Electroencephalography for neurological prognostication after cardiac arrest

This thesis focuses on the prognostic value of electroencephalography(EEG) in comatose patients resuscitated after cardiac arrest (CA), using both simplified continuous EEG monitoring (cEEG) and routine EEG. Background: Comatose survivors are admitted to an intensive care unit (ICU) to support vital functions. Postresuscitation care includes target temperature management (TTM) for 24 hours. The degree of brain injury after CA varies among patients. Withdrawal of life-sustaining therapy due to presumed extensive brain injury is the most common cause of death during the hospital stay. Multiple prognostic tools are used to identify patients with a potential for recovery. Next to the neurological examination, EEG is the most commonly used tool to assess prognosis. However, the value of EEG has been limited by varying classification systems, interrater variability and influence of sedation. Methods: In the “coma project” (2004-2008) consecutive patients at the general ICU in Lund were monitored with simplified cEEG from arrival until 120 hours after CA. Pre-defined cEEG patterns at different time points were correlated to outcome. In the TTM trial (2010-2013) where patients were randomized to 33ºC versus 36ºC, a routine EEG was performed in patients still comatose after rewarming. The EEGs were classified into highly malignant, malignant and benign patterns by four EEG specialists from different countries according to the standardized EEG terminology proposed by the American Clinical Neurophysiology Society. The rationale and study design for this EEG evaluation was published. Results: 95 patients in the “coma project” were monitored with simplified cEEG. A continuous background at start of registration or at normothermia strongly predicted a good outcome. All patients with electrographic status epilepticus (ESE) evolving from a burst-suppression background died without regaining consciousness whereas ESE evolving late from an established continuous background was compatible with good outcome. At 8 selected TTM trial sites, routine EEGs were recorded after rewarming in 103 comatose patients. A highly malignant EEG was identified with substantial interrater agreement and had a specificity of 100% to predict poor outcome for all four EEG specialists. Any malignant EEG feature was identified with moderate interrater agreement but had a low specificity to predict a poor outcome (48%). A benign EEG was found in 1% of the patients with a poor outcome. Conclusions: Simplified cEEG provides early positive and negative prognostic information in comatose patients after cardiac arrest. A highly malignant routine EEG after rewarming reliably predicted a poor outcome. An isolated malignant routine EEG feature was not a reliable predictor whereas a benign routine EEG was highly predictive of good outcome

