川合 謙介

It is established that neurogenesis of dentate gyrus is increased after ischemic insult, although the regulatory mechanisms have not yet been elucidated. In this study, we focused on Ezh2 which suppresses gene expression through catalyzing trimethylation of lysine 27 of histone 3. Male gerbils were injected with adeno-associated virus (AAV) carrying shRNA targeting to Ezh2 into right dentate gyrus 2 weeks prior to forebrain ischemia. One week after ischemia, animals were injected with thymidine analogue to label proliferating cells. Three weeks after ischemia, animals were killed for histological analysis. AAV-mediated knockdown of Ezh2 significantly decreased the ischemia-induced increment of proliferating cells, and the proliferated cells after ischemia showed significantly longer migration from subgranular zone (SGZ), compared to the control group. Furthermore, the number of neural stem cells in SGZ significantly decreased after ischemia with Ezh2 knockdown group. Of note, Ezh2 knockdown did not affect the number of proliferating cells or the migration from SGZ in the non-ischemic condition. Our data showed that, specifically after ischemia, Ezh2 knockdown shifted the balance between self-renewal and differentiation toward differentiation in adult dentate gyrus.

The action observation network (AON) has been extensively studied using short, isolated motor acts. How activity in the network is altered when these isolated acts are embedded in meaningful sequences of actions remains poorly understood. Here we utilized intracranial electrocorticography to characterize how the exchange of information across key nodes of the AON-the precentral, supramarginal, and visual cortices-is affected by such embedding and the resulting predictability. We found more top-down beta oscillation from precentral to supramarginal contacts during the observation of predictable actions in meaningful sequences compared to the same actions in randomized, and hence less predictable, order. In addition, we find that expectations enabled by the embedding lead to a suppression of bottom-up visual responses in the high-gamma range in visual areas. These results, in line with predictive coding, inform how nodes of the AON integrate information to process the actions of others.

BACKGROUND: We previously found that vagus nerve stimulation (VNS) strengthened stimulus-evoked activity in the superficial layer of the sensory cortex but not in the deep layer, suggesting that VNS altered the balance between the feedforward (FF) and feedback (FB) pathways. Band-specific oscillatory activities in the cortex could serve as an index of the FF-FB balance, but whether VNS affects cortical oscillations along sensory pathways through neuromodulators remains unclear. HYPOTHESIS: VNS modulates the FF-FB balance through the cholinergic and noradrenergic systems, which modulate stimulus gain in the cortex. METHODS: We investigated the effects of VNS using electrocorticography in the auditory cortex of 34 Wistar rats under general anesthesia while presenting click stimuli. In the time-frequency analyses, the putative modulation of the FF and FB pathways was estimated using high- and low-frequency power. We assessed, using analysis of variance, how VNS modulates auditory-evoked activities and how the modulation changes with cholinergic and noradrenergic antagonists. RESULTS: VNS increased auditory cortical evoked potentials, consistent with results of our previous work. Furthermore, VNS increased auditory-evoked gamma and beta powers and decreased theta power. Local administration of cholinergic antagonists in the auditory cortex selectively disrupted the VNS-induced increase in gamma and beta power, while noradrenergic antagonists disrupted the decrease in theta power. CONCLUSIONS: VNS might strengthen the FF pathway through the cholinergic system and attenuate the FB pathway through the noradrenergic system in the auditory cortex. Cortical gain modulation through the VNS-induced neuromodulatory system provides new mechanistic insights into the effect of VNS on auditory processing.

Insertion of a deep brain stimulating electrode is a commonly performed procedure. Burr hole caps play an important role in this procedure by immobilizing this electrode; however, burr hole caps could form scalp bumps, which can create further complications. The dual-floor burr hole technique could prevent the formation of scalp bumps. This technique has previously been used with older versions of burr hole caps and has proved to be successful. In recent years, modern burr hole caps with an internal electrode locking mechanism have become the mainstay for this procedure. However, modern burr hole caps differ considerably in diameter and shape from older burr hole caps. In the present study, a dual-floor burr hole technique was performed using modern burr hole caps. To accommodate the increase in diameters and changes in the shape of modern burr hole caps, a perforator with a 30-mm diameter was used for shaving the bone, and the bone shaving depth was altered. This surgical technique was applied to 23 consecutive deep brain stimulation surgeries without complications and was thus positively optimized for modern burr hole caps.

