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Objective: Our previous study of monaural auditory evoked magnetic fields (AEFs) demonstrated that hippocampal sclerosis significantly modulated auditory processing in patients with mesial temporal lobe epilepsy (mTLE). However, the small sample size (n = 17) and focus on the M100 response were insufficient to elucidate the lateralization of the epileptic focus. Therefore, we increased the number of patients with mTLE (n = 39) to examine whether neural synchronization induced by monaural pure tone stimulation provides useful diagnostic information about epileptic foci in patients with unilateral mTLE., Methods: Twenty-five patients with left mTLE, 14 patients with right mTLE, and 32 healthy controls (HCs) were recruited. Auditory stimuli of 500-Hz tone burst were monaurally presented to subjects. The AEF data were analyzed with source estimation of M100 responses in bilateral auditory cortices (ACs). Neural synchronization within ACs and between ACs was evaluated with phase-locking factor (PLF) and phase-locking value (PLV), respectively. Linear discriminant analysis was performed for diagnosis and lateralization of epileptic focus., Results: The M100 amplitude revealed that patients with right mTLE exhibited smaller M100 amplitude than patients with left mTLE and HCs. Interestingly, PLF was able to differentiate the groups with mTLE, with decreased PLFs in the alpha band observed in patients with right mTLE compared with those (PLFs) in patients with left mTLE. Right hemispheric predominance was confirmed in both HCs and patients with left mTLE while patients with right mTLE showed a lack of right hemispheric predominance. Functional connectivity between bilateral ACs (PLV) was reduced in both patients with right and left mTLE compared with that of HCs. The accuracy of diagnosis and lateralization was 80%-90%., Conclusion: Auditory cortex subnormal function was more pronounced in patients with right mTLE compared with that in patients with left mTLE as well as HCs. Monaural AEFs can be used to reveal the pathophysiology of mTLE. Overall, our results indicate that altered neural synchronization may provide useful information about possible functional deterioration in patients with unilateral mTLE., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

A new single-cell microarray chip was designed and developed to separate and analyze single adherent and non-adherent cancer cells. The single-cell microarray chip is made of polystyrene with over 60,000 microchambers of 10 different size patterns (31-40 µm upper diameter, 11-20 µm lower diameter). A drop of suspension of adherent carcinoma (NCI-H1650) and non-adherent leukocyte (CCRF-CEM) cells was placed onto the chip, and single-cell occupancy of NCI-H1650 and CCRF-CEM was determined to be 79% and 84%, respectively. This was achieved by controlling the chip design and surface treatment. Analysis of protein expression in single NCI-H1650 and CCRF-CEM cells was performed on the single-cell microarray chip by multi-antibody staining. Additionally, with this system, we retrieved positive single cells from the microchambers by a micromanipulator. Thus, this system demonstrates the potential for easy and accurate separation and analysis of various types of single cells., Competing Interests: The authors declare no conflict of interest.

Water-soluble cyclodextrin (CyD) complexed with porphyrin derivatives with different substituents in the meso -positions showed different photodynamic activities toward cancer cells under illumination at wavelengths over 600 nm, the most suitable wavelengths for photodynamic therapy (PDT). In particular, aniline- and phenol-substituted derivatives had high photodynamic activity because of the efficient intracellular uptake of the complexes by tumor cells. These complexes showed greater photodynamic activity than photofrin, currently the main drug in clinical use as a photosensitizer. These results represent a significant step toward the optimization of porphyrin derivatives as photosensitizers.

[60]Fullerene (C 60 ) derivatives were incorporated into liposomes using a fullerene exchange method involving the transfer of the fullerene from the cavity of two γ-cyclodextrin molecules to a liposome. A lipid-membrane-incorporated C 60 derivative bearing a polar group showed much higher photodynamic activity than the analogous system incorporating pristine C 60 .

In order to produce insulin-secreting cells with a high value of glucose-stimulated insulin secretion (GSIS) from mouse embryonic stem cells, we have developed an optimized 5-stage protocol by referring to culture conditions so far reported elsewhere. This protocol is characterized by 4 points: (1) use of an activin-free medium in the first stage, (2) use of gelatin/fibronectin coated culture dishes in 1-4 stages throughout, (3) removal of undifferentiated cells by cell sorter at the end of 4th stage, and (4) sedimental culture in the 5th stage. GSIS value of the produced cells reached 2.4, that was at a higher rank of those so far reported. The produced cells were transplanted in diabetes model mice but no remedy effect was observed. Then transplantation was conducted in pre-diabetes model mice, in which GSIS was impaired without affecting insulin producing function. The transplantation of 5 × 10(6) cells resulted in a marked improvement of glucose tolerance within 20 days. This effect decreased but was still observed at 120 days post-transplantation. This demonstrates the feasibility of the novel optimized protocol.

Epilepsy is a frequent comorbidity in patients with focal cortical dysplasia (FCD). Recent studies utilizing massive sequencing data identified subsets of genes that are associated with epilepsy and FCD. AKT and mTOR-related signals have been recently implicated in the pathogenic processes of epilepsy and FCD. To clarify the functional roles of the AKT-mTOR pathway in the hippocampal neurons, we generated conditional knockout mice harboring the deletion of Pten (Pten-cKO) in Proopiomelanocortin-expressing neurons. The Pten-cKO mice developed normally until 8 weeks of age, then presented generalized seizures at 8-10 weeks of age. Video-monitored electroencephalograms detected paroxysmal discharges emerging from the cerebral cortex and hippocampus. These mice showed progressive hypertrophy of the dentate gyrus (DG) with increased expressions of excitatory synaptic markers (Psd95, Shank3 and Homer). In contrast, the expression of inhibitory neurons (Gad67) was decreased at 6-8 weeks of age. Immunofluorescence studies revealed the abnormal sprouting of mossy fibers in the DG of the Pten-cKO mice prior to the onset of seizures. The treatment of these mice with an mTOR inhibitor rapamycin successfully prevented the development of seizures and reversed these molecular phenotypes. These data indicate that the mTOR pathway regulates hippocampal excitability in the postnatal brain.

