Self-blame-Selective Hyperconnectivity Between Anterior Temporal and Subgenual Cortices and Prediction of Recurrent Depressive Episodes

IMPORTANCE Patients with remitted major depressive disorder (MDD) were previously found to display abnormal functional magnetic resonance imaging connectivity (fMRI) between the right superior anterior temporal lobe (RSATL) and the subgenual cingulate cortex and adjacent septal region (SCSR) when experiencing self-blaming emotions relative to emotions related to blaming others (eg, indignation or anger toward others). This finding provided the first neural signature of biases toward overgeneralized self-blaming emotions (eg, feeling guilty for everything), known to have a key role in cognitive vulnerability to MDD. It is unknown whether this neural signature predicts risk of recurrence, a crucial step in establishing its potential as a prognostic biomarker, which is urgently needed for stratification into pathophysiologically more homogeneous subgroups and for novel treatments. OBJECTIVE To use fMRI in remitted MDD at baseline to test the hypothesis that RSATL-SCSR connectivity for self-blaming relative to other-blaming emotions predicts subsequent recurrence of depressive episodes. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study from June 16, 2011, to October 10, 2014, in a clinical research facility completed by 75 psychotropic medication-free patients with remitted MDD and no relevant comorbidity. In total, 31 remained in stable remission, and 25 developed a recurring episode over the 14 months of clinical follow-up and were included in the primary analysis. Thirty-nine control participants with no personal or family history of MDD were recruited for further comparison. MAIN OUTCOMES AND MEASURES Between-group difference (recurring vs stable MDD) in RSATL connectivity, with an a priori SCSR region of interest for self-blaming vs other-blaming emotions. RESULTS We corroborated our hypothesis that during the experience of self-blaming vs other-blaming emotions, RSATL-SCSR connectivity predicted risk of subsequent recurrence. The recurring MDD group showed higher connectivity than the stable MDD group (familywise error-corrected P < .05 over the a priori SCSR region of interest) and the control group. In addition, the recurring MDD group also exhibited RSATL hyperconnectivity with the right ventral putamen and claustrum and the temporoparietal junction. Together, these regions predicted recurrence with 75% accuracy. CONCLUSIONS AND RELEVANCE To our knowledge, this study is the first to provide a robust demonstration of an fMRI signature of recurrence risk in remitted MDD. Additional studies are needed for its further optimization and validation as a prognostic biomarker.