Fronto-amygdala Functional Connectivity is Negatively Associated with Anxiety Symptoms in Girls with High Testosterone Levels

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

Abstract

Introduction: During early adolescence, sex differences emerge in levels of anxiety symptoms, particularly generalized (GAD) and social anxiety (SAD) disorders, with girls exhibiting significantly higher levels of symptoms than boys (Beesdo-Baum et al., 2012). This is important because high levels of anxiety symptoms during this developmental period increases risk of depression and suicide, especially in girls. It is thus critical to understand the neurodevelopmental mechanisms that could contribute to such sex differences. One possible mechanism may be the effects of pubertal hormones on fronto-amygdala functional connectivity, which is reduced in anxious youth (Blackford et al., 2012). In typically developing early adolescents, higher levels of testosterone are associated with reduced fronto-amygdala functional connectivity over a 2-year time span when processing threat-related stimuli (Spielberg et al., 2015). Moreover, in girls, reduction in fronto-amygdala connectivity occurred with a smaller increase of testosterone and the effects were stronger in a subgroup with higher levels of testosterone who self-reported threat sensitivity. Here, we tested the hypothesis that reduced resting state fronto-amygdala functional connectivity would be associated with higher levels of anxiety symptoms as a function of higher levels of testosterone in a sample of eary-adolescent shy/fearful girls. Methods: A sample of 129 adolescent girls (Age: 11-13 yrs old) were recruited as part of a larger study focusing on the neurodevelopment of social threat and social reward processing in temperamentally anxious adolescent girls. Two-thirds of the sample were recruited with high shy/fearful temperament. In 64 participants with complete baseline resting state fMRI data, testosterone saliva assays, and anxiety symptom scores, time series were extracted from six clusters within the bilateral ventromedial prefrontal cortex (vmPFC) (Chase et al., 2019) and anatomially-defined regions-of-interest in the left and right amygdala. Covarying for age, we examined how interactions between baseline levels of testosterone and neural indices of resting state vmPFC-amygdala functional connectivity predicted levels of anxiety symptoms assessed using the total SCARED child report. Results: The reduced vmPFC-amygdala functional conectivity predicted anxiety symptom levels as a function of varying levels of testosterone (B=-1.69, SE=.77, t(59) = -2.19, p = .033). Specifically, for girls with testosterone levels +1 SD above the mean, anxiety symptoms were higher as a function of reduced levels of right amygdala-vmPFC connectivity (Fig. 1). Discussion: Given the role of vmPFC-amygdala circuitry in regulating threat reactivity findings indicate that shy/fearful girls with reduced fronto-amygdala connectivity and higher levels of testosterone may be at increased risk for onset of an anxiety disorder later in adolescence. Results from ongoing follow-up longitudinal assessments will deepen understanding of the neurodevelopmental mechanisms underlying pathways to anxiety disorders in at-risk girls.

Authors

• Cecile D Ladouceur, University of Pittsburgh
  Presenting Author

• Teague Henry, University of Pittsburgh
  Non-Presenting Author

• Elizabeth A. Shirtcliff, Iowa State University
  Non-Presenting Author

• Jennifer S. Silk, University of Pittsburgh
  Non-Presenting Author