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Diffusion weighted imaging (DWI) and dynamic susceptibility contrast-enhanced (DSC) perfusion-weighted imaging (PWI) are commonly employed in clinical practice and in research to give pathophysiological information for patients with acute ischemic stroke. DWI is thought to roughly reflect the severely damaged infarct core, while DSC-PWI reflects the area of hypoperfusion. The volumetric difference between DWI and DSC-PWI is termed the PWI/DWI-mismatch, and has been suggested as an MRI surrogate of the ischemic penumbra. However, due to the application of a contrast agent, which has potentially severe side-effects (e.g., nephrogenic systemic fibrosis), the DSC-PWI precludes repetitive examinations for monitoring purposes. New approaches are being sought to overcome this shortcoming. BOLD (blood oxygen-level dependent) signal can reflect the metabolism of blood oxygen in the brain and hemodynamics can be assessed with resting-state fMRI. The aim of this thesis was to use resting-state fMRI as a new approach to give similar information as DSC-PWI. This thesis comprises two studies: In the first study (see Chapter 2), two resting-state fMRI methods, local methods which compare low frequency amplitudes between two hemispheres and a k-means clustering approach, were applied to investigate the functional damage of patients with acute ischemic stroke both in the time domain and frequency domain. We found that the lesion areas had lower amplitudes than contralateral homotopic healthy tissues. We also differentiated the lesion areas from healthy tissues using a k-means clustering approach. In the second study (see Chapter 3), time-shift analysis (TSA), which assesses time delays of the spontaneous low frequency fluctuations of the resting-state BOLD signal, was applied to give similar pathophysiological information as DSC-PWI in the acute phase of stroke. We found that areas which showed a pronounced time delay to the respective mean time course were very similar to the hypoperfusion area. In summary, we suggest that the resting-state fMRI methods, especially the time-shift analysis (TSA), may provide comparable information to DSC-PWI and thus serve as a useful diagnostic tool for stroke MRI without the need for the application of a contrast agent.

This doctoral thesis aims to demonstrate the relevance of resting-state functional connectivity (RSFC) for the study of brain function. RSFC refers to the spontaneous brain activity structured in intrinsic connectivity networks. These networks mirror task-based activations and show significant variations across several behavioral domains and phenotypical traits. Furthermore, changes in these networks after, for instance, pharmacological manipulations, may disentangle the specific role of several neurotransmitters systems in normal and pathological functional connectivity. While various neuroimaging techniques enable the detection of intrinsic connectivity networks, data-driven methods, such as independent component analysis, provide a robust spatial representation of brain networks that are distinguishable from physiological signals and scanner noise. Within the above-mentioned framework, this thesis presents data from two studies designed to better understand 1) individual differences in decision making reflected in intrinsic network connectivity and 2) variations in intrinsic network connectivity following serotonergic manipulations. The first part is the general introduction where I present the theoretical background, the methodology used in both experiments and an overview of the current research related to the studies of this thesis. The second chapter presents the first study, which examined the relationship between a set of value-based decision-making parameters with large-scale intrinsic connectivity networks. Findings of this study revealed that individuals who prefer to gamble in order to avoid a sure loss, exhibit stronger connectivity between the default mode and left frontoparietal systems to their adjacent brain regions, especially to those involved in prospective thinking, affective decision making and visual processing. The third chapter presents the second experimental study, which examined changes in default mode network connectivity after two tryptophan interventions to increase and decrease brain serotonin synthesis, and a control condition. Results of this study showed decreased functional connectivity between the default mode network and emotion-related regions associated with higher serotonin brain levels. Finally, the fourth chapter includes a general discussion that integrates the significance of the findings from both studies. In this section, limitations and recommendations for future research are also considered before presenting the conclusion that highlights the contribution of this work for unraveling the continuous activity of the resting brain.:1.CONTENTS 1 LIST OF FIGURES 3 LIST OF TABLES 4 ABBREVIATIONS 5 ABSTRACT 7 GENERAL INTRODUCTION 9 1.1. Resting-state functional connectivity: the silent work of the resting brain 9 1.2. Intrinsic connectivity networks 