Neuroscience-informed classification of prevention interventions in substance use disorders: An RDoC-based approach.

Neuroscience has contributed to uncover the mechanisms underpinning substance use disorders (SUD). The next frontier is to leverage these mechanisms as active targets to create more effective interventions for SUD treatment and prevention. Recent large-scale cohort studies from early childhood are generating multiple levels of neuroscience-based information with the potential to inform the development and refinement of future preventive strategies. However, there are still no available well-recognized frameworks to guide the integration of these multi-level datasets into prevention interventions. The Research Domain Criteria (RDoC) provides a neuroscience-based multi-system framework that is well suited to facilitate translation of neurobiological mechanisms into behavioral domains amenable to preventative interventions. We propose a novel RDoC-based framework for prevention science and adapted the framework for the existing preventive interventions. From a systematic review of randomized controlled trials using a person-centered drug/alcohol preventive approach for adolescents, we identified 22 unique preventive interventions. By teasing apart these 22 interventions into the RDoC domains, we proposed distinct neurocognitive trajectories which have been recognized as precursors or risk factors for SUDs, to be targeted, engaged and modified for effective addiction prevention.

Prospective, longitudinal study to isolate the impacts of marijuana use on neurocognitive functioning in adolescents.

Introduction: Policies to legalize possession and use of marijuana have been increasingly supported across the United States. Although there are restrictions on use in minors, many substance abuse scientists anticipate that these policy changes may alter use patterns among adolescents due to its wider availability and a softening of beliefs about its potentially harmful consequences. Despite the possibility that these policies may increase the prevalence of use among adolescents, the effects of marijuana on neurodevelopment remain unclear, clouding arguments in favor of or opposition to these policies. Methods: The present prospective, longitudinal study was designed to isolate the neurodevelopmental consequences of marijuana use from its precursors during adolescence-a period of heightened vulnerability for both substance use and disrupted development due to environmental insults. Early adolescents who were substance-naïve at baseline (N = 529, aged 10-12) were recruited and tracked into adolescence when a subgroup initiated marijuana use during one of three subsequent waves of data collection, approximately 18 months apart. Results: Results suggest that marijuana use may be specifically related to a decline in verbal learning ability in the short term and in emotion recognition, attention, and inhibition in the longer-term. Discussion: These preliminary findings suggest that marijuana use has potential to adversely impact vulnerable neurodevelopmental processes during adolescence. Intensive additional investigation is recommended given that state-level policies regulating marijuana use and possession are rapidly shifting in the absence of good scientific information.

Normalization of Prevention Principles and Practices to Reduce Substance Use Disorders Through an Integrated Dissemination and Implementation Framework.

Major research breakthroughs over the past 30 years in the field of substance use prevention have served to: (1) enhance understanding of pharmacological effects on the central and peripheral nervous systems and the health and social consequences of use of psychoactive substances, particularly for children and adolescents; (2) delineate the processes that increase vulnerability to or protect from initiation of substance use and progression to substance use disorders (SUDs) and, based on this understanding, (3) develop effective strategies and practices to prevent the initiation and escalation of substance use. The challenge we now face as a field is to "normalize" what we have learned from this research so that it is incorporated into the work of those involved in supporting, planning, and delivering prevention programming to populations around the world, is integrated into health and social service systems, and helps to shape public policies. But we wish to go further, to incorporate these effective prevention practices into everyday life and the mind-sets of the public, particularly parents and educators. This paper reviews the advances that have been made in the field of prevention and presents a framework and recommendations to achieve these objectives generated during several meetings of prevention and implementation science researchers sponsored by the International Consortium of Universities for Drug Demand Reduction (ICUDDR) that guides a roadmap to achieve "normalization."

The mediating role of self-regulation on the link between child maltreatment and later substance use among Latinx youth.

BACKGROUND: Children who experience maltreatment are at heightened risk for substance use initiation and mental health disorders later in life. Few studies have assessed the relationship between child maltreatment and substance use among Latinx youth. OBJECTIVE: The current study assessed the potential mediating effect of three aspects of self-regulation (emotional, behavioral, and cognitive) on the association between child maltreatment and substance use and examined whether effects varied depending on maltreatment type and severity. PARTICIPANTS AND SETTING: This study involved a random sample of 504 Latinx youth (52 % girls, 48 % boys) between the ages of 10-12 at the start of the study. METHODS: Study hypotheses were tested through structural equation modeling and bootstrapped random errors using the R programming language. RESULTS: Our results indicated that higher levels of child maltreatment predicted higher levels of later substance use, as mediated by emotional and behavioral dysregulation (ß = 0.09, p < 0.01), but not cognitive regulation. When separating maltreatment by subtype, we found the mediating effect was present for abuse (ß = 0.09, p < 0.01), but not neglect. CONCLUSIONS: Findings contribute to our understanding of potential causal mechanisms for the association between child maltreatment and substance use for Latinx youth.

