La technique Orthogonal Frequency Division Multiplexing (OFDM) a été adoptée par plusieurs systèmes de télécommunications et de diffusion pour sa robustesse, sa capacité à transmettre de hauts débits dans des canaux radiomobiles et pour son efficacité spectrale. Cependant, les signaux OFDM sont caractérisés par des fluctuations importantes, mesurées par le rapport de la puissance crête sur la puissance moyenne (Peak to Average Power Ratio – PAPR) du signal, qui génèrent des distorsions à la sortie de l’amplificateur non-linéaire de puissance (High Power Amplifier - HPA) et ne permettent pas de l’utiliser dans sa zone optimale afin de diminuer sa consommation énergétique. La deuxième génération de la norme Digital Video Broadcasting (DVB-T2) a notamment adopté la technique Tone Reservation (TR) de réduction du PAPR. Son principe consiste à créer un noyau, à partir d’un ensemble de sous-porteuses réservées, qui est ensuite ajouté d’une manière itérative au signal OFDM de façon à réduire les pics du signal et donc son PAPR. Dans la première partie de la thèse, différents algorithmes permettant d’améliorer les performances de cette solution TR DVT-T2 sont proposés. Un premier groupe de solutions, reposant sur la même définition du noyau, comprend : la technique Partial Oversampling and Fractional Shifted Kernels (POFSK) reposant sur un sur-échantillonnage partiel du signal, la technique Dynamic Threshold (DT) qui effectue un calcul dynamique du seuil de troncature et la technique Enhanced Peak Selection (EPS) qui améliore la sélection des pics à réduire. Le deuxième groupe de solutions comprend tout d’abord la technique Individual Carrier Multiple Peaks (ICMP) qui repose sur une nouvelle définition du noyau et utilise un calcul de phase différent permettant la réduction de plusieurs pics en même temps. La technique GICMP est une version optimisée de la technique ICMP qui, en parallélisant les opérations, permet de réduire le délai de traitement et le nombre total d’itérations. Les résultats de simulations et les mesures effectuées sur une plateforme de transmission réelle montrent que, par rapport à la version TR de DVB-T2, l’algorithme GICMP offrait notamment un gain de l’ordre de 2.5 dB en termes de Modulation Error Rate – MER ou permettait une réduction de 10 % de l’énergie consommée par l’amplificateur de puissance à performances identiques. [...] / Orthogonal Frequency Division Multiplexing (OFDM) has been adopted by many telecommunication and broadcasting systems for its robustness, high transmission rates, mobility and bandwidth efficiency. However, OFDM signals are characterized by high power fluctuations, measured by the Peak to Average Power Ratio (PAPR), which cause distortions at the output of the non-linear High Power Amplifier (HPA) and prevent the radio frequency designer to feed the signal at the optimal point of the HPA specifications in order to reduce the energy consumption. The second generation of Digital Video Broadcasting (DVB-T2) adopted two PAPR reduction techniques, one of them is Tone Reservation (TR). TR creates a Kernel from a reserved set of subcarriers. The kernel is then iteratively added to the OFDM signal in such a way to reduce its peaks thus reducing its PAPR. In the first part of the thesis, different algorithms offering better performances compared to the DVB-T2 TR solution are proposed. A first group of solutions introduces changes and enhancements to the TR algorithm adopted in DVB-T2 TR but keeps the same kernel definition. This group includes: the Partial Oversampling and Fractional Shifted Kernels (POFSK) technique which is based on a partial oversampling of the signal, the Dynamic Threshold (DT) technique which allows better algorithm convergence by dynamically computing the PAPR reduction threshold for every OFDM symbol, and the Enhanced Peak Selection (EPS) technique which provides additional PAPR reduction by choosing the appropriate signal peaks to reduce and the peaks to skip. The second group of solutions includes the Individual Carrier Multiple Peaks (ICMP) technique which is based on a special kernel definition that changes from one algorithm iteration to another and uses a different phase calculation approach that allows the reduction of multiple peaks at a time. GICMP is an optimized version of ICMP that allows the parallelization of iterations in such a way to reduce the processing delay and the number of algorithm iterations. The simulation results and real hardware platform measurements of the proposed algorithms showed that, compared to the DVB-T2 TR version, the GICMP algorithm allows a Modulation Error Rate – MER gain of up to 2.5 dB or a 10 % reduction in HPA consumed energy with the same performances.