12 1.3. Independent Component Analysis 17 1.4. Summary: research objectives and study hypotheses 20 STUDY I: Risk seeking for losses modulates the functional connectivity of the default 2.mode and left frontoparietal networks in young males 22 2.1. Abstract 23 2.2. Introduction 24 2.3. Materials and Methods 26 2.4. Results 33 2.5. Discussion 41 2.6. Notes 44 2.7. Supplemental Material Study I 45 3. STUDY II: Acute Tryptophan Loading Decreases Functional Connectivity between the Default Mode Network and Emotion-Related Brain Regions 49 3.1. Abstract 50 3.2. Introduction 51 3.3. Materials and Methods 53 3.4. Results 61 3.5. Discussion 67 3.6. Acknowledgments 71 3.7. Supplemental Material Study II 72 4. GENERAL DISCUSSION 78 4.1. Research objectives and summary of results 78 4.2. Risk seeking for losses is associated with changes in default mode and frontoparietal systems 79 4.3. Higher serotonin brain synthesis decreases DMN connectivity 80 4.4. Integration of findings 81 4.5. Limitations and future directions 83 4.6. General conclusion 85 5. ZUSAMMENFASSUNG 86 Hintergrund 86 Fragestellung 86 Material und Methoden 87 Ergebnisse 88 Schlussfolgerungen 89 6. SUMMARY 90 Background 90 Research question 90 Material and Methods 91 Results 92 Conclusion 92 7.REFERENCES 93 8.ANNEX 113 8.1. Publikationsverzeichnis 113 8.3.Danksagung 115 8.4. Erklärungen zur Eröffnung des Promotionsverfahrens 116 8.5. Erklärung zur Einhaltung gesetzlicher Vorgaben118 8.6. Erklärungen zur Publikation 119

A leading theory for why we sleep focuses on memory consolidation - the process of stabilizing and strengthening newly acquired memories into long-term storage. Consolidation of memory for cognitive strategies and problem-solving skills is enhanced as compared to a period of daytime wakefulness. Importantly, sleep preferentially enhances memory for the cognitive strategy per se, over-and-above the motor skills that are used to execute the strategy. Although it has been known for some time that sleep benefits this type of memory, it is not known how this process unfolds during sleep, or how sleep transforms this memory trace in the brain. Sleep is classified into rapid eye movement (REM) sleep and non-REM (NREM) sleep. The role of REM sleep for consolidation of memory for problem-solving skills remains controversial. In addition, little attention has been paid to the possible distinct roles of phasic REM sleep (i.e., when bursts of eye movements occur) and tonic REM sleep (i.e., the presence of isolated eye movements and the absence of eye movement bursts). REM sleep might favour procedural memory consolidation for cognitive strategies and problem-solving skills, and the specific role of REM sleep in this process might be discernible only by differentiating between phasic and tonic REM states. In addition, fMRI studies have revealed that sleep-related consolidation of the memory trace for simple motor procedural skills is associated with strengthened activity of, and functional connectivity between, key memory-related brain areas (i.e., hippocampal, striatal, and neocortex). However, fMRI techniques have not yet been employed to investigate sleep-related consolidation of procedural memory for cognitive strategies and problem-solving skills. Participants (n=60) performed a procedural memory task involving a cognitive strategy while undergoing functional magnetic resonance imaging (fMRI) before and after a condition of Sleep, Nap, or Wake. Those in the Sleep and Nap condition underwent polysomnography (PSG) to further study the learning-related changes in sleep macrostructure and microstructure. This thesis not only shows that a period of sleep or a nap afford a greater benefit to memory consolidation of a procedural strategy than a period of wake, but more specifically: In Study 1, during sleep, phasic REM sleep theta power was directly associated with overnight improvement on the task, whereas tonic REM sleep sensorimotor rhythm power was greater following a night of learning compared to a non-learning control night. In Study 2, we show that distinct hippocampal, striatal, and cortical areas associated with strategy learning are preferentially enhanced. Study 3 reveals that the functional communication among these brain areas is greater following sleep compared to a daytime nap or day of wakefulness. Sleep-related changes in brain activation and functional connectivity were both correlated with improved performance from before to after a period of sleep. Overall, findings from this thesis support the benefit of sleep at the behavioural and systems level for consolidating procedural memory involving cognitive strategies used to solve problems. The findings suggest that the multifaceted nature of REM sleep must be examined separately by its phasic and tonic states, to identify the active role of REM sleep for consolidating memory. Further, the consolidation of the memory trace is reflected through activation of, and communication between hippocampal, striatal, and neocortical brain areas. In summary, this thesis shows that sleep actively consolidates memory for cognitive strategies and problem-solving skills.

