Дисертації з теми "High Frequency Oscillations (HFO)"

Dopamine replacement therapy is the main method of treating Parkinson’s Disease (PD), however over time this treatment causes increasingly abnormal, involuntary movements. This symptom, known as Levodopa-Induced-Dyskinesia (LID) is associated with aberrant, high frequency oscillations (HFOs) in the motor cortex and basal ganglia, as demonstrated with implanted electrodes in human Parkinson’s patients as well as in a rat model of Parkinson’s Disease. However, despite efforts to determine if the same high frequency oscillations are also present during dyskinesia in the widespread 6-OHDA mouse model of Parkinson’s Disease, studies have been unable to do so. By building and implanting a 64-channel multi-electrode array into a unilateral 6-OHDA lesioned mouse, we were able to record HFOs at 80Hz and >100Hz in the motor cortex, basal ganglia and thalamus in the lesioned hemisphere during LID. We also recorded bilateral HFOs at >100Hz in the intact hemisphere. With this work we show that the same HFOs that are present in the motor cortex and basal ganglia of rats and humans are also present in mice during dyskinesia. This work will act to further validate the 6-OHDA PD-model in mice and provide opportunities to investigate new treatments for Parkinson’s Disease, dyskinesia and other neurological conditions. It will also serve as a model to study a purposed mechanism underlying the information processing in populations of neurons.
Dopaminbehandling är den mest förekommande metoden för att behandla Parkinsons sjukdom men detta orsakar dessvärre en bieffekt i form av gradvis förvärrande ofrivilliga rörelser. Detta beteendemönster kallas för Levodopa-Inducerad-Dyskinesi (LID) och med hjälp av elektrodimplantat i hjärnan, på parkinsonpatienter och djurmodeller av parkinsons, har man kunnat se att beteendet är förknippat med högfrekventa oscilleringar (HFO) av hjärnaktivitet i motorcortex och basala ganglierna. Trots försök att kartlägga om dessa högfrekventa oscilleringar också är närvarande i den populära 6-OHDA musmodellen av Parkinsons sjukdom, så har man hittills inte lyckats demonstrera detta. Genom att bygga och implantera ett elektrodimplantat med 64 kanaler i en ensidigt-leisonerad 6-OHDA musmodell av Parkinsons sjukdom så kunde vi åskådliggöra HFO i motor cortex, basala ganglierna och thalamus i den lesionerade hjärnhalvan under LID. Vi kunde också påvisa HFO som sträckte sig över till den intakta hjärnhalvan, med frekvenser över 100 Hz. Denna forskning ger stöd att 6-OHDA modellen för Parkinsons i möss är valid och ger möjlighet till nya metoder att utforska och behandla Parkinsons, dyskinesi och andra neurologiska åkommor. Studien lägger också grunden för framtida studier som ämnar att undersöka föreslagna mekanismer bakom sättet populationer av neuroner bearbetar information.
ingår i ett projekt finansierat av Vetenskapsrådet #2018-02717

This Master’s thesis deals with investigation of high-frequency oscillations in intracranial electroencephalography in patients with pharmacoresistant epilepsy. It describes individual types of oscillations with respect to their frequency definition, examines their physiological differences and occurrence. In addition to conventional high-frequency oscillations (up to about 600 Hz), it also focuses on oscillations with a frequency component above 1kHz. According to recent studies, these oscillations could have higherspecificity for the determination of pathological tissue in the epileptic brain. The data for this work was obtained by manual labeling and categorization of approximately 1500 sections of the stereoencephalographic record signals of patients undergoing surgical removal of the epileptic foci and subsequently monitored for success in the operation. Differences between individual groups of oscillations and resected or unresected tissues are investigated in this work by methods using calculations of entropy signals or cross frequency coupling. The most significant results were achieved for the classification group (FR + vFR) vs. uFR, methods frequency-amplitude coupling and sample entropy 1. When categorizing according to information about channel resection, the Shannon entropy is the most successful classification parameter.

L’épilepsie est une pathologie dynamique qui s’exprime par une activité anormale des réseaux neuronaux. La période entre crises est caractérisée par une excitabilité transitoire hypersynchrone : les décharges interictales et les oscillations haute-fréquence (HFOs >40Hz). Au cours de ma thèse, j’ai mené une approche multi-niveau pour mieux comprendre les mécanismes de génération des HFOs et leur relation temporelle avec les crises. La première étude a concerné l’exploration in vitro des corrélats cellulaires des HFOs (~200Hz) sur l’hippocampe humain épileptique. Deux mécanismes différents ont été observés au niveau cellulaire en soulignant leur hétérogénéité. Dans une deuxième étude en utilisant des microlectrodes intracrâniennes pendant l’évaluation pré-chirurgicale des patients, nous avons enregistré simultanément le LFP et l’activité multi-unitaire. Les décharges interictales étaient précédées par HFOs (40-120Hz) dans 50% des cas, tous les deux associées à une activité neuronale hétérogène. Une dernière étude a été mise en place pour investiguer la dynamique des HFOs en relation aux crises. A partir d’enregistrements intracrâniens de long-terme, nous avons étudié la modulation de gamma (40-140Hz) par les rythmes plus lents (theta/delta) avant le début de la crise. Nous avons mis en évidence une perturbation dans ce couplage plusieurs minutes avant les crises dans un nombre significatif de patients (13%). En conclusion, les HFOs pathologiques peuvent être générées par des mécanismes différents, sont associées à une activité cellulaire hétérogène, et sont modulés différemment pendant les périodes pré-critiques. Ainsi, leur étude est donc importante pour la compréhension des mécanismes de génération des crises
Epilepsy is a dynamical disease reflecting abnormal activity of neuronal networks. The interictal period (between seizures), is characterized by transient hypersynchronous excitability emerging as interictal discharges and high frequency oscillations (HFOs >40Hz). During my thesis, a multi-level approach was performed, in order to investigate the mechanisms of HFO generation and their temporal relation with seizures. A first study consisted on the exploration of cellular correlates underlying HFOs (~200 Hz) in epileptic slices of human hippocampus. Two different cellular mechanisms were observed, highlighting the heterogeneity of underlying cellular behaviors. In a second study using intracranial microelectrodes during presurgical evaluation of patients, we recorded simultaneously LFP and multi-unit activity. Interictal discharges were preceded by HFOs (40-120Hz) in 50% of cases, both associated to heterogeneous neuronal firing. A final study was performed to investigate the dynamics of HFOs in relation to seizures. From long-term intracranial recordings, we studied the modulation of gamma (40-140Hz) by slower rhythms (theta/delta) before the seizure onset. We showed that a perturbation of this coupling occurs several minutes before the seizure onset for a significant number of patients (13%). We conclude that HFOs in epileptic networks can be generated by different mechanisms, are associated to a heterogeneous cellular firing, and are modulated in a different way during the preictal period. Hence, their study is important for a better understanding of the mechanisms of seizure generation

Un tiers des épileptiques ne voient pas d'amélioration avec les traitements actuels, poussant les médecins à envisager la chirurgie pour enlever la zone cérébrale générant les crises. Les Oscillations à Haute Fréquence (HFO) émergent comme biomarqueur pour localiser ces zones épileptogènes, mais leur détection est difficile en raison de leur rareté et de leur brièveté. En EEG de scalp la faible amplitude du signal complexifie la tâche. Cette thèse vise à automatiser la détection de HFO dans des signaux EEG-HD enregistrés à 1 KHz sur 256 électrodes chez 5 patients. Après marquage visuel des HFO, des modèles de classification entre HFO et bruit de fond ont été explorés. Les connaissances du traitement de signal ont été exploitées pour extraire des caractéristiques du domaine temporel ou fréquentiel. Les caractéristiques les plus pertinentes statistiquement ont été sélectionnées et soumises à des algorithmes supervisés classiques (Régression logistique, forêt aléatoire, MLP, gradient boosting). Ces méthodes ont été comparées à des algorithmes profonds (CNN, LSTM, Attention) générant automatiquement les caractéristiques du signal dans le domaine temporel 1D ou celles des cartes 2D temps fréquence. Tous les modèles montrent des résultats probants, les algorithmes profonds 1D étant plus efficaces avec une sensibilité de 91% et une spécificité de 87%, surpassant les détecteurs d’HFO de surface publiés. L’exécution des meilleurs modèles sur la totalité du signal pour détecter automatiquement les HFO a affiché des résultats prometteurs mais cette partie du travail reste à améliorer pour pallier la rareté des HFO dans les données. Plusieurs pistes de recherche sont proposées
Conditions of a third of epileptics are not improved with current treatments, pushing doctors to consider surgery to remove the brain area generating seizures. High Frequency Oscillations (HFO) are emerging as a biomarker to localize these epileptogenic zones, but their detection is difficult due to their rarity and brevity. In scalp EEG the low amplitude of the signal complicates the task. This thesis aims to automate the detection of HFO in EEG-HD signals recorded at 1 KHz on 256 electrodes in 5 pediatric patients. After visual marking of HFO, classification models between HFO and background noise were explored. Signal processing knowledge has been exploited to extract features from time or frequency domain. The most statistically relevant features were selected and submitted to classic supervised algorithms (Logistic regression, random forest, MLP, gradient boosting). These methods were compared to deep algorithms (CNN, LSTM, Attention) automatically generating signal characteristics in the 1D time domain or those of 2D time-frequency maps. All models show convincing results, with the deep 1D algorithms being more efficient reaching 91% sensitivity and 87% specificity, outperforming previously published surface HFO detectors. Running the best models on the entire signal to automatically detect HFO showed promising results but this part of the work remains to be improved to overcome the HFO rarity in the data. Several lines of research are suggested

Cette thèse est consacrée à l’étude haute fréquence de problèmes de Dirichlet et Neumann pour le système de l’élasticité. On y étudie le phénomène de réflexion au bord au moyen de deux techniques : la sommation de faisceaux gaussiens et les mesures de Wigner. Dans les chapitres 1 et 2, on commence par étudier le problème plus simple de l’équation des ondes scalaire à une vitesse. Sous certaines hypothèses sur les conditions initiales, on construit des solutions approchées par superposition de faisceaux gaussiens. La justification de l’asymptotique se fonde sur une estimation de normes de certains opérateurs intégraux à phases complexes. Pour des conditions initiales plus générales, on utilise les mesures de Wigner pour calculer la densité d’énergie microlocale. On calcule explicitement les transformées de Wigner d’intégrales de faisceaux gaussiens. Le comportement de la densité d’énergie microlocale de la solution exacte se déduit de celui établi pour la solution approchée. Dans le chapitre 3, on utilise les résultats établis pour les sommes infinies de faisceaux gaussiens pour construire une solution approchée pour les équations de l’élasticité et calculer sa densité d’énergie microlocale. L’existence de deux vitesses différentes dans le système de l’élasticité introduit de nouvelles difficultés qui sont traitées dans ce chapitre
This thesis is devoted to the study of the high frequency Dirichlet and Neumann problems for the elasticity system. We study the reflection phenomenon at the boundary by means of two techniques: Gaussian beams summation and Wigner measures. In chapters 1 and 2, we start by studying the simpler problem of the scalar wave equation with one speed. Under some hypotheses on the initial conditions, we build an approximate solution by a Gaussian beams superposition. Justification of the asymptotics is based on norms estimate of some integral operators with complex phases. For more general initial conditions, we use Wigner measures to compute the microlocal energy density. We compute Wigner transforms of Gaussian beams integrals in an explicit way. The behaviour of the microlocal energy density for the exact solution is deduced from the one for the approximate solution. In chapter 3, we use the established results on infinite sums of Gaussian beams to build an approximate solution for the elasticity equations and to compute its microlocal energy density. We treat new difficulties arising from the existence of two different speeds in the elasticity system

