Major depressive disorder (MDD) will soon represent the most costly and debilitating disorder in the world. Yet, a clear model of the mechanisms underlying MDD remains elusive. This lack of clarity obscures efforts to prevent and treat MDD more effectively. This dissertation seeks to advance an integrated model of the mechanisms underlying MDD across cognitive, neural, and genetic levels of analysis. Building on the empirical foundation of cognitive theories of MDD, the dissertation includes three studies that help address questions about the cognitive mechanisms underlying depression vulnerability and maintenance. Specifically, the three studies focus on identifying 1) how elaborative processing biases, including attentional biases and rumination, give rise to specific symptoms of MDD and 2) elucidating biological mechanisms that may give rise to these biases. Together, these studies help advance an integrated model of MDD that, ultimately, may help facilitate the prevention and treatment of this costly and debilitating disorder. / text

Background: The aim of this thesis was to investigate the relationship of moral cognition and emotions to the pathophysiology of major depressive disorder (MDD). Patients with MDD may experience excessive guilt or self-blaming biases despite recovery from the depressed state. Since guilt is a moral emotion thought to motivate altruistic behaviours, it has been hypothesized that elevated self-blame in MDD may result in pathological increases to altruism in some patients. The relationship of self-blame to altruistic choices in individuals with remitted MDD (rMDD), however, has not been established. Guilt has been shown to activate the subgenual cingulate and adjacent septal region (SCSR) which is of known importance to the pathophysiology of MDD. Since MDD is thought to arise from network-level dysfunctions, and moral cognition and emotions are hypothesized to emerge from network-level binding, investigating resting-state SCSR functional connectivity in rMDD patients and healthy control (HC) participants could reveal networks of potential relevance both to MDD and to moral cognition and emotions. Chapter 2: We investigated whether melancholic rMDD patients could be distinguished from non-melancholic and HC groups on the basis of resting-state functional connectivity to an SCSR seed region. Lower SCSR-amygdala connectivity distinguished the melancholic rMDD group from non-melancholic and HC groups. Chapter 3: We investigated whether patients who remained resilient to recurring depressive episodes were distinguishable from recurring episode MDD and HC groups on the basis of resting-state connectivity to an SCSR seed region. Lower interhemispheric SCSR connectivity distinguished the resilient MDD patients from the recurring episode MDD and HC groups. Chapter 4: We measured explicit and implicit preferences for social options with and without altruistic motivations relative to selfish options in the rMDD and HC groups during emotion priming to modulate feelings of guilt. The rMDD patients explicitly preferred prosocial options (i.e., social options and altruism directed towards friends or colleagues) less than HC participants. Regardless of group, guilt priming increased explicit and implicit preferences for altruism towards strangers. Chapter 5: We investigated whether explicit and/or implicit preferences for prosocial options during guilt priming were correlated with resting-state connectivity to an SCSR seed region, and whether this relationship could distinguish the rMDD and HC groups. Across all participants, implicit prosocial choice preference negatively correlated with connectivity between the SCSR and right temporoparietal junction (TPJ). The relationship of SCSR-TPJ connectivity to implicit preferences for social options and for altruism towards friends and colleagues was weaker in the rMDD group compared to the HC group, particularly for implicit altruism. Conclusions: We identified resting-state SCSR networks associated with vulnerability to melancholia and with resilience to recurring depressive episodes. Patients with rMDD explicitly preferred options entailing social withdrawal, a symptom associated with MDD vulnerability. Irrespective of group, guilt motivated altruism towards strangers but not friends and colleagues. Implicit prosociality was negatively associated with connectivity in a social agency network, and the comparatively weak relationships between connectivity and implicit choice preferences in rMDD patients may reflect a vulnerability factor for MDD.