No robust evidence for an interaction between early-life adversity and protective factors on global and regional brain volumes

Andrea P. Cortes Hidalgo*, Henning Tiemeier, Stephen A. Metcalf, Maximilian Monninger, Andreas Meyer-Lindenberg, Pascal M. Aggensteiner, Marian J. Bakermans‑Kranenburg, Tonya White, Tobias Banaschewski, Marinus H. van IJzendoorn, Nathalie E. Holz

*Corresponding author for this work

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Childhood adversity is associated with brain morphology and poor psychological outcomes, and evidence of protective factors counteracting childhood adversity effects on neurobiology is scarce. We examined the interplay of childhood adversity with protective factors in relation to brain morphology in two independent longitudinal cohorts, the Generation R Study (N = 3008) and the Mannheim Study of Children at Risk (MARS) (N = 179). Cumulative exposure to 12 adverse events was assessed across childhood until age 9 years in Generation R and 11 years in MARS. Protective factors (temperament, cognition, self-esteem, maternal sensitivity, friendship quality) were assessed at various time-points during childhood. Global brain volumes and volumes of amygdala, hippocampus, and the anterior cingulate, medial orbitofrontal and rostral middle frontal cortices were assessed with anatomical scans at 10 years in Generation R and at 25 years in MARS. Childhood adversity was related to smaller cortical grey matter, cerebral white matter, and cerebellar volumes in children. Also, no buffering effects of protective factors on the association between adversity and the brain outcomes survived multiple testing correction. We found no robust evidence for an interaction between protective factors and childhood adversity on broad brain structural measures. Small interaction effects observed in one cohort only warrant further investigation.

Original languageEnglish
Article number101166
JournalDevelopmental Cognitive Neuroscience
Publication statusPublished - Dec 2022

Bibliographical note

Funding and Acknowledgments
The authors gratefully acknowledge financial support by a short-term research grant from the German Academic Exchange Service (DAAD) to APCH, a ZonMw VICI grant awarded to HT (project number 016.VICI.170.200), and an award from the Netherlands Organization for Scientific Research (NWO; Spinoza prize) to MHVIJ. MJB-K was supported by the European Research Council (ERC AdG 669249). MHVIJ and MJB-K were also supported by the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the NWO (024.001.003). SAM was supported by an Open Research Award from the Fulbright US Student Program and a Gates Cambridge Scholarship from the Gates Cambridge Trust (Bill & Melinda Gates Foundation grant OPP1144). AML acknowledges grant support by the German Research Foundation (DFG, Research Training Group GRK2350/1 project B02, Collaborative Research Center SFB 1158 project B09, Collaborative Research Center TRR 265 project S02, Grant ME 1591/4-1), German Federal Ministry of Education and Research (BMBF, Grants 01EF1803A, 01ZX1314G, 01GQ1003B), European Union’s Seventh Framework Programme (FP7, Grants 602450, 602805, 115300, HEALTH-F2-2010-241909), Innovative Medicines Initiative Joint Undertaking (IMI, Grant 115008) and Ministry of Science, Research and the Arts of the State of Baden-Wuerttemberg, Germany (MWK, Grant 42-04HV.MED (16)/16/1).

NEH gratefully acknowledges grants from the German Research Foundation (Grant nos. DFG HO 5674/2-1, GRK2350/1), the Radboud University (Radboud Excellence Fellowship) and the Ministry of Science, Research and the Arts of the State of Baden-Württemberg, Germany (Special support program SARS CoV-2 pandemic).

The general design of the Generation R Study received financial support from the Erasmus Medical Center, Rotterdam, the Erasmus University Rotterdam, ZonMw, the Netherlands Organisation for Scientific Research (NWO), and the Dutch Ministry of Health, Welfare and Sport. Neuroimaging and the neuroimaging infrastructure were supported by ZonMw TOP grant awarded to TW (Project no. 91211021). Supercomputing resources were provided by NWO (, Cartesius).

The funding sources were not involved in the study design, data collection, analysis and interpretation, or in the writing of this manuscript and submission for publication.

The authors thank the contribution of children and parents, general practitioners, hospitals, midwives, and pharmacies in Rotterdam for their participation in the Generation R Study.

The authors thank Sibylle Heinzel, Arlette Buchmann, Dorothea Blomeyer, Erika Hohm, Katrin Zohsel, Elisabeth Reichert, Anna Becker, Angelika Bocklage, Andrea Len, Daniel Megally, and Elise Jezycki for conducting and supporting the assessments and the participants of the MARS.

This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation [Grant OPP1144]. Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.

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