Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of \u201cself-limited focal epilepsies.\u201d In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 \ub1 11.46. Two independent general linear model models were created for each patient based on the effect of interest: \u201cindividual CTS\u201d in model 1 and \u201cCTS density\u201d in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical\u2013subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood\u2013oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks

Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG\u2013fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory\u2013motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG\u2013fMRI coregistration. During the \u201cawake session\u201d, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory\u2013motor cortex. During the \u201csleep session\u201d, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical\u2013subcortical network involving the thalamus, basal ganglia, sensory\u2013motor cortex, perisylvian cortex, and cerebellum. In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical\u2013subcortical network related to CTS. In particular, the involvement of a thalamic\u2013perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of \u201cself-limited focal epilepsies.\u201d In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 \ub1 11.46. Two independent general linear model models were created for each patient based on the effect of interest: \u201cindividual CTS\u201d in model 1 and \u201cCTS density\u201d in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical\u2013subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood\u2013oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks

Centrotemporal spikes during NREM sleep: The promoting action of thalamus revealed by simultaneous EEG and fMRI coregistration

Benign childhood epilepsy with centrotemporal spikes (BECTS) has been investigated through EEG\u2013fMRI with the aim of localizing the generators of the epileptic activity, revealing, in most cases, the activation of the sensory\u2013motor cortex ipsilateral to the centrotemporal spikes (CTS). In this case report, we investigated the brain circuits hemodynamically involved by CTS recorded during wakefulness and sleep in one boy with CTS and a language disorder but without epilepsy. For this purpose, the patient underwent EEG\u2013fMRI coregistration. During the \u201cawake session\u201d, fMRI analysis of right-sided CTS showed increments of BOLD signal in the bilateral sensory\u2013motor cortex. During the \u201csleep session\u201d, BOLD increments related to right-sided CTS were observed in a widespread bilateral cortical\u2013subcortical network involving the thalamus, basal ganglia, sensory\u2013motor cortex, perisylvian cortex, and cerebellum. In this patient, who fulfilled neither the diagnostic criteria for BECTS nor that for electrical status epilepticus in sleep (ESES), the transition from wakefulness to sleep was related to the involvement of a widespread cortical\u2013subcortical network related to CTS. In particular, the involvement of a thalamic\u2013perisylvian neural network similar to the one previously observed in patients with ESES suggests a common sleep-related network dysfunction even in cases with milder phenotypes without seizures. This finding, if confirmed in a larger cohort of patients, could have relevant therapeutic implication

L'épilepsie bénigne à pointes centrotemporales : investigation cognitive et études en imagerie fonctionnelle et structurelle

