A central goal of this study was to

A central goal of this study was to characterize the neural mechanisms through which adolescent marijuana use exerts its effects on later emotional functioning. We found that activation in the right prefrontal Cy3-dUTP to negative words mediated the association between heavy marijuana use and both negative emotionality and resiliency at follow-up. Specifically, activation in the right middle frontal gyrus and dorsolateral superior frontal gyrus was lower in heavy users than controls, an effect that was associated with decreased resiliency and increased negative emotionality at follow-up. This area of the prefrontal cortex has been referred to as the caudal dorsolateral prefrontal region (caudal dlPFC) and is closely connected with motor and supplementary motor regions (Petrides, 2005). Prior work has found activation of the caudal dlPFC and associated regions during the reading of high-arousal emotional words (Compton et al., 2003). The supplementary motor and premotor regions are important for emotion processing and empathy (Lamm et al., 2011) and may regulate approach-withdrawal tendencies to emotional stimuli by integrating limbic and motor responses (Oliveri et al., 2003; Rodigari and Oliveri, 2014). A recent meta-analysis found that activation in these regions decreased to negative stimuli in alexithymia, a trait characterized by difficulties with experiencing and processing emotions (van der Velde et al., 2013). The current findings suggest that heavy marijuana use during adolescence may impact caudal dlPFC functioning, impairing the processing and integration of emotional stimuli and lead to increased negative emotionality. Additionally, we found that activation in the occipital cortex to negative emotional stimuli mediated the relationship between marijuana use and later resiliency. Specifically, activation in the cortical region surrounding the calcarine fissure, including portions of the right cuneus and lingual gyrus, was lower in heavy marijuana users than controls. This activation was further associated with decreased resiliency at follow-up, when controlling for resiliency at the time of scan. Although the cuneus and lingual gyrus are classically considered as visual processing and integration regions, there is a large literature associating both regions with aspects of emotion functioning, including the processing of emotional faces (Kitada et al., 2010), high-arousal emotional words (Compton et al., 2003), and emotional film clips (Goldin et al., 2008), as well as the evaluation of one\'s own emotional state (Terasawa et al., 2013a). Cuneus activation has also been associated with the ability to attribute mental states to others, termed “theory of mind” (ToM) (Vollm et al., 2006). A recent study reported that adult marijuana users had differences in brain activation compared with controls during a ToM task, including lower activation in the right cuneus (Roser et al., 2012). Therefore, an impact of heavy marijuana use during adolescence on the functioning of occipital regions involved in the evaluation of emotional stimuli with respect to oneself and to others may impair self-regulation of emotional processes (as measured here with resiliency). In addition to the regions found to mediate later outcome, heavy marijuana users had less activation than controls in the insula to negative words. These findings are consistent with previous work showing adolescent marijuana users had reduced cerebral blood flow in the insula compared with controls (Jacobus et al., 2012). Furthermore, studies of adult marijuana users found less activation in the insula to loss outcomes during a monetary incentive task (Nestor et al., 2010) and to errors in an inhibitory control task (Hester et al., 2009) compared with controls. The insula is critical to the integration of emotional and homeostatic information, and may be involved in translating interoceptive signals into conscious feelings (Critchley et al., 2005; Critchley et al., 2004; Naqvi and Bechara, 2009; Terasawa et al., 2013a). For example, the magnitude of insula activation while participants evaluated their own emotional and bodily states was found to be associated with social anxiety and neuroticism (Terasawa et al., 2013b). Insula activation has also been associated with self-report measures of anxiety (Stein et al., 2007) and anticipation of aversive exposure (Simmons et al., 2006) in anxiety-prone individuals. Here we found less insula activity to negative words in heavy marijuana users compared with controls, which was further associated with more negative emotionality at the time of scan. Together, this evidence suggests that heavy marijuana use may lead to impairment in the integration of emotional experience.