Stereotactic neurosurgery is an established technique, but it has several limitations. In frame-based stereotaxy using a stereotactic frame, frame setting errors may decrease the accuracy of the procedure. Frameless stereotaxy using neuronavigation requires surgeons to shift their view from the surgical field to the navigation display and to advance the needle while assuming a physically uncomfortable position. To overcome these limitations, several researchers have applied augmented reality in stereotactic neurosurgery. Augmented reality enables surgeons to visualize the information regarding the target and preplanned trajectory superimposed over the actual surgical field. In frame-based stereotaxy, a researcher applies tablet computer-based augmented reality to check for the setting errors of the stereotactic frame, thereby improving the safety of the procedure. Several researchers have reported performing frameless stereotaxy guided by head-mounted-display-based augmented reality that enables surgeons to advance the needle at a more natural posture. These studies have shown that augmented reality can address the limitations of stereotactic neurosurgery. Conversely, they have also revealed the limited accuracy of current augmented reality systems for small targets, which indicates that further development of augmented reality systems is needed.

＜文献概要＞Point ・道路交通法第66条は,正常な運転ができないおそれがある状態の運転を禁止しているが,てんかんにおいては運転免許資格の法的基準が設けられており,その基準に則って判断すれば法的には問題ない.・てんかんがあっても,覚醒中に意識や運動が障害される発作が2年以上ない場合は運転免許の拒否は行われない.・てんかん患者に対する福祉制度として,医療費関連,手帳関連,年金補助金関連に大別される.患者の疾病および障害を把握した上で適切な制度を提示することが必要である.

This study aimed to clarify whether short-term neurofeedback training during the acute stroke phase led to prefrontal activity self-regulation, providing positive efficacy to working memory. A total of 30 patients with acute stroke performed functional near-infrared spectroscopy-based neurofeedback training for a day to increase their prefrontal activity. A randomized, Sham-controlled, double-blind study protocol was used comparing working memory ability before and after neurofeedback training. Working memory was evaluated using a target-searching task requiring spatial information retention. A decline in spatial working memory performance post-intervention was prevented in patients who displayed a higher task-related right prefrontal activity during neurofeedback training compared with the baseline. Neurofeedback training efficacy was not associated with the patient's clinical background such as Fugl-Meyer Assessment score and time since stroke. These findings demonstrated that even short-term neurofeedback training can strengthen prefrontal activity and help maintain cognitive ability in acute stroke patients, at least immediately after training. However, further studies investigating the influence of individual patient clinical background, especially cognitive impairment, on neurofeedback training is needed. Current findings provide an encouraging option for clinicians to design neurorehabilitation programs, including neurofeedback protocols, for acute stroke patients.

BACKGROUND: The delivery of adeno-associated virus (AAV) vectors via the cerebrospinal fluid (CSF) has emerged as a valuable method for widespread transduction in the central nervous system. While infusion into the cerebral ventricles is a common protocol in preclinical studies of small animals, the cisterna magna has been recognized as an alternative target for clinical studies, as it can be reached in a less invasive manner using an intrathecal catheter via the subarachnoid space from a lumbar puncture. METHODS: We evaluated the early distribution of fluorine-18-labeled AAV9 vectors infused into the lateral ventricle or cisterna magna of four non-human primates using positron emission tomography. The expression of the green fluorescent protein was immunohistochemically determined. RESULTS: In both approaches, the labeled vectors diffused into the broad arachnoid space around the brain stem and cervical spinal cord within 30 mins. Both infusion routes efficiently transduced neurons in the cervical spinal cord. CONCLUSIONS: For gene therapy that primarily targets the cervical spinal cord and brainstem, such as amyotrophic lateral sclerosis, cisterna magna infusion would be a feasible and effective administration method.

