Generalizable prediction of childhood ADHD symptoms from neurocognitive testing and youth characteristics.

Childhood attention-deficit/hyperactivity disorder (ADHD) symptoms are believed to result from disrupted neurocognitive development. However, evidence for the clinical and predictive value of neurocognitive assessments in this context has been mixed, and there have been no large-scale efforts to quantify their potential for use in generalizable models that predict individuals' ADHD symptoms in new data. Using data drawn from the Adolescent Brain Cognitive Development Study (ABCD), a consortium that recruited a diverse sample of over 10,000 youth (ages 9-10 at baseline) across 21 U.S. sites, we develop and test cross-validated machine learning models for predicting youths' ADHD symptoms using neurocognitive abilities, demographics, and child and family characteristics. Models used baseline demographic and biometric measures, geocoded neighborhood data, youth reports of child and family characteristics, and neurocognitive tests to predict parent- and teacher-reported ADHD symptoms at the 1-year and 2-year follow-up time points. Predictive models explained 15-20% of the variance in 1-year ADHD symptoms for ABCD Study sites that were left out of the model-fitting process and 12-13% of the variance in 2-year ADHD symptoms. Models displayed high generalizability across study sites and trivial loss of predictive power when transferred from training data to left-out data. Features from multiple domains contributed meaningfully to prediction, including neurocognition, sex, self-reported impulsivity, parental monitoring, and screen time. This work quantifies the information value of neurocognitive abilities and other child characteristics for predicting ADHD symptoms and provides a foundational method for predicting individual youths' symptoms in new data across contexts.

Nucleus Accumbens Response to Reward among Children with a Family History of Alcohol Use Problems: Convergent Findings from the ABCD Study® and Michigan Longitudinal Study.

Having a family history of alcohol use problems (FH+) conveys risk for alcohol use in offspring. Reward-related brain functioning may play a role in this vulnerability. The present study investigated brain function in the nucleus accumbens (NAcc) associated with the anticipation of reward in youth with two biological parents with alcohol use problems (FH+2), one biological parent with alcohol use problems (FH+1), and no biological parents with alcohol use problems (FH-). Participants were from the large, national Adolescent Brain Cognitive Development (ABCD) Study (mean age: 9.93; 48% female; FH+2 n = 223, FH+1 n = 1447, FH- n = 9690) and the Michigan Longitudinal Study (MLS), consisting of community-recruited families with high rates of alcohol use disorder (mean age: 10.54; 39.3% female; FH+2 n = 40, FH+1 n = 51, FH- n = 40). Reward anticipation was measured by the monetary incentive delay task. Regression models were used to assess associations between FH status and the anticipation of large rewards in right and left NAcc regions of interest. In both studies, FH+2 youth showed blunted anticipatory reward responding in the right NAcc compared to FH+1 youth. In the MLS, FH+2 youth also had blunted anticipatory reward responding in the right NAcc compared to the FH- group. Convergent results across two separate samples provide insights into a unique vulnerability of FH+2 youth and suggest that binary FH+ versus FH- categorizations may obscure important differences within FH+ youth.

Sex Moderates Reward- and Loss-Related Neural Correlates of Triarchic-Model Traits and Antisocial Behavior.

Abnormalities in responses to reward and loss are implicated in the etiology of antisocial behavior and psychopathic traits. While there is evidence for sex differences in neural response to reward and loss, it remains unclear how sex differences may moderate links between these neural responses and the phenotypic expression of antisocial behavior and psychopathic traits. This study examined sex differences in associations of neural response to reward and loss with antisocial personality symptoms and psychopathic traits. Functional neuroimaging data were collected during a monetary incentive delay task from 158 participants. Among males, during loss anticipation, activation in the left nucleus accumbens was negatively associated with antisocial behavior. Among females, during loss feedback, activation in the left nucleus accumbens and left amygdala was negatively associated with antisocial behavior. These results suggest that phenotypic sex differences in psychopathic traits and antisocial behavior may in part be attributable to different etiological pathways.

Individual-, peer-, and parent-level substance use-related factors among 9- and 10-year-olds from the ABCD Study: Prevalence rates and sociodemographic differences.

