Background Biased attention to threat is found in both individuals with anxiety symptoms and children with the childhood temperament of behavioral inhibition (BI). Although perturbed fronto-amygdala function is implicated in biased attention among anxious individuals, no work has examined the neural correlates of attention biases in BI. Work in this area may clarify underlying mechanisms for anxiety in a sample at risk for internalizing disorders. We examined the relations among early childhood BI, fronto-amygdala connectivity during an attention bias task in young adulthood, and internalizing symptoms, assessed in young adulthood. Methods Children were assessed for BI at multiple age points from infancy through age seven. Based on a composite of observational and maternal report data, we selected 21 young adults classified as having a history of BI and 23 classified as non-BI for this study (N=44). Participants completed an event-related fMRI attention-bias task involving threat (angry faces) and neutral trials. Internalizing symptoms were assessed by self-report and diagnostic interviews. Results The young adults characterized in childhood with BI exhibited greater strength in threat-related connectivity than non-behaviorally inhibited young adults. Between-group differences manifested in connections between the amygdala and two frontal regions: dorsolateral prefrontal cortex and anterior insula. Amygdala-insula connectivity also interacted with childhood BI to predict young adult internalizing symptoms. Conclusions BI during early childhood predicts differences as young adults in threat and attention-related fronto-amygdala connectivity. Connectivity strength, in turn, moderated the relations between early BI and later psychopathology.

The detection of threat is a role that the amygdala plays well, evidenced by its increased response to fearful faces in human neuroimaging studies. A critical element of the fearful face is an increase in eye white area (EWA), hypothesized to be a significant cue in activating the amygdala. However, another important social signal that can increase EWA is a lateral shift in gaze direction, which also serves to orient attention to potential threats. It is unknown how the amygdala differentiates between these increases in EWA and those that are specifically associated with fear. Using functional magnetic resonance imaging, we show that the left amygdala distinguished between fearful eyes and gaze shifts despite similar EWA increases whereas the right amygdala was less discriminatory. Additional analyses also revealed selective hemispheric response patterns in the left fusiform gyrus. Our data show clear hemispheric differences in EWA-based fear activation, suggesting the existence of parallel mechanisms that code for emotional face information.

Importance Marijuana use may alter ventral striatal response to reward, which may heighten susceptibility to substance use disorder (SUD). Cross-sectional studies have reported either increased ventral striatal response to reward or no difference in marijuana users compared with controls. Longitudinal research is needed to resolve the inconsistencies and disentangle preexisting susceptibility from the effects of marijuana use on neural function involved in reward responding. Objective To determine whether marijuana use among young adults prospectively impacts nucleus accumbens (NAcc) activation during reward anticipation. Design Longitudinal study of self-report marijuana use and brain function using functional magnetic resonance imaging (fMRI) at three consecutive time points. Setting Data were obtained from young adult participants in the Michigan Longitudinal Study, an ongoing, prospective study of youth at high risk for SUD and a contrast sample of control families. Participants The sample consisted of 108 young adults (36% female; 78% family history of SUD) who underwent three fMRI scans at approximately age 20 (time 1), 22 (time 2), and 24 (time 3). Main Outcome and Measures We investigated the impact of marijuana use on neural response in the NAcc to reward anticipation during a monetary incentive delay task (MIDT) using a cross-lagged model. Covariates for analyses included sex, age at first scan, family history of SUD, prior marijuana use, and binge drinking (prior and concurrent). This model was also tested separately with the inclusion of cigarette smoking. Results Greater marijuana use was associated with later blunted activation in the NAcc during reward anticipation (time 1 to time 2: β=−0.26, P=0.04; time 2 to time 3: β=−0.25, P=0.01). When we tested the cross-lagged model with the inclusion of prior and concurrent cigarette use, the impact of marijuana use from time 2 to time 3 remained significant and the effect of cigarette use was non-significant. Conclusions and Relevance Our findings indicate that marijuana use is associated with decreased neural response in the NAcc during the anticipation of non-drug rewards. Over time, marijuana use may alter anticipatory reward processing in the NAcc, which may increase risk for continued drug use and later addiction.