BACKGROUND: Despite the increasing availability of effective drugs, around one-third of patients with epilepsy are still resistant to pharmacotherapy. Gene therapy has been suggested as a plausible approach to achieve seizure control, in particular for patients with focal epilepsy. Because seizures develop across wide spans of the brain in many forms of epilepsy, global delivery of the vectors is necessary to tackle such generalized seizures. Neuroligin 2 (NL2) is a postsynaptic cell adhesion molecule that induces or strengthens inhibitory synaptic function by specifically combining with neurexin 1. METHODS: In the present study, we applied an adeno-associated virus (AAV) type 9 vector expressing NL2 to modulate neuronal excitability in broad areas of the brain in epileptic (EL) mice, a model of polygene epilepsy. We administered the AAV vector expressing Flag-tagged NL2 under the synapsin I promoter (AAV-NL2) via cardiac injection 6 weeks after birth. RESULTS: Significant reductions in the duration, strength and frequency of seizure were observed during a 14-week observation period in NL2-treated EL mice compared to untreated or AAV-green fluorescent protein-treated EL mice. No behavioral abnormality was observed in NL2-treated EL mice in an open-field test. Immunohistochemical examination at 14 weeks after AAV-NL2 injection revealed the expression of exogenous NL2 in broad areas of the brain, including the hippocampus and, in these areas, NL2 co-localized with postsynaptic inhibitory molecule gephyrin. CONCLUSIONS: Global brain delivery of NL2 by systemic administration of AAV vector may provide a non-invasive therapeutic approach for generalized epilepsy.

OBJECTIVE: To examine the current medical and psychosocial status of patients with epilepsy, aiming to facilitate appropriate application of the Intractable/Rare Diseases Act of Japan. METHODS: By analysing the cross-sectional data of patients registered in the tertiary hospital-based Epilepsy Syndrome Registry of Japan, we investigated the proportion of patients who met the severity criteria as defined by the Act (seizure frequency of at least once a month, or presence of intellectual/neurological/psychiatric symptoms, or both) and whether there are candidate syndrome/diseases to be added to the existing list in the Act. RESULTS: In total, 2,209 patients were registered. After excluding self-limited/idiopathic epilepsies, 1,851 of 2,110 patients (87.7%) met the severity criteria. The patients were classified into eight main epilepsy syndromes (594 patients), 20 groups based on aetiology (1,078 patients), and three groups without known aetiology (427 patients). Most of the groups classified by syndrome or aetiology had high proportions of patients satisfying the severity criteria (>90%), but some groups had relatively low proportions (<80%) resulting from favourable outcome of surgical therapy. Several small groups with known syndrome/aetiology await detailed analysis based on a sufficiently large enough number of patients registered, some of whom may potentially be added to the list of the Act. SIGNIFICANCE: The registry provides data to examine the usefulness of the severity criteria and list of diseases that are operationally defined by the Act. Most epilepsy patients with various syndromes/diseases and aetiology groups are covered by the Act but some are not, and the list of designated syndromes/diseases should be complemented by further amendments, as suggested by future research.

To date, several researchers have introduced augmented reality navigation (ARN) into neurological surgery. While its application in brain tumor surgery seems promising, reports on its utility have been limited, thus warranting further evaluation. To clarify the stages and approaches in which ARN is useful and assess the effect of presurgical discussion with surgeons, we assessed usefulness using a hand-held ARN system we had developed, which displays three-dimensional (3D) virtual structures overlaid on a real-time image of the surgical field via a tablet PC monitor. The system was tested in 20 patients undergoing various procedures, with the first 10 consecutive cases being unselected and the following 10 cases being selected, for whom 3D models were prepared per the surgeons' request. Thereafter, the surgeons ranked its usefulness during each stage of surgery. Consequently, case selection and presurgical discussions with surgeons considerably improved the usefulness, with the "useful" gradings improving from 50% to 88% across all surgical stages. Accordingly, usefulness improved from 50% to 90%, 67% to 100%, and 40% to 80% during the skin incision and craniotomy, dura incision, and intradural procedure stages, respectively. ARN was useful for superficial tumor resection, but less so for deep-seated tumor resection, except when using the transcortical and interhemispheric approaches. In conclusion, a tablet-type ARN can be useful during skin incisions, craniotomy and dura incisions, superficial tumor resections, and transcortical and interhemispheric approaches for deep-seated tumors. Case selection and presurgical discussions with surgeons were essential for the efficacy of ARN.

