AcknowledgmentsThis project has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no 602805 (Aggressotype) and 603016 (MATRICS). This work reflects only the authors' views and the European union is not liable for any use that may be made of the information contained herein. We gratefully acknowledge and thank all the participants and their families for their enthusiastic participation in the study. AbstractObjective: Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated this association in predefined regions of interest.Method: T1-weighted magnetic resonance images were acquired from 158 children and adolescents with aggressive behavior (ODD/CD) and 96 controls in a multi-centre study. Aggression subtypes were assessed by questionnaires. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool.Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models.Results: In cases only proactive aggression was negatively associated with amygdala volume (b=-11.82, p=0.05), while reactive aggression was negatively associated with insula volume (b=-46.41, p=0.01). Classical group comparison showed that children and adolescents with aggressive behavior had smaller volumes than controls in (bilateral) ventral striatum (p=0.003), ACC (p=0.01), and vmPFC (p=0.003) with modest effect sizes.Conclusions: Aggression was associated with reduced volume in brain regions involved in decision making. Negative associations were found between reactive aggression and volumes in regions involved in threat responsivity and between proactive aggression and regions linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure.