Child and adolescent mood and anxiety symptoms are common and debilitating, with long-term effects on well-being. Research presented in this thesis examines interpersonal cognitive factors in the emergence of anxious and depressive symptoms in late childhood through to early adulthood. The thesis considers this issue using three main approaches. For the first, data are presented showing that biases in the appraisals of social situations are the aspects of interpersonal cognition most closely associated with emotional symptoms. For the second, longitudinal twin data are used to examine genetic and environmental origins of these interpersonal cognitive biases and their temporal prediction of symptoms across a 2-year period. Data show that interpersonal cognitive factors are strongly influenced by non-shared environmental factors, and moreover, predict symptoms across time. The final section of the thesis comprises four studies using Cognitive Bias Modification of Interpretations (CBM-I) training methodology to show that both positive and negative interpretive biases for interpersonal information can be induced in adolescents. Positive biases are shown to persist for at least 24 hours after training, and induced positive and negative biases are shown to differentially predict anxious responses to an experimental stressor. Evidence is also provided to suggest that effects following training positive interpretive biases may transfer to other cognitive measures, namely appraisals of ambiguous emotional faces. Finally, data tentatively show that CBM-I training may be useful in reducing negative interpretations of interpersonal information made by 11-year-old children undergoing the transition to secondary school. In summary, studies in this thesis support the contribution of cognitive biases to mood and anxiety symptoms in childhood and adolescence. They further extend this knowledge by suggesting that these reflect individual-specific (non-shared) environmental risks to predict symptoms across time. These biases may also be amenable to change through training interventions, with some - albeit weak - effects on other cognitive outcomes.

La vasopressine (AVP) et la corticolibérine (CRF) agissent de manière synergique lors de la réponse aux stimuli stressants. Elles régulent de manière concertée la sécrétion d'adrénocorticotrophine hypophysaire et la libération de catécholamines surrénalienne. Dans ces deux structures, les isoformes de récepteurs présents sont les récepteurs V1B et CRF1. Nous avons démontré que deux mécanismes moléculaires sous-tendent la synergie fonctionnelle de l'AVP et du CRF : un croisement des voies de seconds messagers propres à chacun des récepteurs d'une part, et une modification de leurs propriétés pharmacologiques résultant de leur interaction (hétérodimérisation) d'autre part. Pour valider ce dernier mécanisme, nous avons recherché des formes naturelles ou mutées de récepteurs à l'AVP et au CRF conservant leurs propriétés de couplage aux protéines G, mais incapables d'hétérodimériser, et avons analysé les conséquences de cette rupture d'hétérodimérisation sur leur aptitude à agir en synergie. Grâce à une approche de mutagénèse dirigée, nous avons commencé à résoudre la question des portions de récepteurs engagées dans l'hétérodimérisation. Les résultats obtenus apportent les premières évidences permettant de comprendre la synergie AVP/CRF au niveau moléculaire, et particulièrement le rôle de l'hétérodimérisation. L'hétérodimère V1B/CRF1 pourrait être impliqué dans le stress et ses états pathologiques que sont l'anxiété et la dépression. Nous montrons que les récepteurs V1B et CRF1 sont co-exprimés dans les neurones de certaines structures cérébrales régulant ces phénomènes comportementaux. Démontrer l'existence de l'hétérodimère V1B/CRF1 dans des tissus natifs sera la prochaine étape de ce travail. Si elle est validée, le complexe V1B/CRF1 pourra être considéré comme une cible pharmacologique de première importance dans le traitement de l'anxiété et de la dépression. Travail soutenu par l'Institut de Recherches SERVIER et la Fondation pour la Recherche Médicale. / Vasopressin (AVP) and Corticotropin-Releasing Factor (CRF) are involved in the stress response, mainly by regulating ACTH secretion from the pituitary and by increasing catecholamine and corticosteroids secretion from the adrenal medulla. In these two structures, AVP and CRF have been shown to act in synergism via V1B and CRF1 receptors. Recently, our group demonstrated that such synergism operates via both second messenger crosstalk and putative mechanism involving receptors heterodimerization. To further validate this last original mechanism, we monitored the influence of receptor heterodimerization selectivity and of receptor heterodimerization disruption on functional synergism. We also deciphered receptor dimers interface by synthesizing receptor mutants that do not heterodimerize anymore.These results give clues to the comprehension of AVP/CRF synergism at the molecular level and trigger the potential role of receptors heterodimerization in stress-related behaviours. Indeed both V1B and CRF1 are also co-expressed in neurons of relevant brain area. Establishing the physical association of V1B/CRF1 as heterodimers in native tissue, the next step of our project, would be of considerable importance.Work supported by SERVIER (France) an d the FRM.

