Altered Development of Amygdala-Anterior Cingulate Cortex Connectivity in Anxious Youth and Young Adults

Background Connectivity between the amygdala and ventromedial prefrontal cortex (vmPFC) is compromised in multiple psychiatric disorders, many of which emerge during adolescence. To identify what extent the deviations in amygdala-vmPFC maturation contribute to the onset of psychiatric disorders, it is essential to characterize amygdala-vmPFC connectivity changes during typical development. Methods Using an accelerated cohort longitudinal design (1–3 time points, 10–25 years, N=246), we characterized developmental changes of amygdala-vmPFC subregion functional and structural connectivity using resting state fMRI and diffusion-weighted imaging. Results Functional connectivity between the centromedial amygdala and rostral anterior cingulate (rACC), anterior vmPFC, and subgenual cingulate significantly decreased from late childhood to early adulthood in males and females. Age associated decreases were also observed between the basolateral amygdala and rACC. Importantly, these findings were replicated in a separate cohort (10–22 years, N=327). Similarly, structural connectivity, as measured by quantitative anisotropy, significantly decreased with age in the same regions. Functional connectivity between the centromedial amygdala and rACC was associated with structural connectivity in these same regions during early adulthood (ages 22–25). Finally, a novel time-varying coefficient analysis showed that increased centromedial amygdala-rACC functional connectivity was associated with greater anxiety and depression symptoms during early adulthood, while increased structural connectivity in centromedial amygdala-anterior vmPFC white matter was associated with greater anxiety/depression during late childhood. Conclusions Specific developmental periods of functional and structural connectivity between amygdala-prefrontal systems may contribute to the emergence of anxiety and depressive symptoms, and may play a critical role in the emergence of psychiatric disorders in adolescence.

Background Approximately 40-45% of youth with anxiety disorders do not achieve remission (or a substantial reduction in symptoms) following treatment, highlighting the need to identify predictors of treatment response. Given the well-established link between attentional biases and anxiety disorders in youth and adults, the current study examined the neural correlates of directing attention toward and away from emotional faces in relation to pediatric anxiety treatment response. Method Prior to beginning treatment with the selective serotonin reuptake inhibitor (SSRI) sertraline or cognitive behavior therapy (CBT), 37 youth (age 7-19 years) with generalized and/or social anxiety disorder completed a task with conditions that manipulated whether participants were instructed to match emotional faces (explicit emotion processing) or match shapes in the context of emotional face distractors (implicit emotion processing) during functional magnetic resonance imaging. Results Results revealed that reduced activation in superior frontal gyrus (SFG), encompassing the dorsal anterior cingulate cortex (ACC) and dorsomedial prefrontal cortex (PFC), during implicit processing of emotional faces predicted a greater reduction in anxiety severity pre-to-post treatment. Post-hoc analyses indicated that effects were not significantly moderated by type of treatment or anxiety type. Conclusions Findings suggest that less recruitment of SFG, including the dorsal ACC and dorsomedial PFC, during implicit emotion processing predicts a greater reduction in youth anxiety symptoms pre-to-post treatment. Youth who exhibit reduced activation in these areas while matching shapes in the context of emotional face distractors may have more to gain from CBT and SSRI treatment due to preexisting deficits in attentional control. These findings suggest neuroimaging may be a useful tool for predicting which youth are most likely to benefit from anxiety treatment.

Life history theory argues that exposure to early-life adversity (ELA) accelerates development, although existing evidence for this varies. We present a meta-analysis and systematic review testing the hypothesis that ELA involving threat (e.g., violence exposure) will be associated with accelerated biological aging across multiple metrics, whereas exposure to deprivation (e.g., neglect, institutional rearing) and low-socioeconomic status (SES) will not. We meta-analyze 46 studies (n=64,925) examining associations of ELA with pubertal timing and cellular aging (telomere length and DNA methylation age), systematically review 19 studies (n=2276) examining ELA and neural markers of accelerated development (cortical thickness and amygdala-prefrontal cortex functional connectivity) and evaluate whether associations of ELA with biological aging vary according to the nature of adversity experienced. ELA overall was associated with accelerated pubertal timing (d=-0.12) and cellular aging (d=-0.32). Moderator analysis revealed that ELA characterized by threat (d=-0.26), but not deprivation or SES, was associated with accelerated pubertal development. Similarly, exposure to threat-related ELA was associated with accelerated cellular aging (d=-0.43), but not deprivation or SES.Systematic review revealed associations between ELA and accelerated cortical thinning, with threat-related ELA consistently associated with thinning in ventromedial prefrontal cortex, and deprivation and SES associated with thinning in frontoparietal, default, and visual networks.There was no consistent association of ELA with amygdala-PFC connectivity. These findings suggest specificity in the types of early environmental experiences associated with accelerated biological aging and highlight the importance of evaluating how accelerated aging contributes to health disparities and whether this process can be mitigated through early intervention.