Le travail de cette thèse s’inscrit dans le cadre du projet ANR SUSoSTRESS qui a pour objectif la compréhension des mécanismes moléculaireset génétiques sous-jacents à la variabilité individuelle de réponses de stress et a collecté des données longitudinales à plusieurs niveaux biologiquessur une population d’étude porcine (race Large White). La thèse est organisé en deux partie. La première partie s’articule autour de l’analyse de données cliniques et transcriptomiques collectées à plusieurs pas de temps avant et après application de deux types de stress : injection d’ACTH et de LPS. Dans cettepartie, on cherche à développer d’un modèle fonctionnel permettant de décrire et d’intégrer au mieux l’ensemble des sources de variation génétique du fonctionnement de l’axe corticotrope et plus généralement des réponses de stress dans notre population d’étude. Plus précisément, il s’agit d’élaborer un modèle (au sens biologique du terme) décrivant les différentes réponses biologiques de stress et l’influence des variations génétiques (simples et en interaction), dans le but de prédire les leviers les plus efficaces en fonction de l’objectif de sélection. Ce travail a mis en évidence une liste de 65 gènes différentiellement exprimé au cours des réponses au stress, dont un ensemble de 8 gènes liés au au cortisol (l’hormone principale du stress) par NR3C1, le récepteur aux glucocorticoides. Ces gènes sont des biomarqueurs potentiels pouvant être fournis aux éleveurs en tant que leviers de sélection permettant un meilleur équilibre entre amélioration des caractères de production et des caractères de robustesse. La deuxième partie de ce travail s’articule autour du développement d’un outil d’analyse statistiques adapté à l’intégration de données ’omiques longitudinalesavec une variable cible d’intérêt.Nous proposons la «multiway-SIR », qui étend la méthode dual-STATIS, une méthode d’analyse de données cubiques non supervisée, au cadre de la SIR, une méthode de régression semi-paramétrique pouvant être utilisée à des fins exploratoires. Cette méthode est appliquée sur les données cliniques de l’expérience d’ACTHet permet d’y explorer l’influence de la variabilité de la réponse du cortisol à une injection d’ACTH. / This PhD thesis is part of the SUSoSTRESS project. This ANR funded project aims at improving the knowledge about molecular and genetic mechanisms underlying inter-individual variability in stress responses. Longitudinal data were collected at several biological levels on a porcine population (Large White). This work is structured in 2 parts. The first part is built around clinical and transcriptomic longitudinal data analyses collected before and after 2 types of stress factors : ACTH and LPS injection. The aim of this contribution is to develop a functional model describing all sources of genetic variation in the HPA axis activity and in stress responses in our study population.More precisely, it aims at defining a model describing the different biological stress responses and the influence of genetic variations in order to identify the most efficient selection levers according to selection goals. This work allowed for the identification of 65 differentially expressed genes during stress responses. Among them, 8 genes were highly linked to cortisol (the main stress hormone) through NR3C1 (glucocorticoid receptor (GR)). These genes are potential biomarkers and can be communicated to breeders as selection levers for a better trade-off between production and robustness traits in farmanimals. The second part is built around the development of a statistical tool suited for the data integration of repeated omicmeasurements with a real target variable.We introduce the "multiway-SIR" approach which extends the dual-STATIS (an approach to study 3-way datasets) method to the SIR framework (a semi-parametric regression model that can be used in an exploratory way). This method is illustrated on clinical data from the ACTH experiment. It allows for the exploration of the link between clinical variable response over time and inter-individual variability in the cortisol response to an ACTH injection.

