Nucleus accumbens functional connectivity at age 20 is associated with trajectory of adolescent cannabis use and predicts psychosocial functioning in young adulthood.

AIMS: (1) To identify trajectories of cannabis use across adolescence, (2) to measure the influence of cannabis use characteristics on functional connectivity of the nucleus accumbens (NAcc) and (3) to assess whether patterns of functional connectivity related to cannabis use are associated with psychosocial functioning 2 years later. DESIGN: The Pitt Mother and Child Project (PMCP) is a prospective, longitudinal study of male youth at high risk for psychopathology based on family income and gender. SETTING: Participants were recruited between age 6 and 17 months from the Women, Infants and Children Nutritional Supplement program (WIC) in the Pittsburgh, Pennsylvania area. PARTICIPANTS: A total of 158 PMCP young men contributed functional magnetic resonance imaging (fMRI) and substance use data at age 20 years. MEASUREMENTS: Latent class growth analysis was used to determine trajectories of cannabis use frequency from age 14 to 19 years. Psychophysiological interaction (PPI) analysis was used to measure functional connectivity between the NAcc and prefrontal cortex (PFC). Adolescent cannabis use trajectory, recent frequency of use and age of initiation were considered as developmental factors. We also tested whether functional connectivity was associated with depressive symptoms, anhedonia and educational attainment at age 22. FINDINGS: We identified three distinct trajectories of adolescent cannabis use, characterized by stable high, escalating or stable low use. The cannabis use trajectory group had a significant effect on NAcc functional connectivity to the medial PFC (F = 11.32, Z = 4.04, Pfamily-wise error-corrected (FWE-corr)  = 0.000). The escalating trajectory group displayed a pattern of negative NAcc-mPFC connectivity that was linked to higher levels of depressive symptoms (r = -0.17, P < .05), anhedonia (r = -0.19, P < .05) and lower educational attainment (t = -2.77, P < .01) at age 22. CONCLUSIONS: Pattern of cannabis use frequency across adolescence in US youth could have consequences for mood symptoms and educational attainment in early adulthood via altered function in neural reward circuitry.

History of Depression and Frontostriatal Connectivity During Reward Processing in Late Adolescent Boys.

Given that depression in men is associated with risk for seriously adverse consequences, evaluating how putative neural mechanisms of depression-such as reward-related frontostriatal connectivity-may be altered in late adolescent boys with a history of depression is an important research aim. Adolescents and adults with depression have been demonstrated to show blunted striatal response and heightened medial prefrontal cortex (mPFC) activation to winning reward. Function in reward circuits appears to be best understood as coordination of regions within frontostriatal circuitry, and alterations to this circuitry could occur in those with a history of depression. The current study evaluated functional connectivity between the nucleus accumbens and mPFC in a sample of 166 ethnically diverse boys with and without a history of depression. Participants completed an fMRI monetary reward paradigm at age 20. Lifetime history of depression and other psychiatric illnesses was measured prospectively and longitudinally, using structured clinical interviews at 7 time points from ages 8 to 20. Boys with a history of depression showed heightened positive connectivity between the nucleus accumbens and the mPFC relative to boys with no psychiatric history when winning rewards relative to losing rewards. This altered frontostriatal connectivity pattern was also associated with greater number of depressive episodes in the boys' lifetime. History of depression in late adolescent boys may be associated with altered coordination between the nucleus accumbens and mPFC when winning reward. This coordination could reflect oversignaling of the mPFC to dampen typical ventral striatum response or enhance weak ventral striatum response.

Life stress in adolescence predicts early adult reward-related brain function and alcohol dependence.

Stressful life events increase vulnerability to problematic alcohol use, and they may do this by disrupting reward-related neural circuitry. This is particularly relevant for adolescents because alcohol use rises sharply after mid-adolescence and alcohol abuse peaks at age 20. Adolescents also report more stressors compared with children, and neural reward circuitry may be especially vulnerable to stressors during adolescence because of prefrontal cortex remodeling. Using a large sample of male participants in a longitudinal functional magnetic resonance imaging study (N = 157), we evaluated whether cumulative stressful life events between the ages of 15 and 18 were associated with reward-related brain function and problematic alcohol use at age 20 years. Higher cumulative stressful life events during adolescence were associated with decreased response in the medial prefrontal cortex (mPFC) during monetary reward anticipation and following the receipt of monetary rewards. Stress-related decreases in mPFC response during reward anticipation and following rewarding outcomes were associated with the severity of alcohol dependence. Furthermore, mPFC response mediated the association between stressful life events and later symptoms of alcohol dependence. These data are consistent with neurobiological models of addiction that propose that stressors during adolescence increase risk for problematic alcohol use by disrupting reward circuit function.

Prefrontal response and frontostriatal functional connectivity to monetary reward in abstinent alcohol-dependent young adults.

Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence.

Social anhedonia and medial prefrontal response to mutual liking in late adolescents.

Anhedonia, a cardinal symptom of depression defined as difficulty experiencing pleasure, is also a possible endophenotype and prognostic factor for the development of depression. The onset of depression typically occurs during adolescence, a period in which social status and affiliation are especially salient. The medial prefrontal cortex (mPFC), a region implicated in reward, self-relevant processing, and social cognition, exhibits altered function in adults with anhedonia, but its association with adolescent anhedonia has yet to be investigated. We examined neural response to social reward in 27 late adolescents, 18-21years old, who varied in social anhedonia. Participants reported their social anhedonia, completed ratings of photos of unfamiliar peers, and underwent a functional magnetic resonance imaging task involving feedback about being liked. Adolescents with higher social anhedonia exhibited greater mPFC activation in response to mutual liking (i.e., being liked by someone they also liked) relative to received liking (i.e., being liked by someone whom they did not like). This association held after controlling for severity of current depressive symptoms, although depressive severity was also associated with greater mPFC response. Adolescents with higher levels of social anhedonia also had stronger positive connectivity between the nucleus accumbens and the mPFC during mutual versus received liking. These results, the first on the pathophysiology of adolescent anhedonia, support altered neural reward-circuit response to social reward in young people with social anhedonia.