Amygdala Subregion Volumes in Adolescents: The Role of Testosterone and Androgen Receptor Genotype

• In Event: Embracing the Complexities of Adolescence: The Role of Pubertal Maturation and Hormones on Neurodevelopment

Abstract

Introduction: The amygdala is vital to emotional processing, motivation, and social behaviors that continue to develop across childhood and adolescence. Previous studies have reported sex differences and a potential role of testosterone in total amygdala development. However, the amygdala is actual comprised of a heterogeneous set of nuclei, which contain varying degrees of androgen receptor (AR) density in animal models. However, our understanding of how testosterone and genetic differences in AR sensitivity may relate to amygdala subnuclei volumes in humans remains unknown. The goal of the current study was to examine the associations between testosterone, genetic differences in AR sensitivity, and amygdala subnuclei volumes during adolescence. Hypothesis: We hypothesized that testosterone and AR sensitivity would show unique associations with distinct amygdala subnuclei volumes and these effects would differ in males versus females. Study Population: Cross-sectional data of 220 adolescents (females = 102, 46%; ages 10-17) was collected at the Oregon Health and Science University. Methods: Total circulating testosterone and androgen receptor (AR) CAG repeat length – which inversely relates to AR sensitivity – was assessed from morning blood draws. The novel in vivo probabilistic CIT168 atlas was used to segment whole brain T1-weighted MRI images into 9 distinct amygdala subregions. For each sex, separate generalized additive mixed models (GAMM) were used to assess 1) the relationship of free testosterone (FT), age, and their interaction, and 2) AR CAG repeat length, with amygdala subregion volumes, covarying for intracranial volume, socioeconomic status, menses status (in females), and age (in AR models). Results: After correction for multiple comparison, we found sex-specific differences with age-by-FT associations with amygdala subregion volumes. In males, the interaction between age and FT related to volumes of the right total amygdala, lateral amygdala (LA), amygdala transition area (ATA) and corticomedial nucleus (CMN), as well as the left central nucleus (CEN) and basolateral ventral and paralaminar subdivision (BLVPL). An age-by-FT association was only identified for the right ATA in females. For males, age was positively related to volumes of the right total amygdala and left CEN, but with a stronger association seen with increasing levels of FT. For the right ATA, left BLVPL, right CMN, and the right LA, age was negatively associated with volumes at lower levels of FT, whereas no association or stronger positive age associations with volume were seen at higher levels of FT in males. In females age-related increases were seen in ATA volumes at lower FT levels, whereas age-related decreases in volume were found at higher FT levels. Surprisingly, AR repeat lengths, indicative of AR sensitivity, was found to relate with subnuclei volume only in one subregion in females. Specifically, higher AR sensitivity in allele 2 was associated with smaller volumes in the basolateral dorsal and intermediate subregion (BLDI) (p=0.04). Discussion: These findings suggest that different androgen related mechanisms may underlie amygdala subregion volumes in adolescent males and females. Further research is needed to investigate whether sex-specific differences related to testosterone and AR sensitivity in amygdalar volumes relate to social and emotional behavioral outcomes across development.

Authors

• Megan Herting, Children's Hospital Los Angeles
  Presenting Author

• Claire Campbell, University of Southern California
  Non-Presenting Author

• Micheal Tyszka, California Institute of Technology
  Non-Presenting Author

• Bonnie Nagel, Oregon Health & Science University
  Non-Presenting Author