Depression occurs in about one third of patients with stroke and cardiac arrest. Hyperactivity of the stress system is the most commonly observed neuroendocrine change in major depressive disorder (MDD), which involves elevated levels in the cerebrospinal fluid of corticotropin-releasing hormone (CRH), a key stress neurohormone. Substantial evidence suggests that normalization of the stress system may be a requirement for successful treatment of MDD through region-specific changes in the mesocorticolimbic circuitry. Thus, alteration in the stress system may underlie the emotional and functional impairments observed following brain ischemic events. In addition, recent findings suggest that ischemic brain injury triggers a restorative process, creating a cerebral environment similar to that of early brain development, a period characterized by rapid neuronal growth and neuroplasticity, critical to optimize functional recovery of individuals post stroke. In particular brain-derived neurotrophic factor (BDNF), has been shown to play an important role in the pathophysiology of major depression and cerebral ischemia. However, whether CRH can mediate the expression of BDNF in the reparative process triggered by ischemic injury remains to be characterized. Therefore, the purpose of the current thesis is to characterize the effect of pharmacological blockade of CRH signaling at the onset of a global ischemic stroke, on emotional and cognitive behaviors, alteration in the neuroendocrine stress system, and markers of neuroplasticity including BDNF. To do this, an animal model of global cerebral ischemia with subsequent behavioral testing and postmortem brain analysis was used to determine underlying biochemical and behavioral changes modulated by CRH signaling following brain ischemia. This doctoral work will help elucidate the relationship between CRH and BDNF in the context of cerebral ischemia, and may provide insights for therapies targeting the stress system. These studies address considerations such as: the interplay between stress, neuroplasticity and emotionality, and whether global ischemia can affect mood via changes in the HPA axis response.

Endocrine Disrupting Chemicals (EDC) are exogenous agents that mimic endogenous hormone activity in the body. EDC exposure during the critical period of neonatal development can potentially cause life-long neurological, behavioural and physiological disease. This thesis focuses on the EDC Bisphenol A (BPA), a synthetic xenoestrogen widely prevalent in everyday materials that has significant environmental relevance given its ubiquitous presence in humans around the world. The central research question of my thesis is: Does perinatal exposure to BPA affect rat pup development? A rodent model was selected to study the effects of BPA on the adrenal component of the hypothalamic-pituitary-adrenal axis (HPA axis) stress pathway, which has not been extensively studied. Rat dams were divided into five groups (vehicle control (VEH), positive control diethylstilbestrol (DES), BPA 5, BPA 50 and BPA 500 μg/kg bw/day) and dosed daily throughout gestation and for four days of lactation. Rat pups were sacrificed at two time-points at the beginning and the end of the stress hyporesponsive period (SHRP), at postnatal day (PND) 5 and PND 15. Changes in three morphometric parameters (bodyweight, crown-rump (CR) length and anogenital distance (AGD) were assessed based on the factors of Treatment and Sex. Adrenal gland glucocorticoid receptor (GR) and 18SrRNA expression was determined by qPCR in male pups at PND 5 and PND 15. At PND 5, compared to the VEH group, the BPA 50 pups were significantly heavier (ANOVA, Dunnett’s post-hoc) and the DES and BPA 50 pups had significantly longer CR lengths (ANOVA, Dunnetts’ post-hoc). At PND 15, xenoestrogen treatment significantly influenced CR length (ANOVA). At both time-points, males had significantly longer AGD than females, as physiologically expected (ANOVA). Adrenal gland GR expression in male pups was not significantly affected by treatment, but there was an effect of treatment in18SrRNA gene expression at PND 5 (Kruskal-Wallis). Using the Ct method to determine GR and 18SrRNA fold changes, we cautiously suggest that our experimental doses resulted in a non-monotonic dose response to BPA in the PND 5 animals and a monotonic dose response to BPA exposure in the PND 15 animals. This study highly values the importance of investigating the effects of environmentally relevant, low dose BPA exposure during the critical window of development, given the little that is known about potentially permanent alterations to the stress pathway due to exposure during this delicate period of development.

