Instead we cautiously speculate that our results may be

Instead, we cautiously speculate that our results may be attributable to the fact that the impact of tobacco alone on adolescent neural responses may differ from the impact of tobacco in combination with other substances. In line with prior work in this area, the use of multiple substances in synergy may exert a neuroprotective effect (Jacobus et al., 2009), potentially due to the opposing or interactive nature of other substances (i.e., cannabis), when used in tandem with alcohol and/or tobacco (Nestor et al., 2010; Bachtell and Ryabinin, 2001; Penetar et al., 2005). Extending the conclusions of Jacobus and colleagues (Jacobus et al., 2009) that cannabis may protect against alcohol-related neural damage, we suggest that our results may be due to the influence of cannabis upon what would otherwise be deleterious neural alterations associated with tobacco use in our polysubstance groups. Alternatively, our pattern of findings may suggest that adolescent tobacco-only users represent a behaviorally or neurocognitively unique group in terms of reward processing. Indeed, it adenosine triphosphate is possible that given greater restrictions on both tobacco use and tobacco advertising in recent years, regular tobacco-only use (i.e., daily smoking) is less prevalent for adolescents than in decades past (Wakefield et al., 2008). Moreover, without implying causation, tobacco use has also been associated with higher levels of psychopathology (Talati et al., 2013). Given that numerous psychiatric disorders emerge during adolescence (Paus et al., 2008), one could argue that the tobacco-only group may comprise a subset of youth who might be transitioning into psychiatric illness or symptoms (potentially including addiction), and for whom the unique pattern of neural activation during the MID task may be a biomarker (e.g., Whelan et al., 2014; Pizzagalli et al., 2009; Guyer et al., 2012). However, the absence of diagnostic data on this sample precludes definitive conclusions on this possibility. Rather, this is a crucial direction for further work in this area. It is also unclear whether decreased reward responding among tobacco users develops over time as a result of tobacco exposure or represents a neurobiological vulnerability factor for initiating and sustaining smoking (Dagher et al., 2001). Because the participants in this sample are adolescents, and thus relatively new smokers, these results are consistent with the idea that lower reward sensitivity (at least among youth who only use tobacco) may represent a risk factor, at the very least, for initiation and maintenance of regular smoking. Regarding the potential impact of personality factors on reward responding during the MID, we did not observe differences in impulsivity across any of the groups. One interpretation of this finding may be that as a group, high-risk adolescents such as those included herein, demonstrate high levels of impulsivity (White et al., 1994) and substance use (Chassin, 2008), so differences in impulsivity are not apparent across substance use groups due to ceiling effects. Here, all adolescents within each group scored high on impulsivity, suggesting that impulsivity may not be the temperamental feature that differentiates reward processing by substance subgroup for this population. Among polysubstance users, incentive-elicited NAcc responses in the cannabis+tobacco and cannabis+tobacco+alcohol groups showed a stronger parallel to non-substance-using youth than to single-substance users (namely those who only use tobacco). These data are in line with prior studies showing that brain structure among youth who exhibited recent binge drinking and cannabis use were more in line with non-using youth, as compared to alcohol-only users (Jacobus et al., 2009). Although that was not the precise pattern observed here, one interpretation of our findings is that experimentation with multiple substances might be more developmentally typical. Consequently, it may be the case that youth who move toward selecting only one substance, which may be more unusual in this age group, may use for reasons of pre-existing neural risk (e.g., family history; genetic risk factors) rather than due to the social reasons that support or drive more normative adolescent explorations of substance use in this age range. In the present study, we did not explore any potential underlying vulnerability factors (e.g., family history, genetic risk), however, this is an important next step needed to address causation in future studies.