Abstract: Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system

With the emergence of non-invasive methods like magnetic resonance imaging (MRI) and functional MRI (fMRI), there is growing evidence of maturational changes in both neuro-anatomical structures and neural activation patterns. Developmental changes have been shown to last until adolescence. In study 1, we examined the impact of steroids on the developing brain and found that amygdala and hippocampal as well as parietal volumes were associated with circulating testosterone levels. In the studies 2 to 5 we adressed differences in brain activation patterns of attention between children and adults, where children were either normally developing children or children with ADHD. We found differences in the developmental trajectories in the fronto-striatal pathway between children with and without ADHD, as well as an increase in brain connectivity in a fronto- parietal network with adolescence. We conclude, that the puberty might have organizational effects on the developing human brain, which manifests itself in both, brain structure and function.