川合 謙介

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.

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.

Neuromodulation achieved by vagus nerve stimulation (VNS) induces various neuropsychiatric effects whose underlying mechanisms of action remain poorly understood. Innervation of neuromodulators and a microcircuit structure in the cerebral cortex informed the hypothesis that VNS exerts layer-specific modulation in the sensory cortex and alters the balance between feedforward and feedback pathways. To test this hypothesis, we characterized laminar profiles of auditory-evoked potentials (AEPs) in the primary auditory cortex (A1) of anesthetized rats with an array of microelectrodes and investigated the effects of VNS on AEPs and stimulus specific adaptation (SSA). VNS predominantly increased the amplitudes of AEPs in superficial layers, but this effect diminished with depth. In addition, VNS exerted a stronger modulation of the neural responses to repeated stimuli than to deviant stimuli, resulting in decreased SSA across all layers of the A1. These results may provide new insights that the VNS-induced neuropsychiatric effects may be attributable to a sensory gain mechanism: VNS strengthens the ascending input in the sensory cortex and creates an imbalance in the strength of activities between superficial and deep cortical layers, where the feedfoward and feedback pathways predominantly originate, respectively.

PURPOSE: The Japanese authorities require a 2-year seizure-free period for a driver's license in people with epilepsy. To evaluate the stringency of the criteria, we calculated the risk of fatal traffic crashes by epileptic seizure and compared that to the risk of fatal traffic crashes among the general population. METHODS: Nation-wide questionnaire surveys to physicians and their patients with epilepsy were conducted to determine the rate of seizure recurrence after given seizure-free periods, average driving time and the rate of traffic crashes by epileptic seizures. The risk of fatal traffic crashes by epileptic seizures was calculated using the method proposed by the Driving License Committee of the EU. The risk of fatal traffic crashes among subgroups of the general population was calculated using the national statistics available. RESULTS: Valid answers were obtained from a total of 548 patients of 138 epilepsy-specialists and 102 non epilepsy-specialist physicians. The relative risks of fatal traffic crashes in people with epilepsy with 1-year and 2-year seizure-free periods were 1.22 and 1.15, compared to the general population, while the ones in males in their twenties, people aged 60 and over, people aged 65 and over, and people aged 75 and over among the general population were 1.71, 1.31, 1.52 and 2.69, respectively. CONCLUSION: The risk of fatal traffic crashes in people with epilepsy for 1-year and 2-year seizure-free periods was estimated to be lower than that of some age groups in the general population. The increased risk in 1-year seizure freedom from that in 2-year seizure freedom was relatively small.

An epileptic seizure during the course of driving can result in a serious car accident. However, basic data on how epileptic seizures actually affect driving performance is significantly lacking. To understand the relationship, it is crucial to conduct not only behavioral but also electroencephalogram (EEG) analysis during epileptic seizures. Therefore, we developed a mobile driving simulator which makes it possible to record driving-related parameters time-lined with video-EEG. We report a case in which behavioral and EEG changes were successfully recorded during ictal periods of focal impaired awareness seizure in a patient engaged with the system. With the current lack of objective data describing how seizures impair driving performance, such an accumulation of information could improve personalized medical management, influence legal adjudication and assist in the development of driving support systems for people with epilepsy.

Data presented in this article are related to our article entitled "Unilateral posterior reversible encephalopathy syndrome: A case report" [1]. Cases of Posterior Reversible Encephalopathy Syndrome (PRES) involving unilateral lesions are very rare. We searched the PubMed database using keywords such as PRES, unilateral, and asymmetric and found a small number of cases to include in our review. We summarized the characteristics of these reported cases of unilateral PRES, including our case.

Both frame-based stereotaxy and frameless stereotaxy are established surgical procedures. However, they each have their respective disadvantages when used in the biopsy of a deep-seated lesion. To overcome the drawbacks associated with these procedures, we evaluated the feasibility of applying augmented reality (AR) to stereotactic biopsy. We applied our trans-visible navigator (TVN) to frame-based stereotactic biopsy in five cases of deep-seated lesions. This navigation system uses the AR concept, allowing surgeons to view three-dimensional virtual models of anatomical structures superimposed over the surgical field on a tablet personal computer. Using TVN, we could easily confirm a clear trajectory avoiding the important structures as well as the target point's location in the lesion. Use of the stereotactic apparatus allowed the surgeon to easily advance the biopsy probe to the target point. Consequently, a satisfactory histopathological diagnosis without complication was achieved in all cases. In conclusion, applying AR to stereotactic biopsy is feasible and may improve the safety of the procedure.

INTRODUCTION: Epileptologists could benefit from a diagnosis support system that automatically detects seizures because visual inspection of long-term electroencephalograms (EEGs) is extremely time-consuming. However, the diversity of seizures among patients makes it difficult to develop universal features that are applicable for automatic seizure detection in all cases, and the rarity of seizures results in a lack of sufficient training data for classifiers. METHODS: To overcome these problems, we utilized an autoencoder (AE), which is often used for anomaly detection in the field of machine learning, to perform seizure detection. We hypothesized that multichannel EEG signals are compressible by AE owing to their spatio-temporal coupling and that the AE should be able to detect seizures as anomalous events from an interictal EEG. RESULTS: Through experiments, we found that the AE error was able to classify seizure and nonseizure states with a sensitivity of 100% in 22 out of 24 available test subjects and that the AE was better than the commercially available software BESA and Persyst for half of the test subjects. CONCLUSIONS: These results suggest that the AE error is a feasible candidate for a universal seizure detection feature.

