This study aimed to explore the neural bases of the excessive self-focus in major depression. Because the main effects were not relevant to our hypotheses, we will focus on the group × condition interaction. Although both patients and healthy subjects activated the MFG (MNI coordinates: 6, 48, 18) during self-referential processing, the activation of a more dorsal part of the MFG (MNI coordinates: 9, 42, 33), henceforth referred to as dorsomedial frontal gyrus
, was unique to patients, as was the activation of the dorsolateral prefrontal cortex (DLPFC). The more ventral part of the MFG, which was equally activated by self-referential processing in both groups, was part of a larger functional network that was common to patients and controls and included the posterior cingulate cortex. These cortical midline structures are known to be active during both resting state and self-referential processing (Gusnard et al
; Lou et al
; Northoff et al
). There is a reciprocal modulation between these regions and the DLPFC in healthy subjects (Greicius et al
), whereas depressed patients actually displayed an increased functional connectivity between the MFG, the DLPFC and a region overlapping the dorsomedial frontal gyrus and the dorsal ACC. These results suggest that there is an abnormal reciprocal cortico-cortical modulation in major depression (Mayberg, 2003
; Seminowicz et al
The activation of the left DLPFC during self-referential processing, but only in patients, suggests that they require cognitive control during self-referential processing (Lieberman, 2007
). Although neuroimaging studies in depression have generally found decreased activity of the DLPFC at rest, activation studies have shown either increased or decreased activation of the DLPFC (Davidson et al
; Fitzgerald et al
). For instance, depressed patients need greater left DLPFC and dorsal ACC activation to maintain a level of performance similar to controls during a working memory task (Harvey et al
; Matsuo et al
The construct of self-focus was introduced by Duval and Wicklund (1972
) to account for the links between attention to the self and affect. Building on this early model, Carver and Scheier (1998
) proposed that self-focus leads one to consider the discrepancy between his or her current state and a salient standard. Positive affect is experienced if the current state surpasses the standard, whereas negative affect is experienced if the current standing falls short of the standard. Experiencing negative affect generates attempts either to decrease this discrepancy or to avoid self-focus. Depression may then occur when one is unable either to fix the discrepancy or to avoid self-focus (Mor and Winquist, 2002
Whereas the DLPFC is thought to implement cognitive control (Koechlin et al
), the dorsal ACC and the dorsomedial frontal gyrus are thought to implement conflict monitoring (Kerns et al
; Etkin et al
). Self-focus may represent a particular instance of conflict monitoring (Duval and Wicklund, 1972
; Carver and Scheier, 1998
; Mor and Winquist, 2002
), and the absence of any valence effect suggests that this conflict is between the current self and an inner standard, rather than between the current self and the stimulus itself. During the ‘self’ condition, positive and negative personality trait words may equally signal the absence of a personally meaningful state. For instance, the word ‘generous’ is just as likely to elicit self-focus (‘Am I not greedy?’) as the word ‘greedy’ itself. In depressed patients, the self-referential processing performed by the MFG may have required conflict monitoring by the dorsomedial frontal gyrus and the dorsal ACC, whatever the intrinsic valence of the presented word. The extended MFG activation and its increased connectivity with the dorsal ACC may then represent the neural correlates of a secondary compensatory mechanism rather than those of the excessive self-focus per se
. This excessive self-focus may have required further cognitive control by the DLPFC for at least two reasons.
When one's current self falls short of one's own standard, subsequent negative affect may generates attempts either to decrease the discrepancy or to avoid self-focus (Duval and Wicklund, 1972
; Carver and Scheier, 1998
; Mor and Winquist, 2002
). Thus, the dorsomedial frontal gyrus may have issued a call to the DLPFC to reduce the adverse emotional consequences of the discrepancy by either cognitive reappraisal or self-focus inhibition (Ochsner and Gross, 2005
). These two mechanisms may account for the greater functional connectivity between the MFG and the DLPFC in depressed patients. Indeed, a recent fMRI study suggests that depressed patient may activate a larger prefrontal network than healthy subjects during emotional regulation (Johnstone et al
). Further studies should investigate more specifically the role of the DLPFC in depressive self-focus.
A serious limitation of our study is that patients were receiving medications whereas healthy subjects were not. Therefore, our findings need to be replicated in unmedicated patients, as medications may partially account for them. However, sedative drugs were not allowed on the experiment day, and the patients were tested within the first week of receiving their antidepressant treatment. Furthermore, if antidepressants were accounting for the present results, the number of days under antidepressant prior to the study should have been correlated, even slightly, with the dorsomedial frontal gyrus or the DLPFC activity during self-referential processing in depressed patients. We did not find such a correlation, even with a very liberal statistical threshold. It is therefore unlikely that the group × condition interaction, which reached a 50-fold more stringent statistical threshold, was only explained by antidepressants.
Some other methodological limitations should be considered. First, 14 slices of 5
mm thickness were insufficient to cover the whole brain for some subjects. Consequently, some regions were not included in second-level analyses, including the amygdala that was previously found to be activated during self-referential processing in depression (Siegle et al
). Second, because the EPI volumes featured some signal drop in the most ventral part of the MFG, we did not fully explore this region. However, this risk of a type II error does not challenge the significant interaction found in the dorsomedial frontal gyrus. Regarding the risk of a type I error due to multiple comparisons, our findings in the MFG rely on hypotheses-driven analyses performed within an a priori
region and the left DLPFC global maxima survived a FDR correction. Finally, gender was not perfectly matched.
Some theoretical limitations should also be considered. We operationalized self-focus as an increased tendency to engage oneself in self-referential processing. However, self-focus is unlikely to be a single psychological construct (Mor and Winquist, 2002
). For instance, it remains unclear whether self-focus in major depression is a controlled or an automatic process or both. Controlled processes are associated with awareness, intention, effort and the capacity for interruption. Automatic processes lack one or more of these features (Lieberman, 2007
). Here, the present task was weighted toward controlled processes and yielded results relevant for the controlled aspects of the excessive self-focus in depression. Future studies should also include a task weighted toward automatic processes to explore the automatic aspects of this excessive self-focus, as they may rely on different brain regions (e.g. ventral MFG, which was not fully explored in the present study). Further studies should also better characterize categorical (e.g. rumination) as well as dimensional (e.g. duration, intensity) aspects of self-focus. Finally, further studies should explore the neural bases of the depressive self in remitted patients to address trait vs
In summary, we used fMRI and two emotional conditions, either self-referential or not, to explore the neural bases of the excessive self-focus in major depression. Our results provided evidence for an extended cortico-cortical network during self-referential processing in depressed patients, suggesting the involvement of a greater cognitive control. To our knowledge, this is the first study that disambiguates the role of the MFG in the pathophysiology of depression.