Deep learning approach for epileptic seizure detection

Abstract. Epilepsy is the most common brain disorder that affects approximately fifty million people worldwide, according to the World Health Organization. The diagnosis of epilepsy relies on manual inspection of EEG, which is error-prone and time-consuming. Automated epileptic seizure detection of EEG signal can reduce the diagnosis time and facilitate targeting of treatment for patients. Current detection approaches mainly rely on the features that are designed manually by domain experts. The features are inflexible for the detection of a variety of complex patterns in a large amount of EEG data. Moreover, the EEG is non-stationary signal and seizure patterns vary across patients and recording sessions. EEG data always contain numerous noise types that negatively affect the detection accuracy of epileptic seizures. To address these challenges deep learning approaches are examined in this paper. Deep learning methods were applied to a large publicly available dataset, the Children’s Hospital of Boston-Massachusetts Institute of Technology dataset (CHB-MIT). The present study includes three experimental groups that are grouped based on the pre-processing steps. The experimental groups contain 3–4 experiments that differ between their objectives. The time-series EEG data is first pre-processed by certain filters and normalization techniques, and then the pre-processed signal was segmented into a sequence of non-overlapping epochs. Second, time series data were transformed into different representations of input signals. In this study time-series EEG signal, magnitude spectrograms, 1D-FFT, 2D-FFT, 2D-FFT magnitude spectrum and 2D-FFT phase spectrum were investigated and compared with each other. Third, time-domain or frequency-domain signals were used separately as a representation of input data of VGG or DenseNet 1D. The best result was achieved with magnitude spectrograms used as representation of input data in VGG model: accuracy of 0.98, sensitivity of 0.71 and specificity of 0.998 with subject dependent data. VGG along with magnitude spectrograms produced promising results for building personalized epileptic seizure detector. There was not enough data for VGG and DenseNet 1D to build subject-dependent classifier.Epileptisten kohtausten havaitseminen syväoppimisella lähestymistavalla. Tiivistelmä. Epilepsia on yleisin aivosairaus, joka Maailman terveysjärjestön mukaan vaikuttaa noin viiteenkymmeneen miljoonaan ihmiseen maailmanlaajuisesti. Epilepsian diagnosointi perustuu EEG:n manuaaliseen tarkastamiseen, mikä on virhealtista ja aikaa vievää. Automaattinen epileptisten kohtausten havaitseminen EEG-signaalista voi potentiaalisesti vähentää diagnoosiaikaa ja helpottaa potilaan hoidon kohdentamista. Nykyiset tunnistusmenetelmät tukeutuvat pääasiassa piirteisiin, jotka asiantuntijat ovat määritelleet manuaalisesti, mutta ne ovat joustamattomia monimutkaisten ilmiöiden havaitsemiseksi suuresta määrästä EEG-dataa. Lisäksi, EEG on epästationäärinen signaali ja kohtauspiirteet vaihtelevat potilaiden ja tallennusten välillä ja EEG-data sisältää aina useita kohinatyyppejä, jotka huonontavat epilepsiakohtauksen havaitsemisen tarkkuutta. Näihin haasteisiin vastaamiseksi tässä diplomityössä tarkastellaan soveltuvatko syväoppivat menetelmät epilepsian havaitsemiseen EEG-tallenteista. Aineistona käytettiin suurta julkisesti saatavilla olevaa Bostonin Massachusetts Institute of Technology lastenklinikan tietoaineistoa (CHB-MIT). Tämän työn tutkimus sisältää kolme koeryhmää, jotka eroavat toisistaan esikäsittelyvaiheiden osalta: aikasarja-EEG-data esikäsiteltiin perinteisten suodattimien ja normalisointitekniikoiden avulla, ja näin esikäsitelty signaali segmentoitiin epookkeihin. Kukin koeryhmä sisältää 3–4 koetta, jotka eroavat menetelmiltään ja tavoitteiltaan. Kussakin niistä epookkeihin jaettu aikasarjadata muutettiin syötesignaalien erilaisiksi esitysmuodoiksi. Tässä tutkimuksessa tutkittiin ja verrattiin keskenään EEG-signaalia sellaisenaan, EEG-signaalin amplitudi-spektrogrammeja, 1D-FFT-, 2D-FFT-, 2D-FFT-amplitudi- ja 2D-FFT -vaihespektriä. Näin saatuja aika- ja taajuusalueen signaaleja käytettiin erikseen VGG- tai DenseNet 1D -mallien syötetietoina. Paras tulos saatiin VGG-mallilla kun syötetietona oli amplitudi-spektrogrammi ja tällöin tarkkuus oli 0,98, herkkyys 0,71 ja spesifisyys 0,99 henkilöstä riippuvaisella EEG-datalla. VGG yhdessä amplitudi-spektrogrammien kanssa tuottivat lupaavia tuloksia henkilökohtaisen epilepsiakohtausdetektorin rakentamiselle. VGG- ja DenseNet 1D -malleille ei ollut tarpeeksi EEG-dataa henkilöstä riippumattoman luokittelijan opettamiseksi

Measurement of Neurovascular Coupling in Neonates

Neurovascular coupling refers to the mechanism that links the transient neural activity to the subsequent change in cerebral blood flow, which is regulated by both chemical signals and mechanical effects. Recent studies suggest that neurovascular coupling in neonates and preterm born infants is different compared to adults. The hemodynamic response after a stimulus is later and less pronounced and the stimulus might even result in a negative (hypoxic) signal. In addition, studies both in animals and neonates confirm the presence of a short hypoxic period after a stimulus in preterm infants. In clinical practice, different methodologies exist to study neurovascular coupling. The combination of functional magnetic resonance imaging or functional near-infrared spectroscopy (brain hemodynamics) with EEG (brain function) is most commonly used in neonates. Especially near-infrared spectroscopy is of interest, since it is a non-invasive method that can be integrated easily in clinical care and is able to provide results concerning longer periods of time. Therefore, near-infrared spectroscopy can be used to develop a continuous non-invasive measurement system, that could be used to study neonates in different clinical settings, or neonates with different pathologies. The main challenge for the development of a continuous marker for neurovascular coupling is how the coupling between the signals can be described. In practice, a wide range of signal interaction measures exist. Moreover, biomedical signals often operate on different time scales. In a more general setting, other variables also have to be taken into account, such as oxygen saturation, carbon dioxide and blood pressure in order to describe neurovascular coupling in a concise manner. Recently, new mathematical techniques were developed to give an answer to these questions. This review discusses these recent developments