Background: Although a relatively large body of research has identified multiple factors associated with adolescent substance use, less is known about earlier substance-related factors during preadolescence, including curiosity to use substances. The present study examined individual-, peer-, and parent-level domains pertaining to substance use and how these domains vary by sociodemographic subgroups and substance type. Methods: Participants were 11,864 9- and 10-year-olds from the baseline sample of the Adolescent Brain Cognitive Development (ABCD) Study. Youth-reported measures were curiosity to use substances and perceived peer substance use. Parent-reported measures were availability of and rules about substances. Generalized logistic mixed models (GLMM) were used to compare these measures across alcohol, nicotine, and marijuana and across sociodemographic subgroupings (sex, race/ethnicity, household income, and family history of alcohol problems). GLMM was then used to examine predictors of curiosity to use by substance type. Results: The most striking descriptive differences were found between race/ethnicity and income categories (e.g., positive associations between greater income and greater availability of alcohol). In multivariable analyses, greater curiosity to use alcohol was associated with being male, higher household income, perceived peer alcohol use, and easy alcohol availability; greater curiosity to use nicotine was associated with being male, perceived peer cigarette use, easy availability of cigarettes, and no parental rules about cigarette use. Conclusions: This study identified substance use-related individual-, peer-, and parent-level factors among a diverse, national sample. Findings highlight the importance of considering sociodemographic and substance-specific variability and may help identify risk and protective factors preceding adolescent substance use.

Affective Dysregulation Precedes Emergence of Psychosis-Like Experiences in a Community Sample of Young Adults.

Affective dysregulation (AD) among persons with schizophrenia spectrum disorders, involving the tendency to exhibit sensitivity to minor stress and negative affective states, is an important diagnostic feature and relates to poorer functional and clinical outcomes. Studies of persons with elevated risk for psychosis demonstrate similar AD to those with schizophrenia, and literature suggest a potential influence of AD in the transition from psychosis-like symptoms (PLEs) to disorder. Cross-sectional investigations to date have supported the link between AD and psychosis, and longitudinal studies have mostly yielded mixed findings without demonstration of potential causal relationships between AD and psychosis. This study examined the concurrent and predictive relationships between AD and PLE in a community sample of youth (n = 630) with attention to distinct facets of AD as a latent construct, including low resiliency, low reactive control, and negative emotionality, using structural equation to estimate a longitudinal cross-lagged and autoregressive model across 3 study waves from 15 to 24 years of age. As hypothesized, AD in the mid-teen years predicted subsequent PLE 3 years later. In addition, we found that increasing PLE in the end of the teen years related to a subsequent increase in AD in the early 20s. A cross-sectional relationship between AD and PLE in the mid-teen years was also supported. Findings overall describe important relationships between AD and PLE that appear to vary with developmental stage, implicating various factors to inform approaches for identifying youth who may be at risk for subsequent PLE or other mental health conditions.

Differentiated nomological networks of internalizing, externalizing, and the general factor of psychopathology ('p factor') in emerging adolescence in the ABCD study.

BACKGROUND: Structural models of psychopathology consistently identify internalizing (INT) and externalizing (EXT) specific factors as well as a superordinate factor that captures their shared variance, the p factor. Questions remain, however, about the meaning of these data-driven dimensions and the interpretability and distinguishability of the larger nomological networks in which they are embedded. METHODS: The sample consisted of 10 645 youth aged 9-10 years participating in the multisite Adolescent Brain and Cognitive Development (ABCD) Study. p, INT, and EXT were modeled using the parent-rated Child Behavior Checklist (CBCL). Patterns of associations were examined with variables drawn from diverse domains including demographics, psychopathology, temperament, family history of substance use and psychopathology, school and family environment, and cognitive ability, using instruments based on youth-, parent-, and teacher-report, and behavioral task performance. RESULTS: p exhibited a broad pattern of statistically significant associations with risk variables across all domains assessed, including temperament, neurocognition, and social adversity. The specific factors exhibited more domain-specific patterns of associations, with INT exhibiting greater fear/distress and EXT exhibiting greater impulsivity. CONCLUSIONS: In this largest study of hierarchical models of psychopathology to date, we found that p, INT, and EXT exhibit well-differentiated nomological networks that are interpretable in terms of neurocognition, impulsivity, fear/distress, and social adversity. These networks were, in contrast, obscured when relying on the a priori Internalizing and Externalizing dimensions of the CBCL scales. Our findings add to the evidence for the validity of p, INT, and EXT as theoretically and empirically meaningful broad psychopathology liabilities.

Substance use patterns in 9 to 13-year-olds: Longitudinal findings from the Adolescent Brain Cognitive Development (ABCD) study.

