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Background: Intracerebral amyloid β (Aβ) accumulation is considered the initial observable event in the pathological process of Alzheimer's disease (AD). Efficient screening for amyloid pathology is critical for identifying patients for early treatment. This study developed machine learning models to classify positron emission tomography (PET) Aβ-positivity in participants with preclinical and prodromal AD using data accessible to primary care physicians. Methods: This retrospective observational study assessed the classification performance of combinations of demographic characteristics, routine blood test results, and cognitive test scores to classify PET Aβ-positivity using machine learning. Participants with mild cognitive impairment (MCI) or normal cognitive function who visited Oita University Hospital or had participated in the USUKI study and met the study eligibility criteria were included. The primary endpoint was assessment of the classification performance of the presence or absence of intracerebral Aβ accumulation using five machine learning models (i.e., five combinations of variables), each constructed with three classification algorithms, resulting in a total of 15 patterns. L2-regularized logistic regression, and kernel Support Vector Machine (SVM) and Elastic Net algorithms were used to construct the classification models using 34 pre-selected variables (12 demographic characteristics, 11 blood test results, 11 cognitive test results). Results: Data from 262 records (260 unique participants) were analyzed. The mean (standard deviation [SD]) participant age was 73.8 (7.8) years. Using L2-regularized logistic regression, the mean receiver operating characteristic (ROC) area under the curve (AUC) (SD) in Model 0 (basic demographic characteristics) was 0.67 (0.01). Classification performance was similar in Model 1 (basic demographic characteristics and Mini Mental State Examination [MMSE] subscores) and Model 2 (demographic characteristics and blood test results) with a cross-validated mean ROC AUC (SD) of 0.70 (0.01) for both. Model 3 (demographic characteristics, blood test results, MMSE subscores) and Model 4 (Model 3 and ApoE4 phenotype) showed improved performance with a mean ROC AUC (SD) of 0.73 (0.01) and 0.76 (0.01), respectively. In models using blood test results, thyroid-stimulating hormone and mean corpuscular volume tended to be the largest contributors to classification. Classification performances were similar using the SVM and Elastic Net algorithms. Conclusions: The machine learning models used in this study were useful for classifying PET Aβ-positivity using data from routine physician visits. Trial registration: UMIN Clinical Trials Registry (UMIN000051776, registered on 31/08/2023). [ABSTRACT FROM AUTHOR]

Background: Based on the Japan Adjuvant Study Group of Pancreatic Cancer-01 results, S-1 adjuvant chemotherapy has been the standard in resected pancreatic ductal adenocarcinoma (PDAC) patients in Japan and elsewhere, initiated within 10 weeks after surgery. To assess the clinical impact of this timing, we conducted a secondary analysis of a nationwide survey by the Japan Pancreas Society. Methods: A total of 3361 patients were divided into two groups: 2681 (79.8%) initiating the therapy within 10 weeks after surgery (standard) and 680 (20.2%) after 10 weeks (delayed). We compared recurrence-free survival (RFS) and overall survival (OS) using the log-rank test and Cox proportional hazards model with conditional landmark analysis between the groups. Results were verified by adjustment with inverse-probability-of-treatment weighting (IPTW) analysis. Results: The median timing of S-1 adjuvant chemotherapy initiation was 50 days (interquartile range: 38–66). In the standard group, 5-year RFS and OS rates were 32.3–48.7%, respectively, compared with 25.0–38.7% in the delayed group. Hazard ratios (HRs) and 95% confidence intervals were 0.84 (0.76–0.93) for RFS (p < 0.001) and 0.77 (0.69–0.87) for OS (p < 0.001). The IPTW analysis yielded 5-year RFS rates of 32.1% and 25.3% in the standard versus delayed group, respectively [HR = 0.86 (0.77–0.96), p < 0.001] and 5-year OS rates of 48.3% and 39.8%, respectively [HR = 0.81 (0.71–0.92), p < 0.001]. Conclusions: Initiation of S-1 adjuvant chemotherapy in resected PDAC patients within 10 weeks after surgery may offer survival benefit over later initiation. [ABSTRACT FROM AUTHOR]