In this thesis, the form of the current-voltage characteristics and the resulting current oscillations in graphene-hexagonal boron nitride heterostructures are explored by means of theoretical investigation and are supported by experimental observations. The conditions for resonant tunnelling and the effect of device and circuit parameters are examined through simulation of the charge dynamics using the Bardeen Transfer Hamiltonian method. Studies of the effect of induced moir\'e patterns between the crystallographically aligned graphene and the boron nitride lattices are also undertaken, with recommendations for future investigation. It is theoretically shown that samples containing two layers of graphene, separated by hexagonal boron nitride tunnel barriers, produced higher frequency oscillations when the graphene lattices are aligned. This was found to be due to the decrease in wavefunction overlap in the misaligned samples, which is not compensated by the higher density of states available for tunnelling. Chemical doping of the graphene layers are also found to increase the frequency, as it allows the Dirac cones to be brought into alignment for resonant tunnelling with a higher number of states available. It is known that the mismatch in lattice constant between the graphene lattice and the hexagonal boron nitride lattice creates a moir\'e pattern. This, in turn, induces additional Dirac points in the band structure and thus leads to new features in the current-voltage characteristics. The theoretical simulations presented in this thesis are substantiated by recently-published experimental results, and provide insight into possible future high-frequency, room-temperature solid state oscillators and amplifiers. In conclusion, the mechanisms for resonant tunnelling in multiple graphene heterostructures are identified and demonstrated in this work, and provide promising evidence for novel high frequency technologies and further research.

Researchers have recently discovered high frequency oscillations (HFOs) of short duration in the 100-450 Hz band using the intracerebral electroencephalogram of epileptic patients (surgical candidates). New tools are being developed to study this phenomenon. The frequent occurrence of HFOs makes a visual identification tedious and time-consuming. Automated screening is much more efficient, repeatable, and objective. We introduced an original baseline selection method and enhanced two published HFO detection algorithms based on filters and wavelets. We then compared their performance to that of a human reviewer. Ten minutes of electroencephalogram from five patients was acquired by filtering in 0.1-500 Hz band and sampling at 2000 Hz. A human reviewer visually identified HFOs that were considered ground-truths to measure the performance of the two algorithms. The sensitivity and false discovery rate of the filter method were 75.9% and 10.6% respectively, while those for the Wavelet method were 70.8% and 13.1% respectively. Our methods provide satisfactory performance for HFO detection.
Les chercheurs ont découvert récemment des oscillations haute fréquence de courte durée, dans la bande 100-450 Hz, en utilisant des électrodes intracérébrales sur des patients épileptiques (candidats à la chirurgie). Des nouveaux outils ont été développés pour étudier ces phénomènes. Le nombre élevé de ces oscillations rapides fait de leur identification visuelle une tache fastidieuse. La détection automatique est plus efficace, reproductible et objective. Nous avons mis en place une méthode de sélection originale de la ligne de base et amélioré deux algorithmes de détection basés sur l'utilisation de filtres et d'ondelettes. Nous avons par la suite fait la comparaison entre la performance des algorithmes et celle d'un expert. Dix minutes d'électroencéphalogramme de cinq patients ont été enregistrés avec un filtrage de 0.5 à 500 Hz et une fréquence d'échantillonnage de 2000 Hz. Une revue par un neurophysiologiste des oscillations détectées a permis de mesurer les performances des deux algorithmes. La sensibilité et le pourcentage de fausses détections de la méthode avec filtre sont respectivement de 75.9% et 10.6%, alors que pour la méthode avec ondelettes, la sensibilité et le pourcentage de fausses détections sont respectivement de 70.8% et 13.1%. Notre méthode donne des résultats satisfaisants pour la détection d'oscillations haute fréquence.

Friction-induced oscillations occur in many engineering systems, often resulting in noise, vibration, and excessive or uneven wear. This research addresses the suppression of such oscillations, especially with application to braking systems, through the use of high-frequency dither signals. Brake squeal is an annoying and elusive problem too often present in braking systems of automobiles, trucks and aircraft. In previous work, the effectiveness of high-frequency dither to eliminate squeal in an automotive disc brake assembly was demonstrated experimentally. The main features of the dither-squeal cancellation system was the application of a high frequency variation in the brake pressure force accomplished by means of a piezoelectric stack placed behind one of the brake pads. This thesis contains a theoretical and numerical treatment of the application of dither to frictional systems. Two types of systems are investigated. The first is a classic, mass-on-a-moving belt problem, which experiences friction-induced oscillations similar to those encountered in brake applications. The system is first studied using an analytical technique based on the method of averaging. It is shown that, depending on the system, friction, dither-waveform, and belt-speed parameters, dither can stabilize an unstable system. However, in some cases, dither can destabilize an initially stable system. These results are verified numerically using time integration. The second type of system analyzed in this thesis is an annular plate with a rotating frictional device. The method of multiple scales is used to predict subcritical regions of instability; the results are validated using Floquet theory. The thesis treats both tangential and normal dither, the latter being closer to the brake application. It is found that normal dither, in addition to being harder to analyze, is much less effective than tangential dither.

High Frequency Oscillations (HFOs; 80-500Hz) are spontaneous short-duration small-amplitude EEG patterns that are emerging as a biomarker of tissue capable of generating epileptic seizures. In order to propel the clinical utilization and systematic study of HFOs, it is important to develop robust automatic detectors and to provide a framework to ensure stability in their identification; this is the first goal of this thesis. Although HFOs have mostly been studied with intracranial electrodes, they have also been recorded on the scalp. A fundamental question is to understand how is it possible to see these small events on the scalp given the powerful skull attenuation; this is the second goal of this thesis. The first goal is addressed by designing a procedure to systematize the study of HFOs and by developing an automatic detector. A procedure that allows to control for consistency among readers and to evaluate if a selected interval provides stable information, for automatic and visual identification of HFOs, is first presented. This procedure is now routinely used when identifying interictal HFOs. This study is the first to evaluate the minimum duration needed to obtain consistent information when marking the EEG and showed that analyzing 5min of interictal EEG provided the same information as longer intervals. The approach is applicable to any type of EEG event.An automatic detector of HFOs is then described, which takes an original approach in first detecting baseline segments free of oscillatory activity and then using a statistical threshold obtained from these local baselines to detect HFOs. The detector performs better than other detectors, in particular in active channels and in channels without clear baseline. A comparison of existing detectors on the same dataset is presented to analyze their performance, to show that optimizing on a particular type of data improves performance in any detector, and to emphasize the issues involved in validation. The second goal of this thesis is the study of the spatial distribution of cortical activity at the time of scalp HFOs. As HFOs are produced by small brain regions, and since the EEG is greatly attenuated before reaching the scalp, HFOs are mostly recorded with intracranial electrodes. Surprisingly, HFOs have been recently observed also on the scalp EEG. Using simultaneous scalp and intracranial recordings, we showed that even though the generators of HFOs have small spatial extent, they can be observed on the scalp with small amplitude and focal extent. We showed that these small extent events are undersampled on the scalp with the density of standard electrode systems, and on cortical grids with the standard inter-electrode spacing of 1cm. A dense distribution of scalp electrodes seems necessary to fully spatially sample HFOs on the scalp. This opens the possibility of systematically studying HFOs non-invasively. By developing methods for the detection and analysis of HFOs, we expect to improve the systematic study of intracranial and scalp HFOs, moving towards their clinical application as a biomarker of epileptogenic tissue.
Les oscillations de haute fréquence (OHF; 80-500 Hz) constituent des évènements EEG spontanés de courte durée et de faible amplitude qui émergent en tant que biomarqueur du tissu pouvant générer les crises épileptiques. Afin de promouvoir l'utilisation clinique et l'étude systématique des OHF, il est important de développer des détecteurs automatiques fiables et de fournir un cadre visant à garantir la stabilité de leurs résultats. Il s'agit là du premier objectif de la présente thèse. Les OHF ont principalement été étudiées à partir d'électrodes intracrâniennes, mais elles ont également été enregistrées à l'aide d'électrodes placées sur le cuir chevelu. Il convient alors de comprendre comment l'on peut observer ces évènements de faible envergure du fait de l'atténuation importante du crâne, ce qui constitue le second objectif de cette thèse. Pour répondre au premier objectif, nous avons conçu une procédure visant à systématiser l'étude des OHF et avons élaboré un détecteur automatique. Ainsi, nous présentons d'abord une procédure permettant d'assurer l'uniformité entre les lecteurs et d'évaluer si un intervalle choisi offre des renseignements stables pour un repérage visuel et automatique des OHF. À l'heure actuelle, cette procédure est communément utilisée quand les OHF interictales sont repérées. Cette étude est la première à évaluer la durée minimale nécessaire à l'obtention de renseignements cohérents pour le marquage des EEG et elle a démontré que l'analyse de 5 minutes d'EEG interictal offre la même information que des intervalles de plus longue durée. Cette approche est applicable à tout type d'évènements EEG. Nous avons ensuite décrit un détecteur automatique d'OHF, qui suit une approche originale en détectant d'abord des segments de base dénués d'activités oscillatoires avant d'utiliser un seuil statistique obtenu à partir de ces valeurs de base locales pour déterminer les OHF. Ce détecteur est plus efficace que d'autres détecteurs, notamment pour les canaux actifs et les canaux sans valeur de base claire. Une comparaison entre les détecteurs existants pour le même ensemble de données est présentée afin d'analyser leur performance respective, de démontrer que l'optimisation d'un certain type de données améliore l'efficacité de tous les détecteurs et de mettre en évidence les problèmes en jeu dans la validation. Le second objectif de la présente thèse est d'étudier la distribution spatiale de l'activité corticale au moment des OHF enregistrées sur le cuir chevelu. Dans la mesure où les OHF sont produites par de petites régions cérébrales et que l'EEG est fortement atténué avant d'arriver au cuir chevelu, les OHF sont surtout enregistrées à l'aide d'électrodes intracrâniennes. Il est étonnant que dernièrement, des OHF aient également été observées sur des EEG enregistrés sur le cuir chevelu. En se basant sur les enregistrements simultanés sur le cuir chevelu et intracrâniens, nous avons démontré que, même si les régions génératrices d'OHF sont faiblement étendues sur le plan spatial, les OHF peuvent être observées à l'aide d'électrodes placées sur le cuir chevelu avec une faible amplitude et une étendue focale. Nous avons établi que ces évènements de faible étendue sont sous-échantillonnés sur le cuir chevelu avec la densité des systèmes standards d'électrodes et sur les grilles corticales avec l'espacement standard de 1 cm entre les électrodes. Il semble nécessaire d'avoir une répartition dense des électrodes sur le cuir chevelu afin de représenter spatialement de façon exhaustive les OHF enregistrées sur le cuir chevelu. Cela ouvrirait la voie à une étude systématique non invasive des OHF. Avec l'élaboration de méthodes de détection et d'analyse des OHF, nous souhaitons améliorer l'étude systématique des OHF intracrâniennes et du cuir chevelu, dans l'optique d'une application clinique en tant que biomarqueur du tissu épileptogène.

