The goal of this proof-of-concept study was to examine how regulatory focus and a common functional polymorphism affecting DA signaling predicted behavior in a probabilistic reward task. The results confirmed our hypothesis that rs4680 genotype, which biases COMT function and associated DA signaling in the PFC, moderates the degree to which a particular pattern of self-regulatory success experiences affects reward responsiveness. Specifically, our results showed that the combination of success in promotion goal pursuit and Val/Val genotype appears to facilitate responding to reward opportunities in the environment. On the other hand, Met allele carriers did not show an association between regulatory success in pursuing promotion goals and developing a reward-related response bias in our task.
Research examining the nature and consequences of self-regulation may provide a context for interpreting the present findings, both from the perspective of basic science and in regard to potential pathways of vulnerability for mood disorders. For example, we suggest that it is important to recognize that the observed associations among regulatory focus, rs4680 genotype, and reward responsiveness are not readily apparent at the phenotypic level. There was no broad association found between rs4680 genotype and self-regulatory style. This finding is consistent with previous research indicating that regulatory orientation is primarily shaped by accumulated experience with success or failure in goal pursuit and is independent from biological factors such as temperament , and also with the fact that variability in both mechanisms involves trade-offs that manifest in context-specific ways.
In this study, we hypothesized that an interaction of rs4680 genotype and self-regulatory style would result in predictable effects on responses to probabilistic reward feedback. The reward task yielded a reliably quantifiable measure of reward responsiveness, that is, participants’ propensity to modulate behavior as a function of prior reward. Individuals who are more responsive to reward feedback will preferentially select the more frequently rewarded stimulus and thus manifest a stronger response bias across the task. As noted previously, the task is promotion-consistent because outcomes are presented to participants as gain/non-gain – to earn money (instead of to “avoid losing” money). Therefore, individuals who believe that they are successful at achieving promotion goals should manifest a response bias that favors the more rewarded or “rich” stimulus. Interestingly, we did not observe a main effect of rs4680 genotype or promotion orientation on reward responsiveness. Rather, the effect of a history of promotion success on reward responsiveness was found to be moderated by rs4680 genotype (specific to the Val/Val genotype group).
The pattern of findings revealed a terminative interaction, where among individuals reporting relatively low levels of success pursuing promotion goals, the Val/Val genotype was associated with significantly lower response bias than in Met allele carriers. However, among individuals reporting frequent success experiences in the promotion domain, the Val/Val genotype was associated with mean response bias that did not significantly differ than that observed for Val/Met or Met/Met genotypes. Self-reported promotion success did not predict response bias among Val/Met or Met/Met genotypes, which also did not differ from each either. Thus, no Met allele dose effect was observed either as a main effect or as an interaction.
This pattern of results corresponds with the trade-off framework for interpreting COMT-related variability in reward sensitivity that was described above. The Val/Val individuals who reported low levels of promotion success demonstrated significantly lower total response bias scores than Met allele carriers. There is the possibility that Val/Val individuals are more susceptible to fluctuations in DA when rewards are omitted and therefore have greater difficulty integrating reward-related information over time. This would be an example of flexibility and behavioral adaptability being disadvantageous within a particular context, and such a neurobiological profile would be especially maladaptive given a personal history of low promotion success. Thus, Val/Val individuals with low promotion success might constitute a group of individuals who would be particularly vulnerable to anhedonia or reward insensitivity in the face of chronic promotion failure experiences. There is evidence that Val/Val individuals show decreased responsiveness to reinforcers [28, 29], and reduced motivational drive to pursue reinforcers would interfere with successful promotion goal pursuit.
The fact that Met allele carriers did not show modulation of their response bias based on their degree of success in pursuing their promotion goals fits with a “resilience” model. Even in the context of low promotion success, individuals with higher tonic PFC dopamine (Met allele carriers) did not manifest low levels of reward-responsive behavior. However, there is a competing interpretation: that Met allele carriers are not able to increase reward-related responding based on their previous goal-pursuit experiences, which might adversely affect the pursuit of promotion goals. Such an alternative hypothesis is consistent with previous findings of cognitive [24, 25] and affective  inflexibility associated with the Met allele. There may be some relative deficits in reward-related responding for Met allele carriers who have had successful self-regulatory experiences, because those individuals with high promotion success scores exhibited only average response bias scores. The Met allele carriers might have an inability to update or adapt behavior via reward feedback that could create some vulnerability in the face of future self-regulatory challenges or failure experiences.
