Guilt-selective functional disconnection of anterior temporal and subgenual cortices in major depressive disorder
Green S., Lambon Ralph M., Moll J., Deakin J.F.W., Zahn R.
Archives of General Psychiatry. 2012;.
Context: Proneness to overgeneralization of self-blame is a core part of cognitive vulnerability to major depressive disorder (MDD) and remains dormant after remission of symptoms. Current neuroanatomical models of MDD, however, assume general increases of negative emotions and are unable to explain biases towards emotions entailing self-blame (e.g. guilt) relative to those associated with blaming others (e.g. indignation). Recent fMRI studies in healthy participants have shown that moral feelings such as guilt activate representations of social meaning within the right superior anterior temporal lobe (ATL). Furthermore, this area was selectively coupled with the subgenual cingulate cortex and the adjacent septal region (SCSR) during the experience of guilt compared with indignation. Despite its psychopathological importance, the functional neuroanatomy of guilt in MDD is unknown. Objective: Use fMRI to test the hypothesis that in comparison with controls, participants with remitted MDD exhibit guilt-selective SCSR-ATL decoupling as a marker of deficient functional integration. Design: Case-control study from 2008 to 2009. Setting: Clinical Research Facility. Participants: 25 patients with remitted MDD (no medication in 16) with no current co-morbid axis-I disorders, and 22 control participants with no personal or family history of MDD. Main outcome measures: Between-group difference of ATL-coupling with a priori SCSR region of interest (ROI) for guilt vs. indignation. Results: We corroborated the prediction of a guilt-selective reduction in ATL-SCSR coupling in MDD vs. controls (Family-Wise-Error-corrected p=.001 over ROI) and revealed additional medial frontopolar, right hippocampal and lateral hypothalamic areas of decoupling while controlling for medication status and intensity of negative emotions. Lower levels of ATL-SCSR coupling were associated with higher scores on a validated measure of overgeneralized self-blame (Interpersonal Guilt Questionnaire). Conclusions: Vulnerability to MDD is associated with temporo-fronto-limbic decoupling that is selective for self-blaming feelings. This provides the first neural mechanism of MDD vulnerability that accounts for self-blaming biases.