Ictal Functional Neuroimaging of Childhood Absence Epilepsy

Absence seizures in Childhood Absence Epilepsy (CAE) are 5 10 second episodes of impaired consciousness that are characterized on electroencephalography (EEG) by frontally-predominant, 3 4 Hz spike and wave discharges (SWD). The aims of this study were to use simultaneous EEG, functional magnetic resonance imaging (fMRI), and behavioral testing to identify the neural networks involved in absence seizures as well as to examine the timecourse of those ictal fMRI changes. It was hypothesized that absence seizures involve wide-reaching neural networks including the areas traditionally associated with normal attention processing and that absence seizures produce fMRI signal changes not only during the seizure, but before and after it as well. In this study, we recorded 88 absence seizures from a cohort of 42 children with pure CAE. These seizures were recorded as subjects participated in simultaneous EEG-fMRI scanning while engaged in a continuous performance task (CPT) of attentional vigilance or a repetitive tapping task (RTT) requiring repetitive motor activity. Using a novel, voxel-based percent fMRI change analysis combined with a volume of interest analysis, the second-by-second fMRI signal timecourse of the absence seizures were examined across numerous brain regions of interest, from 20 seconds before seizure onset through 40 seconds after seizure onset. EEG frequency analysis revealed seizures with a mean duration of 6.6 seconds and an abrupt onset and ending that were comprised of frontally-predominant, 3 4 Hz SWD. Ictal behavioral testing demonstrated abrupt onset of impairments during periods of SWD. These behavioral impairments were typical of CAE absence seizures in that impairments were greater in the CPT of attentional vigilance (omission error rate, OER = 81%) than in RTT testing (OER = 39 %) (p \u3c 0.003). The ictal fMRI changes we observed varied depending upon the method of fMRI signal analysis used. Using the traditional general liner model, and assuming the standard hemodynamic response (HRF) function, this study replicated results consistent with previous ictal absence fMRI studies showing ictal activations primarily in the thalamus and ictal deactivations in traditional default mode areas. Using a more data-driven, novel voxel-based fMRI percentage change analysis to examine the ictal fMRI timecourse on a second-by-second basis, both ictally as well as pre- and post- ictally, this study, however, demonstrated ictal involvement of diverse brain regions before, during, and after the seizure. Activation was demonstrated up to 16 seconds before seizure onset, starting first in the parietal and orbital-medial frontal cortices and progressing to lateral frontal and lateral temporal cortices followed by the occipital and Rolandic cortices and finally the thalamus. Deactivation followed a similar anatomic progression and lasted up to 17 seconds after the end of SWD. These findings reveal a complex and long-lasting sequence of fMRI changes in CAE absence seizures that are not detectable by conventional HRF modeling and are important in the understanding and eventual treatment of absence seizures associated with CAE

The Hippocampus Participates in a Pharmacological Rat Model of Absence Seizures

The thalamocortical network is responsible for the generation of spike-and-wave discharges (SWDs) in absence epilepsy. Recent studies suggest a potential involvement of the hippocampus, which may explain the variability in the extent of cognitive deficits among patients with absence epilepsy. I hypothesize that the hippocampus may become entrained in spike-and-wave discharges following thalamocortical activation. The gamma-butyrolactone (GBL) rat model of absence seizures was used in this thesis. Following GBL injection, SWDs of 4 to 6 Hz developed in the spontaneous local field potentials (LFPs) recorded by depth electrodes in the thalamus, neocortex and hippocampus. Synchronization of hippocampal, thalamic and neocortical SWDs was revealed by coherence analysis of the LFPs, and multiple unit activity of hippocampal neurons occurred within 250 msec prior to the negative peak of thalamic SWDs. Functional magnetic resonance imaging (fMRI) demonstrated functional connectivity between the hippocampus and the thalamocortical network. Thus, electrophysiological and fMRI activity of the hippocampus were shown to be time-locked to the thalamocortical SWDs, suggesting functional connectivity of the hippocampus and thalamocortical network during GBL-induced absence seizures

