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Early life events can exert a powerful influence on both the pattern of brain architecture and behavioral development. In this study a conceptual framework is provided for considering how the structure of early experience gets \"under the skin,\" The study begins with a description of the genetic framework that lays the foundation for brain development, and then proceeds to the ways experience interacts with and modifies the structures and functions of the developing brain. Much of the attention is focused on early experience and sensitive periods, although it is made clear that later experience also plays an important role in maintaining and elaborating this early wiring diagram, which is critical to establishing a solid footing for development beyond the early years.

Background Adverse psychosocial exposures in early life, namely experiences such as child maltreatment, caregiver stress or depression, and domestic or community violence, have been associated in epidemiological studies with increased lifetime risk of adverse outcomes, including diabetes, heart disease, cancers, and psychiatric illnesses. Additional work has shed light on the potential molecular mechanisms by which early adversity becomes “biologically embedded” in altered physiology across body systems. This review surveys evidence on such mechanisms and calls on researchers, clinicians, policymakers, and other practitioners to act upon evidence. Observations Childhood psychosocial adversity has wide-ranging effects on neural, endocrine, immune, and metabolic physiology. Molecular mechanisms broadly implicate disruption of central neural networks, neuroendocrine stress dysregulation, and chronic inflammation, among other changes. Physiological disruption predisposes individuals to common diseases across the life course. Conclusions Reviewed evidence has important implications for clinical practice, biomedical research, and work across other sectors relevant to public health and child wellbeing. Warranted changes include increased clinical screening for exposures among children and adults, scale-up of effective interventions, policy advocacy, and ongoing research to develop new evidence-based response strategies.

The COVID-19 pandemic priorities have focused on prevention, detection, and response. Beyond morbidity and mortality, pandemics carry secondary impacts, such as children orphaned or bereft of their caregivers. Such children often face adverse consequences, including poverty, abuse, and institutionalisation. We provide estimates for the magnitude of this problem resulting from COVID-19 and describe the need for resource allocation. We used mortality and fertility data to model minimum estimates and rates of COVID-19-associated deaths of primary or secondary caregivers for children younger than 18 years in 21 countries. We considered parents and custodial grandparents as primary caregivers, and co-residing grandparents or older kin (aged 60–84 years) as secondary caregivers. To avoid overcounting, we adjusted for possible clustering of deaths using an estimated secondary attack rate and age-specific infection–fatality ratios for SARS-CoV-2. We used these estimates to model global extrapolations for the number of children who have experienced COVID-19-associated deaths of primary and secondary caregivers. Globally, from March 1, 2020, to April 30, 2021, we estimate 1 134 000 children (95% credible interval 884 000–1 185 000) experienced the death of primary caregivers, including at least one parent or custodial grandparent. 1 562 000 children (1 299 000–1 683 000) experienced the death of at least one primary or secondary caregiver. Countries in our study set with primary caregiver death rates of at least one per 1000 children included Peru (10·2 per 1000 children), South Africa (5·1), Mexico (3·5), Brazil (2·4), Colombia (2·3), Iran (1·7), the USA (1·5), Argentina (1·1), and Russia (1·0). Numbers of children orphaned exceeded numbers of deaths among those aged 15–50 years. Between two and five times more children had deceased fathers than deceased mothers. Orphanhood and caregiver deaths are a hidden pandemic resulting from COVID-19-associated deaths. Accelerating equitable vaccine delivery is key to prevention. Psychosocial and economic support can help families to nurture children bereft of caregivers and help to ensure that institutionalisation is avoided. These data show the need for an additional pillar of our response: prevent, detect, respond, and care for children. UK Research and Innovation (Global Challenges Research Fund, Engineering and Physical Sciences Research Council, Medical Research Council), UK National Institute for Health Research, US National Institutes of Health, and Imperial College London.

We used structural MRI and EEG to examine brain structure and function in typically developing children in Romania (n = 20), children exposed to institutional rearing (n = 29), and children previously exposed to institutional rearing but then randomized to a high-quality foster care intervention (n = 25). In so doing, we provide a unique evaluation of whether placement in an improved environment mitigates the effects of institutional rearing on neural structure, using data from the only existing randomized controlled trial of foster care for institutionalized children. Children enrolled in the Bucharest Early Intervention Project underwent a T1-eighted MRI protocol. Children with histories of institutional rearing had significantly smaller cortical gray matter volume than never-institutionalized children. Cortical white matter was no different for children placed in foster care than never-institutionalized children but was significantly smaller for children not randomized to foster care. We were also able to explain previously reported reductions in EEG α-power among institutionally reared children compared with children raised in families using these MRI data. As hypothesized, the association between institutionalization and EEG α-power was partially mediated by cortical white matter volume for children not randomized to foster care. The increase in white matter among children randomized to an improved rearing environment relative to children who remained in institutional care suggests the potential for developmental \"catch up\" in white matter growth, even following extreme environmental deprivation.

Autism spectrum disorder (ASD) is a complex and heterogeneous disorder, diagnosed on the basis of behavioral symptoms during the second year of life or later. Finding scalable biomarkers for early detection is challenging because of the variability in presentation of the disorder and the need for simple measurements that could be implemented routinely during well-baby checkups. EEG is a relatively easy-to-use, low cost brain measurement tool that is being increasingly explored as a potential clinical tool for monitoring atypical brain development. EEG measurements were collected from 99 infants with an older sibling diagnosed with ASD, and 89 low risk controls, beginning at 3 months of age and continuing until 36 months of age. Nonlinear features were computed from EEG signals and used as input to statistical learning methods. Prediction of the clinical diagnostic outcome of ASD or not ASD was highly accurate when using EEG measurements from as early as 3 months of age. Specificity, sensitivity and PPV were high, exceeding 95% at some ages. Prediction of ADOS calibrated severity scores for all infants in the study using only EEG data taken as early as 3 months of age was strongly correlated with the actual measured scores. This suggests that useful digital biomarkers might be extracted from EEG measurements.

