Sex differences in distributed error-related neural activation in problem-drinking young adults.

BACKGROUND: Detecting and responding to errors is central to goal-directed behavior and cognitive control and is thought to be supported by a network of structures that includes the anterior cingulate cortex and anterior insula. Sex differences in the maturational timing of cognitive control systems create differential periods of vulnerability for psychiatric conditions, such as substance use disorders. METHODS: We examined sex differences in error-related activation across an array of distributed brain regions during a Go/No-Go task in young adults with problem alcohol use (N=69; 34 females; M=19.4 years). Regions of interest previously linked to error-related activation, including anterior cingulate cortex, insula, and frontoparietal structures, were selected in a term-based meta-analysis. Individual differences in their responses to false alarm (FA) inhibitory errors relative to "go" trials (FA>GO) and correct rejections (FA>CR) were indexed using multivariate summary measures derived from principal components analysis. RESULTS: FA>GO and FA>CR activation both revealed a first component that explained the majority of the variance across error-associated regions and displayed the strongest loadings on salience network structures. Compared to females, males exhibited significantly higher levels of the FA>GO component but not the FA>CR component. CONCLUSIONS: Males exhibit greater salience network activation in response to inhibitory errors, which could be attributed to sex differences in error-monitoring processes or to other functions (e.g., novelty detection). The findings are relevant for the further characterization of sex differences in cognitive control and may have implications for understanding individual differences in those at risk for substance use or other cognitive control disorders.

Error-related brain activity associated with obsessive-compulsive symptoms in youth.

BACKGROUND: Subclinical obsessive-compulsive symptoms (OCS) are common in children, and increase risk for later onset of obsessive-compulsive disorder (OCD). In pediatric patients with OCD, neuroimaging research implicates altered neural mechanisms for error-processing, but whether abnormal brain response occurs with subclinical OCS remains poorly understood. METHODS: Using functional magnetic resonance imaging (fMRI), 113 youth (8-18 years; 45 female) from a community sample were scanned during an error-eliciting Go/No-Go task. OCS were assessed dimensionally using the obsessive-compulsive subscale of the Child Behavior Checklist. The association between OCS scores and error-related brain activity was examined at the whole-brain level. RESULTS: Lower OCS scores associated with stronger response to errors in dorsal anterior cingulate cortex (dACC), caudate, putamen, thalamus, and occipital cortex. Additionally, lower OCS related to higher capacity for inhibitory control, as indexed by greater accuracy on No-Go trials during fMRI scanning. The relationship between lower OCS and better accuracy on No-Go trials was mediated by greater error-related dACC activity. CONCLUSIONS: The inverse relationship between OCS and error-related activity in the dACC and extended cortical-striatal-thalamic circuitry may index an adaptive process by which subclinical OCS are minimized in youth. Further, these results identify an observable pattern of brain activity that tracks with subclinical OCS severity. Understanding the link between neural networks for error processing and the normal to abnormal range of OCS may pave the way for brain-based strategies to identify children who are more likely to develop OCD and enable the targeting of preventive strategies to reduce risk.

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.

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.

The role of pubertal timing in the link between family history of alcohol use disorder and late adolescent substance use.

BACKGROUND: Youth who experience puberty earlier than their peers are at heightened risk for substance use during adolescence. However, little is known about whether pubertal timing exacerbates effects of relevant early risk factors, such as family substance use history, as predicted by the "accentuation hypothesis". Using longitudinal data from youth with and without a family history of alcohol use disorder (AUD FHx), we evaluated whether pubertal timing intensifies preexisting familial risk effects on late adolescent substance use. METHODS: Participants were 568 males and 245 females from the Michigan Longitudinal Study. Pubertal timing was indexed by fitting mixed-effects linear models to repeated measures of self-reported Tanner stage. Multilevel models then tested: (a) whether AUD FHx predicted pubertal timing, and (b) whether AUD FHx, pubertal timing, or their interaction predicted alcohol and marijuana use at ages 16-18. RESULTS: AUD FHx was unrelated to pubertal timing in either males or females. In males, alcohol and marijuana use in late adolescence were predicted by AUD FHx and timing, but not their interaction. In females, AUD FHx predicted alcohol-related outcomes, but there were no main or interaction effects of timing. CONCLUSIONS: Pubertal timing does not moderate the link between AUD FHx and late adolescent substance use, in contrast to the accentuation hypothesis. In males, measures of pubertal maturation and familial risk provide unique information for prediction of use. Females displayed no link between pubertal timing and use, which may suggest different risk pathways, or may have been due to the female sample's smaller size.

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.

Neural correlates of inhibitory control in youth with symptoms of food addiction.

Prior research has found that food addiction is associated with reward-related neural differences, but research has yet to examine whether there are also neural differences in inhibitory control. This may be particularly relevant during adolescence as it is a key developmental period where difficulties in inhibitory control are more prevalent. The Yale Food Addiction Scale is a self-report questionnaire that applies substance use disorder diagnostic criteria to certain foods that has also been adapted for children. Here we investigate the association between addictive-like eating and brain functioning during inhibitory control in youth. Seventy-six right-handed participants 8.2-17.8 years (44 male) were recruited. Participants performed a go/no-go task during functional magnetic resonance imaging and completed the Yale Food Addiction Scale for Children, after which they were categorized into two groups according to their scores (No Symptom Group = 0; YFAS-C Group: score ≥ 1). Inhibitory control was probed with a contrast of correct no-go versus go trials. An independent-samples t-test comparing groups revealed a significant difference in three primary clusters, all exclusively in the left hemisphere (No Symptom Group > YFAS-C Group): middle temporal gyrus/occipital gyrus, precuneus/calcarine sulcus, and inferior frontal gyrus. Specifically, the YFAS-C Group showed deactivation in all three clusters. Adolescents who endorse food addiction appear to show hypo-activation in response to the inhibitory control portion of a go/no-go task, which suggests possible inhibitory control difficulties.