Science for policy to protect children in cyberspace.

Cross-disciplinary partnerships are needed to formulate policies that account for developmental vulnerabilities.

Prevention Science and Health Equity: A Comprehensive Framework for Preventing Health Inequities and Disparities Associated with Race, Ethnicity, and Social Class.

The ultimate goal of our public health system is to reduce the incidence of disability and premature death. Evidence suggests that, by this standard, the USA falls behind most other developed countries largely as a function of disparities in health outcomes among significant portions of the US population. We present a framework for addressing these disparities that attributes them, not simply to differences in the behavioral and physical risk factors, but to social, environmental, and structural inequities such as poverty, discrimination, toxic physical setting, and the marketing of harmful products. These inequities result from de facto and instituted public policies. An analysis of the NIH research portfolio indicates a relative lack of investment in experimental evaluations of preventive interventions-especially studies targeting disadvantaged populations. Moreover, experimental research on reducing social inequities is almost entirely lacking. A line of research focusing on the drivers of inequities and their dissolution must include experimental evaluation of strategies for getting policies adopted that will reduce inequities. In conclusion, a summary is provided of the types of research that are needed and the challenges involved in conducting the experimental research that is essential for reducing inequities and disparities and, in turn, prolonging life.

Implementing Adolescent Wellbeing and Health Programs in Schools: Insights from a Mixed Methods and Multiple Informant Study.

Determining the factors that influence implementation of school-based wellbeing and health programs is essential for achieving desired program effects. Using a convergent mixed-methods, multiple informant design, this study considered factors that influence implementation of health programs for ninth grade students and in what ways implementation is differentially perceived by multiple informants (i.e., participants, instructors, and independent observers). Two types of programs-mindfulness and health education-were implemented with ninth graders (N = 70) in three schools situated in low-resourced urban neighborhoods. Study outcomes were derived from four data sources: (1) focus group participants (N = 45); (2) program instructor fidelity ratings; (3) independent observer fidelity ratings and notes; and (4) instructor open-ended session responses. Using thematic and mixed methods integration analyses, we identified themes related to implementation promoting or challenging factors. Theme names differed when data sources were separately analyzed by informant. Mixed methods integration analysis indicated that four themes were common across all informant groups: (1) competent, attentive, and engaging instructors are essential; (2) programs should involve interactive components (e.g., physical activities, applied learning opportunities); (3) adequate time for program delivery is key for student exposure and engagement; and (4) students' availability and preferences should guide program scheduling. A fifth theme, unique to instructor and observer perspectives, was that program implementation was negatively impacted by distractions from multiple sources, including instructors, students, and settings. Recommendations from students, instructors, and observers for implementation optimization are discussed.

A National Strategy for Preventing Substance and Opioid Use Disorders Through Evidence-Based Prevention Programming that Fosters Healthy Outcomes in Our Youth.

The recently released National Drug Control Strategy (2022) from the White House Office of National Drug Control Policy (ONDCP) lays out a comprehensive plan to, not only enhance access to treatment and increase harm reduction strategies, but also increase implementation of evidence-based prevention programming at the community level. Furthermore, the Strategy provides a framework for enhancing our national data systems to inform policy and to evaluate all components of the plan. However, not only are there several missing components to the Strategy that would assure its success, but there is a lack of structure to support a national comprehensive service delivery system that is informed by epidemiological data, and trains and credentials those delivering evidence-based prevention, treatment, and harm reduction/public health interventions within community settings. This paper provides recommendations for the establishment of such a structure with an emphasis on prevention. Systematically addressing conditions known to increase liability for behavioral problems among vulnerable populations and building supportive environments are strategies consistently found to avert trajectories away from substance use in general and substance use disorders (SUD) in particular. Investments in this approach are expected to result in significantly lower rates of SUD in current and subsequent generations of youth and, therefore, will reduce the burden on our communities in terms of lowered social and health systems involvement, treatment needs, and productivity. A national strategy, based on strong scientific evidence, is presented to implement public health policies and prevention services. These strategies work by improving child development, supporting families, enhancing school experiences, and cultivating positive environmental conditions.

