Hippocampal subfield functional connectivity alterations in major depressive disorder: A systematic review and...

Major depressive disorder (MDD) is increasingly conceptualized as a disorder of distributed neural network dysfunction. The hippocampus comprises functionally distinct subfields, yet evidence on subfield-level functional connectivity (FC) abnormalities in MDD remains heterogeneous, partly because studies use different segmentation approaches.

Following PRISMA 2020, we systematically searched PubMed and Scopus for English-language studies published from January 2020 to August 2026 examining FC involving hippocampal subfields or subregions in depression. We summarized segmentation methods, compared atlas-level spatial overlap, performed random-effects meta-analyses where data were comparable, and narratively synthesized case-control and treatment-related findings.

Eighteen studies including 1366 patients with MDD and 935 healthy controls were included. Segmentation approaches differed substantially in hippocampal coverage and granularity. Five studies contributed to exploratory network-specific meta-analyses. FC was lower in MDD for hippocampal subregion-default mode network connections (g = -0.74, 95% CI -0.98 to -0.50) and visual network connections (g = -0.64, 95% CI -0.94 to -0.34). Estimates for salience, limbic, and sensorimotor networks were imprecise and heterogeneous. Narrative findings were bidirectional, while longitudinal studies suggested treatment-related connectivity changes.

MDD is associated with heterogeneous, subregion-specific hippocampal dysconnectivity. Atlas non-equivalence may contribute to variability across studies, supporting more harmonized and method-aware segmentation approaches.