Cholinergic Neurotransmission In Partial Limbic Seizures

Partial limbic seizures impair consciousness, but the mechanism of impairment is not known. Most views hold that structures necessary for consciousness are disrupted by overexcitation from spread of seizure activity. Against this view, we hypothesize that partial limbic seizures cause pathological long-range inhibition of cortical activity. Using a rat model for partial limbic seizures, we demonstrate BOLD fMRI signal increases in the hippocampal seizure focus, but decreases in arousal promoting regions such as the thalamus and midbrain tegmentum. Second, direct single unit recordings from cholinergic neurons in two arousal nuclei, the basal forebrain and the pedunculopontine tegmental nuclei, demonstrate suppressed firing during seizures. Finally, using enzyme-based amperometry, we probe levels of the arousal neurotransmitter acetylcholine in the cortex and thalamus and observe decreased cholinergic neurotransmission during seizures. These findings demonstrate that an arousal center is suppressed during partial limbic seizures and suggest that decreased arousal may lead to impaired consciousness

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

Mechanisms of altered cortical excitability in photosensitive epilepsy

Despite the multiplicity of approaches and techniques so far applied for identifying the pathophysiological mechanisms of photosensitive epilepsy, a generally agreed explanation of the phenomenon is still lacking. The present thesis reports on three interlinked original experimental studies conducted to explore the neurophysiological correlates and the phatophysiological mechanism of photosensitive epilepsy. In the first study I assessed the role of the habituation of the Visual Evoked Response test as a possible biomarker of epileptic visual sensitivity. The two subsequent studies were designed to address specific research questions emerging from the results of the first study. The findings of the three intertwined studies performed provide experimental evidence that photosensitivity is associated with changes in a number of electrophysiological measures suggestive of altered balance between excitatory and inhibitory cortical processes. Although a strong clinical association does exist between specific epileptic syndromes and visual sensitivity, results from this research indicate that photosensitivity trait seems to be the expression of specific pathophysiological mechanisms quite distinct from the “epileptic” phenotype. The habituation of Pattern Reversal Visual Evoked Potential (PR-VEP) appears as a reliable candidate endo-phenotype of visual sensitivity. Interpreting the findings of this study in the context of the broader literature on visual habituation we can hypothesise the existence of a shared neurophysiological background between photosensitive epilepsy and migraine. Future studies to elucidate the relationship between the proposed indices of cortical excitability and specific polymorphisms of excitatroy and inhibitory neurotransmission will need to be conducted to assess their potential role as biomarkers of photosensitivity

EEG-fMRI signatures of spontaneous brain activity in healthy volunteers and epilepsy patients

Background: Functional magnetic resonance imaging (fMRI) provides maps of haemodynamic activity with uniform resolution across the brain. Simultaneous recording of electroencephalography (EEG) during fMRI (EEG-fMRI) was developed to localize spontaneously occurring epileptiform discharges. In focal epilepsy, it can identify candidate brain regions for surgical removal as a treatment option in medically refractory epilepsy; and in generalized epilepsy syndromes reveals those involved during the EEG changes. In healthy subjects, EEG-fMRI has linked spontaneous ongoing EEG activity with fMRI resting state networks. Methods: After method refinements, patients with medically refractory focal epilepsy and those with generalized epilepsy were studied with EEG-fMRI and group analyses performed to identify typical sets of brain regions involved in the epileptic process. Findings: In individual patients with refractory focal epilepsy, EEG-fMRI can produce activity maps including the seizure onset zone and propagated epileptic activity. Clinically, these can be confirmatory of results from alternative diagnostic techniques, or alternatively serve to generate a hypothesis on the potential epileptic focus, but under certain conditions may also be of negative predictive value with respect to surgical treatment success. At the group level in patients with temporal lobe epilepsy and complex partial seizures as well as in patients with generalized epilepsy and absence seizures, altered resting state network activity during EEG changes were found in default mode brain regions fitting well the ictal semiology, because these are known to reduce their activity during states of reduced consciousness. In (1) lateralized temporal lobe epilepsies, (2) an unselected mix of focal epilepsies, and (3) generalized epilepsies, activity increases occurred in typical brain regions suggesting an associated “hub function”, namely ipsilateral to the presumed cortical focus in the hippocampus; in an area near the frontal piriform cortex; and bilaterally in the thalamus, respectively. These findings argue for a network rather than a zone concept of epilepsy

