BrainmappingNeuronal Networks in Children with Continuous Spikes and Waves during Slow Sleep as revealed by DICS and RPDC

CSWS is an age-related epileptic encephalopathy consisting of the triad of seizures, neuropsychological impairment and a specific EEG-pattern. This EEG-pattern is characterized by spike-and-wave-discharges emphasized during non-REM sleep. Until now, little has been known about the pathophysiologic processes. So far research approaches on the underlying neuronal network have been based on techniques with a good spatial but poor temporal resolution like fMRI and FDG-PET. In this study the search for sources participating in the neuronal network of CSWS is done by processing EEG-data with high temporal resolution. This allows not only interferences on the location of the individual sources but also on the direction of information flow between them. DICS is applied to the data to solve the inverse problem in the frequency domain. Afterwards RPDC, based on Granger causality, is implemented to reveal effective connectivity between the sources. 12 patients suffering from CSWS without any proof for macroscopic cerebral pathologies in a T1-MRI were investigated at two points of time, before and after treatment. All results are compared to other studies on the neuronal network of CSWS, to knowledge about genesis of epileptic activity in general and to knowledge about the pathogenesis of related psychiatric syndromes. During the active phase of CSWS the thalamus represents the central hub of the neuronal network, and also the cerebellum and key nodes of the DMN contribute to it. Therefore the results are concordant to the ones of former studies and to assumptions on the genesis of epileptic activity. In addition, pathogenetic parallels are found to autism, ADHD and memory-impairment. After cessation of CSWS, the network consists of exclusively cortical sources. In addition to the SWI the mean absolute source power, the mean coherence strength and the mean RPDC strength could be revealed as reliable indicators for the severity of the encephalopathy

Imaging brain networks in focal epilepsy: a prospective study of the clinical application of simultaneous EEG-fMRI in pre-surgical evaluation

Epilepsy is a common disorder with significant associated morbidity and mortality. Despite advances in treatment, there remain a minority of people with pharmacoresistant focal epilepsy for whom surgery may be beneficial. It has been suggested that not enough people are offered surgical treatment, partly owing to the fact that current non-invasive techniques do not always adequately identify the seizure onset zone so that invasive EEG is required. EEG-fMRI is an imaging technique, developed in the 1990s (Ives, Warach et al. 1993) which identifies regions of interictal epileptiform discharge associated haemodynamic changes, that are concordant with the seizure onset zone in some patients (Salek-Haddadi, Diehl et al. 2006). To date there has been no large scale prospective comparison with icEEG and postoperative outcome. This thesis presents a series of experiments, carried out in a cohort of patients scanned using EEG-fMRI as part of a multi-centre programme, designed to investigate the relationship between EEG-fMRI and intracranial EEG and to assess its potential role in pre-surgical evaluation of patients with focal epilepsy. The results suggested that positive, localised IED-related BOLD signal changes were sensitive for the seizure onset zone, as determined on icEEG, both in patients neocortical epilepsies, but were not predictive of outcome. Widespread regions of positive IEDrelated BOLD signal change were associated with widespread or multifocal abnormalities on icEEG and poor outcome. Patterns of haemodynamic change, identified using both data driven and EEG derived modeling approaches, correspond to regions of seizure onset on icEEG, but improvements for modeling seizures are required. A study of a single seizure in a patient who underwent simultaneous icEEGfMRI, showed similar findings.. An exploratory investigation of fMRI-DCM in EEG-fMRI, suggested it can provide information about seizure propagation and this opens new avenues for the non-invasive study of the epileptic network and interactions with function

The Value of Seizure Semiology in Epilepsy Surgery: Epileptogenic-Zone Localisation in Presurgical Patients using Machine Learning and Semiology Visualisation Tool

