Low-frequency repetitive transcranial magnetic stimulation for seizure suppression in patients with extratemporal lobe epilepsy—A pilot study

SummaryWe evaluated the effect of low-frequency repetitive transcranial magnetic stimulation (rTMS) on seizure frequency in adult patients with medically intractable extratemporal lobe epilepsy (ETLE). Seven patients with medically intractable ETLE received low-frequency rTMS at 0.9Hz, basically two sets of 15min stimulation per day for five days in a week, with the stimulus intensity of 90% of resting motor threshold (RMT). The number of seizures during two weeks before and after the stimulation of one week was compared. Furthermore, RMT and active motor threshold (AMT) were measured before and after rTMS for each daily session. After low-frequency rTMS of one week, the frequency of all seizure types, complex partial seizures (CPSs) and simple partial seizures was reduced by 19.1, 35.9 and 7.4%, respectively. The patients with smaller difference between RMT and AMT before rTMS had higher reduction rate of CPSs. A favorable tendency of seizure reduction, though not statistically significant, during two weeks after low-frequency rTMS was demonstrated in medically intractable ETLE patients. As far as CPSs are concerned, smaller decrease of motor threshold by voluntary muscle contraction was associated with better response to rTMS

Visualization of Painful Experiences Believed to Trigger the Activation of Affective and Emotional Brain Regions in Subjects with Low Back Pain

In the management of clinical low back pain (LBP), actual damage to lower back areas such as muscles, intervertebral discs etc. are normally targeted for therapy. However, LBP may involve not only sensory pain, but also underlying affective pain which may also play an important role overall in painful events. Therefore we hypothesized that visualization of a painful event may trigger painful memories, thus provoking the affective dimension of pain. The present study investigated neural correlates of affect processing in subjects with LBP (n = 11) and subjects without LBP (n = 11) through the use of virtual LBP stimuli. Whole brain functional magnetic resonance imaging (MRI) was performed for all subjects while they were shown a picture of a man carrying luggage in a half-crouching position. All subjects with LBP reported experiencing discomfort and 7 LBP subjects reported experiencing pain. In contrast to subjects without LBP, subjects with LBP displayed activation of the cortical area related to pain and emotions: the insula, supplementary motor area, premotor area, thalamus, pulvinar, posterior cingulate cortex, hippocampus, fusiform, gyrus, and cerebellum. These results suggest that the virtual LBP stimuli caused memory retrieval of unpleasant experiences and therefore may be associated with prolonged chronic LBP conditions

The neural tides of sleep and consciousness revealed by single-pulse electrical brain stimulation

Wakefulness and sleep arise from global changes in brain physiology that may also govern the flow of neural activity between cortical regions responsible for perceptual processing vs planning and action. To test whether and how the sleep/wake cycle affects the overall propagation of neural activity in large-scale brain networks, we applied single-pulse electrical stimulation (SPES) in patients implanted with intracranial EEG electrodes for epilepsy surgery. SPES elicited cortico-cortical spectral responses at high-gamma frequencies (CCSRHG, 80-150 Hz), which indexes changes in neuronal population firing rates. Using event-related causality analysis (ERC), we found that the overall patterns of neural propagation among sites with CCSRHG were different during wakefulness and different sleep stages. For example, stimulation of frontal lobe elicited greater propagation toward parietal lobe during slow wave sleep than during wakefulness. During REM sleep, we observed a decrease in propagation within frontal lobe, and an increase in propagation within parietal lobe, elicited by frontal and parietal stimulation, respectively. These biases in the directionality of large-scale cortical network dynamics during REM sleep could potentially account for some of the unique experiential aspects of this sleep stage. Together these findings suggest that the regulation of conscious awareness and sleep is associated with differences in the balance of neural propagation across large-scale frontal-parietal networks

Correlation between brain functional connectivity and neurocognitive function in patients with left frontal glioma

