Deep brain simulation (DBS) is a widely accepted surgical therapy for Parkinson's disease, dystonia and tremor in Japan. In other countries, DBS has been applied to neuropsychiatric or neurodegenerative diseases, such as Tourette syndrome, depression, obsessive compulsive disorder, Alzheimer disease, etc. So far, these diseases have been treated mainly by neurologists or psychiatrists, however after the invention of DBS, neurosurgeons now play an important role in the treatment of these diseases, especially in Parkinson's disease. Several reports showed that better postoperative outcomes can be obtained when patient is managed by a neurologist who is responsible for stimulation programming and drug adjustments. The therapy should be done while adjusting both the drugs and the stimulation (DBS) simultaneously. Hence, neurologists should be familiar with programming of DBS, as well as the medical therapy.

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Cerebral microbleeds (CMBs) on gradient-echo T₂^* weighted MRI, which are characterized histologically by the presence of hemosiderin around small vessels, are now accepted as a manifestation of cerebral small vessel disease (SVD) pathologies, including hypertensive small vessel disease and cerebral amyloid angiopathy (CAA). CMBs are often detected in patients with stroke, Alzheimer's disease, and mild cognitive impairment. The pathological differences in MBs according to distribution is now well known, with MBs in deep regions considered to be associated with hypertensive arteriopathy, whereas strictly lobar MBs share risk factors with CAA.
Evidence suggests that CMBs should not be considered to be clinically "silent". When CMBs are detected in healthy adults, physicians should recognize that subclinical SVD might have begun in their brain. Chronic hypertension can affect HA-related CMBs, as well as CAA-related CMBs. Furthermore, both types of CMBs are risk factor for intracranial hemorrhage under the antithrombotic drug use. Thus, CMBs should be considered as "warning sign" for inappropriate blood pressure control and antithrombotic drug use.
It seems clear that CMBs should be an important component of future studies to investigate how SVD influence neurodegeneration via neurovascular units in elderly populations.

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Intracerebral hemorrhage (ICH) is a common stroke subtype in Japan. Hypertension is the leading cause. Perindopril Protection Against Recurrent Stroke Study (PROGRESS) revealed that blood pressure (BP) lowering could reduce stroke recurrence by 28% (ICH recurrence by 49%). The guideline for the management of hypertension (JSH2009) recommends BP control of ≤140/90mmHg for patients with prior stroke. BP is frequently elevated in acute ICH, although BP management strategy is controversial. The guideline from the American Stroke Association suggests if systolic BP (SBP) >180mmHg and there is no evidence of elevated intracranial pressure, then consider a modest reduction of BP. A nationwide survey revealed that SBP lowering to ≤160mmHg using intravenous nicardipine in acute ICH is a major strategy in Japan, and the safety was confirmed by a multicenter, prospective, observational study. Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT) and Antihypertensive Treatment of Acute Cerebral Hemorrhage (ATACH) showed the feasibility and safety of early rapid BP lowering to 140mmHg. INTERACT2 and ATACH II are the randomized trials to compare the guideline-based control (<180mmHg) and strict control (<140mmHg). We have just started to enroll patients to ATACH II from Japan on February 2012.

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Novel anticoagulants including dabigatran and rivaroxaban have lower incidence of intracranial hemorrhage compared to warfarin. Therefore, in patients with high risks for intracranial hemorrhage, such as past history of brain infarction, brain hemorrhage, microbleeds on MRI, or concomitant use of antiplatelet, novel anticoagulant may be appropriate. Irrespective of any anticoagulants, it is essential to manage controllable risk factors, such as hypertension, diabetes mellitus, smoking habit, and excessive alcohol drinking. Combination therapy of other antithrombotic agents had better be avoided as long as possible. In emergency of hemorrhage complications, discontinuation of anticoagulants, procedure to stop bleeding, and appropriate intravenous infusion is quite important and lowering blood pressure is also important when intracranial hemorrhage happens. There is no antidote to novel anticoagulants. However, oral activated charcoal may be effective if early after taking medicine. The dabigatran can be dialysed. Some experimental evidences support the role of prothrombin complex concentrate to stop bleeding. However, their usefulness in clinical setting has not been established. Collecting and analyzing data regarding immediate reversal of novel anticoagulants is required in near future.

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All neurologists should know stroke sufficiently since stroke is the leading cause of death or disability, and is the largest number of neurological disease. However, there are number of department of neurology, where neurologists are not interested in stroke. Stroke patients should be managed by neurologists, and neurologists should be certified to have ability to see stroke patients. Neurologists in universities should teach not only symptomatology of stroke but also epidemiology, etiology, pathophysiology, diagnosis, management, and prevention of stroke systematically. Residents in departments of neurology should try to pass specialty board examinations of both neurology and stroke societies. Educational hospitals for neurology are preferred also to be for stroke. In order to train stroke neurologists, societies of neurology and stroke should cooperate overwhelming the barrier. For the reference of these problems, I sent some questionnaires to top leaders of stroke neurology in US and Europe, and received the answers, which were introduced in this symposium.

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There is a significant difference in the number of stroke neurologist between the prefectures in Japan. The fact suggests that some departments of neurology have been not so positive for the training stroke neurologist. Stroke is one of the most common diseases in Japan. The people are eager to be cared by the physicians who are specialized for stroke prevention and treatment. To respond to the social needs, neurologists and neurosurgeons should join to make a stroke team to study each other and to bring along the stroke neurologists.

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Neurologists play a central role in management of stroke patients. However, in Japan, the number of neurologists who are interested in stroke management is not sufficient. In this paper, to raise stroke-conscious neurologists, i.e., neurologists who willingly take care of stroke patients, the roles of undergraduate medical education and postgraduate neurological training are discussed. The key points in neurological education are that stroke provides the best source of brain diseases, symtomatology, and neuroimaging, the best material for understanding of evidence-based medicine, and the model of comprehensive continuous practice from neurological emergency to neurorehabilitation.