Background: Though largely substance-naïve at enrollment, a proportion of the youth in the Adolescent Brain Cognitive Development (ABCD) Study are expected to initiate substance use (SU) as they transition into later adolescence. With annual data from youth 9-13 years-old, this study aims to describe their SU patterns over time. Here, prevalence rates of use are reported, along with predicted odds of use while analyzing common risk-factors associated with youth SU. Methods: The ABCD Study® enrolled 11,876 participants at Baseline (ages 9-10) and has followed them annually. Data through half of the third follow-up visit are available (ages 12-13; n = 6,251). SU descriptives for al psychoactive substances over time are outlined. General estimating equations (GEEs) assessed whether sociodemographic factors, internalizing and externalizing symptoms, and parental SU problems were associated with SU between Baseline and Y2 follow-up. Results: Across time, alcohol and nicotine remain the most used substances. Yearly rates of any SU increased (past year use: 13.9% in Y1; 14% Y2, 18.4% Y3). Cumulatively, by Y3, 39.7% of the cohort reported experimenting (e.g., sipping alcohol) with SU within their lifetime, while 7.4% reported a "full use" (a full alcohol drink, nicotine use, cannabis use, or any other SU) in their lifetime (past-year: 1.9% alcohol, 2.1% nicotine, 1.1% cannabis, 1.2% other substances). GEEs revealed ongoing longitudinal associations between sociodemographic factors, greater externalizing symptoms, and parental drug problems with increased odds of initiating SU. Conclusions: As ABCD participants transition into their teenage years, the cohort is initiating SU at increasing (though still low) rates.

Heterogeneity Within Youth With Childhood-Onset Conduct Disorder in the ABCD Study.

The purpose of this study was to examine if personality traits can be used to characterize subgroups of youth diagnosed with childhood-onset conduct disorder (CD). Participants were 11,552 youth from the Adolescent Brain Cognitive Development study. Data used in this report came from doi: 10.15154/1504041 (M age 9.92; 45.3% female, 49.6% white, 19.0% Hispanic). A subset of this sample (n = 365) met criteria for CD. Latent profile analyses (LPA) were performed on this subgroup (n = 365) to define profiles of individuals with CD based on self-report measures of impulsivity, punishment sensitivity, reward response, and callous-unemotional traits. Follow up analyses determined if these groups differed on clinically relevant variables including psychopathology, environmental risk factors, social risk factors, and neurocognitive functioning. Participants with a CD diagnosis scored significantly higher on psychological, environmental, social, and neurocognitive risk factors. The LPA revealed three unique profiles, which differed significantly on liability for broad psychopathology and domain-specific liability for externalizing psychopathology but were largely matched on environmental and social risk factors. These unique configurations provide a useful way to further parse clinically relevant subgroups within youth who meet criteria for childhood-onset CD, setting the stage for prospective longitudinal research using these latent profiles to better understand the development of youth with childhood-onset CD.

Evidence accumulation and associated error-related brain activity as computationally-informed prospective predictors of substance use in emerging adulthood.

RATIONALE: Substance use peaks during the developmental period known as emerging adulthood (ages 18-25), but not every individual who uses substances during this period engages in frequent or problematic use. Although individual differences in neurocognition appear to predict use severity, mechanistic neurocognitive risk factors with clear links to both behavior and neural circuitry have yet to be identified. Here, we aim to do so with an approach rooted in computational psychiatry, an emerging field in which formal models are used to identify candidate biobehavioral dimensions that confer risk for psychopathology. OBJECTIVES: We test whether lower efficiency of evidence accumulation (EEA), a computationally characterized individual difference variable that drives performance on the go/no-go and other neurocognitive tasks, is a risk factor for substance use in emerging adults. METHODS AND RESULTS: In an fMRI substudy within a sociobehavioral longitudinal study (n = 106), we find that lower EEA and reductions in a robust neural-level correlate of EEA (error-related activations in salience network structures) measured at ages 18-21 are both prospectively related to greater substance use during ages 22-26, even after adjusting for other well-known risk factors. Results from Bayesian model comparisons corroborated inferences from conventional hypothesis testing and provided evidence that both EEA and its neuroimaging correlates contain unique predictive information about substance use involvement. CONCLUSIONS: These findings highlight EEA as a computationally characterized neurocognitive risk factor for substance use during a critical developmental period, with clear links to both neuroimaging measures and well-established formal theories of brain function.

Subtypes of inhibitory and reward activation associated with substance use variation in adolescence: A latent profile analysis of brain imaging data.

