects were compared between intermittent TBS (iTBS) and QPS5, and the inhibitory effects were compared between continuous TBS (cTBS) and QPS50. The motor-evoked potential amplitudes elicited by transcranial magnetic stimulation over the primary motor cortex were measured before the intervention and every 5 min after the intervention for 1 h. To investigate the interindividual variability, the responder/nonresponder/opposite-responder rates were also analyzed., Results: The facilitatory effects of QPS5 were greater than those of iTBS, and the inhibitory effects of QPS50 were much stronger than those of cTBS. The responder rate of QPS was significantly higher than that of TBS. QPS had a smaller number of opposite responders than TBS., Conclusion: QPS is more effective and stable for synaptic plasticity induction than TBS., Competing Interests: Conflict/declaration of interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

I describe quadripulse stimulation (QPS) briefly, and show several examples of its applications, such as rTMS treatment of Parkinson's disease, gait induction by lumbar rTMS, and roles of presupplementary motor area (pre-SMA) and SMA in visuo-motor sequence learning, role of SMA in negative compatibility effect, and role of dendritic back propagation potential in I-wave generation.

Background: The cerebellum is known to play a crucial role in sensori-motor adaptation, which includes the prism adaptation. TRH has been widely used as a treatment for cerebellar ataxia in Japan, however effects of TRH on cerebellar adaptation process have not been studied. Here, we studied effects of TRH treatment on the prism adaptation task., Methods: Eighteen spinocerebellar degeneration (SCD) patients participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the aftereffect (AE) of the prism adaptation task between before and after TRH therapy., Results: TRH therapy improved SARA significantly (p = .005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of "Stance" category score. TRH decreased baseline errors of the prism adaptation task (p = .021), while unaffected AEs (p = .252)., Conclusion: TRH differentially affected clinical cerebellar ataxia including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of sensori-motor adaptation and simple motor execution (clinically evaluated cerebellar ataxia)., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: We retrospectively investigated the utility of the central motor conduction time (CMCT) in detecting upper motor neuron (UMN) involvements in patients with amyotrophic lateral sclerosis (ALS)., Methods: Fifty-two ALS patients and 12 disease control patients participated in this study. Surface electromyograms were recorded from the first dorsal interosseous (FDI) and tibialis anterior (TA) muscles. We stimulated the motor cortex, brainstem, and spinal nerve using transcranial magnetic stimulation (TMS) in order to measure the cortical, brainstem, and spinal latencies. We divided the ALS patients into 2 subgroups (with UMN impairment vs. without UMN impairment) and calculated the rates of abnormal CMCT prolongation judged by their comparison with the normal ranges obtained by the measurement in the control patients., Results: The CMCTs in the FDI and TA were abnormally prolonged in over 40% of the ALS patients with UMN impairment and in nearly 30% of those without UMN impairment., Conclusions: CMCT shows UMN dysfunction in ALS patients without clinical UMN impairment., Significance: TMS still has diagnostic utility in a significant portion of ALS patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Quadripulse stimulation (QPS) is a newly developed stimulation method to induce neural plasticity in humans. One stimulation burst consisting of four monophasic pulses is given every 5 s for 30 min. A total of 360 bursts (1440 pulses) are given in one session. Short-interval QPS potentiates the target cortical excitability and long-interval QPS depresses it. QPS at an inter-pulse interval of 5 ms (QPS5) induces long-term potentiation (LTP)-like effects most efficiently and QPS50 induces long-term depression (LTD)-like effects most effectively in the primary motor cortex. In this mini-review, we briefly introduce QPS: (i) principle and cortical plasticity (stimulators and protocols, synaptic plasticity, underlying mechanisms, meta-plasticity, axonal plasticity, and drug effects), (ii) robust and strong neural plasticity induction (variability, influence of phasic muscle contraction, independency of BDNF polymorphism, sensory cortical plasticity, neural plasticity in the contralateral hemisphere, on-line effects on the brain networks, studies of normal brain physiology, and visuomotor sequence learning), (iii) therapeutic applications to neurological and psychiatric disorders (Parkinson's disease, epilepsy, cerebrovascular disease, and major depression), (iv) safety, and (v) future issues. Based on this evidence, we propose that QPS is currently the most powerful and reliable non-invasive brain stimulation method to induce neural plasticity in humans.

