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Summary: Background: Disturbances in emotion regulation are the hallmarks of major depressive disorder (MDD). The incapacity to control negative emotion in patients has been associated with abnormal hyperactivation of the limbic system and hypoactivation of the frontal cortex. The amygdala and orbital frontal cortex (OFC) are two critical regions of the emotion regulation neural systems. Methods: This study investigated the anatomical basis of abnormal emotion regulation by tracking the fiber tracts connecting the amygdala and OFC. In addition, using dynamic casual modeling on resting‐state fMRI data of 20 MDD patients and equivalent controls, we investigated the exact neural mechanism through which abnormal communications between these two nodes were mediated in MDD. Key Results: The results revealed disrupted white matter integrity of fiber tracts in MDD, suggesting that functional abnormalities were accompanied by underlying anatomical basis. We also detected a failure of inhibition of the OFC on the activity of the amygdala in MDD, suggesting dysconnectivity was mediated through "top‐down" influences from the frontal cortex to the amygdala. Following 8 weeks of antidepressant treatment, the patients showed significant clinical improvement and normalization of the abnormal OFC‐amygdala structural and effective connectivity in the left hemisphere. Conclusions & Inferences: Our findings suggest that pathways connecting these two nodes may be core targets of the antidepressant treatment. In particular, it raised the intriguing question: Does the reversal of structural markers of connectivity reflect a response to antidepressant medication or activity‐dependent myelination following a therapeutic restoration of effective connectivity? [ABSTRACT FROM AUTHOR]