Background: Maternal perinatal mental health has been shown to be associated with adverse consequences for the mother and the child. However, studies considering the effect of DSM-IV anxiety disorders beyond maternal self-perceived distress during pregnancy and its timing are lacking. Aims: To examine the role of maternal anxiety disorders with an onset before birth and self-perceived distress during pregnancy for unfavourable maternal, obstetric, neonatal and childhood outcomes. Study design: DSM-IV mental disorders and self-perceived distress of 992 mothers as well as obstetric, neonatal and childhood outcomes of their offspring were assessed in a cohort sampled from the community using the Munich-Composite International Diagnostic Interview. Logistic regression analyses revealed associations (odds ratios) between maternal anxiety disorders and self-perceived distress during pregnancy with maternal depression after birth and a range of obstetric, neonatal and childhood psychopathological outcomes. Results: Lifetime maternal anxiety disorders were related to offspring anxiety disorders, but not to offspring externalizing disorders. Analyses focussing on maternal DSM-IV anxiety disorders before birth yielded associations with incident depression after birth. In addition, self-perceived distress during pregnancy was associated with maternal depression after birth, preterm delivery, caesarean section, separation anxiety disorder, ADHD, and conduct disorder in offspring. Conclusion: Findings confirm the transmission of anxiety disorders from mother to offspring. Apart from maternal anxiety, self-perceived distress during pregnancy also emerged as a putative risk factor for adverse outcomes. The finding that maternal anxiety disorders before birth yielded less consistent associations, suggests that self-perceived distress during pregnancy might be seen as a putative moderator/mediator in the familial transmission of anxiety.

Social phobia is a common disorder associated with significant psychosocial impairment, representing a substantial public health problem largely determined by the high prevalence, and the lifelong chronicity. Social phobia starts in early childhood or adolescence and is often comorbid with depression, other anxiety disorders, alcohol and substance abuse or eating disorders. This cascade of comorbidity, usually secondary to social phobia, increases the disability associated with the condition. The possibility that social phobia may be a trigger for later developing comorbid disorders directs attention to the need for early effective treatment as a preventive measure. The most recent drug class to be investigated for the psychopharmacological treatment of social phobia is the SSRI group for which there is growing support. The other drug classes that have been evaluated are monoamine oxidase inhibitors (MAOIs), benzodiazepines, and beta-blockers. The SSRIs represent a new and attractive therapeutic choice for patients with generalized social phobia. Recently the first, large scale, placebo-controlled study to assess the efficacy of drug treatment in generalized social phobia has been completed with paroxetine. Paroxetine was more effective in reducing the symptoms than placebo and was well tolerated. Many now regard SSRIs as the drugs of choice in social phobia because of their effectiveness and because they avoid the problems of treatment with benzodiazepines or classical MAOIs.

