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Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity (2019)

Chapter: 2 Healthy Development from Conception Through Early Childhood

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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 78
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 85
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 87
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 88
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 90
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 103
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 104
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 105
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 106
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 107
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 108
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
×
Page 109
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Page 110
Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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Suggested Citation:"2 Healthy Development from Conception Through Early Childhood." National Academies of Sciences, Engineering, and Medicine. 2019. Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity. Washington, DC: The National Academies Press. doi: 10.17226/25466.
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2 Healthy Development from Conception Through Early Childhood INTRODUCTION TO THE SCIENCE FROM PRENATAL THROUGH EARLY CHILDHOOD Fetal and early child development are often conceptualized as a “black box,” in which children simply learn by soaking up information, much like a sponge and water. Developmental science has demonstrated that development is, in fact, an active process and that it starts early. Thus, understanding early development, when biological systems and functions are coming “online,” is essential for ensuring that prevention, interventions, policies, and systems are responsive to the needs of children. This will provide children the best opportunity for healthy outcomes. When the science of early development is coupled with a health equity approach to inform decision making, it provides an opportunity to improve outcomes for children and families in at-risk contexts. The goal of this chapter is to reveal core concepts of brain development and other systems relevant to understanding the impact of disparities on cognitive, social-emotional, and physical health and to describe new scientific advances in this area over the last 20 years. This information can be used by the public and policy makers to better inform effective actions for promoting healthy outcomes. (See Box 2-1 for an overview of this chapter.) BOX 2-1 Chapter in Brief: Healthy Development There are theoretical, technical, and scientific advances over the last 20 years that have been instrumental in rapidly advancing the science of child development. This chapter highlights those advances and provides an overview of the core concepts of brain development and other body systems relevant to understanding the impact of early life adversity on cognitive, social-emotional, and physical health, including the mechanisms that link early life experiences to later outcomes. This information can be used by the public and policy makers to better inform effective actions for advancing health equity. Scientific advances in the last 20–30 years include • Early experiences are essential for building brain connections that underlie biobehavioral health, and current understanding of whole-child development relies on an interplay of organ systems with each other and the environment. • Responses to pre- and postnatal early adversity, such as poverty or maltreatment, are rooted in gene–environment interactions that can result in altered molecular and cellular development during sensitive periods of development. PREPUBLICATION COPY: UNCORRECTED PROOFS 2-1

2-2 VIBRANT AND HEALTHY KIDS • Chronic early adversity has negative impacts on the assembly of certain brain circuits and emotional control, cognitive growth, and stress responsiveness. • Certain body systems involved in cognitive and emotional development are more sensitive to early disturbances that activate stress response networks and provide a basis for both short- and long-term functional consequences of early life stress. • Early adversity can change the timing of critical periods of brain development, impacting the “plasticity” of developmental processes that are driven by experiences in the life of the young child and the family. • Deciphering the mechanisms through which adversity disrupts foundational developmental processes of the whole child and the long-term impact on health, wellness, personal and community relationships, and life-span productivity is being achieved through multidisciplinary, longitudinally designed research that has incorporated principles of human development, including individual differences and differential sensitivity to context. Chapter conclusions in brief: • Healthy development of the child begins in the preconception period and is dependent upon a strong foundation built prenatally. • Among all the factors that may serve to buffer negative outcomes produced by toxic stress, supportive relationships between the child and the adults in life are essential. • When considering the entire life course, it is early experiences, pre- and postnatally, that are the most powerful in working together with individual genetic makeup to influence the physical, mental, and cognitive development of the child. • Science shows that maternal health and well-being is a major contributing factor to the development of the fetus and establishes a foundation for positive or negative child health outcomes. • Based on the abundant science, the influence of access to basic resources prenatally, particularly nutritional, psychosocial, and health care components, is powerful. Resources to help families to limit chronic stress may reduce risk for disrupted development and help close disparities based on race, ethnicity, and socioeconomic status (SES). • New data, combined with previous studies, provides a compelling demonstration that toxic stress substantially increases later-life risk for lower educational achievement and physical illnesses, including obesity and type 2 diabetes, cardiovascular disease (CVD), substance abuse, mental illness, cancer, and infectious disease. In addition to the adverse effects of toxic stress on the brain and nervous system, it also affects every other organ system in the child's body, impacting short and long-term health. Early understanding of children’s development, as postulated by Piaget and many others in the 20th century, consisted of age-specific stages, ruled primarily by maturation and biology (Flavell, 1963). This characterization has undergone profound revisions. The 2000 publication by the National Research Council (NRC) and the Institute of Medicine (IOM), From Neurons to Neighborhoods: The Science of Early Childhood Development, provided a transformational synthesis of existing research to reveal a complexity of factors that influence development beyond previous simplified models. This landmark report integrated a wealth of scientific knowledge on early childhood development to emphasize the continuous, dynamic interaction between the environment and the biological systems of each individual across the life course. The report offered clear recommendations for policy and the future of developmental science that were organized around core principles of child development that remain accurate to this day (NRC and IOM, 2000). The report inspired new science and novel ways to communicate the science to the public, service providers, and policy makers. From Neurons to Neighborhoods spurred research to refine the fields’ understanding of how environmental influences shape child PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-3 development, even at a molecular resolution. The report motivated research to understand how health-promoting environments and responsive relationships enable a strong foundation for healthy child development (i.e., learning, adaptive behaviors, and optimal health), while chronic adversity in the absence of supporting caregivers can lead to increased risk for negative learning and health outcomes, both in childhood and well into adulthood. In the two decades since publication of the report, there has been a convergence of activities that led to many of the advances that will be described in this chapter. First, a wave of neurobiological studies in model systems and in humans underscored that responses to pre- and postnatal early life stress are rooted in genetic and environmental interactions that can result in altered molecular and cellular development that impacts the assembly of circuits during sensitive periods of development (Cameron et al., 2017; McEwen and Morrison, 2013; Shonkoff and Levitt, 2010). The demonstration that certain systems involved in cognitive and emotional development are more sensitive to early disturbances that activate stress response networks, such as the frontal cortex, hippocampus, amygdala, and hypothalamic-pituitary-adrenal (HPA) axis, provided a basis for both short- and long-term functional consequences of early life stress (Chen and Baram, 2016; Shonkoff et al., 2012). Second, life course theory (Ben-Shlomo et al., 2014; Kuh et al., 2003) and the developmental origins of an adult health and disease framework (Gluckman et al., 2007; Halfon et al., 2014) have become more widely adopted. Third, a key policy statement from the American Academy of Pediatrics in 2012 emphasized the important life-span health implications of the impact of early adversity (Shonkoff et al., 2012), declaring a “need for the entire medical community to focus more attention on the roots of adult diseases that originate during the prenatal and early childhood periods” (p. e233). Numerous research teams have clearly documented the effects and some mechanisms through which early childhood adversity affects development. Early adversity, such as maltreatment (Cicchetti, 1996; Teicher et al., 2016) and poverty (Cicchetti and Curtis, 2006; Council on Community Pediatrics, 2016; Gabrieli and Bunge, 2017; Johnson et al., 2016; McEwen and McEwen, 2017), has negative impacts on selective brain circuits and emotional control, cognitive growth, and stress responsiveness. A very new discovery, from multiple animal studies, shows that early adversity can change the timing of critical periods of brain development (Bath et al., 2016; Cameron et al., 2017; Hensch, 2016a; Heun-Johnson and Levitt, 2018), impacting the “plasticity” of developmental processes that are driven by experiences in the life of the young child and their family (Cicchetti, 2015a,b; Cicchetti and Blender, 2006; Pollak et al., 1997) (see Box 2-2). The extensions of the original retrospective Adverse Childhood Experiences (ACEs) Study by CDC and Kaiser Permanente fostered sustained scientific interest in the long-term implications of early childhood adversity (see Chapter 3 for more information). In addition, the prospective Dunedin Multidisciplinary Health and Development (Poulton et al., 2015), the Perry Preschool longitudinal study, and the Abecedarian studies (see Chapter 7 for more information on the Perry Preschool and Abecedarian projects) added to a growing body of scientific evidence that early experiences, positive or negative, have profound long-term effects on physical, mental, and cognitive functions. The U.S. Department of Health and Human Services introduced Healthy People 2020—and, subsequently, Healthy People 2030—which elevated the importance of research on strategies to intervene on health disparities, including among pregnant women and children, by declaring “the elimination of health disparities” as a national goal.1 Taken together, these research endeavors have generated many new questions about when and how early childhood adversity is incorporated biologically to influence long-term outcomes 1 For more information, see https://www.cdc.gov/dhdsp/hp2020.htm (accessed June 17, 2019). PREPUBLICATION COPY: UNCORRECTED PROOFS

