Modeling Radiofrequency Heating of Embolization Coils for the Treatment of Cerebral Aneurysm

RÉSUMÉ: L’anévrisme intracrânien est une déformation de la paroi d'une artère du cerveau qui provoque une dilatation localisée du vaisseau sanguin. Les anévrismes non traités peuvent se déchirer et causer une hémorragie sous-arachnoïdienne (SAH) et, dans certains cas, des accidents vasculaires cérébraux. Les traitements courants sont la chirurgie et les traitements endovasculaires. Le traitement endovasculaire le plus populaire est l'embolisation à l'aide de spirales qui a été proposée par G. Guglielmi en 1991 (ces spirales sont des endoprothèses vasculaires ayant la forme arrondie d'un ressort). Cette méthode, qui est actuellement utilisée pour traiter environ 80% des anévrismes cérébraux, consiste à insérer un cathéter dans l'aorte, puis à le guider vers le vaisseau désiré de façon à insérer des spirales de platine à l'intérieur de l'anévrisme. Ces spirales induisent une coagulation puis l’obstruction de l’anévrysme. Un problème possible est que l'anévrisme ainsi traité peut se recanaliser après quelques mois pour des raisons inconnues. Bien que les mécanismes de la recanalisation demeurent incertains, l'une des hypothèses est que celle-ci provient de l'endothélium et que la dénudation endothéliale pourrait prévenir cette recanalisation. Certaines méthodes de dénudation endothéliales ont déjà été étudiées, telles que l'abrasion mécanique avec le dispositif col-pont anévrismal (aneurismal neck-bridge device, ANBD) et la cryoablation. Ces deux méthodes ont toutefois présenté des résultats non désirés. La nouvelle méthode qui est étudiée dans ce mémoire est l'ablation thermique par courant radiofréquence (radiofrequency ablation, RFA), qui a été suggérée par J. Raymond.----------Abstract: Cerebral aneurysm is a weakness in the wall of a cerebral artery which causes a localized dilation or ballooning of the blood vessel. Untreated aneurysms in the brain may rupture and cause subarachnoid hemorrhage (SAH) and in some cases, stroke. Treatment may be surgical or endovascular treatments. The most popular endovascular treatment is coil embolization, first introduced with controlled detachment by G. Guglielmi in 1991. This method, which is currently used to treat approximately 80% of cerebral aneurysms, consists in inserting a catheter in the aorta and then guiding it to the desired region of the cerebral vasculature to insert small platinum coils inside the aneurysm. These coils induce clotting and occlude the aneurysms. A possible problem is that the occluded aneurysm can be recanalized after some months because of unknown reasons. Though the exact mechanism responsible for recanalization remains unclear, one of the hypotheses is that recanalization is related to the endothelium and that endothelial denudation can prevent recanalization. Some methods of denudation have been previously investigated, such as mechanical abrasion with the aneurismal neck-bridge device (ANBD) and cryoablation. Both methods showed undesirable results. The new method which is investigated in this memoir is radiofrequency ablation (RFA). Based on preliminary in vivo studies, it is believed that RFA can be effective in endothelial denudation and in improving the results of coil embolization. The main objective of our project is to investigate the effects of radiofrequency current applied to an endovascular platinum coil on the temperature distribution of perianeurysmal tissues so as to optimize the energy delivery process. To achieve this goal, inductive and resistive characteristics of the embolization coils, as well as the effects of the length and shape of the electrode on the temperature distribution was investigated using a computer modeling approach. In vitro experiments were also performed to validate the computer simulations. Based on this study, we conclude that platinum coils should not be used for the direct application of RF current. A steel applicator placed in the center of the endovascular coils is more appropriate. Also, an applicator length of 6 to 10 mm is optimized for generation of a uniform temperature distribution. Finally, animal studies should be performed to further investigate this promising approach