Bakgrund: En del elitidrottare, exempelvis inom uthållighetsgrenar, genomför högträningsvolym vilket stressar kroppen. Hög träningsvolym resulterar i högenergiförbrukning vilket kräver ett stort energiintag. Ett otillräckligt energiintag påverkarkroppen fysiologiskt på ett flertal sätt och kan leda till syndromet relativ energibrist iidrott (REI - S). Syftet Studiens syfte var att studera samband mellankroppssammansättning och viloomsättning (RMR) korrelerat till relativ energibrist hossvenska elitidrottare. Metod/Urval: Studien följde en tvärsnittsstudiedesign. Mätning avkroppskomposition (fettmassa och fettfri massa) samt viloomsättning (RMR) utfördes.RMRratio beräknades genom mätt RMR (mRMR) delat på beräknad RMR (pRMR).mRMR beräknades under laborationen och pRMR beräknades genom Cunningham1991ekvationen. Urvalet bestod av 23 svenska elitidrottare från olika sporter med ettåldersspann från 18 år - 43 år. Resultat: Procentuell fettfri massa (FFM %) och RMR -värde korrelerade positivt (r = 0,47, p = 0,023). En negativ måttligt stark korrelationberäknades mellan procentuell fettmassa (FM %) och RMR - värde (r = -0,47, p = 0,024). Slutsats Därmed korrelerade kroppssammansättning och viloomsättning hos svenskaelitidrottare. Viloomsättning korrelerade positivt med FFM % och negativt med FM %. / Background Some elite athletes, such as endurance runners, undergo extreme levels of training volume which stresses the body. High training volume results in high energy expenditure which requires a large energy intake. Consequences of insufficient amounts of energy intake are physiological dysfunctions and may lead to relative energy deficiency in sports (RED- S). Purpose The aim of the study was to research relations between body composition (FM, FFM) and resting metabolic rate (RMR) in correlation with RED-S amongst Swedish elite athletes. Method/Subjects This research follows a cross-sectional study design. Measurements to calculate body composition and RMR were performed. RMRratio was calculated by measured RMR (mRMR) divided by predicted RMR (pRMR). The Cunningham1991 equation was used to calculate pRMR. A total of 23 healthy Swedish elite athletes from different sports were measured, age ranging from 18 - 43 year olds. Results The percentage of fat free mass (FFM %) correlated positively with RMR (r = 0,47, p = 0,023). Percentage of fat mass (FM %) correlated negatively with RMR (r = - 0,47, p = 0,024). Conclusion A correlation between body composition and RMR amongst Swedish elite athletes was discovered. RMR correlated positively with FFM%  and negatively with FM%.