Self-injurious behavior (SIB) is a complex phenotype that occurs with an increasing prevalence of about 7-34% in humans and 10-12% in non-human primates (NHPs). This study evaluated the efficacy of probiotic Lactobacillus reuteri as a treatment for self-injurious behavior (SIB) and sleep disruption in rhesus macaques. The treatment was proposed to alleviate mild self-biting, sleep disruption, and reduce chronically elevated hypothalamic-pituitary-adrenocortical (HPA) axis activity, all hallmark features of monkeys with this condition. The probiotic preparation included two strains of L. reuteri (L. reuteri ATCC PTA 6475 & L. reuteri DSM 17938) containing on average 200 million colony forming units per chewable tablet. The study was conducted on 14 rhesus macaque monkeys (9 males) housed at the University of Massachusetts Amherst. To our knowledge this is the first time that a Lactobacillus strain has been used as a treatment for SIB in rhesus macaques. This study utilizes motion-activated infrared camera technology, modified enzyme-immunosorbent-assays (EIAs) techniques to measure hair cortisol concentrations, and daily behavioral observations to provide an overall assessment of the behavioral, physiological, and sleep associated implications of probiotic treatment on SIB and control non-human primates (NHPs). Administration of L reuteri modestly decreased biting behavior in monkeys with SIB (F(2,12) = 5.64, p= 0.02) and showed overall decrease in nighttime activity across all subjects but did not normalize SIB to nonSIB values. Hair cortisol values are pending. These findings and the findings of previous work further strengthen the argument for probiotics as an efficacious treatment for SIB behavior.

[pt] A avaliação do aporte continental de hidrocarbonetos para a zona costeira pelos corpos hídricos é de grande importância para melhor compreensão das características regionais quanto à ocupação do solo e do impacto que a urbanização exerce sobre um estuário. As distribuições de hidrocarbonetos alifáticos (n-C12 a n-C40) e hidrocarbonetos policíclicos aromáticos (46 HPAs) foram investigadas no material particulado em suspensão (MPS) e sedimentos ao longo de onze meses em seis dos principais rios e dois canais da bacia da Baía de Guanabara. O ΣHPAs variou de 27,59 a 11.514 ng L-1 no MPS e de 14,60 a 64.961 ng g-1 para as amostras de sedimento. Foram determinadas a taxa de exportação média dos rios dos rios e canais, indo de 0,03 t ano-1 observada para o rio Suruí a 1,87 t ano-1 observada para o rio Iguaçu; a contribuição de HPAs para o sedimento parte norte da baía na e as principais fontes de hidrocarbonetos. Avaliações de tipologia e estatísticas permitiram demonstrar a proporção da contribuição de fontes petrogênicas e pirolíticas nas diferentes regiões e quantificar estas contribuições. A taxa de exportação de HPAs dos cinco principais rios ao norte da baía equivale a 3 t ano-1, representando 30 porcento do aporte total anual de HPAs nesta área da Baía de Guanabara. O estudo geocronológico mostra a evolução histórica do aporte de HPAs apontando para a transição da predominância das fontes de combustão no passado para fontes petrogênicas nos anos recente e mostrou que dentre os NHPAs avaliados, apenas os compostos 2-nitrofluoranteno, 3-nitrofluoranteno e 7-nitrobenzo(a)antraceno foram observados na região noroeste enquanto 2-nitronaftaleno, 5-nitroacenafteno e 2-nitrofluoreno foram observados ao sul da baía, sugerindo a deposição preferencial de subprodutos de reações atmosféricas. Pela primeira vez foi estimada a massa de HPAs depositada ao longo do tempo no sedimento da Baía de Guanabara e realizado o estudo de NHPAs servindo como base para estudos futuros. / [en] The evaluation of the hydrocarbons continental input by end members is of great importance for a better understanding the regional characteristics in terms of land use and the impact that urbanization has on an estuary. Aliphatic (n-C12 to n-C40) and polycyclic aromatic hydrocarbons (46 PAH) were investigated in suspended particulate matter (SPM) and sediments for eleven months in six major rivers and two canals in the basin of Guanabara Bay. The ΣPAH ranged 