Background Eight million individuals have focal drug resistant epilepsy worldwide. If their epileptogenic focus is identified and resected, they may become seizure-free and experience significant improvements in quality of life. However, seizure-freedom occurs in less than half of surgical resections. Seizure semiology - the signs and symptoms during a seizure - along with brain imaging and electroencephalography (EEG) are amongst the mainstays of seizure localisation. Although there have been advances in algorithmic identification of abnormalities on EEG and imaging, semiological analysis has remained more subjective. The primary objective of this research was to investigate the localising value of clinician-identified semiology, and secondarily to improve personalised prognostication for epilepsy surgery. Methods I data mined retrospective hospital records to link semiology to outcomes. I trained machine learning models to predict temporal lobe epilepsy (TLE) and determine the value of semiology compared to a benchmark of hippocampal sclerosis (HS). Due to the hospital dataset being relatively small, we also collected data from a systematic review of the literature to curate an open-access Semio2Brain database. We built the Semiology-to-Brain Visualisation Tool (SVT) on this database and retrospectively validated SVT in two separate groups of randomly selected patients and individuals with frontal lobe epilepsy. Separately, a systematic review of multimodal prognostic features of epilepsy surgery was undertaken. The concept of a semiological connectome was devised and compared to structural connectivity to investigate probabilistic propagation and semiology generation. Results Although a (non-chronological) list of patients’ semiologies did not improve localisation beyond the initial semiology, the list of semiology added value when combined with an imaging feature. The absolute added value of semiology in a support vector classifier in diagnosing TLE, compared to HS, was 25%. Semiology was however unable to predict postsurgical outcomes. To help future prognostic models, a list of essential multimodal prognostic features for epilepsy surgery were extracted from meta-analyses and a structural causal model proposed. Semio2Brain consists of over 13000 semiological datapoints from 4643 patients across 309 studies and uniquely enabled a Bayesian approach to localisation to mitigate TLE publication bias. SVT performed well in a retrospective validation, matching the best expert clinician’s localisation scores and exceeding them for lateralisation, and showed modest value in localisation in individuals with frontal lobe epilepsy (FLE). There was a significant correlation between the number of connecting fibres between brain regions and the seizure semiologies that can arise from these regions. Conclusions Semiology is valuable in localisation, but multimodal concordance is more valuable and highly prognostic. SVT could be suitable for use in multimodal models to predict the seizure focus

Stereo-Encephalographic Presurgical Evaluation of Temporal Lobe Epilepsy: An Evolving Science

Drug-resistant epilepsy is present in nearly 30% of patients. Resection of the epileptogenic zone has been found to be the most effective in achieving seizure freedom. The study of temporal lobe epilepsy for surgical treatment is extensive and complex. It involves a multidisciplinary team in decision-making with initial non-invasive studies (Phase I), providing 70% of the required information to elaborate a hypothesis and treatment plans. Select cases present more complexity involving bilateral clinical or electrographic manifestations, have contradicting information, or may involve deeper structures as a part of the epileptogenic zone. These cases are discussed by a multidisciplinary team of experts with a hypothesis for invasive methods of study. Subdural electrodes were once the mainstay of invasive presurgical evaluation and in later years most Comprehensive Epilepsy Centers have shifted to intracranial recordings. The intracranial recording follows original concepts since its development by Bancaud and Talairach, but great advances have been made in the field. Stereo-electroencephalography is a growing field of study, treatment, and establishment of seizure pattern complexities. In this comprehensive review, we explore the indications, usefulness, discoveries in interictal and ictal findings, pitfalls, and advances in the science of presurgical stereo-encephalography for temporal lobe epilepsy

Study of the Hemodynamic Response to Interictal Epileptiform Discharges in Human Epilepsy Using Functional Near Infrared Spectroscopy

