Evidence of Disrupted Hippocampal Gray- and White-Matter Development in Adolescent Anxiety Disorders, Independent From Early-Life Stress

Early-life stress and depression among youths are linked to hippocampal gray- and white-matter alterations. Less is known about hippocampal alterations in adolescent anxiety disorders (Anx) or the role that stress or comorbid depressive disorders (Anx + Dep) might play. Here, structural- and diffusion-MRI along with early-life stress-exposure reports were acquired from 197 adolescents (13.58-17.00 years) with Anx, Anx + Dep, and those without (Controls). A normative model externally validated on a large, healthy sample revealed that Anx were more likely than Controls and Anx + Dep to exhibit undersized hippocampal gray-matter volumes for their ages. Volume reductions among Anx were further localized to subfield CA1. No significant gray-matter differences were observed between Anx + Dep and Controls. Standardized probabilistic tractography in hippocampal white-matter pathways demonstrated that, relative to Controls, Anx and Anx + Dep exhibited lower fractional anisotropy specifically in the cingulum-temporal branch. All effects were specific to hippocampal structures. Group differences were not accounted for by early-life stress exposures, despite Anx and Anx + Dep reporting more than Controls. Findings indicated that gray-matter expansion, principally within CA1, may be disrupted among adolescents with anxiety disorders, but not those with comorbid depression. The progressive strengthening of hippocampal-cortical circuits occurring during adolescence may also be disrupted in adolescents with anxiety disorders, regardless of depression.