Bakgrund: Psykisk ohälsa förekommer i alla åldrar och är ett växande problem. Animal Assisted Therapy (AAT) är en målinriktad, planlagd och strukturerad terapeutisk insats som leds eller utförs av personal inom hälso- och sjukvård, skola eller omsorg. Inom hälso- och sjukvården syftar AAT till att förbättra individens psykiska, fysiska, emotionella och kognitiva förmågor. Syfte: Att kartlägga effekter avseende ångest hos vuxna personer med psykisk ohälsa som genomgår Animal Assisted Therapy. Metod: Litteraturstudien baseras på åtta empiriska interventionsstudier med kvantitativ design. Databassökningar genomfördes i Cinahl, PubMed och PsycInfo. Analysprocessen genomfördes enligt Popenoes analysmodell. Resultat: Samtliga studier resulterade i en minskning avseende ångest. Sex av studierna visade en signifikant minskning inom gruppen som fått AAT och två studier visade en positiv effekt men utan signifikant skillnad. Två studier visade en signifikant skillnad mellan interventions- och kontrollgruppen.  Konklusion: Litteraturstudiens resultat visade att AAT kan reducera ångest hos individer med psykisk ohälsa och kan därför vara ett bra komplement i omvårdnaden hos denna patientgrupp. Ytterligare forskning behövs för att kartlägga hur effektivt AAT är jämfört med befintliga behandlingar. / Background: Mental illness occurs at all ages and is a growing problem. Animal Assisted Therapy (AAT) is a targeted, planned and structured therapeutic intervention led or performed by staff in health care, school or care. Animal Assisted Therapy aims in healthcare to improve the individual's mental, physical, emotional and cognitive abilities. Aim: To map the effects regarding anxiety in adults with mental illness who undergo Animal Assisted Therapy.  Methods: The literature review is based on eight empirical intervention studies with quantitative design. Database search was conducted in Cinahl, PubMed and PsycInfo. The analysis process was carried out according to Popenoe´s analysis model. Results: All studies resulted in decreased anxiety-levels. Six of the studies showed a significant difference within the group that received AAT and two studies showed a positive effect but without a significant difference. Two studies showed a significant difference between the intervention and control groups. Conclusion: The results of the literature study showed that AAT can reduce anxiety in individuals with mental illness and could therefore be a good complement to the care of this patient group. Further research is needed to map how effective AAT is compared to existing treatments.

Experiencing early life adversity (ELA) increases the risk of anxiety disorders, such as generalized anxiety disorder and post-traumatic stress disorder, with disproportionally higher risk in women compared to men. Neurodevelopmental and behavioral outcomes following ELA are multifaceted and are influenced heavily by the type of adversity experienced and sex of the individual. A major contributor to emotional dysfunction and anxiety disorders resulting from ELA are changes in fear and threat circuitry. Children who experienced ELA have been reported to show an accelerated development of the amygdala, a region involved in processing threat, and greater cerebrospinal levels of corticotrophin releasing hormone (Crh), an orchestrator of neuroendocrine and behavioral responses to stress. Work in rodents have linked Crh signaling within the lateral central amygdala (CeAL) with processing and responding to threat, core features disrupted in anxiety-related disorders. Further, sex biases in risk and symptom presentation have been proposed to be related to sexual dimorphic signaling of Crh across the brain that differentially influence a variety of Crh-dependent behaviors. However, it remains unclear what properties of ELA portend differential neurobiological risk, what is the basis of sex-differences for negative outcomes, and how specific mechanistic changes give rise to certain endophenotypes. In this work, I use genetic, cellular, and behavioral approaches to explore the impact of ELA and sex on perinatal development in mice and the functional consequences of altered Crh neuron activity in the CeAL on threat responding in adulthood. In Chapter 1, I review how factors such as sex and type of ELA influence amygdala development and Crh. In Chapter 2, I assess the impact of two forms of ELA, maternal separation (MS) and limited bedding and nesting (LBN) on perinatal development and anxiety-like behavior. Both forms of ELA shifted the timing of somatic maturation and basal CORT levels and led to increased anxiety-like behaviors, but the degree of the impact depended on the sex and type of adversity experienced. In Chapter 3, I demonstrate that a distinguishing feature between types of ELA was the predictability of maternal care. The type of ELA also contributed to sex-differences in Crh related gene expression in the perinatal amygdala. Increased expression was primarily observed in males following MS and in females following LBN. In Chapter 4, I investigate the functional consequences of ELA in the form of LBN on the activity of CeALCrh+ neurons in vivo and their causal role in threat reactivity indexed by the startle response. LBN rearing led to sustained activity of CeALCrh+ in female mice but diminished in male mice. Persistent activity of this population was necessary for and predicted the magnitude of startle responding. In Chapter 5, I discuss important considerations when integrating new advancements in the study of ELA and the use of sex as a biological variable. Collectively, this work deepens our understanding of the neurobiological mechanisms impacted by sex and ELA and holds promise for future strategies that may consider the sex and specific experiences of the individual to target specific endophenotypes and address the underlying root causes of anxiety disorders.

