Aims Current neuroanatomical models explain major depressive disorder (MDD) by abnormalities in neural circuits underlying negative emotions. The unresolved conundrum, however, is to explain why excessive negative feelings occur when MDD patients blame themselves (manifesting as guilt or self-worthlessness), but not when blaming others.

Methods We used fMRI in fully remitted MDD (N=25) and a matched control group (N=22) with low MD vulnerability while controlling for antidepressant medication status. We employed psychophysiological interaction analysis (SPM8) and an anterior temporal lobe (aTL) seed region, previously shown to underpin blame differentiation, to identify brain regions showing coupling (at p=.05 family-wise-error corrected over a priori ROIs) with the aTL during two conditions: (1) guilt, (2) indignation, evoked by written statements presented in the scanner. We controlled the intensity of negative feelings and task performance.

Results We corroborated our hypothesis that MDD patients can be distinguished from controls by functional decoupling between aTL and subgenual cingulate cortex while they experience self-blaming feelings (guilt). This effect was selective for self-blame but did not occur when blaming others (feeling indignation) and therefore explains vulnerability to self-blaming bias.

Conclusions These results shed new light on the pathophysiology of MDD by unravelling the neuroanatomical basis of self-blaming bias.