2-4 VIBRANT AND HEALTHY KIDS and about optimal approaches to address early adversity and racial/ethnic and socioeconomic health disparities. These activities, and others, have pioneered and proliferated a new field of research on the importance of prenatal and early childhood experiences for health across generations. Beyond scientific advances, From Neurons to Neighborhoods can also be credited as the impetus for the establishment of the National Scientific Council on the Developing Child in 2003, which uses science to catalyze public and private activities to promote the healthy development of children (Center on the Developing Child at Harvard University, 2014), to “close the gaps” between what the science says and which actions will promote child well-being. Composed of subsets of members of the From Neurons to Neighborhoods committee and the MacArthur Research Network on Early Brain and Child Development, the Council has a central objective of communicating the science to the public and policy makers. Through an ongoing collaboration with FrameWorks Institute, applying qualitative and quantitative research on communicating the science of brain and child development, a suite of effective “explanatory metaphors” have been developed, including a taxonomy of the stress response: positive, tolerable, and toxic stress (National Scientific Council on the Developing Child, 2014; Shonkoff and Bales, 2011). The term “toxic stress” was proposed to describe “excessive or prolonged activation of the stress response systems” in the absence of buffering protection from adult caregivers (National Scientific Council on the Developing Child, 2014). Unlike positive or tolerable stress, “toxic stress” refers to biological changes in the child that can result in disruption of developing brain architecture and other maturing organs, dysregulation of metabolic processes, and excessive stress system activation. These responses can lead to increased risk for chronic diseases later in life (Shonkoff et al., 2009). These explanatory metaphors have been adopted by the American Academy of Pediatrics (Garner et al., 2012; Shonkoff and Garner, 2012) and helped the science of child development to be incorporated into federal and state legislation that generated evidence-based policies (Thompson, 2016; Center on the Developing Child at Harvard University, 2014). This chapter highlights a selection of important scientific advances since From Neurons to Neighborhoods (NRC and IOM, 2000). Next, key processes of healthy development from conception through early childhood are described, and some of the major biological responses to stressors are summarized. The chapter concludes with a discussion of individual differences in responsiveness and susceptibility. Throughout, the chapter identifies key points in development where disparities in health by race/ethnicity or SES can emerge, which could inform strategies for prevention-oriented interventions. The goal of this chapter is to provide essential information about the state of the science on human development from preconception through early childhood and some of the exciting findings in the past two decades within the fields of neurobiology, social psychology, epidemiology, and others that have contributed to advancing knowledge about how and when to intervene to improve outcomes for children. All of this information needs to be read through the lens of life course theory (Ben-Shlomo and Kuh, 2002), which recognizes that early experiences influence health outcomes within and across generations. It is also important to keep in mind the interconnectedness of brain and body health, as brain activity controls peripheral systems, which in turn affect brain structure and function. The committee provides this evidence to help “bridge the gap” between what science tells us and what actions need to be taken—by policy makers, health care providers, educators, religious leaders, parents, and others—to close disparities and improve outcomes for all children in the United States. At present, many of the new scientific PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-5 advances in neuroscience are still in development, and more study is needed to apply these new findings in clinical and public health practice and to use them to inform policies. In particular, greater effort and more support is needed to develop, implement, and evaluate programs based on scientific discoveries regarding the optimal timing for interventions. The committee could not be comprehensive with regard to coverage of all scientific advances, biological processes of healthy development, biological responses to stressors, and factors associated with individual differences, as each is a complex and active area of research. BOX 2-2 Key Chapter 2 Terms • Adaptive immune system: A portion of the immune system that uses highly specialized cells to eliminate foreign pathogens in the body and that, through exposure to certain pathogens, is able to eliminate those pathogens again in future infections. • Allostasis: The process by which the body responds to internal or external stressors to return to homeostasis, or balance. • Amygdala: A brain structure that is responsible for detecting threats in the environment and preparing the individual for emergency events. • Autonomic nervous system: A network of nerves and ganglia that uses specific neurotransmitters (see below) to regulate internal organ function. The autonomic nervous system has two complementary components: o Parasympathetic nervous system: Often referred to as the “rest and digest” system, the parasympathetic nervous system activates the digestive system, slows breathing, and decreases heart rate. o Sympathetic nervous system: Often referred to as the “fight or flight” system, the sympathetic nervous system prepares the organism for action by propelling blood to the brain and limbs to provide increased oxygen and glucose for energy, slowing digestion, and increasing attentiveness. • Axon: A main component of neurons; relatively long, extended structures that conduct a signal down the length of the neuron and play a key role in how neurons communicate with each other. • Brain plasticity: The process by which neurons within the brain change their gene expression, function, cellular architecture, and connections with other neurons in response to experiences and changes in the environment. • Cellular homeostasis: The notion that, when perturbed by some internal or external stimulus, cells react via feedback loops to achieve physiological balance with their immediate environment. • Chemical signature: A general term used to highlight how epigenetics results in changes to DNA by placing chemical marks to modify how genes are expressed. • Connectome: A general term for the amalgamation of connections between different parts of the brain. • Cortex: The outermost region of the brain that exhibits the greatest expansion in evolution, where billions of neurons reside, trillions of connections are made, and much of the brain’s most complex computational activity takes place. • Cortisol: A key hormone involved in the physiologic stress response. It elevates cell metabolism by binding to receptors in all organs to influence how they function during a “flight or fight” response. In the human brain, specific brain circuits express high levels of the glucocorticoid receptor. When cortisol activates the receptor, this impacts mood, motivation, and threat detection. Cortisol also helps to restore physiological balance after stress and regulates how the body uses carbohydrates, fats, and proteins; inflammation; blood pressure and blood sugar; and the sleep/wake cycle. Excessive exposure to cortisol prenatally also impacts development. • Endogenous versus exogenous: Endogenous materials are produced within an organism or cell (e.g., hormone or neurotransmitter), whereas exogenous materials are introduced from the outside environment (e.g., medication or environmental toxicant). • Epigenetics: The study of how genes are expressed or suppressed based on chemical changes to cells’ DNA due to biological factors that come from changes in the environment, including how these biological factors can be passed down from one generation to the next. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-6 VIBRANT AND HEALTHY KIDS • Gene expression: The mechanism by which DNA (composed of individual genes) is read and then turned into proteins that perform various functions throughout the body. • Genome: An organism’s complete set of DNA, including all of its genes. In humans, all cells that have a nucleus contain a copy of the genome, which consists of a highly organized arrangement of more than 3 million DNA base pairs. • Genome sequencing: The scientific technique of identifying the genes that are present in a genome. This can be a sequence of either an organism’s entire genome or certain parts of it. • Genomics: The study of the structure, expression, and function of specific genes and of the entire collection of genes (genome). • Germ Cells: Embryonic cells that contain half the genetic material (chromosomes) necessary to form a complete organism. In men, they produce sperm, and in women, they produce eggs/ova. • Glia: A category of cells within the brain that do not make connections (synapses) like neurons but do perform many important functions: supporting neuronal metabolic health, contributing to the integrity of the blood-brain barrier to mediate access by blood-borne substances, viruses, and bacteria, controlling access by neurons to chemical neurotransmitters that are released by other neurons, aiding in the conduction of electrical signals, and removing cellular debris. • Innate immune system: A portion of the immune system that removes foreign substances in tissues throughout the body and acts as a physical or chemical inflammatory barrier to infections but is not highly adaptable to a wide variety of infections. • Intergenerational transmission of risk: The concept that epigenetic changes from certain behaviors in a parent may be transmitted from one generation to the next, separate and apart from the genes that are passed down through reproduction. • Lymphatic system: The network of vessels through which waste products and toxins from tissues are drained for removal from the body. • Microbiome: The collection of bacteria that comprise the microbial communities that exist on and within human beings. • Myelination: The process by which oligodendrocytes (a type of glial cell in the brain) and Schwann cells (a type of glial cell outside of the brain) wrap axons with myelin, a protein- and fat-rich insulation substance that increases the speed of information conduction between neurons. • Neuroimaging: A technique that provides structural, functional, or metabolic information and images from living human beings within a brain scanner. • Neurons: Cells within the brain that communicate with each other via chemical signaling and underlie consciousness, sociability, emotion, motivation and reward, and cognition. • Neurotransmitters: Substances synthesized and released by neurons to excite or inhibit other neurons at their points of connection—synapses. • Oligodendrocyte: A glial cell responsible for wrapping the axons of neurons in myelin sheaths in order to aid the speed of electrical conduction between neurons. • Sensitive period: A time in development in which the developing organism is especially likely to undergo change (either positive or negative) in response to some experience or environmental change (e.g., an environmental toxicant, intervention training, or certain nutrients). Sensitive periods for certain functions can extend into adulthood. • Synapse: The connection between neurons, separated by a small gap, in which neurotransmitters and other chemicals are released by one neuron to influence the activity of other neurons with which they connect. This forms the basic unit of communication, resulting in the activation of circuits that process information and leading to a specific functional readout. • Transcriptomics: The scientific field aimed at understanding how and when certain genes are expressed or suppressed. PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-7 SCIENTIFIC AND TECHNOLOGICAL ADVANCEMENTS SINCE FROM NEURONS TO NEIGHBORHOODS The big questions driving research on child development and interventions to improve well-being are the same today as they have been for decades. “What are the influences of genes and experience on child health and development?” “To what degree does the brain exhibit plasticity (i.e., change over time)?” “What are the brain circuits that control specific kinds of behaviors, and how can their functioning be influenced through experience-based interventions and/or medications?” “Why does early experience have lasting disease risk and functional effects into adulthood?” “How does a child’s environment impact development of the brain, immune system, endocrine, metabolism, and cardiovascular systems, as well as physical and mental health?” (See Box 2-3 for highlights of applications of neurobiological research in practice.) Much more is known today than two decades ago about the process of child development, and the explosion of research reports on child development since the publication of From Neurons to Neighborhoods (NRC an IOM, 2000) is remarkable. A PubMed search using just the term “early adversity” generated a list of 2047 research articles,2 96 percent of which were published since 2001. Advances in several related fields of study have developed simultaneously to refine the understanding of child health and development and the responses that each child may have to early adverse experiences. The following section outlines a selection of major developments, including genetics, transcriptomics, epigenetics, neuroimaging, computational modeling, maternal/fetal interactions, advances in longitudinal research, and the study of social interactions and physical environments. Refer to Box 2-2 for definitions of the key terms in bold below. Genetics Technological advances have led to cost-effective methods for capturing whole genome sequences. This has been completed for tens of thousands of human genomes, highlighting remarkable genetic variation among all individuals. Genome sequencing also has revealed a small but consistent set of genes, including HSP90 and FKPB51, both of which are involved in regulating responses to stress activation through the HPA axis. Genome sequencing led to the discovery of specific sequence variations, some of which alter gene expression and are correlated with specific psychiatric disorders and stress lability. The variations in these genes contribute to individual differences in vulnerability and heterogeneity in response to early adverse experiences (Criado-Marrero et al., 2018). For complex outcomes, such as psychopathology, researchers are increasingly exploring polygenic risk (i.e., the combined contribution of many genes that influence brain development and function), rather than single gene variants that have very small contributions to risk. One idea being tested is that polygenic risk “scores” may better predict an individual’s likelihood of a given outcome (Brikell et al., 2018). Genomics has developed in tandem with experimental animal models and clinical discoveries in humans to provide opportunities to study i) genes that control the formation and physiological maturation of neural connections, ii) the molecules responsible for the onset and termination of sensitive periods, iii) the molecular basis for experience-driven synapse formation, elimination (pruning), and stabilization, iv) regulation of inflammatory responses, and v) regulation of hormonal activation 2 Accessed November 12, 2018. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-8 VIBRANT AND HEALTHY KIDS and feedback of the stress response (Bae et al., 2015; Geschwind and Rakic, 2013; Hensch, 2016b; Sudhof, 2018; Sudhof and Malenka, 2008). Epigenetics3 Genomics discoveries were followed rapidly by advanced methods to identify the consequences of differences in how, where, and when specific genes are expressed—that is, the epigenetic (“above the genome”) profile of specific cells (Waddington, 1942, 1957). Initial discoveries recognized that epigenetic changes are chemical signatures (National Scientific Council on the Developing Child, 2010) placed on an individual’s inherited DNA due to environmental experiences and related contributing factors (e.g., nutrition, mental and physical stressors, immune activation, environmental toxicants, enriched environments) (Goldberg et al., 2007). Once thought to be limited in scope and immutable, there are millions of sites on DNA that can be chemically modified epigenetically, and the modifications at these sites can be gained and lost rapidly, or, in many instances, remain stable over the lifetime (Goll and Bestor, 2005). Recent studies have shown that environmental experience influences the genome with specific molecular changes, such as DNA methylation and modifications to chromatin (Goldberg et al., 2007; Heim and Binder, 2012; Kalish et al., 2014; Kumsta, 2019; Miguel et al., 2019). While evidence of these molecular changes has been observed in many studies, the process by which these changes are controlled is complex and not completely understood. Exposures and experiences can result in profound epigenetic modifications that alter the timing and location of expressed or suppressed genes (McEwen, 2017; Miguel et al., 2019). For instance, epigenetics is one mechanism that results in identical twins exhibiting distinct physical and mental traits. Preliminary data suggest that epigenetic changes may explain how early experiences get “under the skin” of individuals for whom physical and brain-related disruptions and disease risk can last a lifetime (McEwen, 2017; Miguel et al., 2019). Research shows that epigenetic changes that alter the DNA chemistry in germ cells of adult humans may be one way that experiences are passed on to the next generation through their children (Donkin et al., 2016). However, the best evidence for such intergenerational transmission comes from animal studies. Epigenetic changes occurring during preconception or during pregnancy can impact the germ cells of the offspring and result in intergenerational transmission of the parental experiences (Weber-Stadlbauer, 2017). Moreover, it has been hypothesized that germ cells of the fetus may be altered during pregnancy, meaning that the mother, and even the child when that child is grown and has children of their own, can pass on influences that occurred several generations previously (Bale, 2015; Rodgers et al., 2015; Rowold et al., 2017). Transcriptomics Keeping in mind that one’s entire genome is in every cell of the body, the study of transcriptomics uses methods to identify how particular genes are expressed over time, in specific types of cells, and under specific circumstances (Li et al., 2018). New methods facilitated the organization of a research consortium that led to a remarkably detailed, open- access atlas4 of gene expression in 16 different human brain areas during pre- and postnatal 3 For a more in-depth discussion on epigenetics and how the environment gets under the skin, see Chapter 3 of the recent report, The Promise of Adolescence: Realizing Opportunity for All Youth, by the Committee on the Neurobiological and Socio-behavioral Science of Adolescent Development and Its Applications (NASEM, 2019). 4 For more information, see http://www.brainspan.org (accessed June 16, 2019). PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-9 development and into adulthood, building a unique bridge between human and model system brain research (Carlyle et al., 2017; Enoch et al., 2014; Li et al., 2018; Vied et al., 2014). For example, the expression of genes responsible for producing the thousands of neuron types in the brain is enriched during the first trimester of pregnancy. As development continues, many of those genes are turned off because neuron production ceases, and other genes are newly expressed that control the initial wiring and building of the unique architecture of the brain. After birth, genes are turned on to cause the rapid formation of synapses, pruning, and the signaling between neurons to process more and more complex information. The ability to relate specific events in development to the changing transcriptome has been accomplished by creating enormous databases of gene expression in the pre- and postnatal human brain and in experimental animal models. These new data offer a detailed directory of gene expression in space and time in the complex and rapidly changing developing brain, thereby providing the framework for ongoing research to determine how the interplay of genetic and environmental factors and experience alters the gene expression that contributes to typical or atypical developmental maturation. Neuroimaging Human and animal neuroimaging have provided the basis for a new understanding of the brain connectome, which defines the breadth and complexity of circuits that relay information between ensembles of neurons. New technologies provide unprecedented resolution of the organization of the connectome in humans, painting a far more complex picture that begins prenatally as early as the third trimester of pregnancy (Kostović et al., 2014; Krsnik et al., 2017) and continues in infancy and toddlerhood as remarkable periods of growth for the brain. Functional maturation of circuits continues throughout childhood, but connectome research, combined with genomics, has identified adolescence as a second period of dynamic changes in brain wiring.5 In humans, it is now understood that while classic diagrams of brain development present a well-delineated blueprint, there is far more variability in infants and toddlers than expected in the timing and extent of development of connectivity within the standard connectome blueprint. This basic neuroimaging research in humans has provided a foundation for determining the impact of disparities resulting from poverty and other social factors on the trajectory of brain growth and development of circuitry (Gabrieli and Bunge, 2017; Hanson et al., 2013; Johnson et al., 2016; Luby et al., 2012). Given the vast heterogeneity between individuals in terms of brain development, drawing generalizations about the overall connectome and its influence on social, emotional, and cognitive maturation remains a key research challenge. Maternal/Fetal and Infant Interactions Prenatal development is marked by a unique relationship between the mother, the fetus, and a transient organ, the placenta. Once thought of as a filtration system of cells contributed mostly by the fetus and blood vessels from both mother and fetus to control the passage of nutrients and other substances, the placenta has been shown by current genomic, cell biological, and physiologic evidence to be an active partner in fetal development and influenced by maternal health. For example, maternal immune activation or persistent stress during pregnancy can alter 5 For a comprehensive discussion of the developing adolescent brain, see NASEM, 2019—forthcoming, May 2019 PREPUBLICATION COPY: UNCORRECTED PROOFS