New evidences of inflammatory mediators in absence epilepsy

L'epilessia dell'assenza appartiene alle forme di epilessia di tipo generalizzato. Crisi di assenza sono caratterizzate a livello elettroencefalografico dall'insorgenza di onde-punta caratteristiche (SWDs) dovute ad una patologica attivit\ue0 sincronizzata del circuito talamo-corticale. Gli studi sono stati effettuati sul modello animale (Wag/Rij), ratti che dal sesto mese d'et\ue0 presentano crisi di epilessia dell'assenza ricorrenti e spontanee. Ratti Wag/rij di quattro mesi d\u2019et\ue0 non ancora epilettici sono stati utilizzati come controllo. La pi\uf9 recente teoria volta a spiegare le cause dell'insorgenza di questa patologia mette in luce il ruolo primario della corteccia cerebrale ed identifica nella regione peri-orale della corteccia somato-sensoriale il focus di inizio delle crisi. Al fine di avvalorare tale teoria, sono stati svolti studi di risonanza magnetica strutturale (T2 e DWI) e funzionale (rCBV e rCBF), esperimenti di spettroscopia di risonanza magnetica (MRS) e analisi del profilo di espressione genica nelle aree cerebrali maggiormente coinvolte in questa patologia. Inoltre, la registrazione e l'analisi di tracciati EEG in seguito al trattamento con IL-1\u3b2 e TNF-\u3b1 hanno messo in luce il ruolo di tali citochine infiammatorie sull'insorgenza e la modulazione delle crisi d'assenza.Absence epilepsy is the most pure form of generalized epilepsy characterized in the EEG by widespread bilaterally synchronous spike-wave discharges (SWDs) caused by thalamo-cortical oscillations. Latest Cortical Focus theory suggests a consistent cortical \u201cfocus\u201d within the peri-oral region of the somatosensory cortex. In order to raise the evidence of a focal cortical theory, structural and functional MRI data were collected in all the cerebral areas involved in spindles generation and propagation in a genetic model of absence epilepsy. Four-months-old WAG/Rij rats were used as control (no SWDs) whereas nine-months-old rats (daily SWDs) were referred as experimental group. In order to exacerbate SWDs episodes, rats were treated with Vigabatrin. Moreover to provides chemical information about different brain regions in Wag/Rij rats, we performed MRS analysis for the measure of the levels of different metabolites which reflects specific cellular and biochemical processes. It has become increasingly obvious during recent decades that genetic factors play a main role in the idiopathic generalized epilepsies, including absence epilepsy. In this view, gene-array analysis for cell signaling pathways involved in SWDs in different cerebral areas, and qPCR data were performed and correlated with EEG data. The actions of proinflammatory cytokines in the CNS are only partially discovered. Some cytokines have been recently shown to affect neurotransmitters or are required to preserve the synaptic strength at excitatory synapses, or affect the expression of various neuropeptides and neurotrophic factors in several brain regions. Changes in the immune system may change the excitability of the CNS and alter the susceptibility of exogenous induced or genetically determined types of epilepsy. Here we investigate the role of two cytokines, IL-1\u3b2 and TNF-\u3b1 in WAG/Rij rats. Our hypothesis is that cerebral blood flow alterations and cytokines/chemokines release can modulate the occurrence of SWDs. Both controls and WAG/Rij rats were injected i.p. by TNF-\u3b1 (2\ub5g/kg) and IL-1\u3b2 (2\ub5g/kg) and EEG was recordered for 72h after the treatment. Furthermore, we analyzed the blood serum by ELISA method for TNF-\u3b1 and IL-1\u3b2 in control and epileptic animals

Characterization of ictal/non-ictal EEG patterns and Neuronal Networks in Childhood Absence Epilepsy

