Testing a Dual Mechanism Model of Adolescent Anxiety Development & Related Sex Differences

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ABSTRACT Anxiety disorders remain one of the most common forms of mental illness and the 6th leading cause of disability worldwide. Anxiety pathology tends to emerge during early adolescence, and this process occurs differentially between the sexes, with rates becoming 2- to 3-fold higher in girls (vs. boys) post-puberty. Thus, identifying adolescence-specific factors that predispose towards anxiety disorders is crucial for identifying at-risk individuals early, before trajectories crystalize, and for providing novel intervention targets. Interestingly, the developmental course of anxiety is inversely related to the maturation of emotion-regulation capacity, with decrements in capacity appearing during the transition into adolescence. We and others have proposed that the development of adolescent anxiety is due, in part, to differences in the maturational trajectories of brain networks supporting emotion regulation (i.e., emotion dysregulation is a key endophenotype for anxiety development). However, the adolescent- and sex-specific neurobiological mechanisms that support the development of emotion regulation, and their implications for the manifestation of anxiety pathology, are not well understood. We will test a model incorporating two risk factors: pubertal testosterone and axonal myelination of prefrontal-subcortical circuits. We will collect longitudinal (3 waves, each 1 year apart) multi-modal (e.g., diffusion, ultra-fast fMRI) neuroimaging data from individuals at the transition into adolescence, half of whom are at high risk for developing an anxiety disorder. Aim 1: We recently proposed a model in which testosterone dampens the effectiveness of key emotion-regulation circuitry, whereas myelination of white matter in that circuit has the opposite effect. Aim 1 will evaluate this model by testing whether (i) increases over time in pubertal testosterone are linked to functional decoupling between orbitofrontal cortex (OFC) and amygdala and (ii) this decoupling predicts emotion dysregulation and consequent anxiety increases. This aim will also test whether sparser baseline myelination of uncinate fasciculus (connecting OFC-amygdala) is linked to weaker functional coupling, higher dysregulation, and anxiety. Aim 2: The biological mechanisms that confer greater risk for anxiety in females remain unknown. Our work in healthy adolescents suggests that females have a higher sensitivity to testosterone in the OFC- amygdala circuit, and there is some evidence of myelination differences in this circuit. Aim 2 will test whether testosterone and myelination have a greater impact on emotion-regulation circuitry/pathological anxiety in girls. Aim 3: It is critical to identify baseline biomarkers predictive of future anxiety development in order to detect at- risk individuals before trajectories crystalize. Aim 3 will test whether testosterone and myelination can be used to predict the emergence of future anxiety. In sum, this project aims to identify neural and hormonal mechanisms responsible for the development of adolescent anxiety. This work has the potential for tremendous public health impact by harnessing cutting-edge methods to uncover and validate novel risk trajectories for anxiety.