We report a case of primary central nervous system vasculitis (PCNSV) diagnosed by second brain biopsy. A 53-year-old man initially presented with left lateral gaze diplopia. Brain MRI revealed multiple enhanced lesions in the bilateral frontal lobe, bilateral basal ganglia, left cerebellum and brainstem. An initial brain biopsy of the right frontal lobe suggested immune-related encephalitis with angiocentric accumulation of chronic inflammatory cells, while malignant lymphoma could not be completely ruled out. The patient deteriorated despite being treated with repeated methylprednisolone pulse therapy, cyclophosphamide, and plasmapheresis. A second brain biopsy of the right temporal lobe was then performed. The biopsied specimens showed vascular wall disruption and fibrinoid necrosis with perivascular inflammatory infiltrates, mainly composed of CD8-positive T cells, and PCNSV was diagnosed. He was treated with high dose corticosteroids, in combination with methotrexate (8 mg/week), which reduced the brain lesions. As brain biopsy is an essential investigation for the histological diagnosis of PCNSV; subsequent biopsies may be required when a histopathological diagnosis has not been obtained by the first biopsy, and further aggressive therapy is being considered.

The hippocampus is well known to be involved in memory, as well as in perceptual processing. To date, the electrophysiological process by which unilateral hippocampal lesions, such as hippocampal sclerosis (HS), modulate the auditory processing remains unknown. Auditory-evoked magnetic fields (AEFs) are valuable for evaluating auditory functions, because M100, a major component of AEFs, originates from auditory areas. Therefore, AEFs of mesial temporal lobe epilepsy (mTLE, n=17) with unilateral HS were compared with those of healthy (HC, n=17) and disease controls (n=9), thereby determining whether AEFs were indicative of hippocampal influences on the auditory processing. Monaural tone-burst stimuli were presented for each side, followed by analysis of M100 and a previously less characterized exogenous component (M400: 300-500ms). The frequency of acceptable M100 dipoles was significantly decreased in the HS side. Beam-forming-based source localization analysis also showed decreased activity of the auditory area, which corresponded to the inadequately estimated dipoles. M400 was found to be related to the medial temporal structure on the HS side. Volumetric analysis was also performed, focusing on the auditory-related areas (planum temporale, Heschl's gyrus, and superior temporal gyrus), as well as the hippocampus. M100 amplitudes positively correlated with hippocampal and planum temporale volumes in the HC group, whereas they negatively correlated with Heschl's gyrus volume in the mTLE group. Interestingly, significantly enhanced M400 component was observed in the HS side of the mTLE patients. In addition, the M400 component positively correlated with Heschl's gyrus volume and tended to positively correlate with disease duration. M400 was markedly diminished after hippocampal resection. Although volumetric analysis showed decreased hippocampal volume in the HS side, the planum temporale and Heschl's gyrus, the two major sources of M100, were preserved. These results suggested that HS significantly influenced AEFs. Therefore, we concluded that the hippocampus modulates auditory processing differently under normal conditions and in HS., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

We report the case of a 17-year-old woman with paroxysmal sympathetic storm (PSS), which was successfully treated with clonidine hydrochloride. The patient was hospitalized for acute disseminated encephalomyelitis in June 2006. Dysphagia led to severe aspiration pneumonia in September 2006, and she suffered cardiopulmonary arrest. She survived but had severe brain damage, with her brain MRI showing diffuse hypoxic encephalopathy. From October 2006, she had several episodes of profound tachypnea (> 60/min), tachycardia (160 to 170 beats/min), hypertension (> 140 mmHg), hyperthermia (39°C), and decerebrate posturing. During the attacks, the levels of catecholamines in the patient's blood and urine were markedly elevated. Accordingly, a diagnosis of PSS associated with hypoxic encephalopathy was made. Her PSS clearly improved after the administration of clonidine hydrochloride (900 μg/day). This case suggests that clonidine hydrochloride, an α2 blocker, may be one therapeutic option for PSS.

A 24-year-old man was referred to our hospital emergency department due to a sudden onset of convulsions after drinking. On arrival he presented status epilepticus and was managed by artificial ventilation. He had no brainstem signs or meningeal irritation. Head MRI showed an old infarction-like lesion in the left occipital lobe, but no abnormal signals on diffusion-weighted images. The patient showed acute rhabdomyolysis (CK 18,000 IU/l) and renal failure, and hemodialysis was started. On 18 day after admission, he was transferred to our department with mild proximal limb muscle weakness and bilateral sensorineural hearing impairment. Electroencephalography demonstrated diffuse intermittent slow wave activities. We suspected a mitochondrial disease because of a significant increase in the lactate/pyruvate ratio (24.1) in the spinal fluid, and identified A3243G mutations in mitochondrial DNA (heteroplasmy 20%) in peripheral white blood cells. We diagnosed his illness as mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). This is a rare case presenting an acute onset of rhabdomyolysis following alcohol intake related to A3243G mitochondrial mutation without preceding stroke-like episodes.