Commentary: Improving the Effectiveness and Utility of the Helping to End Addiction Long-Term (HEAL) Prevention Cooperative: A Full Translational Framework.

The Helping to End Addiction Long-term (HEAL) Prevention Collaborative (HPC) is designed to expedite the development of programs aimed at preventing opioid misuse and opioid use disorder (OUD) in older adolescents and young adults (ages 16-30). Funded by the National Institutes of Health Office of the Director (ODP-NIH), the HPC includes ten outcome studies that focus on distinct interventions to determine their effectiveness and real-world applicability. Also included is a coordinating center at RTI International that supports the individual projects. This commentary highlights the scientific and practical significance of this cooperative and its promise for facilitating the production and implementation of successful interventions. Attributes such as novel program designs, advanced methodologies, addressing unique characteristics of diverse populations, and real-time analysis of data and costs make this cooperative highly innovative. We note, however, that papers in this Supplemental Issue did not specifically address the persistent need to obtain stronger effect sizes than those achieved to date. Existing data captured earlier in development (< 16 years of age) are uncovering interactive neurocognitive and social-contextual mechanisms underlying the phenomena we wish to prevent. HPC projects could be guided by this information to incorporate developmentally appropriate measures of mechanisms shown previously to be influential in targeted outcomes and determine how they are impacted by specific components of their interventions. This mechanistic information can provide a roadmap for constructing interventions that are more precision-based and, thus, more likely to yield greater benefits for a larger number of recipients. Furthermore, an understanding of underlying mechanism(s) promises to shed light on the sources of heterogeneity in outcomes for further intervention refinement. It is quite possible, if not probable, that meaningful measures of underlying processes will reveal subtypes-some with very high effect sizes and others that are much lower-directly enabling program refinements to more directly target mechanisms that portend and explain less favorable outcomes. Described herein is a full-spectrum translational approach which promises to significantly boost effect sizes, a key objective that should be reached prior to scaling.

Baseline brain and behavioral factors distinguish adolescent substance initiators and non-initiators at follow-up.

Background: Earlier substance use (SU) initiation is associated with greater risk for the development of SU disorders (SUDs), while delays in SU initiation are associated with a diminished risk for SUDs. Thus, identifying brain and behavioral factors that are markers of enhanced risk for earlier SU has major public health import. Heightened reward-sensitivity and risk-taking are two factors that confer risk for earlier SU. Materials and methods: We characterized neural and behavioral factors associated with reward-sensitivity and risk-taking in substance-naïve adolescents (N = 70; 11.1-14.0 years), examining whether these factors differed as a function of subsequent SU initiation at 18- and 36-months follow-up. Adolescents completed a reward-related decision-making task while undergoing functional MRI. Measures of reward sensitivity (Behavioral Inhibition System-Behavioral Approach System; BIS-BAS), impulsive decision-making (delay discounting task), and SUD risk [Drug Use Screening Inventory, Revised (DUSI-R)] were collected. These metrics were compared for youth who did [Substance Initiators (SI); n = 27] and did not [Substance Non-initiators (SN); n = 43] initiate SU at follow-up. Results: While SI and SN youth showed similar task-based risk-taking behavior, SI youth showed more variable patterns of activation in left insular cortex during high-risk selections, and left anterior cingulate cortex in response to rewarded outcomes. Groups displayed similar discounting behavior. SI participants scored higher on the DUSI-R and the BAS sub-scale. Conclusion: Activation patterns in the insula and anterior cingulate cortex may serve as a biomarker for earlier SU initiation. Importantly, these brain regions are implicated in the development and experience of SUDs, suggesting differences in these regions prior to substance exposure.

Introducing an adolescent cognitive maturity index.