Decomposing multifractal crossovers

Physiological processes-such as, the brain's resting-state electrical activity or hemodynamic fluctuations-exhibit scale-free temporal structuring. However, impacts common in biological systems such as, noise, multiple signal generators, or filtering by transport function, result in multimodal scaling that cannot be reliably assessed by standard analytical tools that assume unimodal scaling. Here, we present two methods to identify breakpoints or crossovers in multimodal multifractal scaling functions. These methods incorporate the robust iterative fitting approach of the focus-based multifractal formalism (FMF). The first approach (moment-wise scaling range adaptivity) allows for a breakpoint-based adaptive treatment that analyzes segregated scale-invariant ranges. The second method (scaling function decomposition method, SFD) is a crossover-based design aimed at decomposing signal constituents from multimodal scaling functions resulting from signal addition or co-sampling, such as, contamination by uncorrelated fractals. We demonstrated that these methods could handle multimodal, mono- or multifractal, and exact or empirical signals alike. Their precision was numerically characterized on ideal signals, and a robust performance was demonstrated on exemplary empirical signals capturing resting-state brain dynamics by near infrared spectroscopy (NIRS), electroencephalography (EEG), and blood oxygen level-dependent functional magnetic resonance imaging (fMRI-BOLD). The NIRS and fMRI-BOLD low-frequency fluctuations were dominated by a multifractal component over an underlying biologically relevant random noise, thus forming a bimodal signal. The crossover between the EEG signal components was found at the boundary between the δ and θ bands, suggesting an independent generator for the multifractal d rhythm. The robust implementation of the SFD method should be regarded as essential in the seamless processing of large volumes of bimodal fMRI-BOLD imaging data for the topology of multifractal metrics free of the masking effect of the underlying random noise. © 2017 Nagy, Mukli, Herman and Eke

Leveraging Artificial Intelligence to Improve EEG-fNIRS Data Analysis

La spectroscopie proche infrarouge fonctionnelle (fNIRS) est apparue comme une technique de neuroimagerie qui permet une surveillance non invasive et à long terme de l'hémodynamique corticale. Les technologies de neuroimagerie multimodale en milieu clinique permettent d'étudier les maladies neurologiques aiguës et chroniques. Dans ce travail, nous nous concentrons sur l'épilepsie - un trouble chronique du système nerveux central affectant près de 50 millions de personnes dans le monde entier prédisposant les individus affectés à des crises récurrentes. Les crises sont des aberrations transitoires de l'activité électrique du cerveau qui conduisent à des symptômes physiques perturbateurs tels que des changements aigus ou chroniques des compétences cognitives, des hallucinations sensorielles ou des convulsions de tout le corps. Environ un tiers des patients épileptiques sont récalcitrants au traitement pharmacologique et ces crises intraitables présentent un risque grave de blessure et diminuent la qualité de vie globale. Dans ce travail, nous étudions 1. l'utilité des informations hémodynamiques dérivées des signaux fNIRS dans une tâche de détection des crises et les avantages qu'elles procurent dans un environnement multimodal par rapport aux signaux électroencéphalographiques (EEG) seuls, et 2. la capacité des signaux neuronaux, dérivé de l'EEG, pour prédire l'hémodynamique dans le cerveau afin de mieux comprendre le cerveau épileptique. Sur la base de données rétrospectives EEG-fNIRS recueillies auprès de 40 patients épileptiques et utilisant de nouveaux modèles d'apprentissage en profondeur, la première étude de cette thèse suggère que les signaux fNIRS offrent une sensibilité et une spécificité accrues pour la détection des crises par rapport à l'EEG seul. La validation du modèle a été effectuée à l'aide de l'ensemble de données CHBMIT open source documenté et bien référencé avant d'utiliser notre ensemble de données EEG-fNIRS multimodal interne. Les résultats de cette étude ont démontré que fNIRS améliore la détection des crises par rapport à l'EEG seul et ont motivé les expériences ultérieures qui ont déterminé la capacité prédictive d'un modèle d'apprentissage approfondi développé en interne pour décoder les signaux d'état de repos hémodynamique à partir du spectre complet et d'une bande de fréquences neuronale codée spécifique signaux d'état de repos (signaux sans crise). Ces résultats suggèrent qu'un autoencodeur multimodal peut apprendre des relations multimodales pour prédire les signaux d'état de repos. Les résultats suggèrent en outre que des gammes de fréquences EEG plus élevées prédisent l'hémodynamique avec une erreur de reconstruction plus faible par rapport aux gammes de fréquences EEG plus basses. De plus, les connexions fonctionnelles montrent des modèles spatiaux similaires entre l'état de repos expérimental et les prédictions fNIRS du modèle. Cela démontre pour la première fois que l'auto-encodage intermodal à partir de signaux neuronaux peut prédire l'hémodynamique cérébrale dans une certaine mesure. Les résultats de cette thèse avancent le potentiel de l'utilisation d'EEG-fNIRS pour des tâches cliniques pratiques (détection des crises, prédiction hémodynamique) ainsi que l'examen des relations fondamentales présentes dans le cerveau à l'aide de modèles d'apprentissage profond. S'il y a une augmentation du nombre d'ensembles de données disponibles à l'avenir, ces modèles pourraient être en mesure de généraliser les prédictions qui pourraient éventuellement conduire à la technologie EEG-fNIRS à être utilisée régulièrement comme un outil clinique viable dans une grande variété de troubles neuropathologiques.----------ABSTRACT Functional near-infrared spectroscopy (fNIRS) has emerged as a neuroimaging technique that allows for non-invasive and long-term monitoring of cortical hemodynamics. Multimodal neuroimaging technologies in clinical settings allow for the investigation of acute and chronic neurological diseases. In this work, we focus on epilepsy—a chronic disorder of the central nervous system affecting almost 50 million people world-wide predisposing affected individuals to recurrent seizures. Seizures are transient aberrations in the brain's electrical activity that lead to disruptive physical symptoms such as acute or chronic changes in cognitive skills, sensory hallucinations, or whole-body convulsions. Approximately a third of epileptic patients are recalcitrant to pharmacological treatment and these intractable seizures pose a serious risk for injury and decrease overall quality of life. In this work, we study 1) the utility of hemodynamic information derived from fNIRS signals in a seizure detection task and the benefit they provide in a multimodal setting as compared to electroencephalographic (EEG) signals alone, and 2) the ability of neural signals, derived from EEG, to predict hemodynamics in the brain in an effort to better understand the epileptic brain. Based on retrospective EEG-fNIRS data collected from 40 epileptic patients and utilizing novel deep learning models, the first study in this thesis suggests that fNIRS signals offer increased sensitivity and specificity metrics for seizure detection when compared to EEG alone. Model validation was performed using the documented open source and well referenced CHBMIT dataset before using our in-house multimodal EEG-fNIRS dataset. The results from this study demonstrated that fNIRS improves seizure detection as compared to EEG alone and motivated the subsequent experiments which determined the predictive capacity of an in-house developed deep learning model to decode hemodynamic resting state signals from full spectrum and specific frequency band encoded neural resting state signals (seizure free signals). These results suggest that a multimodal autoencoder can learn multimodal relations to predict resting state signals. Findings further suggested that higher EEG frequency ranges predict hemodynamics with lower reconstruction error in comparison to lower EEG frequency ranges. Furthermore, functional connections show similar spatial patterns between experimental resting state and model fNIRS predictions. This demonstrates for the first time that intermodal autoencoding from neural signals can predict cerebral hemodynamics to a certain extent. The results of this thesis advance the potential of using EEG-fNIRS for practical clinical tasks (seizure detection, hemodynamic prediction) as well as examining fundamental relationships present in the brain using deep learning models. If there is an increase in the number of datasets available in the future, these models may be able to generalize predictions which would possibly lead to EEG-fNIRS technology to be routinely used as a viable clinical tool in a wide variety of neuropathological disorders

