Average beta weights from eight clusters showing a significant difference between groups were extracted using MarsBaR and imported into IBM SPSS Statistics v22 for further analysis.In addition,amygdala activation was examined based on a prior study of marijuana use and emotional processing.A mask of left and right amygdala was created using the automated anatomical labeling atlas in Wake Forest University Pickatlas.A threshold of p <.05 was used.In the whole-brain two-sample t-test,the heavy marijuana users had less activation compared with controls during NEG in four clusters: right middle frontal and dorsolateral superior frontal gyri,right middle and superior temporal gyri,right calcarine fissure and surrounding cortex,including cuneus and lingual gyri,and right superior temporal gyrus and insula.During POS,heavy users had less activation in the right inferior parietal lobe and increased activation in the right dorsolateral superior frontal gyrus relative to controls.In the amygdala region of-interest analyses,ebb flow heavy users had less activation in the right and left amygdalae during NEG and in the right and left amygdalae during POS compared with controls.See Table 3 for all whole brain and region of interest results.To determine whether differences in activation to neutral words were impacting these group differences,we conducted an independent samples t-test in SPM8 using the contrast of neutral words vs.rest.Partial correlations between brain activation and emotional functioning at scan time and at follow-up are reported in Table 4.There were negative correlations between negative emotionality measured at scan time and activation in right STG/insula and left amygdala during NEG.There was also a negative correlation between negative emotionality at scan time and activation in right amygdala during POS.
Positive correlations were observed between resiliency measured at follow-up and activation in caudal dlPFC and cuneus/lingual gyrus during NEG.A negative correlation was observed between negative emotionality at follow-up and activation in caudal dlPFC during NEG.No other correlations passed correction for multiple comparisons.Mediation analyses therefore focused on these two brain regions and resiliency and negative emotionality at follow-up.The goal of this work was to investigate the impact of heavy marijuana use during adolescence on later emotional functioning,as well as potential brain function mediators of this effect.Using a prospective design,we investigated two outcomes related to emotional functioning: negative emotionality and resiliency.We found that heavy marijuana users did not differ from controls in emotional functioning early in adolescence when marijuana use was initiated,whereas in late adolescence/early adulthood,heavy users had more negative emotionality and less resiliency than controls.To investigate the impact of adolescent marijuana use on emotion-related brain functioning,we compared neural responses to emotional words in heavy marijuana users and controls.Compared with controls,heavy users had less activation in emotion processing and integration regions,including the right insula,prefrontal cortex,and occipital cortex during the viewing of negative words,and in a region involved in attentional control during the viewing of positive words.Further,we found heightened activation to positive words in the dorsolateral prefrontal cortex among heavy users.Activation in prefrontal cortex during the viewing of negative stimuli mediated an association between marijuana use and both negative emotionality and resiliency at follow-up.
Activation in visual association regions of the occipital cortex mediated an association between marijuana use and later resiliency,but not negative emotionality.A main finding of this prospective study is that marijuana use in adolescence may impact later emotional functioning.Heavy marijuana users scored higher on negative emotionality than controls at the approximate ages of 20 and 23,whereas groups did not differ at approximately age 13,when heavy users initiated use.Furthermore,exploratory analyses revealed that negative emotionality decreased from early adolescence to young adulthood in controls—consistent with normative changes —but not in heavy users.Importantly,we observed an association between greater lifetime marijuana use occasions and higher negative emotionality at age 20,after controlling for early levels of negative emotionality.These findings are in line with other longitudinal work showing that adolescent marijuana users had increased depression,anxiety,and suicidality in young adulthood,but marijuana use was not associated with premorbid differences in negative affect.Thus,the current results add to previous work supporting an association between early marijuana use and later negative affectivity.We also investigated the impact of marijuana use on resiliency,as self-regulation plays a critical role in emotional functioning.We found no difference between groups in resiliency at the age of marijuana initiation,whereas differences emerged in late adolescence/early adulthood,with lower resiliency in the heavy use group.Although conceptualized as a temperament/personality trait,evidence indicates that resiliency improves throughout adolescence and into adulthood in healthy individuals.Furthermore,lifetime occasions of marijuana use was negatively correlated with resiliency,even after taking into account early level of resiliency.Resiliency is inversely related to depression and internalizing problems in children and emerging adults,and positively related to effective social interaction and social status.A reciprocal longitudinal relationship has been demonstrated between resiliency and positive emotionality from adolescence to early adulthood,as well as with the effective management of negative emotions.