Indiana University-Purdue University Indianapolis (IUPUI) / Anxiety disorders are estimated to impact 1 in 4 individuals within their lifetime. For some individuals, repeated episodes of the stress response leads to pathological anxiety and depression. The stress response is linked to increased levels of corticotropin-releasing factor (CRF) in the basolateral nucleus of the amygdala (BLA), a putative site for regulating anxiety and associative processes related to aversive emotional memories, and activation of CRF receptors in the BLA of rats produces anxiety-like behavior. Mimicking repeated episodes of the stress response, sub-anxiogenic doses of urocortin 1 (Ucn1), a CRF receptor agonist, are microinjected into the BLA of rats for five consecutive days, a procedure called priming. This results in 1) behavioral sensitization, such that a previously non-efficacious dose of Ucn1 will elicit anxiety-like response after the 3rd injection and 2) the development of a persistent anxiety-like phenotype that lasts at least five weeks after the last injection without any further treatment. Therefore, the purpose of this thesis was to identify mechanisms involved in the Ucn1-priming-induced anxiogenesis. The first a set of experiments revealed that the anxiety-like behavior was not due to aversive conditioning to the context or partner cues of the testing environment. Next, Ucn1-priming-induced gene expression changes in the BLA were identified: mRNA expression for Sst2, Sst4, Chrna4, Chrma4, and Gabrr1 was significantly reduced in Ucn1-primed compared to Vehicle-primed rats. Of these, Sst2 emerged as the primary receptor of interest. Subsequent studies found that antagonizing the Sstr2 resulted in anxiety-like behavior and activation of Sstr2 blocked acute Ucn1-induced anxiety-like responses. Furthermore, pretreatment with a Sstr2 agonist delayed the behavioral sensitization observed in Ucn1-induced priming but did not stop the development of persistent anxiety-like behavior or the Ucn1-priming-induced decrease in the Sstr2 mRNA. These results suggest that the decrease in Sstr2 mRNA is associated with the expression of persistent anxiety-like behavior but dissociated from the mechanisms causing the behavioral sensitization. Pharmacological studies confirmed that a reduced Sstr2 mediated effect in the BLA is likely to play a role in persistent anxiety and should be investigated further.

Der Beitrag diskutiert kritische theoretische und praktische Aspekte der Komorbidität auf der Grundlage von klinischen und epidemiologischen Befunden zur Komorbidität. Angststörungen weisen statistisch hochsignifikante Assoziationen untereinander sowie mit affektiven, psychotischen Störungen, Eβstörungen sowie Substanzstörungen und Persönlichkeitsstörungen auf. Sie gehen zumeist eindeutig den komorbiden Störungen voraus, so daβ Angststörungen als Risikofaktoren für viele andere Formen psychischer Störungen angesehen werden können. Die möglicherweise kausalen pathogenetischen Mechanismen sind jedoch nach wie vor umstritten und sind offensichtlich vielfältig. Der Beitrag diskutiert vor diesem Hintergrund besonders die möglicherweise kritische Bedeutung von Panikattacken als zentraler «Vulnerabilitätsmarker» nicht nur für die Entwicklung von Angststörungen, sondern auch für affektive Erkrankungen. Hier konnte z.B. nachgewiesen werden, daβ initiale Panikattacken nicht nur die Wahrscheinlichkeit für Rückfälle sekundärer Depressionen erhöhen, sondern auch signifikant die Häufigkeit und Länge depressiver Phasen beeinflussen. Die Vielzahl differenzierter Befunde legt nahe, Komorbidität bei der Eingangs- und Verlaufsdiagnostik ebenso wie bei der Indikationsstellung umfassender zu berücksichtigen.

