On mapping epilepsy : magneto- and electroencephalographic characterizations of epileptic activities

Epilepsy is one of the most common neurological disorder, affecting up to 10 individuals per 1000 persons. The disorder have been known for several thousand years, with the first clinical descriptions dating back to ancient times. Nonetheless, characterization of the dynamics underlying epilepsy remains largely unknown. Understanding these patophysiological processes requires unifying both a neurobiological perspective, as well as a technically advanced neuroimaging perspective. The incomplete insight into epilepsy dynamics is reflected by the insufficient treatment options. Approximately 30% of all patients do not respond to anti-epileptic drugs (AEDs) and thus suffers from recurrent seizures despite adequate pharmacological treatments. These pharmacoresistant patients often undergo epilepsy surgery evaluations. Epilepsy surgery aims to resect the part of the brain that generates the epileptic seizure activity (seizure onset zone, SOZ). Nonetheless, up to 50% of all patients relapse after surgery. This can be due to incomplete mapping of both the SOZ and of other structures that might be involved in seizure initiation and propagation. Such cortical and subcortical structures are collectively referred to as the epileptic network. Historically, epilepsy was considered to be either a generalized disorder involving the entire brain, or a highly localized, focal, disorder. The modern technological development of both structural and functional neuroimaging has drastically altered this view. This development has made significant contributions to the now prevailing view that both generalized and focal epilepsies arise from more or less widespread pathological network pathways. Visualization of these pathways play an important role in the presurgical planning. Thus, both improved characterization and understanding of such pathways are pivotal in improvement of epilepsy diagnostics and treatments. It is evident that epilepsy research needs to stand on two legs: Both improved understanding of pathological, neurobiological and neurophysiological process, and improved neuroimaging instrumentation. Epilepsy research do not only span from visualization to understanding of neurophysiological processes, but also from cellular, neuronal, microscopic processes, to dynamical, large-scale network processes. It is well known that neurons involved in epileptic activities exhibit specific, pathological firing patterns. Genetic mutations resulting in neuronal ion channel defects can cause severe, and even lethal, epileptic syndromes in children, clearly illustrating a role for neuron membrane properties in epilepsy. However, cellular processes themselves cannot explain how epileptic seizures can involve, and propagate across, large cortical areas and generate seizure-specific symptomatologies. A strict cellular perspective can neither explain epilepsy-associated pathological interactions between larger distant regions in between seizures. Instead, the dynamical effects of cellular synchronization across both mesoscopic and macroscopic scales also need to be considered. Today, the only means to study such effects in human subjects are by combinations of neuroimaging modalities. However, as all measurement techniques, these exhibit individual limitations that affect the kind of information that can be inferred from these. Thus, once more we reach the conclusion that epilepsy research needs to rest upon both a neurophysiological/neurobiological leg, and a technical/instrumentational leg. In accordance with this necessity of a dual approach to epilepsy, this thesis covers both neurophysiological aspects of epileptic activity development, as well as functional neuroimaging instrumentation development with focus on epileptic activity detection and localization. Part 1 (neurophysiological part) is concerned with the neurophysiological dynamical changes that underlie development of so called interictal epileptiform discharges (IEDs) with special focus on the role of low-frequency oscillations. To this aim, both conventional magnetoencephalography (MEG) and intracranial electroencephalography (iEEG) with neurostimulation is analyzed. Part 2 (instrumentation part) is concerned with development of cutting-edge, novel on-scalp magnetoencephalography (osMEG) within clinical epilepsy evaluations and research with special focus on IEDs. The theses cover both modeling of osMEG characteristics, as well as the first-ever osMEG recording of a temporal lobe epilepsy patient

Overturning the Notion of White Supremacy in Adventures of Huckleberry Finn

Abstract This essay discusses how Mark Twain in the nove

Detection of interictal epileptiform discharges: A comparison of on-scalp MEG and conventional MEG measurements

Objective: Conventional MEG provides an unsurpassed ability to, non-invasively, detect epileptic activity. However, highly resolved information on small neuronal populations required in epilepsy diagnostics is lost and can be detected only intracranially. Next-generation on-scalp magnetencephalography (MEG) sensors aim to retrieve information unavailable to conventional non-invasive brain imaging techniques. To evaluate the benefits of on-scalp MEG in epilepsy, we performed the first-ever such measurement on an epilepsy patient. Methods: Conducted as a benchmarking study focusing on interictal epileptiform discharge (IED) detectability, an on-scalp high-temperature superconducting quantum interference device magnetometer (high-Tc SQUID) system was compared to a conventional, low-temperature SQUID system. Coregistration of electroencephalopraphy (EEG) was performed. A novel machine learning-based IED-detection algorithm was developed to aid identification of on-scalp MEG unique IEDs. Results: Conventional MEG contained 24 IEDs. On-scalp MEG revealed 47 IEDs (16 co-registered by EEG, 31 unique to the on-scalp MEG recording). Conclusion: Our results indicate that on-scalp MEG might capture IEDs not seen by other non-invasive modalities. Significance: On-scalp MEG has the potential of improving non-invasive epilepsy evaluation. (C) 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V

Randomized Trial Evaluating the Impact of Ribavirin Mono-Therapy and Double Dosing on Viral Kinetics, Ribavirin Pharmacokinetics and Anemia in Hepatitis C Virus Genotype 1 Infection

