The heart of epilepsy: Cardiac comorbidity and sudden death

The research described in this thesis aims to increase understanding of cardiac comorbidities and sudden unexpected death in epilepsy (SUDEP). People with epilepsy have a three-fold increased risk of dying prematurely compared to the general population. Common contributors to this are cardiovascular comorbidities, of which I provide an overview. Cardiovascular conditions and epilepsy can both lead to transient loss of consciousness (TLOC) with overlapping semiology. Particularly, myoclonic jerks which are commonly observed during syncope can be mistaken for signs of epilepsy. A misdiagnosis with detrimental consequences. I provide evidence that a careful analysis of motor phenomena can distinguish the two conditions. SUDEP is the commonest direct epilepsy-related premature death (UK >500 people/year). It typically occurs following convulsive seizures (CS). Most victims are found prone and some suggested people should sleep supine. I assessed video-EEG recordings of 180 CS and demonstrated peri-ictal positions often change, and most ending prone turned during CS. Sleeping supine is thus unlikely to prevent a postictal prone position and reduce risk of SUDEP. Pathomechanisms underlying SUDEP are likely a combination of interacting cardiorespiratory and autonomic factors. People with Dravet syndrome (DS) have a particular high SUDEP risk. I show that 49% of reported deaths in DS are SUDEP cases, most <10 years (78%). In DS, SCN1A mutations are mostly found, encoding a sodium channel expressed in brain and heart. DS mouse models suggest a key role for peri-ictal cardiac arrhythmias in SUDEP. I conducted a multicentre observational study and recorded 547 seizures in 45 DS participants. No major peri-ictal arrhythmias were found. Peri-ictal QTc-lengthening was, however, more common in DS than controls. This may reflect unstable repolarisation and increased propensity for arrhythmias. Prospective data to determine whether these peri-ictal variables can predict SUDEP risk is warranted

On the Dynamics of Epileptic Spikes and Focus Localization in Temporal Lobe Epilepsy

abstract: Interictal spikes, together with seizures, have been recognized as the two hallmarks of epilepsy, a brain disorder that 1% of the world's population suffers from. Even though the presence of spikes in brain's electromagnetic activity has diagnostic value, their dynamics are still elusive. It was an objective of this dissertation to formulate a mathematical framework within which the dynamics of interictal spikes could be thoroughly investigated. A new epileptic spike detection algorithm was developed by employing data adaptive morphological filters. The performance of the spike detection algorithm was favorably compared with others in the literature. A novel spike spatial synchronization measure was developed and tested on coupled spiking neuron models. Application of this measure to individual epileptic spikes in EEG from patients with temporal lobe epilepsy revealed long-term trends of increase in synchronization between pairs of brain sites before seizures and desynchronization after seizures, in the same patient as well as across patients, thus supporting the hypothesis that seizures may occur to break (reset) the abnormal spike synchronization in the brain network. Furthermore, based on these results, a separate spatial analysis of spike rates was conducted that shed light onto conflicting results in the literature about variability of spike rate before and after seizure. The ability to automatically classify seizures into clinical and subclinical was a result of the above findings. A novel method for epileptogenic focus localization from interictal periods based on spike occurrences was also devised, combining concepts from graph theory, like eigenvector centrality, and the developed spike synchronization measure, and tested very favorably against the utilized gold rule in clinical practice for focus localization from seizures onset. Finally, in another application of resetting of brain dynamics at seizures, it was shown that it is possible to differentiate with a high accuracy between patients with epileptic seizures (ES) and patients with psychogenic nonepileptic seizures (PNES). The above studies of spike dynamics have elucidated many unknown aspects of ictogenesis and it is expected to significantly contribute to further understanding of the basic mechanisms that lead to seizures, the diagnosis and treatment of epilepsy.Dissertation/ThesisPh.D. Electrical Engineering 201

Biomarkers in the diagnosis and study of psychogenic nonepileptic seizures: A systematic review