A portable method of specific nucleic acid detection would be very useful for monitoring public health in a variety of settings for point-of-care and point-of-need testing. However, conventional methods for the detection of nucleic acids are not ideal for use in the field, as they require skilled operators and complex equipment. Here, we constructed a method for specific nucleic acid detection using a split G-quadruplex (Gq) structure that can recognize target nucleic acids without competitive reactions in a bimolecular reaction and directly produce a detectable signal based on peroxidase activity. We developed a single signal-transducing molecule with a split Gq-based DNA-nano tweezers (NT) structure that self-assembles from three single-stranded DNAs through simple mixing, and detects its target without requiring any washing steps. A model target, a partial norovirus mRNA (NV-RNA), was specifically recognized by the split Gq-based DNA-NT, causing it to undergo a structural change that restored its peroxidase activity. The peroxidase activity was measured by following the oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), which gave a greenish colorimetric response, and was proportional to the NV-RNA concentration. The lower detection limit was 4 nM. Our results demonstrated the feasibility of detecting specific nucleic acids with a split Gq-based DNA-NT structure as a nucleic acid signal-transducing molecule in a homogenous assay format. Also the target recognition sites of split Gq-based DNA-NT can easily be designed without delicate optimization of tweezers structure. Thus a split Gq-based DNA-NT technique is readily applicable to a basic platform for the development of a portable device., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Although the epileptogenic location of dysembryoplastic neuroepithelial tumors (DNTs) is controversial, it has recently been thought to be located within cortical dysplasia (CD) due to its frequent association with CD. Among the 84 resection surgeries for intractable epilepsy performed in our institution between January 2003 and April 2010, three patients had epileptogenic DNTs. In two cases, chronic subdural electrocorticography (ECoG) was performed, and the ictal onset zone was revealed to be in the cortex around the DNT. The ictal onset zone was resected along with the DNT, and good seizure outcome was achieved. Although histological examination of the ictal onset zone revealed mild gliosis, coexistence of CD was not noted. In the third case, the DNT was located in the left lateral temporal lobe and the intraoperative ECoG revealed frequent paroxysmal activity in the medial temporal lobe. Resection of the lateral temporal lobe involving the tumor did not result in good seizure control. The optimal surgical treatment of DNT is controversial. Some authors consider lesionectomy to be sufficient for good seizure control, whereas others advocate that additional resection of the epileptogenic zone beside the tumor improves outcome. Because the epileptogenic location of DNT varies among cases, it is important to identify its location by preoperative multimodal examinations, including chronic subdural ECoG recordings.

A new homogeneous insulin assay requiring no chemical modification of an insulin recognition domain, which can be applied to continuous monitoring of the time-dependent cellular response in vitro, was developed. The carboxy-terminal α-chain (αCT) segment and first leucine-rich-repeat (L1) domain in the primary binding site on the insulin receptor were genetically fused with a bioluminescent protein (Nanoluc, Nluc) and a fluorescent protein (yellow fluorescent protein, YPet) to produce the insulin-sensing probe proteins Nluc-αCT and L1-YPet. The BRET signal was observed on simple mixing of insulin with these protein probes, in a so-called homogeneous assay. The BRET signal was proportional to the insulin concentration, and the lower detection limit was 0.8 μM. Time-dependent insulin secretion from drug-stimulated MIN6 cells was also successfully monitored continuously with the probe proteins. This BRET-based homogeneous insulin assay method is thus expected to be applicable to drug development by high-throughput screening.

A DNA nano-tweezer (DNA-NT) structure-based target mRNA detection probe, which uses fluorescence resonance energy transfer (FRET) as a detection signal and works as a single molecule, has been developed. This FRET-paired fluorescent dye-modified DNA-NT, self-assembled from three single-stranded DNAs, alters its structure from open to closed states and produces a FRET signal in response to in vitro transcripts of Hes-1 mRNA. Our results showed that the FRET-based DNA-NT detected both GLUT1 mRNA as a pre-fixed target mRNA model and Hes-1 mRNA as a model expressed inside a living cell. These results confirm the feasibility of using the FRET-based DNA-NT for imaging analysis of target mRNA.

"Solitary" meningioangiomatosis (MA) is a rare, benign, hamartomatous lesion of the cerebral cortex and frequently leads to epilepsy. However, the source of the epileptogenicity in meningioangiomatosis remains controversial. We report two surgically-treated meningioangiomatosis cases with medically intractable epilepsy. In both cases, chronic subdural electrocorticogram (ECoG) recordings identified the ictal onset zone on apparently normal cortex, adjacent to and/or above the meningioangiomatosis lesion, not on the meningioangiomatosis lesion itself. The ictal onset zone was resected, along with the MA lesion, and good seizure outcome was achieved. Histological examination of the ictal onset zone revealed the presence of ILAE focal cortical dysplasia (FCD) type IIIc. Our case studies suggest that in the surgical management of epilepsy with meningioangiomatosis, it is important to identify undetected, but epileptogenic, ILAE FCD Type IIIc, using preoperative multimodal examinations, including chronic ECoG recordings.

Vagal nerve stimulation(VNS)is an effective adjunctive therapy for medically intractable epilepsy. However, VNS is a palliative therapy, and craniotomy should preferably be performed when complete seizure remission can be expected after craniotomy. We report here three patients who were referred for VNS therapy, but underwent craniotomy instead of VNS based on the results of a comprehensive preoperative evaluation, and achieved good seizure control. Case 1 was a 48-year-old woman with left temporal lobe epilepsy and amygdalar enlargement. Even though no left hippocampal sclerosis was observed on magnetic resonance imaging, she underwent left anterior temporal lobectomy and hippocampectomy. Case 2 was a 36-year-old woman with multiple bilateral subependymal nodular heterotopias, who underwent resection of the left medial temporal lobe including subependymal nodular heterotopias adjacent to the left inferior horn. Case 3 was a 25-year-old man with posttraumatic epilepsy. As the right hemisphere was most affected, multiple subpial transections were performed on the left frontal convexity. These three patients were referred to us for VNS therapy because there was a dissociation between the interictal electroencephalogram and magnetic resonance imaging findings, or because they had multiple or extensive epileptogenic lesions. Comprehensive preoperative evaluation including ictal electroencephalography can help to identify patients who are suitable candidates for craniotomy.