27.59 to 11,514 ng L-1 for SPM and of 14.60 to 64,961 ng g-1 for the sediment samples. PAH flow rates of the most contaminated rivers and channels ranging of 0,03 t year-1 for Suruí river to 1,87 t year-1 to Iguaçu river; the contribution to the PAH sediment load of the receiving bay, and the main sources of hydrocarbons were determined. Typology and statistical evaluation demonstrated contribution of distinct sources in different regions and allowed quantification of these contributions. Total flow rate for the five major rivers to the bay north amounts to 3 tons year-1 and responds for 30 percent of the total PAH annual input into the northern area of the Guanabara Bay. Geochronological study shows the historical evolution of the PAH contribution pointing to the transition from the predominance of combustion sources in the past to petrogenic sources in recent years and showed that among the nitrated polycyclic aromatic hydrocarbons (NPAHs) evaluated only, 2-nitrofluoranthene, 3-nitrofluoranthene and 7-nitrobenzo(a)anthracene compounds were observed in the region NW while 2-nitronaphthalene, 5-nitroacenaphthene and 2-fluoranthene were observed south of the bay, suggesting preferential deposition of atmospheric reactions byproducts. For the first time PAH mass deposited in the bay sediments has been estimated and conducted the study about NPAHs shall serve as base for future studies.

[pt] As emissões de combustíveis fósseis derivados do petróleo têm um impacto significativo no meio ambiente, nas mudanças climáticas, na poluição do ar e outros. Por isso, existe um grande interesse por fontes alternativas de energia, principalmente aquelas que podem reduzir as emissões de poluentes atmosféricos. Este trabalho teve por objetivo avaliar os perfis das concentrações de poluentes regulamentados (material particulado e CO2) e não regulamentados (benzeno, tolueno, etilbenzeno, xilenos, HPA, hidrocarbonetos alifáticos, aldeídos e metais) originados da queima de diferentes combustíveis em um motor estacionário do ciclo diesel e verificar os possíveis efeitos toxicológicos utilizando células epiteliais brônquica. Os combustíveis utilizados foram: mistura binária diesel com 5 por cento de biodiesel (B5), biodiesel de soja (B100), biodiesel de soja aditivado (B100 adt) e etanol aditivado. Para obter uma maior confiabilidade dos resultados realizou-se a verificação do método para a determinação de monoaromáticos e aldeídos por meio de cromatografia gasosa com detector de ionização de chama (CG-DIC) e cromatografia líquida de alta eficiência (CLAE), respectivamente. O MP foi determinado por gravimetria, Os HPA associados ao MP foram determinados por cromatografia gasosa acoplada a espectrometria de massa (CG-EM), hidrocarbonetos alifáticos (HA) por CG-DIC e metais foram analisados por espectrometria de massa com plasma indutivamente acoplado (ICP-MS). Os perfis das concentrações foram avaliados considerando: o tempo de queima de combustível (15, 30 e 60 min) e, o tempo de armazenamento (7, 14 e 21 dias) a 40 graus Celsius, para avaliar os processos oxidativos que podem ocorrer durante o armazenamento, especialmente no caso do biodiesel. A operação do motor quando ele ainda está frio, por exemplo, em 15 minutos, apresentou maior emissão de MP, benzeno e etilbenzeno para o biodiesel de soja (B100) em comparação com a mistura de diesel com 5 por cento de biodiesel (B5). O estudo dos perfis das concentrações dos compostos mono aromáticos, hidrocarbonetos alifáticos e hidrocarbonetos policíclicos aromáticos (HPA) mostraram resultados semelhantes aos descritos na literatura, em que o combustível B5 emiti mais poluentes do que o biodiesel. No entanto, comparando alguns poluentes individualmente, as emissões de benzeno e etilbenzeno foram maiores para B100 e B100 adt. O B5 apresentou o maior perfil de concentração para a soma HPA na fase gasosa do que na forma particulada em períodos de funcionamento do motor mais longos. O tempo de armazenamento reduziu as emissões de MP em 40 por cento para B100, 20 por cento para B100 adt e 3 por cento para B5. Em relação à concentração de compostos aromáticos, a redução foi de aproximadamente 60 por cento