Background A core vulnerability trait for substance use disorder (SUD) is behavioral disinhibition. Error processing is a central aspect of inhibitory control that determines adaptive adjustment of performance; yet it is a largely overlooked aspect of disinhibition as it relates to risk for SUD. We investigated whether differences in brain activation during both successful and failed inhibition predicts early problem substance use. Method Forty-five 9–12 year olds underwent a functional MRI scan during a go/no-go task. They were then followed over approximately 4 years, completing assessments of substance use. Externalizing behavior was measured at ages 3–8, 9–12 and 11–13. Participants with drug use or problem alcohol use by ages 13–16 (n=13; problem-user group) were individually matched by gender, age, and family history of alcoholism with non-substance-using children (n=13; non-user group). The remaining 19 participants provided an independent sample from which to generate unbiased regions-of-interest for hypothesis testing in the problem-user and non-user groups. Results No differences were observed between groups in activation during correct inhibition compared with baseline. A significant difference arose in left middle frontal gyrus (LMFG) activation during failed inhibition compared with correct inhibition, with the problem-user group demonstrating blunted activation. The problem-user group also had more externalizing problems at ages 11–13. Logistic regression found that activation of LMFG significantly predicted group membership over and above externalizing problems. Conclusions Blunted LMFG activation during performance errors may underlie problems adapting behavior appropriately, leading to undercontrolled behavior, early problem substance use and increased risk for SUD.

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Background Difficulty with impulse control is heightened in children with a family history of alcohol use disorders and is a risk factor for later substance problems. Cross-sectional fMRI studies have shown altered impulse control processing in family history positive adolescents, yet developmental trajectories have yet to be examined. Methods Longitudinal fMRI was conducted in children of alcoholic (FH+; n=43) and control families (FH−; n=30) starting at ages 7-12yr. Participants performed a go/no-go task during fMRI at 1- to 2-yr intervals, with 2-4 scans per subject. We implemented a repeated-measures linear model fit across all subjects to conduct a whole-brain search for developmental differences between groups. Results Performance improved with age in both groups and there were no performance differences between groups. Significant between-group differences in linear age-related activation changes were found in the right caudate, middle cingulate, and middle frontal gyrus. Post-hoc analyses revealed significant activation decreases with age in the caudate and middle frontal gyrus for FH− subjects, and a significant increase with age in middle cingulate activation for the FH+ group. Group differences were evident as early as age 7-12yr, even in alcohol and drug naïve participants, with the FH+ group showing significantly blunted activation compared to FH− subjects at baseline. Conclusions Differences in response inhibition circuitry are visible as early as childhood in FH+ individuals; this continues into adolescence, displaying trajectories that are inconsistent with normal response inhibition development. These patterns precede problem drinking and may be a contributing factor for subsequent substance problems.

Rates of alcohol and other drug use rise sharply throughout adolescence and peak in the early 20s. Likewise, prevalence of first-time substance use disorder (SUD) and past-year SUD both peak between ages 18–23. SUD is associated with a host of negative outcomes and is a serious health concern. Understanding the mechanisms that precede the onset and escalation of substance use is crucial in order to develop more effective prevention and intervention strategies for children and adolescents at risk for SUD. In this review, we discuss recent findings from functional neuroimaging studies in children, adolescents, and emerging adults that focus on uncovering the neural underpinnings of SUD risk. The focus is on inhibitory control and reward circuitry due to their involvement in risk-taking behaviors, which are heightened in adolescence and may facilitate substance use. We discuss convergences in the literature and highlight findings suggesting that the association between SUD risk and neurofunctioning may be moderated by age, gender, and history of substance use. Recommendations for future directions are also discussed.

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.