It is generally accepted that certain viral infections can trigger the development of autoimmune diseases. However, the exact mechanisms by which these viruses induce autoimmunity are still not understood. In this review, we first describe hypothetical mechanisms by which viruses induce some representative autoimmune diseases. Then, we focus on Epstein–Barr virus (EBV) and discuss its role in the pathogenesis of rheumatoid arthritis (RA). The discussion is mainly based on our own previous findings that (A) EBV DNA and its products EBV-encoded small RNA (EBER) and latent membrane protein 1 (LMP1) are present in the synovial lesions of RA, (B) mRNA expression of the signaling lymphocytic activation molecule-associated protein (SAP)/SH2D1A gene that plays a critical role in cellular immune responses to EBV is reduced in the peripheral T cells of patients with RA, and (C) EBV infection of mice reconstituted with human immune system components (humanized mice) induced erosive arthritis that is pathologically similar to RA. Additionally, environmental factors may contribute to EBV reactivation as follows: Porphyromonas gingivalis peptidylarginine deiminase (PAD), an enzyme required for citrullination, engenders antigens leading to the production of citrullinated peptides both in the gingiva and synovium. Anti-citrullinated peptides autoantibody is an important marker for diagnosis and disease activity of RA. These findings, as well as various results obtained by other researchers, strongly suggest that EBV is directly involved in the pathogenesis of RA, a typical autoimmune disease. [ABSTRACT FROM AUTHOR]

Although the physiological meaning of the high potential of mouse embryonic stem cells (ESCs) for meiotic entry is not understood, a rigid safeguarding system is required to prevent ectopic onset of meiosis. PRC1.6, a non‐canonical PRC1, is known for its suppression of precocious and ectopic meiotic onset in germ cells and ESCs, respectively. MGA, a scaffolding component of PRC1.6, bears two distinct DNA‐binding domains termed bHLHZ and T‐box. However, it is unclear how this feature contributes to the functions of PRC1.6. Here, we demonstrated that both domains repress distinct sets of genes in murine ESCs, but substantial numbers of meiosis‐related genes are included in both gene sets. In addition, our data demonstrated that bHLHZ is crucially involved in repressing the expression of Meiosin, which plays essential roles in meiotic entry with Stra8, revealing at least part of the molecular mechanisms that link negative and positive regulation of meiotic onset. [ABSTRACT FROM AUTHOR]

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin ( IL)-6, a pleiotropic cytokine, is highly produced in the tumor-bearing host. Previous studies have indicated that IL-6 suppresses the antigen presentation ability of dendritic cells ( DC) through activation of signal transducer and activator of transcription 3 ( STAT3). Thus, we focused on the precise effect of the IL-6/ STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor-infiltrating CD11b+ CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL-6 gene, downregulated surface expression of human leukocyte antigen ( HLA)- DR, and an attenuated T cell-stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL-6-mediated STAT3 activation reduced surface expression of HLA- DR on CD14+ monocyte-derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL-6-mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL-6-mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL-6/ STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients. [ABSTRACT FROM AUTHOR]

An author index for the October 2, 2007 issue of the periodical "Journal of Gastroenterology & Hepatology" is presented.

