Pro-inflammatory markers interact with spontaneous theta oscillations to predict depression among adolescents

Adolescence is a period of heightened neuroimmune plasticity, during which inflammatory activity may be associated with neural processes relevant to depression risk. To obtain a range of symptoms, adolescents (N = 182; 13-18-years-old) were recruited across three groups: remitted major depressive disorder (MDD; n = 88), current MDD (n = 33), and healthy controls (n = 61). At baseline, participants completed clinical assessments and provided resting-state electroencephalography (EEG) data and saliva for inflammatory assays. Clinical follow-up assessments were completed at 6 and 12 months. Confirmatory factor analysis of IL-1β, IL-6, IL-8, and TNF-α supported a latent pro-inflammatory activity factor (χ²(17) = 21.82, p = 0.192; CFI = 0.99; RMSEA = 0.04; ω = 0.86). Periodic theta power was extracted from the power spectrum and averaged across frontal and centroparietal electrode clusters. Linear mixed-effects models showed that neither inflammatory activity nor theta power were prospectively associated with depressive symptoms. However, inflammatory activity interacted with centroparietal theta power to predict future depressive symptoms (B = -0.395, p = 0.010), such that higher inflammatory activity was associated with greater follow-up depressive symptoms among adolescents with lower centroparietal theta power. The interaction between frontal theta power and inflammatory activity was non-significant (B = 0.271, p = 0.054). Among adolescents with remitted MDD, Cox proportional hazards models indicated that higher centroparietal theta interacted with inflammatory activity to predict depression recurrence (Hazard Ratio [HR] = 0.22, 95% CI: 0.07, 0.72), whereas frontal theta did not interact with inflammatory activity to predict recurrence (HR = 2.42, 95% CI: 0.86, 6.82). Findings suggest that spontaneous theta oscillations may provide a mechanistically grounded framework for stratifying risk and guiding targeted interventions in the context of inflammation-related depression among adolescents.