L’épilepsie bénigne à pointes centrotemporales (EPCT) est la forme la plus fréquente des épilepsies idiopathiques chez l’enfant (Fastenau et al., 2009). Le pronostic de ces patients est bon, notamment en raison de la rémission spontanée de cette épilepsie à l’adolescence; toutefois plusieurs études suggèrent la présence de troubles cognitifs et de spécificités neuroanatomiques. Il n’existe pas actuellement de consensus sur les liens entre leurs troubles cognitifs et leurs particularités neuroanatomiques et neurofonctionnelles. Dans cette thèse, notre but est de préciser le profil des enfants ayant une épilepsie bénigne à pointes centro-temporales, en investiguant les caractéristiques des patients à plusieurs niveaux: cognitif, fonctionnel, structurel. La thèse est composée de quatre articles, dont deux articles empiriques. Notre premier article a pour objectif de recenser les difficultés cognitives et affectives rapportées par les études s’intéressant aux caractéristiques des enfants ayant une épilepsie bénigne. Bien qu’une certaine variabilité soit retrouvée dans la littérature, cette revue démontre qu’une histoire d’épilepsie, même bénigne, peut être un facteur de risque pour le développement cognitif et socio-affectif des enfants. Notre revue de littérature a indiqué des troubles particuliers du langage chez ces enfants, mais aucune étude n’avait auparavant investigué spécifiquement la compréhension de lecture chez les enfants ayant une EPCT, une compétence essentielle dans le cheminement scolaire des enfants. Ainsi, nous avons développé une tâche novatrice de compréhension de lecture de phrases en imagerie par résonnance magnétique fonctionnelle (IRMf), adaptée à la population pédiatrique. Dans notre second article, nous avons validé cette tâche auprès d’enfants sains et nous avons mis en évidence une mobilisation des régions cérébrales généralement engagées dans des tâches langagières chez l’enfant sain, y compris les régions impliquées dans le traitement sémantique (Berl et al., 2010; Blumenfeld, Booth et Burman, 2006). Le troisième article de cette thèse rapporte notre investigation du réseau cérébral activé durant cette nouvelle tâche de compréhension de lecture de phrases en IRMf chez les enfants ayant une EPCT. Nos résultats suggèrent que ces derniers ont recours à l’activation d’un réseau cérébral plus large, présentant des similarités avec celui retrouvé chez les enfants dyslexiques. Par ailleurs, l’activation du striatum gauche, structure généralement associée à la réalisation de processus cognitifs complexes est uniquement retrouvée chez les enfants épileptiques. Étant donné que les enfants ayant une EPCT obtiennent des performances à la tâche d’IRMf équivalentes à celles des enfants sains, il est possible d’émettre l’hypothèse que ces différences d’activations cérébrales soient adaptatives. L’étude des relations entre les résultats neuropsychologiques, la performance à la tâche et les activations cérébrales a mis en évidence des prédicteurs différents entre les deux groupes d’enfants, suggérant qu’ils ne s’appuient pas exactement sur les mêmes processus cognitifs pour réussir la tâche. De plus, nous avons réalisé un travail d’intégration des diverses méthodologies utilisées dans les études en imagerie pondérée en diffusion chez l’enfant épileptique, ce qui constitue le quatrième article de cette thèse. Nous rapportons les diverses applications de cette méthode dans la caractérisation des anomalies structurelles subtiles de la matière blanche chez les enfants épileptiques en général. Les différentes méthodologies employées, les enjeux, et les biais potentiels relatifs aux traitements des données de diffusion y sont discutés. Enfin, pour mieux comprendre l’origine et les marqueurs de cette épilepsie, nous avons étudié les spécificités structurelles des cerveaux des enfants ayant une EPCT à l’aide d’analyses sur les données d’imagerie par résonnance magnétique. Aucune différence n’a été mise en évidence au niveau de la matière grise entre les cerveaux d’enfants sains et ceux ayant une EPCT. À l’inverse, nous rapportons des différences subtiles au niveau de la matière blanche dans notre population d’enfants épileptiques, avec une diminution de l’anisotropie fractionnelle (FA) au niveau temporal inférieur/moyen de l’hémisphère gauche, ainsi que dans l’hémisphère droit dans les régions frontales moyennes et occipitales inférieures. Ces résultats suggèrent la présence d’altérations de la matière blanche subtiles et diffuses dans le cerveau des enfants ayant une EPCT et concordent avec ceux d’autres études récentes (Ciumas et al., 2014).Benign epilepsy with centrotemporal spikes (BECTS) is the most common idiopathic epilepsy in children. Owing to its spontaneous remission during adolescence, prognosis is usually good. However, studies have recently demonstrated cognitive deficits and neuroanatomical abnormalities in BECTS. To date, the relationship between cognitive impairment and brain function and structure in BECTS is unclear owing to a lack of consensus in the literature. The aim of the present thesis was to establish a multidimensional profile of children with BECTS, investigating impairments on a cognitive, functional and structural level as compared to healthy controls. The present thesis is composed of four articles, including two review articles and two empirical articles. Our first review article summarizes the cognitive and behavioural impairments reported by studies investigating the characteristics of children with BECTS. Although some variability was found in the literature, our review demonstrates that a history of childhood epilepsy, even if benign, can be considered as a risk factor for both cognitive and socio-affective development in children. More precisely, our review showed that children with BECTS present specific language impairments. However, none of the studies reviewed investigated reading comprehension in these children, which represent an essential academic skill. Thus, we developed an innovative functional magnetic resonance imaging (fMRI) sentence reading comprehension task, adapted to a pediatric population. In our first empirical article, we validated this task in healthy children. Our results were concordant with those of other studies investigating semantic processing in children (Berl et al., 2010; Blumenfeld et al., 2006). The second empirical article aimed at investigating cerebral reading networks activated in BECTS children during our fMRI sentence-reading comprehension task. Our results suggest that these children activate a larger cerebral reading network as compared to healthy controls, showing similar activation patterns to children with dyslexia while performing a similar task. Moreover, activations in the left striatum, a region generally associated with complex cognitive processes, were found in BECTS children. Given that the performance of these children on the fMRI task was similar to that of healthy controls, we hypothesize that these differences in brain reading network activations are adaptive. We further studied relationships between neuropsychological results, task performance and brain activations. Our results suggest that BECTS children rely on slightly different cognitive processes during task performance as compared to healthy controls. In addition, we performed an integrated review of various methodologies used in diffusion magnetic resonance imaging (dMRI) studies of epileptic children, which constitutes the second review article in the present thesis. We reported various applications of this method in the characterisation of subtle white matter abnormalities in epileptic children in general. The different methodologies utilized, the challenges and the potential biases associated with data processing were discussed. Finally, we investigated structural abnormalities in children with BECTS using MRI data in order to better understand the origin and markers of this epilepsy. No grey matter differences were found between BECTS children and healthy controls. However, we reported subtle white matter differences between groups, such that children with BECTS demonstrated a decreased fractional anisotropy (FA) in the middle/superior temporal region of the left hemisphere as well as in the middle frontal and inferior occipital regions of the right hemisphere. These results suggest subtle and diffuse white matter alterations in BECTS, supporting recently reported results (Ciumas et al., 2014)