In this pilot study (RibaC), 58 hepatitis C virus (HCV) genotype 1 infected treatment-naive patients were randomized to (i) 2 weeks ribavirin double dosing concomitant with pegylated interferon-alpha (pegIFN-alpha), (ii) 4 weeks ribavirin mono-therapy prior to adding pegIFN-alpha, or (iii) standard-of-care (SOC) ribavirin dosing concurrent with pegIFN-alpha. Four weeks of ribavirin mono-therapy resulted in a mean 0.46 log(10) IU/mL HCV RNA reduction differentially regulated across IL28B genotypes (0.89 vs. 0.21 log(10) IU/mL for CC and CT/TT respectively; P = 0.006), increased likelihood of undetectable HCV RNA week 4 after initiating pegIFN-alpha and thus shortened treatment duration (P <0.05), and decreased median IP-10 concentration from 550 to 345 pg/mL (P <0.001). Both experimental strategies impacted on ribavirin concentrations, and high levels were achieved after one week of double dosing. However, by day 14, double dosing entailed a greater hemoglobin decline as compared to SOC (2.2 vs. 1.4 g/dL; P = 0.03). Conclusion: Ribavirin down-regulates IP-10, and may have an antiviral effect differently regulated across IL28B genotypes.Peer reviewe

CCL2 Is Associated with a Faster Rate of Cognitive Decline during Early Stages of Alzheimer's Disease

Chemokine (C-C motif) receptor 2 (CCR2)-signaling can mediate accumulation of microglia at sites affected by neuroinflammation. CCR2 and its main ligand CCL2 (MCP-1) might also be involved in the altered metabolism of beta-amyloid (Aβ) underlying Alzheimer's disease (AD). We therefore measured the levels of CCL2 and three other CCR2 ligands, i.e. CCL11 (eotaxin), CCL13 (MCP-4) and CCL26 (eotaxin-3), in the cerebrospinal fluid (CSF) and plasma of 30 controls and 119 patients with mild cognitive impairment (MCI) at baseline. During clinical follow-up 52 MCI patients were clinically stable for five years, 47 developed AD (i.e. cases with prodromal AD at baseline) and 20 developed other dementias. Only CSF CCL26 was statistically significantly elevated in patients with prodromal AD when compared to controls (p = 0.002). However, in patients with prodromal AD, the CCL2 levels in CSF at baseline correlated with a faster cognitive decline during follow-up (rs = 0.42, p = 0.004). Furthermore, prodromal AD patients in the highest tertile of CSF CCL2 exhibited a significantly faster cognitive decline (p<0.001) and developed AD dementia within a shorter time period (p<0.003) compared to those in the lowest tertile. Finally, in the entire MCI cohort, CSF CCL2 could be combined with CSF Tau, P-tau and Aβ42 to predict both future conversion to AD and the rate of cognitive decline. If these results are corroborated in future studies, CCL2 in CSF could be a candidate biomarker for prediction of future disease progression rate in prodromal AD. Moreover, CCR2-related signaling pathways might be new therapeutic targets for therapies aiming at slowing down the disease progression rate of AD

The Internally Truncated LRP5 Receptor Presents a Therapeutic Target in Breast Cancer

BACKGROUND: Breast cancer is a common malignant disease, which may be caused by a number of genes deregulated by genomic or epigenomic events. Deregulated WNT/beta-catenin signaling with accumulation of beta-catenin is common in breast tumors, but mutations in WNT signaling pathway components have been rare. An aberrantly spliced internally truncated LRP5 receptor (LRP5Delta666-809, LRP5Delta) was shown recently to be resistant to DKK1 inhibition, and was required for beta-catenin accumulation in hyperparathyroid tumors and parathyroid tumor growth. METHODOLOGY/PRINCIPAL FINDINGS: Here we show, by reverse transcription PCR and Western blot analysis, that LRP5Delta is frequently expressed in breast tumors of different cancer stage (58-100%), including carcinoma in situ and metastatic carcinoma. LRP5Delta was required in MCF7 breast cancer cells for the non-phosphorylated active beta-catenin level, transcription activity of beta-catenin, cell growth in vitro, and breast tumor growth in a xenograft SCID mouse model. WNT3 ligand, but not WNT1 and WNT3A augmented the endogenous beta-catenin activity of MCF7 cells in a DKK1-insensitive manner. Furthermore, an anti-LRP5 antibody attenuated beta-catenin activity, inhibited cell growth, and induced apoptosis in LRP5Delta-positive MCF7 and T-47D breast cancer cells, but not in control cells. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the LRP5Delta receptor is strongly implicated in mammary gland tumorigenesis and that its aberrant expression present an early event during disease progression. LRP5 antibody therapy may have a significant role in the treatment of breast cancer

The Role of Film Adaptations in the English Language Classroom : Teaching Print Literature with Multimodal Aids

Literary appreciation is the ability to understand patterns of literature and literary devices, for example symbols and characterization in a text, as well as appreciate the text as a form of art. Without literary appreciation, students will most likely struggle to their reading comprehension and literary repertories, which will make it hard to become competent readers of literature. This essay argues that film adaptations can be used as a multimodal aid in the English Language Classroom in order to help students develop their literary appreciation. The essay claims that students should be able to interpret a professional evocation of the story by employing their multiliteracies. By comparing how the literary devices are used in the print literature and in a film adaptation, such as The Great Gatsby, students can transfer their multiliteracies from the film adaptation when they are reading the story in the print literature. By studying and using a professional interpretation of the print literature through a different medium that students are more proficient in deciphering, they can use it in their own personal evocation of the story when they are reading the print literature