Approximately 20% of the body’s energy consumption is ongoingly consumed by the brain, where the main part is due to the neural activity, which is only increased slightly when doing a demanding task. This ongoingly neural activity are studied with the so called resting-state fMRI, which mean that the neural activity in the brain is measured for participants with no specific task. These studies have been useful to understand the neural function and how the neural networks are constructed and cooperate. This have also been helpful in several clinical research, for example have differences been identified between bipolar disorder and major depressive disorder. Recent research has focused on temporal properties of the ongoing activity and it is well known that neural activity occurs in bursts. In this study, resting-state fMRI data and temporal graph theory is used to develop a point based method (PBM) to quantify these bursts at a nodal level. By doing this, the bursty pattern can be further investigated and the nodes showing the most bursty pattern (i.e hubs) can be identified. The method developed shows a robustness regarding several different aspects. In the method is two different variance threshold algorithms suggested. One local variance threshold (LVT) based on the individual variance of the edge time-series and one global variance threshold (GVT) based on the variance of all edges time-series, where the GVT shows the highest robustness. However, the choice of threshold needs to be adapted for the aims of the current study. Finally, this method ends up in a new measure to quantify this bursty pattern named bursty centrality. The derived temporal graph theoretical measure was correlated with traditional static graph properties used in resting state and showed a low but significant correlation. By applying this method on resting-state fMRI data for 32 young adults was it possible to identify regions of the brain that showed the most dynamic properties, these regions differed between the two thresholding algorithms

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L'activité neuronale partagée entre les différentes régions cérébrales permet d'estimer les patrons d'activation fonctionnelle à l'échelle de réseaux distribués, même en l'absence de paradigme. Constamment rapportés dans la population saine, les réseaux fonctionnels au repos (RSNs) peuvent être utilisés comme objet d'étude pour comprendre la contribution du développement sensoriel atypique sur la communication globale inter-réseau. À ce jour, peu d'études ont exploré l'organisation cérébrale au repos dans le contexte de la surdité. Pourtant, de multiples évidences soutiennent l'importance des entrées sensorielles en début de vie dans la consolidation de l'architecture fonctionnelle du cerveau. L'étude présentée dans ce mémoire a été développée et conceptualisée pour rendre compte de la relation entre la privation sensorielle et l'activité cérébrale spontanée entre les RSNs. À cette fin, 17 personnes avec une surdité congénitale de degré sévère à profond et 18 personnes entendantes non signeurs ont été recrutées et ont effectué 10 minutes d'enregistrement par imagerie magnétique fonctionnelle (IRMf) à l'état de repos. Les estimations de connectivité fonctionnelle de 17 RSNs extraites par une méthode de parcellisation fonctionnelle du cerveau ont été comparées entre les groupes. Le couplage entre les réseaux d'attention dorsale (DAN) et d'attention ventrale (VAN) était significativement plus élevé chez les participants qui présentent une surdité. Ces deux systèmes sont impliqués dans les tâches attentionnelles descendantes (« top-down ») et ascendantes (« bottom-up »), respectivement. Les résultats démontrent une réorganisation du cerveau au sein des réseaux associatifs et proposent une preuve potentielle des substrats neuronaux qui sous-tendraient les performances attentionnelles supérieures des personnes avec une surdité. / Neural activity shared between different brain regions allows estimation of functional activation patterns at the scale of distributed networks, even in the absence of a paradigm. Consistently reported in the healthy population, resting-state functional networks (RSNs) can be studied to understand the contribution of atypical sensory development on global inter-network communication. To date, few studies have explored brain organization at rest in the context of deafness. Yet, numerous evidence supports the importance of early sensory input in the consolidation of the brain's functional architecture. The study presented in this thesis was developed and conceptualized to report on the relationship between sensory deprivation and spontaneous brain activity between RSNs. To this end, 17 individuals with severe to profound congenital hearing loss and 18 non-signer hearing individuals were recruited and performed 10 minutes of functional magnetic imaging (fMRI) recording at rest. Functional connectivity estimates of 17 RSNs extracted by a functional brain parcellation method were compared between groups. The coupling between dorsal attention (DAN) and ventral attention (VAN) networks was significantly higher in deaf participants. These two systems are involved in topdown and bottom-up attentional tasks, respectively. The results demonstrate brain plasticity within associative networks and offer potential evidence of neural substrates that may underlie superior attentional performances observed in individuals with deafness.