Significance Disruptions in stress response system functioning are thought to be a central mechanism by which exposure to adverse early-life environments influences human development. Although rodent models support this possibility, results from human studies have been decidedly mixed. Using data from an experimental study examining whether random assignment to a caregiving environment alters development of the autonomic nervous system and hypothalamic–pituitary–adrenal axis in humans, we provide causal evidence for persistent effects of the early caregiving environment on stress response system functioning in humans with effects that differ markedly from those observed in rodent models. We also provide evidence of a sensitive period in human development during which the environment is particularly likely to alter stress response system development. Disruptions in stress response system functioning are thought to be a central mechanism by which exposure to adverse early-life environments influences human development. Although early-life adversity results in hyperreactivity of the sympathetic nervous system (SNS) and hypothalamic–pituitary–adrenal (HPA) axis in rodents, evidence from human studies is inconsistent. We present results from the Bucharest Early Intervention Project examining whether randomized placement into a family caregiving environment alters development of the autonomic nervous system and HPA axis in children exposed to early-life deprivation associated with institutional rearing. Electrocardiogram, impedance cardiograph, and neuroendocrine data were collected during laboratory-based challenge tasks from children (mean age = 12.9 y) raised in deprived institutional settings in Romania randomized to a high-quality foster care intervention ( n = 48) or to remain in care as usual ( n = 43) and a sample of typically developing Romanian children ( n = 47). Children who remained in institutional care exhibited significantly blunted SNS and HPA axis responses to psychosocial stress compared with children randomized to foster care, whose stress responses approximated those of typically developing children. Intervention effects were evident for cortisol and parasympathetic nervous system reactivity only among children placed in foster care before age 24 and 18 months, respectively, providing experimental evidence of a sensitive period in humans during which the environment is particularly likely to alter stress response system development. We provide evidence for a causal link between the early caregiving environment and stress response system reactivity in humans with effects that differ markedly from those observed in rodent models.

In a randomized controlled trial, we compared abandoned children reared in institutions to abandoned children placed in institutions but then moved to foster care. Young children living in institutions were randomly assigned to continued institutional care or to placement in foster care, and their cognitive development was tracked through 54 months of age. The cognitive outcome of children who remained in the institution was markedly below that of never-institutionalized children and children taken out of the institution and placed into foster care. The improved cognitive outcomes we observed at 42 and 54 months were most marked for the youngest children placed in foster care. These results point to the negative sequelae of early institutionalization, suggest a possible sensitive period in cognitive development, and underscore the advantages of family placements for young abandoned children.

Experience plays an essential role in building brain architecture after birth. The question we address in this paper is what happens to brain and behavior when a young child is deprived of key experiences during critical periods of brain development. We focus in particular on the consequences of institutional rearing, with implication for the tens of millions of children around the world who from an early age experience profound psychosocial deprivation. Evidence is clear that deprivation can lead to a host of both short- and long-term consequences, including perturbations in brain structure and function, changes at cellular and molecular levels, and a plethora of psychological and behavioral impairments.

Brain plasticity is dynamically regulated across the life span, peaking during windows of early life. Typically assessed in the physiological range of milliseconds (real time), these trajectories are also influenced on the longer timescales of developmental time (nurture) and evolutionary time (nature), which shape neural architectures that support plasticity. Properly sequenced critical periods of circuit refinement build up complex cognitive functions, such as language, from more primary modalities. Here, we consider recent progress in the biological basis of critical periods as a unifying rubric for understanding plasticity across multiple timescales. Notably, the maturation of parvalbumin-positive (PV) inhibitory neurons is pivotal. These fast-spiking cells generate gamma oscillations associated with critical period plasticity, are sensitive to circadian gene manipulation, emerge at different rates across brain regions, acquire perineuronal nets with age, and may be influenced by epigenetic factors over generations. These features provide further novel insight into the impact of early adversity and neurodevelopmental risk factors for mental disorders.

Background There is now a growing scientific consensus that the origins of many adult diseases may be attributed to exposure to adversity early in life. Research over the past several decades indicates that many of the most common forms of non-communicable conditions, including both physical and psychiatric disorders, share a common biological foundation involving disruptions to shared biological systems that are likely fundamentally shaped by exposure to early adversity. Main text Despite the enormous promise of existing work, opportunities for clinical translation remain limited. Thus, we argue that it is now crucial to pause and consider the directions in which the field needs to move to ensure continued progress with the aim of protecting at-risk youth against the development of life-long disease. We first review recent work that has meaningfully contributed to a developmental cascade model wherein early life adversity sets off a cascade of dysregulations in the neuroendocrine, immune, and metabolic systems, which bidirectionally influence and are influenced by neural and epigenetic factors. We then outline four key directions for future work that we contend must be emphasized to maximize the clinical impact of this maturing field, including cross-disciplinary collaborations, multi-biomarker approaches, modeling disease processes prior to illness onset, and nuanced characterization of the early environment. Conclusions Recent work highlights nuanced pathways through which early life adversity contributes to the development of a biological foundation underlying risk for non-communicable conditions. We contend that it is crucial to reflect on future research directions to ensure continued progress and opportunities for clinical translation, as the development of an increasingly sophisticated understanding of the pathways linking adversity to illness holds enormous promise for our ability to promote health and prevent disease among at-risk youth.