Parsing anhedonia: effort-based decision-making as a translational model of motivational deficits in Major Depressive Disorder

Abstract

Major Depressive Disorder (MDD) is a persistent, severe mental disorder with approximately 16% lifetime prevalence. Anhedonia has long been recognized as a core feature of the disorder. Described as a reduction in the interest or enjoyment derived from pleasurable activities, clinical assessment of anhedonia has primarily relied on clinician-rated or self-reported hedonic responses to past experiences or laboratory stimuli, despite the well-established clinical observation that anhedonia is often accompanied by reductions in motivation. The lack of attention to possible motivational deficits in anhedonia has hindered efforts to uncover the pathophysiology of this debilitating symptom, as substantial preclinical evidence suggests that motivational and consummatory aspects of reward processing possess distinct neurobiological substrates. In particular, the mesocorticolimbic dopamine (DA) system has long been hypothesized to play a role in the pathophysiology of anhedonic symptoms, but empirical validation of this hypothesis has remained elusive. In this dissertation, I suggest that the lack of a clear demonstration of DA dysfunction in anhedonic depression may result from the reliance on measures of anhedonia that primarily emphasize the subjective experience of pleasure, while preclinical data strongly implicate DA in primarily motivational aspects of reward processing. To address this issue, I introduce a novel behavioral measure that may be used to address motivational deficits in patient populations experiencing anhedonia. Dubbed the Effort Expenditure for Rewards Task (EEfRT or “effort”), this measure was adapted from preclinical effort-based decision-making paradigms that have been successfully used to demonstrate the role of DA function in determining an organism’s willingness to expend physical effort in pursuit of a given reward. Over three empirical studies, I demonstrate that the EEfRT is sensitive to individual differences in reward motivation, which are in turn linked to anhedonic traits, human DA function and clinical depression. The results of these studies offer novel insights into the neurobiological mechanisms underlying motivational aspects of anhedonic symptoms, with important implications for future treatment and prevention.