desses poluentes para B100 e B100 adt. A menor emissão de poluentes foi durante a queima do etanol aditivado. / [en] The emissions of fossil fuels derived from oil have a significant impact on the environment, climate change, air pollution, and others. Therefore, there is great interest in alternative energy sources, especially those that can reduce emissions of air pollutants. The aim of this study was the evaluation of concentration profiles of criteria pollutants, particulate matter (PM) and CO2 and unregulated pollutants (i.e., benzene, toluene, ethylbenzene, xylenes, polycyclic aromatic hydrocarbons (PAH), aliphatic hydrocarbons, aldehyde and metals) originated from burning of different fuels: The evaluated fuels were the binary mixture of fossil diesel with 5 percent biodiesel (B5), biodiesel soybean (B100), additivated biodiesel soybean (B100 adt) and additivated ethanol using a stationary diesel engine cycle, operating at the speed of 1800 rpm and 0 percent load. For a larger reliability of results, the method validation for determination the monoaromatic and aldehydes by gas chromatography flame ionization detection (GC-FID) and high-performance liquid chromatography (HPLC), respectively. PM mass was determinate by gravimetry, PAH associated to the PM were determined by gas chromatography coupled to mass spectrometry (GC-MS), aliphatic hydrocarbons were determined by GC-FID, and metals were determined by inductively coupled plasma mass spectrometry (ICP-MS). The concentration profiles were evaluated considering: 1) burning time (15, 30, and 60 minutes) and; 2) storage time (7, 14, and 21 days) at 40 Celsius Degrees to evaluate the oxidative processes that occur during storage, especially for biodiesel. When it is still cold (i.e., 15 minutes), the operation of the engine showed negative effect on particulate matter (PM), benzene, and ethylbenzene emissions for B100 compared to B5. In this study, the concentration profiles of the monoaromatic, aliphatic hydrocarbons, and PAH showed similar results to those reported in the literature, where B5 fuel emits more pollutants than pure biodiesel. However, comparing some pollutants individually, the benzene and ethylbenzene emissions were higher for B100 and B100 adt. For long engine operation periods, B5 showed the highest concentration profile for the PAH sum in the gaseous in comparison to PAH sum in the particulate phase. The storage time reduced the PM emissions in 40 percent (B100), 20 percent (B100 adt), and 3 percent (B5). Regarding the concentration of aromatics, the reduction was circa 60 percent for B100 and B100 adt. The lowest emission of pollutants was observed for additived ethanol burning.

Posttraumatic stress disorder (PTSD) is a trauma-related disorder that may develop in response to traumatic or stressful events. Dysfunction of the Hypothalamic-Pituitary-Adrenal (HPA) axis has been implicated in the disorder. Studies support such dysfunction as being a consequence of PTSD, rather than a precursor. However, most studies of the HPA are either cross-sectional or have been carried out in adults. The aim of the present study was to identify whether HPA dysregulation interacts with stressful experiences to increase the likelihood of developing PTSD symptoms in a community-recruited sample of healthy adolescent girls. Adolescent girls (N = 550) and one of their parents participated. Adolescents’ clinical symptoms were assessed at baseline and at a nine month follow-up. Saliva samples were collected from all adolescent participants at waking, 30 minutes after waking, and 8 pm on 3 consecutive days. Flattened diurnal slope of cortisol at baseline was associated with increased PTSD symptoms nine months later. Baseline cortisol awakening response (CAR) per se was not prospectively related to developing PTSD symptoms, but its interactions with stressful experience was associated with elevated PTSD symptoms at follow-up. Effects were small and need to be replicated in samples with more severe stressors, as well as more clinical levels of PTSD. Nevertheless, findings suggest that dysregulated basal HPA functioning may be involved in the development of PTSD symptoms.

