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Subclinical depression (SD) has been considered as the precursor to major depressive disorder. Accurate prediction of SD and identification of its etiological origin are urgent. Bursts within the lateral habenula (LHb) drive depression in rats, but whether dysfunctional LHb is associated with SD in human is unknown. Here we develop connectome-based biomarkers which predict SD and identify dysfunctional brain regions and connections. T1 weighted images and resting-state functional MRI (fMRI) data were collected from 34 subjects with SD and 40 healthy controls (HCs). After the brain is parcellated into 48 brain regions (246 subregions) using the human Brainnetome Atlas, the functional network of each participant is constructed by calculating the correlation coefficient for the time series of fMRI signals of each pair of subregions. Initial candidates of abnormal connections are identified by the two-sample  t -test and input into Support Vector Machine models as features. A total of 24 anatomical-region-based models, 231 sliding-window-based models, and 100 random-selection-based models are built. The performance of these models is estimated through leave-one-out cross-validation and evaluated by measures of accuracy, sensitivity, confusion matrix, receiver operating characteristic curve, and the area under the curve (AUC). After confirming the region with the highest accuracy, subregions within the thalamus and connections associated with subregions of LHb are compared. It is found that five prediction models using connections of the thalamus, posterior superior temporal sulcus, cingulate gyrus, superior parietal lobule, and superior frontal gyrus achieve an accuracy >0.9 and an AUC >0.93. Among 90 abnormal connections associated with the thalamus, the subregion of the right posterior parietal thalamus where LHb is located has the most connections ( n  = 18), the left subregion only has 3 connections. In SD group, 10 subregions in the thalamus have significantly different node degrees with those in the HC group, while 8 subregions have lower degrees (  p  < 0.01), including the one with LHb. These results implicate abnormal brain connections associated with the thalamus and LHb to be associated with SD. Integration of these connections by machine learning can provide connectome-based biomarkers to accurately diagnose SD.

Connectome-Based Biomarkers Predict Subclinical Depression and Identify Abnormal Brain Connections With the Lateral Habenula and Thalamus