Anterior cingulate cortex, insula and amygdala seed-based whole brain resting-state functional connectivity differentiates bipolar from unipolar depression

Objective: The frontal-limbic circuit is hypothesized as sub-serving emotional regulation. We performed whole brain resting-state functional connectivity (rs-FC) analysis by studying the key hubs of frontal-limbic circuit: anterior cingulate cortex (ACC), bilateral insula subregions, bilateral amygdala (Amy) as seeds, separately, to discriminate bipolar depression (BipD) from unipolar depression (UniD). Methods: We compared seed-based rs-FC of the frontal-limbic seeds with whole brain among 23 BipD partici- pants; 23 age, gender, and depression severity matched patients with UniD, and 23 healthy controls (HCs). We also used support vector machine learning to study classification based on the rs-FC of ACC, bilateral insula subregions, and bilateral Amy seeds with whole brain. Results: BipD showed increased rs-FC between the left ventral anterior insula (vAI) seed and the left anterior supramarginal gyrus (aSMG) and left postcentral gyrus, as well as increased rs-FC between left amygdala seed and the left aSMG when compared to HCs and UniD. Compared to UniD, BipD was associated with increased rs- FC between right dorsal anterior insula seed and right superior frontal gyrus, as well as increased rs-FC between left posterior insula seed and right precentral gyrus and right thalamus. Combined rs-FC of ACC, bilateral insula subregions and bilateral Amy seeds with the whole brain discriminated BipD from UniD with an accuracy of 91.30%. Conclusions: Rs-FC of the emotional regulation circuit is more widely disturbed in BipD than UniD. Using rs-FC with this circuit may lead to further developments in diagnostic decision-making.