AbstractObjectiveVideo electroencephalography (vEEG) is the gold-standard method for diagnosing psychogenic nonepileptic seizures (PNES), but such assessment is expensive, unavailable in many centers, requires prolonged hospitalization, and many times is unable to capture an actual seizure episode. This paper systematically reviews other non-vEEG candidate biomarkers that may facilitate both diagnosis and study of PNES as differentiated from epileptic seizures (ES).MethodsPubMed database was searched to identify articles between 1980 and 2015 (inclusion: adult PNES population with or without controls, English language; exclusion: review articles, meta-analyses, single case reports).ResultsA total of 49 studies were examined, including neuroimaging, autonomic nervous system, prolactin, other (non-prolactin) hormonal, enzyme, and miscellaneous marker studies. Functional MRI studies have shown PNES is hyperlinked with dissociation and emotional dysregulation centers in the brain, although conflicting findings are seen across studies and none used psychiatric comparators. Heart rate variability suggests increased vagal tone in PNES when compared to ES. Prolactin is elevated in ES but not PNES, although shows low diagnostic sensitivity. Postictal cortisol and creatine kinase are nonspecific. Other miscellaneous biomarkers (neuron specific enolase, brain derived neurotropic factor, ghrelin, leptin, leukocytosis) showed no conclusive evidence of utility. Many studies are limited by lack of psychiatric comparators, size, and other methodological issues.ConclusionNo single biomarker successfully differentiates PNES from ES; in fact, PNES is only diagnosed via the negation of ES. Clinical assessment and rigorous investigation of psychosocial variables specific to PNES remain critical, and subtyping of PNES is warranted. Future investigational and clinical imperatives are discussed

Advanced neuroimaging techniques in epilepsy

PURPOSE OF REVIEW: We review significant advances in epilepsy imaging in recent years. RECENT FINDINGS: Structural MRI at 7T with optimization of acquisition and postacquisition image processing increases the diagnostic yield but artefactual findings remain a challenge. MRI analysis from multiple sites indicates different atrophy patterns and white matter diffusion abnormalities in temporal lobe and generalized epilepsies, with greater abnormalities close to the presumed seizure source. Structural and functional connectivity relate to seizure spread and generalization; longitudinal studies are needed to clarify the causal relationship of these associations. Diffusion MRI may help predict surgical outcome and network abnormalities extending beyond the epileptogenic zone. Three-dimensional multimodal imaging can increase the precision of epilepsy surgery, improve seizure outcome and reduce complications. Language and memory fMRI are useful predictors of postoperative deficits, and lead to risk minimization. FDG PET is useful for clinical studies and specific ligands probe the pathophysiology of neurochemical fluxes and receptor abnormalities. SUMMARY: Improved structural MRI increases detection of abnormalities that may underlie epilepsy. Diffusion, structural and functional MRI indicate the widespread associations of epilepsy syndromes. These can assist stratification of surgical outcome and minimize risk. PET has continued utility clinically and for research into the pathophysiology of epilepsies

The Investigation of Human Scent from Epileptic Patients for the Identification of a Biomarker for Epileptic Seizures

Studies have shown that some canines have the ability to predict seizures in people with epilepsy, and that canines can be trained to recognize changes in humans before an epileptic seizure and make these predictions. It is not known with any certainty to what the canines are alerting. However, canines’ exceptional sense of smell and their ability to discriminate human scent is well established. Therefore, it is possible that the canines could be responding to an olfactory cue, such as the release of some volatile organic compounds (VOCs) prior to the onset of a seizure. Individuals release a wide array of VOCs, both odorous and non-odorous, from their bodies. The odorous VOCs collectively make up human scent and a number of these VOCs have been identified as biomarkers of different diseases. Evidence suggests that canines can perceive these biomarkers, leading to early detection of underlying physical ailments before individuals are aware of their own symptoms. The main purpose of this study was to use headspace solid phase microextraction (HS-SPME) with gas chromatography-mass spectrometry (GC-MS) to analyze hand odor, saliva and breath samples from epileptic with and without seizure activity to determine if the human scent profiles resulting from a seizure event differs from the scent profiles in the absence of seizure activity. the HS-SPME-GC-MS method was also used to analyze and compare hand odor, saliva and breath samples of healthy individuals and epilepsy patients to determine if the profiles can be differentiated. Comparison of the VOCs in each specimen from healthy individuals and epileptic patients revealed compounds that could be used as potential biomarkers to differentiate between healthy and epileptic individuals. Comparison of the VOCs in each specimen from epileptic patients with and without seizure activity revealed compounds that could be used as potential biomarkers for epileptic seizures. Finally, canine trials were used to verify that these compounds are indeed biomarkers