2-10 VIBRANT AND HEALTHY KIDS placental cell gene expression and function (Hoffman, 2016). Depending upon stage, the placenta expresses 40-60 percent of the human genome and produces cytokines, hormones, neurotransmitters, and growth factors that are necessary for healthy fetal development (Gonzalez et al., 2018; Jones, 2019; Paquette et al., 2018; Zhao et al., 2019). These genes are subject to environmentally regulated epigenetic changes; exposure to toxicants, nutrient status, high stress, or infection can result in altered gene expression through epigenetic changes (Bale, 2015). Thus, while the organ clearly is involved in regulating transport of maternally produced substances, the placenta also serves a critical resource for organ development and maturation of functions to ready the fetus for birth (Bonnin et al., 2011; Bonnin and Levitt, 2011; Goeden et al., 2016; Nugent and Bale, 2015). Developmentally, the maternal-placental-fetal relationship begins between the third and fourth week postconception, through a complex process of extraembryonic cell differentiation and vascularization that results in the implantation in the maternal uterus. Given that the main functional cell of the placenta, the trophoblast, is embryonic in origin and that there are thousands of genes expressed in the placenta, any gene mutation that could functionally disrupt the embryo also can impact placental function (McKay, 2011). Intergenerational Transmission of Risk Evidence from both animals and humans indicates that adverse social/psychological and physical exposures in one generation can alter risks for psychopathology, maladaptive behavior, and chronic disease in the next generation (i.e., the children of individuals who endured severe threat have elevated rates for psychiatric disorders and dysregulated physiology, despite an absence of direct exposure) (Boyce and Kobor, 2015; Burton and Metcalfe, 2014; Franklin et al., 2010; Matthews and Phillips, 2012; Santavirta et al., 2018; Yehuda and Bierer, 2007; Yehuda et al., 2014). For example, research has documented that 1) adolescents born to women who experienced severe child abuse are at higher risk of smoking and overweight/obesity(Roberts et al., 2014) and 2) there is altered cortisol expression among children who were in utero at the time of the 2001 World Trade Center attack in New York City (Yehuda et al., 2005), and 3) there are differences in stress reactivity in children of women affected by the Dutch Hunger Winter (Painter et al., 2006). These excess risks may emerge through a variety of mechanisms that are not mutually exclusive, such as altered parenting behaviors, lower socioeconomic position, epigenetic pathways (described above), or an altered fetal environment. Adverse experiences before and during pregnancy can influence maternal stress-related physiology, including immune activation and endocrine disruptions (Entringer, 2013; Entringer et al., 2010, 2015; Hantsoo et al., 2019; Howerton and Bale, 2012). Increasing evidence suggests that maternal immune and endocrine activity during pregnancy (including the under- or overproduction of cortisol and levels of pro- or anti-inflammatory cytokines) are associated with adverse birth outcomes (Bastek et al., 2011; Wadhwa et al., 2011), the child’s brain (Buss et al., 2017) and cognitive development (Gilman et al., 2017; Rudolph et al., 2018), and future risk for chronic disease (Entringer et al., 2013, 2015), providing support for embryonic and fetal life as sensitive periods for the intergenerational transmission of adverse maternal experiences (Buss et al., 2017; Entringer et al., 2010; Meaney, 2001). Much of this work is preliminary, and further research needs to be conducted before drawing concrete conclusions about intergenerational transmission of risk. At present, there is a limited understanding of how plastic or modifiable these intergenerational risk factors are and why some individuals are resilient to intergenerational risks whereas others are not. This is an area of active research that has elevated the importance of applying the life course approach to health and development, and by further understanding the PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-11 pathways of both risk and resilience, scientists may uncover social, behavioral, or pharmacologic interventions that can interrupt the intergenerational transmission of the effects of stress on the developing embryo and fetus. Later in the chapter, the section on Biological Mechanisms of Healthy Development presents a more extensive discussion on the role of the placenta and how it can be influenced by social experiences. Computational Methods There has been a rapid increase in the capacity to collect and analyze enormous datasets with social and biological information. These datasets may be developed through research consortia that can involve dozens of investigators from around the world or from the linkage of administrative files, de-identified electronic health records (McGregor et al., 2013; Roden et al., 2008), and other sources (McCarty et al., 2011). In parallel, engineers and computer scientists have advanced sophisticated computational methods, including signal processing and machine learning, to extract predictable patterns that relate to outcomes of interest (Krishnan et al., 2017; Tseng et al., 2013; Van Essen et al., 2013). For example, connectomics and genomics have depended heavily on these methods, and the rapid advances in collecting physiological data from children (EEG, eye tracking, wearable devices to monitor physical activity, sleep habits, stress, and metabolic activity) also have benefited from the advanced analytical methods that help identify patterns of maturation of brain architecture and function (Bagot et al., 2018; Frazier et al., 2018; Hosseini et al., 2016; Medland et al., 2014; O'Driscoll et al., 2013; Wee et al., 2017). These measures have been used to predict risk for behavioral and cognitive disturbances later in development. Relatedly, there is growing interest in using machine learning and predictive risk modeling methods to identify children in adverse environments and predict risk or resilience (Amrit et al., 2017; Gillingham, 2016; Schwartz et al., 2017). For example, advanced analytical methods have been applied to produce highly sensitive and specific metrics for the prospective diagnosis of fetal alcohol spectrum disorder (Zhang et al., 2019). However, there is still much more research needed to determine how well these methods may be applied to determine underlying causal mechanisms. Finally, meta-analytic approaches are using new analytical methods to synthesize the results of multiple independent studies and are now widely employed to inform evidence-based recommendations, policies, and programs for children. For example, meta-analyses have been used to summarize the effects of center-based early education (Grindal et al., 2016; Schindler et al., 2015) and parenting programs (Casillas et al., 2016; Chen and Chan, 2016). BOX 2-3 To What End—Examples of Application of Neurobiological Research in Practice 1. The discovery of molecules responsible for putting the “brakes” on critical period timing have led to clinical studies that manipulate the function of certain brakes in order to demonstrate that critical periods can be reopened far later in life than previously believed. 2. Eye tracking, coupled with machine learning and neural network algorithms, has been used to discover patterns of scene viewing that serve as a sensitive and specific signature to identify children who have normal facial morphology but were exposed to alcohol during fetal development and exhibit cognitive difficulties. 3. Neuroimaging and behavioral data were combined to demonstrate continued maturation of executive functions. These studies clarified the component skills and have led to a flurry of PREPUBLICATION COPY: UNCORRECTED PROOFS

2-12 VIBRANT AND HEALTHY KIDS intervention strategies to train working memory, mental flexibility, and inhibitory control in toddlers, children, adolescents, and young adults. 4. The neurobiology of early adversity led to discoveries of genetic variants that increase vulnerability in the response to ACEs. Hsp-90 and FKBP5 were discovered as partner regulators of the hormonal response to stress by controlling glucocorticoid receptor signaling, and sequence single nucleotide polymorphisms (SNPs) predict response to early environmental stressors, which can increase the risk for adult depression and anxiety disorders. To support preventative efforts, current research studies in clinical settings are underway to determine the effectiveness of genetic screening, combined with history of ACEs, to identify those individuals at greatest risk for recurring and treatment-resistant depression. 5. The advances in the neurobiology of sociability and the burgeoning research area of infant– mother and infant–father synchrony have led to foundational discoveries about the importance of a child’s environment of relationships. There are many more studies and direct community applications of targeting both child and caregiver in interventions—for example, multidimensional therapeutic foster care or coaching to promote healthy caregiver–infant bidirectional, responsive interactions. Advances in Longitudinal Research Investments by National Institutes of Health, the Department of Education, numerous private foundations, and other agencies have resulted in a substantial growth in child development research using longitudinal data from prospective cohort studies with large subgroups of racial/ethnic minority children and stratified-probability samples. These studies have documented more extensively the pervasiveness of health disparities in these populations and the mechanisms by which these disparities arise. For example, the Eunice Kennedy Shriver National Institute of Child Health (NICHD) supports the Fragile Families and Child Well-being Study, a birth cohort of nearly 5,000 children in 20 large U.S. cities that used a stratified random sample, with an oversample of nonmarital births (McLanahan et al., 2003). Baseline interviews for this study occurred between 1998–2000, and follow-up is still ongoing. The Institute of Education Sciences, an independent evaluation arm of the Department of Education, conducts the Early Childhood Longitudinal Study (ECLS) program, which has generated large representative cohorts for studies of child development for the United States, from birth onward (Tourangeau et al., 2009). Longitudinal studies are critical to understand both normative developmental processes and those involving deviations from the norm. These studies facilitate examination of changes across development within individuals and subgroup differences in within-person changes over time (Lerner et al., 2009). Prospective studies are critical for documenting what changes—in brain, behavior, or health—are due to normal developmental progression and what changes are caused by chronic family-level stressors, structural inequalities, and/or positive environmental stimuli. Longitudinal data, combined with advances in statistical methods for identifying underlying pathways, have made it possible to show the lasting impact of early adverse experiences and to ask questions about mediating processes that underlie the association between early childhood adversity and poor health or educational outcomes (Danese et al., 2009; Iacono et al., 2008; Poulton et al., 2015). In parallel, longitudinal data have shown that for children who have been exposed to severe adversity, such as maltreatment, providing appropriate care can reverse early damage, even to biological systems, such as brain functioning (Cicchetti and Curtis, 2006; Cicchetti and Handley, 2017). PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-13 In spite of these advances, it is important to note that U.S. investment in large birth cohort studies lags severely behind European countries. One new study, launched in 2016, is the Environmental influences on Child Health Outcomes (ECHO) Program. It is a 7-year research initiative focused on understanding the effects of environmental exposures on child health and development, and it draws on existing U.S. cohorts. The cohort studies that compose ECHO collectively include approximately 50,000 children and will address environmental exposures in relation to four pediatric outcomes with high relevance to public health: pre-, peri- and postnatal outcomes, neurodevelopment (i.e., cognition, emotion, and behavior), upper- and lower-airway function, and obesity. Of note, many longitudinal studies of child development have been the product of interdisciplinary collaborations, which have become increasingly common. An example is the long-term follow-up of the Perry Preschool6 project, which started in the 1960s (Gramlich, 1986; Schweinhart et al., 1985). This longitudinal study of the effects of a randomized control trial (RCT) is the result of a long-term collaboration between educational researchers and practitioners, developmental psychologists, and economists. The latest follow-up of the intervention administered at 3 and 4 years of age still yields positive results on the life trajectory of its participants at age 40, including more positive health outcomes, improved employment trajectory, and less crime involvement (Belfield et al., 2006; Social Programs That Work, 2017). Consistent with these findings, the Carolina Abecedarian Project—a randomized study of an early childhood intervention for economically disadvantaged children with long-term follow- up—found that children randomly assigned to the early intervention displayed lower cardiovascular and metabolic risk factors in their mid-30s, with effects most pronounced for men (Campbell et al., 2014). Baby’s First Years,7 launched in 2018 and funded by both private and public grants, is a new longitudinal study that seeks to establish causal links between parental income level and brain development in very young children. Advances in the Study of Social Interactions Since From Neurons to Neighborhoods was published, researchers have introduced a number of novel topics and measurement approaches that have advanced the understanding of early development and consequences for later physical and mental health outcomes. In particular, there has been a shift of focus to the well-being of salient caregivers as “a dependent variable” in research and associated interventions. In other words, rather than continuing to report (as psychologists had over decades) that a good relationship with the primary caregiver is the single most important protective process in promoting resilience among children whose life circumstances render them at risk, there is now explicit focus on the question of what it is that helps parents maintain good parenting when they are struggling with high ongoing stress. How can we promote resilience among the adults primarily responsible for raising children in stressful life circumstances (for reviews, see Luthar et al., 2015 and Luthar and Eisenberg, 2017)? Relatedly, intervention approaches are going beyond simply teaching parents what they should and should not do in didactic parenting classes or even imparting approaches to regulate their own affect (via mindfulness or trying to cope effectively with their own ongoing life stressors). Increasingly, programs are also seeking to provide the support that parents need to successfully negotiate the many challenges in sustaining good parenting behaviors with multiple children and 6 For more information, see https://highscope.org/perry-preschool-project (accessed March 29, 2019). 7 For more information, see https://www.babysfirstyears.com (accessed April 18, 2019). PREPUBLICATION COPY: UNCORRECTED PROOFS

