An Examination of Child and Adolescent Neurodevelopment Through National Institutes of Health Studies

Parents have many urgent questions about their children’s health and development. How much screen time is too much? How much sleep is too little? Should my child engage in sports with a high risk of concussion? What are the immediate or long-term effects of using drugs such as marijuana or vaping nicotine? Can parents’ past drug use affect their child’s health? Understandably, pediatricians, educators, and policy makers would also like answers to these same questions. Until recently, however, science has been unable to answer them with confidence.

Fully understanding the effects of exposure to substances, screens, social stressors, or environmental pollutants, as well as factors such as sleep, physical activity, mild head injury, and extracurricular activities, requires not just correlating these effects and factors with outcomes (eg, grades and IQ) but also examining the developing brain and doing so repeatedly over time among the same persons. These studies have been a substantial challenge because of the expense of conducting neuroimaging among sufficiently large study populations, especially during the course of many years. Also lacking until recently has been the capacity to store, share, and analyze the enormous quantities and complexity of data generated from brain imaging, genetics, and deep phenotyping, which are required for such an ambitious research project.

However, technological leaps are moving biomedical research into a new era in which massive studies only imagined in previous decades are now within reach. The Adolescent Brain Cognitive Development (ABCD) study¹ of children aged 9 and 10 is well underway, and the HEALthy Brain and Child Development (HBCD) study,² a study of children beginning at birth, is in its planning phase. Together, these studies are poised to provide answers to myriad questions about the interplay of genetics, environments, substance exposures, race, ethnicity, other social determinants of health, and many other factors on health and other outcomes during the first 2 decades of life, while providing normative data on the variability of brain developmental trajectories.

The ABCD study was conceived for several reasons, chief among them concerns about the effects of adolescent alcohol and marijuana use on the still-developing adolescent brain. As the first US states were legalizing marijuana for recreational use and intense public interest in that drug’s harms and possible therapeutic uses ensued, public health experts faced urgent questions about the increased availability of marijuana and its possible increased use by adolescents. Delayed maturation of the prefrontal cortex relative to other regions makes young persons more prone to seek new experiences—a normal and (mostly) healthy part of growing up and becoming independent. But adolescence is precisely when the circuits linking the prefrontal regions to the basal ganglia and limbic regions are established and, perhaps, are most susceptible to perturbation by exposure to substances and multiple other environmental influences.

Thus, the leaders of 3 National Institutes of Health (NIH) institutes concerned directly or indirectly with addiction—the National Institute on Drug Abuse (NIDA), the National Institute on Alcohol Abuse and Alcoholism, and the National Cancer Institute—agreed in 2014 that the time was ripe for a massive longitudinal study of adolescent brain development, one that would be sufficiently powered to determine how exposure to substances affects developmental trajectories. It was quickly realized that a study of the kind being envisioned would be capable of addressing many important issues in human health and development, and other NIH institutes and centers—the National Institute of Mental Health, the NIH Office of Behavioral and Social Science Research, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Heart, Lung, and Blood Institute—as well as the Centers for Disease Control and Prevention joined to support a large multisite study to evaluate the effects and interplay of numerous environmental influences, genetics, and behaviors during the second decade of life.³

In 2015, NIDA awarded 13 grants for the creation of 19 research project sites, a coordinating center, and a data analysis and informatics center. The number of sites has grown to 21. Participant recruitment began in 2016; in 2018, ABCD completed its recruitment of nearly 12 000 9- and 10-year-old children and began follow-up assessment 6 months after the baseline assessment. This cohort will continue to be followed for 10 years with periodic (ie, every 3-6 months) questionnaires and behavioral assessments, magnetic resonance imaging scans every other year, collection of biospecimens for genetic and other analyses, and tracking of health, cognition, and other outcomes.

By recruiting participants before the initiation (if any) of substance use, this study will be uniquely positioned to investigate temporal relationships and shed light on potential causal factors that previous studies have been ill-equipped to tackle. It will enable us to more confidently answer questions such as whether drug use predisposes persons to mental illness or vice versa. And by including more than 1000 pairs of twins, researchers will be able to better disentangle the effect of genetics and the environment on neurodevelopmental outcomes. The massive data set on typically developing adolescent brains during a 10-year period will also give medicine an invaluable new resource: a baseline against which pediatric neurologists and developmental pediatricians can track patients’ neurodevelopment, in much the same way that height and weight curves are used to track children’s physical growth and maturation.