A single pulse of TMS or direct electric stimulation over M1 causes repetitive synchronized firing of corticospinal tract (CST) neurons. Two mechanisms for the repetitive firing have been proposed: a cascade of synaptic inputs to the pyramidal neurons and a single reverberating circuit of interneurons. Here, we propose another possibility in which bursting of CST neurons is produced by dendritic Ca 2+ -spikes. Backpropagation of the initial action potential (I1-wave) from the soma interacts with synaptic input in the dendrites to initiate a dendritic calcium spike. These Ca 2+ -spikes produce a burst of somatic action potentials that starts about 1.5 ms after the initial discharge of the neuron, which may produce the later I-waves., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Mobile phones are indispensable for daily life, and the adverse effects of the electromagnetic field (EMF) emitted by mobile phones have been a great concern. We studied the effects of long-term evolution (LTE) -like EMF for 30 min on an awake electroencephalogram (EEG). Thirty-eight healthy volunteers, aged 20-36 years old, participated in this study. The maximum local SAR (specific absorption rate) averaged over 10-g mass was 2.0 W/kg. The EEG was recorded before and after real or sham exposures. The effects of exposure conditions (real or sham) and the recording time (before, during, and after exposure) on each EEG power spectrum of θ, α, and β frequency ranges were analyzed. The θ and α band waves were enhanced after both exposure conditions. These results may be explained by the participants' drowsiness during the EEG recording in both exposures. We conclude that an LTE-like exposure for 30 min in this study showed no detectable harmful effects on awake EEGs in healthy humans., (Copyright © 2020. Published by Elsevier B.V.)

Usually, cortical rhythmic activities are studied with local field potentials. To overcome small amplitude of EEGs easily disturbed by several factors, we developed a new method to study motor cortical rhythm using Motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS). We, here, review triad-conditioning TMS technique for investigating the intrinsic rhythm of the human primary motor cortex (M1). MEP was recorded from the first dorsal interosseous muscle (FDI). TMS was applied over the M1 to study its frequency dependency. In the intervention condition, the subthreshold, same intensity three conditioning stimuli separated by a certain interval were given prior to the supra-threshold test stimulus. In the control condition, the test stimulus was given alone. MEPs were compared between the two conditions. In healthy volunteers, triad-conditioning stimulus (TCS) at an interval of 25 ms induced MEP facilitation, whereas the other intervals TCS induced no facilitation. This frequency dependent facilitation may reflect some intrinsic rhythm of M1 (25 ms, i.e. 40 Hz). In cortical myoclonus, the 40 ms TCS induced facilitation whereas 25 ms TCS induced no facilitation, which is consistent with abnormal rhythm of M1 at 25 Hz (40 ms interval) reported previously. In Parkinson's disease (PD), 25 ms TCS evoked no facilitation. Triad-conditioning TMS may enable us to investigate the intrinsic rhythmic activity of M1 and its abnormality., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

