title: A testosterone-related structural brain phenotype predicts aggressive behavior from childhood to adulthood.
abstract: Structural covariance, the examination of anatomic correlations between brain regions, has emerged recently as a valid and useful measure of developmental brain changes. Yet the exact biological processes leading to changes in covariance, and the relation between such covariance and behavior, remain largely unexplored. The steroid hormone testosterone represents a compelling mechanism through which this structural covariance may be developmentally regulated in humans. Although steroid hormone receptors can be found throughout the central nervous system, the amygdala represents a key target for testosterone-specific effects, given its high density of androgen receptors. In addition, testosterone has been found to impact cortical thickness (CTh) across the whole brain, suggesting that it may also regulate the structural relationship, or covariance, between the amygdala and CTh. Here, we examined testosterone-related covariance between amygdala volumes and whole-brain CTh, as well as its relationship to aggression levels, in a longitudinal sample of children, adolescents, and young adults 6-22 years old. We found: (1) testosterone-specific modulation of the covariance between the amygdala and medial prefrontal cortex (mPFC); (2) a significant relationship between amygdala-mPFC covariance and levels of aggression; and (3) mediation effects of amygdala-mPFC covariance on the relationship between testosterone and aggression. These effects were independent of sex, age, pubertal stage, estradiol levels and anxious-depressed symptoms. These findings are consistent with prior evidence that testosterone targets the neural circuits regulating affect and impulse regulation, and show, for the first time in humans, how androgen-dependent organizational effects may regulate a very specific, aggression-related structural brain phenotype from childhood to young adulthood.
authors.affiliation: Department of Psychiatry and Department of Obstetrics-Gynecology, McGill University, Montreal, QC H3A 1A1, Canada. Electronic address: tuong.v.nguyen@mcgill.ca.
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Brain Development Cooperative Group,(1) USA; Department of Child and Adolescent Psychiatry, University of California in Los Angeles, Los Angeles, CA 90024, USA.
authors.forename: James T
authors.initials: JT
authors.lastname: McCracken
authors.affiliation: University of Vermont, College of Medicine, Burlington, VT 05405, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Albaugh
authors.affiliation: Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Kelly N
authors.initials: KN
authors.lastname: Botteron
authors.affiliation: Brain Development Cooperative Group,(1) USA; University of Vermont, College of Medicine, Burlington, VT 05405, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hudziak
authors.affiliation: McGill University Health Centre and Montreal Neurological Institute, Department of Psychiatry and Department of Neurology, McGill University, Montreal, QC H3A 1A1, Canada; McConnell Brain Imaging Centre, Montreal Neurological Institute, Montreal, QC H3A 2B4, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Ducharme
mesh_terms: D000293:Adolescent; D000374:Aggression / Q000502:physiology* / Q000523:psychology; D000679:Amygdala / Q000473:pathology*; D001007:Anxiety / Q000523:psychology; D001921:Brain / Q000473:pathology; D002648:Child; D002652:Child Behavior / Q000502:physiology* / Q000523:psychology; D003863:Depression / Q000523:psychology; D004958:Estradiol / Q000378:metabolism; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D016014:Linear Models; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D010641:Phenotype; D017397:Prefrontal Cortex / Q000473:pathology*; D013739:Testosterone / Q000378:metabolism*; D055815:Young Adult
chemical_list: D013739:Testosterone; D004958:Estradiol
keywords: Amygdala; Androgen; Human brain; Prefrontal cortex; Puberty; Structural covariance