High frequency oscillations (HFOs: 80-500 Hz), ictogenesis and epileptogenesis

Mesial temporal lobe epilepsy (MTLE), one of the most common forms of focal epilepsy, is characterized by recurrent seizures that originate from limbic structures such as the hippocampus, the amygdala or the entorhinal cortex. Around 30% of MTLE patients do not benefit from antiepileptic drug therapy and are, thus, potential candidates for surgical removal of the epileptogenic zone but approximately 30% of them do not become seizure free. Therefore, it is of paramount importance to understand the mechanisms underlying MTLE to develop new therapeutical interventions.Interictal spikes, and more recently high-frequency oscillations (HFOs, 80-500 Hz), recorded from MTLE patients and in animal models mimicking this disorder are markers of abnormal patterns of neural network activity. In addition, studies of HFOs and interictal spikes can reveal information about the mechanisms underlying ictogenesis and epileptogenesis. In my thesis, by employing the pilocarpine model of MTLE and the systemic administration of either 4-Aminopyridine (4AP) or picrotoxin. I addressed the role of interictal spikes and HFOs in ictogenesis, and epileptogenesis.The main findings of my studies can be summarized as follows:I first developed an automated method for detecting HFOs during pre-ictal, ictal, and post-ictal periods; this method, which employs a reference period before the seizure onset for signal normalization, provides results that are more similar to visual analysis in detecting HFOs compared to other automated methods.Employing this method, I discovered that two main types of seizure onsets in pilocarpine treated rats, namely low-voltage fast and hypersynchronous onset patterns, are associated with different HFO types.The results obtained in the pilocarpine treated rats were confirmed and replicated with the systemic injection of 4-aminopyridine (4AP) or picrotoxin. Specifically, I discovered that 4AP-induced low-voltage fast seizures are mostly associated to ripples, whereas hypersynchronous seizures induced with picrotoxin are mostly associated to fast ripples.Finally, I identified specific changes in interictal spikes and HFOs during the transition from latent to chronic period; these changes may indeed reflect pathophysiological modifications occurring in limbic structures that are implicated in epileptogenesis.Altogether, my findings demonstrated that: (i) there are specific changes in network excitability occurring during low-voltage fast-onset and hypersynchronous-onset seizures, and that these differences can be pinpointed in vivo by analyzing HFOs, and (ii) possible changes in synaptic plasticity in limbic structures during epileptogenesis are reflected by alterations in interictal spikes and HFOs. I anticipate that my findings will open new perspectives in epilepsy diagnostic approaches as well as in developing new antiepileptic drugs for controlling epileptic seizures.L’épilepsie mésiale temporale (EMT), l'une des formes les plus courantes d’épilepsie focale, se caractérise par des crises récurrentes dont l’origine se situe dans les structures limbiques telles que l'hippocampe, l'amygdale ou le cortex entorhinal. Environ 30% des patients ayant l’EMT demeurent réfractaires au traitement et sont donc des candidats potentiels à l'ablation chirurgicale de la zone épileptogène. Cependant, 30% de ces patients demeurent toujours épileptiques après la chirurgie. Par conséquent, il est d'une importance primordiale de comprendre les mécanismes sous-jacents à l’EMT, afin de développer de nouvelles interventions thérapeutiques.Les pointes interictales, et plus récemment les oscillations à haute fréquence (OHF, 80-500 Hz), enregistrées chez les patients atteints d’EMT et dans les modèles animaux reproduisant ce trouble, sont considérées comme marqueurs d’une activité pathologique des réseaux neuronaux. En effet, les OHF et les pointes interictales révèlent des informations sur les mécanismes sous-jacents à l’ictogenèse et l’épileptogenèse. Dans ma thèse, à l’aide du modèle animal de l’EMT à la pilocarpine et par l'administration systémique de 4-aminopyridine (4AP) ou de picrotoxine, j'ai adressé le rôle des pointes interictales et des OHF au cours de l’ictogenèse et de l'épileptogénèse. Les principales conclusions de mes études peuvent être résumées comme suit:J’ai d'abord développé une méthode automatisée pour détecter les OHF lors de la période pré-ictale, ictale et post-ictale; cette méthode, qui emploie une période de référence avant le début de la crise pour la normalisation du signal, donne des résultats davantage similaires à ceux obtenus par l'analyse visuelle que les autres méthodes automatisées. Grâce à cette méthode, j’ai découvert que deux types principaux de crises chez des rats traités à la pilocarpine, à savoir les crises à bas voltage haute fréquence et hypersynchrone, sont associées à différents patrons d’occurrence des OHF (80-500 Hz).Les résultats obtenus chez les rats traités à la pilocarpine ont été confirmés et reproduits par l'injection systémique de 4-aminopyridine (4AP) ou par l’injection de picrotoxine. Plus précisément, j’ai découvert que les crises à bas voltage haute fréquence induites par la 4AP sont souvent associées à des oscillations entre 80-200 Hz, alors que les crises hypersynchrone induites par la picrotoxine sont principalement associées aux oscillations entre 250-500 Hz.Enfin, j’ai identifié des changements spécifiques dans les pointes interictales et dans les OHF lors du passage de la période de latence à la période chronique. Ces changements pourraient refléter les modifications physiopathologiques qui se produisent dans les structures limbiques impliquées dans l'épileptogénèse.Dans l’ensemble, les résultats ont démontré que: (i) il existe des changements spécifiques de l'excitabilité des réseaux neuronaux survenant durant les crises à bas voltage et à haute fréquence ainsi que durant les crises hypersynchrones, et que des différences existent in vivo en analysant les OHF, et (ii) les modifications possibles de la plasticité synaptique dans les structures limbiques au cours de l’épileptogénèse sont reflétées par des altérations dans l’occurrence des pointes interictales et des OHF. Je pense que mes résultats ouvriront de nouvelles perspectives dans le diagnostic de l’épilepsie ainsi que dans le développement de nouveaux traitements antiépileptiques pour contrôler les crises récurrentes