2-14 VIBRANT AND HEALTHY KIDS across multiple decades (for examples of such programs, see Corso et al., 2015; Kaminski et al., 2013; Luthar et al., 2007, 2017). An emerging field of research suggests that there is a biological basis to healthy caregiver–child relationships and that caregiver–child synchrony in biological processes such as EEG or heart rate variability can help children to develop control of their behavior and emotions. The science of caregiver–child synchrony advances previous views that a child’s central nervous system is primarily responsible for developing self-regulation (Welch, 2016). This research suggests that children display dysregulated behavior due to deficient coregulation from nonoptimal caregiver relationships and that coregulation can be improved via interventions, such as the Family Nurture Intervention, developed by Martha Welch and colleagues (2014, 2015). Although there are a number of neuroendocrine changes that occur during the process of parenting, a substantial amount of this research has focused on oxytocin measures in the infant and caregiver. In addition to oxytocin’s roles in the birthing process, lactation, and maternal care in mammals, studies have demonstrated that oxytocin (and its close neuropeptide relative vasopressin) facilitates affiliative social behavior through modulation of the activity of specific forebrain circuits (Feldman and Bakermans-Kranenburg, 2017; Hammock et al., 2005; Insel, 2010b; King et al., 2016; Numan and Young, 2016). Both observational and experimental research studies suggest that oxytocin influences the synchrony between caregivers and children, and it is also associated with sensitivity of caregiving and amount of contact (Feldman and Bakermans-Kranenburg, 2017). Researchers are exploring how specific caregiver health conditions (e.g., postpartum depression) or social experiences (e.g., traumatic experiences in early childhood) influence oxytocin, other neuroendocrine hormones related to nurturing behaviors, and caregiver–infant synchrony and how interventions may target these processes to improve caregiver–child relationships. Another major advancement is that there has been a growing appreciation for the role of culture for the development of children (Coll et al., 1996). In the study of children and families in the United States outside of the white middle class (i.e., minority families, based on race/ethnicity, immigrant status, sexual orientation, and others at both socioeconomic [SES] extremes) there has been a growing emphasis on potent culturally specific risk and protective factors and processes (see Velez-Agosto et al., 2017), especially those that can be harnessed in beneficial interventions. As an example, the American Psychologist devoted a special issue to marginalization, defined “as a multidimensional, dynamic, context-dependent, and diverse web of processes, rooted in power imbalance and systematically directed toward specific groups and individuals, with probabilistic implications for development” (Causadias and Umaña-Taylor, 2018). The special section contains a rich collection of articles addressing issues related to various marginalized groups, including recent immigrants and youth from different ethnic and racial minority groups. In another recent special section in Research in Human Development, Cunningham (2019) compiled papers addressing “myths and realities associated with human development research and theorizing” encompassing “diverse perspectives on sexual minority youth, resilience and risk for youth in high-achieving schools (HASs), a reconceptualization of hostility in African American parenting styles, a critical examination of diversity and contact for students attending racial/ethnically diverse schools, and a thoughtful consideration of contextual factors associated with aggressive attitudes and prosocial behaviors in African American males” (p. 1). Many of these studies move the conceptualization of “children or family at risk” to “children and family living in at-risk conditions.” The “problem” to be “fixed” is not the child and/or family but the at-risk conditions within which they live, an important paradigm shift for PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-15 prevention, early identification, and prevention. (On a related topic, there have also been advances in connecting racism to child and adult health outcomes; see Box 2-4.) BOX 2-4 Racism and Child Health Another major scientific advancement in the science of health disparities since From Neurons to Neighborhoods is the research linking racism to child and adult health outcomes (Pachter and Coll, 2009; Paradies et al., 2015; Priest et al., 2013; Williams and Mohammed, 2013). Much of the impetus for the work on the effects of racism on children’s development stemmed from the critical analyses of the prevalent use of the deficits model to understand health disparities in minority children (García Coll, 1990; McLoyd, 1990; Ogbu, 1981; Spencer and Markstrom-Adams, 1990). Beginning in the 1990s, several theoretical models and empirical work started to place the burden on the social and environmental conditions where the majority of the minority populations in the United States lived (Coll and Szalacha, 2004; García Coll et al., 1996; Stein et al., 2016). McLoyd’s work showed that the stress associated with poverty explained harsh parenting among African American families. These segregated communities had a majority of families living below the poverty line, with schools, health care, recreation, housing, and transportation facilities below standards or with fewer resources than where predominantly white, middle-class populations lived. Health disparities were now considered a function of these environmental conditions and not the parents and children themselves. Most of these social and environmental conditions are now seen as a function of pervasive institutional and interpersonal racism (Pager and Shepherd, 2008). Similarly, scientists have denounced the use of race and ethnicity as variables in biological research (Collins, 2004; Foster and Sharp, 2004), noting that “historical racial categories that are treated as natural and infused with notions of superiority and inferiority have no place in biology” (Yudell et al., 2016, p. 565). A large body of scientific evidence has documented that both institutional racism and interpersonal experiences of discrimination can influence the health and well-being of both children and adults in multiple ways, including reducing access to material resources and services that promote long- term health and development and acting as a psychosocial stressor that can lead to worse outcomes over time (Priest et al., 2013; Williams and Mohammed, 2009). Studies of children and adolescents indicate that experiences of discrimination are positively associated with depression and anxiety and negatively associated with positive mental health outcomes, such as self-esteem and resilience (Priest et al., 2013). Research also suggests that parental experiences of discrimination are associated with child and adolescent mental health and socio-emotional outcomes (Heard-Garris et al., 2018; Tran, 2014), as well as some indicators of physical health (Priest et al., 2012; Slopen et al., 2019). There are also a diverse set of health outcomes in adults resulting from racism (Williams et al., 2019). Measures for experiences of racism and discrimination in children have relied mostly on parent- or self-reported answers to survey questions (Fisher et al., 2000; Pachter et al., 2010; Williams et al., 1997). These instruments are subjected to social desirability, recall biases, and other potential issues associated with self-reports. Some research in adults has begun to combine traditional measures of racial discrimination with implicit measures, in order to advance understanding of how conscious and unconscious experiences of racism influence outcomes (Krieger, 2012; Krieger et al., 2010). Future research is needed to examine whether similar approaches are useful for children and adolescents. Advances in the Study of Physical Environments Although the family remains a major determinant of the child’s outcomes, studies following more comprehensive theoretical models (e.g., Bronfenbrenner, 1979; Bronfenbrenner and Evans, 2000; Ferguson et al., 2013) have documented the importance of neighborhood contexts on family interactions and child development. Neighborhood context can be characterized as positive and negative, and it can reflect the physical or built environment and psychosocial characteristics. It has become increasingly common for researchers to link PREPUBLICATION COPY: UNCORRECTED PROOFS