Targeted resequencing as diagnostic tool in patients with epilepsy

Epilepsy is one of the most common neurological disorder, affecting 5–8/1.000 individuals worldwide. Approximately 20–30 % of epilepsy cases are caused by acquired conditions such as stroke, tumor or head injury, but the remaining 70–80 % of cases are believed to be due to one or more genetic factors. In the last decade, advances in genomic technologies have led to a rapid increase in understanding of epilepsy genetics and to date, to the best of our knowledge, about 1000 genes have been associated with epilepsy. The aim of this study is to determine the contribution of some currently known disease-causing genes in a cohort of Italian patients affected by syndromic or non-syndromic forms of epilepsy. We designed a genes panel for Targeted Resequencing (TRS) containing 85 relevant epilepsy genes responsible for the most common epilepsy phenotypes known so far. A cohort of 49 patients (23 male and 26 female) with a clinical diagnosis of epilepsy, including both sporadic and familial cases, has been enrolled for the study and analyzed by TRS. This approach allowed us to identify variants in 25/49 (51%) patients analyzed. In detail, disease-causing mutations (classified as pathogenic or likely pathogenic following the American College of Medical genetics guidelines), has been identified in 10/25 (40%) affecting the genes ARX, GAMT, KCNQ2, MECP2, SCN1A, POLG, SPTAN1, STXBP1 and TCF4, while variants of uncertain clinical significance (VUS) has been identified in the remaining 15/25 patients (60%) affecting the genes ATP1A2, CACNB4, CLN3, CLN6, CNTN4, CACNA1H, CNTNAP2, GRIN2A, GRIN2B, KCNMA1, LIAS, POLG, PNKP, PRICKLE2, SCN1A, SCN2A, SPTAN1, SCN9A, TSC1. Next Generation Sequencing technologies have revolutionized our approach to genetic epilepsies both from research than clinical perspective. The identification of novel mutations in known epilepsy associated genes is useful to increase our knowledge about the molecular mechanisms of the disease. More importantly, our study highlight once again the utility of next generation sequencing in establishing an etiological basis in clinically and genetically heterogeneous conditions such as epilepsy. Knowing the genetic basis of the disease can be valuable not only for diagnosis but also for guiding treatment and, above all, estimating recurrence risk