La prise illicite de drogues opiacées est un problème majeur de santé publique dans le monde. L’apparition du syndrome de sevrage aux opiacés (SAO) suite à l’arrêt de prise d’opiacés est considérée comme élément clef dans la vulnérabilité associée à la rechute de prise d’opiacés. En effet le syndrome de SAO est caractérisé par des altérations comportementales et neurobiologiques en réponse au stress qui sont déterminantes dans le phénomène de dépendance aux opiacés. Le système corticotropin-releasing factor (CRF) est un coordinateur central des circuits de réponse au stress par l’intermédiaire de ses deux récepteurs le: CRF1 et CRF2. L’objectif de cette thèse est de déterminer le rôle du récepteur CRF2 dans l’apparition des états affectifs négatifs et des désordres motivationnels impliqués dans la rechute de la consommation de drogues opioïdes lors du SAO.Nous avons démontré par une série d’expériences conduite chez des souris invalidées au récepteur CRF2 (CRF2-/-), que la délétion génétique du récepteur CRF2-/- éliminait les états dysphoriques ainsi que les altérations moléculaires induites par le SAO sans détériorer les réponses neuroendocriniennes qui sont primordiales lors des adaptations aux stress associées au sevrage. De surcroît, nous avons trouvé que les souris CRF2-/- entrainées dans une procédure de tâche opérante dirigée vers l’obtention d’une nourriture palatable, montraient une diminution des troubles motivationnels induits par le SAO. Plusieurs rapports montrent que chez l’Homme, les évènements stressants apparaissant lors d’une période de sevrage provoquent une rechute de la consommation d’alcool ou de drogues. Nous avons développé un modèle murin qui montrait un rétablissement de recherche de nourriture palatable suite à une procédure de stress appliquée pendant une période de SAO. Par ailleurs, nous avons observé un dimorphisme sexuel du rôle du récepteur CRF2 dans le rétablissement de recherche de nourriture palatable, suite au stress, longtemps après un SAO.Les résultats de ce travail de thèse nous permettent de mettre en avant le récepteur CRF2 comme possible cible thérapeutique dans le traitement de la dépendance aux opiacés. / Opiate illicit use represents one of the most severe sanitary problems throughout the world. Among humans, the emergence of the opiate withdrawal (OW) syndrome after cessation of opiate intake is considered as one of the key motivational elements that lead to the vulnerability to opiates relapse. Therefore, the OW is characterized by a various alterations of the behavioral and neurobiological homeostasis responses to stress which are determinants in opiate dependence. The Corticotropin-releasing factor (CRF) system is the major coordinator of stress-responsive circuitry. Through its two receptors CRF1 and CRF2, the CRF system has recently emerged as major contributor in the development of components of the OW syndrome. The aim of this thesis is to determine the role of CRF2 receptor in the negative affective states and motivational disorders implicated in opiate relapse during OW.Behavioral and biological experiments were conducted in CRF2 receptor-deficient mice (CRF2-/-). We reported that genetic deletion of the CRF2 receptor eliminates dysphoria and molecular alterations elicited by OW without impairing brain, neuroendocrine and autonomic stress-coping responses to withdrawal. Using behavioral approaches of operant responding to highly palatable food (HPF) we found that CRF2-/- reduces motivational disorders induced by intermittent morphine injections and withdrawal. Finally, we described a mouse model of stress-induced food reinstatement seeking behavior during prolonged OW. Furthermore, we reported a gender dimorphism in the role of the CRF2 receptor in the stress-induced reinstatement of HPF seeking behavior long-lasing after opiate treatment.These findings underscore the importance of CRF2 receptor as possible effective treatment of the critical problem of opiate dependence.

Background: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. Methods: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. Results: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. Conclusion: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRVbiofeedback for alcohol dependence in addition to rehabilitation. Trial registration: The original randomized controlled trial was registered in the German Clinical Trials Register (DRKS00004618). This one-year follow-up survey has not been registered.