2-16 VIBRANT AND HEALTHY KIDS measures of neighborhood social and structural environments to individual-level data on children. As long as families are willing to share an address, researchers are able to draw on information from the Census and other free and proprietary data sources in order to characterize a child’s social and physical environment. When this field of research began, most studies focused on neighborhood SES (e.g., the proportion of the population in the Census tract that is below the federal poverty line), as this measure is associated with the physical infrastructure of the community, noise and pollution, amenities such as parks and groceries, and availability of health centers and early childhood education (Evans, 2004; Evans et al., 2010). However, use of neighborhood SES as a proxy for neighborhood quality and conditions does not provide sufficient information about the mechanisms of action—that is, the specific pathway through which neighborhoods influence child health. The majority of research on neighborhood SES and health is observational, but there are a few exceptions, including the Moving to Opportunity study (Chetty et al., 2016; Ludwig et al., 2011). The Project on Human Development in Chicago Neighborhoods (PHDCN)—an interdisciplinary study that began in 1995 and aimed to explore how families, schools, and neighborhoods influence child and adolescent development—was among the first to provide an intensive investigation of neighborhood conditions, related to economic, social, organizational, political, and cultural structures and how communities change over time. The investigators conducted systematic social observations by videotaping one side of each block within the selected 80 Chicago neighborhood clusters, and they maintained observer logs about the activities of residents and the presence of detracting elements (e.g., garbage, abandoned cars). This study identified neighborhood collective efficacy and social capital as important aspects of neighborhood social organization for child and adolescent outcomes (Sampson et al., 1999; Sampson and Raudenbush, 1997, 1999). Since PHDCN, researchers have begun to characterize neighborhood social and physical information for health research using Google Street View (Rundle et al., 2011; Rzotkiewicz et al., 2018), which has the benefits of being lower cost and more efficient, although it can be limited by resolution and availability for a given temporal period. There has also been a substantial amount of research to examine child health in relation to neighborhood violence or crime, which can be derived from police crime reports (Beck et al., 2016; Goldman-Mellor et al., 2016; McCoy et al., 2015). Some studies use surveys to assess parental perceptions of neighborhood safety (Christian et al., 2015). Other research has focused on the physical neighborhood environment, such as opportunities for physical activity, access to healthy food, density of fast food, air quality, and presence of natural environments (e.g., green space) (Gascon et al., 2016; Gorski Findling et al., 2018; McCracken et al., 2016; Sallis et al., 2018). While some studies use single measures of neighborhood context, other studies rely on more complex indexes, such as the Childhood Opportunity Index (Acevedo-Garcia et al., 2014, 2016). This measure—developed by diversitydatakids.org and the Kirwan Institute for the Study of Race and Ethnicity—combines 19 component indicators related to education, health and environment, and social and economic context to rank neighborhoods (defined by Census tract) to other neighborhoods within the metropolitan area (Acevedo-Garcia et al., 2014; Beck et al., 2017a,b). PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-17 BIOLOGICAL MECHANISMS OF HEALTHY DEVELOPMENT Introduction Development is an interplay between biology and the profound impact that experiences have on biological systems. There are basic biologically driven mechanics that involve the production and specialization of cells that serve as the ingredients to build different organ systems, such as the brain, heart, digestive system, and kidneys. These systems are ultimately responsible for performing specific functions and become specialized over different periods of developmental time. This developmental process begins prenatally, and for the most complex organ—the brain—it extends into young adulthood. The developmental process is designed to promote maximal functioning and survival of the individual. The challenges an individual faces from infancy to adulthood are numerous and varied, and through the powerful biology- experience relations, development establishes both functional and adaptive capacities in order to adjust to the environment and to future experiences. Optimal functioning and robust adaptability to the environment are signatures of healthy development. No matter which organ system or cell type are considered, a core principle of development involves the regulation of the expression of the 23,000 genes in each person’s genome at specific times, and in specific combinations, in order to achieve optimal functioning of each organ system. It is important to re-emphasize here that the genome is composed mostly of regions of DNA that do not code for proteins but rather are responsible for using information from experiences and the environment to regulate gene expression. Gene expression is the first step toward producing proteins, which are the primary functional units of specialized cells that characterize each organ system. Thus, while all cells contain the identical genetic material (DNA code), gene expression and production of proteins varies greatly between types of cells, which specialize during development to perform specific functions. Because the brain is massively complex, with billions of neurons and trillions of connections, at least 85 percent of the genome is expressed at various times and locations during development (Negi and Guda, 2017), whereas, other organ systems may express far fewer genes in order to perform their functions. This orchestrated temporal and spatial expression of genes depends upon maintaining healthy cellular homeostasis and accessing nutrients that serve as the building blocks for proteins and eventually organ systems. Research has shown that regulation of fundamental metabolic processes, including mitochondrial function in the brain and periphery, is essential for cellular adaptations to developmental psychosocial stress that can impact mental and physical health (Eisner et al., 2018; Picard and McEwen, 2018). The most productive means to facilitate early healthy development include providing access to healthy nutrition, avoiding factors that can be detrimental to nutritional status for mother and fetus over the course of pregnancy, limiting chronic stress, and offering access to quality health care. Proper nutrition is needed postnatally through childhood as well. Moreover, disrupting the fetal-placental-maternal biological relationship through infection, toxicants, alcohol, nicotine, or poor diet increases risk for altering a typical, healthy developmental trajectory. Thus, improving physical environments to limit exposure risk and providing access to high-quality maternal health care during pregnancy is an additional essential ingredient for healthy development. These well-researched factors make up a strategy for viewing early development through a “prevention lens” that ultimately leads to reduced risk for later physical, mental, and cognitive disorders. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-18 VIBRANT AND HEALTHY KIDS Recent studies, mostly in animal models, indicate that the developmental process starts even prior to conception (Chan et al., 2018). Certain stressors, including psychosocial factors, toxicants, or drug exposure, can impact reproductive cells through an epigenetic process that ultimately may alter the expression of the genes that are inherited by the embryo. This suggests that parental behavior may impact how a child’s genes are ultimately expressed and therefore what the child’s biology and behavior will be. This transgenerational impact on development requires studies in humans before firm conclusions are made, but the research indicates that maternal and paternal experiences prior to conception may be an important factor to consider for programs that promote family health and welfare. The following sections outline how several biological systems, those most relevant to this committee’s report, develop between gestation and puberty and serve as a baseline for understanding how early environmental stressors and adversity affect child development and the emergence of health disparities: maternal physiologic adaptations during pregnancy and the nervous, immune, endocrine, and reproductive systems. Note that in addition to psychosocial stressors in the environment of a developing child, adversity may include limited or no physical activity, exposure to toxicants, including alcohol and nicotine, and chronic disruption of bodily physiological functions, such as sleep (Feldman et al., 2014; Jones et al., 2019; McEwen and Getz, 2013; Thompson et al., 2009). Each of the following sections describe typical processes from the prenatal period through early childhood and how the system may be impacted by experiences that disrupt typical development. Maternal Physiologic Adaptations During Pregnancy Remarkable changes take place in women during pregnancy to accommodate the needs of the developing fetus. A woman’s heart pumps out 30 to 50 percent more blood every minute, while her lungs take more air with each deep breath, in order to deliver oxygen and nutrients to the baby (Cheung, 2013; Costantine, 2014). Her kidney functions also improve by 50 percent to filter out more waste products and toxins from the blood (Cheung and Lafayette, 2013). Her immune system is dampened to avoid rejection of the fetus, while she becomes progressively insulin resistant, which allows an increasing amount of blood glucose to stay in the bloodstream to nourish the growing fetus. A comprehensive review of maternal adaptations is beyond the scope of this report, but it is important to note that how well a woman’s body can adapt to these physiologic changes during pregnancy is closely related to her overall health going into the pregnancy. For example, a healthy heart can readily adjust to the increased workload, but a diseased heart will have a much more difficult time; heart disease is a leading cause of maternal death in the United States. Pregnancy predisposes blood to clotting, but the risk of severe complications from thromboembolism and pulmonary embolus is substantially increased in women with pre-existing conditions, such as hypertension, diabetes, or obesity. Pregnancy causes a physiologic anemia, which can be exacerbated by ongoing iron deficiency, thereby increasing the risk of having a low birth weight (LBW) baby. The insulin resistance in pregnancy is made worse if a woman enters pregnancy overweight, obese, or with preexisting diabetes mellitus; fetal exposure to excess blood glucose has been associated with adverse birth outcomes and obesity and diabetes later in life (Garcia-Vargas et al., 2012). As we will discuss in Chapter 5, advancing health equity in birth and child health outcomes first requires improving preconception health for all women. One of the most important adaptations during pregnancy is the formation of the placenta, an organ that is responsible for controlling access of maternal-derived factors to the fetus and PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-19 also serves as a source of growth factors and other molecules that support healthy fetal development. The placenta begins to form very early in pregnancy, and disruption of this process has been associated with pregnancy complications, such as intrauterine growth restriction (IUGR) and preeclampsia (Sharma and Sharma, 2016). At term, approximately 600–700 mL of blood flows through the placenta, delivering oxygen and nutrients to the baby (Wang and Zhao, 2010). The placenta also acts as a critical regulator of maternal–fetal interactions and resource allocation. For example, if a pregnant women experiences acute stress, the placenta shields the fetus from overexposure to maternal cortisol by turning up the activity and expression of a placental enzyme called 11β-hydroxysteroid dehydrogenase type-2 (HSD11B2), which inactivates cortisol as it passes through the placenta. However, chronic stress has been found to be associated with reduced activity and expression of placental HSD11B2, suggesting that the placenta’s built-in ability to limit fetal exposure to maternal cortisol may be diminished in the face of chronic stress (Cuffe et al., 2012; O'Donnell et al., 2012; Welberg et al., 2005). Nervous System Development The neurobiological processes that build the brain share some common elements with other organ systems, such as producing specialized cells (e.g., neurons and glia) with functions specific to that organ system. However, understanding of neurodevelopment lags behind the understanding of other organ systems, in large part because the brain is extraordinarily complex. Experimental studies in model systems have identified basic mechanisms and the genes that are involved in specializing areas of the developing brain into what will make up function regions, the production of a diversity of neuron types, and the initial wiring of circuits that occurs prenatally (Kast and Levitt, 2019; Kolodkin and Tessier-Lavigne, 2011). Identification of mutations in some of these same genes in humans have validated the highly conserved nature of the ingredients that are responsible for the initial brain blueprint (Doan et al., 2018; Geschwind and Rakic, 2013; Jayaraman et al., 2018; Rubenstein and Rakic, 2013). Genes and their protein products involved in later events, including the extended period of synaptogenesis (the formation of synapses) have been identified and studied experimentally (Akins and Biederer, 2006; Favuzzi and Rico, 2018; Sudhof, 2018). For all the advances in the basic understanding of neurodevelopment, there is a knowledge gap in determining the many ways in which the environment and experience are woven into the developmental process. Figure 2-1 is a diagram showing development from the first trimester to puberty, with respect to both neurodevelopment and the development of other biological systems. Within a few weeks of conception in the first trimester, neurons begin to be produced. By 10–12 weeks gestation, most of the neurons that make up the brain are generated (Bystron at al., 2008; Stiles, 2008). Specific types of neurons in structures like the cerebellum, hippocampus, and olfactory bulb continue to be produced prenatally. Unlike many other types of the cells in the human body, once formed, neurons lose the capacity to renew themselves, even if injured (a small number of neurons in the olfactory bulb and hippocampus represent limited exceptions). Because the neurons are “born” at sites in the developing brain that are different from their final position, all neurons migrate using a combination of mechanical guides, the extended processes of radial glial cells, and molecules that serve as guidance cues. This migration process begins as soon as neurons are produced, and as the brain grows through the second trimester, the later- produced neurons take longer to reach their final position. This developmental process is further complicated because newly formed neurons not only migrate but simultaneously extend a long process—the axon—that will connect each neuron to its appropriate target. At the same time, the PREPUBLICATION COPY: UNCORRECTED PROOFS

2-20 VIBRANT AND HEALTHY KIDS receiving end of the neuron—the dendrite—develops but takes much longer to reach maturity, in sync with the formation of individual neural connections—the synapses. Throughout each of these developmental stages, additional sets of genes are expressed that drive a specific process to completion. Many of the earliest born neurons will regulate peripheral organ function (e.g., heart, lungs, gastrointestinal tract). Connections are formed between these neurons and their targets in the first trimester as the targets continue to develop. By the beginning of the second trimester, long connections from the hypothalamus to the autonomic brain stem are formed, providing the capacity for top-down regulation of what are called the sympathetic and parasympathetic nervous systems—in essence, the systems that control the “fight or flight” and “rest and digest” responses. FIGURE 2-1: Human development of the brain and other organ systems from prenatal to pubertal periods NOTE: Arrows represent time frames of approximate onset (darker shading) and completion (lighter shading) of specific developmental events for neural (green) and nonneural (blue) systems. For the neural components, above the line represents events that occur within the prenatal period, and below the line represents events that extend into postnatal periods. By the second and third trimesters, sensory systems are connected from the periphery to the brain’s cerebral cortex—the most complex part of the brain with the greatest neuronal diversity, which processes complex information from all of the senses. Toward the end of fetal development in the third trimester, the basic blueprint of neuronal connections is initiated, during a temporally extended process of synapse formation that continues through 2–3 years postnatally (Levitt and Eagleson, 2018; Silbereis, 2016). The human neocortex contains approximately 20 billion neurons, each with an average of several thousand synapses and connected with thousands of kilometers of dendrites and axons (Tang et al., 2001). By birth, sensory systems are sufficiently wired to be able to take in information from the infant’s environment and begin to process the most salient stimuli (for example, visual, tactile, PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-21 and auditory stimuli of the primary caregiver that are experienced in temporal lockstep with satisfying the hunger, thirst, and warmth needs). The nervous system continues to build by adding more synapses, ultimately reaching its greatest synapse density during toddlerhood. Experimental studies in animals shows that experiences can influence the initial organization of and sheer number of synapses (Berbari et al., 2005; Turner and Greenough, 1985). In early human infant development, differences in growth parameters of gray and white matter have been shown to be influenced by experience in the human cerebral cortex (Brito and Noble, 2014; Hair et al., 2015), which assumes synaptogenesis changes due to experience. In humans, more than 1 million synapses are added per second for this 2–3 year period (Center on the Developing Child at Harvard University, n.d.-a). During early childhood, and as an individual approaches the onset of puberty, the number of synapses remains relatively stable, but this does not imply that no developmental activity is taking place. Instead, experience-driven processes impact maturation by influencing which specific genes are expressed and therefore how synapses process information. Over time, synapses that become activated more frequently and in concert with other synapses processing the same information become more stable and better at processing; those that are used less, on the other hand, are eliminated (Katz and Shatz, 1996). Remarkably, both early spontaneous and patterned activity (from sensory stimuli in the environment) influence synapse formation and stabilization (Leighton and Lohmann, 2016). In all mammalian species examined, including humans, synapse pruning (i.e., the controlled elimination of certain synapses) in the cerebral cortex begins before puberty, with a reduction of approximately 40 percent by the end of adolescence (Bourgeois, 1997). A core concept that has emerged from decades of neurobiological studies of the development and reorganization of connectivity is that environmental factors, which include fetal, postnatal, and child experiences, regulate the expression of genetic predispositions, and these experiences can dramatically change outcomes. This underlies the mechanism through which early exposure to chronic stressors and trauma so powerfully influences developmental processes in the brain and periphery. The research also makes clear that brain development and maturation depends upon experience—what Greenough labeled “experience-expectant” development (Greenough et al., 1987). Myelination is an often-overlooked developmental process. Myelination entails forming the insulation around axons and is essential for increasing the capacity for rapid and efficient transmission of information in neural circuits (Bercury and Macklin, 2015). During the entire postnatal period discussed above (Gogtay et al., 2004), the glial cells responsible for myelination (Miller et al., 2012)—the oligodendrocytes in the brain and Schwann cells in the periphery—becomes its most active, forming the sheath around axons that promotes more rapid signaling between neurons. Myelin is composed mostly of protein and lipids (i.e., fats) to form the ensheathing membranes; myelination is highly dependent upon nutritional status, experience, and other environmental factors (McLaughlin et al., 2017). Neurons are among the most metabolically active cells in the body, so they too are highly dependent upon nutritional status. Myelination begins and ends in different regions of the nervous system at different times postnatally (Yeung et al., 2014), with the axon tracts beneath the frontal lobes taking the longest; myelination in this region can extend into the third decade of life (Miller et al., 2012). The timing of myelination completion corresponds to the reduction or ending of sensory critical periods, suggesting that myelin not only facilitates improved information processing but also participates in the maturation of synapse networks. This correlation has been tested experimentally by reversing myelination, resulting in reopening the critical period (McGee et al., 2005). This suggests that for human brain regions that have long periods of circuit myelination (such as PREPUBLICATION COPY: UNCORRECTED PROOFS

