Inflammation, fronto-amygdala connectivity, and negative affective reactivity to daily stress in adolescents.

Background: Maladaptive affective responses to daily stress in adolescence are a robust risk factor for the development of psychopathology. Importantly, however, adolescents vary widely in the magnitude of their affective reactivity to stress. Although peripheral inflammation and fronto-amygdala circuitry during emotion regulation are both plausible biological contributors to this variability, no study has yet integrated inflammatory markers, neural metrics of emotion regulation, and real-world assessments of stress and affect to examine how these systems interact to shape affective reactivity to stress in adolescents' daily life. Methods: Adolescents (N = 124; 60% female) aged 13.07-20.10 years (M = 16.20) completed a 14-day ecological momentary assessment (EMA) protocol assessing stressor occurrence, stress severity, and momentary affect. A subset of participants provided peripheral blood samples assayed for C-reactive protein (CRP) to index systemic inflammation (N = 85), and a further subset completed an fMRI affect-labeling task to quantify task-related functional connectivity between the amygdala and lateral prefrontal cortex (LPFC; N = 68). Multilevel models tested whether higher CRP predicted stronger within-person coupling of stress and negative affect (NA), and whether LPFC-amygdala connectivity moderated this association. Results: Higher stress severity predicted higher NA, and greater inflammation potentiated these stress-related increases in NA. A three-way interaction with DLPFC-amygdala connectivity may further moderate this association, but the effect did not survive correction for multiple comparisons, and the sample was underpowered to test it reliably. Conclusions: Inflammation was linked to stronger coupling of daily stress and negative affect in adolescents. Whether fronto-amygdala connectivity adds to this remains untested at adequate power.