The present study identified subgroups based on inhibitory and reward activation, two key neural functions involved in risk-taking behavior, and then tested the extent to which subgroup differences varied by age, sex, behavioral and familial risk, and substance use. Participants were 145 young adults (18-21 years old; 40.0% female) from the Michigan Longitudinal Study. Latent profile analysis (LPA) was used to establish subgroups using task-based brain activations. Demographic and substance use differences between subgroups were then examined in logistic regression analyses. Whole-brain task activations during a functional magnetic resonance imaging go/no-go task and monetary incentive delay task were used to identify beta weights as input for LPA modeling. A four-class model showed the best fit with the data. Subgroups were categorized as: (1) low inhibitory activation/moderate reward activation (39.7%), (2) moderate inhibitory activation/low reward activation (22.7%), (3) moderate inhibitory activation/high reward activation (25.2%), and (4) high inhibitory activation/high reward activation (12.4%). Compared with the other subgroups, Class 2 was older, less likely to have parental alcohol use disorder, and had less alcohol use. Class 4 was the youngest and had greater marijuana use. Classes 1 and 3 did not differ significantly from the other subgroups. These findings demonstrate that LPA applied to brain activations can be used to identify distinct neural profiles that may explain heterogeneity in substance use outcomes and may inform more targeted substance use prevention and intervention efforts.

Neuromodulation of brain activation associated with addiction: A review of real-time fMRI neurofeedback studies.

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-nf) has emerged in recent years as an imaging modality used to examine volitional control over targeted brain activity. rtfMRI-nf has also been applied clinically as a way to train individuals to self-regulate areas of the brain, or circuitry, involved in various disorders. One such application of rtfMRI-nf has been in the domain of addictive behaviors, including substance use. Given the pervasiveness of substance use and the challenges of existing treatments to sustain abstinence, rtfMRI-nf has been identified as a promising treatment tool. rtfMRI-nf has also been used in basic science research in order to test the ability to modulate brain function involved in addiction. This review focuses first on providing an overview of recent rtfMRI-nf studies in substance-using populations, specifically nicotine, alcohol, and cocaine users, aimed at reducing craving-related brain activation. Next, rtfMRI-nf studies targeting reward responsivity and emotion regulation in healthy samples are reviewed in order to examine the extent to which areas of the brain involved in addiction can be self-regulated using neurofeedback. We propose that future rtfMRI-nf studies could be strengthened by improvements to study design, sample selection, and more robust strategies in the development and assessment of rtfMRI-nf as a clinical treatment. Recommendations for ways to accomplish these improvements are provided. rtfMRI-nf holds much promise as an imaging modality that can directly target key brain regions involved in addiction, however additional studies are needed in order to establish rtfMRI-nf as an effective, and practical, treatment for addiction.

Developmental maturation of inhibitory control circuitry in a high-risk sample: A longitudinal fMRI study.

BACKGROUND: The goal of this work was to characterize the maturation of inhibitory control brain function from childhood to early adulthood using longitudinal data collected in two cohorts. METHODS: Functional MRI during a go/no-go task was conducted in 290 participants, with 88 % undergoing repeated scanning at 1- to 2-year intervals. One group entered the study at age 7-13 years (n = 117); the other entered at age 18-23 years (n = 173). 33.1 % of the sample had two parents with a substance use disorder (SUD), 43.8 % had one parent with an SUD, and 23.1 % had no parents with an SUD. 1162 scans were completed, covering ages 7-28, with longitudinal data from the cohorts overlapping across ages 16-21. A marginal model with sandwich estimator standard errors was used to characterize voxel-wise age-related changes in hemodynamic response associated with successful inhibitory control. RESULTS: There was significant positive linear activation associated with age in the frontal, temporal, parietal, and occipital cortices. No clusters survived thresholding with negative linear, positive or negative quadratic, or positive or negative cubic contrasts. CONCLUSIONS: These findings extend previous cross-sectional and small-scale longitudinal studies that have observed positive linear developmental trajectories of brain function during inhibitory control.

Alcohol expectancies mediate the association between the neural response to emotional words and alcohol consumption.