2-22 VIBRANT AND HEALTHY KIDS frontal-lobe-associated circuits, in which executive functions continue to develop into young adulthood), extended periods of plasticity continue (Diamond, 2013). Plasticity The circuits of the brain undergo initial construction prenatally and remain relatively immature until postnatal periods, when experience drives remarkable growth that is reflected in formation of extensive connections (synapses) that form at a rate of at least 1 million per second during the first 2 years (Center on the Developing Child at Harvard University, n.d.-b,c). The role of experience in the development of functional circuits was established half a century ago in landmark studies of the visual system (reviewed by Hensch, 2016b; Hensch and Bilimoria, 2012). Binocular vision requires the use of both eyes by the infant to form an accurate representation of the visual world. This occurs during a sensitive or critical period, when there is heightened plasticity for changes in the fine details of circuits that will establish functioning for a lifetime. Since that time, neuroscience research has shown that all sensory and motor circuits, as well as those involved in social and emotional behaviors, cognition, motivation and reward, executive functioning, and even stress responsiveness, develop through experience-dependent mechanisms that involve heightened plasticity. Moreover, circuits remain open to change for different periods of time—sensory functions that are essential for the infant and toddler to perceive and respond to the environment are built first, followed by gross and fine motor and basic cognitive functions that provide the baby with opportunities to respond in more and more complex ways to experiences that provide input to the brain. This concept reflects the basic developmental rule that simple skills beget more complex skills, the paramount exemplar being language: from phoneme discrimination, to motor imitation, to making sounds that become part of a repertoire in which sounds become associated with objects, to objects becoming associated with words as the child begins the process of integrating language with more complex cognitive skills. It is important to emphasize that certain experiences, including physical exercise, are not necessarily limited in impact within certain periods and can be drivers of brain plasticity across the life-span. The evidence in basic and clinical research is compelling, showing effects on both physical well-being and cognitive and social-emotional capacities (Khan and Hillman, 2014; McEwen and Getz, 2013). For all of these steps, there are heightened sensitive periods when experiences that occur over and over are the most potent. Periods have a beginning, a peak of varying length, and then a stretch of reduced plasticity, when change can occur but in a far more limited fashion and with much greater effort. Think about learning a second language for the first time as an adolescent or adult. For all circuits that will be responsive to either positive or negative experiences, critical period shifts can occur that result in more rapid maturation or longer times of remaining open. Neither outcome of changes in plastic periods is beneficial. Note that genetic factors also can change circuit maturation (Heun-Johnson and Levitt, 2018), which then causes a different response to early experience, as if events were occurring in an older individual. In a model of early adversity (Bath et al., 2016), precocious maturation of molecular and behavioral measures were induced by early adversity. Disrupting neuronal metabolism in certain types of neurons prolongs the visual system’s critical period plasticity (Morishita et al., 2015). All of these experimental studies mean that the normal periods of heightened plasticity are out of synch with the timing of when normal experiences are supposed to have optimal impact on circuit development. In humans, early adversity affects circuits that underlie specific functions in different ways (Nelson et al., 2014), with the timing of interventions (e.g., the Bucharest Early PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-23 Intervention Project, which has done extensive research on the timing of placement in quality foster care after experiencing neglect in an orphanage) (Almas et al., 2018; Nelson et al., 2007; Wade et al., 2018; Zeanah et al., 2003) having a lasting effect on the quality of executive functioning, stress responsiveness, and attachment-related behaviors. Here, the impact on critical periods can only be hypothesized, but based on measures years later, it is likely that the timing of optimal sensitivity to experiences is changed in relation to specific functional domains. The concept that altered neural development, through genetic and experience-dependent mechanisms, establishes different sensitivity to later-life adversity has been suggested for postadolescent onset psychiatric disorders (Keshavan et al., 2014) and more recently for ACEs (Danese et al., 2009; Loria et al., 2014; Morrison et al., 2017; Shalev and Belsky, 2016). The second adversity may be related to normal challenges or other life experiences that all of us endure and to which those without early adverse experiences are able to adapt. The mechanisms through which this vulnerability is read out has recently been addressed in a new set of animal studies (Peña et al., 2017). These demonstrate that there are early molecular changes in specific brain reward circuits due to early life stress that are responsible for the negative impact of later- endured juvenile social defeat (bullying) to produce depressive-like symptoms. For both human and animal studies, it is important to note that while early adverse experiences can have both acute and long-term impacts on mental and physical health, men and women may express these changes in different ways (for example, externalizing or internalizing behaviors, respectively), which need to be accounted for in any intervention programs. Immune System Development The newborn immune system is shaped largely by the gut microbiome, which is initially primed by the vaginal or skin maternal microbiome during childbirth (depending upon birth process) and early life, such as through breastfeeding (Miller, 2017). The gut microbiome refers to the vast collection of microbes that populate the gastrointestinal system and contribute to whole-body physiology. Molecules produced by the immune system impact various aspects of brain development, with strong evidence for mediating the formation and molecular adaptation of neural connections. The immune system also plays a role in the response of the brain and body to early life stress. In addition to the development of neurons and their connections with the periphery, the fetus’ immune system undergoes rapid development in the first years of life and is yet another system that may be impacted by early adversity and stress (Simon et al., 2015). The innate immune system—which includes specialized cells, such as resident neutrophils, macrophages, and monocytes—develops in the fetal stage, though it is not robust enough to ward off most external pathogens. Of course, this lack of strong innate immunity may also provide the substrate for healthy microbiota to develop symbiotically with the newborn infant; the bacteria colonizing the gut, skin, and mucosa, for instance, assist in digestion and protection from other pathogens. Children’s adaptive immune systems—governed by the lymphatic system—are relatively undeveloped at the time of birth, rendering them prone to bacterial, viral, and fungal infections soon after birth. At this time, the fetal adaptive immune system is prepared for “training” by the maternal microbiome, which occurs rapidly after birth via vaginal, skin, or mammary exposure (Lynch and Pedersen, 2016). Throughout childhood, children are exposed to countless microbes that are either summarily dismissed by the immune system without notice or produce a robust immune response that primes the immune system to protect the body against similar pathogens in the future. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-24 VIBRANT AND HEALTHY KIDS The immune system can be trained to cope with certain challenges. For example, the “hygiene hypothesis” suggests that the prevalence of asthma has increased dramatically in certain parts of the world where children are no longer exposed to microbes that can train the immune system (Harding, 2006). In the face of other challenges, the nervous system activates the HPA axis, which can lead to suppressed immune functioning and thus increased susceptibility to infections (Cohen et al., 2007; Thompson, 2014). When children experience sustained exposure to challenges (e.g., chronic stressors, such as poverty or maltreatment), HPA axis activity may become blunted, which can reduce inhibition of inflammation and lead to elevated levels of chronic low-grade inflammation (Koss and Gunnar, 2018; Miller et al., 2011). In the past two decades, researchers have attempted to clarify (1) the relationship between social stressors and inflammation and other immune markers in children (Slopen et al., 2012) and (2) the role of immune system in the development of neurodevelopmental (Entringer et al., 2015; Gilman et al., 2017) and psychiatric disorders (Danese and Baldwin, 2017; O'Connor et al., 2014) and the cardiovascular and atherosclerotic disease process (Hansson and Hermansson, 2011; Pearson et al., 2003). There is now evidence from longitudinal research that inflammation tracks from childhood to adulthood (Juonala et al., 2006) and that chronic inflammation is a risk factor for a wide range of diseases, including cardiovascular diseases and depression (Dantzer et al., 2008; Libby et al., 2002). Endocrine System Development The endocrine system is composed of several glands that secrete hormones—signaling molecules—that reach their target organs through the circulatory system to modulate every physiological function, such as growth and development, reproduction, stress responses, and metabolism. A key characteristic of the endocrine system is that it operates on feedback loops to allow the hormones to perform a function (e.g., the “fight or flight” stress response) and then resets to be ready for the next event that may trigger an endocrine response. In all mammals, including humans, the hypothalamus and pituitary are the center of control for the endocrine system. Because they impact many stages of development, the organs of the endocrine system themselves develop early on, in the first trimester of gestation. Moreover, early in the first trimester, the placenta produces the same releasing factor proteins that are synthesized in the hypothalamus of nonpregnant women. These proteins control the production and release of hormones from the pituitary and peripheral tissues in the mother and the fetus. Neuroendocrine hormone markers are evident by the second trimester. The endocrine systems work in concert with the autonomic nervous system to regulate organ function. Autonomic regulation can be measured in the late second trimester and throughout the third trimester and is intact and operational at the time of birth (DiPietro, 2015). The autonomic neurotransmitters norepinephrine, epinephrine, and acetylcholine and the endocrine hormones reach their targets via body circulation. Thus, they affect metabolic processes through their binding to membrane protein receptors that are expressed by target cells in the brain and other organs as early as the second trimester. Related to the stress response via cortisol production, activation of the glucocorticoid receptors in the hippocampus and hypothalamus serve as classic feedback loops to reduce hormone production in order to reset the stress response capacity. Research in humans and animals shows that overexposure to stress hormones and autonomic neurotransmitters during prenatal or early postnatal development can result in a fetal programming response, which includes epigenetic changes in the genes that encode the stress hormone receptors. This process produces long-term changes in receptor expression and less PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-25 robust negative feedback to limit stress hormones’ chronic effects (for examples, see Maternal and Fetal/Infant Interactions, above) (Meaney and Ferguson-Smith, 2010). In contrast, high levels of maternal care documented in animal studies shows that the stress response system is capable of better management of later-life stress (Meaney, 2001; Plotsky et al., 2005; Plotsky and Meaney, 1993). Reproductive System Development The development of the reproductive system also begins early in gestation, in the first trimester. In the first 2 months of pregnancy, differentiation between male and female gonadal development occurs, which continues into the second and third trimesters. As noted above, animal studies show that intergenerational transmission of the impact of adversity during pregnancy can influence the mother, the fetus, and, if the developing gonads are affected, the offspring of the fetus when he or she matures into a reproductive adult. Sexual differentiation is controlled primarily by levels of testosterone, estrogen, and androgen, a process that can be influenced by exogenous chemicals similar in structure to these hormones. Among women, the ovarian follicle pool develops during the prenatal period; therefore, in-utero exposures may impact the size and quality of the follicle pool and influence the timing of ovarian loss and menopause (Bleil et al., 2018). For example, studies show that in-utero cigarette smoking exposure (Strohsnitter et al., 2008), famine (Yarde et al., 2013), and extremes of birth weight (Tom et al., 2010) are associated with earlier menopause. There is also evidence to suggest that maternal metabolic factors during pregnancy, including obesity and pregnancy hyperglycemia, are also associated with the timing of puberty (Kubo et al., 2018). There has been a trend toward an earlier age of puberty for boys and girls in the United States that is not yet fully understood, and currently 9 years of age is within the normal range for onset of puberty (Herman-Giddens et al., 1997, 2012). Adverse social experiences in early and middle childhood—including socioeconomic adversity (Hiatt et al., 2017; Kelly et al., 2017; Sun et al., 2017) and child maltreatment (Mendle et al., 2016; Noll et al., 2017)—as well as exposure to endocrine-disrupting chemicals (Buttke et al., 2012) are associated with earlier pubertal development (Ellis and Giudice, 2019). In the United States and elsewhere, the age of puberty is earlier among racial/ethnic minority children (Herman-Giddens et al., 1997, 2012; Kelly et al., 2017; Reagan et al., 2012). These patterns by early childhood adversity and race/ethnicity may have implications for health disparities into adulthood (Bleil et al., 2017; Golub et al., 2008), as earlier puberty is associated with increased risk for depression (Wang et al., 2016) and substance use (Cance et al., 2013) during adolescence and numerous chronic disease outcomes in adulthood, including diabetes, cardiovascular diseases, and cancer (Canoy et al., 2015; Day et al., 2015; Elks et al., 2013). Conclusion 2-1: Scientific research demonstrates healthy development of the child begins preconception and is dependent upon a strong foundation built prenatally. Therefore, access for the family to high-quality resources to limit chronic stress reduces risk for disrupted development and has the potential to close disparities based on race/ethnicity and socioeconomic status. Research findings show that specific types of resources are key to best outcomes, including healthy food, standard of care with a woman’s health professional, maternal stress-reducing strategies, parenting education, and coaching. Research also has revealed that supportive relationships after birth are major contributors to healthy child development and building resilience. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-26 VIBRANT AND HEALTHY KIDS BIOLOGICAL MECHANISMS OF STRESS When the brain perceives a stressor, it induces a response that calls on multiple biological systems that, in the short term, are critical for adaptation and survival—sometimes defined as the “fight or flight” response. This stress response is a normal and healthy part of human biology. The spectrum of the stress response includes positive, tolerable, and toxic stress (Center on the Developing Child at Harvard University, 2005) and is governed by a complex interplay between the severity and duration of the stressor, individual genetic differences, gene–environment interaction, family environmental factors, developmental experiences, and the availability of buffering and coping strategies and resources. Positive and tolerable stress responses are characterized by a return to homeostasis, while the toxic stress response may induce lasting changes in brain architecture and function and in organ system development. Specific endocrine, immune, and brain cell populations produce bioactive chemicals that signal through their receptor proteins, which are present on cells throughout the body. These signals control cellular metabolism and physiological activity, which, in the short term, is a positive adaptation to the stressor. Chronic activation of the stress response system can lead to risk for short- and long-term poor health outcomes beyond the early childhood period, including dysregulation of neuroendocrine and immune system development, altered cardiovascular functioning, metabolic dysregulation related to obesity and type 2 diabetes, changes to the gut microbiome, and epigenetic modifications that alter gene expression (Black, 2003; Campbell et al., 2014; Dinan and Cryan, 2012; Taylor et al., 2011; Vaiserman, 2015). There are individual differences in risk caused by chronically activated stress response systems, due in part to variation in the intrinsic sensitivity of the child, and physiological adaptive capacities that can be impacted by supportive environments (as discussed in greater detail below). Activation of the stress response involves circuits in the brain that are essential for threat detection (amygdala), emotional regulation (frontal cortex), neuroendocrine regulation to produce cortisol (hypothalamus, pituitary, and adrenal—HPA axis), feedback to shut down the stress response (hippocampus), and the vagal complex in the brain stem that sends information to peripheral organs, such as the heart, lungs, and gastrointestinal systems (Cameron, 2009; Dedovic et al., 2009; Forsythe et al., 2014; Goodman et al., 2013). The Sympatho-Adreno- Medullary (SAM) responds to stress by producing and secreting adrenaline and noradrenaline through the vascular system. Adaptive responses of the SAM axis include increased arousal, alertness, and vigilance, improved cognition, focused attention, enhanced analgesia, and inhibition of appetite, feeding, digestion, growth, reproduction, and immunity (Chrousos, 2009). Adaptive responses of the HPA axis include regulation of cognitive, behavioral, affective, cardiovascular, and immune system functioning (Kudielka and Kirschbaum, 2005; McEwen et al., 2015). See Figure 2-2 for a diagram illustrating the stress response pathway. PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-27 FIGURE 2-2: Stress response pathway NOTES: HPA axis = hypothalamic pituitary adrenal axis; SAM axis = sympathoadrenomedullary axis; AVP = arginine vasopressin; CRH = corticotropin-releasing hormone; ACTH = adrenocorticotropin hormone. Reprinted from Advances in Pediatrics, 63/1, Bucci et al. Toxic Stress in Children and Adolescents, 403-428, Copyright (2016), with permission from Elsevier. SOURCE: Bucci et al., 2016. Dysregulation of the Stress Response Severe or chronic activation of the stress response, in the absence of adequate caregivers who serve as buffers to the stress activation, can lead to disruption of homeostatic mechanisms and long-term changes to brain architecture and organ systems (the toxic stress response) (Shonkoff et al., 2012). Early life stress can also result in epigenetic changes that can sensitize the individual to stress and adversity, alter the development of many organ systems, and impact the response to subsequent stressors later in the life course (see Epigenetics, above) (National Scientific Council on the Developing Child, 2014). Exposure to high levels of adversity in early childhood is associated with the following multisystemic disruptions, with some of these changes PREPUBLICATION COPY: UNCORRECTED PROOFS

