Neurobiological mechanisms of adverse mental health outcomes following early regulatory problems

An intriguing and modifiable risk factor for later psychopathology is the early regulation of bodily functions, such as the sleep-wake cycle, self-soothing and food ingestion. Crucially, the regulation of bodily functions goes awry in about 20% of infants leading to regulatory problems (RPs) with crying, sleeping and/or feeding. About 2-8% of infants and toddlers experience multiple or prolonged RPs. Mounting evidence shows that RPs can have adverse long-term effects on behavioural, emotional and/or social outcomes. However, despite the substantial relevance for individuals’ mental health, and the high potential for early intervention, comprehensive generalizable findings on adverse effects of early RPs are still missing. Studies have typically assessed single populations, ignored neurobiology, and treated problems and disorders as distinct and isolated categories, despite comorbidity, heterogeneity and continuity within and between the categories. Reliable findings that could impact health policies would require large prospective studies, needing substantial effort and cost. However, these investments would be unwarranted as re-using and combining existing data represents a highly efficient solution. The proposed project will investigate the impact of early RPs on mental health outcomes from childhood to adulthood, examining multimodal neurobiological markers as possible underlying mechanisms. We will go beyond the state- of-the-art in three ways. Firstly, we will analyse rich phenotypic and neuroimaging data of three population-based studies from three countries (Generation R, ALSPAC and BLS). To enable cross-timepoint and cross-dataset brain surface analysis, we will develop novel robust vertex-wise mixed modelling, meta-analysis and federated mega- analysis tools as part of an existing open-source R package. Secondly, we will examine neurobiological pathways of the RP-mental health association, via brain structure (i.e., cortex morphology) and function (i.e., intrinsic functional connectivity). Thirdly, we will employ the hierarchical dimensional HiTOP framework to characterise adverse outcomes of early RPs with better precision and generalisability. This will result in new findings on the neurobiology and effects of RPs on dimensional mental health phenotypes, and crosswalk models for the research community. The findings will provide novel insights and potential prevention strategies for undesirable infant-to-adult trajectories.