Epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) are age-related epileptic encephalopathy characterized by the development of various psychomotor regressions in close temporal concordance with the appearance of the electroencephalogram (EEG) pattern of CSWS (Tassinari et al., 2000). This EEG pattern consists in sleep-related activation and diffusion of spike-wave discharges during usually more than 85% of non-rapid eye movement (non-REM) sleep (Tassinari et al., 2000). A minority of the CSWS cases has been associated to cortical or thalamic lesions (symptomatic cases), while in the other cases, the aetiology is unknown. We reported two families combining benign childhood epilepsy with centro-temporal spikes (BCECS), which is the most common form of idiopathic epilepsy in childhood, and cryptogenic epilepsy with CSWS in first-degree relatives. As idiopathic epilepsies are by definition epilepsies related to a genetic predisposition, these data suggests the existence of a continuum ranging from asymptomatic carriers of centro-temporal spikes to cryptogenic epilepsies with CSWS. This hypothesis is further supported by common clinical characteristics between BCECS and epilepsies with CSWS (Fejerman et al., 2000). Epileptic syndromes with CSWS are characterized by an acute phase defined by the emergence of psychomotor deficits, various types of seizures and CSWS activity at around three to eight years of age (Holmes and Lenck-Santini, 2006; Veggiotti et al., 2001). This acute phase is followed by a recovery phase in which patients’ clinical condition improves together with the remission of CSWS pattern, which spontaneously occur at around 15 years of age but may be prompted by using antiepileptic drugs (AED) including corticosteroids (Holmes and Lenck-Santini, 2006; Veggiotti et al., 2001). This biphasic evolution suggests that CSWS activity largely contributes to the psychomotor deficits observed in these patients (Holmes and Lenck-Santini, 2006; Van Bogaert et al., 2006). However, some authors still consider CSWS activity as an epiphenomenon reflecting the underlying brain pathology, rather than the direct cause of the psychomotor regression (Aldenkamp and Arends, 2004). The pathophysiological mechanisms of how CSWS activity could actually lead to psychomotor regression are still poorly understood. Functional cerebral imaging techniques such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), represent unique ways to non-invasively study the impact of epileptic activity on normal brain function. The PET technique using [18F]-fluorodeoxyglucose (FDG) gives information about the regional neuronal glucose consumption via the neurometabolic coupling while the fMRI technique studies the regional perfusional changes directly related to specific events of interest via the neurovascular coupling. We applied both FDG-PET and EEG combined with fMRI (EEG-fMRI) techniques to epileptic children with CSWS to better approach the functional repercussions of CSWS activity on neurophysiological functions and to determine the potential pathophysiological link between CSWS activity and psychomotor regression. In a first FDG-PET study, we determined the regional cerebral glucose metabolic patterns at the acute phase of CSWS in 18 children. We found three types of metabolic patterns: the association of focal hypermetabolism with distinct hypometabolism in 10 patients, focal hypometabolism without any associated area of increased metabolism in five children, and the absence of any significant metabolic abnormality in three patients. The hypermetabolic brain areas were anatomically related to an EEG focus. This anatomical relationship was clearly less consistent for hypometabolic regions. The metabolic abnormalities involved mainly the associative cortices. The metabolic heterogeneity found in these children could be due to the use of corticosteroids before PET as it was significantly associated with the absence of focal hypermetabolism. At the group level, patients with at least one hypermetabolic brain areas showed significant increased metabolism in the right parietal region that was associated to significant hypometabolism in the prefrontal cortex. This finding was interpreted as a phenomenon of remote inhibition of the frontal lobes by highly epileptogenic and hypermetabolic posterior cortex. This hypothesis was supported by effective connectivity analyses which demonstrated the existence of significant changes in the metabolic relationship between these brain areas in this group of children compared to the control group or to the group of children without any significant hypermetabolic brain area. This remote inhibition hypothesis would be reinforced by the demonstration, at the recovery phase of CSWS, of a common resolution of hypermetabolism at the site of epileptic foci and hypometabolism in distant connected brain areas. We