In the present pilot study, we investigated subject reward processing and the COMT Val158Met polymorphism in abstinent cannabis-dependent inpatients and individuals who smoke with the well-established reward paradigm of the MID Task and found the commonly activated brain regions for this task (Table 4; 37). The aim was to take reward processing into account dimensionally across different forms of addiction, rather than only focusing on overarching mental disorder categories. The study focused on the application of the RDoC as well as the feasibility to assess subject reward processing.

Subjective reward processing did not differ between nicotine and cannabis in any dimension. Nonetheless, the results suggest that the most likely dimensions for differences in a larger sample are effort gain and satisfaction about gain. Because of the small sample size and other methodical limitations, the claim was not to draw a statistical inference for genetic neuroimaging and the sample size was set to a minimum of 24 participants. The sample size should not have been set in terms of cannabis and nicotine use, but the COMT genotype. In the total sample, homozygotes for 158Met were not more satisfied with the achieved gain than carriers of the other genotypes, which is probably due to the sample size. However, genotypes nominally differ for cigarettes per day and motivation with the highest number of cigarettes and the lowest motivation rank for homozygotes of 158Met. Tentatively, one might assume that homozygotes for 158Met may have less negative subjective effects of nicotine and thus smoke more (38). Reduced motivation in homozygotes of 158Met has previously been found in men of a Swedish sample (39). For individuals who smoke, cigarettes per day and motivation correlated negatively. The profile of nicotine changes from stimulant to sedative with increasing dosage (40). The present correlation can thus be attributed to the “Nesbitt’s paradox” (38). Cannabis also affects motivation (41). Therefore, cigarettes and motivation were putatively not associated with cannabis dependence. In individuals who smoke, cigarette use correlated negatively and motivation positively with the activation of the right inferior frontal gyrus during feedback no loss. The right inferior frontal gyrus has been assigned to self-control, reward prediction errors, and sensation seeking and high sensation seekers are less sensitive to punishment (42–45). Higher cigarette use may hence imply lower self-control and response inhibition. Moreover, the present results suggest that motivation may be high precisely when predictions do not occur regardless of negative consequences.

For anticipation gain vs. loss, individuals who smoke had increased activation of the right insula compared with cannabis dependents. Acute THC increases perfusion in the insula with stronger increases for Val/Met heterozygotes (46). In anticipating rewards, insula activation is associated with motivational salience and sensitivity to reward magnitude (47, 48). Acute nicotine sensitizes and chronic smoking enhances the right insular response to gain and loss anticipation (11, 49). In contrast, activation of the left insular is reduced through acute cannabidiol and correlates with the salience of reward anticipation (48). The different contrast of anticipation gain vs. loss in the present study rather than gain vs. neutral cues in previous studies could be due to the diminished success probability of 50% (37). The current results suggest an overall desensitizing effect of the co-use of nicotine and cannabis on the insula and a decrease in salience for reward anticipation.

