Puberty-related development of fronto-amygdala circuitry in anxious youth: A multimodal neuroimaging study with ultra-high resolution MRI scanner (7T)

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Summary Anxiety disorders, which onset during childhood or adolescence, often persist into adulthood, and increase the risk of depression and suicide. Early adolescence, with the onset of puberty, is an important period for the development and/or exacerbation of anxiety symptoms – i.e., Generalized Anxiety Disorder (GAD) and Social Anxiety Disorder (SAD) – with higher levels of symptoms in girls than boys. During this time, fronto-amygdala circuitry, which supports emotion regulation, undergoes important maturational changes. Although alterations in this circuitry has been reported in anxiety disorders, the neurodevelopmental mechanisms underlying the sex differences in levels of anxiety symptoms remain poorly understood. Compared to non-anxious youth, anxious youth exhibit greater amygdala activation and reduced fronto-amygdala functional connectivity when processing threat-related stimuli. Such reduced top–down modulation of amygdala activity to threat has been linked in anxious adults to elevated concentrations in γ-aminobutyric acid (GABA) and glutamate in the ventromedial prefrontal cortex (vmPFC) and amygdala, respectively. It has also been linked, including in anxious youth, to reduced integrity of white matter tracts connecting vmPFC and amygdala (i.e., uncinate fasciculus and cingulum). While vmPFC inhibition of amygdala activity increases with age, we and others have shown in healthy and at- risk youth that increases in pubertal hormones, particularly testosterone, are associated with reduced vmPFC- amygdala functional connectivity to threat. We will test the model that increases in pubertal hormones during early adolescence will exacerbate alterations in fronto-amygdala circuitry in anxious youth and contribute to greater threat reactivity and increases in anxiety symptoms, especially in girls. We test this hypothesis in a sample of medication-free 140 adolescents (50% female), varying in levels of anxiety, with 2/3 oversampled for clinical levels of GAD and SAD symptoms. We will repeatedly assess participants at five timepoints. At baseline and approximately 2 years later, we will assess anxiety (clinical interviews, questionnaires), pubertal status (Tanner, self-report), pubertal hormones (DHEA, testosterone, and estradiol), threat reactivity in a real-world context with physiological and subjective measures of threat reactivity, and neural indices of vmPFC-amygdala circuitry (fMRI during threat processing and at rest, white matter connectivity, and magnetic resonance spectroscopy (MRS) measures of GABA and glutamate). Change in symptoms will be assessed bi-annually via online questionnaires over 2 years post baseline visit. We use an ultra high-field MRI at 7 Tesla, which will yield unprecedented characterization of vmPFC-amygdala neurodevelopment in anxious youth. We will also explore the effects of pubertal hormones, anxiety, and threat reactivity on whole brain functional networks and examine how each of the neural indices relate to each other over time. Our goals are consistent with the RDoC initiative and NIMH Strategy 2.2, encouraging identification of early biological and environmental risk and protective factors and their underlying mechanisms to inform the continued development of prevention and intervention.