Children show substantial variation in the rate of physical, cognitive, and social maturation as they traverse adolescence and enter adulthood. Differences in developmental paths are thought to underlie individual differences in later life outcomes, however, there remains a lack of consensus on the normative trajectory of cognitive maturation in adolescence. To address this problem, we derive a Cognitive Maturity Index (CMI), to estimate the difference between chronological and cognitive age predicted with latent factor estimates of inhibitory control, risky decision-making and emotional processing measured with standard neuropsychological instruments. One hundred and forty-one children from the Adolescent Development Study (ADS) were followed longitudinally across three time points from ages 11-14, 13-16, and 14-18. Age prediction with latent factor estimates of cognitive skills approximated age within ±10 months (r = 0.71). Males in advanced puberty displayed lower cognitive maturity relative to peers of the same age; manifesting as weaker inhibitory control, greater risk-taking, desensitization to negative affect, and poor recognition of positive affect.

Capitalizing on Neuroplasticity Across Development to Redirect Pathways from Juvenile Justice Involvement.

Adolescence is an exquisitely sensitive period of development during which pathways branch toward success in school and prosocial pursuits or, conversely, toward behavior problems and involvement in high-risk activities and systems, such as juvenile justice (JJ). Adverse childhood experiences (ACEs) such as poverty, family dysfunction, and child maltreatment, have been strongly and repeatedly associated with JJ involvement. A significant body of research from neuroscience has established that ACEs can alter facets of neurodevelopment that undergird self-regulation throughout childhood and adolescence, thereby increasing susceptibility to behaviors that attract attention of the JJ system. Because the ability to intervene prior to system-entrenchment is crucial to disrupting an adverse developmental pathway, we look toward neuroscience to offer insights into how to do so more effectively. In this chapter, evidence is summarized that informs an understanding of how neurodevelopmental pathways may lead to JJ involvement. Because neurodevelopment is malleable in response to both detrimental and positive experiences, there is potential for well-targeted interventions to normalize brain and cognitive development, especially during sensitive periods of maturation. This discussion is followed by a proposed research agenda to determine how to exploit these critical windows of opportunity to divert youth from persistent antisocial behavior and JJ involvement. Lastly, a review of neuroscience findings regarding the ability of intervention to strengthen brain systems that modulate self-regulation is presented. This research has direct practical significance with potential to be translated into meaningful policy change.

Effects of OPRM1 and DRD2 on brain structure in drug-naïve adolescents: Genetic and neural vulnerabilities to substance use.

Genetic variants in the opioid receptor mu 1 (OPRM1) and dopamine receptor d2 (DRD2) genes are implicated in behavioral phenotypes related to substance use disorders (SUD). Despite associations among OPRM1 (rs179971) and DRD2 (rs6277) genes and structural alterations in neural reward pathways implicated in SUDs, little is known about the contribution of risk-related gene variants to structural neurodevelopment. In a 3-year longitudinal study of initially SU-naïve adolescents (N = 129; 70 females; 11-14 years old), participants underwent an MRI structural scan at baseline and provided genetic assays for OPRM1 and DRD2 with SU behavior assessed during follow-up visits. Baseline differences in key reward-related brain regions (i.e., bilateral caudate and cingulate cortex) were detected in those with genetic liability for SU in OPRM1 who went onto engage in SU at subsequent waves of data collection. In addition, main effects of OPRM1, DRD2, and SU were related to variability in structure of the putamen, anterior cingulate, and nucleus accumbens, respectively. These data provide preliminary evidence that genetic risk factors interact with future SU to confer structural variability prior to SU in regions commonly implicated in risk for SU and the development of SUDs.

Differences in late adolescent psychopathology among youth with histories of co-occurring abuse and neglect experiences.

BACKGROUND: Knowledge about the impacts of child abuse and neglect (CAN) experiences on late adolescent psychopathology has been limited by a failure to consider the frequent co-occurrence of CAN types and potential unique impacts of specific combinations. OBJECTIVE: Using person-centered analyses, we aimed to identify unobserved groups of youth with similar patterns of lifetime CAN experiences before age 16 and differences in psychopathology symptom counts between groups two years later. PARTICIPANTS AND SETTING: Participants were 919 adolescent-caregiver dyads (56% female; 56% Black, 7% Latina/o, 13% mixed/other). METHODS: Prospective, multi-informant data, including child protective services records and caregiver and youth reports were collected, and youth completed a diagnostic interview at age 18. RESULTS: Latent Class Analyses classified adolescents into four distinct groups based on patterns of physical neglect, supervisory neglect, and physical, sexual, and psychological abuse: "Low-Risk" (37%), "Neglect" (19%), "Abuse" (11%), and "Multi-type CAN" (33%). The Multi-type CAN class had significantly more major depressive, generalized anxiety, and nicotine use symptoms than the Low-Risk class, and more post-traumatic stress, antisocial personality, and illicit substance use symptoms, than Low-Risk and Neglect classes. The Abuse class had significantly more generalized anxiety and attention deficit/hyperactivity symptoms than the Low-Risk class, and more major depressive, antisocial personality, and illicit substance use symptoms, than Low-Risk and Neglect classes. The Neglect class did not have elevated psychopathology symptoms. CONCLUSION: Findings highlight important differences in the associations between lifetime CAN experience patterns and psychopathology. Researchers should explore mechanisms underlying psychopathology that are impacted by different CAN experience patterns.