Cette étude a été divisée en 2 parties principales. Dans la première partie, nous examinons la relation entre l'activité des sources neuronales et les HFOs observés sur les électrodes intracérébrales. La deuxième partie traite de l'étude des conditions d'observabilité des HFO sur les électrodes du cuir chevelu. Les simulations ont montré que le modèle de champ neuronal proposé est capable de générer des HFOs montrant une forte ressemblance avec les signaux réels dans les deux cas EEG (cuir chevelu) et SEEG (intracérébral). De plus, nous avons pu relier les mécanismes physiopathologiques (GABA dépolarisant, inhibition directe, activité désynchronisée des populations neuronales) aux différentes caractéristiques morphologiques et spectrales des HFOs intracérébrales. Une hypothèse unifiée pour la production des HFOs et des pointes intercritiques est également formulée. Enfin, nous avons réussi à établir les conditions nécessaires sur l'activité temporelle et l'organisation spatiale des sources neuronales pour observer des HFOs sur les électrodes intracérébrales.En ce qui concerne la deuxième partie, la baisse inexpliquée de fréquence dans les HFOs collectées sur les électrodes du cuir chevelu a été abordée. Nous avons constaté que les mécanismes «non oscillatoires» de la génération de HFOs sont à l'origine de la faible fréquence (<200Hz) des HFOs du cuir chevelu et que le rapport signal / bruit (SNR) influe fortement sur la fréquence des oscillations. De plus, nous avons étudié la topographie des HFOs sur les électrodes du cuir chevelu et analysé comment cette topographie est affectée par différents paramètres (étendue spatiale épileptique, SNR, géométrie 3D). Enfin, nous avons montré que les HFOs du cuir chevelu peuvent être utilisés efficacement pour identifier la zone épileptique lorsque le rapport signal sur bruit des signaux enregistrés est suffisamment élevé. Une perspective de ce travail est l'identification non-invasive de la zone épileptique sans la nécessité d'enregistrements intracérébraux pré-chirurgicaux.Pour les deux études (HFO observés sur les électrodes intracérébrales et du cuir chevelu), un logiciel original et convivial a été développé. Ce logiciel a fortement facilité la simulation des signaux dans l'environnement cerveau/électrode virtuel, signaux obtenus en résolvant le problème direct de l’EEG (projection de la contribution électrique des sources neuronales sur les capteurs)
This study was divided into 2 main parts. In the first part, we address the relationship between the activity of neuronal sources and the HFOs observed on intracerebral electrodes. The second part deals with the investigation of observability conditions of HFOs on scalp electrodes. Simulations showed that the proposed neural field model is capable of generating HFOs showing strong resemblance with real signals in both cases EEG (scalp) and SEEG (intracerebral). Moreover, we were able to relate the pathophysiological mechanisms (depolarizing GABA, feedforward inhibition, desynchronized activity of neuronal populations) to different morphological and spectral features of intracerebral HFOs. A unified hypothesis for generation of HFOs and interictal spikes is also formulated. Finally, we managed to establish the necessary conditions about the temporal activity and the spatial organization of neuronal sources and about for HFOs to be observed on intracerebral electrodes. Regarding the second part, the unexplained drop in frequency in the collected HFOs on scalp electrodes was addressed. We found that the “non-oscillatory” mechanisms of the HFO generation is behind the low frequency (<200Hz) in scalp HFOs and that signal to noise ratio (SNR) heavily impacts the frequency of the oscillations. Moreover, we studied the topography of HFOS on scalp electrodes and analyzed how this topography is affected by different parameters (epileptic spatial extent, SNR, 3D geometry). Finally we showed that scalp HFOs can be effectively used to identify the epileptic zone when the SNR of the recorded signals is sufficiently high. A perspective to this work is the non-invasive identification of epileptic zone without the need for presurgical intracerebral recordings. For the purpose of both studies (HFOs observed on intracerebral & scalp electrodes) an original and user-friendly software package was developed. This software strongly facilitated the simulation of signals in the virtual brain/electrode environment obtained by solving the (S)EEG forward problem (projection of the electric contribution of neuronal sources onto electrode contacts)

Oscillations are widely observed in brain activities, but their spatiotemporal organisation properties and functional roles remain elusive. In this thesis, we first investigate gamma oscillations (30 - 80 Hz) by combined empirical and modelling studies. Array recordings of local field potentials in visual motion-processing cortical area MT of marmoset monkeys reveal that gamma bursts form localised patterns with superdiffusive propagation dynamics. To understand how these gamma burst patterns emerge, we investigate a spatially extended, biophysically realistic circuit model that quantitatively captures the superdiffusive propagation of gamma burst patterns as found in the recordings. We further demonstrate that such gamma burst dynamics arise from the intrinsic non-equilibrium nature of transitions between asynchronous and propagating wave states. These results thus reveal novel a spatiotemporal organisation property of gamma bursts and their underlying mechanisms. We further illustrate that such non-equilibrium transitions in the spatially extended circuit model mechanistically account for a range of dynamical properties of sharp-wave ripples (100-250 Hz) and that sharp-wave ripples with superdiffusive dynamics underlie efficient memory retrievals. Furthermore, by incorporating short-term synaptic plasticity into the spatially extended circuit model, we find that in the dynamical regime near the transition of circuit states, large endogenous fluctuations emerging from the circuit can quantitively reproduce and explain the variability of working memory across items and trials as found experimental studies. In addition, our circuit model reproduces and explains several other key neural and behavioural features of working memory, such as the capacity limit of working memory and gamma bursts that are coupled to theta oscillations. These results establish a dynamical circuit mechanism of working memory and provide novel experimentally testable predictions.

Nous étudions l’influence d’une rétroaction optique à conjugaison de phase dans une diode laser. Ce type de rétroaction a été peu étudié et nous montrons ici qu’il donne des résultats intéressants, permettant de débloquer du contenu à haute fréquence. Cela pourrait mener à de meilleures performances dans des systèmes de génération de nombres aléatoires utilisant du chaos optique
We study the influence of phase-conjugate feedback in a laser diode. This type of feedback has not been studied a lot and yet we show here that it can give interesting results. It unlocks oscillations at high frequencies. This could lead to an improvement in the performance of random number generators based on optical chaos

Tato práce se zabývá automatickou detekcí vysokofrekvenčních oscilací jakožto moderního elektrofyziologického biomarkru epileptogenní tkáně v intrakraniálním EEG, jehož vizuální detekce je zdlouhavý proces, který je ovlivněn subjektivitou hodnotitele. Epilepsie je jedním z nejčastějších neurologických onemocnění postihující 1 % obyvatelstva. Přestože jsou přibližně dvě třetiny případů léčitelné farmakologicky, zbylá třetina pacientů je odkázána zejména na léčbu chirurgickým zákrokem, pro nějž je zapotřebí přesně lokalizovat ložisko patologické tkáně. Vysokofrekvenční oscilace jsou v posledním desetiletí studovány pro jejich potenciál lokalizace patologické tkáně. Součástí této práce je shrnutí dosavadního výzkumu vysokofrekvenčních oscilací a výčet detektorů používaných ve výzkumu. V rámci práce byly vyvinuty či vylepšeny tři detektory vysokofrekvenčních oscilací, na jejichž popis navazuje evaluace z hlediska shody s manuální detekcí, přesnosti výpočtu příznaků oscilací a schopnosti lokalizace patologické tkáně. V závěru práce jsou představeny vyvinuté metody vizualizace vysokofrekvenčních výskytu oscilací a stručně uvedeny dosažené vědecké výsledky.

Thesis (S.B.)--Massachusetts Institute of Technology, Dept. of Physics, 2006.
Includes bibliographical references (p. 93-94).
GRS 1915+105 is an accreting black-hole in a binary system located in the Milky Way. It is one of the most variable X-ray sources known, and 12 variability classifications have been defined, many of which appear to be repetitive cycles of accretion instability. We study one particular variability type, the p cycle, which is selected for its high frequency quasi-periodic oscillations (HFQPOs) and recurring double-peak flare in the light curve. We investigate the primary properties of the 82 p-type observations collected by RXTE. The range in flare recurrence time () is 33.73 s < T < 122.49 s, with <> ± asample = 65.44 ± 19.83 s. The flaring fraction , defined by percent of cycle exposure > 1.2*mean count rate, ranges 12.11% < ( < 37.61%, with <> ± asample = 20.05 ± 5.33%. We find a correlation between T and ( which divides the 82 observations into three sub-classes: pi; slow with low , P2; fast with low , and P3; fast with high . The evolution between sub-classes suggests two driving mechanisms, an unknown mechanism limiting T > 33 s and a process consistent with the Eddington limit that increases (at the lower limit of ) for the p3 group.
(cont.) For each subclass we study the emission properties in four phase zones of the p cycle, where the phases are defined on the basis of the X-ray count rate (X) and soft color (S; rates at 6-12 keV / 2-5 keV). Two HFQPOs in the p cycle are isolated to different zones and sub-classes: one at 67 Hz is localized to the second (hard-spectrum) flare, and another QPO at 150 Hz in the low X, low S phase zone of the pi group. All phase zones display low-frequency QPOs, and they are particularly strong in the low-X, low-S zone (7.5 Hz) and the low-X, high-S zone (10.5 Hz). Classifications of X-ray spectral states for each zone indicate no zones in the thermal state, flaring zones (high X) in the steep power law (SPL) state, and quiet zones (low X) in either the hard or hard:SPL intermediate state. We conclude that the p cycle provides special opportunities to further study an instability cycle that is driven, in part, by the Eddington limit and that portions of the cycle contain the mechanism that produces two different HFQPOs. Further investigations should be made with increased phase resolution and with additional strategies to define the phases of the p cycle.
by Jonathan Zachary Gazak.
S.B.

