Clinical Response to Neurofeedback in Major Depression Relates to Subtypes of Whole-Brain Activation Patterns During Training.

Major Depressive Disorder (MDD) presents a significant public health challenge. Real-time functional magnetic resonance imaging neurofeedback (rtfMRI-NF) shows promise as a treatment for this disorder, although its mechanisms of action remain unclear. This study investigated whole-brain response patterns during rtfMRI-NF training to explain interindividual variability in clinical efficacy in MDD. We analyzed data from 95 participants (67 active, 28 control) with MDD from previous rtfMRI-NF studies designed to increase left amygdala activation through positive autobiographical memory recall. We focused on whole-brain activation patterns during two critical epochs of the neurofeedback procedure: activation during the self-regulation period and transient responses to feedback signal presentation. Through a systematic process involving feature selection, manifold extraction, and clustering with cross-validation, we identified subtypes within these patterns. Significant symptom reduction was observed in the active group ( t =-4.404, d =-0.704, p <0.001) but not in the control group ( t = -1.609, d =-0.430, p =0.111); however, left amygdala activation did not account for the variability in clinical efficacy. Subtyping analysis revealed two subtypes in regulation activation and three subtypes in brain responses to feedback signals (regulation: F =8.735, p =0.005; feedback response: F =5.326, p =0.008; interaction: F =3.471, p =0.039). Subtypes associated with significant symptom reduction were characterized by selective increases in control regions, including lateral prefrontal areas, and decreases in regions associated with self-referential thinking, such as default mode areas. These findings suggest that large-scale brain activity is more critical for clinical efficacy than the level of activation in the neurofeedback target region during training. Tailoring neurofeedback training to incorporate these patterns could significantly enhance its therapeutic efficacy.