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.

Sex Differences in the Developmental Neuroscience of Adolescent Substance Use Risk.

Adolescence is a period associated with the initiation and escalation of substance use and is also a time during which substantial changes take place in neural development, personality and behavior. Although rates of substance use between adolescent girls and boys do not differ substantially, there is evidence for sex differences in underlying vulnerability pathways associated with the development of substance use disorder. Here we review sex differences in adolescent brain development and how these differences may contribute to different risk pathways between females and males that emerge during this developmental period. We also discuss methodological considerations in the study of sex differences in brain and behavior and their implications for interpretation. We close by highlighting promising areas for future work.

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.

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.

Reduced brain activation during inhibitory control in children with COMT Val/Val genotype.

INTRODUCTION: Behavioral undercontrol is a well-established risk factor for substance use disorder, identifiable at an early age well before the onset of substance use. However, the biological mechanistic structure underlying the behavioral undercontrol/substance use relationship is not well understood. The enzyme catechol O-methyltransferase (COMT) catabolizes dopamine and norepinephrine in the prefrontal cortex and striatum, brain regions involved in behavioral control. The goal of this work was to investigate the association between genetic variation in COMT functioning and fronto-striatal brain functioning during successful inhibitory control, a critical aspect of behavioral control. METHODS: Participants were 65 (22 female) 7-12 year olds who were genotyped for the functional COMT Val158Met (rs4680) single-nucleotide polymorphism and underwent functional magnetic resonance imaging while performing a go/no-go task. The majority of the sample (80%) had at least one parent with a history of alcohol use disorder and were thus at heightened risk for substance use disorders. RESULTS: There was a significant main effect of genotype on brain activation in left and right putamen during successful versus failed inhibition and in right inferior frontal gyrus/insula during successful inhibition versus baseline. Follow-up tests revealed that Met homozygotes had greater activation in each region relative to Val homozygotes. CONCLUSIONS: These results are relevant for understanding how specific genes influence brain functioning related to underlying risk factors for substance use disorders and other disinhibitory psychopathologies.

Association of Marijuana Use With Blunted Nucleus Accumbens Response to Reward Anticipation.

IMPORTANCE: Marijuana use may alter ventral striatal response to reward, which might heighten susceptibility to substance use disorder. Longitudinal research is needed to determine the effects of marijuana use on neural function involved in reward response. OBJECTIVE: To determine whether marijuana use among young adults prospectively affects nucleus accumbens (NAcc) activation during reward anticipation. DESIGN, SETTING, AND PARTICIPANTS: One hundred eight young adults were recruited from the Michigan Longitudinal Study, an ongoing study of youth at high risk for substance use disorder and a contrast sample of control families. Participants underwent 3 consecutive functional magnetic resonance imaging scans at approximate ages of 20 (time 1), 22 (time 2), and 24 (time 3) years. Self-report data on marijuana and other drug use occasions were collected annually since age 11 years. MAIN OUTCOMES AND MEASURES: Cross-lagged models were used to test the association of marijuana use with neural response in the NAcc to reward anticipation during a monetary incentive delay task controlling for sex, age, other substance use, and family history of substance use disorder. RESULTS: Of 108 participants, 39 (36.1%) were female and mean (SD) age at baseline was 20.1 (1.4) years. Greater marijuana use was associated with later blunted activation in the NAcc during reward anticipation (time 1 to time 2: ß = -0.26, P = .04; time 2 to time 3: ß = -0.25, P = .01). When the cross-lagged model was tested with the inclusion of previous and concurrent cigarette use, the effect of marijuana use from time 2 to time 3 remained significant (ß = -0.29; P = .005) and the effect of cigarette use was nonsignificant. CONCLUSIONS AND RELEVANCE: The findings of this study indicate that marijuana use is associated with decreased neural response in the NAcc during the anticipation of nondrug rewards. Over time, marijuana use may alter anticipatory reward processing in the NAcc, which may increase the risk for continued drug use and later addiction.

Brain activation to negative stimuli mediates a relationship between adolescent marijuana use and later emotional functioning.

This work investigated the impact of heavy marijuana use during adolescence on emotional functioning, as well as the brain functional mediators of this effect. Participants (n=40) were recruited from the Michigan Longitudinal Study (MLS). Data on marijuana use were collected prospectively beginning in childhood as part of the MLS. Participants were classified as heavy marijuana users (n=20) or controls with minimal marijuana use. Two facets of emotional functioning-negative emotionality and resiliency (a self-regulatory mechanism)-were assessed as part of the MLS at three time points: mean age 13.4, mean age 19.6, and mean age 23.1. Functional neuroimaging data during an emotion-arousal word task were collected at mean age 20.2. Negative emotionality decreased and resiliency increased across the three time points in controls but not heavy marijuana users. Compared with controls, heavy marijuana users had less activation to negative words in temporal, prefrontal, and occipital cortices, insula, and amygdala. Activation of dorsolateral prefrontal cortex to negative words mediated an association between marijuana group and later negative emotionality. Activation of the cuneus/lingual gyrus mediated an association between marijuana group and later resiliency. Results support growing evidence that heavy marijuana use during adolescence affects later emotional outcomes.