BACKGROUND: The neurotransmitter noradrenaline (NA) mediates arousal, attention and mood and exerts anti-inflammatory and neuroprotective effects. Its projections reach hypothalamic nuclei which regulate the neuroendocrine stress response. Changes in noradrenergic signalling were reported in multiple sclerosis (MS) and psychiatric illness and may account for the high prevalence of comorbid depression and fatigue in MS patients. Associated studies of our study group—investigating stress response in obese and non-obese subjects—have shown increased activity of the stress axes including an association between hypothalamic-pituitary-adrenal (HPA) axis responsiveness and central noradrenaline transporter. OBJECTIVES: (i) To evaluate central NA transporter (NAT) availability in vivo in immunotherapy-naïve relapsing-remitting multiple sclerosis (RRMS) patients compared to healthy controls (HC), (ii) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and the arginine-vasopressin surrogate (AVP) copeptin in patients with RRMS and clinically isolated syndrome (CIS) compared to HC, (iii) to test whether HPA axis responsiveness is differentially associated to NAT availability in RRMS patients and HC. METHODS: 22 patients (11 RRMS, 11 CIS) were enrolled and compared to 22 sex- and age-matched HC. (i) Positron emission tomography (PET) was performed in 11 RRMS and 12 HC applying the NAT-selective radiotracer S,S-[11C]O-methylreboxetine ([11C]MRB) for intergroup comparison. (ii) All patients underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters, and copeptin after dexamethasone intake were derived. (iii) MRB-PET imaging data were correlated to curve indicators and copeptin obtained from the dex/CRH test in RRMS patients. RESULTS: (i) RRMS patients show increased NAT availability in almost all subcortical regions, reaching statistical significance in the thalamus, amygdala, putamen and pons/midbrain. No association with clinical or psychometric variables was found. (ii) Immunotherapy-naïve RRMS patients show no significant changes in cortisol, ACTH or copeptin indices. (iii) There is no correlation between HPA axis indicators and NAT availability in RRMS patients. In HC, NAT availability correlated positively with cortisol curve indicators. CONCLUSION: This study supports the evidence for increased NAT availability in immunotherapy-naïve RRMS patients compared to HC. The increased NAT availability was shown in the subcortical brain regions (relevant to attention and emotional regulation) of the RRMS patients. In this cohort, no correlation with physical or psychometric scores was found. It will be further of interest, if these NAT changes longitudinally predispose to the psychiatric comorbidities which are frequently seen in MS patients or if they do in larger, more heterogenous sample sizes. Our cohort of early RRMS and CIS did not display a statistically significant alteration in the HPA axis responsiveness compared to HC. No association between NAT availability and HPA axis responsiveness could be detected in RRMS patients.:TABLE OF CONTENTS LIST OF ABBREVIATIONS…………………….………………………………………......4 LIST OF FIGURES…..….………………………….….……..…………………………..…5 I BIBLIOGRAPHIC DESCRIPTION…………………………..……………………………6 II INTRODUCTION…..…..………………………………………………………….............7 2.1 Multiple sclerosis — Background and scope……………....…………………..........7 2.1.1 Diagnostic criteria, subtypes and clinical features……….............….…………....7 2.1.2 Multiple sclerosis and its impact on daily life: fatigue.…...…...….............………9 2.2. Noradrenaline — neurotransmitter and immunomodulator…...…………….........10 2.2.1 Noradrenaline in the context of multiple sclerosis…………………….................11 2.2.2 Noradrenaline in the context of neuroinflammation and neurogenesis.............12 2.3 Noradrenaline transporter as regulator of noradrenergic transmission….…........13 2.3.1 Noradrenaline transporter imaging……………………………............................14 2.4 Neuroendocrine stress response……...…..……………………..……..……….......14 2.4.1 Noradrenaline in the context of stress response regulation…...........................15 2.4.2 Stress axis regulation in multiple sclerosis……….............……….....................16 III METHODS……………......……………………………………………………..……....19 3.1 Objectives and hypotheses.....……..…………………………………………….......19 3.2 Study design………………..….....………………………………….…..…………….20 3.3 Hypothalamic-pituitary-adrenal axis assessment using the combined dexamethasone/CRH test…….