SUMMARY Introduction: There has recently been a great deal of interest in the role of synchronous high-frequency gamma oscillations in brain function. This interest has been motivated by an increasing body of evidence, that oscillations which are synchronous in phase across separated neuronal populations, may represent an important mechanism by which the brain binds or integrates spatially distributed processing activity which is related to the same object. Many models of schizophrenia suggest an impairment in the integration of brain processing, such as a loosening of associations, disconnection, defective multiple constraint organization, or cognitive dysmetria. This has led to recent speculation that abnormalities of high-frequency gamma synchronization may reflect a core dimension of the disturbance underlying this disorder. However, examination of the phase synchronization of gamma oscillations in patients with schizophrenia has never been previously undertaken. Method: In this thesis a new method of analysis of gamma synchrony was introduced, which enables the phase relationships of oscillations in a specific frequency band to be examined across multiple scalp sites as a function of time. This enabled, for the first time, the phase synchronization of gamma oscillations across widespread regions, to be studied in electrical brain activity measured at the scalp in humans. Gamma synchrony responses were studied in electroencephalographic (EEG) data acquired during a commonly employed conventional auditory oddball paradigm. The research consisted of two sets of experiments. In the first set of experiments, data from 100 normal subjects, consisting of 10 males and 10 females in each age decade from 20 to 70, was examined. These experiments were designed to characterize the gamma synchonizations that occurred in response to target and background stimuli and their functional significance in normal brain activity, and to exclude the possibility of these findings being due to electromyogram (EMG) or volume conduction artifact. The examination of functional significance involved the development of an additional new analysis technique. In the second set of experiments, data acquired from 35 patients with schizophrenia and 35 matched normal controls was analyzed. The purpose of these experiments was to determine whether patients showed disturbances of gamma synchrony compared to controls, and to establish the relationship of any such disturbances to medication levels, symptom profiles, duration of illness, and a range of psychophysiological variables. Results: In the 100 normals, responses to target stimuli were characterized by two bursts of synchronous gamma oscillations, an early (evoked) and a late (induced) synchronization, with different topographic distributions. Only the early gamma synchronization was seen in response to background stimuli. The main variable modulating the magnitude of these gamma synchronizations from epoch to epoch was pre-stimulus EEG theta (3-7 Hz) and delta (1-3 Hz) power. Early and late gamma synchrony were also associated with N1 and P3 ERP component amplitude across epochs. Across subjects, the early gamma synchronization was associated with shorter latency of the ERP components P2, N2 and P3, smaller amplitude of N1 and P2, and smaller pre-stimulus beta power. The control analyses showed that these gamma responses were specific to a narrow frequency range (37 to 41 Hz), and were not present in adjacent frequency bands. The responses were not generated by EMG contamination or volume conduction. In the 35 patients with schizophrenia, significant abnormalities of both the early and late synchronizations were observed compared to the 35 normal controls, with distinctive topographic characteristics. In general, early gamma synchrony was increased in patients compared to controls, and late gamma synchrony was decreased. These gamma synchrony disturbances were not related to medication level or the four summed symptom profile scores (positive, negative, general and total). They were, however, associated with duration of illness, becoming less severe the longer the patient had suffered from the disorder. The disordered gamma synchrony in patients was not secondary to abnormalities in other psychophysiological variables, but appeared to represent a primary disturbance. Discussion: The early synchronization may relate to the binding of object representations in early sensory processing, or, given that a constant inter-stimulus interval was employed, may be anticipatory and related to active memory. The late response is probably involved in binding in relation to activation of the internal contextual model involved in late expectancy/contextual processing (context updating or context closure) for target stimuli. The across epochs effects may relate to whether the focus of attention immediately prior to stimulus presentation is internal or is directed at the task. The across subjects effects suggest that a larger magnitude of the early gamma synchronization might indicate that the subject maintains a more stable and less ambiguous internal representation of the environment, that reduces the complexity of input and facilitates target/background discrimination and subsequent processing. The early gamma synchronization findings in patients with schizophrenia suggest that anticipatory processing involving active memory and forward-prediction of the environment is subject to over-binding or the formation of inappropriate associations. The late synchronization disturbances may reflect a fragmentation of contextual processing, and an inability to maintain contextual models of the environment intact over time. Conclusion: This research demonstrates the potential importance of integrative network activity as indexed by gamma phase synchrony in relation to normal cognition, and the possible broad relevance of such activity in psychiatric disorders. In particular, the application in this study to patients with schizophrenia showed that an impairment of brain integrative activity (missing links) might be a key feature of this illness.

This semestral thesis deals with visualization of intracranial EEG. In the first part, theoretical basics of EEG is mentioned. After that, image registration, as a needed tool for visualization is described followed by research of methods of visualization of high frequency oscilations from intracranial EEG. Finally, method for visualization of high frequency oscilations from EEG in real MRI patient scans is designed and implemented.

Touchant plus de 50 millions de personnes dans le monde, l’épilepsie est un problème majeur de santé publique. Un tiers des patients souffrent d’épilepsie pharmaco-résistante. Une chirurgie visant à enlever la région cérébrale à l’origine des crises – la zone épileptogène – est considérée comme l’option de référence pour rendre libre de crises ces patients. Le taux d’échec chirurgical non négligeable a poussé la recherche d’autres marqueurs. Un marqueur potentiel est les oscillations à haute fréquence (HFOs). Une HFO est une brève oscillation entre 80-500 Hz qui dure au moins 4 périodes enregistrée en EEG intracérébrale. Par leur caractère très bref, le marquage visuel de ces petites oscillations est fastidieux et chronophage.. Il semble impératif de trouver un moyen de détecter automatiquement ces oscillations pour étudier les HFOs sur des cohortes de patients. Aucun détecteur automatique existant ne fait cependant l’unanimité. Durant cette thèse, nous avons développé un nouveau moyen de visualiser les HFOs grâce à une normalisation originale de la transformée en ondelettes pour ensuite mieux les détecter automatiquement. Puis, nous avons mise en place une stratégie pour caractériser et valider des détecteurs. Enfin, nous avons appliqué le nouveau détecteur à une cohorte de patients pour déterminer la fiabilité des HFOs et des pointes épileptiques - le marqueur standard - dans la prédiction de la zone épileptogène. La conclusion de cette thèse est que les HFOs ne sont pas meilleurs que les pointes épileptiques pour prédire la zone épileptogène mais que combiner ces deux marqueurs permettait d’obtenir un marqueur plus robuste
Epilepsy is a major health problem as it affects 50 million people worldwide. One third of the patients are resistant to medication. Surgical removal of the brain areas generating the seizure – the epileptogenic zone – is considered as the standard option for these patients to be seizure free. The non-negligible rate of surgical failure has led to seek other electrophysiological criteria. One putative marker is the high-frequency oscillations (HFOs).An HFO is a brief oscillation between 80-500 Hz lasting at least 4 periods recorded in intracerebral EEG. Due to their short-lasting nature, visually marking of these small oscillations is tedious and time-consuming. Automatically detecting these oscillations seems an imperative stage to study HFOs on cohorts of patients. There is however no general agreement on existing detectors.In this thesis, we developed a new way of representing HFOs thanks to a novel normalisation of the wavelet transform and to use this representation as a base for detecting HFOs automatically. We secondly designed a strategy to properly characterise and validate automated detectors. Finally, we characterised, in a cohort of patients, the reliability of HFOs and epileptic spikes - the standard marker - as predictors of the epileptogenic zone using the validated detector. The conclusion of this thesis is that HFOs are not better than epileptic spikes in predicting the epileptogenic zone but combining the two leads to a more robust biomarker

The present work focuses on the numerical resolution of the acoustic or elastic wave equation in a piece-wise homogeneous medium, splitted by interfaces. We are interested in a high-frequency setting, introduced by strongly oscillating initial conditions, for which one computes the distribution of the energy density by a so-called kinetic approach (based on the use of a Wigner transform). This problem then reduces to a Liouville-type transport equation in a piece-wise homogeneous medium, supplemented by reflection and transmission laws at the interfaces. Several numerical techniques and ranges of application are also reviewed. The transport equation which describes the evolution of the energy density in the phase space positions _ wave vectors is numerically solved by finite differences. This technique raises several difficulties related to the conservation of the total energy in the medium and at the interfaces. They may be alleviated by dedicated numerical schemes allowing to reduce the numerical dissipation by either a global or a local approach. The improvements presented in this thesis concern the interpolation of the energy densities obtained by transmission on the grid of discrete wave vectors, and the correction of the difference of variation scales of the wave celerity on each side of the interfaces. The interest of the foregoing developments is to obtain conservative schemes that also satisfy the usual convergence properties of finite difference methods. The construction of such schemes and their effective implementation constitute the main achievement of the thesis. The relevance of the proposed methods is illustrated by several numerical simulations, that also emphasize their efficiency for rather coarse meshes.

Ce travail présente une étude de la dynamique interfaciale de gouttes oscillantes dans une plage étendue de fréquences, en particulier dans le domaine des hautes fréquences. Nous avons développé une méthode de caractérisation de la dynamique des oscillations de gouttes, en présence d’un forçage externe imposé, sous la forme de variations de volume périodiques de faible amplitude sur une goutte attachée à l’extrémité d’un capillaire. Cette méthode permet d’identifier les modes d’oscillation des gouttes et d’en mesurer les fréquences et les taux d’amortissement. Cette méthode a été appliquée à différents systèmes liquide-liquide, en l’absence ou en présence de surfactants. Dans ce dernier cas, elle permet d’évaluer l’effet du comportement viscoélastique des interfaces sur la dynamique des oscillations. Ainsi 3 types d’interfaces ont été identifiés. Pour les interfaces de premier type (heptane/eau sans ajout de surfactant), chaque mode propre est modélisé par un oscillateur linéaire peu amorti. Les fréquences propres et les taux d’amortissement sont bien prédits par la théorie linéaire. Les interfaces de types 2 et 3 sont obtenues en ajoutant du pétrole brut à la phase dispersée. Les surfactants naturellement présents dans le pétrole (asphaltènes, résines) s’adsorbent à l’interface et lui confèrent des propriétés viscoélastiques. Pour les interfaces jeunes (type 2, moins de 20 minutes de vieillissement), les fréquences propres mesurées restent bien prédites par la théorie, qui considère des interfaces non contaminées, tandis que les taux d’amortissement sont de loin supérieurs aux valeurs théoriques. D’autre part, les interfaces vieillies (type 3) présentent des modes propres différents avec des fréquences de résonance supérieures à celles des interfaces jeunes. Dans ce cas, la dynamique de l’interface à haute fréquence est régie par l’élasticité du réseau formé par les espèces amphiphiles du pétrole brut. Les oscillations libres d’une goutte en ascension dans une phase externe stagnante, pour un système liquide-liquide sans ajout de surfactants, ont été étudiées. Les valeurs mesurées de la fréquence d’oscillation des 4 premiers modes sont en adéquation avec la théorie linéaire. Cependant les valeurs mesurées du taux d’amortissement sont très élevées par rapport aux valeurs théoriques, pour une interface non contaminée. En effet, des espèces résiduelles adsorbées à l’interface provoquent l’apparition d’un gradient de tension interfaciale par effet Marangoni et par suite une production de vorticité plus intense dans les couches-limites, ce qui conduit à l’augmentation de l’amortissement des oscillations
We present an experimental study of oscillating drop interfacial dynamics at a wide frequency range, especially at high frequency. A characterization method of drops oscillation dynamics has been developed. The oscillations are generated by imposing low amplitude periodic variation of volume to a drop which is attached to a capillary tip. The present method is based on the identification of the drop eigenmodes and the determination of their frequencies and damping rates. It has been applied to characterize several liquid-liquid systems. Three types of interface have been identified. For interfaces of type 1 (heptane/water without added surfactant), each eigenmode is modelled by a weakly damped linear oscillator. Eigenfrequencies and damping rates are well predicted by the linear theory. Interfaces of Types 2 and 3 are obtained by adding crude oil to the disperse phase. Oil native surfactants (asphaltenes, resins) adsorb on the drop interface and provide the latter with viscoelastic behaviour. For young interfaces (type 2 with aging time below 20 minutes), eigenfrequencies remain well predicted by the theory, which deals with non contaminated interfaces, whereas the measured damping rates are significantly higher than the theoretical values. On the other hand, aged interfaces (type 3) exhibit different eigenmodes, of which eigenfrequencies are much higher than the resonance frequencies measured for the young interfaces. At high frequency, the dynamics of aged interfaces are governed by the elasticity of the network constituted by the crude oil amphiphilic species, while the dynamics of young interfaces are governed by interfacial tension. Freely decaying oscillations of a rising drop in a liquid at rest without added surfactant were also considered. Measured frequencies for the first four eigenmodes are in good agreement with the linear theory. However, measured damping rates are much higher than the theoretical rates for non contaminated interfaces. In fact, residual adsorbed species at the heptane/water interface induce Marangoni effects and thus gradients of interfacial tension. Therefore, vorticity production within the boundary layers is enhanced, which explains the observed increase of the oscillation damping rates

