Generalized anxiety disorder (GAD) is a debilitating illness characterized by persistent and exaggerated worrying. It can disruptively interfere with everyday functioning, and is associated with poor health, and negative financial and social outcomes. As one of the most common anxiety disorders, GAD affects millions of Americans each year with a 12-month prevalence of 3.1%. Compared to the stable rates in children and younger adolescents, new onset of GAD increases substantially from 16 to 26 years of age, suggesting the transition from late adolescence to early adulthood as a key high-risk stage for GAD. Amygdala-frontal circuitry, particularly functional interactions between the amygdala and anterior cingulate cortex (ACC), plays a critical role in threat processing and emotional regulation, and has been centrally implicated in anxiety disorders. Specifically, adult-like connectivity/activity in the ACC appears to emerge in late adolescence, and gradually develops into adulthood as an effective top-down inhibitory regulation. It is possible that developmental deviations of the amygdala-ACC interaction may trigger the development of GAD during the transition from late adolescence to early adulthood. Therefore, a cross-sectional multimodal study (fMRI+MRS [functional MRI + magnetic resonance spectroscopy]) is designed to examine the developmental trajectories of amygdala-ACC circuitry in healthy (N = 40) and anxious (N = 40) participants between 16 to 26 years old. The overarching objective of this study is to uncover an integrated functional-neurochemical biomarker for healthy versus anxious development. Specifically, fMRI will be used to measure the functional connectivity between the amygdala and the ACC in response to social threats; 1H-MRS will be used to measure the concentrations of the primary excitatory neurotransmitter glutamate and the primary inhibitory neurotransmitter GABA (?- aminobutyric acid) in the ACC. Disrupted functional connectivity and imbalanced neurochemistry as identified in this study can serve as objective and developmentally sensitive markers for identifying at-risk individuals for early intervention and prevention of GAD. The integrated functional-neurochemical biomarker of healthy and anxious development can also guide the development of novel treatments targeting at the glutamatergic and GABAergic systems from a neurodevelopmental perspective.
This is a neuroimaging study exploring functional connectivity and neurochemical changes related to development and anxiety from adolescence to young adulthood. The results can be used to inform early intervention and prevention of generalized anxiety disorder, and to develop treatment strategies from a neurodevelopmental perspective. 6
