abstract: From time immemorial, epilepsy has persisted to be one of the greatest impediments to human life for those stricken by it. As the fourth most common neurological disorder, epilepsy causes paroxysmal electrical discharges in the brain that manifest as seizures. Seizures have the effect of debilitating patients on a physical and psychological level. Although not lethal by themselves, they can bring about total disruption in consciousness which can, in hazardous conditions, lead to fatality. Roughly 1\% of the world population suffer from epilepsy and another 30 to 50 new cases per 100,000 increase the number of affected annually. Controlling seizures in epileptic patients has therefore become a great medical and, in recent years, engineering challenge. In this study, the conditions of human seizures are recreated in an animal model of temporal lobe epilepsy. The rodents used in this study are chemically induced to become chronically epileptic. Their Electroencephalogram (EEG) data is then recorded and analyzed to detect and predict seizures; with the ultimate goal being the control and complete suppression of seizures. Two methods, the maximum Lyapunov exponent and the Generalized Partial Directed Coherence (GPDC), are applied on EEG data to extract meaningful information. Their effectiveness have been reported in the literature for the purpose of prediction of seizures and seizure focus localization. This study integrates these measures, through some modifications, to robustly detect seizures and separately find precursors to them and in consequence provide stimulation to the epileptic brain of rats in order to suppress seizures. Additionally open-loop stimulation with biphasic currents of various pairs of sites in differing lengths of time have helped us create control efficacy maps. While GPDC tells us about the possible location of the focus, control efficacy maps tells us how effective stimulating a certain pair of sites will be. The results from computations performed on the data are presented and the feasibility of the control problem is discussed. The results show a new reliable means of seizure detection even in the presence of artifacts in the data. The seizure precursors provide a means of prediction, in the order of tens of minutes, prior to seizures. Closed loop stimulation experiments based on these precursors and control efficacy maps on the epileptic animals show a maximum reduction of seizure frequency by 24.26\% in one animal and reduction of length of seizures by 51.77\% in another. Thus, through this study it was shown that the implementation of the methods can ameliorate seizures in an epileptic patient. It is expected that the new knowledge and experimental techniques will provide a guide for future research in an effort to ultimately eliminate seizures in epileptic patients. / Dissertation/Thesis / Doctoral Dissertation Electrical Engineering 2016

Class of 2015 Abstract / Objectives: Guidelines from the Brain Trauma Foundation recommend that after traumatic brain injury (TBI) patients should be given seizure prophylaxis for up to seven days. Currently, phenytoin is the first line therapy for this indication. However, levetiracetam is increasingly being used as an alternative because it does not require serum concentration monitoring and has a desirable safety profile. Studies evaluating levetiracetam have used a loading dose, followed by a maintenance dose of 1000 mg every 12 hours. The primary objective of this study was to evaluate the efficacy of low-dose (500 mg every 12 hours) levetiracetam for seizure prophylaxis after TBI. Methods: This was a retrospective cohort study conducted in a tertiary care, academic institution that is designated as a level 1 trauma center. Institutional review board approval was obtained prior to data collection. Consecutive patients with TBI between 2010 and 2012, who received levetiracetam for seizure prophylaxis, were included. Patients who met at least one of the following criteria were included: cortical contusion on computerized tomography scan, subdural hematoma, epidural hematoma, intracerebral hematoma, depressed skull fracture, penetrating head injury, or Glasgow Coma Scale (GCS) of 10 or less. Patients were excluded if they were less than 16 years of age, had a previous head injury, previous neurosurgery, history of seizure, or anti-seizure medication, or were given a loading dose of levetiracetam, or given a maintenance dose greater than 500 mg every 12 hours. The primary outcome was the occurrence of a seizure within seven days of TBI. A one-sample test of proportions was used to compare the rate of seizures while being treated with levetiracetam to a hypothesized value of 3.6 percent (from previous trials), using an a priori alpha for 0.05. Results: There were a total of 146 patients included in the study, who were treated with levetiracetam 500 mg every 12 hours. The median age was 51 years (interquartile range 31 to 65 years), 110 (75 percent) were male, and the median GCS on admission was 11 (interquartile range 5 to 14). The mechanisms of injury were fall (n equals 49), motor vehicle or motorcycle collisions (n equals 42), pedestrian or bicyclist (n equals19), assault (n equals16), suicide attempt (n equals 2), and other (n equals18). The median time to first dose of levetiracetam was 4 hours after injury (interquartile range 1 to 13 hours). After initiation of levetiracetam, there were 5 (3.4 percent) patients who had a seizure within seven days. This was not significantly different than the hypothesized population value (p equals 0.910). The median length of stay was 13 days (interquartile range 9 to 21) and 7 (4.8 percent) patients died during hospitalization. Conclusions: A low-dose of levetiracetam 500 mg every 12 hours after TBI was effective for early seizure prevention. This regimen may be an appropriate alternative to phenytoin or traditional dose levetiracetam for this indication. Future, prospective studies are needed to confirm these findings.