In this communication, I first summarize the mechanisms underlying human voluntary movements and define the involuntary movements (medical term)., Classification of Human Movements: Human movements are classified into two main kinds: intentional movements and non-intentional movements in which the involuntary movements are included. Non-intentional movements have many kinds of movement: normal non-intentional movements (associate movements, mirror movements or juggling knees etc.), several reflexes (spinal tendon, spinal flexion, spino-bulbo-spinal, cortical reflexes and startle response) and pathological non-intentional movements which should be treated (so called "involuntary movements" in clinical practice, medical term of involuntary movement)., Voluntary Movements: The final motor commands for movements are mediated by several descending motor pathways. These final pathways are modified, regulated by two main loops (basal ganglia loop and cerebellar loop)., Involuntary Movements (medical Term): The involuntary movements are produced by a non-intentional, pathological activation anywhere within the final common pathways or the above two loops. I would like to personally divide those into four major groups., Tremor: Some oscillation mechanisms may produce tremor: one site oscillation or loop oscillation., Myoclonus: Sudden, brief, shock-like involuntary movements arising from anywhere from the cortex to the muscle., Chorea/ballism: Suddenly appearing, irregular, phasic movements which are usually mimicked by normal subjects., Dystonia/athetosis: Sustained, long duration muscle contraction sometimes associated with torsion components., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Objective: Transcranial magnetic stimulation (TMS) activates brain structures non-invasively. Computational models can be used to elucidate the activation site; however, the exact activation site is controversial. The aim is to present an imaging technique of the TMS activation cortical site estimation using individualized multi-scale realistic head models based on experimentally-derived TMS fields., Approach: The induced electric field (EF) was computed using subject-specific head models and experimental-specific TMS coil configuration during suprathreshold stimulation for relaxed muscles. The experimentally-derived EFs were used to calculate the activation of pyramidal tract model embedded in the head models to derive the activation site on the cortical surface at the macroscopic level., Main Results: The TMS activation site was located at the anterior wall of the central sulcus, which agreed with a concurrent TMS/fMRI study. In contrast, the EF strength was not entirely consistent with TMS/fMRI studies. Multiscale physical modelling is a feasible imaging technique to investigate the activation site for TMS., Significance: By combining subject-specific multiscale modelling with experimental TMS measurements, we showed that this method could serve as a TMS imaging technique at suprathreshold condition.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Patients with Parkinson's disease (PD) and multiple system atrophy both present predominantly with parkinsonism at early stages, whereas cerebellar symptoms are largely masked in multiple system atrophy with parkinsonism (MSAP). We sought to determine whether the velocity profiles of saccades could be used to differentiate between these two disorders, revealing the underlying basal ganglia and/or cerebellar dysfunction and brainstem pathology in these disorders., Methods: Sixteen MSA-P patients, 63 PD patients, and 36 age-matched normal subjects performed the visually guided (VGS) and memory-guided saccade (MGS) tasks. Targets were presented at eccentricities of 5, 10, 20, and 30 degrees. The amplitude, peak velocity, and duration of saccades were compared among subject groups. Duration was further subdivided into acceleration and deceleration periods, corresponding to the times before and after peak velocity. These parameters correlated with the severity of Parkinsonism as assessed by the UPDRS motor score., Results: Hypometria predominated in both PD and MSAP patients, whereas hypermetria, frequently noted in cerebellar ataxia, was rarely observed. Saccades in MSAP were characterized both by prolonged acceleration and deceleration periods with reduced peak velocity. In contrast, the velocity profile of PD patients was characterized mainly by the prolonged deceleration period. The changes observed in velocity profiles of MGS deteriorated with advancing severity of parkinsonism in MSAP and PD patients., Conclusion: Saccade profiles provide useful information for differentiating between PD and MSAP at early stages. While the changes in velocity profiles may be explained by the cerebellar and brainstem pathology in MSAP, the changes in velocity profile in both PD and MSAP correlated significantly with increasing severity of Parkinsonism in both disorders, suggesting a link with striatonigral pathology., Significance: The differential changes in saccade velocity profiles of MSAP and PD may be used as a measure indexing the progression of cerebellar and basal ganglia dysfunction as well as for assessing the functional improvement when clinical treatment becomes available., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: McLeod syndrome is a rare X-linked recessive acanthocytosis associated with neurological manifestations including progressive chorea, cognitive impairment, psychiatric disturbances, seizures, and sensorimotor axonal polyneuropathy. However, no studies have investigated the functioning of central sensorimotor tracts in patients with McLeod syndrome., Case Presentation: A 66-year-old man had experienced slowly progressive chorea and gait disturbance due to lower limb muscle weakness since his early fifties. Blood examinations showed erythrocyte acanthocytosis and the reduction of Kell antigens in red blood cells. Brain magnetic resonance imaging showed atrophy of the bilateral caudate nuclei and putamen. The diagnosis of McLeod syndrome was confirmed by the presence of a mutation of the XK gene on the X chromosome. Somatosensory-evoked potential and transcranial magnetic stimulation studies demonstrated that the central sensory and motor conduction times were abnormally prolonged for the lower extremity but normal for the upper extremity., Conclusions: This is the first report of the involvement of the central sensorimotor tracts for the legs in a patient with McLeod syndrome. The clinical neurophysiological technique revealed the central sensorimotor tracts involvements clinically masked by neuropathy.