Recent reports suggest that Staphylococcus haemolyticus can cause infective endocarditis (IE). However, no data are available regarding infectious intracranial aneurysm (IIA) following S. haemolyticus endocarditis. Endovascular coiling is a challenging approach for the treatment of IIA. We describe the case of a 63-year-old woman who suddenly developed aphasia and dysarthria following an acute cerebral infarction in her left insular and temporal cortex. After a total hysterectomy at the age of 39, the patient had suffered from recurrent bacterial pyomyositis in her legs. At admission, there was no evidence of cerebral aneurysm, as assessed by magnetic resonance angiography, and no vegetation, as assessed by transesophageal echocardiography (TEE), resulting in an incorrect diagnosis. However, subarachnoid hemorrhage and development of cerebral aneurysm in the left middle cerebral artery occurred within 1 week of hospitalization. Continuous positive blood culture results and a second TEE finally revealed that IE was caused by S. haemolyticus. Coil embolization of the IIA was successful on day 26 after symptom onset; after this procedure, the patient began to recover. This case demonstrates that S. haemolyticus-induced endocarditis can cause IIA. Endovascular coiling is a potentially effective approach to treat IIA.

This study investigated the number of epilepsy surgeries performed over time in Japan, and conducted a questionnaire survey of the Japan Neurosurgical Society (JNS) training program core hospitals to determine the current status and future objectives of surgical therapies and epilepsy training programs for physicians in Japan. This article presents part of a presentation delivered as a presidential address at the 44th Annual Meeting of the Epilepsy Surgery Society of Japan held in January 2021. The number of epilepsy surgeries performed per year has increased in Japan since 2011 to around 1,200 annually between 2015 and 2018. The questionnaire survey showed that 50% of the responding hospitals performed epilepsy surgery and 29% had an epilepsy center, and that these hospitals provided senior residents with education regarding epilepsy surgery. The presence of an epilepsy center in a hospital was positively correlated with the availability of long-term video electroencephalography monitoring beds as well as the number of epilepsy surgeries performed at the hospital. In regions with no medical facilities offering specialized surgical therapies for epilepsy, the JNS training program core hospitals may help improve epilepsy diagnosis and treatment. They may also increase the number of safe and effective surgeries by establishing epilepsy centers that can perform long-term video electroencephalography monitoring, providing junior neurosurgeons with training regarding epilepsy, and playing a core role in surgical therapies for epilepsy in tertiary medical areas in close cooperation with neighboring medical facilities.

43歳女性。糖尿病の既往をもつ。尿崩症と下垂体機能低下症の入院加療中に突然激しい頭痛が出現した。頭痛は遷延し、頭部MRIを行ったところ、既知のトルコ鞍部嚢胞性病変が増大しており、当科へ紹介となった。病歴やMRI所見から頭蓋咽頭腫、ラトケ嚢胞、下垂体後葉腫瘍を鑑別に挙げ、経鼻内視鏡的経蝶形骨洞手術が行われた。その結果、病理組織学的にラトケ嚢胞を背景とした下垂体膿瘍と診断された。術後は抗生剤による治療を4週間行い、術後半年経過現在、再発は認められていない。

BACKGROUND: The DYNC1H1 gene encodes the heavy chain of cytoplasmic dynein 1, a core structure of the cytoplasmic dynein complex. Dominant DYNC1H1 mutations are implicated in Charcot-Marie-Tooth disease, axonal, type 20, spinal muscular atrophy, lower extremity-predominant 1, and autosomal dominant mental retardation 13 with neuronal migration defects. We report two patients with DYNC1H1 mutations who had intractable epilepsy and intellectual disability (ID), one with and one without pachygyria. CASE REPORTS: Patient 1 had severe ID. At the age of 2 months, she presented myoclonic seizures and tonic seizures, and later experienced atonic seizures and focal impaired-awareness seizures (FIAS). EEG showed slow waves in right central areas during myoclonic seizures. Brain MRI revealed pachygyria, predominantly in the occipital lobe. After callosal transection her atonic seizures disappeared, but FIAS remained. Patient 2 was diagnosed with autism spectrum disorder (ASD) and severe ID. At the age of 7 years, he presented generalized tonic-clonic seizures, myoclonic seizures, and FIAS. Interictal EEG showed generalized spike-and-wave complexes, predominantly in the left frontal area. Brain MRI was unremarkable. Exome sequencing revealed novel de novo mutations in DYNC1H1: c.4691A > T, p.(Glu1564Val) in Patient 1 and c.12536 T > C, p.(Leu4179Ser) in Patient 2. CONCLUSIONS: DYNC1H1 comprises a stem, stalk, and six AAA domains. Patient 2 is the second report of an AAA6 domain mutation without malformations of cortical development. The p.(Gly4072Ser) mutation in the AAA6 domain was also reported in a patient with ASD. It may be that the AAA6 domain has little effect on neuronal movement of DYNC1H1 along microtubules.