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I discussed on requisites for the reader of stroke team.
Acute stroke management in a stroke unit (SU) can reduce the mortality and morbidity, and improve the long-term ADL and quality of life (QOL). The SU is a ward specializing in stroke where multidisciplinary stroke team performs intensive medical treatment and early rehabilitation. It is generally recommended that a manager or head in a hospital department should meet several requirements including achievements of theses, a license for his/her medical specialty, activities in scientific societies, etc. In addition, the most important for the leader of a stroke team is the ability to teach young stroke neurologists and other stroke team members with enthusiasm, confidence, politeness, and a tender heart. The theory of the group dynamics indicates that only a powerful reader can educate powerful followers, and vice versa.

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A stroke is an emergency disease and a battle against time. Therefore we do not have long time to evaluate neurological evaluation. Neurologic evaluation is the most important process for the diagnosis of stroke patients. When we see stroke patients, we assess neurological findings and suspect the responsible brain lesions and artery before neuroimaging studies. This process is very important for not only stroke specialists, but also neurologists and NIHSS score is widely used as stroke score for neurological severity. Specially, when stroke patient is treated with t-PA, NIHSS score is used as inclusion or exclusion criteria for t-PA therapy.
Examinations that stroke physician should acquire are neurosonography such as TCD, TCCS, carotid echo, and echocardiography, MRI and CT as neuroimaging, and cerebral angiography, and perfusion MRI, SPECT and PET as brain perfusion. In particular, the diagnosis of brain MRI and CT is essential, and cerebral angiography and ultrasound is important for the physician. SPECT, PET, and the perfusion MRI can evaluate the brain perfusion.
IV-t-PA therapy and endovascular therapy are very important for stroke patients. Therefore, skills related to IV-t-PA therapy and endovascular therapy are necessary for acute stroke treatment. A neurologist treating stroke patients must acquire the above skills.

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In the beginning of this century, a dramatic increase of age-related serious neurological disorders including stroke and vascular dementia is expected in concomitant with continuous increase of older-age population. In order to harmonize several strategies to combat these neurological disorders in a reasonable way, it is critically important to promote lifetime education of stroke medicine for neurologist who has main responsibility to treat stroke patients. In the present presentation, to meet the changing medical needs of our population, I attempted to summarize recent progress of stroke neurology concerning acute stroke management, neurorehabilitation and prevention of stroke recurrence and focused on the importance of understanding evidence-based-medicine for stroke management. The crucial role of several guidelines to renew and standerdize essential knowledge of stroke management was addressed to promote stroke team approach including neurologist, neurosurgeon, stroke nurse and rehabilitation staffs.

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Alzheimer's disease (AD) is the most common form of age-related dementia, characterized by progressive memory loss and cognitive disturbance. According to the amyloid cascade hypothesis, a prevailing theory of AD pathology, accumulation of toxic Aβ42, in the brain is the initiator of AD pathogenesis, subsequently leading to the formation of neurofibrillary tangles, and consequently neuronal loss. Mutations of presenilin 1 (PS1) and presenilin 2 (PS2), which are catalytic components of γ-secretase, are causative factors for autosomal dominant early-onset familial AD (FAD). Induced pluripotent stem cell (iPSC) technology provides a new method for elucidating the molecular basis of human diseases, including neurodegenerative diseases. Here we generate iPSCs from fibroblasts of FAD patients with mutations in PS1 (A246E) and PS2 (N141I), and characterize the differentiation of these cells into neurons. We find that FAD-iPSC-derived differentiated neurons have increased toxic Aβ42 secretion, recapitulating the molecular pathogenesis of mutant presenilins. Furthermore, secretion of Aβ42 from these neurons sharply responds to γ secretase inhibitors and modulators, indicating the potential for identification and validation of candidate drugs. Our findings demonstrate that the FAD-iPSC-derived neuron is a valid model of AD and provides an innovative strategy for the study of late-onset neurodegenerative diseases.

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Disease modeling of ALS using patient-specific iPS cells provides several insight into ALS pathogensis^1)～3). Solutions, including rapid differentiation from iPS cells to motor neurons⁴⁾, to technical hurdle of iPS cell technology⁵⁾ will advance the field of disease modeling of ALS.

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Human artificial chromosomes (HACs) are stable episomal gene vectors that can carry large gene inserts. We have reported complete correction of a genetic deficiency following the transfer of a HAC carrying the genomic dystrophin sequence (DYS-HAC) into induced pluripotent stem (iPS) cells derived from either a Duchenne muscular dystrophy (DMD) model mouse or a human DMD patient. The engineered iPS cells could differentiate in immunodeficient nude mice, and human dystrophin expression was detected in muscle-like tissues. Furthermore, chimeric mice generated from the engineered cells showed tissue-specific expression of dystrophin.
Recently, Giulio's group has isolated and characterized a population of blood vessel-associated stem cells, called mesoangioblasts, that can differentiate into multiple mesoderm cell types, including skeletal muscle. The DYS-HAC was transferred to mesoangioblasts from the DMD-model mouse. Thus, when delivered in the arterial circulation, mesoangioblasts crossed the blood vessel wall and participated in skeletal muscle regeneration, ameliorating signs of muscular dystrophy in the DMD model mice. Most recently, the iPS cells from a DMD patient corrected with the DYS-HAC, were successfully differentiated to mesoangioblasts.
Therefore, autologous transfer of genetically corrected iPS cells and muscle progenitor cells will be desirable therapeutic cells because immune suppression would not be required.