For feedback gain, individuals who smoke had increased activation of the right insula compared with cannabis-dependent inpatients. For reward feedback, the insula is involved in affective responding (37). The right anterior insula mediates interoceptive awareness (50). It integrates affective value with bodily states for reward-related adaptive behavior (51, 52). In the total sample, the activation of the right insula during feedback gain correlated negatively with gain expectancy and positively with satisfaction about the achieved gain. This finding indicates that the right insula interconnects gain expectancy with the evaluation of the reward-related performance and outcome independent of the substance. Additionally, the gain of the second test run correlated negatively with gain expectancy and positively with satisfaction. Higher gain expectancy at the beginning reduces reinforcement and thus motivation over the course of the MID Task, which impairs task monitoring and performance. Moderate or lower expectations have the opposite effect and therefore increase satisfaction with the outcome. The insula and interoceptive awareness are also crucial for drug cravings (53–55). The insula elicits conscious interoceptive urges, such as drug craving in response to rewarding and drug stimuli, respectively. For cannabis-dependent inpatients, gain expectancy correlated negatively with satisfaction and abstinence. Satisfaction correlated positively with consumption. These associations suggest a sensitizing effect of cannabis on subjective reward processing with an increase in gain expectancy and satisfaction. The dose-dependent increase in satisfaction is putatively due to the acute psychoactive effect of cannabis (56). Acute subjective changes in relaxation and perception caused by cannabis are also related to its effect on the insula (46). Positive subjective drug expectancies impair decision-making of addicted patients (57). The impairment consists of an overreliance on habits at the expense of goal-directed behavior and may be particularly symptomatic for early abstinence. As subjects had no experience with the MID Task (7), rationally, they should have quoted a middle gain expectancy. The negative correlation between abstinence and gain expectancy confirms drug-associated habitual biases during early abstinence. Moreover, insular functioning is highly dependent upon dopamine transmission and aberrant activation indicates impaired cue processing (58). Higher-than-predicted rewards generate positive prediction errors and elicit brief dopamine activations, whereas lower-than-predicted rewards generate negative prediction errors and induce decreases in activity (12). Accurately predicted rewards do not change the activity. For cannabis-dependent inpatients, gain expectancy correlated negatively with the activation of the right anterior cingulate cortex during the anticipation of gain vs. loss. The anterior cingulate cortex is involved in error monitoring and is affected by nicotine and cannabis (59, 60). For error monitoring, the expectation about an action is compared with the outcome and a deviation elicits the correction of behavioral responses (61). Any expectancy such as the current gain expectancies distract per se from task performance. Higher gain expectancies may additionally shift and bias attention toward cues for monetary gain under the neglect of losses. In consideration of the diminished success probability of 50%, however, it is just as important to avoid losses, as it is to gain money. Increased activity of the anterior cingulate cortex may suggest that cannabis-dependent inpatients with lower gain expectancy differentiated more effectively between gain and loss cues and thus, equally focused on and endeavored to avoid losses.

At first glance, the assessment of subjective reward processing seems exceptionally challenging. Subjective reward values such as preferences, needs, or emotional valence are unobservable, highly individual, and thus indefinable by physical reward parameters (12). In the present study, this issue was methodically resolved with visual analog scales (VAS) or self-reports, comparable reward cues, and a constant reinforcement rate. The variable gain instead of a predefined gain for all subjects was a limitation of the study. Nevertheless, the results suggest that subjective value is not completely detached from reward parameters, but a quotient between value and parameter: previous gain expectancies namely modulate the subsequent reward evaluation. Abnormalities in reward processing are prototypical for addictions and comprise a sensitizing effect of cannabis on subjective reward processing with an increase in gain expectancy and satisfaction according to the present results. Higher gain expectancies, whether cannabis-induced or not, reduce reinforcement, motivation, and satisfaction of the outcome and the insula might function as an inverse balance between expectation and satisfaction. The COMT Val158Met polymorphism might influence motivation. Any expectation distracts from task performance by affecting error monitoring and response correction of reward-related behavior negatively. Addiction research suggests that expectations or biases might be traced back to the overreliance on habits at the expense of goal-directed behavior. The same bias and overreliance on habits were reported for non-clinical obsessive-compulsive symptoms (62). Obtaining goals or basic needs in an appropriate manner is rewarding, and the pursuit of a goal defines motivation (4). Therefore, cognitive biases and the underlying neural mechanisms of error monitoring, response correction, and goal attainment might be the most fundamental target points of mental functioning and treatment.

In the RDoC framework, subjective reward processing can be assigned to the domain of the negative and positive valence systems. The COMT Val158Met polymorphism, the reward system including the insula, performance in the MID Task, and self-reports were utilized as units of analysis. Subjective value is not detached from reward parameters but is a modulated from expectancy and reward by the insula. The insula is crucial for the interconnection of expectance and evaluation and aberrant activation might imply incongruence. Cognitive biases and the underlying neural mechanisms are thus the most fundamental target point for treatments, interventions, and cognitive behavioral therapy in further research. Examples of initial approaches are Cognitive Bias Modification and Emotional Bias Modification (63–65). These approaches are likely to be intensively extended and to be future of RDoC diagnostics and predominantly neural psychotherapy.