Objectives: For characterizing the association between parenting and offspring social phobia (SP), contrasting maternal vs. paternal contributions, putative predictors of unfavorable parenting behaviors and its specificity for SP are warranted to delineate targeted prevention and intervention strategies. Methods: A population-based sample of 1053 adolescents was followed-up using the M-CIDI. Parenting was assessed via questionnaire in offspring passing the high risk period for SP-onset. Natal complications and childhood serious health problems as assessed by maternal reports were hypothesized to relate to unfavorable parenting. Results: The pattern of maternal overprotection, paternal rejection and lower emotional warmth was associated with SP, but not with other offspring anxiety disorders. Natal complications were related to overprotection and lower emotional warmth; trend-level associations emerged for serious health problems and unfavorable parenting. Conclusions: Paternal behavior appears particularly relevant for SP. The pattern of maternal overprotection, paternal rejection and lower emotional warmth was observed in SP only, suggesting that its detailed assessment provides a promising opportunity for targeted prevention and intervention in SP.

In this thesis, I investigate the genetics of neuropsychiatric disorders by analysing large data sets derived from high-throughput experiments, using novel comparative genomics approaches. In the first project, I explore characteristics of rare, de novo copy number variants identified among autism patients by employing various bioinformatics resources including Mouse Genome Informatics phenotypes, Gene Ontology terms, and protein-protein interactions. I describe how I objectively identified a number of mouse model phenotypes that are significantly associated with autism, and that provide insight into the aetiologies for both copy number deletions and duplications. In the second project, I investigate the genetics of obsessive-compulsive disorder by resequencing genomic regions of human case-control cohorts and the best spontaneous disease model organisms, namely dogs with canine compulsive disorder, and breed-matched controls. Targeted sequencing experiments yielded a large number of high-quality genetic variants in both humans and dogs. I prioritised variants and genes using case- control comparisons and functional annotations such as types of mutation, evolutionary conservation status and regulatory marks. In turn, I generated several hypotheses that are experimentally tractable. Replication of these findings in a larger cohort is necessary, although it lies beyond the scope of this thesis. Results from both projects indicate that the analytical frameworks employed in this thesis could be profitably applied to other neuropsychiatric disorders.

Les troubles anxieux sont parmi les troubles psychiatriques les plus souvent diagnostiqués chez les adolescents. Ces troubles sont souvent accompagnés de nombreuses comorbidités, dont des difficultés de sommeil. L’objectif principal de cette thèse est de caractériser l’activité corticale à l’éveil et pendant le sommeil à l’aide de l’EEG quantifié chez une population d’adolescents présentant un trouble anxieux, et de la comparer à un groupe témoin d’adolescents. Dans un second temps, on cherche à savoir si l’activité EEG des patients anxieux corrèle avec différentes mesures cliniques. Deux études permettent de répondre à ces objectifs, une première portant sur l’activité EEG au cours de l’éveil, et une seconde portant sur l’activité EEG au cours du sommeil (SL et SP). La première étude démontre que l’activité EEG des deux groupes ne présente pas de différence à l’EEG le soir. Par contre, le matin, les patients anxieux présentent une activité significativement supérieure à celle des contrôles aux électrodes centrales (0,75-10 Hz et 13-20 Hz) ainsi qu’aux électrodes occipitales (2,5-7,75 Hz). Dans la seconde étude, nous avons analysé l’activité EEG absolue et relative en SL et en SP. Nous avons trouvé une activité absolue significativement supérieure à l’EEG de la région centrale chez les participants du groupe anxieux : en SLP (stades 3 et 4) sur l’ensemble des bandes de fréquence, en stade 2 sur les bandes de fréquence thêta, alpha et beta seulement. Finalement, en SP, les différences sont trouvées en alpha et beta, et non en thêta et delta. Les résultats obtenus à ces deux études suggèrent la présence de mécanismes de synchronisation et de filtrage inadéquats au niveau de la boucle thalamo-corticale, entraînant une hypervigilance du SNC. Quant aux corrélations entre l’activité EEG et les mesures cliniques, les résultats obtenus dans les deux études révèlent que les fréquences lentes (thêta et delta) de l’activité d’éveil le matin corrèlent à la fois avec l’anxiété de trait et d’état et les fréquences rapides (Alpha et Beta) de l’EEG du sommeil corrèlent sélectivement avec l’anxiété d’état. Il semble donc exister un lien entre les mesures cliniques et l’activité EEG. Une hausse d’activité EEG pourrait être un indicateur de la sévérité accrue des symptômes anxieux. / Anxiety disorders are among the most diagnosed psychiatric disorders in the adolescent population. These disorders are often accompanied by different comorbidities, such as sleep problems. The main objective of this thesis is to characterize the cortical activity during wake and sleep, using quantified EEG, in a population of adolescents presenting an anxiety disorder, and to compare these results to those of a control group of adolescents. Secondly, we wish to verify if the EEG activity of the anxious participants correlates with different clinical measures. Two different studies are conducted in order to attain our objectives, the first one being on the EEG activity during wake, and the second being on the EEG activity during sleep (slow wave sleep and rapid eye movement sleep). The first study reveals that the EEG activity from both groups does not differ in the evening. However, in the morning, anxious participants display an increased activity on central electrodes (0.75-10 Hz and 13-20 Hz), and on occipital electrodes (2.5-7.75 Hz). In the second study, we demonstrate that anxious participants show an increased absolute EEG activity on central electrodes: in slow wave sleep (stages 3 and 4), it is found on all frequency bands, in stage 2, it is found on the theta, alpha and beta frequency bands. Finally, in rapid eye movement sleep, the differences are only in alpha and beta, and not in theta and delta. These data suggest the impairment of thalamo-cortical gating mechanisms in adolescents with anxiety disorders, leading to CNS hyperarousal. As for the correlations between the EEG activity and the clinical measures, the results from our studies reveal that the slow frequencies (theta and delta) of morning wake EEG correlate with both trait and state anxiety, while fast frequencies (alpha and beta) from the sleep EEG correlate specifically with state anxiety. Thus, there appears to be an association between EEG activity and clinical measures. An increased EEG activity could be an indicator of the severity of the anxious symptoms.

