Early-life adversity is a well-established correlate of later mental ill-health, yet developmental outcomes are highly heterogeneous. This review advances a developmental brain health framework that shifts emphasis from disorder endpoints to lifespan regulatory capacity, integrating evidence across developmental neuroscience, clinical science, translational psychiatry, public health and social context (section 1). We outline core principles of developmental plasticity, including critical and sensitive periods and the distinction between experience-expectant and experience-dependent processes (section 2).
We synthesise how early adversity becomes clinically expressed and biologically embedded through interacting behavioural, epigenetic, neuroimmune, and neurosocial pathways. By distinguishing downstream neurobiological correlates of risk from mechanisms that regulate plasticity itself, we delineate where human evidence is strong and where inference relies on biologically proximal experimental models (section 3). The contribution of this review is integrative and translational rather than proposing a new theory: we clarify how emerging regulatory mechanisms, including multisystem stress regulation, social neurobiological pathways, and neuroimmune modulation, fit within established developmental frameworks and inform brain health-relevant intervention targets.
Complementary developmental-adaptation models are integrated as linked levels of description, converging on a life-course perspective in which brain health emerges from cumulative, timing-sensitive biology-experience interactions (section 4). Translation is anchored in concrete developmental pathways, with a focused attention to parental mental health, pregnancy, and parent-child co-regulation as modifiable contexts through which supportive environments may recalibrate regulatory systems (section 5). We conclude with timing-sensitive, family-inclusive implications for prevention (section 6), and priorities for testable, lifespan-oriented models supported by multimodal biomarkers and equitable policy (section 7).
MC and ETC are supported by University of Buenos Aires and CONICET. GASM is supported by the Dr. Bryan Kolb Chair in Neuroscience, University of Lethbridge.
BRHVdB is supported by SBO project S003524N of the Research Foundation Flanders (Fonds voor Wetenschappelijk Onderzoek (FWO)-Vlaanderen) and by COST Action CA22114, funded by European Cooperation in Science and Technology. Laboratorio de Neuroepigenética y Adversidades Tempranas, Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN), CONICET-Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Buenos Aires, Argentina Department of Obstetrics and Gynecology and Institute on Human Development and Disability, University of Washington, Seattle, WA, USA Health Stream Analytics, LLC, Seattle, WA, USA Department of Neuroscience and Canadian Centre for Behavioural Neuroscience, University of Lethbridge, Lethbridge, Canada Laboratorio de Programación Perinatal del Neurodesarrollo. Instituto de Biología Celular y Neurociencias “Prof.
Universidad de Buenos Aires, Buenos Aires, Argentina Department of Psychiatry & Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, USA Research Group Health Psychology and Leuven Brain Institute, Faculty of Psychology and Educational Science, KU Leuven, Leuven, Belgium MGF holds US patents on maternal-foetal health monitoring and equity in several pregnancy health start-ups. The authors declare that there are no other competing interests associated with the manuscript. During the first draft and the revisions, the authors used AI for literature search (Consensus, Endnote), language editing and improvement of clarity and coherence (ChatGPT).
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