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Stroke is a major neurologic disorder. Induced pluripotent stem (iPS) cells can be produced from basically any part of patients, with high reproduction ability and pluripotency to differentiate into various types of cells, suggesting that iPS cells can provide a hopeful therapy for cell transplantation. However, transplantation of iPS cells into ischemic brain has not been reported. In this study, we showed that the iPS cells fate in a mouse model of transient middle cerebral artery occlusion (MCAO). Undifferentiated iPS cells (5×10(5)) were transplanted into ipsilateral striatum and cortex at 24 h after 30 mins of transient MCAO. Behavioral and histologic analyses were performed at 28 day after the cell transplantation. To our surprise, the transplanted iPS cells expanded and formed much larger tumors in mice postischemic brain than in sham-operated brain. The clinical recovery of the MCAO+iPS group was delayed as compared with the MCAO+PBS (phosphate-buffered saline) group. iPS cells formed tridermal teratoma, but could supply a great number of Dcx-positive neuroblasts and a few mature neurons in the ischemic lesion. iPS cells have a promising potential to provide neural cells after ischemic brain injury, if tumorigenesis is properly controlled.

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Anti-signal recognition particle (SRP) antibody, detected in 5-8% of patients with clinical diagnosis of myositis, had been associated with severe and refractory myositis. However, it has been accepted that anti-SRP myopathy should be separated from myositis based on histological features of necrotizing myopathy. We reviewed clinical features of 27 patients with anti-SRP myopathy, and analyzed disease progression and neurological outcome. Anti-SRP antibodies in serum were detected by RNA immunoprecipitation assay using extracts of K562 cells. Of the 27 patients, 5 (18.5%) showed chronic progressive muscle weakness as well as atrophy of limbs and trunk muscles from a younger age with more severe neurological outcomes compared to the other 22 patients with the subacute form. A subset of patients with anti-SRP myopathy can show a chronic progressive form associated with severe clinical deficits.

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The term "myofibrillar myopathies (MFM)" was proposed in 1996 to a group of myopathies that have common pathological changes. The muscle biopsy shows cytoplasmic hyaline inclusions with various sizes and shapes, best observed in trichrome-stained sections. Immunohistochemical study shows deposits of desmin and some sets of myofibrillar and non-myofibirllar proteins in or around these inclusions. The electron microscopy displays unique dappled and electron-dense structures.
MFM mutations have been identified in genes encoding desmin, αB-crystallin, myotilin, ZASP, filamin C, Bag3 and FHL1. They are proteins present in the Z-disk, which correlates the findings suggesting that disruption the Z-disk occurs first, followed by accumulation of degenerative products of myofibrils. Some of the gene products are essential for maintaining the structural integrity of myofibrils against mechanical stress, and others function as a molecular chaperone or a co-chaperone. In the latter cases, apoptotic or pre-apoptotic myonuclear changes are frequently found. The gene abnormalities await to be determined in more than a half of MFM patients.
Although clinical features are variable in MFM as a whole, they show some homogeneity in mutations of the same molecule. We must note that MFM patients are often associated with cardiac conduction defects, cardiomyopathy and respiratory insufficiency.

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Facioscapulohumeral muscular dystrophy (FSHD) is a common autosomal dominant muscular dystrophy caused by truncation of D4Z4 repeat array on chromosome 4q35. Facial and shoulder-girdle muscles are preferentially affected but clinical symptoms are quite variable even within the same family. Asymmetrical muscle involvement is also characteristic in this disease. There are no disease specific changes on muscle pathology, and genetic diagnosis is performed by the southern blotting analysis.
Recent advances provide us several ideas on possible pathomechanisms of this complicated disease. There are several genes on chromosome 4q35 region including DUX4 within D4Z4 repeats. Transcription of these genes is usually repressed by epigenetic modifications of this chromosomal region and also accumulation of transcriptional repressors to the repeat array. Shortening of the D4Z4 repeats observed in FSHD can cause structural changes of this chromosomal region, reduced recruitment of repressors, and expression of noncoding RNA which can enhance transcription of the genes on chromosome 4q35 region. Actually, increased mRNA expression levels of 4q35 genes was reported in FSHD cells, together with their undesirable roles on muscles by overexpression models. Further analysis is required to elucidate the precise pathomechanisms of FSHD.

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Congenital myasthenic syndromes (CMS) are caused by germline mutations of molecules expressed at the neuromuscular junction (NMJ). Mutations in 11 molecules encoded by 15 genes have been reported in association with CMS. CMS can be classified into four clinical categories. First, missense mutations in the acetylcholine receptor (AChR) subunits lead to slow- and fast-channel syndromes. Second, mutations in the AChR subunits, rapsyn, agrin, MuSK, Dok-7, plectirn, and GFPT1 lead to endplate AChR deficiency. Third, collagen Q (ColQ) anchors acetylcholinesterase (AChE) to the synaptic basal lamina and mutations in COLQ lead to endplate AChE deficiency. By exploiting the synaptic basal lamina-targeting signal of ColQ, we recently reported that the exogenously administered AChE/ColQ complex can be specifically localized to the NMJ. The protein-anchoring therapy can be potentially applicable to a wide spectrum of defective extracellular matrix molecules. Fourth, CMS associated with episodic apnea is caused by mutations in choline acetyltransferase (ChAT) and skeletal muscle voltage-gated sodium channel (Na_V1.4). In the past two years, we diagnosed 15 cases with CMS in Japan, and identified mutations in 12 patients. All the mutations except for one are unique to Japanese patients. We assume that more CMS cases still remain undiagnosed in Japan.