Experimental Model of Status Epilepticus Induced by Intermittent Electrical Stimulations of the Deep Prepiriform Cortex Cause Seizure Susceptibility in Hippocampus.Purpose: Prolonged febrile convulsions, or an episode of status epilepticus (SE) at any age, may increase future susceptibility to seizures emerging from the mesial temporal lobe. Although many animal models of SE have been described, the causes of temporal lobe epilepsy (TLE) presently are unclear. Previously, we reported that in a model of SE induced by intermittent electrical massed stimulation (MS) of the deep prepiriform cortex (DPC), hippocampal neuronal loss was evident (Inoue et al., 1992). Aminophylline pretreatment before electrical stimulation produced SE effectively. In the present experiment, we examined whether MS of the DPC with our stimulation protocol resulted in delayed development of seizure susceptibility in the hippocampus by using retest stimulations.Methods: Experiments were performed on 12 male Sprague–Dawley rats weighing 280–360 g. Tripolar electrodes were implanted stereotaxically into the left DPC and left ventral hippocampus under pentobarbital anesthesia. Experiments were started 2 weeks after surgery, and the animals were divided into two groups: a stimulated group (n= 6) and an unstimulated control (n= 6). Afterdischarge threshold (ADT) of the DPC was determined 2 h before the start of the MS protocol by using an ascending stair-step procedure. The stimulated group was pretreated with aminophylline (30 mg/kg, i.p.) 30 min before stimulation. Thereafter, the left DPC was stimulated under the following conditions: ADT+25μA, 20-Hz, 20-s biphasic square pulses, separated by a 40-s interstimulus interval. The maximum number of stimulations was limited to 100. If the self-sustained ictal discharges remained continuously for 10 min, no further stimulation was given. Seizure severity and EEG signals were observed at 1, 3, 6, and 24 h after the cessation of MS to check for prolonged convulsion. The control animals also were observed and monitored after aminophylline treatment without electrical stimulation. Two and 8 weeks after the SE, electrical stimulation (retest) was applied to the ventral hippocampus of each rat. Retest stimulation consisted of 10 stimulation epochs, using the same conditions as those for the MS protocol. With each stimulation, the seizure stage was scored according to a modification of Racine scale (Racine, 1972): 0, no response or immobility; 1, chewing, eye closure, facial twitches; 2, head nodding; 3, clonus of one forelimb; 4, bilateral clonus accompanied by rearing; and 5, rearing and falling. All data were presented as mean± SD.Results: No difference in ADT was found between the control and the stimulated groups before induction of SE. During the MS paradigm, five of six stimulated rats reached stage 4/5 (secondarily generalized). SE was achieved in all stimulated animals. Retest stimulation at 2 and 8 weeks after MS revealed that the total duration of AD originating from the ventral hippocampus was significantly longer in the stimulated group than in the control (2 weeks after MS; 248.1± 39.6 vs. 152.3± 67.8 s; 8 weeks after MS, 272.8± 64.5 vs. 152.9± 69.4 s, respectively; p<0.05). Mean seizure severity also was significantly higher in the stimulated group than in the control (2.2± 1.8 vs. 0.3± 0.5, 3.5± 1.8 vs. 1.2± 1.5, respectively, p<0.05), mostly showing stage 5 seizures originating from the hippocampus. Furthermore, electrographic interictal discharges were observed in some stimulated rats at 8 weeks after SE induction.Conclusions: These data demonstrate that electrical stimulation of an extrahippocampal limbic structure (the DPC) distant from the hippocampus can produce long-term seizure susceptibility in the ventral hippocampus. We propose that this model of SE will be useful for studying the mechanisms underlying the origin of TLE. Effect of Continuous Electrical Focus Stimulation to the Amygdala in a Model of Temporal Lobe Epilepsy.Purpose:To determine the seizure-suppressing effects of continuous electrical stimulation of the epileptic focus in the amygdala, focus stimulations were applied in a rat model of temporal lobe epilepsy induced by microinjection of kainic acid into the amygdala.Methods:Stainless-steel cannulas were inserted stereotaxically into the left amygdala of Wistar male rats (weight, 240–340 g). Seven days after the surgery, video-EEG monitoring was started. Kainic acid (0.8 mg) was then injected into the amygdala through the cannula, resulting in limbic status epileptics for 24 h. The animals were divided into two groups: a focus stimulation group (group A, seven rats) and a nonstimulation group (group B, three