thus performed a second FDG-PET study to determine the evolution of cerebral metabolism in nine children recovering from CSWS. At the acute phase of CSWS, all children had a metabolic pattern characterized by the association of focal hypermetabolism with distinct focal hypometabolic areas. The evolution to CSWS recovery was characterized by a complete or almost complete regression of both hypermetabolic and hypometabolic abnormalities. At the group level, the altered effective connectivity found at the acute phase between focal hypermetabolism (centro-parietal regions and right fusiform gyrus) and widespread hypometabolism (prefrontal and orbito-frontal cortices, temporal lobes, left parietal cortex, precuneus and cerebellum) markedly regressed at recovery. These results were of particular interest because they strongly suggested that the metabolic abnormalities observed during the acute phase of CSWS were mainly related to the neurophysiological effects of CSWS activity and not to the underlying cause of the epileptic disease. Moreover, this study confirmed that phenomena of remote inhibition do occur in epileptic syndromes with CSWS. EEG-fMRI is a functional cerebral imaging technique that allows non-invasive mapping of haemodynamic changes directly associated to epileptic activity. In a first EEG-fMRI study, we determined the clinical relevance of the perfusional changes linked to interictal epileptic discharges in a group of seven children with pharmacoresistant focal epilepsy. This study showed that the EEG-fMRI technique is a promising tool to non-invasively localize the epileptic focus and its repercussion on normal brain function in children with epilepsy. Then, to further demonstrate the involvement of CSWS activity in the neurophysiological changes detected by FDG-PET, we used the EEG-fMRI technique to study the perfusional changes directly related to the epileptic activity in an epileptic girl with CSWS. This patient developed a cognitive and behavioural regression in association with a major increase in frequency and diffusion of the spike-wave discharges during the awake state (spike index: 50-75%) and non-REM sleep (spike index: 85-90%). The patient’s neuropsychological profile was dominated by executive dysfunction and memory impairment. During runs of secondarily generalized spike-wave discharges, EEG-fMRI demonstrated deactivations in the lateral and medial fronto-parietal cortices, posterior cingulate gyrus and cerebellum together with focal relative activations in the right frontal, parietal and temporal cortices. These results suggested that the neuropsychological impairment in this case could be related to specific cortical dysfunction secondary to the spread of the epileptic activity from focal hypermetabolic foci. Taken together, both FDG-PET and EEG-fMRI investigations performed in epileptic children with CSWS have shown increases in metabolism/perfusion at the site of the epileptic focus that were associated to decreases in metabolism/perfusion in distinct connected brain areas. These data highly suggest that the neurophysiological effects of CSWS activity are not restricted to the epileptic focus but spread to connected brain areas via a possible mechanism of surrounding and/or remote inhibition. This mechanism is characterised by an epilepsy-induced inhibition of neurons that surround or are remote from the epileptic focus and connected with it via cortico-cortical or polysynaptic pathways (Witte and Bruehl, 1999). The existence of surrounding and remote inhibition phenomena have been well documented in different types of animal models of focal epilepsy using various functional cerebral imaging methods such as autoradiography or optical imaging (Bruehl et al., 1998; Bruehl and Witte, 1995; Witte et al., 1994). Their occurrence in human epilepsy have also been suspected in temporal or extra-temporal lobe epilepsies using FDG-PET, EEG-fMRI or single photon emission computed tomography (SPECT) (Blumenfeld et al., 2004; Schwartz and Bonhoeffer, 2001; Van Paesschen et al., 2003; Van Paesschen et al., 2007). Moreover, the demonstration of the regression of distant hypometabolic areas after surgical resection or disconnection of the epileptic focus further suggest that such inhibition mechanism do occur in epilepsy (Bruehl et al., 1998; Jokeit et al., 1997). On a clinical point of view, the demonstration of the existence of such inhibition mechanisms in epilepsies with CSWS brings new important insights for the understanding of the pathophysiological mechanisms involved in the psychomotor regression observed in these conditions. Indeed, these data highly suggest that the psychomotor regression is not only related to the neurophysiological impairment at the site of the epileptic foci but also to epilepsy-induced neurophysiological changes in distant connected brain areas.

No description available.