Objective: Age-related changes are well documented in the primary somatosensory cortex (SI). Based on previous somatosensory evoked potential studies, the amplitude of N20 typically increases with age probably due to cortical disinhibition. However, less is known about age-related change in the secondary somatosensory cortex (SII). The current study quantified age-related changes across SI and SII mainly based on oscillatory activity indices measured with magnetoencephalography., Methods: We recorded somatosensory evoked magnetic fields (SEFs) to right median nerve stimulation in healthy young and old subjects and assessed major SEF components. Then, we evaluated the phase-locking factor (PLF) for local field synchrony on neural oscillations and the weighted phase-lag index (wPLI) for cortico-cortical synchrony between SI and SII., Results: PLF was significantly increased in SI along with the increased amplitude of N20m in the old subjects. PLF was also increased in SII associated with a shortened peak latency of SEFs. wPLI analysis revealed the increased coherent activity between SI and SII., Conclusions: Our results suggest that the functional coupling between SI and SII is influenced by the cortical disinhibition due to normal aging., Significance: We provide the first electrophysiological evidence for age-related changes in oscillatory neural activities across the somatosensory areas., (Copyright © 2013 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Electroencephalography (EEG) is the primary means by which epileptic activity in the brain is measured. The frequency of epileptic discharges is influenced by vigilance and biological rhythms. When checking for epileptic activity using EEG, measurements must be repeated and recordings made during sleep are recommended if epileptic discharges do not readily appear. Epileptic discharges must be classified as generalized or focal discharges, and discriminated from non-epileptic discharges such as vertex sharp transients, positive occipital sharp transients, 14 & 6 positive spike discharge, and artifacts. Attention should be paid to small sharp spikes, 6Hz spike and slow wave, focal slow waves, and generalized rhythmic slow waves, which should all be considered variants of epileptic activity. EEG provides information regarding focal and generalized brain dysfunction in addition to epileptic activity. Because the misreading of EEG may negatively affect the lives of patients, reading the EEG correctly is quite important.

The sensory projections from the oral cavity, pharynx, and larynx are crucial in assuring safe deglutition, coughing, breathing, and voice production/speaking. Although several studies using neuroimaging techniques have demonstrated cortical activation related to pharyngeal and laryngeal functions, little is known regarding sensory projections from the laryngeal area to the somatosensory cortex. The purpose of this study was to establish the cortical activity evoked by somatic air-puff stimulation at the laryngeal mucosa using magnetoencephalography. Twelve healthy volunteers were trained to inhibit swallowing in response to air stimuli delivered to the larynx. Minimum norm estimates was performed on the laryngeal somatosensory evoked fields (LSEFs) to best differentiate the target activations from non-task-related activations. Evoked magnetic fields were recorded with acceptable reproducibility in the left hemisphere, with a peak latency of approximately 100ms in 10 subjects. Peak activation was estimated at the caudolateral region of the primary somatosensory area (S1). These results establish the ability to detect LSEFs with an acceptable reproducibility within a single subject and among subjects. These results also suggest the existence of laryngeal somatic afferent input to the caudolateral region of S1 in human. Our findings indicate that further investigation in this area is needed, and should focus on laryngeal lateralization, swallowing, and speech processing., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Eleven of 16 rats showed spontaneous seizures arising in the hippocampus from postnatal day47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. Alterations in the levels of glutamatergic and GABA-ergic receptors were investigated during growth. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. This model should enable better clarification of the mechanisms underlying the development of human epilepsy.

Recent resting-state functional MRI (rs-fMRI) studies have demonstrated that the human brain is composed of several essential large-scale functional brain networks, including the "default-mode network". We analyzed electrocorticogram data from four patients with intractable focal epilepsy and compared the extent of these large-scale functional brain networks with propagation pathways of ictal discharge. We found that large-scale functional brain networks had markedly similar spatial patterns compared with multisite ictal fast activity, suggesting that some epileptic activity propagates along large-scale functional brain networks. Given that decreased functional connectivity in large-scale functional brain networks has been reported in patients with focal epilepsy, ictal propagation may lead to chronic alteration of normal functional networks in the brain.

We report a case of a 22-year-old male who was transferred to our hospital in a comatose state following successive seizures. Low blood glucose had been detected upon his arrival at the previous hospital. He became responsive 12 days after the onset of coma. Upon regaining consciousness he exhibited severe dysarthria and several interhemispheric disconnection signs such as intermanual conflict, left-hand dysgraphia, left hemispatial neglect confined to the right hand, impaired interhemispheric transfer, and unilateral constructional apraxia of the right hand. Brain MRI disclosed T2-weighted and diffusion-weighted hyperintense lesions with reduced apparent diffusion coefficients in the bilateral centrum semiovale, splenium of the corpus callosum, right posterior limb of the internal capsule, and bilateral middle cerebellar peduncles. As the MRI findings vanished, his interhemispheric disconnection signs gradually resolved. Abdominal imaging studies revealed a pancreatic tumor, which was later endocrinologically diagnosed as an insulinoma. This is an extremely rare report of interhemispheric disconnection signs due to hypoglycemic encephalopathy. The lesions in the bilateral centrum semiovale likely contributed to the interhemispheric disconnection signs., (© 2013.)