rats). In group A, a continuous electrical stimulation (0.1 mA, 200 Hz, 1 ms biphasic) to the left amygdala was delivered during limbic seizure status 2 h after kainic acid injection. Each video-EEG monitoring was continued for 7 h after the focus stimulation. In group B, the video-EEG monitoring was also performed for 7 h. The behavior of the rats and the EEG findings recorded by the video-EEG monitoring system were analyzed. The frequency, duration, and stages of the seizures were also analyzed. After the experiments, all rats were perfused with 10% formalin solution, and the brains were processed for histologic study.Results:Kainic acid injection resulted in limbic seizure status in all rats. The continuous amygdala stimulation used in the present study produced no clinical changes or EEG seizure in the amygdala. In group A, each focus stimulation resulted in a decrease in the seizure frequency of the limbic seizure status compared with that in the nonstimulation group. However, no apparent change was noted in seizure intensity or seizure duration.Conclusions:These results demonstrated that the frequency of limbic seizure status could be reduced by continuous electrical stimulation to the epileptic focus in the amygdala. High-frequency electrical stimulation to the epileptic focus in the amygdala produced no clinical symptoms. The procedure seemed less invasive than focus resection by the surgery. This technique has potential applicability for treatment of intractable temporal lobe epilepsy in humans. The Transmission of Periodic Interictal-Like Burst Activity Induced by Carbachol Local Application to the Entorhinal Cortex in Combined Hippocampus–Entorhinal Cortex Slices.Purpose:During the progression of epileptic seizures, particularly during the secondary generalization of temporal lobe epilepsy, epileptic activity spreads broadly from the epileptogenic region to other areas of the brain. Although much research has been done on inducing and observing epileptiform activity, little development has occurred in accurately quantifying its propagation from one region to another.Methods:In this study, we performed extracellular recordings on combined entorhinal-hippocampal (EC-HC) slices obtained from commissural kindled and control Wistar rats to determine the transmission of epileptiform activity from the EC to the dentate gyrus (DG). We used a local application of carbachol (20 mM) through the recording pipette onto layers II/III of the EC to induce periodic interictal burst-like epileptic activity without affecting the local circuitry of the DG. This activity appeared in the DG simultaneously. After knife cutting between the DG and the EC, the activity disappeared because the connecting pathway was severed. To quantify the transmission of epileptiform activity, we developed a method using an all-point histogram of the recorded field potentials. This histogram plots the amplitude of all points occurring during a fixed segment (800 ms) of continuous digitized recording through a DC amplifier. The“transmission index (TI)” is calculated by dividing the areas of the histograms obtained in the two recording sites.Results:Once this epileptic activity was induced by carbachol local application to the EC, the TI to the DG was stable in each of the experiments. In slices obtained from kindled animals, the TI was significantly higher than that in controls, indicating a facilitated transmission of epileptic activity in kindled EC-HC axis. We performed local application of bicuculline (BMI, 20 mM) to the granule cell layer of the DG in the same manner as carbachol to investigate theγ-aminobutyric acid (GABA)A receptor function in the transmission of this epileptic activity. Neither the wave form of interictal burst-like activity transmitted from the EC nor the TI was affected by the local application of BMI in the granule cell layer of the DG, although polyspikes appeared by electrical stimuli to the hilus after BMI application. However, during the local application of BMI, the DG generated spontaneous bursts independent of the activity transmitted from the EC.Conclusions:Thus in the absence of somatic GABAA receptor–mediated inhibition, local neural circuitry in the DG generates spontaneous activity independent of the epileptic activity transmitted from the EC. A New Working Hypothesis: Anomalous Hyperpolarization Could Induce Abnormal Paroxysmal Discharges.Purpose:We have demonstrated the long-lasting burst discharge of the hippocampal interneuron prior to the initiation of the seizure discharge, and the abnormal active property of the pyramidal dendrites during and after kindling (S. Kogure.Epilepsy Res1997; 27:139–48). An interesting in vitro study was