The safety and high efficiency of adeno-associated virus (AAV) vectors has facilitated their wide scale use to deliver therapeutic genes for experimental and clinical purposes in diseases affecting the central nervous system (CNS). AAV1, 2, 5, 8, 9, and rh10 are the most commonly used serotypes for CNS applications. Most AAVs are known to transduce genes predominantly into neurons. However, the precise tropism of AAVs in the dentate gyrus (DG), the region where persistent neurogenesis occurs in the adult brain, is not fully understood. We stereotaxically injected 1.5 × 1010 viral genomes of AAV2, 5, or rh10 carrying green fluorescent protein (GFP) into the right side of gerbil hippocampus, and performed immunofluorescent analysis using differentiation stage-specific markers one week after injection. We found that AAV5 showed a significantly larger number of double positive cells for GFP and Sox2 in the DG, compared to the AAV2 and rh10 groups. On the other hand, AAVrh10 presented a substantially larger number of double positive cells for GFP and NeuN in the DG, compared to AAV2 and AAV5. Our findings indicated that AAV5 showed high transduction efficiency to neural stem cells and precursor cells, while AAVrh10 showed much higher efficiency to mature neurons in the DG.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Primary central nervous system lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma, but its diagnosis is challenging in some cases. A brain biopsy is the gold standard for diagnosing PCNSL, but its invasiveness can be problematic. Thus, noninvasive imaging examinations have been developed for the pre-surgical diagnosis of PCNSL, including gadolinium-enhanced magnetic resonance imaging (MRI), 123I-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (123I-IMP SPECT), and positron emission tomography with 18F-fluorodeoxyglucose (18F-FDG PET). Here, we report the case of a 71-year-old woman with negative imaging findings for PCNSL, but who was diagnosed with PCNSL by a brain biopsy and histological analysis. Her imaging results were negative for gadolinium-enhanced cranial MRI, with low uptake in 123I-IMP SPECT and hypometabolism in 18F-FDG PET. However, a stereotactic brain biopsy from an abnormal lesion revealed that many round cells had infiltrated into the brain. Moreover, many infiltrating cells were positive for cluster of differentiation (CD)20 and CD79a, and proliferation marker protein Ki-67-positive cells accounted for nearly 80% of all cells. Based on these results, our final pathological diagnosis was PCNSL. The present case highlights the possibility of a PCNSL diagnosis even when all imaging-related examinations display negative results.

Rosette-forming glioneuronal tumors (RGNTs) are benign WHO grade 1 tumors that occur in the ventricular system, particularly the fourth ventricle. RGNTs and dysembryoplastic neuroepithelial tumors (DNTs) are both categorized as neuronal and mixed neuronal-glial tumors and may be difficult to distinguish. Coexistence of the two tumor types has been reported. Here, we report a pediatric case of RGNT with DNT-like features showing intraventricular dissemination. The tumor occurred in the medial temporal lobe and presented with specific pathological glioneuronal elements including floating neurons, which are typical in DNTs, but was diagnosed as RGNT because of the presence of neurocytic rosettes. Genetic analysis detected fibroblast growth factor receptor 1 internal tandem duplication (FGFR1-ITD) of the tyrosine kinase domain, which was previously reported to be specific for DNT. RGNTs with FGFR1-ITD may show atypical clinical presentation and pathological features.

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders.