Focal cortical dysplasia (FCD) is an important cause of intractable epilepsy. Previous rat studies have utilized freeze lesioning of neonatal animals to model FCD; however, such models are unable to demonstrate spontaneous seizures without seizure-provoking events. Therefore, we created an animal model with multiple FCD, produced during embryonic development, and observed whether spontaneous seizures occurred. Furthermore, we examined the relationship between FCD and epileptogenesis using immunohistochemistry. At 18 days postconception, a frozen metal probe was placed bilaterally on the scalps of Sprague-Dawley rat embryos through the uterus wall to produce multiple FCD. Electroencephalogram (EEG) and video recording were performed from postnatal day (P) 35 to P77. Brain tissues were examined immunohistochemically at P28 and P78 using semiquantitative densitometry. Eleven of 16 rats (68.8%) showed spontaneous seizures arising in the hippocampus from P47. Movement cessation followed by sniffing and mastication, culminating in wet-dog shaking, was seen during the hippocampal EEG discharges. FCD was observed in the bilateral frontoparietal lobes. The expression levels of N-methyl-d-aspartate receptor (NMDAR) subunits 1, 2A, 2B, the glutamate/aspartate transporter and the glial glutamate transporter 1 (GLT1) at FCD sites were increased at P28 and P78. There were no major histological abnormalities in the hippocampi compared with those in the cortex. However, the expression levels of NMDAR 2A and 2B were increased at P28. Levels of NMDAR1, 2A and 2B, the glutamate/aspartate transporter and GLT1 were also increased at P78. We created an animal model showing spontaneous seizures without a provoking event except for the existence of cortical dysplasia, and without a genetic or general systematic cause like MAM injection or irradiation. The seizures resembled human temporal lobe epilepsy both clinically and on EEG. Alterations in the levels of glutamatergic and GABAergic receptors were investigated during growth. This model should enable better clarification of the mechanisms underlying the development of human epilepsy., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Parainfectious or autoimmune striatal lesions have been repeatedly described in children. We report a 7-year-old girl with painful muscle spasms, leading to the diagnosis of childhood stiff-person syndrome (SPS). Striatal lesions were demonstrated by diffusion-weighted magnetic resonance imaging (MRI) and single-photon emission computed tomography but not by conventional MRI. Autoantibodies against glutamic acid decarboxylase (GAD) were absent. Steroid pulse therapy and high-dose intravenous immunoglobulin resolved all the symptoms with slight sequelae. Childhood SPS may be characterized by absent anti-GAD antibodies and a transient benign clinical course, and it may have a pathomechanism distinct from that in adult SPS., (Copyright © 2012 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

The analysis of epileptic discharges in magnetoencephalography with minimum norm estimates (MNE) is expected to provide more precise localization of epileptic discharges compared with electroencephalographic estimations. However, the clinical feasibility of MNE remains unclear. In this study, we aimed to elucidate the onset and propagation patterns of interictal spikes using MNE. Seven patients with intractable epilepsy whose epileptogenicity was assumed to exist in the convexity of the cerebral cortex were studied. For MNE and electrocorticography (ECoG), we characterized the propagation patterns of interictal epileptic discharges according to the area in which they originated and where they extended; we then examined whether the propagation patterns observed in MNE were identified by ECoG. We also examined the relationship between the positions of spikes estimated by the equivalent current dipole (ECD) method and MNE. Among the seven patients, nine propagation patterns of epileptic discharges were observed by MNE, all of which were also identified by ECoG. In seven patterns, the epileptic activity propagated around the initial portion. However, in two patterns, the center of activities moved according to propagation with maintained activity of the initial portion. The locations of spikes identified by the ECD method were within the areas estimated by MNE when the epileptic activity propagated. However, the ECD method failed to detect onset activities identified by MNE in three of nine patterns. Thus, MNE is more useful as a means of presurgical evaluation for epilepsy than the ECD method because it can delineate the onset of epileptic activities as shown in ECoG.

Patients with epilepsy are at high risk for major depression relative to the general population, and both disorders are associated with changes in adult hippocampal neurogenesis, although the mechanisms underlying disease onset remain unknown. The expression of fosB, an immediate early gene encoding FosB and ΔFosB/Δ2ΔFosB by alternative splicing and translation initiation, is known to be induced in neural progenitor cells within the subventricular zone of the lateral ventricles and subgranular zone of the hippocampus, following transient forebrain ischemia in the rat brain. Moreover, adenovirus-mediated expression of fosB gene products can promote neural stem cell proliferation. We recently found that fosB-null mice show increased depressive behavior, suggesting impaired neurogenesis in fosB-null mice. In the current study, we analyzed neurogenesis in the hippocampal dentate gyrus of fosB-null and fosB(d/d) mice that express ΔFosB/Δ2ΔFosB but not FosB, in comparison with wild-type mice, alongside neuropathology, behaviors, and gene expression profiles. fosB-null but not fosB(d/d) mice displayed impaired neurogenesis in the adult hippocampus and spontaneous epilepsy. Microarray analysis revealed that genes related to neurogenesis, depression, and epilepsy were altered in the hippocampus of fosB-null mice. Thus, we conclude that the fosB-null mouse is the first animal model to provide a genetic and molecular basis for the comorbidity between depression and epilepsy with abnormal neurogenesis, all of which are caused by loss of a single gene, fosB.