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Aggregation and accumulation of amyloid-β peptide (Aβ) in the brain are triggering events leading to the pathological cascade of Alzheimer's disease (AD). Aβ accumulates in AD brains and forms amyloid plaques, which consist mostly of amino-terminally truncated and/or modified Aβs, among which Aβ3pyroglutamate (Aβ3pE) is a major product. Thus, the N-terminal structures of accumulated species of Aβ are different from those secreted from neurons. Aβ3pE-42 is more hydrophobic, more easily self-aggregated (250-fold), and is more resistant to proteolytic degradation (4-fold) than Aβ1-42. Therefore, Aβ3pE appears to act as a seed for the formation of oligomers and amyloid plaques. Aβ is physiologically degraded via the neprilysin-mediated pathway in the brain. However, if neprilysin activity is low, a compensatory metabolic pathway is up-regulated, in which exopeptidases, such as aminopeptidase or dipeptidyl peptidase, and glutaminyl cyclase (QC) may be involved, generating Aβ3pE. It is reported that QC is up-regulated with AD development. Recent study revealed that administration of synthetic QC inhibitor reduced total amyloid burden in the brains of APP transgenic mice (Tg2576) via inhibition of Aβ3pE production and also alleviated impaired cognitive function. Thus, inhibition of Aβ3pE formation appears to be a novel target for therapy and prevention of AD.

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Genetic and biological studies provide strong evidence that the deposition of amyloid-β peptide (Aβ) contributes to the etiology of Alzheimer's disease (AD). Thus, drugs that regulate the brain Aβ levels could provide effective disease-modifying therapy for AD. Aβ is generated from amyloid-β precursor protein (APP) by β- and γ-secretases. Several γ-secretase inhibitors have been developed as AD therapeutics. However, simple inhibition of γ-secretase would have adverse consequences, as γ-secretase is involved in several signaling pathways including Notch signaling. In 2010, the development of semagacestat, a γ-secretase inhibitor, was halted. Preliminary results from Phase III studies showed that semagacestat failed to slow disease progression, and it was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living. Furthermore, semagacestat treatment was associated with an increased risk of skin cancer. Thus, alternative compounds that indirectly modulate γ-secretase activity without affecting Notch are attracting attention. However, molecular mechanism of these compounds still remains unclear. To develop therapeutics with superior specificity and high potency for AD, we have been analyzing the mode of actions of known compounds, structure-and-function relationship of the γ-secretase complex and possible rational design of γ-secretase inhibitors and modulators using chemical biology.

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Based on the amyloid cascade hypothesis, immunotherapy targeting amyloid β (Aβ) for Alzheimer's disease (AD) has been developed. It was reported that active immunization using Aβ peptide attenuates amyloid deposits and memory impairment in AD model mice. However, active immunization of patients with AD (AN-1792) was halted due to adverse effects in which a subset of patients developed meningoencephalitis. In order to avoid autoimmune encephalitis, passive immunotherapy using humanized monoclonal antibodies with specificity to Aβ are in clinical trials. We also developed an anti-Aβ monoclonal antibody 3.4A10, which react with AD brain-specific Aβ oligomers. On the other hand, some studies showed that immunotherapy approach targeting tau could attenuate pathology in AD model mouse. Here we introduce a current trend of immunotherapy for AD.

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To elucidate involvement of tau protein in neurodegenerative processes in Alzheimer disease and related disorders, self-assembly process and degradative process of tau protein were examined. To understand the mechanisms of the aggregation, binding affinity of tau protein to 14-3-3 protein, which converts tau to a filamentous or aggregated form. was investigated employing a surface plasmon resonance assay. Phosphorylation of tau by protein kinase A increased affinity of tau to 14-3-3, whereas the phosphorylation attenuated formation of filaments or aggregates. FTDP-17 mutation increased affinity of unphosphorlated tau to 14-3-3, compared to wild typed unphosphorylated tau. However the phosphorylation increased its affinity further to the similar level of the affinity of phosphorylated wild typed tau. Similarly the phosphorylation also attenuated formation of filaments or aggreeagates from FTDP-17 mutated tau. To understand the mechanisms of the intracellular accumulation, possible involvement of proteases were studied. Among several proteases, puromycin-sensitive aminopeptidase (PSA) was found as a predominant regulator of degradation of tau protein. In addition FTDP-17 mutation increased phosphorylation of tau proten in cells, and attenuated intracellular degradation of tau protein. These results suggest that self-assembly and accumulation of tau protein are regulated by phosphorylation, and FTDP-17 mutation affects those complexed processes.

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Recent studies of functional neuroimaging and clinical neurophysiology have implied that functional recovery after stroke is associated with use-dependent plasticity of the damaged brain. However the property of the reorganized neural network depends on site and size of the lesion, which makes it difficult to assess what the adaptive plasticity is. From clinical point of view there is accumulating randomized controlled trials for the benefit of task-oriented rehabilitative intervention including constraint-induced movement therapy, robotics, and body-weight supported treadmill training. However dose-matched control intervention is usually as effective as a specific intervention. This raises a question regarding the specificity of a task-oriented intervention. Second question is whether such intervention goes beyond the biological destiny of human. Specifically there is no known strategy enhancing recovery of severely impaired hand. To augment functional gain, several methods of neuro-modulation may bring break-through on the assumption that they induce greater adaptive plasticity. Such neuro-modulative methods include neuropharmacological modulation, brain stimulation using transcranial magnetic stimulation and direct current stimulation, peripheral nerve stimulation, neurofeedback using real-time fMRI and real-time fNIRS, and brain-machine interface. A preliminary randomized controlled trial regarding real-time feedback of premotor activities revealed promising results for recovery of paretic hand in patients with stroke.