Background: Transcranial magnetic stimulation (TMS) plays an important role in treatment of mental and neurological illnesses, and neurosurgery. However, it is difficult to target specific brain regions accurately because the complex anatomy of the brain substantially affects the shape and strength of the electric fields induced by the TMS coil. A volume conductor model can be used for determining the accurate electric fields; however, the construction of subject-specific anatomical head structures is time-consuming., Objective: The aim of this study is to propose a method to estimate electric fields induced by TMS from only T1 magnetic resonance (MR) images, without constructing a subject-specific anatomical model., Methods: Very large sets of electric fields in the brain of subject-specific anatomical models, which are constructed from T1 and T2 MR images, are computed by a volume conductor model. The relation between electric field distribution and T1 MR images is used for machine learning. Deep neural network (DNN) models are applied for the first time to electric field estimation., Results: By determining the relationships between the T1 MR images and electric fields by DNN models, the process of electric field estimation is markedly accelerated (to 0.03 s) due to the absence of a requirement for anatomical head structure reconstruction and volume conductor computation. Validation shows promising estimation accuracy, and rapid computations of the DNN model are apt for practical applications., Conclusion: The study showed that the DNN model can estimate the electric fields from only T1 MR images and requires low computation time, suggesting the possibility of using machine learning for real-time electric field estimation in navigated TMS., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) induces changes in cortical excitability for minutes to hours after the end of intervention. However, it has not been precisely determined to what extent cortical plasticity prevails spatially in the cortex. Recent studies have shown that rTMS induces changes in "interhemispheric" functional connectivity, the resting-state functional connectivity between the stimulated region and the symmetrically corresponding region in the contralateral hemisphere. In the present study, quadripulse stimulation (QPS) was applied to the index finger representation in the left primary motor cortex (M1), while the position of the stimulation coil was constantly monitored by an online navigator. After QPS application, resting-state functional magnetic resonance imaging was performed, and the interhemispheric functional connectivity was compared with that before QPS. A cluster of connectivity changes was observed in the stimulated region in the central sulcus. The cluster was spatially extended approximately 10 mm from the center [half width at half maximum (HWHM): approximately 3 mm] and was extended approximately 20 mm long in depth (HWHM: approximately 7 mm). A localizer scan of the index finger motion confirmed that the cluster of interhemispheric connectivity changes overlapped spatially with the activation related to the index finger motion. These results indicate that cortical plasticity in M1 induced by rTMS was relatively restricted in space and suggest that rTMS can reveal functional dissociation associated with adjacent small areas by inducing neural plasticity in restricted cortical regions., Competing Interests: The authors have declared that no competing interests exist.

After experiencing upper respiratory-tract symptoms, a 41-year-old woman developed encephalitis with consciousness disturbance and respiratory failure. She had external ophthalmoplegia and facial diplegia. Magnetic resonance imaging revealed a brainstem lesion with spared longitudinal pontine bundles. Abnormal findings of the brainstem auditory-evoked potentials and blink reflex supported brainstem damage. The patient was positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. Repeated immunological treatments improved her symptoms, but severe orthostatic hypotension emerged. A head-up tilt test revealed no arginine vasopressin response to hypotension. The atypical symptoms of this case highlighted that the brainstem is one of the pivotal regions in anti-NMDAR encephalitis.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: The masked-priming paradigm is used to test unconscious inhibitory processes of the brain. A tendency towards responses that are incompatible with the prime, designated as negative compatibility effect (NCE), emerges when the perception of a priming visual stimulus is "masked" afterwards. This effect presumably stems from a subliminal inhibitory process against the masked-prime. Prior lesions as well as activation studies suggest a key role of SMA in this effect., Objective: This study was conducted to elucidate a causal role of SMA in the subliminal response inhibition represented by the NCE., Methods: Using a repeated-measures pre-post design with a group of healthy people, physiological measures (resting and active motor thresholds and motor evoked potential (MEP) amplitude) and behavioral ones (choice reaction time (CRT), positive compatibility effect (PCE) and NCE) were obtained before and after three quadripulse stimulation (QPS), namely sham, M1-QPS, and SMA-QPS, on different days. CRT and PCE served as indices for different aspects of motor execution., Results: Motor thresholds were not altered after any QPS, although the M1-QPS increased MEP amplitude. Neither CRT nor PCE was altered significantly after QPS protocols. NCE was abolished after the SMA-QPS., Conclusions: Abolished NCE after the SMA-QPS in the absence of MEP changes suggests that (1) SMA plays a cardinal role in the NCE, and (2) the network involved in NCE is different from that of MEP generation., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To identify XK pathologic mutations in 6 patients with suspected McLeod syndrome (MLS) and a possible interaction between the chorea-acanthocytosis (ChAc)- and MLS-responsible proteins: chorein and XK protein., Methods: Erythrocyte membrane proteins from patients with suspected MLS and patients with ChAc, ChAc mutant carriers, and normal controls were analyzed by XK and chorein immunoblotting. We performed mutation analysis and XK immunoblotting to molecularly diagnose the patients with suspected MLS. Lysates of cultured cells were co-immunoprecipitated with anti-XK and anti-chorein antibodies., Results: All suspected MLS cases were molecularly diagnosed with MLS, and novel mutations were identified. The average onset age was 46.8 ± 8 years, which was older than that of the patients with ChAc. The immunoblot analysis revealed remarkably reduced chorein immunoreactivity in all patients with MLS. The immunoprecipitation analysis indicated a direct or indirect chorein-XK interaction., Conclusions: In this study, XK pathogenic mutations were identified in all 6 MLS cases, including novel mutations. Chorein immunoreactions were significantly reduced in MLS erythrocyte membranes. In addition, we demonstrated a possible interaction between the chorein and XK protein via molecular analysis. The reduction in chorein expression is similar to that between Kell antigens and XK protein, although the chorein-XK interaction is a possibly noncovalent binding unlike the covalent Kell-XK complex. Our results suggest that reduced chorein levels following lack of XK protein are possibly associated with molecular pathogenesis in MLS.