Electrical brain stimulation is used in a variety of clinical situations, including cortical mapping for epilepsy surgery, cortical stimulation therapy to terminate seizure activity in the cortex, and in deep brain stimulation therapy. However, the effects of stimulus parameters are not fully understood. In this study, we systematically tested the impact of various stimulation parameters on the generation of motor symptoms and afterdischarges (ADs). Focal electrical stimulation was delivered at subdural cortical, intracortical, and hippocampal sites in a rat model. The effects of stimulus parameter on the generation of motor symptoms and on the occurrence of ADs were examined. The effect of stimulus irregularity was tested using random or regular 50Hz stimulation through subdural electrodes. Hippocampal stimulation produced ADs at lower thresholds than neocortical stimulation. Hippocampal stimulation also produced significantly longer ADs. Both in hippocampal and cortical stimulation, when the total current was kept constant with changing pulse width, the threshold for motor symptom or AD was lowest between 50 and 100Hz and higher at both low and high frequencies. However, if the pulse width was fixed, the threshold did not increase above 100Hz and it apparently continued to decrease through 800Hz even if the difference did not reach statistical significance. There was no significant difference between random and regular stimulation. Overall, these results indicate that electrode location and several stimulus parameters including frequency, pulse width, and total electricity are important in electrical stimulation to produce motor symptoms and ADs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To establish the first evidence-based diagnostic criteria for atopic myelitis (AM) enabling it to be discriminated from myelitis-onset multiple sclerosis (MS), which is a difficult differential diagnosis., Methods: Sixty-nine consecutive AM patients examined from 1996 to 2010 at Kyushu University hospital, who fulfilled the empirical definition of AM (2003), and 51 myelitis-onset MS patients in whom allergen-specific IgE was measured, were enrolled. The first available brain MRI findings were compared between the two. Then, we compared the clinical and laboratory features between the 16 AM cases who did not meet the Barkhof brain MRI criteria for MS after more than 5 years follow-up and 51 myelitis-onset MS cases. Based on the discriminative findings, we established diagnostic criteria for AM and calculated the sensitivity and specificity., Results: AM patients had a significantly lower frequency of Barkhof brain lesions on baseline MRI than myelitis-onset MS patients. AM patients had a significantly higher frequency of present and/or past history of atopic disease and hyperIgEemia, and higher cerebrospinal fluid levels of interleukin 9 and CCL11/eotaxin, but a lower frequency of oligoclonal IgG bands than myelitis-onset MS patients. Our proposed diagnostic criteria for AM demonstrated 93.3% sensitivity and 93.3% specificity for AM against myelitis-onset MS, with 82.4% positive predictive value and 97.7% negative predictive value., Conclusion: Our first evidence-based criteria for AM show high sensitivity and specificity, and would be useful clinically., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We report a 29-year-old man who presented with a 2-year history of progressive stiffness and painful spasms limited to the bilateral lower limbs, exaggerated by auditory and tactile stimuli. His deep tendon reflexes were slightly increased in both lower extremities. His plantar response was flexor. His serum and cerebrospinal fluid were negative for anti-glutamic acid decarboxylase antibodies. Electromyography of antagonist muscle pairs in his distal lower limbs revealed a failure of reciprocal inhibition. We used transcranial magnetic stimulation with a paired-pulse paradigm, delivered to the cortical area of the upper and lower limbs, and revealed significantly enhanced facilitation only in the area of his lower limbs, but not that representing his upper limbs. His symptoms were improved substantially by 20mg/day of oral diazepam. To our knowledge this is the first report of a patient with hyperexcitability limited to the lower limb motor system in a patient with stiff-leg syndrome., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Adult neurologists routinely encounter cases of epilepsy. Appropriate therapy based on a correct diagnosis is very important, and is aided by knowledge of seizure semiology and the correct reading of EEG findings. Many factors need to be considered when deciding upon a treatment regime for adult epilepsy patients, such as employment, marriage, child bearing status, and co-existent disease in elderly patients. Four new antiepileptic drugs (AEDs), which have been used in other countries for more than 10 years, have been authorized for use over the past few years in Japan. Because new AEDs also have interactions and side effects, administration to patients must be carried out based on an understanding of drug actions and interaction mechanisms. Surgical treatment should be considered for drug resistant patients, especially for those suffering from temporal lobe epilepsy with hippocampal sclerosis. For drug resistant patients who are not candidates for resection therapy, we can undertake vagus nerve stimulation therapy, which has recently been authorized for use in Japan. Other electrical stimulation therapies, targeting the anterior nucleus of thalamus, hippocampus and epileptic neo-cortex, have been investigated and are now under study in the USA. Neurologists should be aware of such newly introduced therapies in giving a better quality of life for epilepsy patients.

Epilepsy is a common disease with a high incidence of about one percent. Knowledge of seizure semiology and correct reading of EEG findings are important for diagnosis of epilepsy. Because the primary therapy for epilepsy is antiepileptic drugs (AEDs), including several ones that are newly permitted in Japan, we need to prescribe them based on an understanding of their actions and interaction mechanisms. However, we also need to consider early surgical treatment for temporal lobe epilepsy with hippocampal sclerosis. In the therapeutic decision for adult epilepsy patients many factors such as employment, marriage, child bearing, and co-existent disease need to be considered. The present review provides an overview of the basis of epilepsy practice for neurologists treating adults with epilepsy, including a discussion of new AEDs, epilepsy surgery, women with epilepsy, and epilepsy in the elderly.

We report a 68-year-old man who exhibited mild dysarthria and mild right hemiparesis resulted from hypoperfusion of the left hemisphere. An MR angiography showed a severe stenosis at the second portion of left middle cerebral artery (MCA). After the beginning of treatment, the patient suffered from hoarseness, followed by breathing failure. The laryngeal fiber exhibited right vocal cord paresis. Unilateral cortico-bulbar tract dysfunction does not typically cause vocal cord palsy. However, several cases indicate the involvement of a dominant projection from the contralateral cortico-bulbar tract to the vocal cord. In the present case, hypoperfusion of the left hemisphere might have temporarily produced right vocal cord palsy, considering the stenosis of the left MCA.

Charles Bonnet syndrome refers to visual hallucinations in patients with visual acuity loss or visual field loss without dementia. We report a case of Charles Bonnet syndrome following syphilitic optic neuritis. A 62-year-old man was admitted to our hospital suffering acute bilateral visual loss in a few months. On admission, he was almost blind and his optic discs were found to be atrophic on fundoscopy. In addition to increased cell counts and protein concentration in cerebrospinal fluid (CSF), serum and CSF rapid plasma reagin tests were positive. A diagnosis of syphilitic optic neuritis was made and he was treated with intravenous penicillin G (24 million units per day for 14 days) without any recovery. After treatment finished, he began to experience complex, vivid, elaborate and colored visual hallucinations. He recognized these visions as unreal and felt distressed by them. No cognitive impairment was observed on several neuropsychological tests. We diagnosed the patient as suffering from Charles Bonnet syndrome. Brain MRI revealed diffuse mild atrophy of the cerebral cortex and multiple T2 high signal intensity lesions in the deep cerebral white matter. Single photon emission computed tomography revealed decreased regional cerebral blood flow in bilateral medial occipital lobes. Administration of olanzapine resulted in a partial remission of visual hallucinations. Charles Bonnet syndrome following syphilitic optic neuritis is rare. In the present case, visual loss and dysfunction of bilateral medial occipital lobes may have triggered the visual hallucinations, which were alleviated by olanzapine.

