Clarifying Relations Between Core Features of Psychopathy and Substance (Mis)use: A Replication and Extension in Two Large Independent Samples.

Two studies examined the consistency of associations between specific components of psychopathy and two indices of drug use: (a) abstinence and (b) severity (i.e., counts) of lifetime substance use disorder (SUD) symptoms. Participants were 418 male county jail inmates in Illinois (Study One) and 354 male state prison inmates in New Mexico (Study Two). Across samples, lifestyle and antisocial trait ratings were associated with a reduced likelihood of abstinence from most substances. Lifestyle traits were also uniquely associated with severity of substance dependence ratings. Consistent with prior research, interpersonal traits were uniquely related to cocaine indices in both samples. Furthermore, analyses revealed negative associations between the affective features of psychopathy and alcohol dependence in one sample (Study Two), and illicit substance use across samples. These findings demonstrate the robustness of the associations between the interpersonal and affective features of psychopathy and specific aspects of substance (mis)use.

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.

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.

Systematic review of structural and functional neuroimaging studies of cannabis use in adolescence and emerging adulthood: evidence from 90 studies and 9441 participants.

Cannabis use peaks in adolescence, and adolescents may be more vulnerable to the neural effects of cannabis and cannabis-related harms due to ongoing brain development during this period. In light of ongoing cannabis policy changes, increased availability, reduced perceptions of harm, heightened interest in medicinal applications of cannabis, and drastic increases in cannabis potency, it is essential to establish an understanding of cannabis effects on the developing adolescent brain. This systematic review aims to: (1) synthesize extant literature on functional and structural neural alterations associated with cannabis use during adolescence and emerging adulthood; (2) identify gaps in the literature that critically impede our ability to accurately assess the effect of cannabis on adolescent brain function and development; and (3) provide recommendations for future research to bridge these gaps and elucidate the mechanisms underlying cannabis-related harms in adolescence and emerging adulthood, with the long-term goal of facilitating the development of improved prevention, early intervention, and treatment approaches targeting adolescent cannabis users (CU). Based on a systematic search of Medline and PsycInfo and other non-systematic sources, we identified 90 studies including 9441 adolescents and emerging adults (n = 3924 CU, n = 5517 non-CU), which provide preliminary evidence for functional and structural alterations in frontoparietal, frontolimbic, frontostriatal, and cerebellar regions among adolescent cannabis users. Larger, more rigorous studies are essential to reconcile divergent results, assess potential moderators of cannabis effects on the developing brain, disentangle risk factors for use from consequences of exposure, and elucidate the extent to which cannabis effects are reversible with abstinence. Guidelines for conducting this work are provided.

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.

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.

Effects of the cannabinoid receptor agonist CP-55,940 on incentive salience attribution.

RATIONALE: Pavlovian conditioned approach paradigms are used to characterize the nature of motivational behaviors in response to stimuli as either directed toward the cue (i.e., sign-tracking) or the site of reward delivery (i.e., goal-tracking). Recent evidence has shown that activity of the endocannabinoid system increases dopaminergic activity in the mesocorticolimbic system, and other studies have shown that sign-tracking behaviors are dependent on dopamine. OBJECTIVES: Therefore, we hypothesized that administration of a cannabinoid agonist would increase sign-tracking and decrease goal-tracking behaviors. METHODS: Forty-seven adult male Sprague-Dawley rats were given a low, medium, or high dose of the cannabinoid agonist CP-55,940 (N = 12 per group) or saline (N = 11) before Pavlovian conditioned approach training. A separate group of rats (N = 32) were sacrificed after PCA training for measurement of cannabinoid receptor type 1 (CB1) and fatty acid amide hydrolase (FAAH) using in situ hybridization. RESULTS: Contrary to our initial hypothesis, CP-55,940 dose-dependently decreased sign-tracking and increased goal-tracking behavior. CB1 expression was higher in sign-trackers compared with that in goal-trackers in the prelimbic cortex, but there were no significant differences in CB1 or FAAH expression in the infralimbic cortex, dorsal or ventral CA1, dorsal or ventral CA3, dorsal or ventral dentate gyrus, or amygdala. CONCLUSIONS: These results demonstrate that cannabinoid signaling can specifically influence behavioral biases toward sign- or goal-tracking. Pre-existing differences in CB1 expression patterns, particularly in the prelimbic cortex, could contribute to individual differences in the tendency to attribute incentive salience to reward cues.