Cette thèse est composée de deux parties. Dans la première partie, nous proposons une théorie pour l'interaction entre l'apprentissage par renforcement et les processus de régulation homéostatique. En fait, la régulation efficace de l'homéostasie interne et la défendre contre les perturbations a besoin des stratégies comportementales complexes pour obtenir des ressources physiologiquement épuisés. À cet égard, il est essentiel que les processus cérébraux de régulation homéostatique et les processus d'apprentissage associatifs travaillent de concert. Nous proposons une théorie computationnelle normative pour régulation homéostatique par l'apprentissage associatif, où la stabilité physiologique et l'acquisition de récompense s'avèrent les mêmes objectifs, réalisables simultanément. En théorie, le cadre résout la question de longue date de la façon dont le comportement manifeste est modulée par l'état interne, et comment les animaux apprennent à agir de manière prédictive pour empêcher des défis homéostasie potentiels (répondre par anticipation). Il fournit en outre une explication normative pour choix intertemporel, aversion au risque, la concurrence entre les systèmes de motivation, et le manque de motivation pour l'injection intraveineuse de produits alimentaires. Neurobiologiquement, la théorie suggère une explication pour le rôle de l'interaction par orexine entre les circuits hypothalamiques et les noyaux dopaminergiques du mésencéphale, comme une interface entre les états internes et les comportements motivés. Dans la deuxième partie de la thèse, nous utilisons le modèle présenté dans la première partie, comme base du développement d'une théorie de la dépendance à la cocaïne. Nous soutenons que la dépendance à la cocaïne provient du système de régulation homéostatique être détourné par les effets pharmacologiques de la cocaïne sur le cerveau. Nous démontrons que le modèle réussit à expliquer une variété des aspects comportementaux et neurobiologiques de la dépendance à la cocaïne , à savoir la grandissant de l’administration de cocaine sous les conditions de long accès a cocaïne, fonction dose-réponse pour la cocaïne , rechute à l'addiction à la cocaïne provoquée par amorçage, et l'interaction entre la disponibilité du récepteur de la dopamine D2 et dépendance à la cocaïne. / This thesis is composed of two parts. In the first part, we propose a theory for interaction between reinforcement learning and homeostatic regulation processes. In fact, efficient regulation of internal homeostasis and defending it against perturbations requires complex behavioral strategies to obtain physiologically-depleted resources. In this respect, it is essential that brains homeostatic regulation and associative learning processes work in concert. We propose a normative computational theory for homeostatically-regulated reinforcement learning (HRL), where physiological stability and reward acquisition prove to be identical objectives achievable simultaneously. Theoretically, the framework resolves the long-standing question of how overt behavior is modulated by internal state, and how animals learn to predictively act to preclude prospective homeostatic challenges (anticipatory responding). It further provides a normative explanation for temporal discounting of reward, and accounts for risk-aversive behavior, competition between motivational systems, taste-induced overeating, and lack of motivation for intravenous injection of food. Neurobiologically, the theory suggests a computational explanation for the role of orexin-based interaction between the hypothalamic circuitry and the midbrain dopaminergic nuclei, as an interface between internal states and motivated behaviors. In the second part of the thesis, we use the HRL model presented in the first part, as the cornerstone for developing an Allostatic Reinforcement Learning (ARL) theory of cocaine addiction. We argue that cocaine addiction arises from the HRL system being hijacked by the pharmacological effects of cocaine on the brain. We demonstrate that the model can successfully capture a wide range of behavioral and neurobiological aspects of cocaine addiction, namely escalation of cocaine self-administration under long- but not short-access conditions, U-shaped dose-response function for cocaine, priming-induced reinstatement of cocaine seeking, and interaction between dopamine D2 receptor availability and cocaine seeking.

