(PS4-94) Interactive Association of Childhood Adversity and Peripheral Inflammation with Orbitofrontal Cortex Response to Reward Among Adolescents at Risk for Major Depression

Background: Reward-inflammation models of depression suggest that the combination of  elevated peripheral inflammation and low reward responsiveness confers risk for depression. Examination of this relationship during adolescence is critical, as adolescents experience increases in depressive symptoms and disorder onset, as well as normative maturation of reward systems. Adversity exposure is linked to changes in neuroimmune functioning and may influence the relationship between peripheral inflammation and reward anticipation in reward-relevant brain regions (e.g., nucleus accumbens [NAc] and orbitofrontal cortex [OFC)]). Recent studies of the link between inflammation and neural response to reward have focused on adolescents with a broad range of self-reported reward sensitivity. However, no studies have specifically examined adolescents with low trait reward sensitivity previously shown to be at risk for major depression. To address this gap, this study examined whether adversity exposure and peripheral inflammation levels interact to predict NAc and OFC response to reward anticipation among such high-risk adolescents.

Method: The sample included 128 adolescents, aged 13-16 years (M = 15.14, SD = 0.9, 57% Female), with no history of a major depressive episode confirmed by diagnostic interview. Adolescents were oversampled for those at risk for major depression based on low trait reward sensitivity. Participants completed a fasting blood draw to assess levels of peripheral inflammation, including C-reactive protein, Interleukin (IL)-6, IL-10, and tumor necrosis factor-alpha. Following previous conventions, log-transformed and z-standardized inflammatory biomarkers were aggregated into a composite score. Participants also completed the Monetary Incentive Delay task during fMRI to assess neural response to monetary reward anticipation. Participants self-reported demographics and adversity exposure on the Childhood Life Events Scale (CLES). fMRI data were processed using an internal pipeline and estimates of functional activation during reward anticipation represent gain vs. neutral anticipation contrasts quantified as t-scores. All analyses controlled for sex assigned at birth and body mass index (BMI).

Results: As hypothesized, inflammation significantly interacted with CLES total scores to predict lower OFC activation during monetary reward anticipation (b = -.025, SE = .008, p = .002, ΔR² = .040). This association was particularly strong among participants with high (+1 SD) adversity exposure (b = -.037, SE = .067, p = .008). In contrast, we did not detect a significant inflammation-by-CLES interaction for NAc activation (b = .00036, SE = .0094, p = .9, ΔR² = .017).

Conclusion: Our findings complement previous studies highlighting the relationship between inflammation and reward-related brain activity, and suggest that high adversity exposure may enhance neuroimmune relationships. Future analyses should explore the temporal relationship between adversity exposure and onset of depressive symptoms to investigate if attenuated reward responsiveness and elevated inflammation may mediate this relationship.