……...........……….....................................................21 3.4 Questionnaires……...…………………….....…………………………………………22 3.4.1 Beck-Depression-Inventory……………….............……….………………………22 3.4.2 Würzburger Erschöpfungsinventar bei MS….…………..….............……………22 3.5 PET imaging, imaging data processing and analysis………………….....………..23 3.6 Statistical analysis………………….………………………………………….....……23 IV RESULTS………….......……………………………………………….........................24 4.1 Changes of central noradrenaline transporter availability in immunotherapy-naïve multiple sclerosis patients – Publication….....……...…………24 4.2 HPA axis responsiveness does not differ between HC and RRMS or CIS patients…...………………………………...……………………………………….25 4.3 In RRMS patients, noradrenaline transporter availability of selected brain regions does not correlate with neuroendocrine indicators of stress responsiveness, but do positively correlate in healthy controls………………..….…..25 V SUMMARY………………….…………………………………………………………….31 5.1 Significantly changed noradrenaline transporter availability in RRMS patients in brain regions relevant to attention, vigilance and mood………….............31 5.2 Noradrenaline transporter availability is not significantly associated with psychometric and physical scores……..…………………...........................................32 5.3 HPA responsiveness does not significantly differ between early-stage RRMS patients, CIS patients and healthy controls………..…………………..............32 5.4 NAT DVR of selected brain regions do not reveal a significant association to HPA response in RRMS patients, but in healthy controls………...……..................33 5.5 Limitations..………………………………………………………………………….....35 5.6 Future directions…………………………………………………………………….....35 VI PUBLICATION BIBLIOGRAPHY…….……………………....…………….................36 VII ANHANG…….………..…...…..………..………………………………………………49 7.1 Publikationen…………..……….....…..……………………………………................49 7.1.1 Publikationen als Ko-Autorin…...…………..………..............…………………….50 7.1.1.1 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls……..50 7.1.1.2 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity...............................................................................51 7.2 Erklärung zum wissenschaftlichen Beitrag der Promovendin zur Publikationspromotion…………...........………………………………………………52 7.3 Erklärung über die eigenständige Abfassung der Arbeit...…....…………...…......53

The present thesis examines evidence for the self-relaxation assumption of Personality-Systems-Interactions (PSI) theory, i.e. the involvement of the self-system in the intuitive downregulation of negative affect. Chapter 1 introduces PSI a self-regulation theory that explains personality and behavior according to the dynamic interplay of neuropsychological systems. Chapter 2 provides an evaluation of the Implicit Positive and Negative Affect Test (IPANAT) that indirectly assesses affect via judgments about the phonetic resemblance between artificial pseudo-words and mood adjectives. The test shows remarkable reliability for each scale as well as good factorial, construct and criterion-based validity. Chapter 3 presents an experiment that investigates the extent to which self-activation (experimental presentation of self-referential terms such as my bed, my body, etc.) after stress exposure affects negative and positive affect as measured by both the IPANAT and an explicit affect scale. As compared to neutral terms (the bed, the body, etc.) in the control group, self-referential terms led to a decrease in negative affect and an increase in positive affect according to the IPANAT but not according to the explicit measure. The results are discussed with respect to the intuitive nature of self-relaxation. Chapter 4 includes a study that examines the relationships between inter-individual differences in self-functioning (adult attachment security, self-determination, self-esteem) and the cortisol response to an acute stressor and awakening in the morning. Self-functioning in terms of attachment security was negatively related to the acute stress cortisol response and, along with self-determination and self-esteem, positively related to the awakening cortisol response. A hypothesized link between the hippocampus, which has been shown to be especially important for cortisol regulation and the retrieval of episodic memory, and the self-system is discussed.