Neuroimaging for Epilepsy Diagnosis and Management

This chapter will cover the neuroimaging techniques and their application to the diagnostic work up and management of adults and children with new onset or chronic epilepsy. We will focus on the specific indications and requirements of different imaging techniques for the diagnosis and pre-surgical work up of pharmacoresistant focal epilepsies. We will discuss the sensitivity, specificity and prognostic value of imaging features, benign variants and artefacts, and the possible diagnostic significance of non-epileptogenic lesions. This chapter is intended to be relevant for day-to-day practice in average clinical circumstances, with emphasis on MRI and most commonly used functional neuroimaging techniques

Advanced Magnetic Resonance Imaging and Quantitative Analysis Approaches in Patients with Refractory Focal Epilepsy

Background Epilepsy has a high prevalence of 1%, which makes it the most common serious neurological disorder. The most difficult to treat type of epilepsy is temporal lobe epilepsy (TLE) with its most commonly associated lesion being hippocampal sclerosis (HS). About 30-50% of all patients undergoing resective surgery of epileptogenic tissue continue to have seizures postoperatively. Indication for this type of surgery is only given when lesions are clearly visible on magnetic resonance images (MRI). About 30% of all patients with focal epilepsy do not show an underlying structural lesion upon qualitative neuroradiological MRI assessment (MRI-negative). Objectives The work presented in this thesis uses MRI data to quantitatively investigate structural differences between brains of patients with focal epilepsy and healthy controls using automated imaging preprocessing and analysis methods. Methods All patients studied in this thesis had electrophysiological evidence of focal epilepsy, and underwent routine clinical MRI prior to participation in this study. There were two datasets and both included a cohort of age-matched controls: (i) Patients with TLE and associated HS who later underwent selective amygdalahippocampectomy (cohort 1) and (ii) MRI-negative patients with medically refractory focal epilepsy (cohort 2). The participants received high- resolution routine clinical MRI as well as additional sequences for gray and white matter (GM/WM) structural imaging. A neuroradiologist reviewed all images prior to analysis. Hippocampal subfield volume and automated tractography analysis was performed in patients with TLE and HS and related to post-surgical outcomes, while images of MRI- negative patients were analyzed using voxel-based morphometry (VBM) and manual/automated tractography. All studies were designed to detect quantitative differences between patients and controls, except for the hippocampal subfield analysis as control data was not available and comparisons were limited to patients with persistent postoperative seizures and those without. Results 1. Automated hippocampal subfield analysis (cohort 1): The high-resolution hippocampal subfield segmentation technique cannot establish a link between hippocampal subfield volume loss and post-surgical outcome. Ipsilateral and contralateral hippocampal subfield volumes did not correlate with clinical variables such as duration of epilepsy and age of onset of epilepsy. 2. Automated WM diffusivity analysis (cohort 1): Along-the-tract analysis showed that ipsilateral tracts of patients with right/left TLE and HS were more extensively affected than contralateral tracts and the affected regions within tracts could be specified. The extent of hippocampal atrophy (HA) was not related to (i) the diffusion alterations of temporal lobe tracts or (ii) clinical characteristics of patients, whereas diffusion alterations of ipsilateral temporal lobe tracts were significantly related to age at onset of epilepsy, duration of epilepsy and epilepsy burden.Patients without any postoperative seizure symptoms (excellent outcomes) had more ipsilaterally distributed WM tract diffusion alterations than patients with persistent postoperative seizures (poorer outcomes), who were affected bilaterally. 3. Automated epileptogenic lesion detection (cohort 2): Comparison of individual patients against the controls revealed that focal cortical dysplasia (FCD) can be detected automatically using statistical thresholds. All sites of dysplasia reported at the start of the study were detected using this technique. Two additional sites in two different patients, which had previously escaped neuroradiological assessment, could be identified. When taking these statistical results into account during re-assessment of the dedicated epilepsy research MRI, the expert neuroradiologist was able to confirm these as lesions. 4. Manual and automated WM diffusion tensor imaging (DTI) analysis (cohort 2): The analysis of consistency across approaches revealed a moderate to good agreement between extracted tract shape, morphology and space and a strong correlation between diffusion values extracted with both methods. While whole-tract DTI-metrics determined using Automated Fiber Quantification (AFQ) revealed correlations with clinical variables such as age of onset and duration of epilepsy, these correlations were not found using the manual technique. The manual approach revealed more differences than AFQ in group comparisons of whole-tract DTI-metrics. Along-the-tract analysis provided within AFQ gave a more detailed description of localized diffusivity changes along tracts, which correlated with clinical variables such as age of onset and epilepsy duration. Conclusions While hippocampal subfield volume loss in patients with TLE and HS was not related with any clinical variables or to post-surgical outcomes, WM tract diffusion alterations were more bilaterally distributed in patients with persistent postoperative seizures, compared to patients with excellent outcomes. This may indicate that HS as an initial precipitating injury is not affected by clinical features of the disorder and automated hippocampal subfield mapping based on MRI is not sufficient to stratify patients according to outcome. Presence of persisting seizures may depend on other pathological processes such as seizure propagation through WM tracts and WM integrity. Automated and time-efficient three-dimensional voxel-based analysis may complement conventional visual assessments in patients with MRI-negative focal epilepsy and help to identify FCDs escaping routine neuroradiological assessment. Furthermore, automated along-the-tract analysis may identify widespread abnormal diffusivity and correlations between WM integrity loss and clinical variables in patients with MRI-negative epilepsy. However, automated WM tract analysis may differ from results obtained with manual methods and therefore caution should be exercised when using automated techniques