Directing attention to movement outcomes (external focus; EF), not body movements (internal focus; IF), is a better cognitive strategy for motor performance. However, EF is not effective in some healthy individuals or stroke patients. We aimed to identify the neurological basis reflecting the individual optimal attentional strategy using functional near-infrared spectroscopy. Sixty-four participants (23 healthy young, 23 healthy elderly, and 18 acute stroke) performed a reaching movement task under IF and EF conditions. Of these, 13 healthy young participants, 11 healthy elderly participants, and 6 stroke patients showed better motor performance under EF conditions (EF-dominant), whereas the others showed IF-dominance. We then measured prefrontal activity during rhythmic hand movements under both attentional conditions. IF-dominant participants showed significantly higher left prefrontal activity than EF-dominant participants under IF condition. In addition, receiver operating characteristic analysis supported that the higher activity in the left frontopolar and dorsolateral prefrontal cortices could detect IF-dominance as an individual's optimal attentional strategy for preventing motor performance decline. Taken together, these results suggest that prefrontal activity during motor tasks reflects an individual's ability to process internal body information, thereby conferring IF-dominance. These findings could be applied for the development of individually optimized rehabilitation programs.

Auditory contextual processing has been assumed to be based on a hierarchical structure consisting of the primary auditory cortex, superior temporal gyrus (STG), and frontal lobe. Recent invasive studies on mismatch negativity (MMN) have revealed functional segregation for auditory contextual processing such as neural adaptation in the primary auditory cortex and prediction in the frontal lobe. However, the role of the STG remains unclear. We obtained induced activity in the high gamma band as mismatch response (MMR), an electrocorticographic (ECoG) counterpart to scalp MMN, and the components of MMR by analyzing ECoG data from patients with refractory epilepsy in an auditory oddball task paradigm. We found that MMR localized mainly in the bilateral posterior STGs, and that deviance detection largely accounted for MMR. Furthermore, adaptation was identified in a limited number of electrodes on the superior temporal plane. Our findings reveal a mixed contribution of deviance detection and adaptation depending on location in the STG. Such spatial considerations could lead to further understanding of the pathophysiology of relevant psychiatric disorders.

Survivin, a member of the inhibitors of apoptosis protein gene family, inhibits the activity of caspase, leading to a halt of the apoptotic process. Our study focused on the neuroprotective effect of survivin after transient middle cerebral artery occlusion (MCAO) with intraparenchymal administration of an adeno-associated virus (AAV) vector. His-tagged survivin was cloned and packaged into the AAV-rh10 vector. Four-week-old Sprague-Dawley rats were injected with 4 × 109  vg of AAV-GFP or AAV-His-survivin into the right striatum and were treated 3 weeks later with transient MCAO for 90 min. Twenty-four hours after MCAO, functional and histological analyses of the rats were performed. The result showed that rats that had been treated with AAV-green fluorescent protein (GFP) and those that had been treated with AAV-His-survivin did not show a significant difference in neurological scores 24 hr after MCAO, however, infarction volume was significantly reduced in the AAV-His-survivin group compared to that in the AAV-GFP group. Although the neutrophil marker myeloperoxidase did not show a significant difference in the ischemic boundary zone, cells positive for active caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were significantly decreased in the AAV-His-survivin group. In conclusion, survivin overexpression in the ischemic boundary zone induced by using an AAV vector has the potential for amelioration of ischemic damage via an antiapoptotic mechanism.

Adeno-associated virus (AAV) is an ideal vector for gene transduction into the central nervous system because of its safety and efficiency. While it is currently widely used for clinical trials and is expected to become more widespread, the appropriate combination of viral serotypes and promoters have not been fully investigated. In this study, we compared the transduced gene expression of AAVrh10 to AAV5 in gerbil hippocampus using three different promoters, including cytomegalovirus (CMV), chicken β-actin promoter with the CMV immediate-early enhancer (CAG), and the Synapsin 1 (Syn1) promoter. Four-week-old male gerbils underwent stereotaxic injection with 1 × 1010 viral genome of AAV carrying green fluorescent protein (GFP). Quantification of the GFP-positive areas 3 weeks after injection showed that AAVrh10-CMV and AAVrh10-CAG were the most efficient (p < 0.001, compared with the control) and AAVrh10-Syn1 and AAV5-CMV were the next most efficient (p < 0.05, compared with the control). On the other hand, AAV5-Syn1 showed little expression, which was only observed at the injected site. In conclusion, we should note that some combinations of viral capsids and promoters can result in failure of gene delivery, while most of them will work appropriately in the transgene expression in the brain.

＜文献概要＞I.はじめに 難治性てんかんに対してさまざまな刺激療法が行われてきたが,現在,普及し拡大を続けている植込み型デバイスは,迷走神経刺激療法(vagus nerve stimulation:VNS)のシステム(VNS Therapy System. LivaNova USA, Inc., Houston, TX, USA)である.1980年代から基礎研究が進められ,欧州では1994年,米国では1997年に正式に認可された.VNSの治験は本邦においても1993〜1997年にかけて行われ,認可申請されたが,承認を得るには時間を要した.2006年10月から始まった厚生労働省の「医療ニーズの高い医療機器等の早期導入に関する検討会」の第2回会合(2007年2月)でVNSが取り上げられ,これによって本邦においてもようやく日の目を見ることとなった.2010年1月に薬事法承認,同年7月に保険適用となったことで保険償還が可能となり,急速に普及していった.VNSのデバイスは,本邦での治験の頃はNeuroCybernetic Prosthesis(Model 100)というプロトタイプであったが,2010年から実際に使われ始めたのは小型化されたDemipulse(Model 103)で