Revisiting Resting-State Functional Connectivity of the Amygdala and Subgenual Anterior Cingulate Cortex in Depressed Adolescents and Adults

Background: Adolescent depression is a growing public health concern, and neuroimaging offers a promising approach to its pathology. We focused on the functional connectivity of the amygdala and subgenual anterior cingulate cortex (sgACC), which is theoretically important in major depressive disorder (MDD), but empirical evidence has remained inconsistent. This discrepancy is likely due to the limited statistical power of small sample sizes.

Methods: We rigorously examined sgACC-amygdala connectivity in depressed adolescents and adults using data from the Healthy Brain Network (n=321; 170 females), the Adolescent Brain Cognitive Development study (n=141; 56 females), the Boston Adolescent Neuroimaging of Depression and Anxiety study (n=108; 75 females), and the REST-meta-MDD project (n=1436; 880 females). Linear mixed models, Bayesian factor analyses, and meta-analysis were employed to assess connectivity.

Results: Our analyses revealed that sgACC-amygdala connectivity in adolescents with MDD was comparable to that in healthy controls, whereas adults with recurrent MDD exhibited reduced connectivity. Resampling analysis demonstrated that small sample sizes (i.e., n<30 MDDs) tend to inflate effects, potentially leading to misinterpretations.

Conclusions: These findings clarify the state of sgACC-amygdala connectivity in MDD and underscore the importance of refining neurocognitive models separately for adolescents and adults. The study also highlights the necessity for large-scale replication studies to ensure robust and reliable findings.