Neural vulnerability to stress in adolescents: a longitudinal study using polyconnectomic scoring of depression risk

Background Adolescence is a sensitive period of brain development when perceived stress can shape emotional and cognitive outcomes. However, it remains unclear how neural vulnerability modulates these effects. Methods In a longitudinal cohort of 407 adolescents, we assessed perceived stress, emotional symptoms, and cognitive function at baseline and follow-up. Neural vulnerability was indexed using polyconnectomic scoring for major depressive disorder (PCS-MDD), derived from large-scale functional connectivity patterns. An independent cohort of 80 adolescents with clinically diagnosed depressive disorders was included to explore the generalizability of the findings. Results At baseline, perceived stress was strongly associated with anxiety ( β = 0.59, p < 0.001) and depressive symptoms ( β = 0.55, p < 0.001), and was modestly associated with lower performance across multiple cognitive domains. Longitudinally, increases in perceived stress were robustly associated with increases in anxiety ( β = 0.56, p < 0.001) and depressive symptoms ( β = 0.52, p < 0.001). Moreover, PCS-MDD significantly moderated these associations (anxiety symptoms: p = 0.025, ΔR 2 = 0.008; depressive symptoms: p < 0.001, ΔR 2 = 0.023). Additionally, baseline PCS-MDD was significantly associated with follow-up anxiety ( β = 0.13, p = 0.024) and depressive symptoms ( β = 0.11, p = 0.043). Exploratory analyses further indicated that perceived stress was most strongly associated with depressive symptoms among adolescents with clinically diagnosed depressive disorders and higher PCS-MDD. Conclusions Higher PCS-MDD is associated with greater variability in stress-related emotional outcomes during adolescence. These results suggest that neural vulnerability may moderate the emotional correlates of stress and underscore the potential relevance of personalized interventions targeting stress regulation in youth with elevated vulnerability profiles.