The purpose of the study involves measuring the threshold for electric currents (i.e., current perception threshold or CPT) under several stimulating current frequencies. Specifically, current perception threshold (CPT) was measured in 53 healthy volunteers between the ages of 21 and 67. The stimulation currents were applied on the right index finger with stimulus frequencies in the range of 50 Hz - 300 kHz. The method of limits and method of constant stimuli were combined to measure the CPT. In a manner consistent with the findings obtained by previous studies, the results indicated that CPT was higher in men than in women and in older individuals than in young subjects. Bioelectromagnetics. 9999:XX-XX, 2019. © 2019 Bioelectromagnetics Society., (© 2019 Bioelectromagnetics Society.)

A 68-year-old man visited our hospital emergency department with consciousness disturbance. He was diagnosed as bacterial meningitis with septic shock, and initial empirical antibacterial therapy was initiated immediately. Streptococcus pneumoniae. was cultured from the cerebrospinal fluid (CSF), and brain MRIs showed pyogenic ventriculitis. Even though CSF findings improved, he was still in coma and finally died with pneumonia. It is unknown how pyogenic ventriculitis affects the course of bacterial meningitis. We analyzed total 11 inpatients with bacterial meningitis associated with or without the pyogenic ventriculitis, including the present patient, in our hospital. Severity of clinical symptoms and CSF findings might determine the duration of antimicrobial administration, regardless of whether pyogenic ventriculitis existed or not.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30-0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions. SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI ("parcellation-based network analysis"), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions., (Copyright © 2019 the authors 0270-6474/19/392509-13$15.00/0.)

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 A 2A 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.

Clinicians are increasingly recognizing impulse control disorders (ICDs) as a complication of dopaminergic treatment in Parkinson's disease (PD). Considering the pivotal role of dopamine in reward information processing, ICDs may originate from dysregulation of reward-oriented behavior, and the behavioral changes may be reflected in shifts of psychological risk preference during decision-making. We used a behavioral economics paradigm to evaluate quantitatively the risk preferences of PD patients in levodopa on and off states. We also examined age-matched healthy controls. We found that levodopa increased the subjective value and prolonged the decision time in PD patients. These effects are apparently not explained by kinematic improvements but are attributed to psychological shifts of risk preferences and increased attention during risky decision-making. The risk preferences of healthy controls were similar to those of PD on levodopa treatment. The risk preferences of PD patients were not correlated with the scores of routine cognitive batteries, suggesting that dopamine-sensitive risk preferences are independent of cognitive capacities as measured by conventional batteries, including general intelligence, memory, and frontal functioning. By contrast, apathy and ICD partially predicted the risk attitude in PD patients, suggesting a common background of limbic origin behind these properties. The present results demonstrated that dopamine deficiency in off-state PD leads to risk-avoiding behavior and levodopa treatment increases the risk preferences. Behavioral economics framework is useful to evaluate short-term psychological changes in response to levodopa in PD patients.

Parkinson's disease (PD) patients experience various symptoms including extrapyramidal motor disturbances and cognitive impairments, which cause difficulties in daily life. However, PD patients have rarely been studied under realistic task situations that require high-level interaction of cognitive and motor skills. The aim of this study was to investigate the contribution of cognitive and motor factors to the performance of PD patients under high cognitive and kinematic loads. Twenty-six PD patients and 14 control subjects participated in the study. The PD patients performed a task involving hitting targets and avoiding distractors in levodopa On and Off states. A robotic manipulandum device recorded the numbers of target and distractor hits and hand kinematics, including movement area and speed. Performance on standard cognitive batteries and the Movement Disorder Society - Unified Parkinson's Disease Rating Scale motor scores were examined. The results indicated that the PD patients hit significantly fewer targets and more distractors than did the controls ( p < 0.05). In PD patients, the average hand speed was slower and the area of hand movement was smaller than those of the control subjects ( p < 0.001). Levodopa significantly increased the average hand speed and movement area ( p < 0.01), but levodopa had an insignificant effect on the number of correct targets hit and erroneous distractor hits. The scores of cognitive batteries predicted the performance with regard to both targets hit and distractor avoidance. Our results were indicative of a dynamic interaction between cognitive and kinematic skills while the PD patients performed a virtual reality game. Single-dose levodopa enhanced kinematic capacity, and the global intelligence level predicted game performance.

