Increased resting-state brain entropy (BEN) in mild to moderate depression was decreased by nonpharmacological treatment

Brain entropy (BEN) reflects the irregularity of brain activity. The neural mechanisms of depression of nonpharmacological treatments remain largely elusive. We employed BEN to evaluate neural changes in mild to moderate depression and their modulation by nonpharmacological interventions. Resting-state fMRI assessed BEN in 29 patients with mild to moderate depression at baseline and follow-up. Among them, 14 received nonpharmacological treatment, while 15 remained untreated. BEN was also evaluated in 20 matched healthy controls (HCs). Baseline BEN differences between patients and HCs were identified using two-sample t-tests. Significant regions were selected as regions of interest (ROIs). Repeated measures ANOVA tested treatment-induced BEN changes in these ROIs. The results indicate that compared to HCs, patients showed higher baseline BEN in the left dorsomedial prefrontal cortex (DMPFC), left amygdala (AMY)/putamen, and right hippocampus/parahippocampal cortex (HPC/PHPC). Treated patients had higher baseline BEN in the DMPFC than untreated patients. At follow-up, treated patients showed reduced BEN across all ROIs and reduced depression levels as measured by Beck Depression Inventory (BDI). In contrast, untreated patients demonstrated no changes and remained significantly higher BEN than HCs across all ROIs. Further analysis showed that higher BEN in DMPFC and AMY/putamen recovered to levels comparable to HCs, though BDI remained higher in treated patients. These findings suggest that bottom-up emotion dysregulation in depression is effectively mitigated by nonpharmacological treatment targeting top-down emotion regulation mediated by the prefrontal-limbic network. This study reveals that BEN can serve as an effective neural biomarker throughout the onset, progression, and recovery processes of depression. Highlights Depression is linked to increased brain entropy in prefrontal-limbic network. Nonpharmacological treatment normalizes elevated BEN of prefrontal-limbic network in depression. Prefrontal-limbic BEN can serve as an effective neural biomarker for onset, progression, and recovery processes of depression.