Rethinking functional connectivity: neural circuits in major depressive disorder revealed by a novel gray-white-gray...

Traditional studies on brain functional connectivity in major depressive disorder (MDD) predominantly focused on gray matter (GM), often overlooking the critical role of white matter (WM). The integrative gray-white-gray (G-W-G) communication connectivity framework highlighted WM as a key bridge influencing whole-brain communication.

G-W-G communication framework was constructed using signals of GM and WM from resting-state functional magnetic resonance imaging data of 325 MDD patients and 177 healthy controls, then applied to explore its clinical relevance in symptomatology and treatment response.

The results revealed that G-W-G communication connectivity in MDD was disrupted, primarily mediated by functional disruptions in WM, including the anterior limb of the internal capsule, sagittal stratum, cingulum, splenium of the corpus callosum, fornix, and superior longitudinal fasciculus. Notably, the left anterior limb of the internal capsule potentially bridged disrupted connectivity and suicidal symptoms, while several G-W-G connections showed potential for predicting antidepressant efficacy.

Future investigations with larger, multi-center cohorts are warranted to validate the present findings. Additionally, longitudinal and multimodal approaches are needed to clarify the causal role of the G-W-G framework in the pathophysiology and treatment of MDD.

By treating GM and WM as an integrated functional network, the G-W-G neural circuits provide novel insights into the pathophysiology of MDD, highlight its potential as a target for clinical intervention.