RÉSUMÉ L'imagerie spectroscopique proche infrarouge fonctionnelle (ISPIf) s'est imposée comme technique d’imagerie neuronale prometteuse. Cette dernière permet une surveillance non invasive de l'évolution chronique de l'activité hémodynamique corticale. Durant la dernière décennie, ISPIf combiné avec l'électroencéphalographie (EEG) a été appliqué dans le contexte de l'épilepsie humaine, et a permi d’explorer le lien entre l’activité neurale et hémodynamique. Cependant, la plupart des travaux antérieurs sont uniquement axés sur l'étude des crises d'épilepsie qui sont aléatoires et se produisent rarement pendant un test de l’EEG-ISPIf. Cette thèse cherche à évaluer la capacité de l'EEG-ISPIf à observer les changements hémodynamiques associés aux décharges épileptiformes intercritiques (DEIs), et à déterminer si ces DEIs peuvent également être utilisés pour extraire de l'information additionnelle servant à la localisation du site d’un foyer épileptique. En se basant sur des données multimodales EEG-ISPIf recueillies sur un grand échantillon de patients (40), combiné à l'utilisation d'un modèle linéaire généralisé (MLG), une première étude a permis la quantification préliminaire de la sensibilité et la spécificité de la technique en utilisant la détection des zones cérébrales activées par des DEIs pour la localisation de la région du foyer épileptique. Dans un sous-groupe de 29 patients atteints au niveau de la région néocorticale, lorsque mesuré durant des évènements de DEIs, des diminutions de la concentration d’hémoglobine désoxygénée (HbR) (chez 62% des sujets) et des augmentations de la concentration de l’hémoglobine oxygénée (HbO) (chez 38% des sujets) ont été observées. De plus, cette variation en HbR et HbO était significativement plus forte dans la région du foyer épileptique (qui donc pourrait conduire à une localisation du foyer épileptique) dans 28% / 21% des patients. Ces estimations modestes de la sensibilité et de la spécificité suggèrent que l'utilisation d'une fonction de réponse hémodynamique (FRH) canonique n’est pas optimale dans l’analyse des DEIs par MLG classique. Par conséquent, une seconde approche a été explorée dans le cadre d’une deuxième étude par modélisation des variations spécifiques à chaque patient dans la construction de la réponse hémodynamique associée aux DEIs. Un terme quadratique a également été ajouté au modèle pour tenir compte de la non-linéarité de la réponse associée à une fréquence plus élevée d’évènements lors de l'enregistrement. Ces nouveaux modèles ont d'abord été validés numériquement par simulations, avant d’être appliqués à l'analyse de données de cinq patients sélectionnés. Lorsque comparée à la FRH canonique, l'utilisation de la FRH spécifique au patient dans l'analyse MLG a non seulement amélioré considérablement les scores statistiques et les étendues spatiales des----------ABSTRACT Functional near-infrared spectroscopy (fNIRS) has emerged as a promising neuroimaging technique as it allows non-invasive and long-term monitoring of cortical hemodynamics. For the last decades, fNIRS combined with electroencephalography (EEG) has been applied in the context of human epilepsy, and has yielded good results. However, most previous work only focused on the study of epileptic seizures which are random and seldom occur during EEG-fNIRS testing. This thesis sought to evaluate the potential of EEG-fNIRS in observing the hemodynamic changes associated with interictal epileptiform discharges (IEDs), and to determine whether these IEDs can also be used to extract useful information in the localization of the epileptic focus site. Based on the EEG-fNIRS data collected from a relatively large number of patients (40) and using a standard general linear model (GLM) approach, the first study of this thesis provided preliminary estimates of the sensitivity and the specificity of EEG-fNIRS in detecting brain areas activated by IEDs and in localizing the epileptic focus region. In the 29 patients with neocortical epilepsies, significant deoxygenated hemoglobin (HbR) concentration decreases and oxygenated hemoglobin (HbO) concentration increases corresponding to IEDs were observed in 62% and 38% of patients respectively. This HbR/HbO response was most significant in the epileptic focus region among all the activations, and thus could lead to successful identification of the epileptic focus site in 28%/21% of the patients. These modest estimates of the sensitivity and the specificity suggested that using a standard GLM with a canonical hemodynamic response function (HRF) might not be the optimal method in the analysis of IEDs. Therefore, the second study of this thesis made a first attempt to model the patient-specific variations in the shape of the hemodynamic response to IEDs. A quadratic term was also added to the model to account for the nonlinearity in the response when frequent IEDs were present in the recording. The new models were first validated through carefully designed simulations, and were then applied in the data analysis of five selected patients. Compared with the canonical HRF, including patient-specific HRFs in the GLM analysis not only significantly improved the statistical scores and the spatial extents of existing activations, but also was able to detect new brain regions activated by IEDs on all of the five patients. These improvements in activation detection also helped obtain more accurate focus localization results in some cases