The association between neurocognitive function (NCF) impairment and brain cortical functional connectivity in glioma patients remains unclear. The correlations between brain oscillatory activity or functional connectivity and NCF measured by the Wechsler Adult Intelligence Scale full-scale intelligence quotient scores (WAIS FSIQ), the Wechsler Memory Scale-revised general memory scores (WMS-R GM), and the Western aphasia battery aphasia quotient scores (WAB AQ) were evaluated in 18 patients with left frontal glioma using resting-state electroencephalography (EEG). Current source density (CSD) and lagged phase synchronization (LPS) were analyzed using exact low-resolution electromagnetic tomography (eLORETA). Although 2 and 2 patients scored in the borderline range of WAIS FSIQ and WMS-R GM, respectively, the mean WAIS FSIQ, WMS-R GM, and WAB AQ values of all patients were within normal limits, and none had aphasia. In the correlation analysis, lower WMS-R GM was associated with a higher LPS value between the right anterior prefrontal cortex and the left superior parietal lobule in the beta1 band (13-20 Hz, R = - 0.802, P = 0.012). These findings suggest that LPS evaluated by scalp EEG is associated with memory function in patients with left frontal glioma and mild NCF disorders

Steatogenesis in adult-onset type II citrullinemia is associated with down-regulation of PPARα

AbstractSLC25A13 (citrin or aspartate–glutamate carrier 2) is located in the mitochondrial membrane in the liver and its genetic deficiency causes adult-onset type II citrullinemia (CTLN2). CTLN2 is one of the urea cycle disorders characterized by sudden-onset hyperammonemia due to reduced argininosuccinate synthase activity. This disorder is frequently accompanied with hepatosteatosis in the absence of obesity and ethanol consumption. However, the precise mechanism of steatogenesis remains unclear. The expression of genes associated with fatty acid (FA) and triglyceride (TG) metabolism was examined using liver samples obtained from 16 CTLN2 patients and compared with 7 healthy individuals. Although expression of hepatic genes associated with lipogenesis and TG hydrolysis was not changed, the mRNAs encoding enzymes/proteins involved in FA oxidation (carnitine palmitoyl-CoA transferase 1α, medium- and very-long-chain acyl-CoA dehydrogenases, and acyl-CoA oxidase 1), very-low-density lipoprotein secretion (microsomal TG transfer protein), and FA transport (CD36 and FA-binding protein 1), were markedly suppressed in CTLN2 patients. Serum concentrations of ketone bodies were also decreased in these patients, suggesting reduced mitochondrial β-oxidation activity. Consistent with these findings, the expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of hepatic lipid metabolism, was significantly down-regulated. Hepatic PPARα expression was inversely correlated with severity of steatosis and circulating ammonia and citrulline levels. Additionally, phosphorylation of c-Jun-N-terminal kinase was enhanced in CTLN2 livers, which was likely associated with lower hepatic PPARα. Collectively, down-regulation of PPARα is associated with steatogenesis in CTLN2 patients. These findings provide a novel link between urea cycle disorder, lipid metabolism, and PPARα

Associations between Optimism and Attentional Biases as Measured by Threat-Avoidance and Positive-Search Tasks

Evidence suggests that optimism has a positive impact on health status. Attentional bias modification (ABM) may be beneficial for enhancing optimism, but its effective application requires a detailed investigation of the association between attentional bias and optimism. This study aimed to determine the association between attentional bias and optimism based on different task types. Eighty-four participants completed the attentional bias measures using the dot-probe task (DPT), emotional visual search task (EVST) paradigms, and psychological assessments. Optimism was assessed using the Life Orientation Test-Revised with subscales for optimism and pessimism. Pearson’s correlation coefficient and multivariate linear regression analysis were applied to investigate the association between optimism and attentional bias. Neither the attentional bias derived from DPT nor EVST was significantly correlated with optimism total score or subscales. Regression analysis also showed no association between attentional bias and optimism (DPT, β = 0.12; EVST, β = 0.09), optimism subscales (DPT, β = 0.09; EVST, β = 0.17), or pessimism subscales (DPT, β = −0.10; EVST, β = 0.02). Our findings showed no evidence that attentional biases derived from either the DPT or EVST measures are associated with optimism or pessimism. Further studies are needed to effectively adapt the ABM to enhance optimism