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Because recovery of upper extremity (UE) function to a practical level has been difficult in many stroke patients, compensatory approaches have been emphasized. Based on researches indicating greater potential for brain plasticity, newer approaches targeting at functional restoration have been attempted. However, no intervention has been shown to be effective to improve hand function.
We therefore devised a therapeutic approach to facilitate the use of the hemiparetic hand in daily life by combining EMG triggered electrical stimulation with a wrist splint, called hybrid assistive neuromuscular dynamic stimulation (HANDS). With HANDS, we demonstrated improved motor function, spasticity, functional scores and neurophysiological parameters in chronic stroke. With a RCT, we also demonstrated its effectiveness in subacute stroke.
However, to be its candidates, electromyogram must be recorded from finger extensors, and it cannot be applied to patients with complete paralysis. For them, we recently developed a Brain Machine Interface (BMI) neurorehabilitation system. Based on analysis of volitionally decreased amplitudes of sensory motor rhythm during motor imagery involving extending the affected fingers, real-time visual feedback is provided. In patients with severe hemiparesis, we demonstrated its effectiveness with clinical scales, neuroimaging and electrophysiological studies. These newer interventions might offer useful neurorehabilitative tools for hemiparetic UE.

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The use of electrical motor cortex stimulation (EMCS) for post-stroke pain was established in Japan and has spread globally. EMCS has been used for the treatment of neuropathic pain, Parkinson's syndrome, and recovery of motor paresis. Since 2000, repetitive transcranial magnetic stimulation (rTMS) has been developed for the treatment of various neurological disorders. rTMS is a non-invasive method with almost no adverse effects. In the USA, rTMS of the left dorsolateral prefrontal cortex was approved for the treatment of major depression in 2008. rTMS of the primary motor cortex (M1) has been studied worldwide for the treatment of neuropathic pain, Parkinson's disease, motor paresis after stroke, and other neurological problems. For neuropathic pain, high-frequency rTMS of M1 is safe and significantly effective for consecutive 14 days. After cessation of rTMS, pain gradually returned within two weeks. For 'Kaifukuki' rehabilitation, high-frequency rTMS of affected M1 seemed to be effective for recovery of hand function. And even after cessation of rTMS, the recovery would be better than usual rehabilitation for two weeks. New methods and devices for rTMS therapy are under development, and rTMS of the M1 is likely to be established as an effective therapy for some neurological disorders.

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Neurofeedback is defined as a method to read out information from the brain and feed the information back to the brain. This technology has developed in the past ten years and attracted considerable attention as potential treatments for rehabilitation and psychiatric disease. We recently invented the decoded neurofeedback (DecNef) method, a new neurofeedback technique using functional magnetic resonance imaging. With DecNef, subjects were trained to regulate their brain activation pattern in a specific area and lead the pattern to a target state. We found that the DecNef training for several days leads to perceptual improvement that corresponds to the induced target state. DecNef enables us to test cause-and-effect relationships between neural activation in a target brain area and changes in perception, cognition, and behavior. In this sense, this method can be a powerful tool in cognitive and systems neuroscience. In addition, the concept of DecNef, leading a neural activation pattern to a specific state, can be applied for a variety of fields including engineering and medical treatment.

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Functional near-infrared spectroscopy (fNIRS) may be suited for functional monitoring during swallowing as it is comparatively immune to body movement. However, still fNIRS measurement on swallowing poses a technical problem that it may often involve motion artifacts. Although there is no single way to solve this problem, technical insights have been available form related studies in the past. Here we introduce two examples for analyzing data rich in motion artifacts putting emphasis on temporal structures of the data. The first is about fNIRS assessment of language function during overt naming tasks. Since data were temporally continuous, we adopted a general linear model with regression to a canonical hemodynamic response function to extract cortical activations related to overt naming tasks. The second example is about fNIRS assessment on go/no-go task performance with or without methylphenidate administration in Attention Deficit Hyperactivity Disorder (ADHD) children. Since data were disrupted by unexpected motion artifacts, we simplified temporal data structures by averaging to extract only robust signals. Thus, we indicated that the optimum analytical strategy varies depending on the temporal structures of the data.

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The present study tested whether electrical stimulation increases the number of voluntary repetitive swallows in humans and if summation of peripheral inputs increases the number of swallows. In addition, the potential of initiating both voluntary and involuntary swallowing was compared and the effect of chewing behaviors on the initiation of swallowing evoked by the electrical stimulation was evaluated. Facilitatory effect of both the mid- and hypo-pharyngeal stimulation was much larger than that of mid-pharyngeal stimulation. The longer the pulse duration was, the larger the number of swallows was, suggesting temporal and spatial summation of peripheral inputs into the swallowing center. There was a wide variation in the number of swallows among subjects. The number of reflexively evoked swallowing (i.e., involuntary swallow) by pharyngeal stimulation also varied greatly, and there was a significant linear correlation in the number of swallows between voluntary and involuntary swallowing, which suggests that the swallowing central pattern generator is a common component of both neuronal networks and therefore is responsible for inter-individual variations. The chewing strongly inhibited the initiation of swallows. Although it should be clarified how the chewing behaviors modulate swallowing function, these data suggest the functional interaction between chewing and swallowing centers.

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Aspiration pneumonia is a major health problem in the elderly. A swallowing disorder, such as a delayed triggering of the swallowing reflex, predisposes in patients with aspiration pneumonia. Swallowing reflex was delayed when the temperature of the food is close to body temperature. The actual swallowing time shortened when the temperature difference increases. The improvement of swallowing reflex by temperature stimuli could be mediated by the temperature-sensitive TRP channel at pharynx. The administration of capsaicin as an agonist stimulus of TRPV1, a warm temperature receptor, decreased the delay in swallowing reflex. Food with menthol, agonist of TRPM8 which is a cold temperature receptor, also decreased the delay in swallowing reflex. Olfactory stimulation such as black pepper was useful to improve the swallowing reflex for people with low ADL levels or with decreased consciousness. Thus, we found anti-aspiration drugs with various site of actions on the hierarchical structure of neuronal control of swallowing. By combining anti-aspiration drugs and swallowing rehabilitations, we developed a protocol to start eating more efficiently and safely. Implementation of this protocol would help avoid re-aspiration in many elderly people with aspiration pneumonia. The combination of various anti-aspiration drugs may improve the swallowing disorders and prevent aspiration pneumonia.