The anterior N2 is a component of the event-related brain potential (ERP) elicited by visual novel stimuli. Previous studies have reported that the stimuli that were viewed for longer periods of time elicited a larger anterior N2 than the stimuli viewed for shorter periods of time. To scrutinize this relationship between the ERP and viewing duration in response to visual materials, 18 university students were asked to look at various random polygons one-by-one for as long as they wished. ERPs time-locked to stimulus onset were averaged separately for three levels of complexity (12-, 24-, and 48-sided polygons). We found that the more complex the stimulus, the larger the anterior negativity (N2, 200-300 ms) and the posterior positivity (late positive potential [LPP], 400-800 ms), and the longer the viewing duration. However, when ERPs were calculated separately for the stimuli viewed for longer or shorter than the median viewing time of each participant at each complexity level, no amplitude differences were found in either component. These results suggest that the previously reported correlation between the anterior N2 and visual duration is spurious and produced by a third variable, namely, the perceptual demand of the eliciting stimulus such as complexity., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

We report a case of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) concomitant with acquired von Willebrand syndrome. A 33-year-old man developed motor and sensory polyneuropathy with electrophysiological conduction slowing. At this time, M-protein was absent He was diagnosed with CIDP and received intravenous immunoglobulin and subsequent oral corticosteroids, which resulted in almost complete remission for over 10 years. At the age of 44, he presented with chronic anemia. Laboratory tests and colonoscopy revealed that he had acquired von Willebrand syndrome with monoclonal gammopathy of undetermined significance (IgG lambda type) and colon cancer. Bleeding symptoms were.resolved with intravenous immunoglobulin, but not with supplementation of factor VIII. Shortly after successful excision of the cancer, CIDP and acquired von Willebrand syndrome simultaneously recurred. Intravenous immunoglobulin produced rapid improvement of both neurological and hematological abnormalities. Concurring CIDP and acquired von Willebrand syndrome in the present case may indicate that the conditions have a partly common immunological background including monoclonal gammopathy and a potential common autoantibody-mediated mechanism. Alternatively, dysfunction of von Willebrand factor may increase blood-nerve barrier permeability, inducing the recurrence of CIDP.

We report a 78-year-old woman who had episodes of nonconvulsive status epilepticus (NCSE) with dizziness. At 75 years of age, she had first seizure, but was not well examined. At 78 years of age, she had brief myoclonic jerks of her arms, soon after awakening, in May. She suffered from strong dizziness and was admitted in our hospital at the end of June. The symptoms regressed with bed rest in few days and she was discharged. However, she was admitted again with dizziness in the middle of July. There were no myoclonic jerks of her arms or legs and she could converse and interact normally, but was slightly disoriented (JCS: 2). Blood test, Cerebrospinal fluid analyses and brain MRI were normal. An EEG showed frequent intermittent generalized multiple spikes and slow wave complexes and a 3-4 Hz generalized spike and slow wave complexes every 2-4 seconds during whole 20 minutes record. Intravenous injection of 5 mg diazepam terminated status immediately. Thereafter, she was treated with sodium valproate (400 mg/day). Her symptoms improved, and interictal epileptic discharges extremely decreased. Late-onset NCSE of generalized epilepsy is rare. We discussed this case as an important case for diagnosis of NCSE with subtle symptom of dizziness.

Individuals with autism spectrum disorder (ASD) have severe difficulties in social interaction and communication, as well as restricted and/or stereotyped patterns of behavior. Previous studies have suggested that abnormal neural connectivity might be associated with higher information processing dysfunction involving social impairment. However, the white matter structure in ASD is poorly understood. To explore this, we conducted a voxel-based, whole-brain diffusion tensor imaging (DTI) analysis to determine fractional anisotropy (FA), λ(1), λ(2) and λ(3) in high-functioning children with ASD compared with age-, gender-, and handedness-matched healthy control participants. We then investigated whether DTI parameters were associated with behaviorally measured social function. We found that FA and λ(1) were significantly lower in the ASD group than in the control group in the white matter around left dorsolateral prefrontal cortex (DLPFC), posterior superior temporal sulcus/temporo-parietal junction, right temporal pole, amygdala, superior longitudinal fasciculus, occipitofrontal fasciculus, mid- and left anterior corpus callosum, and mid- and right anterior cingulate cortex. The FA value in the left DLPFC was negatively correlated with the degree of social impairment in children with ASD. Higher λ(1) values were observed in the cerebellar vermis lobules in the ASD group. The white matter alterations in children with ASD were around cortical regions that play important roles in social cognition and information integration. These DTI results and their relationship to social impairment add to evidence of cerebral and cerebellar white matter structural abnormalities in ASD., (Copyright © 2010 Elsevier B.V. All rights reserved.)

A 31-year-old woman with Crohn's disease that had been refractory to drug therapies for 7 years had been treated with infliximab for a year. She was admitted to our hospital because of truncal ataxia and bulbar palsy, which presented following aseptic meningitis. Neurological examination revealed abducens paresis on the left, gaze-evoked nystagmus on upward and rightward gaze, right facial muscle weakness, bulbar palsy, weakness in the right upper extremity, limb ataxia predominantly on the left side, diminished sense in the lower extremities predominantly on the right, diffuse hyperreflexia in all extremities. Antibodies to Epstein-Barr virus (EBV) in serum demonstrated a previous infection pattern, and EBV-DNA was detected in peripheral blood and cerebrospinal fluid (CSF) by PCR. CSF analysis indicated pleocytosis, an elevation of IgG index and a marked increase in the level of myelin basic protein. FLAIR MRI images revealed multiple hyperintense lesions in the brainstem, subcortical white matter, and cervical spinal cord. Accordingly, we diagnosed her as having acute disseminated encephalomyelitis (ADEM), associated with reactivated EBV infection. Although gancyclovir, plasma exchange and intravenous high dose immunoglobulins were not effective, repetitive use of methylprednisolone pulse therapy alleviated her symptoms and the abnormal MRI lesions. It is suggested that the reactivated EBV infection caused by infliximab may have contributed to the development of ADEM in this case. Besides the demyelinating event directly induced by anti-TNF-alpha therapy, we should pay attention to the occurrence of reactivated EBV-triggered ADEM during anti-TNF-alpha therapy.