Simultaneous intracranial EEG and fMRI of interictal epileptic discharges in humans

Simultaneous scalp EEG–fMRI measurements allow the study of epileptic networks and more generally, of the coupling between neuronal activity and haemodynamic changes in the brain. Intracranial EEG (icEEG) has greater sensitivity and spatial specificity than scalp EEG but limited spatial sampling. We performed simultaneous icEEG and functional MRI recordings in epileptic patients to study the haemodynamic correlates of intracranial interictal epileptic discharges (IED). Two patients undergoing icEEG with subdural and depth electrodes as part of the presurgical assessment of their pharmaco-resistant epilepsy participated in the study. They were scanned on a 1.5 T MR scanner following a strict safety protocol. Simultaneous recordings of fMRI and icEEG were obtained at rest. IED were subsequently visually identified on icEEG and their fMRI correlates were mapped using a general linear model (GLM). On scalp EEG–fMRI recordings performed prior to the implantation, no IED were detected. icEEG–fMRI was well tolerated and no adverse health effect was observed. intra-MR icEEG was comparable to that obtained outside the scanner. In both cases, significant haemodynamic changes were revealed in relation to IED, both close to the most active electrode contacts and at distant sites. In one case, results showed an epileptic network including regions that could not be sampled by icEEG, in agreement with findings from magneto-encephalography, offering some explanation for the persistence of seizures after surgery. Hence, icEEG–fMRI allows the study of whole-brain human epileptic networks with unprecedented sensitivity and specificity. This could help improve our understanding of epileptic networks with possible implications for epilepsy surgery

Multifokale Epilepsie ist mit einer gesteigerten funktionellen Konnektivität assoziiert: eine kombinierte EEG-fMRT-Studie

Multifokale epileptische Aktivität ist ein ungünstiges Merkmal einer Vielzahl von epileptischen Syndromen (Lennox-Gastaut-Syndrom, West Syndrom und schwere fokale Epilepsien) und geht mit einer generellen Vulnerabilität des Gehirns für pathologische Synchronisation einher. Die zu Grunde liegenden Mechanismen der multifokalen Aktivität sind bisher noch ungenügend erforscht. In dieser Arbeit sollte untersucht werden, ob pathologische Konnektivität innerhalb der Hirnregionen des Default mode Netzwerkes sowie Thalamus, Hirnstamm und retrosplenialer Cortex Individuen für multifokale epileptische Aktivität prädisponiert. Hierfür wurden insgesamt 33 Kinder mit multifokaler und monofokaler (Kontrollgruppe) Epilepsie mittels kombiniertem EEG-fMRT während des Schlafs untersucht. Patienten mit monofokaler Epilepsie waren charakterisiert durch starke Korrelationen zwischen den korrespondierenden interhemisphärischen homotopen Regionen. Dieses Muster mit ausgeprägter Kurzdistanz- und schwacher Langdistanz-Konnektivität ähnelt dem Konnektivitätsmuster, welches für gesunde Kinder beschrieben ist. Patienten mit multifokaler epileptischer Aktivität zeigten hingegen erheblich stärkere Korrelationen zwischen einer Vielzahl von Regionen des DMN sowie dem Thalamus und Hirnstamm mit signifikantem Anstieg der langstreckigen Konnektivität im Vergleich zu den Kindern mit monofokaler epileptischer Aktivität. Innerhalb der Gruppe der Patienten mit multifokaler Epilepsie gab es keine Unterschiede hinsichtlich der funktionellen Konnektivität zwischen Patienten mit oder ohne Lennox-Gastaut-Syndrom. Diese Studie zeigt, dass multifokale Aktivität mit einer gesteigerten funktionellen Konnektivität des Hirns auf den langen Distanzen assoziiert ist. Daraus lässt sich schlussfolgern, dass diese ausgeprägte funktionelle Konnektivität die generelle Vulnerabilität des Hirns für pathologische Synchronisation darstellt