Medial prefrontal cortex circuitry in inflammation-associated major depressive disorder: Brain-immune interactions...

Major depressive disorder (MDD) is a leading cause of disability worldwide, characterized by marked clinical and biological heterogeneity. Inflammation represents one key mechanism contributing to MDD, with a substantial proportion of patients exhibiting elevated inflammatory biomarkers. Inflammatory signaling affects neurotransmitter systems and neural circuits involved in reward, motivation, arousal, and threat processing, thereby linking to neurovegetative and motivational symptoms and reduced treatment responsiveness. The medial prefrontal cortex (mPFC) is a recurring node across inflammation-related symptom dimensions and provides a tractable focus for examining how inflammatory burden intersects with prefrontal, striatal, and limbic dysfunction. Sex may further moderate this brain-immune relationship through differences in stress susceptibility, brain structure and function, and inflammatory activity. Given the inconsistent effects of anti-inflammatory agents, noninvasive neuromodulation offers a targeted strategy for inflammation-associated MDD. Bottom-up transcutaneous auricular vagus nerve stimulation may regulate autonomic-immune signaling and ascending network pathways, whereas top-down high-definition transcranial direct current stimulation may modulate prefrontal plasticity and engage mPFC-centered circuitry. In this review, we synthesize evidence on peripheral and central inflammatory involvement in MDD, with emphasis on mPFC-centered circuit vulnerability and sex as a moderator of brain-immune interactions, and evaluate the translational rationale for complementary bottom-up and top-down stimulation in patients with elevated inflammatory burden. We also highlight key priorities for future research, including patient enrichment, outcome alignment, target engagement, parameter optimization, and sex-related variables to advance precision and stratified therapeutics in depression.