Medial prefrontal cortex and the self in major depression

Self-focus (i.e. the process by which one engages oneself in self-referential processing) is a core issue in the psychopathology of major depression. The cortical midline structures, including the medial prefrontal cortex (MPFC), play a key role in self-referential processing in healthy subjects. Four functional magnetic resonance imaging studies recently found either an increased or a decreased MPFC activation during self-referential processing in depressed patients compared to healthy controls. Building on critical differences in experimental settings, we argue that these conflicting results are indeed consistent with two modes of elevated MPFC activation in major depression. An elevated tonic ventral MPFC activation, as uncovered by an event-related design, may embody automatic aspects of depressive self-focus, such as attracting attention to self-relevant incoming information. An elevated phasic dorsal MPFC activation, as uncovered by a block-based design, may embody more strategic aspects of depressive self-focus, such as comparing the self with inner standards. Additionally, strategic self-focus in depression may recruit the anterior cingulate cortex and more lateral regions of the prefrontal cortex. An aberrant functional connectivity of the dorsal MPFC may underlie this lack of reciprocal inhibition between the cognitive control network and the default mode network. Altogether, these results suggest that self-focus in depression may emerge as a process competing for brain resources due to a lack of inhibition of the default mode network, resulting in detrimental effects on externally-oriented cognitive processes. Follow-up studies are warranted to determine the trait vs. state nature of these biomarkers and their ability to predict treatment outcome.