Global autobiographical amnesia is a rare disorder that is characterized by a sudden loss of autobiographical memories covering many years of an individual's life. Generally, routine neuroimaging studies such as CT and MRI yield negative findings in individuals with global autobiographical amnesia. However, in recent case reports, functional analyses such as SPECT and fMRI have revealed changes in activity in various areas of the brain when compared with controls. Studies using iomazenil (IMZ) SPECT with individuals with global autobiographical amnesia have not been reported. We report the case of a 62-year-old Japanese woman with global autobiographical amnesia who had disappeared for ∼4 weeks. [123I]-IMZ SPECT showed reduced IMZ uptake in her left medial temporal lobe and no significant reduction on N-isopropyl-[123I] p-iodoamphetamine (IMP) SPECT in the identical region. Because IMZ binds to the central benzodiazepine receptor, this dissociation between IMZ and IMP SPECT was thought to reflect the breakdown of inhibitory neurotransmission in the left medial temporal lobe. Moreover, when the woman recovered most of her memory 32 months after fugue onset, the IMZ SPECT-positive lesion had decreased in size. Because the woman had long suffered verbal abuse from her former husband's sister and brother, which can also cause global autobiographical amnesia, it is difficult to conclude whether the IMZ SPECT-positive lesion in the left medial temporal lobe was the cause or the result of her global autobiographical amnesia. Although only one case, these observations suggest that IMZ SPECT may be useful in uncovering the mechanisms underlying global autobiographical amnesia.

Patients with drug-resistant focal onset epilepsy are not always suitable candidates for resective surgery, a definitive intervention to control their seizures. The alternative surgical treatment for these patients in Japan has been vagus nerve stimulation (VNS). Besides VNS, epileptologists in the United States can choose a novel palliative option called responsive neurostimulation (RNS), a closed-loop neuromodulation system approved by the US Food and Drug Administration in 2013. The RNS System continuously monitors neural electroencephalography (EEG) activity at the possible seizure onset zone (SOZ) where electrodes are placed and responds with electrical stimulation when a pre-defined epileptic activity is detected. The controlled clinical trials in the United States have demonstrated long-term utility and safety of the RNS System. Seizure reduction rates have continued to improve over time, reaching 75% over 9 years of treatment. The incidence of implant-site infection, the most frequent device-related adverse event, is similar to those of other neuromodulation devices. The RNS System has shown favorable efficacy for both mesial temporal lobe epilepsy (TLE) and neocortical epilepsy of the eloquent cortex. Another unique advantage of the RNS System is its ability to provide chronic monitoring of ambulatory electrocorticography (ECoG). Valuable information obtained from ECoG monitoring provides a better understanding of the state of epilepsy in each patient and improves clinical management. This article reviews the developmental history, structure, and clinical utility of the RNS System, and discusses its indications as a novel palliative option for drug-resistant epilepsy.

Background: In recent years, young neurosurgeons have had few opportunities to gain experience with clipping surgeries. The first author was sometimes surprised that she could not predict the anatomical relationships between the aneurysm and vessels during actual surgery. This study investigated the differences between the expected and actual operative findings during clipping surgery for aneurysms of the middle cerebral artery. Methods: Medical records for 15 patients who underwent rotational three-dimensional (3D) digital subtraction angiography (3D-DSA) before the clipping surgery were analyzed after the surgery. The anatomical relationships between the aneurysm and parent arteries were defined by the intraoperative findings just before clipping. The viewing direction to obtain this definitive perspective (virtual viewing direction) was measured. The angle between this viewing direction and the coordinate axis was denoted as the "virtual angle for clipping (VAC)." Results: The VAC between the X-axis and viewing direction on the XY-plane (VAC-XY) ranged from -43° to +73° (mean, +27°), and the angle between the XY-plane and viewing direction (VAC-Z) ranged from +25° to -34° (mean, 5.5°). The difference between the VAC-XY and mean angle was significantly larger in cases with hidden branches behind the aneurysm. In these cases, the virtual viewing direction visualized the neck of the aneurysm. There is no correlation between M1 length and VAC-XY or VAC-Z discrepancy. Conclusion: 3D-DSA or 3D computed tomography angiography images visualizing the neck of the aneurysm should be obtained in combination with images obtained from the standard oblique angle.