We report a 77-year-old man who suffered from Parkinson's disease for 12 years. Four years after the disease onset, he started to show excessive hobbyism of painting. His painting skills improved along with escalating enthusiasm. He even held a personal exhibition of his paintings. Dopaminergic treatment was increased as he developed wearing-off phenomenon. Six years after the disease onset, he developed dopamine dysregulation syndrome (DDS). In the same year, he underwent surgery for subthalamic deep brain stimulation. DDS did not improve and he did not lose enthusiasm for painting after surgery. Switching from ropinirole to rotigotine improved the DDS, but did not affect the excessive enthusiasm. At the age of 76, he started to have difficulty in completing the paintings. He had an uncontrollable urge to overlay paint strokes until the colors blurred and the paper was torn. In neuropsychological examinations, Mini-Mental State Examination score was above the cutoff, but Frontal Assessment Battery suggested motor perseveration and disinhibition. In summary, the patient's excessive enthusiasm for painting emerged in association with impulse control disorder (ICD) by dopamine agonist therapy, and subsequent change in his painting style appeared to be related with motor perseveration and/or further escalation of ICD.

A 33-year-old woman developed progressive weakness in the proximal limbs with myalgia and morning stiffness. Physical examination revealed low-grade fever, heliotrope eyelids and mechanic's hand. On neurological examination, she showed Medical Research Council grade 4 weakness in the shoulder girdle, proximal limb muscles, and grade 4 weakness in the abdominis muscle according to Daniels's scale. Laboratory tests revealed elevated serum creatine kinase (6,824 IU/l) and positive anti-PL-7 antibody. A needle electromyography study detected short motor unit potentials of myogenic pattern with abundant fibrillations and positive sharp waves. Whole-body MRI detected high intensity signals in the muscles of the shoulder girdle, proximal limbs, and thoracoabdominal trunk on short-tau inversion recovery sequence images. We diagnosed her as anti-PL-7 myopathy. After treatments with steroid, immunosuppressant, and immunoglobulin, her symptoms improved and abnormal MRI signals were normalized. Although MRI is known to be useful for detection of asymptomatic muscular inflammation in myositis, thoracoabdominal muscles are generally not covered in routine evaluation. To our knowledge, ours is the first case to detect acute inflammation of the thoracoabdominal muscles in antisynthetase syndrome. The present study suggests that whole-body MRI is useful for comprehensive evaluation of muscular involvement and longitudinal assessment for treatment outcomes.

In recent years, human exposure to electromagnetic fields (EMF) at intermediate frequencies (300 Hz-10 MHz) has risen, mainly due to the growth of technologies using these fields. The current safety guidelines/standards defined by international bodies (e.g. ICNIRP and IEEE) established basic restrictions for limiting EMF exposure. These limits at intermediate frequencies are derived from threshold values of the internal electric field that may produce transient effects, such as the stimulation of the nervous system. However, there are some discrepancies between the basic restrictions of those guidelines/standards. The aim of this study is to investigate the excitation thresholds of the nervous system exposed to intermediate-frequency electromagnetic fields, with the purpose of extrapolating the threshold-frequency curves which are compared with existing basic restrictions prescribed by the international guidelines/standards. Our investigation was based on transcranial magnetic stimulation (TMS) experiments, physiological measurements, and individualized MRI-based computer simulations for the determination of brain stimulation thresholds. The combined approach with established biological axon models enabled the extrapolation of the measured thresholds for sinusoidally varying electric fields. The findings reveal that the exposure limits are significantly conservative for the brain, especially at frequencies in the range of 300 Hz-5 kHz.