Adolescent Stress Reduces Adult Morphine-Induced Behavioral Sensitization in C57BL/6J Mice.

Deaths related to opioid use have skyrocketed in the United States, leading to a public health epidemic. Research has shown that both biological (genes) and environmental (stress) precursors are linked to opioid use. In particular, stress during adolescence-a critical period of frontal lobe development-influences the likelihood of abusing drugs. However, little is known about the biological mechanisms through which adolescent stress leads to long-term risk of opioid use, or whether genetic background moderates this response. Male and female C57BL/6J and BALB/cJ mice were exposed to chronic variable social stress (CVSS) or control conditions throughout adolescence and then tested for morphine locomotor sensitization or morphine consumption in adulthood. To examine possible mechanisms that underlie stress-induced changes in morphine behaviors, we assessed physiological changes in response to acute stress exposure and prefrontal cortex (PFC) miRNA gene expression. Adolescent stress did not influence morphine sensitization or consumption in BALB/cJ animals, and there was limited evidence of stress effects in female C57BL/6J mice. In contrast, male C57BL/6J mice exposed to adolescent CVSS had blunted morphine sensitization compared to control animals; no differences were observed in the acute locomotor response to morphine administration or morphine consumption. Physiologically, C57BL/6J mice exposed to CVSS had an attenuated corticosterone recovery following an acute stressor and downregulation of twelve miRNA in the PFC compared to control mice. The specificity of the effects for C57BL/6J vs. BALB/cJ mice provides evidence of a gene-environment interaction influencing opioid behaviors. However, this conclusion is dampened by limited locomotor sensitization observed in BALB/cJ mice. It remains possible that results may differ to other doses of morphine or other behavioral responses. Long-term differences in stress reactivity or miRNA expression in C57BL/6J mice suggests two possible biological mechanisms to evaluate in future research.

Latent Class Analysis of Individual-Level Characteristics Predictive of Intervention Outcomes in Urban Male Adolescents.

Preventive intervention research dictates that new techniques are needed to elucidate what types of interventions work best for whom to prevent behavioral problems. The current investigation applies a latent class modeling structure to identify the constellation of characteristics-or profile-in urban male adolescents (n = 125, aged 15) that interrelatedly predict responses to a brief administration of an evidence-based program, Positive Adolescent Choices Training (PACT). Individual-level characteristics were selected as predictors on the basis of their association with risk behaviors and their implication in intervention outcomes (e.g., mental health, stress exposure, temperament, cognitive function, stress reactivity and emotion perception). Outcome measures included virtual reality vignettes and questionnaire-style role play scenarios to gauge orientations around aggressive conflict resolution, communication, emotional control, beliefs supporting aggression and hostility. A three-class model was found to best fit the data: "NORMative" (NORM), with relatively low symptomatology; "Mental Health" problems (MH-I) with elevated internalizing symptoms; and "Mental Health-E + Cognitive Deficit" (MH-E + Cog) with elevated mental health symptoms paired with cognitive decrements. The NORM class had positive PACT effects for communication, conflict resolution, and aggressive beliefs. Moderation was evidenced by lack of positive PACT effects for the MH-I and MH-E + Cog groups. Also, PACT classes with MH issues showed marginally significant worsening of aggressive beliefs compared to control students in the same class. Results suggest that a latent class model may identify "signatures" or profiles of traits, experiences and other influences that collectively-and more realistically-predict variable intervention outcomes with implications for more effectively targeting interventions than singular factors.

The moderating role of socioeconomic status on level of responsibility, executive functioning, and cortical thinning during adolescence.

