Structural connectivity correlates of response to electroconvulsive therapy in treatment-resistant depression

Electroconvulsive therapy (ECT) remains the most effective intervention for treatment-resistant depression (TRD). We investigated whether cortico-limbic structural connectivity is associated with ECT response. Twenty-nine TRD patients underwent bifrontal ECT and baseline probabilistic tractography assessing connectivity between amygdala, anterior insula (aINS), orbitofrontal cortex (OFC), posterior cingulate cortex (PCC), posterior ventrolateral (VLPFC) and dorsolateral prefrontal cortex (DLPFC), subgenual cingulate cortex (SGCC) and thalamus. Stronger connectivity within a subnetwork comprising bilateral OFC, bilateral aINS, left SGCC and right DLPFC was associated with poorer ECT response showing predictive value for treatment outcome. Conversely, thalamus-PCC connectivity is related to greater baseline severity and better ECT response. In TRD, depressive symptom scores negatively correlated with fronto-limbic-thalamic connectivity. Our findings highlight a fronto-limbic subnetwork whose hyperconnectivity may reflect maladaptive regulation limiting neuromodulation efficacy. In contrast, thalamic connectivity may act as a hub linking fronto-limbic and default mode network circuits, potentially facilitating receptive pathways supporting therapeutic response and guiding anatomically precise neuromodulation strategies.