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Malfunctions of the basal ganglia cause movement disorders, such as Parkinson's disease and dystonia. Several models have been proposed to explain the pathophysiology of these disorders: (1) Firing rate model: activity imbalance between the direct and indirect pathways changes the mean firing rate of output nuclei of the basal ganglia and induces hypokinetic or hyperkinetic movement disorders; (2) Firing pattern model: oscillatory and/or synchronized activity observed in the basal ganglia disturbs information processing in the basal ganglia, resulting in motor symptoms; (3) Dynamic activity model: movement-related activity changes through the direct and indirect pathways disrupt balance between movement-related inhibition and surrounding excitation in the output nuclei, and induce motor symptoms. Each model will be critically discussed in this review.

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Remarkable effectiveness of deep brain stimulation (DBS) for Parkinson's disease (PD) has occupied the interest of many scientists and their efforts for elucidating its mechanism have given us a lot of clues for understanding of pathophysiology of PD. The early idea that DBS inhibits neuronal activity of the stimulated nucleus was based on the observation that it shows similar effects as lesions, standing behind the so-called firing rate model of PD pathophysiology. However, it has been also revealed that DBS induces changes indicative of activation of outputs from the stimulated structure, which is inconsistent with the firing rate model. On the other hand, recent studies have demonstrated abnormal discharge pattern in the subthalamic nucleus and the globus pallidus of parkinsonian state, such as burst and oscillation, and its suppression by DBS. These support an idea that the pathological discharge interrupts normal information flow in the basal ganglia. Taken together, changes of firing pattern in the basal ganglia may be crucial for the PD pathophysiology, not a simple increase or decrease in firing rates. Besides, since DBS seems to affect the entire system of the basal ganglia and more, it is necessary to approach its mechanism with a systems-wide view.

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The repetitive transcranial magnetic stimulation (rTMS) has been studied as a method to induce plasticity changes in the human brain. And rTMS is expected as a therapeutic tool for Parkinson's disease, depression, intractable pain and others.
We reported a new rTMS protocol, quadripulse stimulation (QPS), is more effective. QPS consists of repeated trains of four monophasic TMS pulses separated by inter-stimulus intervals of 5 ms (QPS-5) and 50 ms (QPS-50), inducing bidirectional motor cortical plasticity in an ISI dependent. QPS-5 leads to the potentiation effect. QPS-50 leads to a depression effect.
We investigated the changes of plasticity induced by QPS in patients with Parkinson's disease and the healthy volunteer with oral administration of levodopa.
In patients with Parkinson's disease the effect of QPS-5 and QPS-50 was attenuated at Off period. However, when the On period it was recovered. In healthy subjects, effect of QPS was enhanced by levodopa, both QPS-5 and QPS-50.

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Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an adult-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. The testosterone-dependent nuclear accumulation of polyglutamine-expanded AR protein is central to the pathogenesis. This hypothesis is supported by pre-clinical studies showing that testosterone deprivation ameliorates motor neuron degeneration in animal modes of SBMA. In a randomized placebo-controlled multi-centric clinical trial, leuprorelin, which suppresses secretion of testosterone, showed no definite effect on motor functions, although there was the improvement of swallowing function in a subgroup of patients whose disease duration was less than 10 years. Elucidation of the entire disease mechanism, early initiation of therapeutic intervention, and sensitive outcome measures to evaluate drug effect appear to be the key to a successful translational research on SBMA.

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Distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy, for which new nomenclature "GNE myopathy" is now proposed, is an autosomal recessive disease that preferentially affects tibialis anterior and hamstrings muscles in young adults. The disease is caused by mutations, mostly missense, in GNE gene that encodes a protein with two enzymatic activities in sialic acid biosynthetic pathway: UDP-GlcNAc 2-epimerase and ManNAc kinase. Accordingly, sialic acid production is reduced in patients' cells and cells are hyposialylated. This hyposialylation status can be recovered by simply giving sialic acid. Furthermore, myopathic manifestations were virtually completely suppressed by oral administration of sialic acid in our model mice. Similar efficacy was seen also by ManNAc, precursor of sialic acid, or sialyllactose, a conjugate form of sialic acid. Based upon these in vitro and in vivo results, phase I clinical trial for sialic acid supplementation therapy for human patients was performed in October 2010-June 2011 in Japan and in September 2011-April 2012 in the US, the latter using slow release tablets of sialic acid. Natural history of the patients needs to be established for precise evaluation of the efficacy in the near future phase II clinical trial.

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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by selective loss of motor neurons. Approximately 20% of familial ALS cases are linked to mutations in Cu/Zn superoxide dismutase (SOD1) gene. Previously, we developed a transgenic rat model of ALS overexpressing mutant SOD1 protein. The rat model facilitates preclinical ALS research employing various therapeutic approaches such as intrathecal administration, cell transplantation, and viral vector-mediated gene transduction to the affected central nervous system.
Hepatocyte growth factor (HGF) is a pleiotropic growth factor and also a potent survival-promoting factor for motor neurons. To examine its therapeutic effect on ALS, we administered human recombinant HGF (hrHGF) to the transgenic ALS rats. In contrast with vehicle-treated rats, continuous intrathecal infusion of hrHGF attenuated spinal motor neuron degeneration and prolonged the duration of the disease, even with administration from the onset of symptoms.
To translate the strategy to human treatment, we performed dose-finding and safety studies using non-human primate model of contusive cervical spinal cord injury. Introducing exogenous HGF protein also revealed a distinct therapeutic effect with functional recovery. Given the therapeutic potential of hrHGF on ALS, we started a novel phase I clinical trial for ALS patients in Tohoku University Hospital.