It is possible,therefore,that adolescent marijuana use may impact emotional functioning partially through an influence on resiliency; however further work in a larger sample is required to determine these longitudinal relationships.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 cortex 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 and is closely connected with motor and supplementary motor regions.Prior work has found activation of the caudal dlPFC and associated regions during the reading of high-arousal emotional words.The supplementary motor and premotor regions are important for emotion processing and empathy and may regulate approach-withdrawal tendencies to emotional stimuli by integrating limbic and motor responses.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.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,high-arousal emotional words,and emotional film clips,pot drying as well as the evaluation of one’s own emotional state.Cuneus activation has also been associated with the ability to attribute mental states to others,termed “theory of mind”.
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.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.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.Furthermore,studies of adult marijuana users found less activation in the insula to loss outcomes during a monetary incentive task and to errors in an inhibitory control task 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.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.Insula activation has also been associated with self-report measures of anxiety and anticipation of aversive exposure 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.Activation of the amygdala was also reduced in heavy marijuana users compared to controls—an effect observed for both negative and positive words.Along with the insula,the amygdala is part of a network involved in translating interoceptive responses to emotional stimuli into emotional experience.Blunted amygdala response has been observed in individuals with difficulties experiencing and processing emotions.Acutely,cannabidiol,a psychoactive component of cannabis,has been shown to decrease amygdala activation to anxiety-inducing emotional stimuli; this effect was further associated with a reduction in electrodermal activity,supporting links among marijuana,amygdala functioning,and interoceptive response to emotion.Furthermore,prior evidence indicates that the impact of marijuana use on amygdala-mediated emotional responding is not restricted to negative stimuli.Gruber et al.reported less amygdala activation in adult heavy marijuana smokers compared with controls to both happy and angry faces presented below the level of conscious processing.Here we found less amygdala activation to both positive and negative words in heavy marijuana users compared with controls,which further correlated with negative emotionality.Therefore,marijuana may have an impact on amygdala functioning that impairs general emotional arousal and integration.
The finding of an association between negative emotionality and reduced activation of the insula and amygdala is opposite to effects described in the depression and anxiety literature,which reports enhanced activation to negative stimuli.However,a longitudinal study of individuals with comorbid major depression and marijuana dependence found that greater marijuana use was associated with reduced amygdala activation to emotional stimuli.This suggests that the mechanism through which marijuana impacts negative emotionality differs from the mechanism underlying depression and anxiety.For example,the associations between insula and amygdala functioning and negative emotionality in the current study may be more pertinent to differences in the experience and processing of emotions rather than depression and anxiety.Finally,heavy marijuana users showed reduced activity in the right inferior parietal lobule and greater activation in the right dlPFC during the viewing of positive words.The inferior parietal cortex is part of an attentional system involved in the automatic allocation of attention to task-relevant information,whereas the dlPFC is involved in more effortful attentional control.Thus,the current results suggest a decrease in automatic attention to positive words in heavy users with a corresponding increase in effortful attentional control necessary to attend to the task.This is consistent with prior work demonstrating heightened activation of right-hemisphere prefrontal attentional control circuitry in adolescent marijuana users,which may reflect the need for increased effort in attending to task-related stimuli.The results of this study should be considered with a few limitations in mind.First is the relatively small sample size,suggesting that results should be interpreted as somewhat preliminary,and further,that additional differences between groups may have been missed.Furthermore,although there is evidence of sex differences in the impact of marijuana on emotional functioning,this study was not adequately powered to investigate sex as a moderator.It will be important to address this issue in future work.Second,the control group included individuals who had occasional marijuana use in adolescence.The impact of low levels of marijuana use on brain development is not known; therefore an ideal control group would have no marijuana use.However,given the high levels of comorbid alcohol and marijuana use in adolescence,it was infeasible to create a marijuana-naïve control group while maintaining similar levels of alcohol use across groups.Third,the majority of participants in this study had a family history of AUD,which may limit the generalizability of results to those at heightened risk for behavioral and emotional problems.Using aprospective design,we found that heavy marijuana users who began using in adolescence had higher negative emotionality and lower resiliency in their early twenties.Furthermore,differences in neural responses to emotionally-laden words mediated the associations between marijuana use and later negative emotionality and resiliency in these subjects.Because marijuana use is on the rise while perceptions of harm are decreasing,this is timely work.It adds to a growing body of evidence pointing to adverse effects of adolescent marijuana use on emotional functioning and is the first to characterize the functional neural correlates of these effects prospectively.