Evidence that further clarifies the deficient

Evidence that further clarifies the deficient regulation of emotional reactivity by prefrontal control regions in MDD comes from studies of task-based functional connectivity (FC). Rather than examining which regions are more active in one task than another, FC examines the correlation of activity between jak stat pathway regions over time (either during tasks or during rest), with the assumption that strong correlations across time are indicative of communication between those regions in the performance of some function. Task-based FC measures, such as psychophysiological interaction (PPI) analyses (Friston et al., 1997), examine how FC between regions changes across different psychological task states. In the case of emotion regulation, this technique can demonstrate how the functional relationship between response and regulation regions changes between passive and effortful regulation states. If, during regulation, increased prefrontal activation is associated with decreased amygdala activation, this negative correlation may indicate prefrontal regulation of amygdala activity – an interpretation that is directly supported if task-based FC data shows that this pattern is more pronounced during regulation trials than passive viewing trials. Task-based FC studies of emotion regulation in MDD reveal a pattern of altered regulation of bottom-up processing regions, particularly the amygdala. One study found that during emotional reappraisal, adults with MDD showed a positive correlation between amygdala and VMPFC activity during reappraisal while controls showed the more typical negative correlation (Johnstone et al., 2007). In another study, adolescents with MDD showed more positive connectivity between the right amygdala and left MFG, hippocampus, posterior cingulate, and sACC than controls during emotional reappraisal. However, during maintenance of a negative emotion (no down-regulation necessary), control subjects showed more positive FC between amygdala and bilateral insula and right prefrontal regions than MDD (Perlman et al., 2012). Further, another study found that healthy adults showed strong coupling between the amygdala and right DLPFC during reappraisal, such that increased DLPFC activation was associated with decreased amygdala activation during reappraisal. In contrast, medicated MDD patients showed reduced coupling between those regions, with less DLPFC activation and less of a decrease in amygdala activity during reappraisal (Erk et al., 2010). Together, these task-based FC studies suggest that the negative correlation between prefrontal and amygdala activation that normally accompanies effective emotion regulation is diminished in MDD. While the above literature suggests the existence of differences between MDD and healthy groups in neural correlates of reappraisal, understanding individual differences in emotion regulation within MDD may further elucidate the factors underlying impaired reappraisal processes in this illness. In other words, although on average individuals with MDD are more likely to use maladaptive emotion regulation strategies such as rumination, there is important variation across individuals with MDD. As described above, brooding rumination is associated with attentional inflexibility (Whitmer and Banich, 2007) and impaired emotional disengagement (Vanderhasselt et al., 2011) – both key aspects of reappraisal. In healthy adults, greater use of brooding rumination has been associated with increased DLPFC activity during emotional disengagement, consistent with the hypothesis that increased attentional control may be required for disengagement in high ruminators (Vanderhasselt et al., 2011). In non-emotional conflict monitoring tasks, rumination in MDD adults has been associated with decreased amplitude of the N2 ERP component associated with recruiting cognitive control (Alderman et al., 2015). Further, induced brooding rumination in MDD adults is associated with greater activation in DLPFC, orbitofrontal cortex, and subgenual anterior cingulate (sACC) than in controls (Cooney et al., 2010), as rumination may make emotion regulation more difficult. The sACC is associated with self-referential thinking (Ochsner and Gross, 2005) and is considered part of the default-mode network. It is more active in the absence of cognitive tasks (Raichle et al., 2001), when individuals are more likely to focus on autobiographical thoughts (Mazoyer et al., 2001), but is down-regulated during cognitive tasks. Excessive sACC activity has been associated with symptom severity in MDD (Matthews et al., 2009), while deep brain stimulation inhibiting sACC activity in treatment-resistant MDD can lead to remission of depression (Mayberg et al., 2005). Thus, the association of increased DLPFC and sACC activation with rumination in MDD suggests that trait measures of rumination may be particularly closely associated with altered regulation of emotion in MDD.