Brain development is exquisitely sensitive to psychosocial experiences, with implications for neurodevelopmental trajectories, for better or worse. The premise of this investigation was that the level of responsibility in adolescence may relate to brain structure and higher-order cognitive functions. In a sample of 108 adolescents, we focused on cortical thickness (using FreeSurfer) as an indicator of neurodevelopment in regions previously implicated in executive functioning (EF) and examined performance on an EF task outside of the scanner, in the context of level of responsibility. We further investigated whether socioeconomic status (SES) and family stress moderated the relationship between responsibility and brain structure or EF. Findings revealed that greater responsibility was related to thinner left precuneus and right middle frontal cortex. In lower SES adolescents, greater responsibility predicted thinner left precuneus and right middle frontal cortex, which have been consistently implicated in EF. Higher SES adolescents did not show structural differences related to responsibility, however, they did exhibit better EF performance. It may be that circumstances surrounding the need for greater responsibility in lower SES households are detrimental to neurodevelopment compared to higher SES households. Alternatively, responsibility may act as a protective factor that bolsters cortical thinning in regions related to EF.

The Pivotal Role of Prevention Science in This Syndemic.

Never before has the value of prevention science become so apparent to the populace, particularly in simultaneous fashion across all nations. A general understanding of what prevention represents in true form has lagged well behind the science and, in fact, few outside of the field recognize that there is actually a significant body of research that undergirds preventative practices, programs and policies. The current pandemic and the uneven impacts on underserved and marginalized populations has highlighted the need for proactive approaches to prevent underlying conditions that increase risk for infection, worsen the wide ranging harms from the virus, and significantly exacerbate disparities that characterize many nations. To ensure uptake of the science by end-users (e.g., community stakeholders, practitioners, policymakers), who operate the levers that determine whether resources and services are distributed equitably across societies' sectors, prevention scientists have a unique and powerful role to play. This commentary on the special issue, focused on the "culture of prevention," considers the broader issues covered in the set of original articles in light of the ongoing COVID-19 pandemic. Toward that end, I also outline two interrelated "calls to action" for prevention scientists. The first call is to concertedly apply a race equity lens to all aspects of our research, a need that is particularly critical given that our field is inherently actionable and, as such, evidence amassed has potential to equalize the playing field for disadvantaged and marginalized groups. The second acknowledges the need for prevention scientists to learn how to effectively communicate scientific knowledge to the public and policymakers to compellingly advocate for reforms guided by the science. A powerful, research-backed collective advocacy can effectively sway action of governing bodies in addressing disparities and inequities for constituents who have no voice.

Social Emotional Learning Program Boosts Early Social and Behavioral Skills in Low-Income Urban Children.

Social emotional learning (SEL) programs are increasingly being implemented in elementary schools to facilitate development of social competencies, decision-making skills, empathy, and emotion regulation and, in effect, prevent poor outcomes such as school failure, conduct problems, and eventual substance abuse. SEL programs are designed to foster these abilities in children with a wide range of behavioral, social, and learning needs in the classroom, including children who are economically disadvantaged. In a previous study of kindergartners residing in a high-poverty community (N = 327 at baseline), we observed significant behavioral improvements in children receiving an SEL program-The PATHS® curriculum (PATHS)-relative to an active control condition within one school year. The present investigation sought to determine whether these improvements were sustained over the course of two school years with intervention and an additional year when intervention was no longer provided. Further, using multilevel models, we examined whether baseline measures of neurocognition and stress physiology-known to be adversely impacted by poverty-moderated heterogeneous outcomes. Finally, a preliminary linear regression analysis explored whether neurocognition and physiological stress reactivity (heart rate variability, HRV) predict change in outcomes postintervention. Results confirmed that students who received PATHS sustained significant behavioral improvements over time. These effects occurred for the full sample, irrespective of putative baseline moderators, suggesting that children in high-risk environments may benefit from SEL interventions irrespective of baseline cognitive functioning as a function of overall substantial need. Of interest is that our exploratory analysis of change from waves three to four after the intervention concluded brought to light possible moderation by baseline physiology. Should subsequent studies confirm this finding, one plausible explanation may be that, when an intervention providing protective effects is withdrawn, children with higher HRV may not be able to regulate physiological stress responses to environmental challenges, leading to an uptick in maladaptive behaviors. In reverse, children with lower HRV-generally associated with poorer emotion regulation-may incur relatively greater gains in behavioral improvement due to lesser sensitivity to the environment, enabling them to continue to accrue benefits. Results are discussed in the context of possible pathways that may be relevant to understanding the special needs of children reared in very low-income, high-stress neighborhoods.