A comparison between automated detection methods of high-frequency oscillations (80-500 Hz) during seizures

High-frequency oscillations (HFOs, ripples: 80-200 Hz, fast ripples: 250-500 Hz) recorded from the epileptic brain are thought to reflect abnormal network-driven activity. They are also better markers of seizure onset zones compared to interictal spikes. There is thus an increasing number of studies analysing HFOs in vitro, in vivo and in the EEG of human patients with refractory epilepsy. However, most of these studies have focused on HFOs during interictal events or at seizure onset, and few have analysed HFOs during seizures. In this study, we are comparing three different automated methods of HFO detection to two methods of visual analysis, during the pre-ictal, ictal and post-ictal periods on multiple channels using the rat pilocarpine model of temporal lobe epilepsy. The first method (method 1) detected HFOs using the average of the normalised period, the second (method 2) detected HFOs using the average of the normalised period in 1 s windows and the third (method 3) detected HFOs using the average of a reference period before seizure onset. Overall, methods 2 and 3 showed higher sensitivity compared to method 1. When dividing the analysed traces in pre-, ictal and post-ictal periods, method 3 showed the highest sensitivity during the ictal period compared to method 1, while method 2 was not significantly different from method 1. These findings suggest that method 3 could be used for automated and reliable detection of HFOs on large data sets containing multiple channels during the ictal period. (C) 2012 Elsevier B.V. All rights reserved

Dynamics of interictal spikes and high-frequency oscillations during epileptogenesis in temporal lobe epilepsy

Mesial temporal lobe epilepsy (MTLE) is characterized in humans and in animal models by a seizure-free latent phase that follows an initial brain insult; this period is presumably associated to plastic changes in temporal lobe excitability and connectivity. Here, we analyzed the occurrence of interictal spikes and high frequency oscillations (HFOs; ripples: 80-200Hz and fast ripples: 250-500Hz) from 48h before to 96h after the first seizure in the rat pilocarpine model of MTLE. Interictal spikes recorded with depth EEG electrodes from the hippocampus CA3 area and entorhinal cortex (EC) were classified as type 1 (characterized by a spike followed by a wave) or type 2 (characterized by a spike with no wave). We found that: (i) there was a switch in the distribution of both types of interictal spikes before and after the occurrence of the first seizure; during the latent phase both types of interictal spikes predominated in the EC whereas during the chronic phase both types of spikes predominated in CA3; (ii) type 2 spike duration decreased in both regions from the latent to the chronic phase; (iii) type 2 spikes associated to fast ripples occurred at higher rates in EC compared to CA3 during the latent phase while they occurred at similar rates in both regions in the chronic phase; and (iv) rates of fast ripples outside of spikes were higher in EC compared to CA3 during the latent phase. Our findings demonstrate that the transition from the latent to the chronic phase is paralleled by dynamic changes in interictal spike and HFO expression in EC and CA3. We propose that these changes may represent biomarkers of epileptogenicity in MTLE. Copyright © 2014 Elsevier Inc. All rights reserved