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FTLD is a purely anatomically defined concept, being unrelated to the underling cellular pathology; the sine qua non is only the presence of main lesions in the frontal and temporal lobes. FTLD, therefore, is destined to include various maladies that involve the two areas. Cases reported by Arnold Pick, "Pick's disease", are a prototype of FTLD. Because of lack of histopathological description of the brains in his reports, however, the nomenclature brought about a great confusion in its nosology; the history of establishing the concept of FTLD was that of how to seperate genuine Pick's disease. After a long chaos, the present molecular neuropathology has ultimately resolved this problem by clarifying protein constituents of neuronal and glial aggregates in FTLD. TDP-43 was first found in ALS and ALS with dementia (ALSD), and soon FUS/TLS was detected in some TDP-43-negative FTLD-U groups. At the present time, FTLD consists of three main subgroups; 1) FTLD-tau, which includes Pick disease, PSP, CBD, etc., 2) FTLD-TDP, which is subdivided into types A-D, with ALSD belonging to type B, and 3) FTLD-FUS, the members of which are aFTLD-U, NIFID, and BIBD. Further discovery of yet-undetected proteins of some FTLD-U subsets will add more subclasses.

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Recently, critical RNA-binding proteins that are directly associated with the pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) have also been identified, including TAR DNA-binding protein (TDP-43), fused in sarcoma/translated in liposarcoma (FUS) protein and ataxin-2. TDP-43 and FUS are normally localized in the nucleus, in sites affected by ALS and FTLD-U, but both are mislocalized to the cytoplasm and form cytoplasmic inclusions. They are transported to the nucleus via nuclear import receptors, but also contribute to the formation of stress granules (SGs), which are intracytoplasmic structures incorporating RNA. C-terminal truncations of TDP-43 eliminate the nuclear transport signal and cause mislocalization of the protein to the cytoplasm, where it accumulates and forms SGs. ALS-associated FUS mutations impair nuclear transport and cause mislocalization of FUS to the cytoplasm, where it also contributes to assembly of SGs. Furthermore, the ALS susceptibility factor ataxin-2 is recently identified as a potent modifier of TDP-43 toxicity and growing evidence indicates that intermediate-length polyglutamine expansions in ataxin-2 are a genetic risk factor for ALS. Interestingly, ataxin-2 is also a cytoplasmic RNA-binding protein and a constituent protein of SGs, suggesting that it is a part of the common pathological cascade formed by TDP-43, FUS and ataxin-2. Thus, we propose that aberrant distribution of the RNA-binding proteins TDP-43, FUS, and ataxin-2 into the cytoplasm leads to impairment of the RNA quality control system, forming the core of the ALS/FTLD-U degenerative cascade.

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FTLD consists of three clinical types: behavioural variant FTD, progressive non-fluent aphasia (PNFA) and semantic dementia (SD). The latter two types manifest aphasia. Thus, it is quite important to pertinently assess the symptoms of aphasia and related impairments for diagnosis of FTLD. The most important point for diagnosis of PNFA is existence of anarthria/apraxia of speech, which is a focal symptom of the left prefrontal gyrus and underlying white matter. With the progression of the disease word generation and comprehension is deteriorating. SD shows Gogi aphasia when the lesion have predilection of left temporal lober atrophy. We investigated 28 patients without any antecedents causing speech/language impairments, who developed primary progressive aphasia. All the patients underwent a routine neurological and neuropsychological examinations and related symptoms such as orofacial apraxia, frontal lobe signs, dysphasia and so on were assessed. The results indicated that 20 patients were diagnosed as PNFA, and they were subdivided into three clinical groups. One group developed naming impairment and orofacial apraxia in several years after onset, and followed with various frontal symptoms. Another group showed anterior opereculum syndromes within two years after onset. The third group retained pure anarthria/apraxia of speech for many years without any other symptoms.

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Progressive type multiple sclerosis (MS) is usually divided into primary progressive MS (PPMS) and secondary progressive MS (SPMS), and the two types might be different pathologic entities. Some disease modifying therapies may be effective for progressive type MS. However, no class I evidence is currently available on initiating treatment for patients with either of the progressive types, and current treatment options for progressive type MS are limited. Moreover, there have been few curative treatments for various disabilities the disease cause. In the current situation, health-related quality of life (HRQOL) is an important issue for patients, and physicians should pay attention to improving this aspect of their life. In the near future, drugs for axonal regeneration and remyelination may become treatment options for patients with progressive type MS.

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Neuromyelitis optica (NMO), an inflammatory demyelinating disease of the central nervous system, is characterized by relapsing optic neuritis and transverse myelitis. The detection of pathogenic anti-aquaporin-4 (AQP4) antibody distinguishes NMO from other demyelinating disorders, such as multiple sclerosis. Although early administration of high-dose intravenous methyl-prednisolone may improve symptoms that occur during relapses, the application of plasmapheresis is often required for sufficient recovery from each attack. The management of relapses is done with early steroid treatment, typically 1g intravenous methyl-prednisolone for 3 to 5 days followed by oral prednisone. Relapses that do not respond to intravenous steroids could benefit from plasmapheresis. Treatments for the prevention that have been used to date for NMO have generally been immunosuppressive drugs rather than immunomodulatory agents that are commonly used for multiple sclerosis (MS). Although low dose oral prednisolone is reported to be effective for prevention in Japanese NMO, non-steroidal immuno-suppressive agents are recommended in other countries to be changed from prednisolone within six months to avoid the side effects of steroids.