BACKGROUND: Both positive expectancies regarding the effects of alcohol and internalizing problems, including negative emotionality and deficits in emotion regulation, are known risk factors for alcohol use disorder (AUD). The current study is the first to investigate how neural response to emotional stimuli may impact alcohol expectancies and risk for AUD. METHODS: Functional neuroimaging data was collected during an emotional word task from 168 emerging adults (M age = 19.65; 66% male). Activation to negative versus neutral words and positive versus neutral words was extracted for analyses. Participants also reported on their alcohol expectancies and information regarding alcohol use and problems was collected prospectively throughout adolescence and into adulthood (up to age 30). RESULTS: Decreased activation in the inferior frontal gyrus (IFG) to negative versus neutral words was associated with increased post-scan alcohol consumption, measured as average drinks per year. There was a significant indirect effect of positive alcohol expectancies on the association between IFG activation and post-scan alcohol consumption, even when controlling for quantity of alcohol consumption prior to the scan. CONCLUSIONS: These results are the first to provide evidence that positive alcohol expectancies account for variance shared between brain regions associated with emotion processing and increased drinking behaviors. Alcohol expectancies may provide a modifiable target for treatments to decrease the link between deficits in emotion regulation and increased alcohol use.

Therapist and computer-based brief interventions for drug use within a randomized controlled trial: effects on parallel trajectories of alcohol use, cannabis use and anxiety symptoms.

BACKGROUND AND AIMS: Despite their high comorbidity, the effects of brief interventions (BI) to reduce cannabis use, alcohol use and anxiety symptoms have received little empirical attention. The aims of this study were to examine whether a therapist-delivered BI (TBI) or computer-guided BI (CBI) to address drug use, alcohol consumption (when relevant) and HIV risk behaviors, relative to enhanced usual care (EUC), was associated with reductions in parallel trajectories of alcohol use, cannabis use and anxiety symptoms, and whether demographic characteristics moderated reductions over time. DESIGN: Latent growth curve modeling was used to examine joint trajectories of alcohol use, cannabis use and anxiety symptoms assessed at 3, 6 and 12 months after baseline enrollment. SETTING: Hurley Medical Center Emergency Department (ED) in Flint, MI, USA. PARTICIPANTS: The sample was 780 drug-using adults (aged 18-60 years; 44% male; 52% black) randomly assigned to receive either a TBI, CBI or EUC through the HealthiER You study. INTERVENTIONS AND COMPARATOR: ED-delivered TBI and CBIs involved touchscreen-delivered and audio-assisted content. The TBI was administered by a Master's-level therapist, whereas the CBI was self-administered using a virtual health counselor. EUC included a review of health resources brochures in the ED. MEASUREMENTS: Assessments of alcohol use (10-item Alcohol Use Disorders Identification Test), cannabis use (past 30-day frequency) and anxiety symptoms (Brief Symptom Inventory-18) occurred at baseline and 3-, 6- and 12-month follow-up. FINDINGS: TBI, relative to EUC, was associated with significant reductions in cannabis use [B = -0.49, standard error (SE) = 0.20, P < 0.05) and anxiety (B = -0.04, SE = 0.02, P < 0.05), but no main effect for alcohol use. Two of 18 moderation tests were significant: TBI significantly reduced alcohol use among males (B = -0.60, SE = 0.19, P < 0.01) and patients aged 18-25 years in the TBI condition showed significantly greater reductions in cannabis use relative to older patients (B = -0.78, SE = 0.31, P < 0.05). Results for CBI were non-significant. CONCLUSIONS: Emergency department-based therapist-delivered brief interventions to address drug use, alcohol consumption (when relevant) and HIV risk behaviors may also reduce alcohol use, cannabis use and anxiety over time, accounting for the overlap of these processes.

Frontostriatal Resting State Functional Connectivity in Resilient and Non-Resilient Adolescents with a Family History of Alcohol Use Disorder.

Objectives: Youth with parental substance use disorder (family-history positive [FH+]) are at an elevated risk for substance use problems, but not all FH+ youth experience this outcome. Frontostriatal brain networks involved in inhibitory control and reward responsivity underlie risk-taking behaviors, but the role of these networks in substance use heterogeneity among FH+ youth has not been examined. The present study examined resting state functional connectivity (RSFC) in frontostriatal networks in FH+ youth with and without risky substance use. Methods: Participants were 36 FH+ adolescents (mean age 14.96 years at the scan date; 36% female) from a longitudinal, community-based functional magnetic resonance imaging study enriched for parental alcohol use disorder. Groups were based on the absence (resilient) or presence (high-risk) of at least one occasion of any substance use by age 14 and also use of at least two different types of substances by the most recent substance use assessment (mean age 16.89 years). Bilateral masks of the dorsolateral prefrontal cortex (DLPFC) and the nucleus accumbens were used for seed-based RSFC due to the importance of these regions in executive control and salience networks, respectively. Results: Compared with FH+/high-risk youth, FH+/resilient youth displayed greater connectivity between the left DLPFC seed and the left posterior cingulate cortex. No other brain regions showed significantly different RSFC between resilient and high-risk groups. Conclusion: FH+/resilient youth showed stronger synchrony between brain regions associated with cognitive control, particularly those associated with flexible adaptation of thoughts and behaviors. Although preliminary, the results of this study set the stage for a continued focus on risk-group heterogeneity to better identify neural markers of resilience against substance use problems in vulnerable populations.