The results from this study illustrate that an integrative approach to COMT variability and self-regulation has the potential to reveal novel pathways of psychological vulnerability. Self-regulation involves a complex set of processes including goal selection and pursuit, cognitive and emotional control, and ongoing decision-making . Factors such as reward responsiveness, impulsivity/distractibility, and affective resilience can impact how goals are pursued and how feedback about progress is managed, and individual variability in COMT has been shown to affect all of these processes. A research strategy that applies individual differences information from genetic sources to studies of ongoing, situationally-embedded self-regulation might yield context-sensitive examples of when these processes break down and produce regulatory dysfunction and, possibly, clinical disorders.
Regions in the PFC, particularly the OFC, are involved in responsiveness to motivationally salient feedback and shifts in goal pursuit originating from bottom-up processes (e.g., ) as well as top-down processes (e.g., ). Thus, the OFC is likely to be a site that mediates the interaction between individual differences in regulatory focus and rs4680 genotype to produce reward-related behavior, and at least one study  has observed that clinically depressed individuals manifest attenuated left OFC activation in response to their own promotion goals.
The significant interaction between promotion success and rs4680 genotype was detected even in the hierarchical multiple regression models that included other regulatory focus variables as covariates. These analyses were particularly important to differentiate promotion success from prevention success, which were substantially correlated (r=.74, p<.001). Despite the intercorrelation, it was success in attaining promotion goals, and not successful prevention goal attainment, that predicted reward responsiveness for the Val/Val genotype. RFT postulates fundamental differences between the promotion and prevention systems with regard to the targets of goal pursuit (e.g., “ideals” vs. “oughts”), the strategies used to pursue them (“making good things happen” vs. “keeping bad things from happening”), and the motivational impetus that underlies goal pursuit (eagerness vs. vigilance). These behavioral and cognitive distinctions appear to be accompanied by differences in cortical activation when promotion vs. prevention goals are primed [11, 13], although additional research is needed to characterize the shared and unique neural circuitry associated with these two hypothetical cognitive/motivational systems. Such research, in combination with a genetic/neurobiological level of analysis, could help to elucidate pathways by which self-regulatory dysfunction could lead to the onset and maintenance of mood disorders.
There are several limitations of this study that should be acknowledged. First, the relatively small sample size leaves us vulnerable to statistical noise including false positives. However, this is more problematic in the absence of significant effects (i.e., false negatives), which could simply reflect inadequate power, and thus one should use caution when interpreting non-significant results such as the lack of main effects. The fact that we found significant effects robust to the influence of covariates suggests the observed interaction between self-regulatory style and rs4680 genotype is valid. Nevertheless, replication of the effects described herein is necessary to further the possible utility of our interaction model for understanding clinically relevant outcomes (e.g., risk for mood disorders). Second, because the genetic analyses were restricted to a Caucasian-only sample, generalizability may be limited. It will be of interest to examine this effect in non-Caucasian samples. Third, although the task provided a well-validated operationalization of the experience of responding to reward feedback, its external validity as a proxy of goal pursuit behavior is understandably limited. Previous studies of the neurobiological substrates underlying regulatory focus relied on idiographic stimuli that captured individuals’ personal goals [11, 13], and the degree to which earning money was a goal of the participants in this study was implied by their participation but not explicitly verified. A future study could extend these findings by obtaining genetic information on participants who undergo neuroimaging when exposed to their goals, or using another kind of goal-pursuit task such as anagram solving that is related to perseverance and conscious decision-making about effort and motivation. In addition, a future exploration of these effects should include measures of potential important contributory variables such as stressful life events (particularly during development) and state-level anxiety, as these both could impact the development and manifestation of one’s regulatory focus.