br Methods br Results br Discussion The goal of

Methods
Results
Discussion The goal of this e1 activating enzyme study was to examine whether amygdala habituation during an emotional face-processing task differed between adolescents with an internalizing disorder and adolescents with CSA-related PTSD, and to compare the patterns of amygdala habituation with healthy control group adolescents. This is important because adolescents with internalizing disorders show only partial overlap in symptomatology with adolescents with CSA-related PTSD (Lindert et al., 2014), since the latter experienced childhood sexual abuse and subsequently developed PTSD. Possibly, the experience of CSA relates to different neurobiological mechanisms for emotion processing. Consistent with prior studies (Breiter et al., 1996; Fischer et al., 2003), healthy adolescents showed a habituation effect in the amygdala when viewing emotional faces: activation in the amygdala was significantly higher during run1 then during run2/run3. This effect was present for all emotional faces, so not solely for fearful faces, which is in line previous studies (Breiter et al., 1996). This might suggest that habituation to emotional faces may be a general pattern that is related to, for example, the novelty of the emotional faces which adapts over time. Previous research showed that amygdala response for novel neutral faces is larger than for familiar neutral faces, but in both cases amygdala activation declined over time (Schwartz et al., 2003). Therefore, Schwartz et al. (2003) suggest that one function of the amygdala is to detect new events that might be important. Contrary to prior reports (McClure et al., 2007; Monk et al., 2008a,b; Thomas et al., 2001), the INT group did not show a general higher amygdala response to emotional faces than the CNTR adolescents. This finding was surprising, however, we previously reported that self-reported levels of anxiety and not diagnosis per se predicted amygdala activation (van den Bulk et al., 2014). Possibly, individual differences in depression and anxiety symptomatology or the inclusion of different types of anxiety disorders suppressed group differences in amygdala activation. Another explanation can be found in the current task design: we used a task design in which participants rated their subjective feeling while some studies have shown that attention load (such as answering questions or rating the emotional faces) influences amygdala activation (Costafreda et al., 2008; Sauer et al., 2013). We did include a passive viewing condition. However, not enough trials were available to examine habituation during passive viewing. Future research should further investigate habituation, for example, by using a passive viewing task with a sufficient number of trials per run. Furthermore, End labeling would be interesting to further examine the effect of constrained and unconstrained conditions on amygdala activation. In the current study, we collapsed the analyses across state questions to have enough trials left for the habituation analyses, which prevented us from examining the effect of state questions on amygdala activation and habituation. Future research should further examine the effect of state questions. To do so, it might be interesting to include two face processing tasks: one in which participants have to passively view emotional faces and another one in which participants have to regulate their emotions or have to answer questions in response to the emotional faces. The results of these two tasks can then be compared and more knowledge can be acquired about the influence of cognitive load on amygdala activation and habituation. Finally, future research should include larger samples with a wide variety of subtypes of anxiety disorders and an equal distribution of males/females. The innovative aspect of the current study was that we included both adolescents with internalizing disorders and adolescents with CSA-related PTSD. Although the overlap in reported symptomatology between these groups is high, the adolescents with CSA-related PTSD experienced childhood sexual abuse and subsequently developed CSA-related PTSD. Previous research has demonstrated that people who experienced childhood maltreatment show heightened patterns of amygdala activation (Hart and Rubia, 2012; van Harmelen et al., 2013) and that experiencing childhood maltreatment often leads to the development of CSA-related PTSD in combination with internalizing disorders (Lindert et al., 2014). With respect to the behavioural data (subjective scoring of emotional faces), we showed that adolescents who experienced CSA report the same elevated level of fear to fearful faces as depressed/anxious adolescents. However, they responded slower to the emotional faces compared to the INT an CNTR group on neurobiological level adolescents with CSA-related PTSD showed higher amygdala activation at the beginning of the task (initial increase) compared to CNTR group and INT group, but similar activation as CNTR group near the end of the task (relatively fast habituation).