Cette étude s’intéresse au lien entre les dynamiques cérébrales et les capacités cognitives, cette problématique a déjà été explorée auparavant en imagerie cérébrale, notamment à l’aide de tâches effectuées pendant l’imagerie. Cependant la caractérisation de l’activité spontanée a principalement été faite soit avec une faible précision spatiale (capteur EEG/MEG), soit en IRMf qui a une faible résolution temporelle. L’objectif de cette thèse est de caractériser l’activité spontanée au repos au niveau cortical associée à différents processus cognitifs et leur performance. Le second chapitre cherche à établir les corrélats neuronaux de la performance de la mémoire au repos à l’aide des puissances spectrales localisées au niveau des sources corticales. Le troisième chapitre cherche à répliquer les méthodes utilisées dans l’article 1 avec les mêmes participants, mais dans un autre domaine cognitif afin d’établir les corrélats neuronaux de la fluence verbale ainsi que de discriminer une composante verbale et exécutive. Ces deux composantes ont été mises en évidence en utilisant une factorisation avec un test purement exécutif (Trail making test- condition 4) et un autre purement verbal (richesse du vocabulaire). Dans le quatrième chapitre, nous répliquons encore la méthode de l’article 1 avec les mêmes sujets, mais sur un test d’apprentissage verbal. Lors de l’apprentissage verbal, deux stratégies d’apprentissage (sériel et sémantique) possibles sont utilisées de manière concurrente, nous avons cherché à établir si des différences comportementales se traduisaient par des patrons d’activation différents. Dans le cinquième chapitre, nous avons cherché à établir des différences fonctionnelles entre les survivants de la leucémie et des sujets contrôles, puis à établir un lien entre la neurotoxicité et le déficit cognitif rencontré chez cette population, finalement nous avons établi un modèle intégrant neurotoxicité, performance cognitive et marqueur neurophysiologique fonctionnel cérébral. Cette recherche aura approfondi les connaissances sur l’état de repos et principalement fourni les premiers travaux qui mettent en lien l’activité cérébrale spontanée au repos au niveau des sources corticales avec plusieurs tests neuropsychologiques comportementaux. Les résultats ont amené des patrons d’activation spatio-fréquentielle différents, démontrant des spécificités reliées à certains tests comportementaux ou des traitements de l’information (sériel ou sémantique). Finalement les travaux sur les survivants de la leucémie ont montré que l’état de repos pouvait caractériser le fonctionnement des déficits cognitifs à long terme et être un marqueur de remédiation pour de futurs traitements. / This study is interested in the link between brain dynamics and cognitive abilities. This problem has already been explored before in brain imaging, notably with the help of task performed during imaging. However, the characterization of spontaneous activity has mainly been done either with weak spatial resolution (EEG/MEG sensor) or in fMRI which has a low temporal resolution. The objective of this thesis is to characterize the spontaneous activity at rest at the cortical level associated with different cognitive processes and their performance. The second chapter seeks to establish the neural correlates of resting memory performance using spectral powers localized at cortical sources. The third chapter seeks to replicate the methods used in article 1 with the same participants but in another cognitive domain in order to establish the neural correlates of verbal fluency as well as to discriminate a verbal and an executive component. These two components were highlighted using a factorization with a purely executive test (Trail making test-condition 4) and another purely verbal one (vocabulary richness). In the fourth chapter, we replicate the method of article 1 with the same subjects, but on a verbal learning test. During verbal learning, two possible learning strategies (serial and semantic) are used concurrently, we sought to establish whether behavioural differences translate into different activation patterns. In the fifth chapter, we sought to establish functional differences between leukemia survivors and control subjects, then to search for a link between neurotoxicity and the cognitive deficit encountered in this population; finally we established a model integrating neurotoxicity, cognitive performance and functional neurophysiological brain markers. This research will have deepened the knowledge on the resting state and mainly provided the first works that link the spontaneous brain activity at rest at the level of cortical sources with several behavioural neuropsychological tests. The results led to different spatio-frequential activation patterns, showing specificities related to certain behavioural tests or information processing (serial or semantic). Finally, work on leukemia survivors has shown that resting states could characterize the functioning of long-term cognitive deficits and be a remediation marker for future treatments.

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