Les troubles anxieux figurent parmi les psychopathologies les plus fréquentes chez les enfants. Ils peuvent avoir de graves répercussions sur leur développement et, à long terme, ils tendent à persister ainsi qu’à s’aggraver. L’évitement est un moyen souvent utilisé par les personnes anxieuses, adultes ou enfants, afin de tenter d’échapper à l'objet de leur peur et ainsi faire diminuer leur niveau d’anxiété. Les schémas cognitifs dysfonctionnels reliés à l’anxiété, et à l’origine de l’évitement, se développent tôt chez l’enfant et sont en partie reliés aux interactions parent-enfant. La présente recherche vise à examiner, à l’aide d’une analyse séquentielle des interactions, la dépendance entre les comportements d’anxiété et d’évitement chez les membres de 20 dyades parent-enfant, dont les enfants sont âgés entre 4 et 7 ans. La tâche d’interaction, une histoire à compléter par les membres de la dyade, a la capacité de susciter des émotions anxieuses chez les participants. Les résultats de cette étude ne permettent pas de démontrer une dépendance entre les comportements d’anxiété et d’évitement des parents et ceux des enfants. La discussion présente des éléments de réflexion sur des pistes de recherche à explorer. / Anxiety disorders are common among children. They can have serious consequences on their development, and tend to persist or even get worst over time. Avoidance behaviors are often used by anxious people, including children, to escape the object of their fear and to decrease their anxiety level. Dysfunctionnal anxious cognitions that support avoidance tend to develop early in childhood and are partially related to parent-child interactions. The objective of the present study was to examine sequential dependency between anxious and avoidant behaviours, by means of sequential analysis of parent-child interactions. The sample included 20 parent-child dyads, children being aged between 4 and 7 years. A story-completion task was administered in order to arouse anxious feelings in participants. Results of the present study did not suggest a dependency between anxious and avoidant behaviours among dyads. The discussion proposes avenues for future research to explore.