Observing mouth movements has strikingly effects on the perception of speech. Any mismatch between sound and mouth movements will result in listeners perceiving illusory consonants (McGurk effect), whereas matching mouth movements assist with the correct recognition of speech sounds. Recent neuroimaging studies have yielded evidence that the motor areas are involved in speech processing, yet their contributions to multisensory illusion remain unclear. Using functional magnetic resonance imaging (fMRI) and transcranial magnetic stimulation (TMS) in an event-related design, we aimed to identify the functional roles of the motor network in the occurrence of multisensory illusion in female and male brains. fMRI showed bilateral activation of the inferior frontal gyrus (IFG) in audiovisually incongruent trials. Activity in the left IFG was negatively correlated with occurrence of the McGurk effect. The effective connectivity between the left IFG and the bilateral precentral gyri was stronger in incongruent than in congruent trials. The McGurk effect was reduced in incongruent trials by applying single-pulse TMS to motor cortex (M1) lip areas, indicating that TMS facilitates the left IFG-precentral motor network to reduce the McGurk effect. TMS of the M1 lip areas was effective in reducing the McGurk effect within the specific temporal range from 100 ms before to 200 ms after the auditory onset, and TMS of the M1 foot area did not influence the McGurk effect, suggesting topographical specificity. These results provide direct evidence that the motor network makes specific temporal and topographical contributions to the processing of multisensory integration of speech to avoid illusion. SIGNIFICANCE STATEMENT The human motor network, including the inferior frontal gyrus and primary motor cortex lip area, appears to be involved in speech perception, but the functional contribution to the McGurk effect is unknown. Functional magnetic resonance imaging revealed that activity in these areas of the motor network increased when the audiovisual stimuli were incongruent, and that the increased activity was negatively correlated with perception of the McGurk effect. Furthermore, applying transcranial magnetic stimulation to the motor areas reduced the McGurk effect. These two observations provide evidence that the motor network contributes to the avoidance of multisensory illusory perception., (Copyright © 2018 the authors 0270-6474/18/389679-10$15.00/0.)

Background: Paired associative stimulation (PAS) induces long-term potentiation (LTP)-like effects when interstimulus intervals (ISIs) between electrical peripheral nerve stimulation and transcranial magnetic stimulation (TMS) to M1 are approximately 21-25 ms (PAS LTP ). It was previously reported that two forms of motor learning (i.e., mode-free and model-based learning) can be differentially modulated by PAS LTP depending on the different synaptic inputs to corticospinal neurons (CSNs), which relate to posterior-to-anterior (PA) or anterior-to-posterior (AP) currents induced by TMS (PA or AP inputs, respectively). However, the effects of long-term depression (LTD)-inducing PAS with an ISI of approximately 10 ms (PAS LTD ) on motor learning and its dependency on current direction have not yet been tested., Objective: To investigate whether, and how, PAS LTD affects distinct types of motor learning., Methods: Eighteen healthy volunteers participated. We adopted the standard PAS using suprathreshold TMS with the target muscle relaxed, as well as subthreshold PAS during voluntary contraction, which was suggested to selectively recruit PA or AP inputs depending on the orientation of the TMS coil. We examined the effects of suprathreshold and subthreshold PAS LTD on the performance of model-free and model-based learning, as well as the corticospinal excitability, indexed as the amplitudes of motor evoked potentials (MEPs)., Results: PAS LTD inhibited model-free learning and MEPs only when subthreshold AP currents were applied. The PAS LTD protocols tested here showed no effects on model-based learning., Conclusions: PAS LTD affected model-free learning, presumably by modulating CSN excitability changes, rather than PA inputs, which are thought to be related to model-free learning., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Deep brain stimulation (DBS) can provide insights into the workings of the basal ganglia (BG) by interfering with their function. In patients with Parkinson's disease (PD) treated with DBS of the subthalamic nucleus, we studied the effect of DBS on scanning eye movements., Methods: In the visual memory task, subjects viewed images of various complexities for later recall. In visual search tasks, subjects looked for and fixated one odd target ring, embedded among 48 Landolt rings, which either stood out or not from the distractors. We compared the parameters of scanning saccades when DBS was on and off., Results: In the visual memory task, DBS increased the amplitude of saccades scanning simple but not complex drawings. In the visual search tasks, DBS showed no effect on saccade amplitude or frequency., Conclusions: Saccades when viewing simple images were affected by DBS since they are internally guided saccades, for which the involvement of BG is large. In contrast, saccades when viewing complex images or during visual search, made with the help of visual cues in the images (externally guided saccades) and less dependent on BG, were resistant to the effect of DBS., Significance: DBS affects saccades differentially depending on the task., (Copyright © 2018. Published by Elsevier B.V.)

