Modulating Amygdala Responses in Major Depressive Disorder using Naturalistic Neurofeedback with Emotional Faces

Emotion regulation is critical to mental health, and its disruption can lead to psychiatric conditions such as major depressive disorder (MDD). MDD encompasses diverse symptoms, including anhedonia and anxiety, which may be associated with distinct patterns of altered neural activity. Interventions that address the neural mechanisms underlying these symptom dimensions may improve treatment efficacy. We investigated an adaptive, naturalistic real-time functional magnetic resonance imaging neurofeedback paradigm designed to differentially target anhedonia and anxiety through bidirectional amygdala regulation. Unlike conventional abstract feedback, our approach used emotional faces whose expressions changed dynamically according to ongoing amygdala activity, embedding neural self-regulation within a socially relevant emotional context. In this parallel-group study, 21 patients with MDD received one of two neurofeedback conditions. In the Happy-up group, patients attempted to increase amygdala activity by making a neutral face happier to enhance positive emotional responding. In the Fear-down group, patients attempted to decrease amygdala activity by making a fearful face less fearful to reduce negative emotional reactivity. Both groups showed the expected pattern of neural regulation during neurofeedback, with greater amygdala activity during Happy upregulation and decreasing amygdala activity during Fear downregulation. Following the intervention, patients showed reductions in depression severity, anxiety, and anhedonia, and more positive evaluations of neutral and happy faces. However, improvements in anhedonia and anxiety did not differ significantly between groups. These findings show bidirectional amygdala regulation through naturalistic neurofeedback in MDD. Although symptom-specific clinical effects were not established, the observed clinical improvements underscore the therapeutic potential of this approach.