To ensure the greatest possible scientific benefit from this substantial investment, anonymized data generated by the ABCD study are being made available to the wider research community. Interim curated data were first released in February 2018, and baseline data from the full cohort were made available in April 2019. As of October 2019, the ABCD data releases had yielded 19 peer-reviewed publications, including 8 by researchers who were not part of the teams conducting the data acquisition. Among the topics into which we are already gaining insight are potential early indicators of psychotic-like experiences,^4,5 the relationship between screen time and neurodevelopment,⁶ and sex differences in hippocampal volume and in the relationship between sports participation and depression.⁷

Such a large and multidimensional study of adolescent exposures and neurodevelopment naturally invites a “prequel.” Here again, the shifting landscape of drug use and addiction in the United States provided one of the catalysts to consider a study of neurodevelopment and other outcomes during the first decade of life. An alarming number of babies have been exposed prenatally not only to alcohol but also to opioids because of the mother’s use or misuse of opioids. Apart from the gravest risks from a mother’s overdose, the number of newborns requiring hospitalization and treatment for neonatal abstinence syndrome has soared—increasing from 21 732 in 2012 to 32 000 in 2014.^8,9 The longer-term effects of prenatal opioid exposure and neonatal abstinence syndrome, as well as other environmental and social effects on parents, families, young children, and communities, is a big question mark for medicine and human development.

The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Environmental Influences on Child Health Outcomes program have launched a series of clinical studies to evaluate the medical and social needs of infants who were exposed to opioids in utero.¹⁰ These studies include comparative effectiveness studies of various medication strategies and nonpharmacologic approaches, along with a 2-year follow-up funding opportunity that includes neuroimaging. This project, which is part of the NIH Helping End Addiction Long-term (HEAL) Initiative,¹¹ is known as Advancing Clinical Trials in Neonatal Opioid Withdrawal Syndrome, or ACT NOW.¹²

In addition, lessons learned from the ABCD study are providing a roadmap for designing a similar study in young children, to answer similar questions about prenatal drug and alcohol exposures, other environmental exposures, social support systems or lack thereof, social determinants of health, and genetics and their effects on neurodevelopment. The HBCD study, funded in part through the NIH HEAL Initiative, aims to recruit 7500 mothers in their second trimester and/or after the birth of their children and follow the children and their families during their first decade of life. Numerous NIH institutes and centers have joined this effort, including NIDA, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Mental Health, the NIH Office of Behavioral and Social Science Research, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Neurological Disorders and Stroke, and the National Institute of Environmental Health Sciences. The HBCD study will use a similar design as the ABCD study, including repeated neuroimaging and extensive behavioral assessments that are age appropriate for this cohort. With its large size and scope, the HBCD study will bring the same power as the ABCD study, answering a similarly ambitious range of research questions about this critical window of early development.

Beyond the neurodevelopmental effects of various types of prenatal substance and environmental exposure (vs no exposure), the HBCD study will allow the investigation of factors that may mitigate the negative effects of stressful environments (eg, food and housing insecurity, exposure to violence, and neglect) or environmental chemicals on brain development, providing clues to factors associated with resilience by race/ethnicity, socioeconomic status, and geographic location. The study will provide insight into the genes that drive development and how genetic influences interact with social contexts, environmental exposures, nutrition, and physical activity or inactivity. As with the ABCD study, the HBCD study will also yield a data set of normative brain development and health in children for use as benchmarks by pediatricians and neurologists, and the data will be made available to the wider research community for secondary analyses.

Study researchers will face many unique challenges ranging from navigating the legal and ethical complexities of studying pregnant women and young mothers who may be using drugs to the practical difficulties of performing brain scans on infants and young children. Lessons learned from the 2-year follow-up of families enrolled in the ACT NOW study will be integrated into the HBCD study design. In addition, a planning phase will precede the HBCD study. Grants were issued in 2019 to 29 research teams that will focus on finding solutions to methodological and bioethical challenges and determining how best to recruit and retain diverse populations, including populations at high risk for substance use and psychiatric disorders. Apart from the legal and practical questions, grantees will be tasked with finding ways to optimize participant retention, establish partnerships with state agencies and treatment programs, and provide referrals for drug-using participants to treatment resources. The goal is to solicit proposals for research grants in 2021 and begin participant recruitment for the HBCD study later that year or in early 2022.

The tools now at our disposal enable us to pose ambitious scientific questions that seemed unanswerable just a decade or two ago. With drug misuse and addiction now dominating the national conversation, the insights that the ABCD and HBCD studies will provide about the risks and protective factors for substance use and substance use disorders will empower parents, educators, and health care providers to take effective preventive actions and inform the prevention of other health risk behaviors and mental illness. Data from these studies will also add to our understanding of countless other dimensions of child and adolescent health and neurodevelopment, generating and answering questions that we cannot yet fathom or formulate.