title: Sex-specific associations of testosterone with prefrontal-hippocampal development and executive function.
abstract: Testosterone is thought to play a crucial role in mediating sexual differentiation of brain structures. Examinations of the cognitive effects of testosterone have also shown beneficial and potentially sex-specific effects on executive function and mnemonic processes. Yet these findings remain limited by an incomplete understanding of the critical timing and brain regions most affected by testosterone, the lack of documented links between testosterone-related structural brain changes and cognition, and the difficulty in distinguishing the effects of testosterone from those of related sex steroids such as of estradiol and dehydroepiandrosterone (DHEA). Here we examined associations between testosterone, cortico-hippocampal structural covariance, executive function (Behavior Rating Inventory of Executive Function) and verbal memory (California Verbal Learning Test-Children's Version), in a longitudinal sample of typically developing children and adolescents 6-22 yo, controlling for the effects of estradiol, DHEA, pubertal stage, collection time, age, handedness, and total brain volume. We found prefrontal-hippocampal covariance to vary as a function of testosterone levels, but only in boys. Boys also showed a specific association between positive prefrontal-hippocampal covariance (as seen at higher testosterone levels) and lower performance on specific components of executive function (monitoring the action process and flexibly shifting between actions). We also found the association between testosterone and a specific aspect of executive function (monitoring) to be significantly mediated by prefrontal-hippocampal structural covariance. There were no significant associations between testosterone-related cortico-hippocampal covariance and verbal memory. Taken together, these findings highlight the developmental importance of testosterone in supporting sexual differentiation of the brain and sex-specific executive function.
authors.affiliation: Department of Psychiatry and Department of Obstetrics-Gynecology, McGill University Health Center (Royal Victoria Hospital at the Glen site), McGill University, Montreal, QC, Canada, H4A 3J1. Electronic address: tuong.v.nguyen@mcgill.ca.
authors.forename: Tuong-Vi
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: Department of Psychology, McGill University, Montreal, QC, H4A 3J1, Canada.
authors.forename: Jimin
authors.initials: J
authors.lastname: Lew
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: University of Vermont, College of Medicine, Burlington, VT, 05405, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Hudziak
authors.affiliation: McConnell Brain imaging Centre, Montreal Neurological Institute, Montreal, QC, H3A 2B4, Canada.
authors.forename: Vladimir S
authors.initials: VS
authors.lastname: Fonov
authors.affiliation: McConnell Brain imaging Centre, Montreal Neurological Institute, Montreal, QC, H3A 2B4, Canada.
authors.forename: D Louis
authors.initials: DL
authors.lastname: Collins
authors.affiliation: McConnell Brain imaging Centre, Montreal Neurological Institute, Montreal, QC, H3A 2B4, Canada; McGill University Health Centre, Department of Psychiatry and Department of Neurology & Neurosurgery, McGill University, Montreal, QC, H3A 1A1, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Ducharme
authors.affiliation: 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
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000254:growth & development*; D006803:Human Development / Q000502:physiology*; D006801:Humans; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008297:Male; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000254:growth & development*; D012737:Sex Factors; D013739:Testosterone / Q000502:physiology*; D014706:Verbal Learning / Q000502:physiology*; D055815:Young Adult
chemical_list: D013739:Testosterone
keywords: Adolescents; Androgen; Cognition; Gonadarche; Human brain; Puberty