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.

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.

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.

Brain Activity, Low Self-Control, and Delinquency: An fMRI Study of At-Risk Adolescents.

PURPOSE: A vast literature finds that low self-control is associated with a myriad of antisocial behaviors. Consequently, increasing attention has focused on the causes of low self-control. While criminologists have directed significant attention to studying its social causes, fewer studies have considered its neural bases. METHODS: We add to this nascent body of research by using data collected on an at-risk sample of adolescents participating in the ongoing Michigan Longitudinal Study. We examine the functioning of prefrontal and limbic regions of the brain during failed inhibitory control, assessed using the go/no-go task and functional magnetic resonance imaging, in relation to low self-control and self-reported delinquency. RESULTS: Results indicate that greater activation localized in the anterior cingulate cortex (ACC) during failed inhibitory control is negatively associated with low self-control. Moreover, the association between ACC activity and later delinquency is mediated through low self-control. CONCLUSIONS: Findings of this study demonstrate the utility of integrating neuroscientific and criminological perspectives on the causes of antisocial behavior. Concluding remarks address the theoretical and policy implications of the findings, as well as directions for future research.

Pathways to Youth Behavior: The Role of Genetic, Neural, and Behavioral Markers.

Neural and temperamental mechanisms through which a genetic risk marker in the γ-amino butyric acid α2 receptor subunit (GABRA2) impacts adolescent functioning were investigated. Participants (N = 80; 29 female) completed an emotional word task during functional magnetic resonance imaging. Behavioral control, negative emotionality, and resiliency temperament constructs were assessed. Externalizing and internalizing problems were the outcomes. Those with the GABRA2 minor allele had reduced activation to positive words in the angular gyrus, middle temporal gyrus, and cerebellum, and to negative words in frontal, parietal, and occipital cortices. Reduced activation in the angular gyrus predicted greater negative emotionality and, in turn, elevated externalizing problems. Reduced activation in the inferior parietal cortex predicted greater resiliency and, in turn, low externalizing problems.

Review of Neurobiological Influences on Externalizing and Internalizing Pathways to Alcohol Use Disorder.

PURPOSE OF REVIEW: Two developmental courses through which alcohol use disorder (AUD) may emerge include externalizing and internalizing pathways. We review recent neuroimaging studies of potential neural risk factors for AUD and link findings to potential behavioral risk factors for AUD. RECENT FINDINGS: There is evidence that early-emerging weakness in prefrontal functioning and later-emerging differences in reward-system functioning contribute to an externalizing risk pathway. Stress may be an important contributor in the internalizing pathway through a blunting of reward-related activation, which may act alone or in combination with heightened emotion-related reactivity. SUMMARY: This review highlights areas for future work, including investigation of the relative balance between prefrontal and subcortical circuitry, attention to stages of AUD, and consideration of environmental factors such as stress and sleep. Particularly important is longitudinal work to understand the temporal ordering of associations among brain maturation, behavioral risk, and alcohol use.

Callous-Unemotional Traits Modulate Brain Drug Craving Response in High-Risk Young Offenders.

Adults with psychopathy have a high propensity for substance abuse, generally starting from a young age. This investigation tested hypotheses about differences in the neural responses associated with drug craving among high-risk young offenders with histories of abuse of stimulants and other drugs as a function of psychopathic traits. Fifty-four male adolescents (44 with a history of stimulant abuse and 10 controls) incarcerated at a maximum-security facility (M age = 17.08 years) completed a drug-cue exposure task while brain hemodynamic activity was monitored using functional magnetic resonance imaging (fMRI) with a mobile MRI scanner stationed at the facility. Psychopathic traits were assessed using the Hare Psychopathy Checklist: Youth Version (PCL:YV). In the stimulant abuser group, drug cues elicited activity in classic reward circuitry. Consistent with studies of adult psychopathic traits and substance abuse, there was a negative association between PCL-YV scores and hemodynamic response related to drug craving in the amygdala and ACC in youth with a history of stimulant abuse. However, there were considerably more negative associations between the PCL:YV and hemodynamic response among youth than adults and this was primarily due to callous-unemotional traits rather than interpersonal or behavioral traits. The implications for how personality traits modulate motivations for drug-seeking behavior among adolescent offenders are discussed.

