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Objective: Although lithium has been a commonly prescribed neurotrophic/neuroprotective mood-stabilizing agents, its effect on spontaneous brain activity in patients with bipolar depression remains un-clear. The aim of this study is to reveal the basic mech-anism underlying the pathological influences of lithium on resting-state brain function of bipolar depression pa-tients. Methods:97 subjects including 9 bipolar depres-sion patients with lithium treatment, 19 bipolar depres-sion patients without lithium treatment and 69 healthy controls, were recruited to participate in this study. Amplitude of low-frequency fluctuation ( ALFF ) and fractional amplitude of low-frequency fluctuation ( fALFF) were used to capture the changes of spontane-ous brain activity among different groups. In addition, further analysis in terms of Hamilton Depression Rating Scale, the number of depressive episodes, and illness duration in pooled bipolar depression patients were con-ducted, which combined FLEF and fALEF to identify the basic neural features of bipolar depression patients. Results: It was observed from the imaging results that both the bipolar depression patients receiving lithium treatment and healthy control subjects showed signifi-cantly decreased ALFF/fALFF values in the right anteri-or cingulate cortex and right middle frontal gyrus com-pared to that from the bipolar depression patients with-out lithium treatmetn. The ALFF values of the right middle temporal gyrus was also found to be negative re-lated to the number of depressive episode and the total episodes. Conclusions:Our findings suggested that the bipolar depression subjects were identified to have ab-normal ALFF/ fALFF in the cortico-limbic systems, in-cluding regions like right anterior cingulate cortex, bi-lateral middle frontal gyrus, right orbital frontal gyrus, and right middle temporal gyrus. In addition, it was al-so revealed that the decreased ALFF/fALFF in the right anterior cingulate cortex and right middle frontal gyrus might be a biomarker that is related to the lithium effects.