Imaging functional and structural networks in the human epileptic brain

Epileptic activity in the brain arises from dysfunctional neuronal networks involving cortical and subcortical grey matter as well as their connections via white matter fibres. Physiological brain networks can be affected by the structural abnormalities causing the epileptic activity, or by the epileptic activity itself. A better knowledge of physiological and pathological brain networks in patients with epilepsy is critical for a better understanding the patterns of seizure generation, propagation and termination as well as the alteration of physiological brain networks by a chronic neurological disorder. Moreover, the identification of pathological and physiological networks in an individual subject is critical for the planning of epilepsy surgery aiming at resection or at least interruption of the epileptic network while sparing physiological networks which have potentially been remodelled by the disease. This work describes the combination of neuroimaging methods to study the functional epileptic networks in the brain, structural connectivity changes of the motor networks in patients with localisation-related or generalised epilepsy and finally structural connectivity of the epileptic network. The combination between EEG source imaging and simultaneous EEG-fMRI recordings allowed to distinguish between regions of onset and propagation of interictal epileptic activity and to better map the epileptic network using the continuous activity of the epileptic source. These results are complemented by the first recordings of simultaneous intracranial EEG and fMRI in human. This whole-brain imaging technique revealed regional as well as distant haemodynamic changes related to very focal epileptic activity. The combination of fMRI and DTI tractography showed subtle changes in the structural connectivity of patients with Juvenile Myoclonic Epilepsy, a form of idiopathic generalised epilepsy. Finally, a combination of intracranial EEG and tractography was used to explore the structural connectivity of epileptic networks. Clinical relevance, methodological issues and future perspectives are discussed

Visual Exploration And Information Analytics Of High-Dimensional Medical Images

Data visualization has transformed how we analyze increasingly large and complex data sets. Advanced visual tools logically represent data in a way that communicates the most important information inherent within it and culminate the analysis with an insightful conclusion. Automated analysis disciplines - such as data mining, machine learning, and statistics - have traditionally been the most dominant fields for data analysis. It has been complemented with a near-ubiquitous adoption of specialized hardware and software environments that handle the storage, retrieval, and pre- and postprocessing of digital data. The addition of interactive visualization tools allows an active human participant in the model creation process. The advantage is a data-driven approach where the constraints and assumptions of the model can be explored and chosen based on human insight and confirmed on demand by the analytic system. This translates to a better understanding of data and a more effective knowledge discovery. This trend has become very popular across various domains, not limited to machine learning, simulation, computer vision, genetics, stock market, data mining, and geography. In this dissertation, we highlight the role of visualization within the context of medical image analysis in the field of neuroimaging. The analysis of brain images has uncovered amazing traits about its underlying dynamics. Multiple image modalities capture qualitatively different internal brain mechanisms and abstract it within the information space of that modality. Computational studies based on these modalities help correlate the high-level brain function measurements with abnormal human behavior. These functional maps are easily projected in the physical space through accurate 3-D brain reconstructions and visualized in excellent detail from different anatomical vantage points. Statistical models built for comparative analysis across subject groups test for significant variance within the features and localize abnormal behaviors contextualizing the high-level brain activity. Currently, the task of identifying the features is based on empirical evidence, and preparing data for testing is time-consuming. Correlations among features are usually ignored due to lack of insight. With a multitude of features available and with new emerging modalities appearing, the process of identifying the salient features and their interdependencies becomes more difficult to perceive. This limits the analysis only to certain discernible features, thus limiting human judgments regarding the most important process that governs the symptom and hinders prediction. These shortcomings can be addressed using an analytical system that leverages data-driven techniques for guiding the user toward discovering relevant hypotheses. The research contributions within this dissertation encompass multidisciplinary fields of study not limited to geometry processing, computer vision, and 3-D visualization. However, the principal achievement of this research is the design and development of an interactive system for multimodality integration of medical images. The research proceeds in various stages, which are important to reach the desired goal. The different stages are briefly described as follows: First, we develop a rigorous geometry computation framework for brain surface matching. The brain is a highly convoluted structure of closed topology. Surface parameterization explicitly captures the non-Euclidean geometry of the cortical surface and helps derive a more accurate registration of brain surfaces. We describe a technique based on conformal parameterization that creates a bijective mapping to the canonical domain, where surface operations can be performed with improved efficiency and feasibility. Subdividing the brain into a finite set of anatomical elements provides the structural basis for a categorical division of anatomical view points and a spatial context for statistical analysis. We present statistically significant results of our analysis into functional and morphological features for a variety of brain disorders. Second, we design and develop an intelligent and interactive system for visual analysis of brain disorders by utilizing the complete feature space across all modalities. Each subdivided anatomical unit is specialized by a vector of features that overlap within that element. The analytical framework provides the necessary interactivity for exploration of salient features and discovering relevant hypotheses. It provides visualization tools for confirming model results and an easy-to-use interface for manipulating parameters for feature selection and filtering. It provides coordinated display views for visualizing multiple features across multiple subject groups, visual representations for highlighting interdependencies and correlations between features, and an efficient data-management solution for maintaining provenance and issuing formal data queries to the back end