Ictal direct current shifts contribute to defining the core ictal focus in epilepsy surgery

難治てんかん焦点の新しいバイオマーカー「発作時DC電位」 --国内5施設の共同研究での世界初の成果--. 京都大学プレスリリース. 2022-09-05.Identifying the minimal and optimal epileptogenic area to resect and cure is the goal of epilepsy surgery. To achieve this, EEG analysis is recognized as the most direct way to detect epileptogenic lesions from spatiotemporal perspectives. Although ictal direct-current shifts (icDCs; below 1 Hz) and ictal high-frequency oscillations (icHFOs; above 80 Hz) have received increasing attention as good indicators that can add more specific information to the conventionally defined seizure-onset zone, large cohort studies on postoperative outcomes are still lacking. This work aimed to clarify whether this additional information, particularly icDCs which is assumed to reflect extracellular potassium concentration, really improve postoperative outcomes. To assess the usefulness in epilepsy surgery, we collected unique EEG datasets recorded with a longer time constant of 10 sec using an alternate current amplifier. 61 patients [15 with mesial temporal lobe epilepsy and 46 with neocortical epilepsy] who had undergone invasive presurgical evaluation for medically refractory seizures at five institutes in Japan, were retrospectively enrolled in this study. Among intracranially implanted electrodes, the two core electrodes of both icDCs and icHFOs were independently identified by board-certified clinicians based on unified methods. The occurrence patterns, such as their onset time, duration, and amplitude (power) were evaluated to extract the features of both icDCs and icHFOs. Additionally, we examined whether the resection ratio of the core electrodes of icDCs and icHFOs independently correlated with favorable outcomes. A total of 53 patients with 327 seizures were analyzed for wide-band EEG analysis, and 49 patients were analyzed for outcome analysis. icDCs were detected in the seizure-onset zone more frequently than icHFOs among both patients (92% vs. 71%) and seizures (86% vs. 62%). Additionally, icDCs significantly preceded icHFOs in patients exhibiting both biomarkers, and icDCs occurred more frequently in neocortical epilepsy patients than in mesial temporal lobe epilepsy patients. Finally, although a low corresponding rate was observed for icDCs and icHFOs (39%) at the electrode level, complete resection of the core area of icDCs significantly correlated with favorable outcomes, similar to icHFO outcomes. Our results provide a proof of concept that the independent significance of icDCs from icHFOs should be considered as reliable biomarkers to achieve favorable outcomes in epilepsy surgery. Moreover, the different distribution of the core areas of icDCs and icHFOs may provide new insights into the underlying mechanisms of epilepsy, in which not only neurons but also glial cells may be actively involved via extracellular potassium levels

SORL1 Is Genetically Associated with Late-Onset Alzheimer’s Disease in Japanese, Koreans and Caucasians

