The default mode network and self-referential processes in depression

Abstract

The recently discovered default mode network (DMN) is a group of areas in the human brain characterized, collectively, by functions of a self-referential nature. In normal individuals, activity in the DMN is reduced during nonself-referential goal-directed tasks, in keeping with the folk-psychological notion of losing one's self in one's work. Imaging and anatomical studies in major depression have found alterations in both the structure and function in some regions that belong to the DMN, thus, suggesting a basis for the disordered self-referential thought of depression. Here, we sought to examine DMN functionality as a network in patients with major depression, asking whether the ability to regulate its activity and, hence, its role in self-referential processing, was impaired. To do so, we asked patients and controls to examine negative pictures passively and also to reappraise them actively. In widely distributed elements of the DMN [ventromedial prefrontal cortex prefrontal cortex (BA 10), anterior cingulate (BA 24/32), lateral parietal cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but not control subjects, exhibited a failure to reduce activity while both looking at negative pictures and reappraising them. Furthermore, looking at negative pictures elicited a significantly greater increase in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed than in control subjects. These data suggest depression is characterized by both stimulus-induced heightened activity and a failure to normally down-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.

Fig. 1.

Task-induced activity in the default mode network. The DMN is shown in light blue. The top left image shows the medial surface right hemisphere whereas the top right image shows the lateral surface left hemisphere. The bottom left shows the lateral surface right hemisphere whereas the bottom right image shows the medial surface left hemisphere. All regions are shown in Table 1 (group differences) or Table S1 (regions without group difference effects). As indicated by the legend, superimposed red colored regions show areas within the DMN where task-induced differences distinguished depressed and control subjects. The remaining regions had no group differences but had activity decreases in the regulate condition only (yellow), in the look condition only (green), in both the regulate and look conditions (brown), or had activity increases in both the regulate and look conditions (fuschia).

Fig. 2.

Time–activity curves are shown for a subset of regions in Fig. 1. (A–F) Time–activity curves plot percent fMRI signal change (y axis) vs. time in seconds (x axis). Regions compare passive viewing of negative pictures to passive viewing of neutral pictures (look) (Upper), compare passive viewing of negative pictures to regulation of emotion (regulate), and time within trial that reflected modulations of task-related activation (Lower). (A–C) As indicated, there was less of a decrease in activity in depressed compared with control subjects in left ventromedial prefrontal cortex (BA10) (A), right rostral anterior cingulate (B), and left lateral temporal cortex (C). (D–F) There was a greater increase in depressed subjects in the look condition (Upper) for the left amygdala (D), left parahippocampus (E), and right hippocampus (F). The greater activity during the regulate condition (Lower) was only significant in the L parahippocampus. The regulate condition difference (Lower) was only significant in the left parahippocampus.

Fig. 3.

Anatomical connections of the medial prefrontal network in the macaque adapted from Saleem et al. (23). The superimposed ROI in red are the areas in the current study (also shown in Fig. 1) in which depressed subjects differed from controls. The medial prefrontal cortex and its connected regions are part of the DMN and have extensive interconnections with each other and visceral control areas.