2-28 VIBRANT AND HEALTHY KIDS occurring as early as infancy (e.g., changes to brain structure), while others are not evident until later in life (e.g., hypertension): • Neurologic: There are structural and functional changes to stress-sensitive regions of the brain (McEwen and Morrison, 2013; National Scientific Council on the Developing Child, 2014). • Endocrine: There is excessive activation of both the SAM and HPA axes, associated with loss of feedback inhibition of the HPA axis, increased levels of CRH, and disruption of the daily cortisol pattern, leading to abnormally lower morning cortisol levels, elevated afternoon cortisol levels, and an overall increase in cortisol exposure. Over time, excess HPA activation may recede, leading to low or deficient HPA axis response. HPA axis overactivity is associated with suppression of thyroid function. High doses of early adversity are associated with changes in reproductive function through the HPA axis’ effect on gonadotropins and/or cytokine suppression of reproductive function (Dedovic et al., 2009; Kudielka and Kirschbaum, 2005; Slopen et al., 2014). • Immune function: There is dysregulation of neuro-endocrine-immune relations, leading to increased proinflammatory cytokines and inhibition of anti-inflammatory pathways. In addition, humoral (antibody production) and cell-mediated acquired immunity can be impaired. High levels of early adversity in childhood are associated with increased risk of autoimmune disease in adulthood (Nusslock and Miller, 2016; Padgett and Glaser, 2003). • Cardiometabolic: There is insulin resistance, obesity, glucose intolerance, reduced control over blood lipid levels, and hypertension (Non et al., 2014; Woo Baidal et al., 2016). Buffering the Stress Response From a population health perspective, ameliorating the toxic stress response and understanding the biological mechanisms by which toxic stress can be prevented or mitigated is of high priority. Importantly, research suggests several mechanisms to buffer against toxic stress. One mechanism—studied in depth in animal models—is social relationships (Gunnar and Fisher, 2006). Research on resilience has clearly demonstrated that the single most important protective factor for children facing adversity is a strong, secure relationship with at least one parent; this helps foster positive outcomes across domains ranging from psychological adjustment to positive peer relationships (Cicchetti, 2013; Luthar et al., 2015; Masten, 2018; Sroufe, 2005). Moreover, a child who is securely attached to a primary caregiver is more likely to have high self-esteem, emotion regulation skills, and a positive outlook later in life (Sroufe, 2005). It also has been demonstrated that supportive relationships early in life play an important role in buffering stress responses, thereby allowing children to more easily confront stressful situations (Hostinar et al., 2014). (See Chapter 4 for an in-depth discussion on caregiver and social connections.) Some studies have shown an effect of social buffering on regulating the HPA axis, autonomic nervous system, and immune functioning, though more research is needed for more in-depth assessment of neuro-endocrine-immune, metabolic, and genetic regulatory functions (Hennessy et al., 2009; Hostinar et al., 2014; Kikusui et al., 2006). While the mechanisms through which nurturing relationships buffer against toxic stress are likely to be complex, some studies have shown that the neuropeptide hormones oxytocin and PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-29 vasopressin play important roles in affiliative social behavior (Gunnar and Hostinar, 2015) (Bartz et al., 2011; Ross et al., 2009a,b; Ross and Young, 2009), though experimental work in social neuroscience is challenging (Insel, 2010a). Studies in animals and humans have shown that oxytocin and/or vasopressin play a role social memory, pair bonding, empathy, altruism, emotion regulation, and trust (De Dreu and Kret, 2016; Donaldson and Young, 2008; Hostinar et al., 2014; Israel et al., 2012; Quirin et al., 2011; Rodrigues et al., 2009; Snowdon et al., 2010). It is thought that increased oxytocin counteracts the biological underpinnings of toxic stress, including increased inflammation, cardiovascular dysfunction, oxidative stress, and alterations in brain structure and function (Detillion et al., 2004; Donaldson and Young, 2008; Heinrichs et al., 2003; Hostinar et al., 2014; Mantella et al., 2004). Social buffering to toxic stress, and its action through oxytocin and vasopressin (Gobrogge and Wang, 2015), is still an ongoing area of research, as is intergenerational transmission of trauma and trauma-related stress (Kim and Strathearn, 2017). For example, how such mechanisms change with development still remains to be determined (Gunnar and Hostinar, 2015). Still, this evidence suggests that interventions to create strong social relationships may ward against the long-term impacts of ACEs and other chronic adversity over the course of child development and into adulthood. More research is needed to understand other buffers against toxic stress (e.g., sleep, exercise, nutrition) and the biological mechanisms through which they operate; prefrontal cortex plasticity is one such mechanism (McEwen and Morrison, 2013). Conclusion 2-2: Among all the factors that may serve to buffer negative outcomes produced by toxic stress, supportive relationships between the child and the adults in their life are essential. Biological Measures of Stress in Children In the decades since From Neurons to Neighborhoods, there have been substantial efforts to understand the biological changes that occur in response to early adversity (Danese and McEwen, 2012; NRC and IOM, 2000), at least in part inspired by the goal of developing valid, minimally invasive, low-burden measures of biological stress and neurobiological functioning in children that can be used to identify individuals at risk for poor long-term outcomes and, importantly, the impact of early life intervention (Shonkoff, 2010; Shonkoff et al., 2009). An increasing number of developmental studies with children now collect biological measures of stress, aiming to study how social experiences relate to changes in the biology of the child that may not cause immediate, gross disturbances (i.e., biological alterations that increase risk for subsequent chronic diseases) but rather set up the brain and peripheral systems for later emergence of physical and mental health problems over time. This research shows that traumatic experiences (such as child maltreatment) or prolonged exposure to chronic stress (such as poverty) can result in a chronically activated physiological stress response, which has a host of downstream consequences across biological systems. Some of this research has applied the concept of “allostasis” or “allostatic load,” which provides a method to evaluate the cumulative biological impact, or “wear and tear” on the body, as the result of a given social exposure (Danese and McEwen, 2012; McEwen, 1998). As noted in previous sections of this chapter, both animal and human research has demonstrated that early life stress contributes to altered brain development (i.e., structure and function) and therefore to allostatic load. PREPUBLICATION COPY: UNCORRECTED PROOFS