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [ 123 I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

The rhythm of the internal clock is considered to be determined by the basal ganglia, with some studies suggesting slower internal clock in Parkinson's disease (PD). However, patients may also show motor hastening when they walk (festination) or are engaged in repetitive tapping, indicating faster ticking of the internal clock. Is the internal clock slower or faster in PD? The purpose of this study was to answer this question, i.e., how fast and slow a rhythm they can synchronize with, especially with reference to the limit of sensorimotor synchronization or temporal integration, representing the threshold of slower pace they can entrain into their motor actions, which is known to lie between 2 and 3 s in normal subjects but not yet studied in PD. We employed a synchronized tapping task that required subjects to tap the key in synchrony with repetitive tones at fixed interstimulus intervals (ISI) between 200 and 4800 ms. Twenty normal subjects and sixteen PD patients were enrolled, who were classified into early and advanced PD groups by UPDRS-III (early: 15 or less, advanced: more than 15). The ISI at which the response changes from synchronizing with the tones to lagging behind them was considered to be the limit of temporal integration. Early PD patients responded ahead of the tones (negative asynchrony), which became more apparent with repeated tapping. This suggested "faster" ticking clock even in the presence of the pacing tones. In normal subjects, the limit of temporal integration was around 2-3 s: below this, subjects could synchronize with the tones, while above it they had difficulty in synchronization. In early PD patients, the limit of temporal integration was significantly longer than in normal subjects, pointing to their enhanced ability to synchronize also with slower paces of tones, but advanced PD patients had significantly shortened limits, suggesting that advanced patients lost this ability. In conclusion, the limit of temporal integration is initially longer but gets shorter as the disease progresses. It can be explained by the hastening of the internal clock at the earlier stages of PD, followed by the loss of temporal integration.

Background: Transcranial magnetic stimulation (TMS) activates target brain structures in a non-invasive manner. The optimal orientation of the TMS coil for the motor cortex is well known and can be estimated using motor evoked potentials. However, there are no easily measurable responses for activation of other cortical areas and the optimal orientation for these areas is currently unknown., Objective: This study investigated the electric field strength, optimal coil orientation, and relative locations to optimally stimulate the target cortex based on computed electric field distributions., Methods: A total of 518,616 stimulation scenarios were studied using realistic head models (2401 coil locations × 12 coil angles × 18 head models). Inter-subject registration methods were used to generate an atlas of optimized TMS coil orientations on locations on the standard brain., Results: We found that the maximum electric field strength is greater in primary somatosensory cortex and primary motor cortex than in other cortical areas. Additionally, a universal optimal coil orientation applicable to most subjects is more feasible at the primary somatosensory cortex and primary motor cortex. We confirmed that optimal coil angle follows the anatomical shape of the hand motor area to realize personalized optimization of TMS. Finally, on average, the optimal coil positions for TMS on the scalp deviated 5.5 mm from the scalp points with minimum cortex-scalp distance. This deviation was minimal at the premotor cortex and primary motor cortex., Conclusion: Personalized optimal coil orientation is preferable for obtaining the most effective stimulation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: To investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS)., Methods: A total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset-to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale-Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model., Results: Compared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p ≥8 μV (0.82 years) than in those with N20p-P25p <8 μV (1.68 years, p = 0.0002, log-rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival ( p = 0.002)., Conclusion: Sensory cortex hyperexcitability predicts short survival in patients with ALS., (© 2018 American Academy of Neurology.)

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.

Electro-oculogram (EOG) has been widely used for clinical eye movement recording, especially horizontal saccades, although the video-oculography (VOG) has largely taken the place of it nowadays due to its higher spatial accuracy. However, there are situations in which EOG has clear advantages over VOG, e.g., subjects with narrow eye clefts or having cataract lenses, and patients with movement disorders. The present article shows that if properly implemented, EOG can achieve an accuracy almost as good as VOG with substantial stability for recording, while circumventing problems associated with VOG recording. The present paper describes a practical method for recording horizontal saccades using oculomotor paradigms with high accuracy and stability by EOG in neurological patients. The necessary measures are to use an Ag-AgCl electrode with a wide plastic fringe capable of reducing noise, and to wait for sufficient light adaptation to occur. This waiting period also helps to lower the impedance between the electrodes and the skin, thereby ensuring stable signal recorded as time goes by. Furthermore, re-calibration is performed as needed during the task performance. Using this method, the experimenter can avoid drifts of signals, as well as contamination of artifacts or noise from the electromyogram and electroencephalogram, and can collect sufficient data for clinical evaluation of saccades. Thus when implemented, EOG can still be a method of high practicability that can be widely applied to neurological patients, but may be effective also for studies in normal subjects.