Targeting the dopaminergic midbrain with precision 7-Tesla biofeedback training in depression: A proof-of-principle randomized controlled trial.

The significant heterogeneity of major depressive disorder (MDD) requires the development of interventions that directly target underlying cognitive or neurobiological mechanisms. This work tested the efficacy of self-modulation of the dopaminergic midbrain with high-field 7-Tesla functional MRI biofeedback in a randomized, controlled, proof-of-principle trial that targeted motivation regulation. A total of N = 62 unmedicated participants (MDD and healthy controls) were randomized to receive either Active or Sham 7-Tesla functional MRI biofeedback and completed clinical assessments pre- and up to 30-days post-training. Factor analysis of clinical symptom change revealed a single latent clinical improvement factor that was significantly improved in the Active MDD compared to the Sham MDD group, immediately post-training (β = 15.85, t = 2.31, p = 0.03), and at 24-hours post-training (β = 22.84, t = 2.45, p = 0.02); effects were diminished and no longer significant at 7-day and 30-day follow-ups. Results of specific phenotypic clinical analysis revealed that depressed mood (F = 5.04, p = 0.029) and negative affect (F = 5.21, p = 0.027), but not positive affect, were most improved by the Active biofeedback intervention. Active biofeedback training engaged functional coupling over time between the VTA and the lateral frontal cortex in the MDD group (F = 6.03, p = 0.017), and greater overall VTA regulation was associated with clinical improvement (R = 0.268, p = 0.048). Together, these results indicate the potential utility of dopaminergic midbrain-based biofeedback training for improvement of mood and negative affect in MDD.