recently reported that the hyperpolarization-dependent Na/Ca current (Ih) occurred in the apical dendrites of the hippocampal pyramidal cells (H. Tsubokawa et al.J Physiol1999; 517:135-42). Because the physiological functions of Ih are still unknown in vivo, we have a paradoxical hypothesis that anomalous hyperpolarization could induce abnormal paroxysmal discharges. To test the hypothesis, effects of Ih blockers such as CsCl and ZD7288 on the electrically induced paroxysmal discharge (PAD) were examined in the rabbit hippocampal CA1 region.Methods:Thirty-five male adult rabbits were used. They were anesthetized with pentobarbital sodium, immobilized withd-tubocurarine, and placed in a stereotaxic apparatus on artificial respiration. A pair of concentric injecting electrodes was introduced into each side of the dorsal hippocampal CA1 region and used for stimulating as well as recording hippocampal EEGs. The injection of 1 mM/10 mM/100 mMCsCl, 100μ MZD7288, and saline was made with a speed of 50μl/min for 1 min. The stimulus train for PAD was 1-ms pulses of 50 Hz for 1 s. The stimulation started at 100μA and was continued with 30- to 40-μA steps until PADs were observed at all the recording electrodes, whereby the intensity of the stimulation was defined as PADs threshold. The locations of all electrodes were histologically checked by means of blue spots produced by the ferricyanide reaction. We performed all the experiments under appropriate conditions according to the Declaration of Helsinki.Results:In 30 cases, the injecting electrode locations were histologically identified in the stratum radiatum or lacunosum moleculare of the CA1. The averaged PADs threshold in the control group (n= 10) was 161± 8 (mean± SEM)μA before, and 169± 8μA after the saline injection. In contrast, the PADs threshold significantly (p<0.01) increased to a level of 316± 9μA after injecting 100 mMCsCl (n= 7), while retaining nearly the control level (167± 7μA) before the injection. A similar effect was observed in cases (n= 6) of 10 mMCsCl injection (132± 6μA before and 318± 10μA after the injection: p<0.01), but a relatively weak effect was obtained in cases (n= 4) of 1 mMCsCl injection (125± 7 vs. 195± 7μA: p<0.05). According to CsCl concentration, the effective period of each drug was extended. ZD7288 is well known as one of more specific Ih blockers than CsCl. The same dose of 100μ MZD7288 induced a similar effect on the PADs threshold: 187± 9μA before and 343± 12μA after the injection (n= 3: p<0.01).Conclusions:We obtained the significant increment of PADs threshold in the CsCl as well as ZD7288 injection groups. In addition, ZD7288 raised the threshold with lower concentration than did CsCl, which was supported by in vitro studies that the concentration of enough ZD7288 to block Ih channels was∼1/10 to 1/100 times compared with that of CsCl. It is, therefore, concluded that Ih blockers such as CsCl and ZD7288 can increase the PADs threshold. Our data suggest that Ih plays an important role in seizure generation, which supports our paradoxical hypothesis that an anomalous hyperpolarization generates abnormal excitation. [ABSTRACT FROM AUTHOR]

Benefit of Simultaneous Recording of EEG and MEG in Dipole Localization.Purpose:In this study, we tried to show that EEG and magnetoencephalography (MEG) are clinically complementary to each other and that a combination of both technologies is useful for the precise diagnosis of epileptic focus.Methods:We recorded EEGs and MEGs simultaneously and analyzed dipoles in seven patients with intractable localization-related epilepsy ranging in age from 5 to 19 years. MEG dipoles were analyzed by using a BTI Magnes 148 channel. EEG dipoles were analyzed by using a realistically shaped four-layered head model (scalp-skull-fluid-brain) built from 1.7-mm slice magnetic resonance imaging (MRI). Both EEG and MEG dipoles were analyzed by the single-dipole model. The MEG and EEG dipole localizations were co-registered with MRI of the patient's brain. When EEG could not detect any clear epileptic discharges, the dipole analyses were performed at the corresponding points to the epileptic discharges found with MEG, and vice versa.Results:(a) In two of seven patients, MEG could not detect any epileptiform discharges, whereas EEG showed clear spikes. However, in one of these two patients, dipoles estimated from the MEG data corresponding to the early phase of EEG spikes clustered at a location close to that of the EEG-detected dipole. In the other patient, MEG could not detect a dipolar field corresponding to the early phase of a single EEG spike. Therefore averaging techniques were applied to 38 MEG segments, by using 38 EEG spikes as markers, and