Background: A randomized controlled study (RCT) recently showed that short-term heart rate variability (HRV) biofeedback in addition to standard rehabilitation care for alcohol dependence can reduce craving, anxiety and improve cardiovascular autonomic function. In this one-year follow-up study we aimed to explore whether completion of 2-week HRV-Biofeedback training is associated with long-term abstinence. Furthermore, we sought to identify potential predictors of post-treatment abstinence. Methods: We conducted a survey on abstinence in patients with alcohol dependence 1 year after completion of an RCT comparing HRV-biofeedback in addition to inpatient rehabilitation treatment alone (controls). Abstinence rates were compared and analysed for association with demographic data as well as psychometric and autonomic cardiac assessment before and after completion of the biofeedback training using bivariate and multivariate regression analyses. Results: Out of 48 patients who participated in the RCT, 27 patients (9 females, ages 42.9 ± 8.6, mean ± SD) completed our one-year follow-up. When including in the analysis only patients who completed follow-up, the rate of abstinence tended to be higher in patients who underwent HRV-biofeedback 1 year earlier compared to those who received rehabilitative treatment alone (66.7% vs 50%, p = ns). This non-significant trend was also observed in the intention-to-treat analysis where patients who did not participate in the follow-up were assumed to have relapsed (46,7% biofeedback vs. 33.3% controls, p = ns). Neither cardiac autonomic function nor psychometric variables were associated with abstinence 1 year after HRV-biofeedback. Conclusion: Our follow-up study provide a first indication of possible increase in long-term abstinence after HRVbiofeedback for alcohol dependence in addition to rehabilitation. Trial registration: The original randomized controlled trial was registered in the German Clinical Trials Register (DRKS00004618). This one-year follow-up survey has not been registered.

Background: Lithium augmentation is a first-line strategy for depressed patients resistant to antidepressive therapy, but little is known about patients’ subsequent long-term course or outcome predictors. We investigated long-term outcomes of unipolar depressed patients who had participated in a study on the effects of lithium augmentation on the hypothalamic-pituitary-adrenocortical system using the combined dexamethasone/corticotrophin-releasing hormone (DEX/CRH) test. Methods: Twelve to 28 months (mean 18.6 ± 4.6 months) after lithium augmentation, 23 patients were assessed with a standardized interview, of which 18 patients had complete DEX/CRH test results. Relapse was diagnosed by DSM-IV criteria (Structured Clinical Interview for DSM-IV; SCID I). Results: Only 11 patients (48%) had a favorable follow-up, defined as absence of major depressive episodes during the observation period. Patients with a favorable and an unfavorable course did not differ in clinical or sociodemographic parameters, endocrinological results or continuation of lithium. However, fewer previous depressive episodes tended to correlate (p = 0.09) with a favorable course. Conclusion: Results from studies using the DEX/CRH test to predict relapse in depressed patients treated with antidepressants were not replicated for lithium augmentation. Our finding could reflect the elevation of DEX/CRH results by lithium, independent of clinical course. Limitations of the study are its small sample size, the heterogeneous clinical baseline conditions and the lack of lithium serum levels. The fact that lithium continuation did not predict the course might be related to the difference between the efficacy of lithium in controlled studies and its effectiveness in naturalistic settings. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

The objective was to examine duloxetine 60–120mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (≥50% reduction in Hamilton Anxiety Rating Scale total score to ≤11 and “much”/“very much improved” ratings for the last 2 visits of open-label phase) were randomly assigned to receive duloxetine or placebo for a 26-week double-blind continuation phase. Relapse was defined as ≥2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P≤0.001) and worsened on each outcome measure (P≤0.001, all comparisons). Duloxetine 60–120 mg/day treatment was efficacious and reduced risk of relapse in patients with GAD.

No description available.