A eletroencefalografia (EEG) é uma das evidências tomadas na avaliação de indicação cirúrgica, em casos de pacientes portadores de epilepsia refratária a medicamentos, que pode auxiliar na localização da área responsável pela origem das crises epilépticas. Ao longo das últimas décadas, além das bandas de frequências já tradicionalmente avaliadas (até cerca de 40Hz), a EEG tem despertado o interesse de pesquisadores também para bandas de frequências mais altas. Passaram a ser encontradas evidências de que oscilações de alta frequência, conhecidas por HFO (High Frequency Oscillations), podem ser usadas como biomarcadores de epilepsia. Diversos estudos têm sido realizados em busca de uma melhor compreensão sobre HFO, a fim de viabilizar sua utilização em aplicações clínicas. Entretanto, características não lineares e de complexidade, que podem contribuir na análise de sinais com origem em sistemas biológicos, não têm sido investigadas neste tipo de sinais. Este estudo propôs a investigação de características extraídas de sinais de EEG com presença de HFO, de pacientes portadores de epilepsia refratária, através de métodos considerados como de análise não linear. Análise de Dinâmica Simbólica, Análise de Flutuações Destendenciadas (DFA), Entropia Multiescala (MSE) e Análise qSDiff foram aplicadas em segmentos de sinais de EEG intracraniano, amostrados a 5kHz, de pacientes portadores de epilepsia refratária, e também em alguns sinais simulados de características conhecidas para fins de comparação. Os resultados dos diferentes métodos investigados apontaram características semelhantes entre os segmentos de EEG analisados e séries simuladas de ruído browniano, sugerindo que os sinais de EEG em geral têm perfil bastante suavizado, são não estacionários e exibem correlações de longo alcance. Foram também levantadas evidências de que tanto HFO quanto os segmentos de EEG onde estão inseridas têm padrões mais regulares de variação e são menos complexas que segmentos de EEG sem HFO, sugerindo a degradação da complexidade fisiológica desta região cerebral, que poderia estar relacionada com mecanismos fisiopatológicos da epilepsia. Todos os métodos investigados sugeriram que as características e propriedades não lineares, relacionadas a complexidade inerente dos sinais de EEG, podem ser úteis na análise de HFO, principalmente pelas evidências de que estas características se alteram nas HFO, quando comparadas ao restante do sinal onde elas se encontram e também a outros sinais sem sua presença.
Electroencephalography (EEG) is one of the evidences taken in the evaluation of surgical indication, in cases of patients with drug refractory epilepsy, which may help in locating the area responsible for the origin of epileptic seizures. Over the last few decades, in addition to the frequency bands that have traditionally been evaluated (up to about 40Hz), the EEG has attracted researchers also to higher frequency bands. Evidence has been found that high frequency oscillations (HFO), can be used as biomarkers of epilepsy. Many studies have been carried out in search of a better understanding about HFO, in order to make it feasible to use in clinical applications. However, nonlinear and complex features, which may contribute to the analysis of signals originating from biological systems, have not been investigated in this type of signals. This study proposed the investigation of features extracted from EEG signals with HFO of patients with refractory epilepsy, using nonlinear analysis methods. Symbolic Dynamics Analysis, Detrended Fluctuation Analysis (DFA), Multiscale Entropy (MSE) and qSDiff Analysis were applied to segments of intracranial EEG signals, sampled at 5kHz, from patients with refractory epilepsy, as well as some features-known simulated signals for comparison purposes. Results of the different investigated methods pointed out similar features between the analyzed EEG segments and the simulated series of Brownian noise, suggesting that EEG signals, in general, have a very smoothed profile, are nonstationary and exhibit long- range correlations. Evidence has also been raised that both HFO and the EEG segments where they are inserted have more regular patterns of variation and are less complex than EEG segments without HFO, suggesting the degradation of the physiological complexity of this brain region, which could be related to pathophysiological mechanisms of epilepsy. All the investigated methods suggested that nonlinear features and properties, related to the inherent complexity of EEG signals, may be useful in HFO analysis, mainly because of the evidence that these features change in HFOs when compared to the rest of the signal where they are and other signals without their presence.

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Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico
Crises epil?pticas s?o eventos parox?sticos do sistema nervoso central (SNC) caracterizadas por uma descarga el?trica neuronal anormal, com ou sem perda de consci?ncia e com sintomas cl?nicos variados. Nas epilepsias do lobo temporal as crises tem in?cio focal, em estruturas do sistema l?mbico. Dados cl?nicos e experimentais mostram que essas regi?es apresentam morte neuronal (esclerose hipocampal), reorganiza??o sin?ptica (brotamento aberrante das fibras musgosas) e gliose reativa, sendo esses marcadores biol?gicos da zona epileptog?nica. Registros extracelulares mostram que al?m das altera??es anat?micas mencionadas acima, a zona epileptog?nica tamb?m apresenta oscila??es de alta frequ?ncia patol?gicas (pOAF). As pOAF s?o oscila??es transientes (50 100 ms de dura??o), de baixa amplitude (200 μV - 1.5 mV) e de frequ?ncias vari?veis (80 800 Hz). A rela??o entre essas oscila??es e a g?nese das crises espont?neas ainda ? desconhecida. O objetivo do presente trabalho foi avaliar os efeitos da estimula??o el?trica intracerebral (EIC) nas pOAF e frequ?ncia de crises espont?neas de animais cronicamente epil?pticos (modelo da epilepsia do lobo temporal). Atualmente, a EIC ? utilizada no tratamento de dist?rbios do movimento (e.g., doen?a de Parkinson) e em alguns casos de dor cr?nica, e experimentalmente, no tratamento das epilepsias de dif?cil controle. A hip?tese de trabalho dessa disserta??o ? de que a indu??o de depress?o de longa dura??o por EIC, ao reduzir a excitabilidade neuronal local, modular? as pOAF, bem como a frequ?ncia de crises espont?neas. Para isso, comparamos as caracter?sticas espectrais das pOAF e a frequ?ncia de crises espont?neas antes e depois de um protocolo de 12 horas de estimula??o el?trica de baixa frequ?ncia (0,2 Hz) aplicado na via perforante. De fato, esse protocolo reduziu a amplitude do potencial de a??o coletivo registrado no giro denteado (GD) do hipocampo dorsal em 45% (amplitude m?dia da primeira e da ?ltima hora de estimula??o: 7,3 ? 3,0 mV e 4,1 ? 1,5 mV, respectivamente; p<0,05; teste t). O monitoramento cont?nuo do potencial de campo local, realizado no GD e em CA3 simultaneamente, mostrou que o protocolo de estimula??o empregado foi eficaz em (i) aumentar a dura??o (64,6 ? 9,3 ms vs. 70,5 ? 11,5 ms) e reduzir (ii) a entropia (3,72 ? 0,28 vs. 3,58 ? 0,30), (iii) o ?ndice pOAF (0,20 ? 0,08 vs. 0,15 ? 0,07) e (iv) o modo espectral (237,5 ? 15,8 Hz vs. 228,7 ? 15,2 Hz) das pOAF (valores do GD, expressos como m?dia ? desvio-padr?o, para os per?odos pr? e p?s estimula??o respectivamente; p<0,05; teste t). Ainda, este protocolo reduziu significativamente a frequ?ncia de crises espont?neas (1,8 ? 0,4 vs. 1,0 ? 0,3 crises/hora; pr? e p?s estimula??o, respectivamente; p<0,05; teste t). Curiosamente, observamos um aumento na dura??o m?dia das crises espont?neas ap?s o t?rmino do protocolo (39,7 ? 6,0 vs. 51,6 ? 12,5 s; pr? e p?s estimula??o respectivamente; p<0,05; teste t). Estes resultados sugerem que a redu??o da excitabilidade neuronal, por meio de protocolos de estimula??o el?trica, altera o perfil espectral das pOAF. Esse efeito foi acompanhado de redu??o na frequ?ncia de crises espont?neas. Apesar de preliminar, o presente trabalho contribui para o refinamento de terapias baseadas em EIC para indiv?duos com epilepsia

La nécessité d’une meilleure compréhension du mécanisme d’entrainement pour l’instabilité à basse fréquence observée dans un écoulement dans une tuyère sur-détendue a été discutée. Le caractère instable de l’onde de choc/couche limite reste un défi pratique important pour les problèmes des écoulements dans les tuyères. De plus, pour une couche limite turbulente incidente donnée, ce type d’écoulement présente généralement des mouvements de choc à basse fréquence plus élevées qui sont moins couplés aux échelles de temps de la turbulence en amont. Cela peut être bon du point de vue d’un expérimentateur, en raison de difficultés à mesurer des fréquences plus élevées, mais c’est plus difficile d’un point de vue calcul numérique en raison de la nécessité d’obtenir des séries temporelles plus longues pour résoudre les mouvements à basse fréquence. En excellent accord avec les résultats expérimentaux, une série de calcul LES de très longue durée a été réalisée, il a été clairement démontré l’existence de mouvements énergétiques à basse fréquence et à large bande près du point de séparation. Des efforts particuliers ont été faits pour éviter tout forçage à basse fréquence en amont, et il a été explicitement démontré que les oscillations de choc à basse fréquence observées n’étaient pas liées à la génération de turbulence d’entrée, excluant la possibilité d’un artefact numérique. Différentes méthodes d’analyse spectrales, et en décomposition en mode dynamique ont été utilisées pour montrer que les échelles de temps impliquées dans un tel mécanisme sont environ deux ordres de grandeur plus grandes que les échelles de temps impliquées dans la turbulence de la couche limite, ce qui est cohérent avec les mouvements de basse fréquence observés. En outre, ces échelles de temps se sont avérées être fortement modulées par la quantité de flux inversé à l’intérieur de la bulle de séparation. Ce scénario peut, en principe, expliquer à la fois l’instabilité des basses fréquences et sa nature à large bande
The need for a better understanding of the driving mechanism for the observed low-frequency unsteadiness in an over-expanded nozzle flows was discussed. The unsteady character of the shock wave/boundary layer remains an important practical challenge for the nozzle flow problems. Additionally, for a given incoming turbulent boundary layer, this kind of flow usually exhibits higher low-frequency shock motions which are less coupled from the timescales of the incoming turbulence. This may be good from an experimenter’s point of view, because of the difficulties in measuring higher frequencies, but it is more challenging from a computational point of view due to the need to obtain long time series to resolve low-frequency movements. In excellent agreement with the experimental findings, a very-long LES simulation run was carried out to demonstrate the existence of energetic broadband low-frequency motions near the separation point. Particular efforts were done in order to avoid any upstream low-frequency forcing, and it was explicitly demonstrated that the observed low-frequency shock oscillations were not connected with the inflow turbulence generation, ruling out the possibility of a numerical artefact. Different methods of spectral analysis and dynamic mode decomposition have been used to show that the timescales involved in such a mechanism are about two orders of magnitude larger than the time scales involved in the turbulence of the boundary layer, which is consistent with the observed low-frequency motions. Furthermore, those timescales were shown to be strongly modulated by the amount of reversed flow inside the separation bubble. This scenario can, in principle, explain both the low-frequency unsteadiness and its broadband nature