Evolution of interictal activity in models of mesial temporal lobe epilepsy

Interictal activity and seizures are the hallmarks of focal epileptic disorders (which include mesial temporal lobe epilepsy, MTLE) in humans and in animal models. Interictal activity, which is recorded with cortical and intracerebral EEG recordings, comprises spikes, sharp waves and high-frequency oscillations, and has been used in clinical practice to identify the epileptic zone. However, its relation with seizures remains debated. Moreover, it is unclear whether specific EEG changes in interictal activity occur during the time preceding the appearance of spontaneous seizures. This period, which is termed “latent”, has been studied in rodent models of MTLE in which spontaneous seizures start to occur following an initial insult (most often a status epilepticus induced by convulsive drugs such as kainic acid or pilocarpine) and may mirror epileptogenesis, i.e., the process leading the brain to develop an enduring predisposition to seizure generation. Here, we will address this topic by reviewing experimental studies performed in MTLE models. Specifically, we will review data highlighting the dynamic changes in interictal spiking activity and high-frequency oscillations occurring during the latent period, and how optogenetic stimulation of specific cell populations can modulate them in the pilocarpine model. These findings indicate that interictal activity: (i) is heterogeneous in its EEG patterns and thus, presumably, in its underlying neuronal mechanisms; and (ii) can pinpoint to the epileptogenic processes occurring in focal epileptic disorders in animal models and, perhaps, in epileptic patients

Quantifying seizure termination patterns reveals limited pathways to seizure end

ObjectiveDespite their possible importance in the design of novel neuromodulatory approaches and in understanding status epilepticus, the dynamics and mechanisms of seizure termination are not well studied. We examined intracranial recordings from patients with epilepsy to differentiate seizure termination patterns and investigated whether these patterns are indicative of different underlying mechanisms.MethodsSeizures were classified into one of two termination patterns: (a) those that end simultaneously across the brain (synchronous), and (b) those whose termination is piecemeal across the cortex (asynchronous). Both types ended with either a burst suppression pattern, or continuous seizure activity. These patterns were quantified and compared using burst suppression ratio, absolute energy, and network connectivity.ResultsSeizures with electrographic generalization showed burst suppression patterns in 90% of cases, compared with only 60% of seizures which remained focal. Interestingly, we found similar absolute energy and burst suppression ratios in seizures with synchronous and asynchronous termination, while seizures with continuous seizure activity were found to be different from seizures with burst suppression, showing lower energy during seizure and lower burst suppression ratio at the start and end of seizure. Finally, network density was observed to increase with seizure progression, with significantly lower densities in seizures with continuous seizure activity compared to seizures with burst suppression.SignificanceBased on this spatiotemporal classification scheme, we suggest that there are a limited number of seizure termination patterns and dynamics. If this bears out, it would imply that the number of mechanisms underlying seizure termination is also constrained. Seizures with different termination patterns exhibit different dynamics even before their start. This may provide useful clues about how seizures may be managed, which in turn may lead to more targeted modes of therapy for seizure control

The Role of Superficial and Deep Layers in the Generation of High Frequency Oscillations and Interictal Epileptiform Discharges in the Human Cortex

Describing intracortical laminar organization of interictal epileptiform discharges (IED) and high frequency oscillations (HFOs), also known as ripples. Defining the frequency limits of slow and fast ripples. We recorded potential gradients with laminar multielectrode arrays (LME) for current source density (CSD) and multi-unit activity (MUA) analysis of interictal epileptiform discharges IEDs and HFOs in the neocortex and mesial temporal lobe of focal epilepsy patients. IEDs were observed in 20/29, while ripples only in 9/29 patients. Ripples were all detected within the seizure onset zone (SOZ). Compared to hippocampal HFOs, neocortical ripples proved to be longer, lower in frequency and amplitude, and presented non-uniform cycles. A subset of ripples (≈ 50%) co-occurred with IEDs, while IEDs were shown to contain variable high-frequency activity, even below HFO detection threshold. The limit between slow and fast ripples was defined at 150 Hz, while IEDs' high frequency components form clusters separated at 185 Hz. CSD analysis of IEDs and ripples revealed an alternating sink-source pair in the supragranular cortical layers, although fast ripple CSD appeared lower and engaged a wider cortical domain than slow ripples MUA analysis suggested a possible role of infragranularly located neural populations in ripple and IED generation. Laminar distribution of peak frequencies derived from HFOs and IEDs, respectively, showed that supragranular layers were dominated by slower (< 150 Hz) components. Our findings suggest that cortical slow ripples are generated primarily in upper layers while fast ripples and associated MUA in deeper layers. The dissociation of macro- and microdomains suggests that microelectrode recordings may be more selective for SOZ-linked ripples. We found a complex interplay between neural activity in the neocortical laminae during ripple and IED formation. We observed a potential leading role of cortical neurons in deeper layers, suggesting a refined utilization of LMEs in SOZ localization