To discover susceptibility genes of late-onset Alzheimer’s disease (LOAD), we conducted a 3-stage genome-wide association study (GWAS) using three populations: Japanese from the Japanese Genetic Consortium for Alzheimer Disease (JGSCAD), Koreans, and Caucasians from the Alzheimer Disease Genetic Consortium (ADGC). In Stage 1, we evaluated data for 5,877,918 genotyped and imputed SNPs in Japanese cases (n = 1,008) and controls (n = 1,016). Genome-wide significance was observed with 12 SNPs in the APOE region. Seven SNPs from other distinct regions with p-values ,261025 were genotyped in a second Japanese sample (885 cases, 985 controls), and evidence of association was confirmed for one SORL1 SNP (rs3781834, P=7.3361027 in the combined sample). Subsequent analysis combining results for several SORL1 SNPs in the Japanese, Korean (339 cases, 1,129 controls) and Caucasians (11,840 AD cases, 10,931 controls) revealed genome wide significance with rs11218343 (P=1.7761029) and rs3781834 (P=1.0461028). SNPs in previously established AD loci in Caucasians showed strong evidence of association in Japanese including rs3851179 near PICALM (P=1.7161025) and rs744373 near BIN1 (P = 1.3961024). The associated allele for each of these SNPs was the same as in Caucasians. These data demonstrate for the first time genome-wide significance of LOAD with SORL1 and confirm the role of other known loci for LOAD in Japanese. Our study highlights the importance of examining associations in multiple ethnic populations

PPAR beta/delta activation of CD300a controls intestinal immunity

Macrophages are important for maintaining intestinal immune homeostasis. Here, we show that PPAR beta/delta (peroxisome proliferator-activated receptor beta/delta) directly regulates CD300a in macrophages that express the immunoreceptor tyrosine based-inhibitory motif (ITIM)-containing receptor. In mice lacking CD300a, high-fat diet (HFD) causes chronic intestinal inflammation with low numbers of intestinal lymph capillaries and dramatically expanded mesenteric lymph nodes. As a result, these mice exhibit triglyceride malabsorption and reduced body weight gain on HFD. Peritoneal macrophages from Cd300a(-/-) mice on HFD are classically M1 activated. Activation of toll-like receptor 4 (TLR4)/MyD88 signaling by lipopolysaccharide (LPS) results in prolonged IL-6 secretion in Cd300a(-/-) macrophages. Bone marrow transplantation confirmed that the phenotype originates from CD300a deficiency in leucocytes. These results identify CD300a-mediated inhibitory signaling in macrophages as a critical regulator of intestinal immune homeostasis

One-Step Detection of the 2009 Pandemic Influenza A(H1N1) Virus by the RT-SmartAmp Assay and Its Clinical Validation

<div><h3>Background</h3><p>In 2009, a pandemic (pdm) influenza A(H1N1) virus infection quickly circulated globally resulting in about 18,000 deaths around the world. In Japan, infected patients accounted for 16% of the total population. The possibility of human-to-human transmission of highly pathogenic novel influenza viruses is becoming a fear for human health and society.</p> <h3>Methodology</h3><p>To address the clinical need for rapid diagnosis, we have developed a new method, the “RT-SmartAmp assay”, to rapidly detect the 2009 pandemic influenza A(H1N1) virus from patient swab samples. The RT-SmartAmp assay comprises both reverse transcriptase (RT) and isothermal DNA amplification reactions in one step, where RNA extraction and PCR reaction are not required. We used an exciton-controlled hybridization-sensitive fluorescent primer to specifically detect the HA segment of the 2009 pdm influenza A(H1N1) virus within 40 minutes without cross-reacting with the seasonal A(H1N1), A(H3N2), or B-type (Victoria) viruses.</p> <h3>Results and Conclusions</h3><p>We evaluated the RT-SmartAmp method in clinical research carried out in Japan during a pandemic period of October 2009 to January 2010. A total of 255 swab samples were collected from outpatients with influenza-like illness at three hospitals and eleven clinics located in the Tokyo and Chiba areas in Japan. The 2009 pdm influenza A(H1N1) virus was detected by the RT-SmartAmp assay, and the detection results were subsequently compared with data of current influenza diagnostic tests (lateral flow immuno-chromatographic tests) and viral genome sequence analysis. In conclusion, by the RT-SmartAmp assay we could detect the 2009 pdm influenza A(H1N1) virus in patients' swab samples even in early stages after the initial onset of influenza symptoms. Thus, the RT-SmartAmp assay is considered to provide a simple and practical tool to rapidly detect the 2009 pdm influenza A(H1N1) virus.</p> </div