Identifying lesions in paediatric epilepsy using morphometric and textural analysis of magnetic resonance images

We develop an image processing pipeline on Magnetic Resonance Imaging (MRI) sequences to identify features of Focal Cortical Dysplasia (FCD) in patients with MRIvisible FCD. We aim to use a computer-aided diagnosis system to identify epileptogenic lesions with a combination of established morphometric features and textural analysis using Gray-Level Co-occurrence Matrices (GLCM) on MRI sequences. The model will be validated on paediatric subjects. Preliminary morphometric analysis explored the use of computational models of established MRI features of FCD in aiding identification of subtle FCD on MRI-positive subjects. Following this, classification techniques were considered. The 2-Step Naive Bayes classifier was found to produce 100% subjectwise specificity and 94% subjectwise sensitivity (with 75% lesional specificity, 63% lesional sensitivity). Thus it correctly rejected 13/13 healthy subjects and colocalized lesions in 29/31 of the FCD cases with MRI visible lesions, with 63% coverage of the complete extent of the lesion using supplied lesional labels

Étude des effets de volume partiel en IRM cérébrale pour l'estimation d'épaisseur corticale

The work developed in this thesis is within the scope of magnetic resonance imaging (MRI) acquisition and image processing for the automated analysis of brain structures. The measurement of structural modifications with time such as cortical atrophy requires the application of image processing algorithms. They must compensate for MRI artifacts such as intensity inhomogeneities or partial volume (PV) effects to allow for brain tissues segmentation then cortical thickness estimation. We suggest a new PV model relying on the physics of acquisition named bi-exponential model that differs from the commonly used linear model by modelling brain tissues and image acquisition. It requires the use of two differently contrasted and perfectly coregistered images. This model has been validated with simulations and physical and digital phantoms in a first place. In parallel, the recent MP2RAGE sequence provides two coregistered images and their combination results in a bias-field corrected image as well as a T1 map of the scanned tissues. We tested our model with in vivo MP2RAGE data and demonstrated that using the linear PV model leads to a systematic gray matter proportion underestimation in PV voxels. These errors result in cortical thickness underestimation. Our results favor the following assumption: PV modelling with MP2RAGE images must differ from the usual linear PV model applied for images obtained from more classic sequences. The bi-exponential model is an adapted solution to this particular sequence.Les travaux réalisés dans cette thèse se situent à l'interface des domaines de l'acquisition en imagerie par résonance magnétique (IRM) et du traitement d'image pour l'analyse automatique des structures cérébrales. La mesure de modifications structurelles telles que l'atrophie corticale nécessite l'application d'algorithmes de traitement d'image. Ceux-ci doivent compenser les artefacts en IRM tels que l'inhomogénéité du signal ou les effets de volume partiel (VP) pour permettre la segmentation des tissus cérébraux puis l'estimation d'épaisseur corticale. Nous proposons une nouvelle modélisation de VP proche de la physique de l'acquisition baptisée modèle bi-exponentiel qui vient concurrencer le traditionnel modèle linéaire. Il nécessite l'utilisation de deux images de contrastes différents parfaitement recalées. Ce modèle a été validé sur des simulations et des fantômes physique et numérique dans un premier temps. Parallèlement, la récente séquence MP2RAGE permet d'acquérir deux images co-recalées par acquisition et leur combinaison aboutit à l'obtention d'une image insensible aux inhomogénéités du signal et d'une carte de T1 des tissus imagés. Nous avons testé notre modèle sur des données in vivo MP2RAGE et avons montré que l'application du modèle linéaire de VP conduit à une sous-estimation systématique de la substance grise à l'échelle du voxel. Ces erreurs se propagent à l'estimation d'épaisseur corticale, biomarqueur très sensible aux effets de VP. Nos résultats plaident en faveur de l'hypothèse suivante : la modélisation de VP pour les images MP2RAGE doit être différente de celle employée pour des images obtenues avec des séquences plus classiques. Le modèle bi-exponentiel est une solution adaptée à cette séquence particulière