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Epilepsies are neurological disorders characterized by recurrent and spontaneous seizures due to an abnormal electric activity in a brain network. The mesial temporal lobe epilepsy (MTLE) is the most prevalent type of epilepsy in adulthood, and it occurs frequently in association with hippocampal sclerosis. Unfortunately, not all patients benefit from pharmacological treatment (drug-resistant patients), and therefore become candidates for surgery, a procedure of high complexity and cost. Nowadays, the most common surgery is the anterior temporal lobectomy with selective amygdalohippocampectomy, a procedure standardized by anatomical markers. However, part of patients still present seizure after the procedure. Then, to increase the efficiency of this kind of procedure, it is fundamental to know the epileptic human brain in order to create new tools for auxiliary an individualized surgery procedure. The aim of this work was to identify and quantify the occurrence of epilepticform activity -such as interictal spikes (IS) and high frequency oscillations (HFO) - in electrocorticographic (ECoG) signals acutely recorded during the surgery procedure in drug-resistant patients with MTLE. The ECoG recording (32 channels at sample rate of 1 kHz) was performed in the surface of temporal lobe in three moments: without any cortical resection, after anterior temporal lobectomy and after amygdalohippocampectomy (mean duration of each record: 10 min; N = 17 patients; ethic approval #1038/03 in Research Ethic Committee of Federal University of S?o Paulo). The occurrence of IS and HFO was quantified automatically by MATLAB routines and validated manually. The events rate (number of events/channels) in each recording time was correlated with seizure control outcome. In 8 hours and 40 minutes of record, we identified 36,858 IS and 1.756 HFO. We observed that seizure-free outcome patients had more HFO rate before the resection than non-seizure free, however do not differentiate in relation of frequency, morphology and distribution of IS. The HFO rate in the first record was better than IS rate on prediction of seizure-free patients (IS: AUC = 57%, Sens = 70%, Spec = 71% vs HFO: AUC = 77%, Sens = 100%, Spec = 70%). We observed the same for the difference of the rate of pre and post-resection (IS: AUC = 54%, Sens = 60%, Spec = 71%; vs HFO: AUC = 84%, Sens = 100%, Spec = 80%). In this case, the algorithm identifies all seizure-free patients (N = 7) with two false positives. To conclude, we observed that the IS and HFO can be found in intra-operative ECoG record, despite the anesthesia and the short time of record. The possibility to classify the patients before any cortical resection suggest that ECoG can be important to decide the use of adjuvant pharmacological treatment or to change for tailored resection procedure. The mechanism responsible for this effect is still unknown, thus more studies are necessary to clarify the processes related to it
As epilepsias s?o dist?rbios neurol?gicos caracterizados por crises espont?neas e recorrentes, resultantes de uma atividade el?trica anormal de uma rede neural. Dentre os diferentes tipos de epilepsia, a epilepsia mesial do lobo temporal (EMLT) ? a mais observada em adultos, sendo frequentemente associada ? esclerose hipocampal. Infelizmente, nem todos os pacientes s?o beneficiados pelo tratamento farmacol?gico (pacientes f?rmaco-resistentes). Para estes sujeitos, uma alternativa ? a realiza??o de cirurgia, um procedimento de alta complexidade e elevado custo. Atualmente, o procedimento mais realizado ? a lobectomia temporal anterior com amigdalo-hipocampectomia seletiva, uma cirurgia padronizada por marcos anat?micos. Entretanto, uma parcela dos pacientes continua a apresentar crises incapacitantes ap?s o tratamento cir?rgico. Desta forma, para aumentar a efici?ncia deste tipo de tratamento, ? fundamental a compreens?o do enc?falo humano epil?ptico com vistas a se criar ferramentas que auxiliem na realiza??o de procedimentos individualizados. O objetivo do presente trabalho foi identificar e quantificar a ocorr?ncia de atividade epileptiforme - esp?culas interictais (EI) e oscila??es de alta frequ?ncia (OAF) - em registros eletrocorticogr?ficos (ECoG) realizados durante procedimento cir?rgico em pacientes com EMLT refrat?ria ao tratamento farmacol?gico. Registros ECoG (32 canais a uma taxa de amostragem de 1 kHz) foram realizados na superf?cie do lobo temporal em 3 momentos cir?rgicos: no c?rtex intacto, ap?s lobectomia temporal anterior e ap?s amigdalo-hipocampectomia (dura??o m?dia de cada um desses registros: 10 min; N=17 pacientes). A ocorr?ncia de EI e OAF foi quantificada automatica-mente, por meio de rotinas em MATLAB, e validadas manualmente. A taxa de ocorr?ncia em cada um dos tempos cir?rgicos foi correlacionada com o resultado cir?rgico quanto ao controle das crises, num seguimento de 2 anos. De um total de 8 h e 40 min de registro, identificamos 36.858 EI e 1.756 OAF. Observamos que os pacientes que ficaram livres de crises no p?s-operat?rio apresentaram maior quanti-dade de OAF antes da cirurgia do que aqueles que continuaram a ter crises; por?m, n?o diferiram quanto a frequ?ncia, morfologia e distribui??o de EI. A ocorr?ncia de OAF no registro basal apresentou melhor desempenho que as EI na previs?o do controle total das crises no p?s-operat?rio (EI: AUC = 57%, S = 71% , E = 70% vs OAF: AUC = 77%, S = 100%, E=70%). O mesmo foi observado com a varia??o da ocorr?ncia entre os momentos pr?- e p?s-ressec??o (EI: AUC = 54%, S = 71%, E = 60% vs OAF: AUC = 84%, S = 100%, E = 80%). Nesse caso, o classificador foi capaz de identificar todos os pacientes livres de crises (N = 7) , apresentando apenas dois falsos positivos. Desta forma, podemos concluir que as OAF, juntamente com as EI, podem ser encontradas no registro ECoG intra-operat?rio, mesmo na presen?a de anest?sicos e em uma curta sess?o de registro. Al?m disso, a observa??o de que a ocorr?ncia desses eventos no in?cio da cirurgia permite classificar o paciente quanto ao progn?stico cir?rgico abre caminho para aplicar o ECoG intra-operat?rio, por exemplo, na decis?o sobre o uso de tratamento farmacol?gico adjuvante ou da convers?o para ressec??es individualizadas. No entanto, o mecanismo respons?vel por esse efeito ainda ? desconhecido, logo novos estudos s?o necess?rios para melhor esclarec?-lo

Epilepsy is one the most common neurological disorders. For patients suffering from epilepsy who are medically intractable, in certain cases surgical resection of pathologic brain tissue is one remaining possibility. Prior to surgery, intracranial Electroencephalography (IEEG) study is conducted to localize seizure-generating zones. IEEG typically consists of studying epileptiform spikes and seizure discharges; however some researchers have observed short bursts of high frequency oscillations (HFOs), mostly in the range of 100-500 Hz in the seizure generating areas. A retrospective correlation analysis between the post-surgical outcome and HFO generating tissue supports the idea that HFO events may play a fundamental role in epilepsy and epileptogenesis. Recently, HFO events have been scored visually by clinicians. Typically, it is necessary to record IEEG for several days or weeks to collect sufficient epileptiform activities for precise evaluation. Needless to say, manual review of the data makes visual scoring an extremely tiresome process in which subjectivity is inevitable. Due to the recent explosion of HFO research, the development of algorithms for automatic detection of HFO events poses a great benefit to researchers and clinicians. In the literature, two methods have been widely used for automatic detection of HFO events based on the energy of the signal in the 100-500 Hz frequency band. In this thesis, we present three new methods for automatic detection of HFO events based on the sharpness property of the IEEG signals. By using simulated and real-data signals, the performance of the proposed methods are compared to the existing energy-based approaches using sensitivity and specificity metrics. Additionally, we present the clinical implication of the HFO event detections for four epileptic patients. The results indicate that the performance of the proposed detectors are robust and stable and do not deteriorate in the presence of the noise and artifacts.

博士
國立清華大學
生命科學系
96
High-frequency oscillation (HFO) up to 600 Hz in grouped neurons have been observed in the brain areas of vertebrates and central nerve system of invertebrates. Many studies indicate electrical synapses play key roles. With the participation of chemical synapses, neuronal oscillation can be easily generated either by computer simulation or real electrophysiological measurement. However, many reports indicate that HFO is independent of chemical synapse, but depend on gap junction and intrinsic properties of ion channels of participating neurons. Although several mechanisms have been suggested from computer simulations, no one has been verified in real neurons. It is even difficult to understand how HFO is initiated. Here we demonstrate how a paired-spike induces HFO in a gap-junction-coupled network which formed a closed loop and contained only three cells. Furthermore, HFO up to 626 Hz in an electrically coupled network of crayfish was also displayed without the involvement of chemical synapses. In fact, the oscillation only depends on weakly-coupled gap junctions and associated behaviors of spike propagation during refractory period of preceding action potential. For initiating oscillations, it is absolutely essential that the second spike is elicited during the refractory period. Even a spike is elicited; it suffers from slow propagation speed and a tendency for failure through low conductance junctions. Thus, paired-spikes with a short spike interval induce only one trans-junctional spike. At distant synaptic sites, two trans-junctional spikes are triggered because the spike interval increases with spike propagation. Consequently, trans-junctional spikes collide in a gap-junction-coupled network. The remaining single spike reverberates in a loop that serves as an oscillation centre. Since HFO is generated by spike reverberation in a closed loop. The oscillating frequency is decided by the spike traveling time through the closed loop of oscillating center. Further analysis by both simulation and electrophysiological experiment indicated that a simple insertion of spike into the oscillating spikes was verified being able to terminate the paired-spike-elicited HFO. This simple method might provide a valuable hint for the treatment of epilepsy.