Im Rahmen dieser Dissertation wurde retrospektiv die Minimale Resterkrankung von Patienten mit akuter myeloischer Leukämie und Myelodysplastischen Syndrom nach allogener Stammzelltransplantation mit minimaler Konditionierung untersucht. Hierfür wurden vier unterschiedliche Methoden zur Detektion der Minimalen Resterkrankung analysiert. Nach Etablierung einer quantitativen Real-Time PCR für das Wilms Tumor Gen 1 (WT1) im peripheren Blut wurden diese Ergebnisse mit bereits routinemäßig erhobenen Daten des Chimärismus im Gesamtknochenmark und in CD34+ Zellen sowie der Fluoreszenz-in-situ-Hybridisierung (FISH) krankheitsspezifischer chromosomaler Aberrationen von insgesamt 88 Patienten verglichen und statistisch ausgewertet. Es konnte gezeigt werden, dass die Genexpressionanalysen des WT1 sowie die Chimärismusanalysen ein Rezidiv im Gegensatz zu den FISH Analysen vier Wochen im Voraus detektieren können. In Reiceiver Operating Curve Analysen wurden eine WT1 Expression von > 24 WT1/10.000 ABL1 Kopien und der Abfall des CD34+ Spenderchimärismus von ≥ 5% als diagnostisch stärkste Methoden identifiziert. In uni- und multivariaten Analysen von insgesamt 20 Parametern wurden die beiden Methoden als unabhängige Variablen für ein frühes Rezidiv, progressionsfreies Überleben und Gesamtüberleben bestätigt. Kombiniert man beide Methoden, so kann bei jeweiligem negativen Testergebnis ein Rezidiv innerhalb der nächsten vier Wochen nahezu ausgeschlossen werden.

Fixed retainer after orthodontic treatment is an increasing retention appliance. For the mandibular incisors there are two different fixed retainers that are commonly used, either a canine-to-canine retainer bonded only to the canines or a twistflex retainer bonded to each of the mandibular incisors and canines. Increased mandibular incisor irregularity seems to be a continuous process throughout life even in untreated patients. The natural physiological changes during aging causes changes like those that occur after orthodontic treatment and the removal of retainers. There are few long-term studies that have compared patients who have had a mandibular fixed retainer with patients without retention appliance after treatment, and then compared the treated patients with untreated subjects.The overall aim of this thesis was to compare and evaluate two different mandibular fixed retainers and also to compare orthodontically treated cases with untreated long-term. This thesis is based on two studies and a PAR Index evaluation was presented in the frame story:Paper I is a retrospective longitudinal study done on dental casts and lateral head radiographs from patients who had received either a canine-to-canine retainer or a twistflex retainer after treatment. Different variables were measured, were Little’s Irregularity Index was the main outcome measure. The measurements were done at four different occasions, were the last registration was 12 years after treatment, i.e. 9 years after removal of retainer. Paper II is also a retrospective longitudinal study with three different groups, one group received a fixed mandibular retainer, one group did not receive any retention appliance after treatment and the third group was untreated subjects. Measurements were done on dental casts and lateral head radiographs at four different occasions to analyze dental and skeletal changes 12 years after treatment. Also here Little’s Irregularity Index was the main outcome measure. PAR Index evaluation is done to evaluate the stability of orthodontic treatment outcome after treatment and long-term for two different retainer groups and one non-retention group. The following conclusions were drawn: Paper I•Both the canine-to-canine retainer and the twistflex retainer can be recommended since both are equally effective during retention period.•None of the retention types prevent long-term changes of mandibular incisor irregularity or available space for the mandibular incisors after removal of the retainers.•No differences in bonding failures between the two retainers were found. Paper II•There were no differences found 12 years after treatment in Little’s Irregularity Index for the mandibular incisors between the group that had a retainer and the group that had no retainer after treatment•In the untreated group, Little’s Irregularity Index was increased over time but not to the same extent as in the treated groups. •The crowding before treatment did not explain the crowding at the last registration.•The use of mandibular retainers for two to three years does not appear to prevent long-term relapse. •If the patient wants to constrain the changes that come with natural development, then lifelong retention is needed.•The overjet and overbite were stable long-term.PAR Index evaluation•Twelve years after treatment the mean reduction in PAR score was over 70 per cent only for the groups who had a mandibular retainer after treatment. However, the non-retention group had a PAR score of 66 per cent.•There were more cases in the retention groups that were ”greatly improved and/or improved” 12 years after treatment compared to the non-retention group. After treatment between 16 and 23.3 per cent of all the cases were ”worse or not improved”. Twelve years after treatment between 36 and 43.6 per cent of the total cases were ”worse or not improved”.