Previous research indicates that humans develop a phonological library in infancy. As humans grow into adulthood, their phonological library becomes well established. Upon encountering phonemes from a new language, humans process these phonemes by comparison to their native phonological library. Event-related potentials (ERP), specifically the mismatch negativity, have been shown to indicate that this process of comparing non-native phonemes to our native phonological library is not improved through learning the new language as an adult. An alternative explanation may be that there is an underlying change in the neural generators as the non-native phonemes are learned, but that this change is not reflected in the ERP. The current study seeks to examine this hypothesis through the simultaneous collection of ERP and blood-oxygen-level-dependent functional MRI (fMRI) data. The findings of the ERP and fMRI data are inconclusive. The study also explores the processing of diphthongs, a category of phonemes rarely tested before, through both behavioral and neuroimaging methods. The study presents behavioral data demonstrating that non-native diphthongs are processed based upon the separate elements of the phonemes, rather than as complete units.

La caractérisation de la structure du cerveau humain et les motifs fonctionnelles qu’il fait apparaitre est un défi central pour une meilleure compréhension des pathologies du réseau cérébral telle que l’épilepsie du lobe temporal. Cette caractérisation pourrait aider à améliorer la prédictibilité clinique des résultats d’une chirurgie visant à traiter l’épilepsie.Le fonctionnement du cerveau peut être étudié par l’électroencéphalographie (EEG) ou par l’imagerie de résonance magnétique fonctionnelle (IRMf), alors que la structure peut être caractérisé par l’IRM de diffusion (IRMd). Nous avons utilisé ces modalités pour mesurer le fonctionnement du cerveau pendant une tache de reconnaissance de visages et pendant le repos dans le but de faire le lien entre les modalités d’une façon optimale en termes de résolution temporale et spatiale. Avec cette approche on a mis en évidence une perturbation des relations structure-fonction chez les patients épileptiques.Ce travail a contribué à améliorer la compréhension de l’épilepsie comme une maladie de réseau qui affecte le cerveau à large échelle et non pas au niveau d’un foyer épileptique local. Dans le futur, ces résultats pourraient être utilisés pour guider des interventions chirurgicales mais ils fournissent également des approches nouvelles pour évaluer des traitements pharmacologiques selon ses implications fonctionnelles à l’échelle du cerveau entier. / The understanding human brain structure and the function patterns arising from it is a central challenge to better characterize brain network pathologies such as temporal lobe epilepsies, which could help to improve the clinical predictability of epileptic surgery outcome.Brain functioning can be accessed by both electroencephalography (EEG) or functional magnetic resonance imaging (fMRI), while brain structure can be measured with diffusion MRI (dMRI). We use these modalities to measure brain functioning during a face recognition task and in rest in order to link the different modalities in an optimal temporal and spatial manner. We discovered disruption of the network processing famous faces as well a disruption of the structure-function relation during rest in epileptic patients.This work broadened the understanding of epilepsy as a network disease that changes the brain on a large scale not limited to a local epileptic focus. In the future these results could be used to guide clinical intervention during epilepsy surgery but also they provide new approaches to evaluate pharmacological treatment on its functional implications on a whole brain scale.

