<italic>COMT</italic> Genotype and Self-Regulation Interactions: Pathways to Psychological Vulnerability

The present series of studies offers a perspective on how a particular functional genetic polymorphism, COMT Val158Met, interacts with individual differences in self-regulation to affect the mechanisms underlying successful versus unsuccessful goal pursuit. Individual differences in the mechanisms that underlie self-regulation can be understood as more or less beneficial for goal pursuit depending on the context. For example, relatively high levels of cognitive flexibility can facilitate self-regulation in certain situations (e.g., where a new strategy needs to be employed) but can be detrimental in others (e.g., where excessive flexibility results in distraction from continuing efforts needed to attain the goal). The functional role of the COMT Val158Met polymorphism can also be conceptualized as a trade-off where the adaptiveness of the Val- or Met-like dopaminergic signaling profiles is determined by features of the environment as well as by the individual's goals. By integrating across biological and behavioral levels of analysis, we can expand our understanding of individual differences in tendencies for successful versus unsuccessful self-regulation. In particular, COMT by self-regulation interactions constitute a particularly fruitful line of investigation to better understand goal pursuit, mood, and vulnerability.

Self-regulation is a theoretical construct that can be used to integrate behavioral findings with research on neurobiological processes and genetic variation, particularly COMT, in order to more fully examine behavior across multiple levels of analysis. Individual differences in self-regulation have been shown to have reliably identifiable neural correlates (e.g., Eddington, Dolcos, Cabeza, Krishnan, & Strauman, 2007), and many of the factors contributing to successful or dysfunctional goal pursuit have their basis in psychological processes directly affected by COMT. Some of these processes under investigation here include responding to rewards, utilizing feedback, and flexibly changing a pattern of responses under motivationally challenging conditions. There are also trait-like differences in neural network connectivity based on the interaction between COMT and self-regulatory variables.

The three studies that comprise this dissertation examined how COMT genotype can moderate the effect of previous regulatory experiences (i.e., success or failure at achieving one's personal goals) on behavior and brain function, using regulatory focus theory (Higgins, 1997) as a model of self-regulation. The first study (Goetz, Hariri, Pizzagalli, & Strauman, 2013) examined how one's experience of successful goal pursuit moderated the impact of COMT genotype on reward responsive behavior. This experiment utilized a probabilistic reward task to measure the participants' ability to alter their behavior in response to reinforcement, which serves as an index of their sensitivity to environmental feedback of success. This responsiveness was seen particularly for those individuals who have had previous experiences of success pursuing rewarded goals if they also had the COMT Val/Val genotype, which is associated with more flexible behavior.

The second study (Davis, Tharp, Hariri, & Strauman, in preparation) used priming to create a motivationally salient context of either promotion (related to ideal goals) or prevention (related to ought goals) in order to assess genotype group differences on a cognitive control task. The results showed that relatively flexible Val/Val individuals exhibited behavioral slowing when challenged by a motivational context that requires vigilance, i.e., after priming by a prevention failure. By contrast, relatively rigid Met/Met individuals exhibited behavioral slowing in response to a context that demands eagerness and openness to opportunities for positive feedback, i.e., after priming by a past promotion failure experience.

The third study explored how the interaction of COMT and regulatory focus variables may reveal insights into resting state neural network connectivity, ultimately leading to a deeper understanding of individual differences in goal pursuit behavior. Several nodes within the executive control and default mode networks show different patterns of connectivity based on previous goal pursuit success, COMT genotype, and their interaction. Because the neural networks that underlie successful goal pursuit are also moderated by COMT genotype, we can conclude that behaviors relevant to goal pursuit, such as the reward responsive and cognitive control behaviors explored in the previous studies, are likely supported by trait-like systems instantiated at the level of the brain. This provides further justification for exploring the interplay between COMT genotype and the promotion and prevention self-regulation systems, and points to several future directions of behavioral and fMRI investigation.