Concurrent and developmental correlates of psychopathic traits using a triarchic psychopathy model approach.

Psychopathy refers to a heterogeneous set of harmful dark traits and behaviors, including superficial charm, callousness, irresponsibility, and antisocial behavior. The triarchic psychopathy model (TriPM) posits that psychopathy is the combination of 3 traits: boldness, disinhibition, and meanness. However, little research has examined the concurrent and developmental correlates of these traits. We developed TriPM scales from the NEO Personality Inventory-Revised using an empirical-derived approach in a high-risk sample of 561 young adults (ages 17-25; 70.2% male). Concurrent correlates and developmental precursors of each scale were examined longitudinally using cross-informant reports from 3 critical developmental periods (ages 3-5; 9-11; 15-17). Using this approach, we identified consistent developmental precursors and concurrent correlates of boldness, including lower reactive control, fewer internalizing traits, and greater resiliency. Additionally, starting in adolescence we found that disinhibition was related to lower reactive control, more externalizing problems, substance use, and internalizing traits. Finally, although meanness demonstrated some expected concurrent relationships with criterion variables in early adulthood (e.g., lower adaptive functioning), we identified few consistent developmental precursors of meanness. Thus, a NEO-based approach to measuring the TriPM was successful in delineating boldness, disinhibition, and, to a lesser extent, meanness cross-sectionally during early adulthood. However, only boldness showed relative stability from developmental precursors in early childhood to our TriPM scale in early adulthood. (PsycINFO Database Record

Effects of the serotonin transporter gene, sensitivity of response to alcohol, and parental monitoring on risk for problem alcohol use.

The serotonin transporter-linked polymorphic region (5-HTTLPR) of the serotonin transporter gene (SLC6A4) has been previously associated with alcohol-related risk. Most findings point to short (S) allele carriers being at increased risk for negative alcohol outcomes relative to long allele homozygotes, although some work indicates a more complex relationship. The current prospective study aimed to clarify how and under what circumstances variations in 5-HTTLPR transmit risk for various alcohol-related outcomes. Participants were 218 adolescents and young adults (29% female) enrolled in the Michigan Longitudinal Study. We tested a moderated mediation model with 5-HTTLPR as the predictor, Self-Rating of the Effects of Alcohol (SRE) score as the mediator, alcohol-related outcomes as the dependent variables, parental monitoring as the moderator of the SRE to alcohol outcomes path, and prior drinks, sex, age, and body mass index as covariates. Four alcohol-related outcomes were tested. The S allele was associated with higher SRE scores (i.e., lower response to alcohol). Parental monitoring was a significant moderator: At low levels of parental monitoring, higher SRE scores predicted more drinks consumed and binge drinking episodes. At high levels of monitoring, higher SRE scores were significantly related to fewer alcohol-related problems. Findings suggest that one mechanism by which 5-HTTLPR variation transmits alcohol-related risk is through level of response to alcohol. Furthermore, the strength and direction of this effect varied by level of parental monitoring, indicating that even in the presence of genetic and physiological vulnerability, parents can influence the likelihood of offspring developing problematic alcohol-related behaviors.

Sex differences in the development of emotion circuitry in adolescents at risk for substance abuse: a longitudinal fMRI study.

There is substantial evidence for behavioral sex differences in risk trajectories for alcohol and substance use, with internalizing factors such as negative affectivity contributing more to female risk. Because the neural development of emotion circuitry varies between males and females across adolescence, it represents a potential mechanism by which underlying neurobiology contributes to risk for substance use. Longitudinal functional magnetic resonance imaging was conducted in males and females (n = 18 each) with a family history of alcohol use disorders starting at ages 8-13 years. Participants performed an affective word task during functional magnetic resonance imaging at 1- to 2-year intervals, covering the age range of 8.5-17.6 years (3-4 scans per participant). Significant age-related sex differences were found in the right amygdala and right precentral gyrus for the negative vs neutral word condition. Males showed a significant decrease in both amygdala and precentral gyrus activation with age, whereas the response in females persisted. The subjective experience of internalizing symptomatology significantly increased with age for females but not for males. Taken together, these results reveal sex differences in negative affect processing in at-risk adolescents, and offer longitudinal neural evidence for female substance use risk through internalizing pathways.