Um eine Entscheidung zu treffen, muss Information interpretiert und in eine Handlung übersetzt werden. Dafür wird die a priori Wahrscheinlichkeit bezüglich der Entscheidungsalternativen in den Prozess der Entscheidungsfindung integriert und löst Mechanismen der Handlungsvorbereitung aus. In der vorliegenden Dissertation habe ich untersucht, welche Vorbereitungsprozesse aufgrund von wahrscheinlichkeitsbasierter Vorinformation stattfinden und welche Gehirnareale mit der Integration dieser Information assoziiert sind. Um diese Fragen zu beantworten, habe ich eine Verhaltensstudie, eine Studie mit Ableitung des Elektroenzephalogramms (EEG) und eine Studie mittels der funktionellen Magnetresonanztomographie (fMRT) mit simultaner Ableitung des EEGs durchgeführt. Die Versuchspersonen bearbeiteten währenddessen eine Zahlenvergleichsaufgabe mit einem Hinweisreiz, der Wahrscheinlichkeitsinformation bezüglich der erforderlichen Antwort enthielt. Die Reaktionszeit wurde durch die wahrscheinlichkeitsbasierte Vorinformation des Hinweisreizes parametrisch moduliert (Studie 1). Daraus lässt sich schlussfolgern, dass Vorbereitungsprozesse in Abhängigkeit der Wahrscheinlichkeitsinformation stattfinden. Die EEG Studie (Studie 2) ergab einen parametrischen Effekt von Wahrscheinlichkeitsinformation auf die Amplitude der Contingent Negative Variation (CNV), einer EEG-Komponente, die Vorbereitungsprozesse auf prämotorischer Ebene reflektiert. Darüber hinaus fand sich mittels einer Dipolquellenanalyse ein Dipol im anterioren Cingulum (ACC), dessen Aktivität ebenfalls durch die Wahrscheinlichkeitsinformation parametrisch moduliert war. Diese Ergebnisse lassen auf prämotorische Vorbereitungsprozesse aufgrund von Wahrscheinlichkeitsinformation schließen. In den fMRT-Ergebnissen zeigte sich eine parametrisch modulierte neuronale Aktivierung im posterioren Teil des medial-frontalen Kortex (pMFC), die auf eine Kontrollfunktion zur Handlungsanpassung dieses Areals zurückgeführt werden kann (Studie 3a). Um dynamische Fluktuationen der Wahrscheinlichkeitsverarbeitung zu untersuchen, wurde die CNV Amplitude der Einzeltrials in das Modell der fMRT-Analyse integriert (Studie 3b). Die CNV Amplitude korrelierte mit der neuronalen Aktivität in einem Netzwerk, bestehend aus frontalen, parietalen und striatalen Arealen, das mit allgemeiner wahrscheinlichkeitsunabhängiger Handlungsvorbereitung im Zusammenhang steht. Dagegen zeigten sich im dorsolateralen Präfrontalkortex (DLPFC), im inferioren frontalen Gyrus (IPG) und im inferioren Parietallappen (IPL) Aktivierungen, die sich auf die dynamische Integration von Wahrscheinlichkeitsinformation zurückführen lassen. / To prepare actions in advance, prior information about the probability of decision alternatives is integrated into the decision-making process. In the present dissertation, I investigated preparatory processes elicited by prior probability (PP) and the neural basis of PP processing. In three studies, I collected behavioral data and, furthermore, recorded electroencephalographic (EEG) data separately as well as simultaneously with functional magnetic resonance imaging (fMRI). While applying these methods, participants had to perform a number comparison task with a precue delivering PP about a subsequent response-demanding stimulus. The probability precue elicited the preparation of the response, as shown by the parametrical modulation of response time (RT) depending on PP (Study 1). The EEG study (Study 2) revealed a parametrical effect of PP on the contingent negative variation (CNV) during the foreperiod, which is an indicator for premotor response preparation. Furthermore, a dipole was located in the anterior cingulate cortex (ACC) with its activity parametrically modulated by PP. These EEG results suggest that PP influences premotor response preparation in a parametrical fashion. An analysis of fMRI data showed that neural activity in the posterior medial frontal cortex (pMFC) increased with increasing PP (Study 3a), which is attributed to a monitoring function of this region with respect to behavioral adjustment and initiation of response preparation depending on the PP. By applying an EEG-informed fMRI analysis (Study 3b), I focused on trial-to-trial fluctuations in PP processing and general response preparation as represented by the single-trial CNV amplitude. I found that the CNV amplitude was correlated with neural activity in a network consisting of frontal, parietal, and striatal regions reflecting general preparatory processes independently of PP. Parts of the network, namely, the dorsolateral prefrontal cortex (DLPFC), the inferior frontal gyrus (IFG), and the inferior parietal lobule (IPL), showed activations, which exclusively represented the contributions of PP to the CNV amplitude fluctuations. These results suggest that PP elicits premotor response preparation and activates the pMFC parametrically signaling the need for behavioral adjustment. In contrast, DLPFC, IFG, and IPL are involved in dynamically fluctuating PP processing mechanisms.

