Real-time fMRI-informed self-regulation of the ventromedial prefrontal cortex using positive episodic future thinking enhances motivation

Motivational deficits including anhedonia and avolition represent persistent challenges across psychiatric disorders, often resistant to conventional interventions. Here, we developed a novel brain-based precision intervention combining real-time fMRI neurofeedback with positive episodic future thinking to target the ventromedial prefrontal cortex (vmPFC), a region that critically regulates motivation via anticipated pleasure and value computation. A pre-registered randomized sham-controlled double-blind real-time fMRI trial (n=61) with personalized vmPFC targets demonstrated that the neurofeedback group rapidly acquired regulatory control over the vmPFC, leading to significantly higher activity of this region and enhanced anticipated pleasure and regulatory efficacy. Effects were maintained in the absence of feedback, underscoring the therapeutic potential. Network analyses revealed strengthened vmPFC-putamen connectivity following the training, reflecting network-level plasticity in motivational learning circuits. Results demonstrate rapid acquisition of vmPFC self-regulation and enhanced motivation through an ecologically-valid and pathway-specific strategy and underscore the therapeutic potential of personalized neurofeedback for motivational dysfunctions. (Clinical trials: NCT06787248 )