Incessant transitions between active and silent states in cortico-thalamic circuits and altered neuronal excitability lead to epilepsy

La ligne directrice de nos expériences a été l'hypothèse que l'apparition et/ou la persistance des fluctuations de longue durée entre les états silencieux et actifs dans les réseaux néocorticaux et une excitabilité neuronale modifiée sont les facteurs principaux de l'épileptogenèse, menant aux crises d’épilepsie avec expression comportementale. Nous avons testé cette hypothèse dans deux modèles expérimentaux différents. La déafférentation corticale chronique a essayé de répliquer la déafférentation physiologique du neocortex observée pendant le sommeil à ondes lentes. Dans ces conditions, caractérisées par une diminution de la pression synaptique et par une incidence augmentée de périodes silencieuses dans le système cortico-thalamique, le processus de plasticité homéostatique augmente l’excitabilité neuronale. Par conséquent, le cortex a oscillé entre des périodes actives et silencieuses et, également, a développé des activités hyper-synchrones, s'étendant de l’hyperexcitabilité cellulaire à l'épileptogenèse focale et à des crises épileptiques généralisées. Le modèle de stimulation sous-liminale chronique (« kindling ») du cortex cérébral a été employé afin d'imposer au réseau cortical une charge synaptique supérieure à celle existante pendant les états actifs naturels - état de veille ou sommeil paradoxal (REM). Dans ces conditions un mécanisme différent de plasticité qui s’est exprimé dans le système thalamo-corticale a imposé pour des longues périodes de temps des oscillations continuelles entre les époques actives et silencieuses, que nous avons appelées des activités paroxysmiques persistantes. Indépendamment du mécanisme sous-jacent de l'épileptogenèse les crises d’épilepsie ont montré certaines caractéristiques similaires : une altération dans l’excitabilité neuronale mise en évidence par une incidence accrue des décharges neuronales de type bouffée, une tendance constante vers la généralisation, une propagation de plus en plus rapide, une synchronie augmentée au cours du temps, et une modulation par les états de vigilance (facilitation pendant le sommeil à ondes lentes et barrage pendant le sommeil REM). Les états silencieux, hyper-polarisés, de neurones corticaux favorisent l'apparition des bouffées de potentiels d’action en réponse aux événements synaptiques, et l'influence post-synaptique d'une bouffée de potentiels d’action est beaucoup plus importante par rapport à l’impacte d’un seul potentiel d’action. Nous avons également apporté des évidences que les neurones néocorticaux de type FRB sont capables à répondre avec des bouffées de potentiels d’action pendant les phases hyper-polarisées de l'oscillation lente, propriété qui peut jouer un rôle très important dans l’analyse de l’information dans le cerveau normal et dans l'épileptogenèse. Finalement, nous avons rapporté un troisième mécanisme de plasticité dans les réseaux corticaux après les crises d’épilepsie - une diminution d’amplitude des potentiels post-synaptiques excitatrices évoquées par la stimulation corticale après les crises - qui peut être un des facteurs responsables des déficits comportementaux observés chez les patients épileptiques. Nous concluons que la transition incessante entre des états actifs et silencieux dans les circuits cortico-thalamiques induits par disfacilitation (sommeil à ondes lentes), déafférentation corticale (épisodes ictales à 4-Hz) ou par une stimulation