Mitochondrial dysfunction is significantly associated with neurological deficits and age-related neurological diseases. While mitochondria are dynamically regulated and properly maintained during neurogenesis, the manner in which mitochondrial activities are controlled and contribute to these processes is not fully understood. Mitochondrial transcription factor A (TFAM) contributes to mitochondrial function by maintaining mitochondrial DNA (mtDNA). To clarify how mitochondrial dysfunction affects neurogenesis, we induced mitochondrial dysfunction specifically in murine neural stem cells (NSCs) by inactivating Tfam. Tfam inactivation in NSCs resulted in mitochondrial dysfunction by reducing respiratory chain activities and causing a severe deficit in neural differentiation and maturation both in vivo and in vitro. Brain tissue from Tfam-deficient mice exhibited neuronal cell death primarily at layer V and microglia were activated prior to cell death. Cultured Tfam-deficient NSCs showed a reduction in reactive oxygen species produced by the mitochondria. Tfam inactivation during neurogenesis resulted in the accumulation of ATF4 and activation of target gene expression. Therefore, we propose that the integrated stress response (ISR) induced by mitochondrial dysfunction in neurogenesis is activated to protect the progression of neurodegenerative diseases.

Aromatic l-amino acid decarboxylase (AADC) is an essential dopamine-synthesizing enzyme. In children with AADC deficiency, the gene delivery of AADC into the putamen, which functionally interacts with cortical regions, was found to improve motor function and ameliorate dystonia. However, how the restoration of dopamine in the putamen in association with cortico-putaminal networks leads to therapeutic effects remains unclear. Here, we examined neuroimaging data of eight patients with AADC deficiency (five males and three females, age range 4-19 years) who received the AADC gene therapy of the bilateral putamen in an open-label phase 1/2 study. Using high-resolution positron emission tomography with a specific AADC tracer, 6-[18F]fluoro-l-m-tyrosine (FMT), we showed that FMT uptake increased in the broad area of the putamen over the years. Then, with the structural connectivity-based parcellation of the putaminal area, we found that motor improvement is associated with dopaminergic restoration of the putaminal area that belongs to the prefrontal cortico-putaminal network. The prefrontal area dominantly belongs to the frontoparietal control network, which contributes to cognitive-motor control function, including motor initiation and planning. The results suggest that putaminal dopamine promotes the development of an immature motor control system, particularly in the human prefrontal cortex that is primarily affected by AADC deficiency.

Background: Vagus nerve stimulation (VNS) is an established palliative surgical treatment for refractory epilepsy. Recently, pairing VNS with rehabilitation received growing attention for their joint effect on neural plasticity. However, objective biological measurements proving the interaction between VNS effects and cortical recruitment are lacking. Studies reported that VNS induced little blood flow increase in the cerebral cortex. Objective: This study tested the hypothesis that pairing VNS with a cognitive task amplifies task-induced cerebral blood flow (CBF). Methods: This study included 21 patients implanted with vagus nerve stimulator to treat refractory epilepsy. Near-infrared spectroscopy (NIRS) with sensors on the forehead measured CBF changes in the frontal cortices in response to VNS. Cerebral blood flow was measured when VNS was delivered during a resting state or a verbal fluency task. We analyzed the VNS effect on CBF in relation to stimulation intensity and clinical responsiveness. Results: We observed no CBF change when VNS was delivered during rest, irrespective of stimulation intensity or responsiveness. Cerebral blood flow changed significantly when a verbal fluency task was paired with VNS in a stimulation intensity-dependent manner. Cerebral blood flow changes in the non-responders showed no intensity-dependency. Conclusion: Our results could be an important biological proof of the interaction between VNS effects and cortical recruitment, supporting the validity of pairing VNS with rehabilitation.