Die pädiatrische Akute Lymphatische Leukämie ist heutzutage gut behandelbar. Trotzdem ist die Prognose im Falle eines Rezidives weiterhin schlecht. Die häufigsten extramedullären Orte für Rezidive sind das zentrale Nervensystem und der Hoden. Um ein Rezidiv im Hoden zu verhindern, ist es nötig die zellulären und molekularen Vorgänge zu verstehen. Dafür wurde Patientenmaterial auf seine Expression bestimmter Oberflächenmoleküle analysiert. Verglichen wurden Proben von Patienten mit verschiedenen Rezidiv-Arten. Um die funktionellen Aspekte der Hodenphysiologie auf die Leukämiezellmigration und -lokalisation zu untersuchen wurde ein PDX-ALL Mausmodel mit Hodenbeteiligung etabliert. Um potenziell involvierte Chemokin-Chemokinrezeptor-Achsen zu identifizieren, wurden 55 Knochenmarksproben von Patienten untersucht. Die Expressionsmuster der Rezeptoren wurde mittels Durchflusszytometrie analysiert. Es wurde festgestellt, dass CXCR4 meistens sehr hoch exprimiert wird. Deshalb wurde anschließend der Einfluss der CXCR4-CXCL12 Achse in in vitro Versuchen mit Hilfe primären Hodenstromas untersucht. Um verschiedene Subpopulationen zu untersuchen, wurde die Isolation von Hodenmakrophagen, Sertoli Zellen und Peritubulären Zellen aus der Maus etabliert und ihr Einfluss auf ALL Zellen untersucht. Es wurde festgestellt, dass Hodenmakrophagen bei Tumorkontakt ihren Phänotyp zugunsten einer tumorfördernden Subpopulation verändern. Zu guter Letzt wurde ein adaptives PDX-ALL Mausmodel mit Hodenbeteiligung entwickelt. Dabei wurden die Hoden von vorpubertären Mäusen bevorzugt infiltriert. Die Bedeutung der CXCR4-CXCL12 Achse für die Hodeninfiltration wurde in einem in vivo Versuch validiert. Während Knochenmark und Milz nach einer anti-CXCR4 Gabe kleine ALL Populationen aufwiesen, war der Hoden komplett Tumor-frei. Das Model kann für Versuche genutzt werden, um weitere Signalwege zu identifizieren, welche in die Hoden gerichtete Migration und das Überleben der Zellen involviert sind. / Advancing therapy strategies led to event-free-survival increase of paediatric acute lymphoblastic leukaemia (ALL). Relapses that occur are often drug resistant and come with poor prognosis. Extramedullary sites for relapse are the central nervous system (CNS) and the testis. To prevent testicular relapse, factors responsible for the infiltration and survival need to be discovered. Primary patient material was analysed with regard to differential expression of surface molecules on leukemic cells from BM. To analyse functional aspects of testis physiology on leukemic cell migration and localisation an adoptive PDX-ALL mouse model with testicular involvement was established. To identify potential chemokine-chemokine receptor axes responsible for the leukaemia cell migration towards the testis, a characterization of 55 patient BM samples was performed. The expression pattern of chemokine receptors on BM derived leukaemia cells was compared by flow cytometry. CXCR4 was identified to be highly expressed on patients cells, regardless of the subclass of relapse. Relevance of the CXCR4-CXCL12 axis was studied in vitro. Primary testicular stroma cultures were available, which provided a useful tool to examine testis directed migration. Isolation of testicular macrophages, Sertoli cells and peritubular cells was established and their impact on ALL cell survival was analysed. The macrophages were found to alter their phenotype upon ALL cell contact towards a tumour favourable subtype. Most importantly, a murine adoptive patient-derived xenograft (PDX)-ALL cell transfer model with testicular involvement was established. Testes of pre-puberty mice were preferentially infiltrated. Blocking CXCR4 with an antibody validated relevance of the CXCR4-CXCL12 signalling axis. The testis showed no infiltration in anti-CXCR4 treated animals. The mouse model will be useful to identify and validate further signalling pathways, participating in testis directed migration and survival.