There is increasing evidence for altered brain resting state functional connectivity in adolescents with disruptive behavior. While a considerable body of behavioral research points to differences between reactive and proactive aggression, it remains unknown whether these two subtypes have dissociable effects on connectivity. Additionally, callous-unemotional traits are important specifiers in subtyping aggressive behavior along the affective dimension. Accordingly, we examined associations between two aggression subtypes along with callous-unemotional traits using a seed-to-voxel approach. Six functionally relevant seeds were selected to probe the salience and the default mode network, based on their presumed role in aggression. The resting state sequence was acquired from 207 children and adolescents of both sexes [mean age (standard deviation) = 13.30 (2.60); range = 8.02-18.35] as part of a Europe-based multi-center study. One hundred eighteen individuals exhibiting disruptive behavior (conduct disorder/oppositional defiant disorder) with varying comorbid attention-deficit/hyperactivity disorder (ADHD) symptoms were studied, together with 89 healthy controls. Proactive aggression was associated with increased left amygdala-precuneus coupling, while reactive aggression related to hyper-connectivities of the posterior cingulate cortex (PCC) to the parahippocampus, the left amygdala to the precuneus and to hypo-connectivity between the right anterior insula and the nucleus caudate. Callous-unemotional traits were linked to distinct hyper-connectivities to frontal, parietal, and cingulate areas. Additionally, compared to controls, cases demonstrated reduced connectivity of the PCC and left anterior insula to left frontal areas, the latter only when controlling for ADHD scores. Taken together, this study revealed aggressionsubtype-specific patterns involving areas associated with emotion, empathy, morality, and cognitive control.

Objective: There is increasing evidence for altered resting state functional connectivity (rsFC) in adolescents with disruptive behavior. Despite considerable ongoing behavioral research suggesting also important differences relating to reactive and proactive aggression, the corresponding rsFC correlates have not been studied to date. We therefore examined associations between these aggression subtypes along with subdimensions of callous-unemotional (CU) traits and rsFC using predefined seeds in aggression-related salience network (SN) and default mode network (DMN). Method: Aggression subtypespecific whole-brain rsFC of SN and DMN seeds was investigated in a resting state sequence (mean acquisition time = 8 min 25 sec) acquired from 207 children and adolescents of both sexes aged 8 -18 years (mean age (SD) = 13.30 (2.60) years; range = 8.02 -18.35) in a multi-center study. One hundred eighteen individuals exhibited disruptive behavior (conduct disorder/oppositional defiant disorder) with different levels of comorbid ADHD symptoms, 89 were healthy. Results: Compared to healthy controls, cases demonstrated reduced DMN and -after controlling for ADHD scores -SN seed-based rsFC with left hemispheric frontal clusters. We found increased and distinct aggression-subtype specific rsFC patterns. Specifically, reactive and proactive aggression correlated with distinct SN and DMN seed-based rsFC patterns. CU dimensions led to different DMN and SN rsFC with clusters including frontal, parietal, and cingulate areas. Conclusions: This first study investigating reactive and proactive aggression along with CU dimensions reveals new subtype-specific whole-brain rsFC patterns in brain regions Werhahn et al. 4 linked to processes like emotion, empathy, moral, and cognitive control. Keywords: reactive and proactive aggression; callous-unemotional traits; default mode network; amygdala; functional connectivity.  Increasing evidence suggests mainly reduced resting state functional connectivity (rsFC) in adolescents with disruptive behavior in regions of the default mode network (DMN) and salience network (SN). While some rsFC studies evaluated the neural correlates of CU traits, reactive and proactive (RA/PA) forms of aggression have been neglected to date. We investigated DMN and SN seed-based rsFC in a large multicenter sample of children and adolescents, considering RA/PA behaviors along with CU traits. We found reduced rsFC in aggressive cases compared to controls in frontal clusters, with one pattern depending on the additional control for ADHD scores. Within cases, we found subtype-specific whole-brain rsFC patterns in brain regions previously linked to emotion, empathy, moral, and cognitive control.

Background. Disruptive behavior in children and adolescents can manifest itself in reactive (RA) and proactive (PA) aggression and is modulated by callous-unemotional (CU) traits and comorbidity. Research on aggression subtype-specific neural correlates is limited and the role of comorbid symptoms largely neglected.Methods. The current multi-center study extended previous efforts by investigating unrestricted resting state functional connectivity (rsFC) alterations. The large sample (n = 207) of children and adolescents aged 8 -18 years (mean age = 13.30 ± 2.60 years) included 118 cases with disruptive behavior (80 diagnosed with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptoms were added as covariates. We measured changes in global and local voxelto-voxel rsFC using functional magnetic resonance imaging at 3T (mean acquisition time = 8 min 25 sec).Results. Compared to controls, cases demonstrated altered rsFC including frontal areas when anxiety but not ADHD symptoms were considered. Within cases, RA and PA scores related to changes in global and local rsFC in central gyrus and precuneus previously linked to aggression-related impairments. CU trait severity correlated with global rsFC alterations including inferior and middle temporal gyrus implicated in empathy, emotion, and rewardrelated activity. Importantly, most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety problems were also accounted for.Conclusions. The current study clarifies that distinct though overlapping brain connectivity measures can disentangle differing manifestations of aggressive behavior. Moreover, our results highlight the importance of considering comorbid symptoms for detecting aggressionrelated rsFC alterations. Werhahn et al. 5