this produced a clear dipolar field on averaged MEGs. The location of dipoles estimated for this dipolar field corresponded well with the epileptogenic area indicated by this patient's clinical features. (b) In two of seven patients, EEG showed only intermittent high-voltage slow waves (HVSs) without definite spikes. However, MEG showed clear epileptiform discharges preceding these EEG-detected HVSs. Dipoles estimated for these EEG-detected HVSs showed unstable localization but were located close to the MEG-detected dipoles. (c) In one patient, surgery was performed. In this case, both EEG and MEG showed clear epileptic spikes in the bilateral frontal lobe. EEG showed bilateral HVS bursts in the frontal area, whereas MEG showed clear epileptiform discharges preceding these EEG-detected HVS bursts. Both dipoles estimated for the ascending phase of these EEG-detected HVS bursts and EEG epileptic spikes were located in the bottom of the left frontal mesial lobe close to the location of the MEG-estimated dipoles. Thus for these epileptic discharges, good correspondence was found between the findings of EEG and MEG dipoles. Furthermore, SPECT and MRI also detected the abnormal area in the left frontal mesial lobe. However, dipole analysis also was performed for a separate set of high-voltage discharges observed on MEG. These discharges were not accompanied by measurable EEG discharges. Neither SPECT nor MRI could verify the existence of an epileptogenic area corresponding to the dipoles estimated for these MEG-detected discharges. Thus, as far as the dipoles for these high-voltage discharges were concerned, there was some lack of correspondence between EEG and MEG dipole findings. Surgery was performed on the left mesial frontal area according to measurements taken with subdural and deep electrodes. At the time of writing, this patient has been seizure free for 6 months.Conclusions:Simultaneous recording of MEG and EEG with dipole modeling is more useful for accurate determination of epileptic focus than is either technique alone. Magnetoencephalographic Analysis of Interictal Epileptic Spikes: Comparative Analysis Using a Single-Dipole Method and a Statistical SAM Method.Purpose:In general, the single-dipole model is used to estimate the position of epileptic foci by magnetoencephalography (MEG). In this model, estimated dipoles are points on the cerebral cortex, whereas epileptic foci are considered to have the volume of∼6 cc. In this study, we used spatial filtering and statistical analysis to investigate the spatial distribution of epileptic foci.Methods:Ten cases of localization-related epilepsy (two frontal, two temporal, two occipital, one parietal, and three rolandic) were investigated. Informed consent was obtained in each case. Thirty interictal spikes with similar morphology and distribution were recorded from each subject by using a 64-channel whole-head MEG system equipped with third-order SQUID gradiometers (model 100; CTF Systems, Inc., Canada). Signals were digitized at a sampling rate of 625 or 1,250 Hz and analyzed off-line. The following two methods were used for analysis: (a) Estimation of the current dipoles by using a single-dipole model, and (b) the statistical SAM (synthetic aperture magnetometry; CTF, Canada) method. The region of interest was set to include the entire cerebrum with a 5-mm voxel resolution. The signal power of each voxel was estimated by SAM, using a spatial filter. Changes in the beta band signal power between the spike phase (200 ms, including each spike) and the prespike phase (200 ms before each spike) of each voxel were statistically analyzed by using Student'sttest. The distribution oftvalues obtained from each voxel was superimposed on individual MRI images.Results:By using the statistical SAM method, the position and spatial distribution of epileptic foci were superimposed on MRI images in each case. These results correlated well with the position of estimated dipoles obtained by the single-dipole method in many cases. In subjects with localized cerebral lesions, the statistical SAM method revealed precise information of the spatial relation between epileptic foci and brain lesions.Conclusions:The single-dipole method has been very useful and widely accepted for the analysis of interictal epileptic spikes. Whereas the results obtained from the single dipole method are reliable in many cases, complicated results may lead to a difficult interpretation. For example, different positions of dipoles may be estimated from the different phases of the same spike. Although the statistical SAM method does not reveal the direction of the current and is poor in temporal resolution, this method demonstrates the three-dimensional