Shared neural network dysfunctions in treatment-resistant major depression and alcohol use disorder: Resting-state fMRI evidence and implications for neuromodulation

Abstract

Treatment-resistant depression (TRD) and alcohol use disorder (AUD) frequently coexist, complicating clinical management and contributing to poor outcomes. Despite their distinct clinical presentations, converging neuroimaging evidence indicates shared neural circuit dysfunctions. This review synthesizes resting-state functional magnetic resonance imaging (fMRI) findings, highlighting disruptions within and between core intrinsic brain networks-the default mode network (DMN), salience network (SN), and central executive network (CEN)-as well as subcortical-limbic circuitry. Both TRD and AUD feature reduced anterior-posterior DMN connectivity (mPFC-PCC), impaired CEN function (particularly within the DLPFC), and aberrant SN connectivity (anterior insula, ACC). Altered limbic interactions involving the amygdala, hippocampus, and striatum further reflect common mechanisms of heightened reward sensitivity and emotional dysregulation. Conventional pharmacotherapies demonstrate limited efficacy, underscoring the need for novel approaches. Neuromodulation, particularly deep transcranial magnetic stimulation (dTMS), has emerged as a promising intervention targeting these shared circuit abnormalities. While current evidence remains preliminary, integrating neuroimaging biomarkers, multimodal methods, and longitudinal designs will be crucial for refining treatment precision. This review highlights the translational potential of circuit-based interventions, offering a framework for personalized neuromodulation strategies to improve outcomes in patients with TRD, AUD, and their frequent comorbidities.

Keywords: Alcohol use disorder; Functional connectivity; Neuromodulation; Resting-state fMRI; Treatment-resistant depression.