Einfluss genetischer Variation von GLRB rs7688285 und NOS1 ex1f-VNTR auf neurale Korrelate der Furchtkonditionierung und -extinktion bei Personen mit Panikstörung und Agoraphobie im Kontext expositionsbasierter kognitiver Psychotherapie sowie neurale Korrelate verzögerter Furchtextinktion in einer multizentrischen Studie

Background: Panic disorders (PD) with and without agoraphobia (AG) belong to the mental disorders with the highest prevalence, have serious individual influence and represent a huge socio-economic burden. A significant part of the individual vulnerability for anxiety disorders can be traced back to genetic factors. Candidate genes like GLRB and NOS1 are identified as potential risk factors. However, it is still unclear which impact these risk factors have on neural and psycho-physiological levels as well as in the context of current PD/AG diagnosis and to what extent psychotherapy can influence those correlates. GLRB regulates a receptor in the central nervous system that mediates postsynaptic inhibition. NOS1 as a very complex gene is associated with a variety of functions and is investigated as a risk factor for many disorders, e. g. anxiety disorders. A well established theoretical model of fear acquisition is fear conditioning, where the individual learns to associate a previously neutral stimulus (conditioned stimulus, CS) with a temporally paired aversive stimulus (unconditioned stimulus, US). The CS becomes the threat signal CS + that similar like the US leads to a fear reaction and triggers defensive behavior to prevent future harm. An established CS + /US-association as well as the conditioned fear reaction can be inhibited by extinction training in which the CS + is presented repeatedly without the US. This mechanism is the key component of successful exposure-based cognitive behavioral therapy (CBT). How exactly extinction processes manifest themselves on the neural level and how extinction training can be optimized for therapy is part of ongoing research. Studies on the neural correlates of fear suggest the existence of a network of fear expression and regulation including e. g. the amygdala (emotional expression), the cingulate cortex (emotional and cognitive regulation) and the hippocampus (memory). Objective: Goal of this dissertation was investigating the psycho-pathology of PD/AG and its neurobiological fundamentals by exploring genetic traits (rs7688285, NOS1 ex1f-VNTR) on PD/AG as well as fundamental extinction processes. In the process, neural correlates of altered fear conditioning and extinction as well as method validation were of particular interest. In the long run, the results can contribute to developing efficient and individualized therapy options and preventive measures and thus reduce the individual and societal burden of PD/AG. Methods: This dissertation summarizes three studies using functional magnetic resonance imaging (fMRI), that were conducted in the context of the German research associations «Panic Net» and «PROTECT AD». Fear acquisition and extinction learning associated with the single nucleotide polymorphism rs7688285 coding for GLRB (article I) and the promotor polymorphism NOS1 ex1f VNTR (article II) in patients with PD/AG and healthy subjects were investigated at two measurement points (pre and post CBT in patients) in neural (article I and II), behavioral, autonomic, subjective and clinical (article I) parameters with an experimental fear conditioning and extinction paradigm. Additionally, in healthy subjects, neural correlates of delayed extinction learning after consolidation and subjective parameters were investigated in a 2-day-paradigm (article III). In article I and II, general effects of the genes as well as differential learning effects in the context of current PD/AG diagnosis and its treatment with CBT were of interest. In article III, correlates of the extinction process and reinstatement of fear as well as stability and reliability of these correlates over different measurement points and locations were investigated. Results: Article I and II showed that the rs7688285 allelic variation was associated in the hippocampus, motor cortex, insula and anterior cingulate cortex (ACC) as well as the NOS1 ex1f VNTR allelic variation in amygdala and hippocampus with general, diagnosis specific and diagnosis-dependent differential learning effects. Among carriers of the rs7688285 A-allele, patients and healthy subjects showed converse activation in differential learning. On the level of symptom severeness, neither before nor after exposure-based CBT gene-associated effects were found. On the neural level, however, there was a therapy-dependent activation change in the ACC. In the behavioral test, carriers of the A-allele showed subjective higher fear increase and higher heart rate acceleration. NOS1 ex1f VNTR associated effects were especially present during the extinction training phase. Carriers of the homozygous S-allele genotype showed much lower and patients overall higher neural activation. Differential effects were found especially in patients carrying the S/S-genotype showing in higher activation on the safety signal CS - which is discussed to be a pathological over-generalization. Article III showed that fear extinction learning was reliable associated over measurement time points and locations with activation decrease in the insula and cingulate cortex. Effects of a reinstatement of fear were found in the ACC. The neural effects were correlated with corresponding changes in subjective ratings. Conclusions: In sum, the studies presented here provide evidence for general and specific impact of genetic variability on fear conditioning and extinction processes in healthy subjects and patients with PD/AG. Allelic variations in rs7688285 respectively NOS1 ex1f VNTR possibly are a pre-dispositional risk factor for the development and retention of PD/AG. Thereby, altered processes in the neural fear network play a central role. Neural correlates of delayed fear extinction learning can be reliably investigated in fMRI and the presented paradigm provides a solid experimental basis for the investigation of neural mechanisms in anxiety disorders and optimizations in exposure-based CBT. The presented work contributes to a deeper understanding of the neurobiological mechanisms and etiopathogenesis in PD/AG.