碩士
國立高雄師範大學
物理學系
100
The high frequency signals were observed in an a-cut microchip Nd:YLF laser subjected to fiber-feedback. As the fiber length increased, the high frequency signals decreased. The optical beam is reflected by a fiber, which acts as an external Fabry-Perot cavity. This beam is then injected back into the Nd:YLF cavity, where it is mixed with the light inside the cavity, causing a beat frequency. The beat frequency is corresponding to the observed high frequency component.

碩士
臺灣大學
電機工程學研究所
98
Interleaved buck converters have been popularly used in the voltage regulators for powering the recent central processing units (CPUs) used in computer with energy-saving features. An interleaved power converter configuration features high efficiency, fast transient responses, distributed power dissipation, and easy modularity. Combining these features with the energy-saving measures adopted in recent CPUs such as dynamic loading and adaptive-voltage-position (AVP) really makes the whole computer system energy-efficient. However, the combination of an interleaved converter configuration and the dynamic CPU load may cause serious problems with phase current oscillating at beat frequency; i.e., the difference frequency of the converter switching frequency and the dynamic-load frequency. The focus of this thesis is to investigate such a problem in a recently reported High-Gain Peak Current Control (HGPCC) scheme. HGPCC is an attractive scheme for achieving AVP control which has been used in recent years to reduce the CPU losses in computers applications. In the thesis, a multi-frequency model of the pulse-width-modulator was used in the modeling of this converter to take into account the feedback control effects of side-band signal (i.e., the beat-frequency signal) into considerations. A review of the oscillation problems was given for the conventional voltage-mode and peak-current-control interleaved converters. The HGPCC configuration was then modeled in details. It was concluded from the modeling effort that the HGPCC scheme has no suppression effect on the beat-frequency oscillation. A modified HGPCC configuration was then proposed to mitigate this problem while retaining all the basic features of original HGPCC. Simulations and experimental results were presented at the end to verify the model and the validity of the proposed modified HGPCC. Future research directions were also pointed out at the end of the thesis.

The observation that a group of psychomimetic drugs like phencyclidine or ketamine transiently induces symptoms of acute schizophrenia had led to a glutamatergic dysfunction hypothesis in pharmacological models of psychosis. Since then many studies have shown ketamine dependent local changes in brain functioning. One of them is emergence of the high frequency oscillations (HFO), neuronal cell population activity that synchronizes in a rhythm over 80 Hz. This research project focuses on investigating neuronal mechanism of HFO generation in olfactory areas, which seems to be one of the strongest sources of this fast rhythmic activity. First, I show that ketamine-xylazine (KX) anesthesia provides an alternative model to study electrophysiological changes in rodents evoked by NMDA receptor blockers like ketamine. My studies present that KX dependent fast oscillations in olfactory areas is not limited to rodents, but it also occurs in other mammal, in the cat olfactory bulb (OB). Negligible HFO power in the thalamus and visual cortex of the KX anesthetized cats confirms that the OB is a suitable site for detailed investigation and corroborates my further studies in rodents. Simultaneous local field potential (LFP) and thermocouple recordings demonstrate that HFO is dependent on nasal airflow and appears in bursts modulated by a slow (<3 Hz) local rhythm. Multielectrode studies spanning almost the entire dorsal-ventral axis of the OB and current source density (CSD) analysis revealed that HFO is stronger in ventral areas of the bulb and associated with dipole generator in the mitral/tufted cells layer. Simultaneous recordings from the OB and the anterior piriform cortex revealed another dipole-like source of the HFO. This may partially explain the presence of ketamine-dependent HFO in neighboring brain structures. Pharmacological microinfusion of selective GABA and AMPA antagonists in OB has shown that HFO bursts were dependent on excitatory-inhibitory synaptic activity, indicating local inhibitory interactions in OB are necessary for rhythm synchronization. Finally, I showed HFO was preserved in the OB despite surgical removal of the piriform cortex, which strongly indicates that the OB is an independent HFO generator. I conclude that ketamine-dependent HFO, in the OB are driven by nasal airflow and local dendrodendritic interactions. HFOs are receiving increased attention for their role in health and disease. Ketamine-dependent changes in oscillatory activity have been widely studied in the context of psychoses and more recently in treatmentresistant depression. My thesis proposes a new way to investigate HFO in mammalian brain under anesthesia. The findings shed light on the fundamental mechanisms underlying the generation of ketamine-dependent HFO in a novel context. Further, this thesis provides a framework for future studies to investigate ketamine rhythms using experimental techniques, such as intracellular recordings, usually inaccessible in awake states.
Zaobserwowano, że część z objawów schizofrenii pokrywa się z zaburzeniami psychicznymi pojawiającymi się po anestezji ketaminowej lub po podaniu innych blokerów receptorów NMDA, takich jak fencyklidyna. Powiązanie tej zależności dało początek nowej hipotezie mechanizmu schizofrenii, związanej z działaniem receptorów glutaminergicznych. Wiele kolejnych badań przy użyciu ketaminy wykazało, że ma ona znaczący wpływ na funkcjonowanie układu nerwowego. Jednym z efektów działania ketaminy jest wywoływanie neuronalnych oscylacji wysokoczęstotliwościowych (HFO) o częstości powyżej 80 Hz. Głównym tematem moich badań jest wyjaśnienie mechanizmu generacji HFO w obszarach węchowych u zwierząt doświadczalnych. Dotychczasowe badania wykazały, że oscylacje te są szczególnie silne w opuszce węchowej w porównaniu do innych części mózgu gryzoni. Swoje badania rozpocząłem od pokazania, że HFO wywołane ketaminą mogą być z powodzeniem rejestrowane pod anestezją ketaminowo-ksylazynową (alternatywny model ketaminowy) i oprócz zmniejszonej częstości, wykazują wysokie podobieństwo do HFO w stanie czuwania gryzoni. Ponadto wykazałem, że HFO mogą być także zarejestrowane u kotów pod anestezją i są znacząco silne w rejonach opuszki węchowej. Równocześnie nie zaobserwowano obecności tych szybkich rytmów w obszarze wzgórza i kory wzrokowej kota. Wyniki te wskazują na szczególna rolę rejonów węchowych, więc dalsze badania skoncentrowałem na dokładnym poznaniu mechanizmu generacji HFO w opuszce węchowej szczura. Jednoczesne rejestracje z termopar w przegrodzie nosowej i elektrod umieszczonych w opuszce pokazały, że moc HFO jest modulowana przez lokalne wolne oscylacje oddechowe ($<$ 3 Hz). Rejestracje wielokanałowe elektrodami rozmieszczonymi na prawie całej brzuszno-grzbietowej osi opuszki węchowej oraz analizy rozkładu źródeł prądowych (CSD) wskazały na znaczący udział części warstwy komórek mitral/tufted, jednak jedynie tych położonych w brzusznej części opuszki. Jednoczesne rejestracje z przedniej części kory gruszkowatej (anterior piriform cortex) i opuszki pozwoliły na odkrycie nowego źródła generacji HFO o bipolarnym rozkładzie prądów. Wynik ten może wyjaśniać dlaczego HFO jest możliwe do zarejestrowania także w obszarach mózgu położonych niedaleko kory gruszkowatej. Badania prowadzone przy użyciu metod mikroinfuzji selektywnych blokerów receptorów GABA i AMPA, wskazały na szczególną rolę połączeń międzykomórkowych, zarówno hamujących jak i pobudzających, niezbędnych do synchronizacji komórek w rytmie HFO. Wynik ten wskazuję na lokalny mechanizm generacji, co potwierdziłem kolejnym badaniem, w którym pokazałem, że odcięcie głównych odśrodkowych połączeń z mózgu do opuszki nie wpływa na generację HFO wewnątrz opuszki. Na podstawie otrzymanych wyników wywnioskowałem, że HFO wywołane ketaminą są generowane przy udziale rytmów oddechowych i ich synchronizacja jest możliwa dzięki połączeniom dendrodendrytycznym wewnątrz opuszki węchowej. Badanie oscylacji HFO staje się coraz bardziej popularne w kontekście ich udziału w chorobach psychicznych, ale także ogólnie fizjologii mózgu. Wpływ ketaminy na oscylacje układu nerwowego był badany jako model psychozy, ale ostatnio także jako próba wyjaśnienia antydepresyjnego działania ketaminy. W mojej pracy zaproponowałem nową metodę badania HFO na mózgach ssaków w stanie anestezji. Wyniki moich badań tłumaczą podstawowy mechanizm generacji tych oscylacji wewnątrz opuszki węchowej. Dodatkowo proponuję nowy model do badania aktywności mózgu po podaniu ketaminy, który pozwala na prowadzenie rejestracji wewnątrzkomórkowych a także inne metody monitorowania pracy mózgu, które znacznej trudniej jest wykorzystać u zwierząt w stanie czuwania.

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 (> 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 (>80 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.