Adolescent Health Risk Behaviors: Convergent, Discriminant and Predictive Validity of Self-Report and Cognitive Measures.

Self-report and cognitive tasks of reward sensitivity and self-regulation have influenced several developmental models that may explain the heightened engagement in risk behaviors during adolescence. Despite some inconsistencies across studies, few studies have explored the convergent, discriminant, and predictive validity of self-report and cognitive measures of these psychological characteristics in adolescence. The present study evaluated the convergent and discriminant validity of self-report and cognitive measures of reward sensitivity and self-regulation among 2017 adolescents (age M = 16.8, SD = 1.1; 56% female; 55% White, 22% Black, 8% Hispanic, 15% other race/ethnic; 49% 10th grade and 51% 12th grade). This study compared the predictive validity of an omnibus measure and specific measures of risk engagement. Convergent and discriminant validity from self-report to cognitive tasks were as predicted, although with weak convergent relationships. As hypothesized, compared to cognitive tasks, self-report measures consistently predicted risky behaviors and explained more variance in the models. These results demonstrate that while cognitive tasks can significantly predict certain risk behaviors, they require increased power to find the very small effects, raising questions about their use as implicit proxies for real world risk behavior.

Reward activation in childhood predicts adolescent substance use initiation in a high-risk sample.

BACKGROUND: Substance use at an early age conveys substantial risk for later substance-related problems. A better understanding of early risk factors could result in more timely and effective intervention. This study investigated the predictive utility of the brain's response to reward anticipation as a risk factor for early substance use initiation. METHODS: Participants were 34 children (25 male) at high risk for alcohol and other substance use disorders from a longitudinal functional magnetic resonance imaging study, scanned at a mean age of 10.5 years (SD = 1.2) when participants were substance-naïve. We used a monetary incentive delay task to examine the hemodynamic response of the nucleus accumbens to gain and loss anticipation. Logistic regression was used to test the hypothesis that these brain response patterns would have predictive utility over and above early externalizing behaviors and family history of substance use disorder, two key risk factors for substance use problems, in differentiating those who initiated substance use before age 16 (n = 18) and those who did not (n = 16). RESULTS: Greater nucleus accumbens activation during monetary gain anticipation in childhood increased the likelihood of initiating substance use during early adolescence (p = .023). The model that comprised neural data in addition to early externalizing behaviors and family history showed significantly better fit than the model without neural data (χ22 = 7.38, p = .025). CONCLUSIONS: Heightened gain anticipation activation in the nucleus accumbens may predispose individuals to early substance use, beyond the risk conveyed by other known factors.

Childhood adversity, externalizing behavior, and substance use in adolescence: Mediating effects of anterior cingulate cortex activation during inhibitory errors.

Childhood adversity can negatively impact development across various domains, including physical and mental health. Adverse childhood experiences have been linked to aggression and substance use; however, developmental pathways to explain these associations are not well characterized. Understanding early precursors to later problem behavior and substance use can inform preventive interventions. The aim of the current study was to examine neurobiological pathways through which childhood adversity may lead to early adolescent problem behavior and substance use in late adolescence by testing two prospective models. Our first model found that early adolescent externalizing behavior mediates the association between childhood adversity and alcohol, cigarette, and marijuana use in late adolescence. Our second model found that activation in the anterior cingulate cortex (ACC) during an inhibitory control task mediates the association between childhood adversity and early adolescent externalizing behavior, with lower ACC activation associated with higher levels of adversity and more externalizing behavior. Together these findings indicate that the path to substance use in late adolescence from childhood adversity may operate through lower functioning in the ACC related to inhibitory control and externalizing behavior. Early life stressors should be considered an integral component in the etiology and prevention of early and problematic substance use.