Real-time fMRI neurofeedback (rtfMRI-NF) has emerged as a promising intervention for psychiatric disorders, yet its clinical efficacy remains underexplored due to limited controls and an incomplete mechanistic understanding. This study aimed to elucidate the whole-brain mechanisms underpinning the effects of rtfMRI-NF on repetitive negative thinking in depression. In a double-blind randomized controlled trial, forty-three depressed individuals underwent NF training targeting the functional connectivity (FC) between the posterior cingulate cortex and the right temporoparietal junction, linked to rumination severity. Participants were randomly assigned to active or sham groups, with the sham group receiving synthesized feedback mimicking real NF signal patterns. The active group demonstrated a significant reduction in brooding rumination scores (p<0.001, d=-1.52), whereas the sham group did not (p=0.503, d=-0.23). While the target FC did not show discernible training effects or group differences, we found that the interaction between brain activities during regulation and the response to the feedback signal was the critical factor in explaining treatment outcomes. Connectome-based predictive modeling (CPM) analysis, incorporating this interaction, successfully predicted rumination changes across both groups. The FCs significantly contributing to the prediction were distributed across broad brain regions, notably the frontal control, salience network, and subcortical reward processing areas. These results underscore the importance of considering the interplay between brain regulation activities and brain response to the feedback signal in understanding the therapeutic mechanisms of rtfMRI-NF. The study not only affirms the potential of rtfMRI-NF as a therapeutic intervention for repetitive negative thinking in depression but also highlights the need for a more nuanced understanding of the whole-brain mechanisms contributing to its efficacy.

Whole-brain Mechanism of Neurofeedback Therapy: Predictive Modeling of Neurofeedback Outcomes on Repetitive Negative Thinking in Depression