sous-liminale chronique (activités paroxysmiques persistantes) crée des circonstances favorables pour le développement de l'épileptogenèse. En plus, l'augmentation de l’incidence des bouffées de potentiels d’actions induisant une excitation post-synaptique anormalement forte, change l'équilibre entre l'excitation et l'inhibition vers une supra-excitation menant a l’apparition des crises d’épilepsie.The guiding line in our experiments was the hypothesis that the occurrence and / or the persistence of long-lasting fluctuations between silent and active states in the neocortical networks, together with a modified neuronal excitability are the key factors of epileptogenesis, leading to behavioral seizures. We addressed this hypothesis in two different experimental models. The chronic cortical deafferentation replicated the physiological deafferentation of the neocortex observed during slow-wave sleep (SWS). Under these conditions of decreased synaptic input and increased incidence of silent periods in the corticothalamic system the process of homeostatic plasticity up-regulated cortical cellular and network mechanisms and leaded to an increased excitability. Therefore, the deafferented cortex was able to oscillate between active and silent epochs for long periods of time and, furthermore, to develop highly synchronized activities, ranging from cellular hyperexcitability to focal epileptogenesis and generalized seizures. The kindling model was used in order to impose to the cortical network a synaptic drive superior to the one naturally occurring during the active states - wake or rapid eye movements (REM) sleep. Under these conditions a different plasticity mechanism occurring in the thalamo-cortical system imposed long-lasting oscillatory pattern between active and silent epochs, which we called outlasting activities. Independently of the mechanism of epileptogenesis seizures showed some analogous characteristics: alteration of the neuronal firing pattern with increased bursts probability, a constant tendency toward generalization, faster propagation and increased synchrony over the time, and modulation by the state of vigilance (overt during SWS and completely abolished during REM sleep). Silent, hyperpolarized, states of cortical neurons favor the induction of burst firing in response to depolarizing inputs, and the postsynaptic influence of a burst is much stronger as compared to a single spike. Furthermore, we brought evidences that a particular type of neocortical neurons - fast rhythmic bursting (FRB) class - is capable to consistently respond with bursts during the hyperpolarized phase of the slow oscillation, fact that may play a very important role in both normal brain processing and in epileptogenesis. Finally, we reported a third plastic mechanism in the cortical network following seizures - a decreasing amplitude of cortically evoked excitatory post-synaptic potentials (EPSP) following seizures - which may be one of the factors responsible for the behavioral deficits observed in patients with epilepsy. We conclude that incessant transitions between active and silent states in cortico-thalamic circuits induced either by disfacilitation (sleep), cortical deafferentation (4-Hz ictal episodes) and by kindling (outlasting activities) create favorable circumstances for epileptogenesis. The increase in burst-firing, which further induce abnormally strong postsynaptic excitation, shifts the balance of excitation and inhibition toward overexcitation leading to the onset of seizures