This dissertation established a state-of-the-art programming tool for designing and training artificial neural networks (ANNs) and showed its applicability to brain research. The developed tool, called NeuralStudio, allows users without programming skills to conduct studies based on ANNs in a powerful and very user friendly interface. A series of unique features has been implemented in NeuralStudio, such as ROC analysis, cross-validation, network averaging, topology optimization, and optimization of the activation function’s slopes. It also included a Support Vector Machines module for comparison purposes. Once the tool was fully developed, it was applied to two studies in brain research. In the first study, the goal was to create and train an ANN to detect epileptic seizures from subdural EEG. This analysis involved extracting features from the spectral power in the gamma frequencies. In the second application, a unique method was devised to link EEG recordings to epileptic and non-epileptic subjects. The contribution of this method consisted of developing a descriptor matrix that can be used to represent any EEG file regarding its duration and the number of electrodes. The first study showed that the inter-electrode mean of the spectral power in the gamma frequencies and its duration above a specific threshold performs better than the other frequencies in seizure detection, exhibiting an accuracy of 95.90%, a sensitivity of 92.59%, and a specificity of 96.84%. The second study yielded that Hjorth’s parameter activity is sufficient to accurately relate EEG to epileptic and non-epileptic subjects. After testing, accuracy, sensitivity and specificity of the classifier were all above 0.9667. Statistical tests measured the superiority of activity at over 99.99 % certainty. It was demonstrated that 1) the spectral power in the gamma frequencies is highly effective in locating seizures from EEG and 2) activity can be used to link EEG recordings to epileptic and non-epileptic subjects. These two studies required high computational load and could be addressed thanks to NeuralStudio. From a medical perspective, both methods proved the merits of NeuralStudio in brain research applications. For its outstanding features, NeuralStudio has been recently awarded a patent (US patent No. 7502763).

In the theoretical part of our study, we provide a systematic review of contemporary methods (pharmacological and non-pharmacological) of ECT augmentation, as scored by three factors - manipulation of the seizure threshold, length of therapeutic seizures and the effect on ECT efficacy measured by the total number of ECT sessions and the rate/quantity of change on used objective/subjective scales. We also provide a summary of possible side effects and risks associated with the use of respective ECT augmentation methods. In the research part of our study, we explore the effect of high frequency transcranial magnetic stimulation on the respective ECT parameters, in a double blinded, placebo controlled, randomised study on a sample of 46 patients treated for a major depressive episode. During ECT titration, we registered a significantly lower seizure threshold in the experimental group, an average decrease in charge by 34.55%, from 34.23mC to 22.4mC, p< 0.001 (Wilcox test). We have not observed a significant effect of HF rTMS on the length of seizure or ECT efficacy. Our study confirms the hypothesis, that the application of HF rTMS briefly before an ECT session reduces the seizure threshold, which might be useful in certain types of patients.

Many dietary supplements being promoted for weight loss contain caffeine-or ephedra-related alkaloids to increase energy and suppress appetite. People may be unaware that supplements can contain caffeine, even if caffeine is not listed as an ingredient. Commonly used herbal dietary supplement ingredients, such as guarana, are natural sources of caffeine. Additions of these natural sources of caffeine to dietary supplements have increased in recent years. We describe a case of possible caffeine-induced seizure in a patient taking an over-the-counter weight loss supplement. A previously healthy 38-year-old female experienced blurring of vision and a new onset grand mal seizure. The patient had a 2-month history of taking the dietary supplement, Zantrex-3™. Zantrex-3™ is advertised as a weight loss supplement, which may provide rapid weight loss and extreme energy in one "power packed pill." Zantrex-3™ is a proprietary blend containing niacin, caffeine, and various herbs. After presenting to the hospital emergency room, the patient's chemistry panel, with the exception of potassium (2.9 mEq/L), was within normal limits. An electroencephalogram (EEG) was unremarkable. The magnetic resonance imaging (MRI) showed possible atrophy in the right frontal lobe. Findings from follow-up MRI and EEG ordered as an outpatient were within normal limits. After discontinuation of Zantrex-3™, the patient has experienced no further seizure activity.

Around 1% of the population worldwide suffer from epilepsy, a condition which is characterized by recurring seizures. The development of reliable biomarkers for both prediction and targeted treatment of seizures is critical, as they can pave the way towards personalized therapy in epilepsy. In addition, sensitive biomarkers can be utilized for the detection of epilepsy in its early stages and allow for early treatment intervention. Various types of biomarkers have been studied in relation to epilepsy, with blood markers emerging as major candidates. Blood biomarkers offer the benefit of being cost and time efficient, in addition to being less invasive to sample in contrast to cerebrospinal fluid markers. Importantly, they can enhance patient diagnosis and prognosis when supplemented with other diagnostic methods, such as EEG. In this pilot study, five blood biomarkers of brain injury are studied in epilepsy, post-stroke epilepsy and single seizure patients. The aim is to analyze whether S100B, NSE, GFAP, NfL and tau are promising indicators of epilepsy after a first seizure in adults. The results present S100B as the most promising biomarker, with potential to predict early epilepsy.

京都大学 / 0048 / 新制・課程博士 / 博士(医科学) / 甲第21692号 / 医科博第96号 / 新制||医科||7(附属図書館) / 京都大学大学院医学研究科医科学専攻 / (主査)教授 渡邉 大, 教授 伊佐 正, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Rasmussen's encephalitis is a rare neurological disease first described in 1958 that is characterized by medico-refractory seizures, focal unilateral cerebral inflammation, and deficits such as hemiparesis. While we still do not have a full understanding of this disease, proposed theories behind its etiology include auto-immune manifestations, immune attack by T cells, and malfunctional alterations in genetic expression. It is classically considered a rare childhood malady with a median age of onset of six years, and cases in adolescents and adults are even rarer, representing up to 10% of all cases to date. In this report, we would like to share a rare case of Rasmussen's encephalitis that occurred in an adolescent. Our 17-year-old male patient presented with signs and symptoms beginning at age 14 and was initially diagnosed with cerebral palsy only to later present with additional symptoms and characteristic EEG and MRI findings that ultimately led to a diagnosis of Rasmussen's encephalitis. Thus, with this case report, our intent is twofold: to shed light on an atypical presentation of an already rare disease, even rarer in adolescents and adults, and to underscore the importance of keeping a broad differential when it comes to evaluating a patient with seizures.

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