La migraine est un désordre neurovasculaire caractérisé par des crises récurrentes de céphalée accompagnées de troubles neurologiques variables dont l'allodynie cutanée.Chez un petit nombre de patients, la migraine passe du stade épisiodique au stade chronique, ou transformation migraineuse. Des études cliniques indiquent que la prévalence de troubles psychiatriques( anxiété/dépression) est plus élevé chez les migraineux chronique que chez le migraineux épisodique. Cependant des telles études ne permettent pas de déterminer le lien de causalité. Le but de ce travail est d'étudier le rôle de la répétition des crises de migraine sur l'apparition d'un état anxio-dépressif et ses mécanismes. Cette étude a été réalisée dans un modèle de migraine chez le rat : injections répétées de soupe inflammatoire (SI) au niveau des méninges.[...]Ces résultats suggèrent que l'apparition de troubles anxio-dépressifs chez le migraineux chronique est une conséquence directe de la répétition des crises. Cette anxiété résulte, entres autres, d'une sensiblisation du MeA impliquant les canaux ASICS1a. Ainsi élucider les mécanismes impliqués dans l'apparition de troubles anxio-dépressifs doit aider à comprendre la transformation migraineuse et améliorer son traitement. / Migraine is a common episode neurovascular disorder that manifest as reccurent attacks of severe headache together with variable neurological symptômes such as cutaneous allodyna. In subgroup of patients, attack frequency increases over time leading to chronic migraine. Clinical studies indicate that patients with episodic migraine are more likely to have anxiety symptoms than patients with episodic migraine..However, in cross-sectional studies, it is not possible to disentangle causal sequence. Our aim is to assess the role oh headache repetition on anxiety/depression symptoms. We use a rat model of migraine : stimulation of meningeal nociceptors by injecting an inflammatory soup (SI)[...]Such anxiety is due, at least in part, to MeA, sensitization involving ASIC1a channels. Dissecting out the mechanisms of the appearance of anxiety/depression symptoms following repeated migraine attacks in thus helping to understand migraine transformation and in turn to improve therapy.

Background: Compliance with CPAP treatment for OSA is not reliably predicted by the severity of symptoms or physiological variables. I conducted a series of studies to examine a range of factors that may affect compliance with CPAP. Methods: I performed a retrospective study examining association of demographic factors and OSA severity with long-term CPAP compliance. In a prospective study, I looked at the correlation of short and long-term CPAP compliance with socio-economic status, education, type D personality, demographics, disease severity, mood and clinician's prediction. I undertook a prospective, cross-over trial comparing the impact of Bi-level PAP therapy in individuals with low tolerance of CPAP. Results: In a retrospective analysis, an improvement in subjective daytime somnolence was correlated with optimal compliance. In the prospective study, median compliance with CPAP at 6 months was 5.6 (3.4- 7.1) hours/night with 73% of subjects using CPAP ≥ 4 hours/night. Compliance with CPAP was not found to be associated with socio-economic class for people in work, type D personality, education, sex, age, baseline sleepiness (ESS score) or disease severity (ODI). The clinician's initial impression had no predictive value for individual patients. Subjects who were long-term unemployed or reporting mood disorders (High Beck's Depression Index scores) were likely to have poor compliance and sub-optimal CPAP usage (OR 4.6, p = 0.011 and OR 1.4. p=0.04 respectively). Subjects experiencing side effects after the first night on treatment showed lower acceptance and subsequent compliance. In the cross-over trial, changing to Bi-level PAP in individuals with suboptimal compliance due to pressure related intolerance, did not lead to an improvement in CPAP compliance. In post-hoc analysis, compliance and comfort were better in the subgroup that complained of difficulty with exhalation on CPAP. Conclusion: My research as presented in this thesis, did not find an association between disease severity (ODI), socio-economic status (for people in employment), education or personality type and CPAP compliance. My research demonstrated that subjects with long-term unemployment, mood disorders and those experiencing side effects on the first night of treatment were likely to have sub-optimal compliance. Changing to Bi-level PAP is only likely to be useful for a sub-group of subjects experiencing pressure related intolerance. More research is needed to explore whether intensive support to individuals with OSA and long term unemployment, as well as mood disorders, may improve compliance.

