Using functional MRI neurofeedback to modulate self-blame in major depressive disorder: A pilot study

Background: Growing evidence implicates self-blame-related neural networks in the pathophysiology of major depressive disorder (MDD). fMRI neurofeedback is an emerging technology with the potential to deliver interventions targeting the neural substrates of self-blame, but its feasibility and potential mechanism in current MDD remain unresolved. Methods: The current pilot study employed a single-session, exploratory neurofeedback trial harnessing the subgenual cingulate cortex (SCC) BOLD activity as the sole training target. Two active interventions were compared. In Intervention A ( n = 10), participants were encouraged during neurofeedback to upregulate their SCC activity during a ‘guilt’ task and downregulate it during an ‘indignation’ task. In Intervention B ( n = 10), participants were encouraged to do the opposite. Results: Clinical scores improved significantly across interventions, although no significant intervention differences were detected. Neurofeedback performance was variable across participants and conditions, with significant group-level regulation in the intended direction observed only for the indignation condition in Intervention B. A whole-brain analysis using a uniform preprocessing pipeline revealed no clusters surviving correction for multiple comparisons. Conclusion: The results support the feasibility of the protocol and suggest that engagement with negative autobiographical memories during SCC-oriented neurofeedback can be delivered safely in this small sample. Group-level target engagement was inconsistent, but the observation that SCC regulation was most achievable during indignation tentatively suggests this region may be more functionally heterogeneous for causal agency representations than commonly assumed. The absence of significant whole-brain effects under a uniform pipeline indicates that any neural changes were not robust at the group level in this small sample. In summary, the study provides preliminary feasibility and safety data, alongside estimates of variance, to inform more adequately powered investigations into SCC-oriented neurofeedback for depression.