Mnoho rozdílných strategií fúze bylo vyvinuto během posledních 15 let výzkumu simultánního EEG-fMRI. Aktuální dizertační práce shrnuje aktuální současný stav v oblasti výzkumu fúze simultánních EEG-fMRI dat a pokládá si za cíl vylepšit vizualizaci úkolem evokovaných mozkových sítí slepou analýzou přímo z nasnímaných dat. Dva rozdílné modely, které by to měly vylepšit, byly navrhnuty v předložené práci (tj. zobecněný spektrální heuristický model a zobecněný prostorovo-frekvenční heuristický model). Zobecněný frekvenční heuristický model využívá fluktuace relativního EEG výkonu v určitých frekvenčních pásmech zprůměrovaných přes elektrody zájmu a srovnává je se zpožděnými fluktuacemi BOLD signálů pomocí obecného lineárního modelu. Získané výsledky ukazují, že model zobrazuje několik na frekvenci závislých rozdílných úkolem evokovaných EEG-fMRI sítí. Model překonává přístup fluktuací absolutního EEG výkonu i klasický (povodní) heuristický přístup. Absolutní výkon vizualizoval s úkolem nesouvisející širokospektrální EEG-fMRI komponentu a klasický heuristický přístup nebyl senzitivní k vizualizaci s úkolem spřažené vizuální sítě, která byla pozorována pro relativní pásmo pro data vizuálního oddball experimentu. Pro EEG-fMRI data s úkolem sémantického rozhodování, frekvenční závislost nebyla ve finálních výsledcích tak evidentní, neboť všechna pásma zobrazily vizuální síť a nezobrazily aktivace v řečových centrech. Tyto výsledky byly pravděpodobně poškozeny artefaktem mrkání v EEG datech. Koeficienty vzájemné informace mezi rozdílnými EEG-fMRI statistickými parametrickými mapami ukázaly, že podobnosti napříč různými frekvenčními pásmy jsou obdobné napříč různými úkoly (tj. vizuální oddball a sémantické rozhodování). Navíc, koeficienty prokázaly, že průměrování napříč různými elektrodami zájmu nepřináší žádnou novou informaci do společné analýzy, tj. signál na jednom svodu je velmi rozmazaný signál z celého skalpu. Z těchto důvodů začalo být třeba lépe zakomponovat informace ze svodů do EEG-fMRI analýzy, a proto jsme navrhli více obecný prostorovo-frekvenční heuristický model a také jak ho odhadnout za pomoci prostorovo-frekvenční skupinové analýzy nezávislých komponent relativního výkonu EEG spektra. Získané výsledky ukazují, že prostorovo-frekvenční heuristický model vizualizuje statisticky nejvíce signifikantní s úkolem spřažené mozkové sítě (srovnáno s výsledky prostorovo-frekvenčních vzorů absolutního výkonu a s výsledky zobecněného frekvenčního heuristického modelu). Prostorovo-frekvenční heuristický model byl jediný, který zaznamenal s úkolem spřažené aktivace v řečových centrech na datech sémantického rozhodování. Mimo fúzi prostorovo-frekvenčních vzorů s fMRI daty, jsme testovali stabilitu odhadů prostorovo-frekvenčních vzorů napříč různými paradigmaty (tj. vizuální oddball, semantické rozhodování a resting-state) za pomoci k-means shlukovacího algoritmu. Dostali jsme 14 stabilních vzorů pro absolutní EEG výkon a 12 stabilních vzorů pro relativní EEG výkon. Ačkoliv 10 z těchto vzorů vypadají podobně napříč výkonovými typy, prostorovo-frekvenční vzory relativního výkonu (tj. vzory prostorovo-frekvenčního heuristického modelu) mají vyšší evidenci k úkolům.

Epileptic syndromes with continuous spikes and waves during slow sleep (CSWS) are age-related epileptic encephalopathy characterized by the development of various psychomotor regressions in close temporal concordance with the appearance of the electroencephalogram (EEG) pattern of CSWS (Tassinari et al. 2000). This EEG pattern consists in sleep-related activation and diffusion of spike-wave discharges during usually more than 85% of non-rapid eye movement (non-REM) sleep (Tassinari et al. 2000). <p>A minority of the CSWS cases has been associated to cortical or thalamic lesions (symptomatic cases), while in the other cases, the aetiology is unknown. We reported two families combining benign childhood epilepsy with centro-temporal spikes (BCECS), which is the most common form of idiopathic epilepsy in childhood, and cryptogenic epilepsy with CSWS in first-degree relatives. As idiopathic epilepsies are by definition epilepsies related to a genetic predisposition, these data suggests the existence of a continuum ranging from asymptomatic carriers of centro-temporal spikes to cryptogenic epilepsies with CSWS. This hypothesis is further supported by common clinical characteristics between BCECS and epilepsies with CSWS (Fejerman et al. 2000).<p>Epileptic syndromes with CSWS are characterized by an acute phase defined by the emergence of psychomotor deficits, various types of seizures and CSWS activity at around three to eight years of age (Holmes and Lenck-Santini, 2006; Veggiotti et al. 2001). This acute phase is followed by a recovery phase in which patients’ clinical condition improves together with the remission of CSWS pattern, which spontaneously occur at around 15 years of age but may be prompted by using antiepileptic drugs (AED) including corticosteroids (Holmes and Lenck-Santini, 2006; Veggiotti et al. 2001). This biphasic evolution suggests that CSWS activity largely contributes to the psychomotor deficits observed in these patients (Holmes and Lenck-Santini, 2006; Van Bogaert et al. 2006). However, some authors still consider CSWS activity as an epiphenomenon reflecting the underlying brain pathology, rather than the direct cause of the psychomotor regression (Aldenkamp and Arends, 2004). The pathophysiological mechanisms of how CSWS activity could actually lead to psychomotor regression are still poorly understood.