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Behçet disease and Sweet disease are multisystem inflammatory disorders involving mucocutaneous tissue as well as nervous system (neuro-Behçet disease and neuro-Sweet disease). Pathological findings in the encephalitis are chiefly perivascular cuffing of small venules by neutrophils, T lymphocytes, and macrphages. Destruction of the brain substrates is mild in neuro-Sweet disease compared with that of neuro-Behçet disease, especially that of chronic progressive subtype. HLA (human leukocyte antigen)-B51 is frequently positive in neuro-Behçet disease, and the frequencies of HLA-B54 and Cw1 in neuro-Sweet disease are significantly higher than not only those in Japanese normal controls but also those in patients with these diseases without nervous complications. These HLA types are considered as risk factors which are directly associated with the etiology of these diseases. Prednisolone is usually used for the treatment of acute phase of both diseases. Methotrexate and infliximab are administered to patients with the chronic progressive type of neuro-Behçet disease. Colchicine and dapsone are prescribed to prednisolone-dependent recurrent cases of neuro-Sweet disease.

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Sarcoidosis is a multisystem inflammatory granulomatous disease that affects the central nervous system (CNS). CNS Involvement occurs in a relatively small number of patients with sarcoidosis but is potentially serious manifestation. Diagnostic criteria usually include histologic identification of a noncaseating epithelioid granuloma, supportive laboratory or neuroimaging tests or both, and a compatible clinical course. Diagnostic criteria proposed by "The Diagnosis Guideline for Sarcoidosis in Japan -2006" can distinguish definite, probable, and possible neurosarcoidosis, and may be now commonly used. Patients with a definite or probable diagnosis of CNS sarcoidosis should start treatment promptly. The pharmacologic regimens for the treatment of neurosarcoidosis are not standardized since no prospective, randomized, controlled trials have been performed in the World. Corticosteroids, however, are typically the first line or therapy and approximately half of patients have substantial benefit. For patients who are refractory to or intolerant of corticosteroid therapy, second-line agents include azathioprine, methotrexate, cyclosporine, cyclophosphamide, and mycophenolate mofetil (MMF). Treatment regimens vary in term of doing, maintenance, and tapering. Radiotherapy or neurosurgical treatment is indicated when medications fail or when life-threatening emergences, such as severe hydrocephalus and elevated intracranial pressure, arise. The combination of infliximab, an anti-TNF-alpha neutralizing antibody, and MMF has recently been used to treat neurosarcoidosis. Treatment option will likely evolve as well-designed studies are undertaken.

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Hashimoto's encephalopathy (HE), which is occasionally associated with chronic thyroiditis (Hashimoto's disease), presents with a variety of neurologic and neuropsychiatric features. We investigated the clinical features and treatments in 80 cases of HE with serum anti-NH₂-terminal of α-enolase [anti-NAE] autoantibodies, a useful diagnostic marker of this disease.
The acute encephalopathy form was the most common clinical phenotype (58%), followed by chronic psychiatric form (17%), cerebellar ataxic form (16%), and other forms such as Creutzfeltd-Jakob disease (CJD)-like form and limbic encephalitis. The common neuropsychiatric features were consciousness disturbance (66%), psychosis (53%) and dementia (38%). Involuntary movements (31%, tremor or myoclonus), seizures (31%) or ataxia (28%) occasionally occurred. Abnormalities on EEG (80%) were common while abnormalities on brain MRI were relatively rare (36%).
On the treatments for HE, steroid therapy was most usually applied and successful. Intravenous immunoglobulin therapy or plasma exchange was successfully applied for the treatment of HE in some cases of HE.
Taken together, we should be aware of the possibility of HE for early diagnosis and tretmetent of this disease.

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To diagnose brachial plexopathies is often challenging for neurologists. The complexity in anatomy of brachial plexus may preclude easy understanding of the anatomic localization, and the clinical features of plexopathy may mimic myelopathies, radiculopathies or neuropathies, which are more common disorders. Furthermore, imaging studies such as MRI or CT have limited utility for localization of disorders. In such situations, electrodiagnostic tests are most useful for determining localization of plexopathies. Nerve conduction studies (NCSs) and needle electromyography will contribute to localization in the brachial plexus and to the differential diagnosis. Especially, the sensory nerve conduction studies (SCSs) are promising, because sensory nerve action potential (SNAP) amplitude will decrease in plexopathies due to Wallerian degeneration of the postganglionic sensory fibers. Another advantage of SCS is the higher sensitivity in a chronic disease process, in which the compound muscle action potential might be preserved due to reinnervation. For the electrodiagnosis using SCSs, a criterion to consider an interside difference exceeding 50% as abnormal has been widely employed, which has not been actually verified. We have investigated the validity of this hypothesis and established the control values. Four cases of plexopathies have been also presented.

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Single-fiber electromyography (SFEMG) is one of the most sensitive diagnostic tests of myasthenia gravis. Single-fiber needle electrodes were used originally, however, disposable concentric needle electrodes have been used increasingly in recent years to avoid infection. We therefore undertook a prospective, multicenter study to establish reference values of concentric needle SFEMG in Japanese subjects for both voluntary and stimulated SFEMG and for two commonly examined muscles, the extensor digitorum communis (EDC) and the frontalis (FRO). 69 normal subjects below the age of 60 years were enrolled at six institutes. The cut-off values for mean consecutive difference (MCD) of individual potentials were calculated using+2.5 SD or 95% prediction limit (one-tail) of the upper 10th percentile MCD value for individual subjects. The recommended cut-off values for individual MCD were 56.8μs for voluntary SFEMG for EDC, 58.8μs for stimulated SFEMG for EDC, 56.8μs for voluntary SFEMG for FRO and 51.0μs for stimulated SFEMG for FRO. This is the first multicenter study reporting reference values for SFEMG using concentric needles.

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