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

Central benzodiazepine receptors in hippocampal sclerosis and idiopathic generalised epilepsies and opiod receptors in reading epilepsy

Background: Epilepsy is the most common serious disease of the brain. In order to better understand the processes and neuronal circuits involved in the pathophysiology of the epilepsies and to provide structural / functional correlations, positron emission tomography (PET) needs to be evaluated in the light of high quality MRI. Aims: To determine the extent and amount of central benzodiazepine/GABAA receptor (cBZR) abnormalities in mesial temporal lobe epilepsy (mTLE) due to hippocampal sclerosis (HS); to quantify cBZR in idiopathic generalised epilepsy (IGE) and the effect of treatment with sodium valproate (VPA); to investigate dynamic changes of opioid receptors in reading epilepsy (RE) at the time of reading-induced seizures. Methods: 11C-flumazenil (FMZ)-PET scans of 37 controls, 25 candidates for temporal lobe resections with HS, and 10 patients with IGE before and after taking VPA, were analysed with statistical parametric mapping (SPM) and a partial-volume-effect (PVE) corrected regions-of-interest approach to quantify FMZ binding to cBZR. Paired 11C-diprenorphine (DPN)-PET scans of 6 control subjects and 5 patients with RE were analysed with SPM to detect significant localised reductions of DPN binding during reading-induced seizures implying a focal release of endogenous opioids. Results: Using SPM, reductions of cBZR were restricted to the sclerotic hippocampus in unilateral mTLE. Using PVE correction loss of cBZR in HS was shown to be over and above that due to neurone loss and hippocampal atrophy. In-vivo 1IC-FMZ-PET correlated well with ex-vivo 3H-FMZ autoradiography in HS. Subtle reductions of cBZR are seen contralaterally in unilateral mTLE in 30%. cBZR in IGE are increased in the cortex and thalamus, and FMZ binding is not affected by VPA. Endogenous opioids are released locally in the left temporo-parietal cortex at the time of reading-induced seizures. Conclusions: The identification of functional abnormalities of major inhibitory neurotransmitter systems, over and above structural abnormalities, has profound implications for the presurgical investigation of patients, in whom MRI does not reveal a relevant underlying lesion. Elucidation of the neurochemical and functional abnormalities underlying seizures assists the design of new anti-epileptic drugs and helps to identify neurochemical abnormalities underlying specific epilepsy syndromes

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

Computer aided diagnosis in temporal lobe epilepsy and Alzheimer's dementia

Computer aided diagnosis within neuroimaging must rely on advanced image processing techniques to detect and quantify subtle signal changes that may be surrogate indicators of disease state. This thesis proposes two such novel methodologies that are both based on large volumes of interest, are data driven, and use cross-sectional scans: appearance-based classification (ABC) and voxel-based classification (VBC).The concept of appearance in ABC represents the union of intensity and shape information extracted from magnetic resonance images (MRI). The classification method relies on a linear modeling of appearance features via principal components analysis, and comparison of the distribution of projection coordinates for the populations under study within a reference multidimensional appearance eigenspace. Classification is achieved using forward, stepwise linear discriminant analyses, in multiple cross-validated trials. In this work, the ABC methodology is shown to accurately lateralize the seizure focus in temporal lobe epilepsy (TLE), differentiate normal aging individuals from patients with either Alzheimer's dementia (AD) or Mild Cognitive Impairment (MCI), and finally predict the progression of MCI patients to AD. These applications demonstrated that the ABC technique is robust to different signal changes due to two distinct pathologies, to low resolution data and motion artifacts, and to possible differences inherent to multi-site acquisition.The VBC technique relies on voxel-based morphometry to identify regions of grey and white matter concentration differences between co-registered cohorts of individuals, and then on linear modeling of variables extracted from these regions. Classification is achieved using linear discriminant analyses within a multivariate space composed of voxel-based morphometry measures related to grey and white matter concentration, along with clinical variables of interest. VBC is shown to increase the accuracy of prediction of one-year clinical status from three to four out of five TLE patients having undergone selective amygdalo-hippocampectomy. These two techniques are shown to have the necessary potential to solve current problems in neurological research, assist clinical physicians with their decision-making process and influence positively patient management