distribution of interictal epileptic spike foci. Furthermore, the statistical SAM method provides automatic MEG analysis of interictal epileptic spikes for distribution images. Widespread Activation–Inactivation of the Brainstem Triggers Recruiting Rhythm in Human Epilepsies.Purpose:We investigated the excitability change of the brainstem before and during the three types of synchronized cortical oscillations (3-Hz spike-and-wave complex,BrainRes1999; spindle oscillation,BrainRes2000; and diffuse polyspike-and-wave complex,BrainRes2001). The investigation was carried out by taking advantage of the characteristics of brainstem auditory evoked potentials (BAEPs): BAEPs are“far-field” evoked potentials not influenced by neuronal activities in the cortex. In this study, we investigated the excitability change of the brainstem corresponding to an epileptic discharge, recruiting rhythm (RR), which was closely linked with convulsive seizures.Methods:Six epilepsy patients, aged from 7 to 15 years, who were diagnosed as having convulsive seizures[generalized tonic(-clonic) seizures], were selected for this study (four primary generalized epilepsies, two frontal lobe epilepsies). Six-channel EEGs (including Cz-A1 and Cz-A2 for BAEPs; bandpass filter, 1.5 Hz–1.5 kHz) were recorded together with an acoustic trigger signal (80 dB binaurally applied clicks, 20 times/s) and stored on a magnetic tape. The data were replayed and sampled (sampling frequency, 10 kHz) through a personal computer, and then analyzed off-line. A segment is defined as 512-point EEG data with a fixed location of one trial of acoustic signal in the following discussion. (I) The onset of RR was selected with a series of 16 segments in four to six sequences of RR. Then BAEPs were averaged and designated as“onset.” (II) As the averaging areas giving“onset” were sequentially shifted backward by two segments, the averaging procedures were repeated. The procedure gave a series of BAEPs, designated as B1 to B26, that preceded the onset of RR. (III) As the averaging areas giving onset were sequentially shifted forward by two segments, the averaging procedures were repeated. The procedure gave a series of BAEPs, designated A1 to A16, that followed the onset of RR. Before each averaging procedure, the EEG trends were subtracted by fitting a seven-order polynomial curve. After this procedure, a series of 43 BAEPs (“B26”...“onset”...“A16”) was obtained before and during RR in a patient. (IV) The background EEGs were averaged between the top segment of B26 and the last segment of A16 by thinning off raw EEG data. (V) The amplitude and area of wave-III and -V were measured and tested for the significance within a series among the patients by one-way repeated measures of analysis of variance (ANOVA). The background EEGs were again averaged among the patients (grand average) for a reference to EEG change.Results:Both parameters (amplitude and area) of both component waves (wave III and V) showed synchronized excitability fluctuations: the parameters increased from B20 (–2.4± 0.4 s), reaching the maxima at B4 (–0.8± 0.4 s) and then rapidly decreased; the emergence of RR corresponded to this decreasing phase.Conclusions:The parameters of wave III are considered a measure of excitability change in the ventral brainstem, and the parameters of wave V are considered that in the dorsal brainstem. Therefore the results suggest that a widespread activation–inactivation process of the brainstem triggers RR, which underlies the tonic phase of convulsive seizures. Investigation for Extracranial Detectability of Magnetoencephalographic Spikes: Comparison with Simultaneously Recorded Electrocorticography.Purpose:We recorded electrocorticography (ECoG) and magnetoencephalography (MEG) simultaneously in two patients to investigate extracranial detectability of MEG spikes for two different sites such as the cerebral convexity and the medial temporal region.Methods:In two patients with localization-related epilepsy who were recorded with long-term video ECoG to localize the epileptic zone for cortical excision, we performed simultaneous recordings of ECoG and MEG. In patient 1, the ictal-onset zone and interictal zone were localized in the superior frontal gyrus. In patient 2, the ictal-onset zone was localized in the left fusiform gyrus, but interictal spikes were recorded in the medial temporal region. The ECoG was recorded with subdural grids and strips with 1-cm interelectrode distance from center to center. The MEG was recorded with a helmet-shaped neuromagnetometer (Vectorview, 4D-Neuroimage, CA, U.S.A.). This device uses 204 planar-type first-order gradiometers. We collected the simultaneous MEG and ECoG data