Tese de Doutoramento em Biologia Experimental e Biomedicina apresentada ao Instituto de Investigação Interdisciplinar da Universidade de Coimbra.
Excitation-inhibition (E-I) balance plays an important role in information processing, neuroplasticity and pathologic conditions. Evidence of E-I imbalance has been reported in a wide array of neuropsychiatric disorders such as autism spectrum disorder (ASD), schizophrenia, neurofibromatosis type 1, depression and attention-deficit/hyperactivity disorder. Of particular interest to us was the currently available evidence of cortical dysfunction in type 2 diabetes patients. Type 2 diabetes mellitus patients are known to have decreased cognitive ability before they develop any evidence of microvascular or macrovascular disease. This could be explained by impaired circuitry and/or E-I balance of certain networks in type 2 diabetes mellitus. It has been reported that patients with type 2 diabetes mellitus have increased levels of GABA in the occipital region in addition to evidence of blood-brain barrier disintegration in such patients. Because of this, type 2 DM was chosen as a disease model to study the possible impacts of the disease on GABAergic system in the occipital region and how that correlate with visual performance. The study of the GABAergic system and its dysfunction in epilepsy is gaining attention for several reasons. First, while GABA is mainly an inhibitory neurotransmitter in the brain it has been shown that it can act as an excitatory neurotransmitter on immature neurons. Second, there is growing evidence of increased GABA concentration in the epileptogenic zone in patients with drug-resistant epilepsy in vivo and ex vivo. Finally, the generation of pathologic and physiologic high frequency oscillations is expected to be related to and maintained by inhibitory postsynaptic potentials that are mediated by GABAA receptors. The second part of this thesis focuses on the study of the GABAergic system in epilepsy patients with drug-resistant disease and how it is related to physiologic or pathologic gamma activity. We chose a cohort of type 2 diabetes mellitus patients who have early diabetic retinopathy. The goal was to assess occipital cortical GABA as a predictor of visual performance in type 2 diabetes mellitus patients. GABA was measured by proton magnetic resonance spectroscopy from the occipital region, and visual performance was assessed in three domains (chromatic, achromatic and speed discrimination). We found for the first-time evidence of achromatic and speed discrimination abnormalities in type 2 diabetes mellitus patients as compared to healthy subjects. Moreover, we reported for the first time a positive correlation between occipital GABA and achromatic/speed discrimination thresholds (higher thresholds mean worse performance). Occipital GABA at baseline was also predictive of visual performance one year later, suggesting that modulating occipital GABA could have a long-term impact on visual performance. The second study to be included in the scope of this thesis focused on BBB permeability in type 2 diabetic patients and its relation to visual performance. The previously mentioned cohort of type 2 DM patients who had evidence of GABAergic dysfunction were included in this subsequent study of BBB integrity. In summary, we showed a relationship between BBB leakage and blood-retinal-barrier leakage, with patients with BRB leakage having higher BBB permeability. Moreover, we showed for the first time that metabolic control is correlated with BBB permeability (poor metabolic control is associated with impaired BBB integrity). Finally, we found that BBB permeability is predictive of visual acuity at baseline, one year and two years later in type 2 diabetics with established BRB leakage. We then moved to study the GABAergic system in a different disease model. In patients with drug resistant epilepsy, we are offered a unique opportunity where we can indirectly measure the function of the GABAergic system by measuring gamma activity with intracranial electroencephalography (EEG). The first study in this disease model focused on physiologic high frequency activity where we tested the relationship between functional topography of high gamma activity and perceptual decision-making. In summary, we found three distinct regional fingerprints of high frequency activity (HFA) in our cohort: a) Lower gamma frequency patterns dominated the anterior semantic ventral object processing, b) low gamma frequency patterns that involve dorsoventral integrating networks, and c) early sensory posterior patterns in the 60 to 250 Hz range. In summary, we show that accurate object recognition/perceptual decision-making is associated with low-gamma frequency activity that has a specific spatiotemporal signature. The second study that belonged to the disease model of drug resistant epilepsy focused on evidence of GABAergic dysfunction in epilepsy and how the modulation of the GABAergic system in the epileptogenic zone affects epileptogenecity and the GABAergic system in other reference brain region (the occipital region). We hypothesized that c-tDCS (cathodal transcranial direct current stimulation) which has an antiepileptic effect would modulate the neurotransmitters responsible for the abnormal and complex local synchrony and abnormal rhythmic activity seen in epilepsy. This is the first study to test for the impact of c-tDCS on physiologic and pathologic gamma activity and to measure GABA, glutamate and glutathione from the epileptogenic zone and occipital region simultaneously after c-tDCS in patients with drug resistant epilepsy. C-tDCS decreased the number of interictal discharges per minute. This was associated with a decrease in GABA concentration in the occipital and epileptogenic zones. We also found that cathodal tDCS stimulation of the epileptogenic zone suppressed grating evoked low gamma activity in the epileptogenic zone and increased it in the distant parieto-occipital regions. In summary, this study provided a window into the mechanism of action of c-tDCS as an antiepileptic and its effects on the GABAergic system and neural oscillatory patterning. In summary, we show that E-I balance is maintained across the different neural networks in a given time frame and alterations in this balance is linked to cognitive impairment and visual performance in type 2 DM, and epileptogenesis in epilepsy patients. Our results also suggest that GABAergic dysfunction in the epileptogenic zone is more than a consequence of epileptogenesis, and could be epileptogenic per se.
O equilíbrio entre excitação e inibição tem um papel importante no processamento de informação, na neuroplasticidade e em certas condições patológicas. Um desequilíbrio entre excitação e inibição tem sido referido em várias condições neuropsiquiátricas, tais como na perturbação do espectro do autismo, esquizofrenia, neurofibromatose de tipo 1, depressão e perturbação de hiperatividade e défice de atenção. A evidência desta disfunção cortical também em pessoas com diabetes mellitus tipo 2 revelou-se de particular interesse para nós. Sabe-se que pessoas com diabetes mellitus tipo 2 apresentam uma habilidade cognitiva diminuída antes até do aparecimento de doença micro ou macrovascular. Isto poderá ser explicado por alterações nos circuitos e/ou desequilíbrio entre excitação e inibição em certas redes neuronais. Estudos mostram que pessoas com diabetes mellitus tipo 2 têm concentrações de GABA aumentadas na região occipital, para além da evidência de disfunção da barreira hematoencefálica. Por estes motivos, a diabetes mellitus tipo 2 foi escolhida como modelo para o estudo do impacto da doença no sistema GABAérgico na região occipital e de como isso se relaciona com o desempenho em testes visuais. O estudo do sistema GABAérgico e a sua disfunção na epilepsia tem ganho atenção por vários motivos. Primeiro, apesar do GABA funcionar como neurotransmissor inibitório, tem sido mostrado que este funciona como neurotransmissor excitatório em neurónios imaturos. Segundo, há cada vez maior evidência da concentração aumentada de GABA na zona epileptogénica em pessoas com epilepsia refratária, sugerida por estudos in vivo e ex vivo. Por último, é expectável que as oscilações de alta frequência, quer de origem patológica quer fisiológica, se formem e sejam mantidas por potenciais pós-sinápticos mediados por recetores GABAA. A segunda parte desta tese refere-se ao estudo do sistema GABAérgico em pessoas com epilepsia refratária e como este se relaciona com a atividade fisiológica e patológica de frequências gamma. Neste trabalho foi incluído um grupo de participantes com diabetes mellitus tipo 2 e com retinopatia diabética. O objetivo era avaliar a concentração de GABA no córtex occipital como preditor do desempenho em testes visuais por estes participantes. A concentração de GABA na região occipital foi medida usando a técnica de espectroscopia por ressonância magnética nuclear e o desempenho em testes visuais foi avaliado em três áreas (visão cromática, acromática e discriminação de velocidade). Os resultados mostraram, pela primeira vez, evidência de diferenças na visão acromática e na discriminação de velocidade em participantes com diabetes mellitus tipo 2 quando comparados com participantes saudáveis. Além disso, foi encontrada pela primeira vez uma correlação positiva entre os níveis de GABA no córtex occipital e os limiares de visão acromática e discriminação de velocidade (maiores limiares significam pior desempenho). Os valores de GABA na região occipital também foram preditivos do desemprenho nos testes visuais quer na primeira avaliação, quer um ano depois, sugerindo que a modulação dos níveis de GABA no córtex occipital pode ter um impacto a longo termo no desempenho visual. O segundo trabalho realizado no âmbito desta tese refere-se ao estudo da permeabilidade da barreira hematoencefálica em pessoas com diabetes mellitus tipo 2 e a sua relação com o desempenho nos testes visuais. Os participantes com diabetes e com evidência de disfunção GABAérgica anteriormente referidos foram incluídos no estudo seguinte acerca da integridade da barreira hematoencefálica. Em suma, os resultados mostraram uma relação entre a integridade da barreira hematoencefálica e a integridade da barreira hemato-retiniana, sendo que participantes com maior ruptura da barreira hemato-retiniana apresentavam maior permeabilidade da barreira hematoencefálica. Além disso, os resultados mostraram pela primeira vez que o controlo metabólico está correlacionado com a permeabilidade da barreira hematoencefálica (pior o controlo metabólico associado a diminuição da integridade da barreira). Por último, em participantes com diabetes tipo 2 e ruptura da barreira hemato-retiniana, os resultados mostraram que a permeabilidade da barreira hematoencefálica é preditiva da acuidade visual quer no primeiro teste quer um e dois anos mais tarde em. Em seguida, o sistema GABAérgico foi estudado tendo outra doença como modelo. A função do sistema GABAérgico pode ser avaliada, de forma indireta, a partir da medição da atividade gamma usando eletroencefalografia intracraniana em pessoas com epilepsia refratária. No primeiro trabalho em que usámos a epilepsia refratária como modelo, estudou-se a atividade fisiológica de alta frequência, testando a relação entre a topografia funcional da atividade gamma alta e tomada de decisão percetual. Em suma, encontraram-se três padrões locais distintos dessa atividade de alta frequência neste grupo de participantes: a) domínio de padrões de frequência gamma baixa no processamento semântico em áreas anteriores e no processamento de objetos em áreas ventrais; b) padrões de frequência gamma baixa envolvendo redes dorsoventrais de integração de informação; c) padrões se surgimento inicial em áreas posteriores nas frequências de 60 a 250 Hz. Em suma, os resultados revelam que o reconhecimento de objetos de forma precisa e a tomada de decisão percetual estão associados a frequências gamma baixas com determinadas características espaciotemporais. O segundo trabalho usando a epilepsia refratária como modelo foi estudada a disfunção GABAérgica na epilepsia e como a modulação do sistema GABAérgico na zona epileptogénica afeta a epileptogenicidade e o sistema GABAérgico noutras áreas de referência (a região occipital). Considerando o efeito antiepilético da c-tDCS (estimulação catódica transcraniana por corrente direta), foi colocada a hipótese de que esta estimulação iria modelar os níveis de neurotransmissores responsáveis pela anormal e complexa sincronia local e pela atividade rítmica anormal comum na epilepsia. Este foi o primeiro trabalho a avaliar o impacto da c-tDCS na atividade gamma fisiológica e patológica e a medir GABA, glutamato e glutationa na zona epileptogénica e na região occipital depois da c-tDCS em participantes com epilepsia refratária. A estimulação c-tDCS diminuiu o número de descargas interictais por minuto. Esta redução revelou-se associada a uma diminuição da concentração de GABA na região occipital e na zona epileptogénica. Os resultados mostraram que a estimulação c-tDCS da zona epileptogénica cancelou a atividade gamma baixa tipicamente evocada por estímulos visuais em grelha na zona epileptogénica e aumentou essa atividade em regiões parieto-occipitais mais distantes. Em suma, este trabalho abre uma janela sobre os mecanismos de ação da estimulação c-tDCS como antiepilético e os seus efeitos no sistema GABAérgico e nos padrões de oscilações neuronais. Em síntese, os trabalhos mostram que o equilíbrio entre excitação e inibição é mantido por interação de diferentes redes neuronais numa dada janela temporal e as alterações desse equilíbrio estão associadas a dificuldades cognitivas e ao desempenho em testes visuais em pessoas com diabetes tipo 2 e à epileptogénese em pessoas com epilepsia. Os nossos resultados também sugerem que a disfunção GABAérgica na zona epileptogénica é mais do que uma consequência da epileptogénese, e poderá ser epileptogénica por si.

Χρονοφασματική και χωροχρονική ανάλυση σύγχρονης (φασικά-κλειδωμένης) υψίσυχνης (γ-ζώνης) ταλαντωτικής ηλεκτροεγκεφαλογραφικής δραστηριότητας σε ανώτερης τάξης oπτικογνωστικές αποκρίσεις του ανθρωπίνου εγκεφάλου διεξαγόμενη με το συνεχή μετασχηματισμό του κυματίου και υλοποιούμενη με προηγμένα εργαλεία πληροφορικής της Βιοϊατρικής Μηχανικής στην ψηφιακή επεξεργασία του ΗΕΓ σήματος.
Spectrotemporal and spatiotemporal analysis of synchronous (phase-locked) high-frequency (gamma-band)oscillatory electroencephalographic activity in higher-order visual cognitive responses of the human brain conducted with the continuous wavelet transform and implemented by advanced informatics tools of Biomedical Engineering in digital EEG signal processing.