2-30 VIBRANT AND HEALTHY KIDS Synthesis Advances in science technologies, big data collection and information technology, and new strategies for analyzing complex data have been instrumental in rapidly advancing the science of brain and child development over the nearly 20 years since From Neurons to Neighborhoods was released to the public (NRC and IOM, 2000). Research findings have revealed the details of how early experiences are essential for building brain connections that underlie biobehavioral health, the role of genetics in development, and a new understanding of whole-child development that relies on organ systems interacting with each other and the environment to establish health and biobehavioral fitness or risk due to early influences of adversity. Conclusion 2-3: Research has changed the discourse to include scientific facts in child development that have determined that when considering the entire life course, it is early experiences, pre- and postnatally, that are the most powerful in working together with an individual’s genetic makeup to influence the physical, mental, and cognitive development of the child. Science also shows that maternal health and well-being is a major contributing factor to the development of the fetus and establishes a foundation for positive or negative child health outcomes. Conclusion 2-4: Based on the abundant science, the influence of access to basic resources prenatally, particularly nutritional, psychosocial, and health care components, is powerful. The new understanding defines three interrelated parts: 1) Chronic activation of the stress response system of primary caregivers, and in the infant and toddler, can occur due to a large number of factors in the environment of the family, including lack of access to quality health care, child care, economic security, community support programs, transportation, stable housing, and healthy nutritional sources; institutional and individual racism and sexism; and community violence; 2) Sustained stress activation can produce a response in the child known as toxic stress, which affects the development of the structural organization and functioning of brain circuits that impact the quality of cognition and social and emotional regulation, including the child’s own stress response, reward, and motivation. The toxic stress response therefore directly impacts the behavioral and psychological well-being of the child; and 3) New data from longitudinal studies, combined with previous work from retrospective analyses of the early life experiences of adults, provides a compelling demonstration that toxic stress response substantially increases later-life risk for physical illnesses, including obesity and type 2 diabetes, cardiovascular disease, substance abuse, mental illness, lower educational achievement, cancer, and infectious disease. In addition to the adverse effects of toxic stress on the brain and nervous system, it also affects every other organ system in the child's body, impacting short and long-term health. PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-31 Individual Differences in Responsiveness and Susceptibility Research over the past two decades clearly shows that what were previously considered to be universal developmental processes (see Chapter 4) do not occur uniformly. Relevant to this focus of this chapter, in part, this can be due to variation in the development trajectory of stress- sensitive brain circuits in infancy, as well as the interplay between genes and environments that mediate the neurobiological and physical impact of positive or negative early life experiences. Thus, heterogeneity with substantial variations is often observed, such as across groups that differ by SES or ethnicity. Diversity brought about by individual and subgroup differences, based on factors such as personal experiences, individual temperament, culture, and the family and community context, can alter the pace and trajectories of developmental biological and psychological processes. For example, humans are predisposed to become attached to our main caregivers, but the quality of interactions between caregiver and child and other environmental conditions can contribute to the development of various types of infant attachment. To consider another example, a rich literature supports the notion that children differ in their temperament: behavioral predispositions can permeate how children react to and process environmental input. From conception, children bring differential responsiveness to—and processing of—their physical and relational context. Infants are described as difficult, inhibited or uninhibited, shy or slow to warm up (Conture et al., 2013). These dispositions carry consequences for adaptability to new environments, relational difficulties, and even long-term mental health problems (Clauss et al., 2015). One research notion from the temperament literature proposes that there are behavioral predispositions that are normative variations across individuals (Durbin and Hicks, 2014). Another theory sees the origin of these individual differences as consequences of exposure to early stress, whereby stress experienced by the mother and fetus before birth conditions the nervous system to respond, perhaps in an exaggerated way, to neutral or mild environmental input (Miller et al., 2011). Recently, there has been an emphasis on elucidating the mechanisms underlying the differential susceptibility to the environment hypothesis. Work by both Belsky and Boyce has advanced understanding of how individual differences in how children process and react to the environment contribute to individual risk and resilience (Boyce, 2019; Bush and Boyce, 2016). Behavioral genetics research defined the contributions of both heritability and environment to the variance in the symptoms and incidence of behavioral disorder diagnoses (Plomin et al., 2001). This core principle is evident in the assessment of typical behavioral characteristics, such as affiliative social behavior. Studies of twins highlight the remarkable variability in specific traits that make up affiliative social behavior (Ebstein et al., 2010), with some elements exhibiting high (~0.7) heritability (prosocial behavior; social responsiveness) and others low (~.3) heritability (empathy; secure attachment). In animal studies, heritability of the behaviors that make up affiliative social behavior exhibits very similar genetic contributions (Knoll et al., 2018). These studies also showed that environmental context plays a particularly important role in modifying behavior—even those with moderate to high heritability. As Bush and Boyce (2016) note, the accumulating biological data from studies of humans and animals has changed the concept from the long-standing diathesis stress model of sensitivity to environment to one that focuses on determining factors that confer individual differences that affect susceptibility and resilience. Stress reactivity, which had been presumed to influence behavioral outcomes in a single direction—negatively—is an important individual difference that can influence responses to different environmental contexts in either a positive or negative direction (Bush and Boyce, PREPUBLICATION COPY: UNCORRECTED PROOFS

2-32 VIBRANT AND HEALTHY KIDS 2014; Ellis et al., 2011; Obradovic et al., 2010). Again, context appears to be a major moderator of biological predispositions, and an ongoing topic of study is why some children adhere to healthy developmental trajectories despite profoundly adverse circumstances while others do not (NASEM, 2015; Cicchetti, 2013; Masten, 2014; Rutter, 2012; Shonkoff, 2016). The importance of individual differences in development points out lessons for practice and policies in efforts to prevent developmental problems and promote positive trajectories (Shonkoff, 2017). A key fact is that universal interventions will be more or less effective depending upon the individual(s) being targeted. Thus, well-designed interventions are those that are sufficiently flexible to take individual differences and heterogeneity into account. The challenge continues to be predicting what specific changes are most likely to produce the best outcomes. For example, the New Hope Project, a welfare reform demonstration based in Milwaukee, WI, was designed to raise families out of poverty, using a work-support intervention that was tailored to the specific needs of each family (Huston et al., 2011). The intervention had multiple components that families would choose from over 3 years, and it was expected that the combination of benefits and services would increase parents’ employment, income, and use of child care and health insurance. In a report to summarize effects over 8 years (i.e., 5 years after the intervention ended), researchers concluded that work supports can positively impact low- income parents and children, even though the economic effects of employment and income were not sustained beyond the 3 years of the intervention. Importantly, positive effects for children appeared during the intervention period and extended to the 8-year follow-up.8 Another example is Filming Interactions to Nurture Development (FIND), a 10-week video-feedback program to promote acquisition of developmentally supportive parenting skills (Fisher et al., 2016; Nese et al., 2016). This behavioral training program is tailored to address individual differences in the types of challenging parenting styles via weekly structured coaching sessions, and findings suggest that it is effective for improving caregiver skills (Fisher et al., 2016). In some cases, individuals have different responses to social or environmental stimuli as the result of age of exposure. Specific time points in development represent “sensitive periods” when risk or protective factors have a maximal influence on cognitive capacities, biology, emotions, and behavior (Ben-Shlomo and Kuh, 2002; Hertzman and Boyce, 2010; Knudsen, 2004; Zeanah et al., 2011). The strongest evidence for the heightened importance of specific periods comes from experiments using laboratory animals (Hertzman and Boyce, 2010) because it is challenging to isolate sensitive periods within observational studies in humans (given that risk factors are often continuous and may in turn elicit subsequent risks). As noted in detail above, the prenatal, postnatal, and early childhood phases are recognized as having sensitive periods that result in brain and behavioral changes. Research is beginning to elucidate how risk factors at different time points may have varying impacts. Although it is generally accepted that developmental timing can influence the effect of a social or environmental risk factor on child health, the majority of studies do not consider how risk or protective factors vary by age. 8 Although the positive effect of this personalized intervention on children’s academic performance and test scores at the 2- and 5-year follow-ups faded, at the 8-year follow-up, children in families assigned to the intervention condition were more likely to be engaged in school and to show positive social behaviors relative to those in families assigned to the control condition, and they were less likely to have to repeat a grade, to be placed in special education, to receive poor grades, or to have cynical attitudes about work (Miller et al., 2008). PREPUBLICATION COPY: UNCORRECTED PROOFS

HEALTHY DEVELOPMENT 2-33 CONCLUSION With advances in science emerging from different disciplines, now more than ever, there is a major need to facilitate new public–private-nonprofit sector relations to build substantial opportunities for the fields of neuroscience, behavioral sciences, and psychology to collaborate. Therefore, the committee recommends: Recommendation 2-1: The National Institutes of Health and other relevant research entities should support the development of public–private partnerships, or other innovative collaborations, to • Build multidisciplinary teams, including but not limited to researchers in neuroscience, endocrinology, immunology, physiology, and metabolism, behavior, psychology, and primary care, to identify the most relevant factors in a child’s complex environment that promote resilience and promote outcomes related to physical and mental health. • Conduct research that measures the impact of chronic stress on all relevant organ systems and determines the specific molecular and biological pathways of interaction during the pre- and postnatal periods, which are directly relevant to potential interventions to address health disparities. This will require recruiting diverse populations, with explicit attention to addressing racial/ethnic and socioeconomic inequities in developmental outcomes. Research with these populations will require researchers and practitioners as co-investigators that are knowledgeable of theoretical models, measures, and the realities of these families and communities. For all studies that typically use expensive biological assessments (e.g., biomarkers as mediators, moderators, or outcomes) for use in interventions, researchers need to strongly consider the ability to apply measures within the context of scaled, community-based interventions to have the broadest possible impact on outcomes for children and their caregivers. For example, there is a major gap in research support for projects that combine modern, noninvasive technologies to measure key domains of brain, behavioral, and psychological development with clinical interventions that promote best outcomes for children and their caregivers. In summary, research advances in neuroscience, immunology, endocrinology, behavior, and psychology in the last two decades provide a new depth of understanding regarding the impact of adverse experiences on developmental processes throughout the life course. Because of these advances, the fields of developmental neuroscience, behavior, and psychology are recognizing the trajectories of development in the context of racial, ethnic, and socioeconomic health disparities. Deciphering the mechanisms through which adversity disrupts foundational developmental processes of the whole child, and the long-term impact on health, wellness, personal and community relationships, and life-span productivity across the life course, is being achieved through multidisciplinary, longitudinally designed research that has incorporated principles of human development, including individual differences and differential sensitivity to context. With this foundation, the chapters that follow provide advances in the research that addresses the role of macro- and micro-level variables in influencing development and outcomes. PREPUBLICATION COPY: UNCORRECTED PROOFS

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Children are the foundation of the United States, and supporting them is a key component of building a successful future. However, millions of children face health inequities that compromise their development, well-being, and long-term outcomes, despite substantial scientific evidence about how those adversities contribute to poor health. Advancements in neurobiological and socio-behavioral science show that critical biological systems develop in the prenatal through early childhood periods, and neurobiological development is extremely responsive to environmental influences during these stages. Consequently, social, economic, cultural, and environmental factors significantly affect a child’s health ecosystem and ability to thrive throughout adulthood.

Vibrant and Healthy Kids: Aligning Science, Practice, and Policy to Advance Health Equity builds upon and updates research from Communities in Action: Pathways to Health Equity (2017) and From Neurons to Neighborhoods: The Science of Early Childhood Development (2000). This report provides a brief overview of stressors that affect childhood development and health, a framework for applying current brain and development science to the real world, a roadmap for implementing tailored interventions, and recommendations about improving systems to better align with our understanding of the significant impact of health equity.

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