Coordination Between Frontolimbic Resting State Connectivity and Hypothalamic-pituitary-adrenal Axis Functioning in Adolescents with and Without Depression

Depression is associated with abnormalities in Hypothalamic-Pituitary-Adrenal (HPA) axis functioning and neural circuitry that underlie the stress response. Resting-state functional connectivity (RSFC) between frontolimbic brain regions captures intrinsic connections that may set the stage for the rallying and regulating of the HPA axis system. This study examined the association between cortisol stress response and frontolimbic (amygdala and ventral and dorsal medial prefrontal cortex [vmPFC and dmPFC respectively]) RSFC in 88 (Age: M = 15.95, SD = 2.04; 71.60% female) adolescents with (N = 55) and without (N = 33) major depressive disorder (MDD). We collected salivary cortisol in the context of a modified Trier Social Stress Test (TSST) paradigm. Key findings were that adolescents with depression and healthy controls showed different patterns of association between amygdala and vmPFC RSFC and HPA functioning: while healthy controls showed a positive relationship between frontolimbic connectivity and cortisol levels that may indicate coordination across neural and neuroendocrine systems, adolescents with depression showed a minimal or inverse relationship, suggesting poor coordination of these systems. Results were similar when examining non-suicidal self-injury subgroups within the MDD sample. These findings suggest that the intrinsic quality of this frontolimbic connection may be related to HPA axis functioning. In MDD, inverse associations may represent a compensatory response in one system in response to dysfunction in the other. Longitudinal multilevel research, however, is needed to disentangle how stress system coordination develops in normal and pathological contexts and how these systems recover with treatment.