Les troubles cognitifs constituent des symptômes quasi constants parmi les patients souffrant de dépression caractérisée. De récentes études indiquent que ces troubles mentaux pourraient bénéficier de la modulation de la signalisation du récepteur sérotoninergique 5-HT4. Dans ce travail de thèse, nous avons dans un premier temps caractérisé les troubles cognitifs dans un modèle d’anxiété/dépression chez la Souris, le modèle CORT. Nous avons ensuite évalué l’efficacité d’un traitement chronique par un agoniste du récepteur 5-HT4, le RS 67333, en comparaison à la fluoxetine, un antidépresseur monoaminergique de référence sur les altérations émotionnelles et cognitives. D’autre part, des données de la littérature indiquent que la cascade de signalisation de la protéine β-arrestine 1 (impliquée dans la désensibilisation et l’internalisation du récepteur 5-HT4) serait un biomarqueur potentiel préclinique/clinique des états dépressifs et de la réponse au traitement antidépresseur. Nous avons donc cherché à définir le phénotype anxio/dépressif et cognitif chez des souris tissus-spécifiques conditionnelles, dont l’expression de la protéine β-arrestine 1 dans les cellules souches du gyrus dentelé a été supprimée. L’ensemble de ces travaux de thèse met en avant le rôle prépondérant de l’activation du récepteur 5-HT4 non seulement dans sa capacité à corriger les symptômes d’anxiété/dépression mais aussi les troubles cognitifs associés à la dépression dans un modèle d’anxiété/dépression chez la Souris. D’un point de vue mécanistique, ces données confirment l’implication de la protéine β-arrestine 1 dans la réponse à la fluoxetine au niveau comportemental et directement au sein du processus de neurogenèse hippocampique chez la souris adulte. Enfin, l’expression de la protéine β-arrestine 1 dans les jeunes neurones de l’hippocampe se révèle aussi être un acteur déterminant dans les processus cognitifs et la réponse à la fluoxetine et au RS 67333. / Cognitive disturbances are often reported as serious incapacitating symptoms by patients suffering from major depressive disorders. Recent studies showed that these mood disorders could benefit from the modulation of 5-HT4 receptor pathway. Here, we performed a complete characterization of cognitive functions in a neuroendocrine mouse model of depression, the CORT model. We then evaluated emotional and cognitive effects of either a chronic 5-HT4 receptor agonist treatment, RS 67333 or fluoxetine, a classical monoaminergic antidepressant. Recent data indicate that β-arrestins proteins could be an important molecular determinant in depressive states and in the effects of antidepressants. We determined emotional and cognitive phenotypes in conditional tissue-specific mice in which expression of β-arrestin 1 in adult hippocampal stem cells was deleted. This work suggests that the 5-HT4 receptor plays a major role to correct not only anxiety/depression-related symptoms but also cognitive alterations in a mouse model of anxiety/depression model. Moreover, these data confirm the involvement of β-arrestin 1 protein in behavioral and neurogenic responses to fluoxetine treatment in adult mice. Finally, β-arrestin 1 protein expression in adult born neuron is critical for cognition and also to fluoxetine and RS 67333 response.

This thesis researches the efficacy of binaural beats for the treatment of chronic non-tumoral pain. The thesis is divided into theoretical and empirical part. The theoretical part discusses the impact of chronic pain on quality of life, psychological aspects of chronic pain and the changes in behaviour. The focus is on the treatment of chronic pain and its limitations. Binaural beats are presented as a new tool for treatment of chronic pain. The empirical part consists of the experiment focused on the effect of theta rhythm binaural beats on participants with chronic non-tumoral pain. The experiment was conducted at Klinika rehabilitace a tělovýchovného lékařství 2.LF UK a FNM. The sample size was 90 participants (N=90). Participants were divided into two groups- with intervention and without intervention. Participants with intervention listened binaural beats for 20 minutes, three times on average during their hospitalization. VAS, GAD- 7, BDI-II, TSK-CZ, Oswestry Disability Index and Emotion Thermometers methods were used. The first measurement took place before the hospitalization, the second before the intervention with binaural beats, then immediately after the intervention and at the end of hospitalization. The main aim of this study was to investigate the efficacy of binaural beats in...

