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
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.