The spatiotemporal dynamics of human focal seizures

Spontaneous human focal seizures can present with a plethora of behavioral manifestations that vary according to the affected cortical regions; however, several key features have been consistently observed. During my doctoral studies, I applied both theoretical and experimental methods to study mechanisms underpinning these consistently seen dynamics. I first analyzed human intracranial EEG recordings, describing statistical methods for measuring their electrophysiological signatures. I next proposed several neurophysiological hypotheses that could explain seizure dynamics and verified them in rodent seizure models. Finally, a computational model was developed, successfully explaining how the complex spatiotemporal evolution of focal seizures emerges from simple neurophysiological principles. In Chapter 1, the long-standing behavioral manifestations and the most up-to-date electrophysiology findings are reviewed. This section details the inspiration for the studies reported in the subsequent chapters. In Chapter 2, I describe several statistical methods for estimating traveling wave velocities. I show most ictal discharges can be described as traveling waves whose velocities contain rich information about the stages of seizure evolution. I compare performance of various statistical methods and propose a robust approach to boost the quality of each method’s estimation results. In Chapter 3, I show how inhibition modulates seizure propagation patterns. Surround inhibition spatially restrains focal seizures and masks excitatory projections of ictal activities. When compromised, two patterns of seizure propagation emerge according to the position of inhibition defects relative to the ictal focus. I show that two distant ictal foci can communicate via physiological connectivity without any chronic rewiring processes – confirming the existence of long-range propagation pathways that could lead to epileptic network formation. In Chapter 4, I show that thalamic inputs might be necessary for interictal epileptiform discharges (IEDs). The relative positions between IEDs and ictal foci indicate that surround inhibition, shown in the previous chapter, can be exhausted by repetitive exposure to ictal projections. In Chapter 5, I propose a neural network model that can explain both long-standing behavioral observations of seizures and account for the most up-to-date electrophysiological recordings of spontaneous human focal seizures. The model relies on few assumptions, all of which are proved or supported in earlier chapters of this thesis. The model explains phasic evolution of seizure dynamics – how the commonly observed patterns arise from simple neurophysiological principles, as well as seizure onset subtypes, traveling wave directions and speeds. The model also predicts how spontaneous seizures might arise from synaptic plasticity. The chapter ends with a discussion of the model’s implications and future work. The thesis is organized in a way that each chapter can be read independently, with Chapter 5 summarizing the central theory spanning the whole study. Each chapter is also tightly linked to a clinically relevant question. In sum, the dissertation’s goal is to provide an in-principle understanding of focal seizure dynamics. With rapid advancement of clinical and experimental tools, I believe this work provides a roadmap for future therapies for epilepsy patients

Dynamics of brain states and cortical excitability in paroxysmal neurological conditions

Epilepsy and migraine are neurological conditions that are characterised by periods of disruption of normal neuronal functioning. Aside from this paroxysmal feature, both conditions share genetic mutations and altered cortical excitability. People with epilepsy appear to be diagnosed with migraine more often than people without epilepsy and, likewise, people with migraine seem to be diagnosed with epilepsy more often than people without migraine. Changes in cortical excitability may help explain the pathophysiological link between both conditions, and could be a biomarker to monitor disease activity. In this thesis, the association between migraine and epilepsy and their relation to cortical excitability is further explored. A meta-analysis of previous population based studies provides epidemiological evidence for the co-occurrence of migraine and epilepsy. The combination of computer modelling with human electroencephalographic recordings offers insight into multi-stability of brain states in epilepsy. Results described in this thesis show that Transcranial Magnetic Stimulation can be used to measure cortical excitability, but that its use as a biomarker of disease activity in epilepsy is limited due to large interindividual variability. By combining Transcranial Magnetic Stimulation with electroencephalography, two novel variables that may contribute to cortical excitability are investigated: phase clustering, which possibly reflecting functional neuronal connectivity, and the non-linear residual of a stimulus-response curve, which may reflect brain state multi-stability. The results presented in this thesis suggest that the higher propensity to global synchronisation is not shared between epilepsy and migraine. These new variables have potential value to differentiate people with epilepsy, but not people with migraine, from normal controls

Phase Synchronization Operator for On-Chip Brain Functional Connectivity Computation

This paper presents an integer-based digital processor for the calculation of phase synchronization between two neural signals. It is based on the measurement of time periods between two consecutive minima. The simplicity of the approach allows for the use of elementary digital blocks, such as registers, counters, and adders. The processor, fabricated in a 0.18- μ m CMOS process, only occupies 0.05 mm 2 and consumes 15 nW from a 0.5 V supply voltage at a signal input rate of 1024 S/s. These low-area and low-power features make the proposed processor a valuable computing element in closed-loop neural prosthesis for the treatment of neural disorders, such as epilepsy, or for assessing the patterns of correlated activity in neural assemblies through the evaluation of functional connectivity maps.Ministerio de Economía y Competitividad TEC2016-80923-POffice of Naval Research (USA) N00014-19-1-215