<p>Functional cerebral imaging techniques such as positron emission tomography (PET) or functional magnetic resonance imaging (fMRI), represent unique ways to non-invasively study the impact of epileptic activity on normal brain function. The PET technique using [18F]-fluorodeoxyglucose (FDG) gives information about the regional neuronal glucose consumption via the neurometabolic coupling while the fMRI technique studies the regional perfusional changes directly related to specific events of interest via the neurovascular coupling. We applied both FDG-PET and EEG combined with fMRI (EEG-fMRI) techniques to epileptic children with CSWS to better approach the functional repercussions of CSWS activity on neurophysiological functions and to determine the potential pathophysiological link between CSWS activity and psychomotor regression.<p>In a first FDG-PET study, we determined the regional cerebral glucose metabolic patterns at the acute phase of CSWS in 18 children. We found three types of metabolic patterns: the association of focal hypermetabolism with distinct hypometabolism in 10 patients, focal hypometabolism without any associated area of increased metabolism in five children, and the absence of any significant metabolic abnormality in three patients. The hypermetabolic brain areas were anatomically related to an EEG focus. This anatomical relationship was clearly less consistent for hypometabolic regions. The metabolic abnormalities involved mainly the associative cortices. The metabolic heterogeneity found in these children could be due to the use of corticosteroids before PET as it was significantly associated with the absence of focal hypermetabolism. At the group level, patients with at least one hypermetabolic brain areas showed significant increased metabolism in the right parietal region that was associated to significant hypometabolism in the prefrontal cortex. This finding was interpreted as a phenomenon of remote inhibition of the frontal lobes by highly epileptogenic and hypermetabolic posterior cortex. This hypothesis was supported by effective connectivity analyses which demonstrated the existence of significant changes in the metabolic relationship between these brain areas in this group of children compared to the control group or to the group of children without any significant hypermetabolic brain area. <p>This remote inhibition hypothesis would be reinforced by the demonstration, at the recovery phase of CSWS, of a common resolution of hypermetabolism at the site of epileptic foci and hypometabolism in distant connected brain areas. We thus performed a second FDG-PET study to determine the evolution of cerebral metabolism in nine children recovering from CSWS. At the acute phase of CSWS, all children had a metabolic pattern characterized by the association of focal hypermetabolism with distinct focal hypometabolic areas. The evolution to CSWS recovery was characterized by a complete or almost complete regression of both hypermetabolic and hypometabolic abnormalities. At the group level, the altered effective connectivity found at the acute phase between focal hypermetabolism (centro-parietal regions and right fusiform gyrus) and widespread hypometabolism (prefrontal and orbito-frontal cortices, temporal lobes, left parietal cortex, precuneus and cerebellum) markedly regressed at recovery. These results were of particular interest because they strongly suggested that the metabolic abnormalities observed during the acute phase of CSWS were mainly related to the neurophysiological effects of CSWS activity and not to the underlying cause of the epileptic disease. Moreover, this study confirmed that phenomena of remote inhibition do occur in epileptic syndromes with CSWS. <p>EEG-fMRI is a functional cerebral imaging technique that allows non-invasive mapping of haemodynamic changes directly associated to epileptic activity. In a first EEG-fMRI study, we determined the clinical relevance of the perfusional changes linked to interictal epileptic discharges in a group of seven children with pharmacoresistant focal epilepsy. This study showed that the EEG-fMRI technique is a promising tool to non-invasively localize the epileptic focus and its repercussion on normal brain function in children with epilepsy. Then, to further demonstrate the involvement of CSWS activity in the neurophysiological changes detected by FDG-PET, we used the EEG-fMRI technique to study the perfusional changes directly related to the epileptic activity