Learning more with less data using domain-guided machine learning: the case for health data analytics

The United States is facing a shortage of neurologists with severe consequences: a) average wait-times to see neurologists are increasing, b) patients with chronic neurological disorders are unable to receive diagnosis and care in a timely fashion, and c) there is an increase in neurologist burnout leading to physical and emotional exhaustion. Present-day neurological care relies heavily on time-consuming visual review of patient data (e.g., neuroimaging and electroencephalography (EEG)), by expert neurologists who are already in short supply. As such, the healthcare system needs creative solutions that can increase the availability of neurologists to patient care. To meet this need, this dissertation develops a machine-learning (ML)-based decision support framework for expert neurologists that focuses the experts’ attention to actionable information extracted from heterogeneous patient data and reduces the need for expert visual review. Specifically, this dissertation introduces a novel ML framework known as domain-guided machine learning (DGML) and demonstrates its usefulness by improving the clinical treatments of two major neurological diseases, epilepsy and Alzheimer’s disease. In this dissertation, the applications of this framework are illustrated through several studies conducted in collaboration with the Mayo Clinic, Rochester, Minnesota. Chapters 3, 4, and 5 describe the application of DGML to model the transient abnormal discharges in the brain activity of epilepsy patients. These studies utilized the intracranial EEG data collected from epilepsy patients to delineate seizure generating brain regions without observing actual seizures; whereas, Chapters 6, 7, 8, and 9 describe the application of DGML to model the subtle but permanent changes in brain function and anatomy, and thereby enable the early detection of chronic epilepsy and Alzheimer’s disease. These studies utilized the scalp EEG data of epilepsy patients and two population-level multimodal imaging datasets collected from elderly individuals

Apport de nouvelles techniques dans l’évaluation de patients candidats à une chirurgie d’épilepsie : résonance magnétique à haut champ, spectroscopie proche infrarouge et magnétoencéphalographie