脊髄係留症候群に対する臀部を術野とする係留解除術では、関節や皮膚の可動性により、術前の診断画像と実際の術野の形状に解離が起こり得る。このため、光学式ナビゲーションであるTrans-visible navigator(TVN)の適用にはレジストレーションの点で課題があった。今回、骨盤における解剖学的ランドマークを用いたレジストレーションを考案し、脊髄係留症候群1例(7歳男児)に対して係留解除術にTVNの適用を試みた。術前のCT、MRIを基に脊髄、および硬膜嚢、腰椎、骨盤の3D画像をDICOM編集ソフトで作製し、TVNに登録した。患者に全身麻酔を導入し腹臥位とした後、尾骨先端部および両上後腸骨棘を触診で同定し、その位置をTVNに登録することでレジストレーションを行った。マーキング段階からTVNを手術支援として導入し、実際の手術においてレジストレーションが可能か、およびTVNの脊髄係留症候群に対する有用性を検証した。その結果、予定した尾骨先端部および両上後腸骨棘による3点の解剖学的ランドマークは、いずれも容易に触診可能で、レジストレーションも可能であった。TVNは計画通り起動し、術者に3D情報を提供することで手術を支援した。術後に新規の神経学的脱落所見はなく、術後7日目に退院となった。退院後の外来にて脊髄係留症状の改善が認められた。

OBJECTIVE: In long-term video-monitoring, automatic seizure detection holds great promise as a means to reduce the workload of the epileptologist. A convolutional neural network (CNN) designed to process images of EEG plots demonstrated high performance for seizure detection, but still has room for reducing the false-positive alarm rate. METHODS: We combined a CNN that processed images of EEG plots with patient-specific autoencoders (AE) of EEG signals to reduce the false alarms during seizure detection. The AE automatically logged abnormalities, i.e., both seizures and artifacts. Based on seizure logs compiled by expert epileptologists and errors made by AE, we constructed a CNN with 3 output classes: seizure, non-seizure-but-abnormal, and non-seizure. The accumulative measure of number of consecutive seizure labels was used to issue a seizure alarm. RESULTS: The second-by-second classification performance of AE-CNN was comparable to that of the original CNN. False-positive seizure labels in AE-CNN were more likely interleaved with "non-seizure-but-abnormal" labels than with true-positive seizure labels. Consequently, "non-seizure-but-abnormal" labels interrupted runs of false-positive seizure labels before triggering an alarm. The median false alarm rate with the AE-CNN was reduced to 0.034 h-1, which was one-fifth of that of the original CNN (0.17 h-1). CONCLUSIONS: A label of "non-seizure-but-abnormal" offers practical benefits for seizure detection. The modification of a CNN with an AE is worth considering because AEs can automatically assign "non-seizure-but-abnormal" labels in an unsupervised manner with no additional demands on the time of the epileptologist.

3Dプリンタを用いて中空で軟らかい血管モデルを作製した脳動脈瘤51例を対象とした。作製法は新たな手法を考案するたびに部分的に変更し、これを用いて手術シミュレーションとトレーニングを行った。また、変更の前後で品質と作製時間を比較した。その結果、多くの症例で手術前シミュレーションについての術者の評価が良好で、特に複雑な構造の動脈瘤に対しての評価が高かった。作製法の変更は考案の度に適宜加えたため、変更前後で品質や作製時間の比較はできなかった。便宜的に初期の3年と後期の3年の症例間で比較したところ、品質に関しては著変はなかった。作製時間に関しては、変更前589±102分、変更後425±99分であり、変更したことでより短縮していた。本モデルは手術シミュレーションに有用と考えられた。

薬剤抵抗性で難治に経過するてんかん症例に対しては、成人・小児に関わらず、積極的な外科手術適応を考慮すべきであるが、特に小児においてはより早期の手術施行が望まれる。なぜなら、重症てんかん発作の持続が小児の精神運動発達を遅滞、時に退行させうるからである。術後無発作を達成するためには、てんかん原性領域を確実に同定し完全に切除する必要がある。重要な脳機能に関与する部位を含んだ根治的切除は重篤な神経学的後遺症を引き起こす可能性があるが、小児期の脳は可塑性が高く術後神経機能の代償性改善が期待しやすい。さらに、抗てんかん薬の長期内服が患児に及ぼしうる悪影響も早期手術が望まれる要因である。一方で、小児てんかん外科手術が、患児のIQや併存する精神神経疾患などに及ぼす影響については今後更なる検討が必要である。本稿では、小児てんかん外科治療の最も適切なタイミングについて、自験例と文献的考察を交えながら述べる。(著者抄録)