Epidemiological data on a wide range of mental disorders from community studies conducted in European countries are presented to determine the availability and consistency of prevalence, disability and treatment findings for the EU. Using a stepwise multimethod approach, 27 eligible studies with quite variable designs and methods including over 150,000 subjects from 16 European countries were identified. Prevalence: On the basis of meta-analytic techniques as well as on reanalyses of selected data sets, it is estimated that about 27% (equals 82.7 million; 95% CI: 78.5–87.1) of the adult EU population, 18–65 of age, is or has been affected by at least one mental disorder in the past 12 months. Taking into account the considerable degree of comorbidity (about one third had more than one disorder), the most frequent disorders are anxiety disorders, depressive, somatoform and substance dependence disorders. When taking into account design, sampling and other methodological differences between studies, little evidence seems to exist for considerable cultural or country variation. Disability and treatment: despite very divergent and fairly crude assessment strategies, the available data consistently demonstrate (a) an association of all mental disorders with a considerable disability burden in terms of number of work days lost (WLD) and (b) generally low utilization and treatment rates. Only 26% of all cases had any consultation with professional health care services, a finding suggesting a considerable degree of unmet need. The paper highlights considerable future research needs for coordinated EU studies across all disorders and age groups. As prevalence estimates could not simply be equated with defined treatment needs, such studies should determine the degree of met and unmet needs for services by taking into account severity, disability and comorbidity. These needs are most pronounced for the new EU member states as well as more generally for adolescent and older populations.

Background: Symptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated. Methods: 238 RLS patients were assessed with a standardized diagnostic interview (Munich- Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18–65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types. Results: RLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1–10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7–7.1), and major depression (OR=2.6; 95% CI=1.5–4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls. Conclusions: The results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.

Background: In 1992, the ICD-10 introduced the concept of mixed anxiety–depression disorder (MAD). However, a study examining the stability of this ICD-10-diagnosis is lacking. Our objective was to examine the 12 month outcome of MAD in comparison to the outcome of depression, anxiety, and comorbid depression and anxiety. Methods: 85 MAD patients, 496 patients with major depression, 296 patients with anxiety disorders, and 306 comorbid patients were reassessed after 12 months. Rates of depression, anxiety, and MAD were compared using χ2-tests. Results: While depressive disorders and anxiety disorders showed relatively high stability, MAD Patients had no higher rates of MAD at follow-up than patients with depression, anxiety or both. Limitations: Detailed information regarding treatment and disorders during the follow-up interval was lacking. Prevalence rates of MAD in single centres were too small for contrasting centres. Conclusions: MAD cannot be seen as a stable diagnosis: Most of MAD patients remit; many of them shift to other diagnoses than depression or anxiety. The ICD-10 criteria have to be specified more exactly.

This thesis focuses on the psychological factors that play a role in the development and maintenance of chronic postsurgical pain in patients after cardiac surgery. The literature review deals with the mechanisms of chronic postsurgical pain, its risk factors, the process of the transformartion of acute pain into chronic pain, and the psychological management of chronic pain after surgery, specifically in the field of cardiosurgery. The thesis focuses in particular on patient-related factors in terms of anxiety or depression before or after the surgery, coping strategies, fear of pain, attachment styles, and how are these factors involved in the development nad maintenance of chronic pain. The empirical part consists of a research of quantitative design conducted at the Department of Cardiac Surgery of the 3rd Faculty of Medicine and FN KV in Prague, which monitors the development of pain in patients after cardiac surgery at the time of discharge, 3 months after the surgery and after 1 year after the surgery, and focuses on the assessment of preoperative and postoperative patient-related factors that contribute to the development and maintenance of chronic pain. The main aim of the research is to identify these psychological factors.