Abstract
BACKGROUND: Increased sensitivity to stress and dysfunctional reward processing are two primary characteristics of major depressive disorder (MDD) that may persist after remission. Preclinical work has established the pivotal role of the striatum in mediating both stress and reward responses. Human neuroimaging studies have corroborated these preclinical findings and highlighted striatal dysfunction in MDD in response to reward but have yet to investigate striatal function during stress, in particular in individuals with recurrent depression. METHODS: A validated mild psychological stress task involving viewing of negative stimuli during functional magnetic resonance imaging was conducted in 33 remitted individuals with a history of recurrent major depressive disorder (rMDD) and 35 matched healthy control subjects. Cortisol and anxiety levels were assessed throughout scanning. Stress-related activation was investigated in three striatal regions: caudate, nucleus accumbens, and putamen. Psychophysiologic interaction analyses probed connectivity of regions with central structures of the neural stress circuitry, such as the amygdala and hippocampus. RESULTS: The task increased cortisol and anxiety levels, although to a greater extent in rMDD individuals than healthy control subjects. In response to the negative stimuli, rMDD individuals, but not controls, also exhibited significantly potentiated caudate, nucleus accumbens, and putamen activations and increased caudate-amygdala and caudate-hippocampus connectivity. CONCLUSIONS: The findings highlight striatal hypersensitivity in response to a mild psychological stress in rMDD, as manifested by hyperactivation and hyperconnectivity with the amygdala and hippocampus. Striatal hypersensitivity during stress might thus constitute a trait mark of depression, providing a potential neural substrate for the interaction between stress and reward dysfunction in MDD.