for 20 and 15 min in patients 1 and 2, respectively. Both ECoG and MEG were analyzed with a bandpass filter between 3 and 45 Hz. We initially selected interictal spikes on ECoG and thereafter analyzed corresponding spikes on MEG. We analyzed the maximal amplitude of ECoG spikes, the number of subdural electrodes involved in the spikes, and the maximal amplitude of MEG spikes. For each MEG spike, the single equivalent current dipole (ECD) was measured by using the single spherical model. We evaluated the dipole moments of spike sources. The spike sources with moment orientation were overlaid onto the patient's magnetic resonance images.Results:In patient 1, 100 (53%) of 188 ECoG spikes in the frontal region were detected on MEG. Seventy-two (72%) MEG spikes required fewer than five subdural electrodes. In patient 2, 31 (26%) of 121 ECoG spikes in the medial temporal region were detected on MEG. Twenty-three (73%) MEG spikes need to involve more than four medial temporal subdural electrodes. The frontal lobe spikes (patient 1) reflect higher amplitude of MEG spikes compared with lower amplitude of those in the medial temporal region (patient 2). The relation between the number of subdural electrodes involved in spikes and the amplitude of MEG spikes had a tendency toward positive correlation. The more extensive spike discharges in frontal lobes project higher-amplitude MEG spikes with statistical significance (r= 0.453, p<0.001) in the frontal lobe (patient 1). MEG spike sources with GOF>75% were 84 (84%) of 100 spikes in patient 1 and 21 (68%) of 31 spikes in patient 2. Mean dipole moments (±SD) were 128± 71 nAm in patient 1 and 271± 51 nAm in patient 2. ECDs of patient 1 made a cluster in the right superior frontal gyrus. These locations were concordant with the interictal zone on ECoG. ECDs oriented tangential to the brain surface in the frontal cortex. In patient 2, 14 of 21 ECDs were localized in the entorhinal and parahippocampal gyri with the dipole moments vertical to those mediobasal temporal cortical surfaces, tangential to the lateral temporal surface. The remaining seven were scattered in the temporal lobe.Conclusions:To detect MEG spikes extracranially, the synchronously activated cortical extent and the current direction of spikes were important. The medial temporal region was less sensitive to MEG measurements than the frontal convexity. Amplitude and Phase Response of Human Amygdala and Orbitofrontal Cortex to Emotional Visual Stimuli.Purpose:Human amygdala and orbitofrontal cortex have been considered the key regions for cognitive processing, including encoding of emotional information. To investigate the function of these regions in processing emotional information, we analyzed local field-potential responses to emotional visual stimuli in human subjects.Methods:All four human subjects had medically intractable epilepsy and were implanted with hybrid clinical research depth electrodes for monitoring epileptic activity in the amygdala or both amygdala and orbitofrontal cortex. The international affective picture system was used for the emotional visual stimuli. Continuous bipolar recordings were obtained on postoperative days 4–14. Obtained local field potentials were convolved with Gabor wavelet at 2-Hz intervals at a center frequency of 20–60 Hz, and instantaneous power envelope and phase angles were calculated from the Gabor transformed data. The power envelope and phase data were used to create statistical time–frequency maps; we also analyzed individual sweeps.Results:We recorded 39 channels from amygdala (left, 24; right, 15) and nine channels from orbitofrontal cortex (all left). The analysis of variance (ANOVA) yielded a significant main effect of emotional categories when measuring power envelope in the gamma frequency range (20–60 Hz) in 12 amygdala channels (30.8%; left, nine; right, three). In these channels, post hoc comparisons showed that responses were mostly specific to the aversive stimuli (p<0.01). Latency of these amygdala responses varied between 100 and 250 ms. Nine channels from orbitofrontal cortex did not show a significant power envelope response to these stimuli. The Phase Entrapment Index between amygdala and orbitofrontal cortex in two channels in one subject showed a significant increase 50–150 ms after stimulus onset in the higher gamma band (36–50 Hz).Conclusions:We found significant responses in the gamma band in the human amygdala, mostly specific to aversive visual stimuli. Gamma synchronization is thought to be a key feature for formation of perception and binding. This result corroborates the important role of the human amygdala in the detection of dangerous, fearful situations. [ABSTRACT FROM AUTHOR]