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Early life stress moderates the relation between systemic inflammation and neural activation to reward in adolescents both cross-sectionally and longitudinally

Neuropsychopharmacology volume 49, pages 532–540 (2024)Cite this article

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Abstract

Elevated levels of systemic inflammation are associated with altered reward-related brain function in ventral striatal areas of the brain like the nucleus accumbens (NAcc). In adolescents, cross-sectional research indicates that exposure to early life stress (ELS) can moderate the relation between inflammation and neural activation, which may contribute to atypical reward function; however, no studies have tested whether this moderation by ELS of neuroimmune associations persists over time. Here, we conducted a cross-sectional analysis and the first exploratory longitudinal analysis testing whether cumulative severity of ELS moderates the association of systemic inflammation with reward-related processing in the NAcc in adolescents (n = 104; 58F/46M; M[SD] age = 16.00[1.45] years; range = 13.07–19.86 years). For the cross-sectional analysis, we modeled a statistical interaction between ELS and levels of C-reactive protein (CRP) predicting NAcc activation during the anticipation and outcome phases of a monetary reward task. We found that higher CRP was associated with blunted NAcc activation during the outcome of reward in youth who experienced higher levels of ELS (β = –0.31; p = 0.006). For the longitudinal analysis, we modeled an interaction between ELS and change in CRP predicting change in NAcc activation across 2 years. This analysis similarly showed that increasing CRP over time was associated with decreasing NAcc during reward outcomes in youth who experienced higher levels of ELS (β = –0.47; p = 0.022). Both findings support contemporary theoretical frameworks involving associations among inflammation, reward-related brain function, and ELS exposure, and suggest that experiencing ELS can have significant and enduring effects on neuroimmune function and adolescent neurodevelopment.

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Fig. 1: Bilateral nucleus accumbens (NAcc) mask.
Fig. 2: ELS and CRP interaction.
Fig. 3: ELS and CRP longitudinal interaction.

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Acknowledgements

We thank Anna Cichocki, Lauren Costello, Miranda Edwards, Jordan Garcia, Abigail Graber, Madelaine Graber, Melissa Hansen, Emma Jaeger, Julian Joachimsthaler, Vanessa Lopez, Amar Ojha, Holly Pham, Michelle Sanabria, Jill Segarra, Lucinda Sisk, Alexess Sosa, Megan Strickland, Giana Teresi, Johanna Walker, and Rachel Weisenburger for their assistance in data collection and management. We also thank Yael Rosenberg-Hasson and Holden Maecker for their assistance with the dried blood spot protocol. Finally, we thank all our participants and their families for participating in this research.

Funding

This research was supported by grants from the National Institute of Mental Health (R37MH101495 to IHG and K01MH117442 to TCH), the Stanford University Precision Health and Integrated Diagnostics (PHIND) Center (to IHG and TCH), the Stanford Institute for Research in the Social Sciences (IRiSS), the Stanford Psychology Norman Anderson Fund, and the National Science Foundation Graduate Research Fellowship Program (NSF GRFP) (all to JPY).

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  1. Department of Psychology, Stanford University, Stanford, CA, USA

    Justin P. Yuan, Saché M. Coury & Ian H. Gotlib

  2. Department of Psychology, University of California, Los Angeles, CA, USA

    Tiffany C. Ho

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JPY and IHG designed the study, JPY led the data processing and analysis, and writing; SMC contributed to data collection and processing, and TCH helped with data analysis and interpretation. All authors contributed to the final manuscript.

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Correspondence to Justin P. Yuan.

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Yuan, J.P., Coury, S.M., Ho, T.C. et al. Early life stress moderates the relation between systemic inflammation and neural activation to reward in adolescents both cross-sectionally and longitudinally. Neuropsychopharmacol. 49, 532–540 (2024). https://doi.org/10.1038/s41386-023-01708-y

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