Network-based analysis of differential white matter connectivity in major depressive disorder with and without comorbid anxiety

Neuropsychopharmacology. 2026 Jan 12. doi: 10.1038/s41386-025-02312-y. Online ahead of print.

ABSTRACT

Current psychiatric neuroimaging supports the view that major depressive disorder (MDD) is a dysconnection syndrome, characterized by structural brain dysconnectivity. Recent studies investigating this question, however, did not evaluate the involvement of comorbid disorders, of which anxiety disorders (ANX) are particularly prevalent. Here, we investigated the structural connectivity alterations observed in MDD with and without comorbid ANX. To this end, we reconstructed structural brain networks of n = 781 individuals with a diagnosis of MDD who had at least one diagnosis of an ANX (n = 249) and those without any diagnosis of ANX (n = 532), as well as n = 906 healthy controls (HC) from structural and diffusion-weighted MRI. The network-based statistic (NBS) toolbox was employed to evaluate network-level differences in structural connectivity among the three groups. Transdiagnostic analyses were conducted to explore the dimensional relationship between anxiety and structural connectivity. NBS revealed decreased structural connectivity in MDD patients without comorbid ANX and increased structural connectivity in MDD patients with comorbid ANX relative to HC, with both effects found in spatially overlapping white matter connections. Transdiagnostic analyses suggested that increases in anxiety were associated with increased structural connectivity across all groups. Our finding that hyperconnectivity rather than hypoconnectivity characterizes the structural connectome of MDD patients with comorbid ANX challenges the applicability of the dysconnection syndrome hypothesis to MDD with comorbid ANX, warranting symptom-based investigations of brain changes in mental disorders.

PMID:41526712 | DOI:10.1038/s41386-025-02312-y