2020 |
Spielberg, Jeffrey Martin |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Testing Dual Mechanism Model of Adolescent Anxiety and Related Sex Differences @ Delaware State University
Anxiety remains one of the most common forms of mental illness and the 6th leading cause of disability. Anxiety tends to emerge during early adolescence, and this occurs differentially between sexes: rates are equal pre-puberty and become 2-fold greater in females. Thus, identifying factors that predispose towards anxiety is crucial for identifying as-risk individuals early. We have proposed that the development of anxiety in adolescence is due, in part, to differences in the maturation of brain networks supporting emotion regulation. However, mechanisms that influence the development of these networks, and their implications for anxiety, are not well understood. We will test a model incorporating two risk factors (pubertal testosterone and axonal myelination) by collecting neuroimaging data from individuals transitioning into adolescence, half of whom are at high risk for developing anxiety . Aim 1: Work from our lab and others in healthy adolescents/ adults indicates that testosterone dampens the effectiveness of key emotion-regulation circuitry, and this dampening predicted anxiety increases. However, it is unclear if this impacts pathological levels of anxiety. Additionally, white matter integrity in this circuitry is weaker in anxiety, likely disrupting the efficiency of communication. Unfortunately, the mechanism by which this occurs remain unknown; we have proposed that weaker integrity impacts anxiety by exacerbating the impact of testosterone. Importantly, a key driver of white matter integrity is myelination, and these circuits begin myelinating during adolescence. Therefore, Aim 1 uses a novel multi-modal myelin measure to test whether testosterone and myelination impact anxiety, as mediated by changes in emotion-regulation circuitry. Aim 2: The mechanisms that confer greater risk for anxiety in females remain unknown. Our work suggests that females have a higher sensitivity to testosterone in key emotion-regulation circuitry. Thus, Aim 2 tests whether testosterone has a greater impact on emotionregulation circuitry/pathological anxiety in girls. In sum, this project aims to identify 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.
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0.99 |
2021 |
Spielberg, Jeffrey Martin |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Testing a Dual Mechanism Model of Adolescent Anxiety Development & Related Sex Differences
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.
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