L'épilepsie constitue le désordre neurologique le plus fréquent après les maladies cérébrovasculaires. Bien que le contrôle des crises se fasse généralement au moyen d'anticonvulsivants, environ 30 % des patients y sont réfractaires. Pour ceux-ci, la chirurgie de l'épilepsie s'avère une option intéressante, surtout si l’imagerie par résonance magnétique (IRM) cérébrale révèle une lésion épileptogène bien délimitée. Malheureusement, près du quart des épilepsies partielles réfractaires sont dites « non lésionnelles ». Chez ces patients avec une IRM négative, la délimitation de la zone épileptogène doit alors reposer sur la mise en commun des données cliniques, électrophysiologiques (EEG de surface ou intracrânien) et fonctionnelles (tomographie à émission monophotonique ou de positrons). La faible résolution spatiale et/ou temporelle de ces outils de localisation se traduit par un taux de succès chirurgical décevant. Dans le cadre de cette thèse, nous avons exploré le potentiel de trois nouvelles techniques pouvant améliorer la localisation du foyer épileptique chez les patients avec épilepsie focale réfractaire considérés candidats potentiels à une chirurgie d’épilepsie : l’IRM à haut champ, la spectroscopie proche infrarouge (SPIR) et la magnétoencéphalographie (MEG). Dans une première étude, nous avons évalué si l’IRM de haut champ à 3 Tesla (T), présentant théoriquement un rapport signal sur bruit plus élevé que l’IRM conventionnelle à 1,5 T, pouvait permettre la détection des lésions épileptogènes subtiles qui auraient été manquées par cette dernière. Malheureusement, l’IRM 3 T n’a permis de détecter qu’un faible nombre de lésions épileptogènes supplémentaires (5,6 %) d’où la nécessité d’explorer d’autres techniques. Dans les seconde et troisième études, nous avons examiné le potentiel de la SPIR pour localiser le foyer épileptique en analysant le comportement hémodynamique au cours de crises temporales et frontales. Ces études ont montré que les crises sont associées à une augmentation significative de l’hémoglobine oxygénée (HbO) et l’hémoglobine totale au niveau de la région épileptique. Bien qu’une activation contralatérale en image miroir puisse être observée sur la majorité des crises, la latéralisation du foyer était possible dans la plupart des cas. Une augmentation surprenante de l’hémoglobine désoxygénée a parfois pu être observée suggérant qu’une hypoxie puisse survenir même lors de courtes crises focales. Dans la quatrième et dernière étude, nous avons évalué l’apport de la MEG dans l’évaluation des patients avec épilepsie focale réfractaire considérés candidats potentiels à une chirurgie. Il s’est avéré que les localisations de sources des pointes épileptiques interictales par la MEG ont eu un impact majeur sur le plan de traitement chez plus des deux tiers des sujets ainsi que sur le devenir postchirurgical au niveau du contrôle des crises.Epilepsy is the most common chronic neurological disorder after stroke. The major form of treatment is long-term drug therapy to which approximately 30% of patients are unfortunately refractory to. Brain surgery is recommended when medication fails, especially if magnetic resonance imaging (MRI) can identify a well-defined epileptogenic lesion. Unfortunately, close to a quarter of patients have nonlesional refractory focal epilepsy. For these MRI-negative cases, identification of the epileptogenic zone rely heavily on remaining tools: clinical history, video-electroencephalography (EEG) monitoring, ictal single-photon emission computed tomography (SPECT), and a positron emission tomography (PET). Unfortunately, the limited spatial and/or temporal resolution of these localization techniques translates into poor surgical outcome rates. In this thesis, we explore three relatively novel techniques to improve the localization of the epileptic focus for patients with drug-resistant focal epilepsy who are potential candidates for epilepsy surgery: high-field 3 Tesla (T) MRI, near-infrared spectroscopy (NIRS) and magnetoencephalography (MEG). In the first study, we evaluated if high-field 3T MRI, providing a higher signal to noise ratio, could help detect subtle epileptogenic lesions missed by conventional 1.5T MRIs. Unfortunately, we show that the former was able to detect an epileptogenic lesion in only 5.6% of cases of 1.5T MRI-negative epileptic patients, emphasizing the need for additional techniques. In the second and third studies, we evaluated the potential of NIRS in localizing the epileptic focus by analyzing the hemodynamic behavior of temporal and frontal lobe seizures respectively. We show that focal seizures are associated with significant increases in oxygenated haemoglobin (HbO) and total haemoglobin (HbT) over the epileptic area. While a contralateral mirror-like activation was seen in the majority of seizures, lateralization of the epileptic focus was possible most of the time. In addition, an unexpected increase in deoxygenated haemoglobin (HbR) was noted in some seizures, suggesting possible hypoxia even during relatively brief focal seizures. In the fourth and last study, the utility of MEG in the evaluation of nonlesional drug-refractory focal epileptic patients was studied. It was found that MEG source localization of interictal epileptic spikes had an impact both on patient management for over two thirds of patients and their surgical outcome