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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 to 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 voxel-to-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 reward-related 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 aggression-related rsFC alterations.

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