We report a case of paraneoplastic neurological syndrome with anti-neuronal antibodies, namely anti-Hu and anti-GluR epsilon 2 antibodies in sera. A 72-year-old male had a transient history of eye movement disorder and sensory neuropathy, which improved spontaneously. Two years later, he was admitted to another hospital because of gait disturbance, numbness of the hands and an attack of unconsciousness with generalized convulsion. He was admitted to our hospital with prolonged consciousness disturbance and muscular weakness of all extremities. On admission his consciousness deteriorated slightly without neck stiffness. His cranial nervous system was normal except for incomplete abduction and elevation of both eyes. The patient had severe distal dominant weakness and atrophy in the muscles of all four limbs. Muscle tonus was decreased and hyporeflexia was noted in the four extremities. Plantar response was extensor. Neither sensory disturbance nor ataxia was observed. Cranial MRI showed T2-weighted high intensity lesions in the bilateral mesial temporal lobes, including the hippocampi. A nerve conduction study revealed motor-dominant peripheral neuropathy with prolonged latency; the amplitudes of compound muscle action potentials were severely reduced in all four limbs and those of sensory nerve action potentials were moderately reduced in the right upper and lower extremities. We also found a left hilar lymphadenopathy showing accumulation of FDG on PET, suggesting a possibility of malignancy. Anti-Hu and anti-GluR epsilon 2 antibodies were detected in sera but not in CSF. We diagnosed him with limbic encephalitis and peripheral neuropathy due to paraneoplastic neurological syndrome and treated him with two courses of intravenous immunoglobulin (IVIg) (400 mg/kg, 5 days). The consciousness disturbance, and prolonged distal latency revealed by motor nerve conduction studies improved slightly. Although the roles of anti-neuronal antibodies in paraneoplastic conditions remain unknown, we consider that IVIg may be worth using to treat cases with anti-Hu and anti-GluR epsilon 2 antibodies.

We report a case of mononeuropathy multiplex with idiopathic thrombocytopenic purpura (ITP). A 78-year-old man developed patches of purpura on his left forearm. His platelet count was 11,000/microl and platelet-associated IgG was elevated. He was diagnosed as having ITP. At the beginning of the following month, he noticed dysesthesia and weakness of his left finger and left lower limb, as well as dysesthesia of his bilateral lower thighs. Neurological examination revealed weakness in the area of the left ulnar nerve and of the left anterior tibial muscle. Dysesthesia presented in the area of the left ulnar nerve and bilateral superficial peroneal nerves. Nerve conduction studies revealed asymmetric axonal sensorimotor neuropathy (mononeuropathy multiplex). A cerebrospinal fluid specimen showed a normal cell count and normal protein level Serum anti-ganglioside antibody was negative. The platelet count gradually increased after the introduction of corticosteroid therapy. His neurological deficits and electrophysiological findings also improved. Immune-mediated neuropathy was suggested as the cause of his mononeuropathy multiplex with ITP.

Induced gamma activity has a key role in the temporal binding of distributed cortico-cortical processing. To elucidate the neural synchronization in the early-stage somatosensory processing, we studied the functional connectivity between the primary and secondary somatosensory cortices (SI and SII) in healthy subjects using magnetoencephalography (MEG) with excellent spatiotemporal resolution. First, somatosensory-evoked magnetic fields were recorded to determine the locations of each cortical activity. Then we analyzed the phase-locking values (PLVs) of the induced gamma activity to assess neural synchrony within the somatosensory cortical network. We also assessed PLVs in patients with multiple sclerosis (MS) to validate our PLV analysis in evaluating the inter-areal functional connectivity, which can often be impaired in MS. The PLVs of the induced gamma activity were calculated for each pair of unaveraged MEG signals that represented the activities of the contralateral SI and bilateral SII areas. Analysis of PLVs between the SI and SII areas showed significantly increased PLVs for gamma-band activities, starting at an early post-stimulus stage in normal controls, whereas this increase in PLVs was apparently diminished in MS. The PLV analysis provided evidence for early-latency, gamma-band neuronal synchronization between the SI and SII areas in normal controls. Our study first demonstrates the gamma-band synchrony in the early-stage human somatosensory processing., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

We report the case of a 30-year-old man who developed severe dysphagia owing to neuroborreliosis. He showed dysphagia, diplopia, hiccups, and walking difficulty Neurological examination revealed mild disturbance of consciousness, diplopia on left lateral gaze, left-side-dominant blephaloptosis, gaze-evoked horizontal nystagmus on left lateral gaze, mild bilateral muscle weakness, palatoplegia, dysphagia, dysarthria, and truncal ataxia An increased pharyngeal reflex caused dysphagia in this patient. An EEG revealed intermittent high amplitude slow wave activity. However, head MRI, blood count, serum chemistry, and cerebrospinal fluid examination showed no abnormality. Initially, brainstem encephalitis with unknown etiology was diagnosed. The hiccups, diplopia, and ptosis were improved by corticosteroid therapy, but other symptoms were refractory to corticosteroid therapy and IVIg. After these immunotherapies, anti-Borrelia IgG and IgM antibodies were found to be positive, and symptoms, including dysphagia, were improved by doxycycline and cefotaxime. Because the clinical symptoms of Borrelia infection are widely variable, neuroborreliosis should be considered in patients with brainstem encephalitis refractory to conventional immunotherapies.