Childhood absence epilepsy (CAE) is one of the most common pediatric epilepsy syndromes found in children. It is associated with distinct seizure semiology and clear electroencephalographic (EEG) features. In CAE patients, differentiating EEG ictal and non-ictal generalised spikes and waves discharges (GSWDs) is however difficult, since these events have an identical appearance. The differentiation of these two events is very important in a clinical setting as it has a direct effect on diagnosis and management strategies of patients. This study focuses on differentiating ictal and non-ictal discharges at sensor and source level using only surface EEG. Twelve CAE patients having both ictal and non-ictal discharges were selected for this study. For all levels of analysis, frequency ranges of 1-30 Hz containing four important frequency bands (delta, theta, alpha and beta) were used. At sensor level, spectral analysis and functional connectivity (FC) based on imaginary part of coherency, were used to evaluate the spectral changes and channel connectivity at the surface, respectively. At source level, the onset zone for ictal and non-ictal discharges were reconstructed using the eLORETA algorithm, and FC was used again to analyse the neuronal networks. Furthermore, we gave a detailed mathematical background of the EEG, forward and inverse problem, along with the mathematical foundation for the eLORETA algorithm. Additionally, for the first time we prove the correctness of the eLORETA algorithm based on the correct regularization problem. At sensor level, ictal discharges showed significantly higher power compared to non-ictal discharges, followed by FC depicting a desynchronization of channel connections (weaker connectivity) for ictal discharges. At source level, a fascinating observation was that ictal and non-ictal discharges have the same source or onset zone in the brain. However, ictal discharges had a stronger source power compared to non-ictal discharges. FC at source level revealed that the connectivity between certain brain regions and the seeds of interest (source maximum and thalamus) was stronger for ictal discharges, compared to non-ictal discharges. This study clearly shows the significant differences between ictal and non-ictal discharges at sensor and source level using only surface EEG. This study would be a great interest to clinicians, since it could be the potential foundation for future diagnostics research for CAE patients

Oscillatory Network Activity in Brain Functions and Dysfunctions

Recent experimental studies point to the notion that the brain is a complex dynamical system whose behaviors relating to brain functions and dysfunctions can be described by the physics of network phenomena. The brain consists of anatomical axonal connections among neurons and neuronal populations in various spatial scales. Neuronal interactions and synchrony of neuronal oscillations are central to normal brain functions. Breakdowns in interactions and modifications in synchronization behaviors are usual hallmarks of brain dysfunctions. Here, in this dissertation for PhD degree in physics, we report discoveries of brain oscillatory network activity from two separate studies. These studies investigated the large-scale brain activity during tactile perceptual decision-making and epileptic seizures. In the perceptual decision-making study, using scalp electroencephalography (EEG) recordings of brain potentials, we investigated how oscillatory activity functionally organizes different neocortical regions as a network during a tactile discrimination task. While undergoing EEG recordings, blindfolded healthy participants felt a linear three-dot array presented electromechanically, under computer control, and reported whether the central dot was offset to the left or right. Based on the current dipole modeling in the brain, we found that the source-level peak activity appeared in the left primary somatosensory cortex (SI), right lateral occipital complex (LOC), right posterior intraparietal sulcus (pIPS) and finally left dorsolateral prefrontal cortex (dlPFC) at 45, 130, 160 and 175 ms respectively. Spectral interdependency analysis showed that fine tactile discrimination is mediated by distinct but overlapping ~15 Hz beta and ~80 Hz gamma band large-scale oscillatory networks. The beta-network that included all four nodes was dominantly feedforward, similar to the propagation of peak cortical activity, implying its role in accumulating and maintaining relevant sensory information and mapping to action. The gamma-network activity, occurring in a recurrent loop linked SI, pIPS and dlPFC, likely carrying out attentional selection of task-relevant sensory signals. Behavioral measure of task performance was correlated with the network activity in both bands. In the study of epileptic seizures, we investigated high-frequency (\u3e 50 Hz) oscillatory network activity from intracranial EEG (IEEG) recordings of patients who were the candidates for epilepsy surgery. The traditional approach of identifying brain regions for epilepsy surgery usually referred as seizure onset zones (SOZs) has not always produced clarity on SOZs. Here, we investigated directed network activity in the frequency domain and found that the high frequency (\u3e80 Hz) network activities occur before the onset of any visible ictal activity, andcausal relationships involve the recording electrodes where clinically identifiable seizures later develop. These findings suggest that high-frequency network activities and their causal relationships can assist in precise delineation of SOZs for surgical resection