Anticipatory and Hedonic Reward Response in Major Depression: Underlying Molecular Correlates and Relationship with Treatment Outcome

Abstract

Reward encompasses multiple psychological processes, including motivation to earn a reward and the hedonic enjoyment of a reward. Animal and human research supports roles for the dopamine and mu-opioid systems in facilitating motivation and hedonics, respectively. Loss of interest (apathy) and pleasure (anhedonia) are core symptoms of Major Depressive Disorder, and patients often present with impairments in one or both of these reward processes. Patient studies suggest that the cortico-striatal network shows disordered responses to reward processing and particularly implicate altered dopamine and opioid function. However, gaps in understanding remain: 1) individual differences in the relationship between reward response and neurotransmitter function in depression and 2) the value of reward response as a predictor of antidepressant treatment response are both important areas for investigation.

This dissertation takes a multimodal neuroimaging approach to investigate the molecular and clinical correlates of disordered reward processing in depression. We utilized two modalities: 1) a well-validated reward paradigm during functional magnetic resonance imaging (fMRI) acquisition to measure neural response to anticipatory and hedonic reward in depressed patients and 2) positron emission tomography (PET) scans to measure dopamine and mu-opioid receptor binding. Participants subsequently completed a 10-week antidepressant treatment regimen.

We investigated the relationship between striatal fMRI responses to reward and DA 2/3 and mu-opioid receptor binding. We replicated fundamental relationships previously established in the literature: we showed that striatal response to reward anticipation is associated with striatal dopamine release and D2/3 receptor availability, whereas striatal response to reward outcome is associated with mu-opioid receptor availability in the thalamus. Furthermore, anterior cingulate response to reward anticipation mediates a previously-established relationship between nucleus accumbens mu-opioid function and antidepressant treatment response.

These results further elucidate the molecular correlates of reward anticipation and hedonics in major depression and establish the anterior cingulate as a mediator of the relationship between mu-opioid function and recovery from depression.