in an epileptic girl with CSWS. This patient developed a cognitive and behavioural regression in association with a major increase in frequency and diffusion of the spike-wave discharges during the awake state (spike index: 50-75%) and non-REM sleep (spike index: 85-90%). The patient’s neuropsychological profile was dominated by executive dysfunction and memory impairment. During runs of secondarily generalized spike-wave discharges, EEG-fMRI demonstrated deactivations in the lateral and medial fronto-parietal cortices, posterior cingulate gyrus and cerebellum together with focal relative activations in the right frontal, parietal and temporal cortices. These results suggested that the neuropsychological impairment in this case could be related to specific cortical dysfunction secondary to the spread of the epileptic activity from focal hypermetabolic foci. <p>Taken together, both FDG-PET and EEG-fMRI investigations performed in epileptic children with CSWS have shown increases in metabolism/perfusion at the site of the epileptic focus that were associated to decreases in metabolism/perfusion in distinct connected brain areas. These data highly suggest that the neurophysiological effects of CSWS activity are not restricted to the epileptic focus but spread to connected brain areas via a possible mechanism of surrounding and/or remote inhibition. This mechanism is characterised by an epilepsy-induced inhibition of neurons that surround or are remote from the epileptic focus and connected with it via cortico-cortical or polysynaptic pathways (Witte and Bruehl, 1999). The existence of surrounding and remote inhibition phenomena have been well documented in different types of animal models of focal epilepsy using various functional cerebral imaging methods such as autoradiography or optical imaging (Bruehl et al. 1998; Bruehl and Witte, 1995; Witte et al. 1994). Their occurrence in human epilepsy have also been suspected in temporal or extra-temporal lobe epilepsies using FDG-PET, EEG-fMRI or single photon emission computed tomography (SPECT) (Blumenfeld et al. 2004; Schwartz and Bonhoeffer, 2001; Van Paesschen et al. 2003; Van Paesschen et al. 2007). Moreover, the demonstration of the regression of distant hypometabolic areas after surgical resection or disconnection of the epileptic focus further suggest that such inhibition mechanism do occur in epilepsy (Bruehl et al. 1998; Jokeit et al. 1997). On a clinical point of view, the demonstration of the existence of such inhibition mechanisms in epilepsies with CSWS brings new important insights for the understanding of the pathophysiological mechanisms involved in the psychomotor regression observed in these conditions. Indeed, these data highly suggest that the psychomotor regression is not only related to the neurophysiological impairment at the site of the epileptic foci but also to epilepsy-induced neurophysiological changes in distant connected brain areas. <p><p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished

In recent years, development of various imaging, recording and stimulation tools are rapidly advancing our knowledge of the human anatomy and its underlying interconnections. As a truly non-invasive tool, Magnetic Resonance Imaging (MRI), is creating new opportunities to understand large scale biological processes with a fine detail. Furthermore, novel materials and microfabrication techniques are allowing researchers to develop tools that record bio-signal or modulate complex physiology with high temporal precision. However, these tools, when used individually can elucidate only a partial view of the human body and the brain. There is a growing need in both the research and clinical community to find ways to perform these modalities together and visualize biological systems across a vast range of spatiotemporal scale. However, severe methodological challenges act as bottlenecks for any such multimodal integration.<br><div><br></div><div>To address this critical need, I have designed an MRI-safe platform for high-fidelity bio-signal recording and electrical stimulation during concurrent MRI imaging. Central to this system are novel miniaturized microelectronic devices, that operate wirelessly in synchrony with MRI scans. The system leverages surplus functionalities of a conventional scanner to integrate with the imaging system and provide a simple and inexpensive solution towards multimodal imaging. This work also describes a systematic approach for development and evaluation of this plug-and-play system through in-vivo experiments in animal models. The clinical relevance of the multimodal imaging platform was further showcased through a study on the mechanism of SUDEP (Sudden death in epilepsy), a terminal complication associated with epilepsy. With future refinements, I expect this platform will provide affordable, accessible, and reliable solutions for multimodal imaging in animals and humans, creating unique opportunities for basic scientific research and clinical diagnosis.<br></div>