Altered dynamic functional connectivity of orbitofrontal cortex underlies olfactory and cognitive impairment in late-life depression

Abstract Background Late-life depression (LLD) and odor identification (OI) dysfunction are risk factors for dementia, but the underlying neural mechanisms remain unclear. This study investigated dynamic functional connectivity (dFC) in olfactory brain regions of LLD patients with and without OI dysfunction and examined how dFC moderates the OI–cognition link. Methods Resting-state functional magnetic resonance imaging data were acquired from 51 LLD patients with OI deficits (LLD-OID), 59 LLD patients without deficits (LLD-noOID), and 51 healthy controls (HC). A sliding-window approach (50 TR width, 1 TR step) was used to estimate dFC variability between the orbitofrontal cortex (OFC) and the whole brain. Bayesian regression and moderation analyses assessed associations among OFC dFC, OI scores, and cognitive measures. Results were robust across window sizes. Results Compared to LLD-noOID and HC, LLD-OID showed decreased OFC–left inferior frontal gyrus dFC variability (P < 0.01) and increased OFC–right middle frontal gyrus (MFG) variability (P < 0.001). Higher OFC–MFG variability was associated with worse OI and cognitive performance and significantly moderated the OI–global cognition relationship (β = 1.06, P = 0.027, 95% CI [0.12, 2.0]). No group differences were found in primary olfactory regions. Conclusion LLD patients with OI dysfunction exhibited more disrupted dFC in secondary olfactory regions compared with those without OI dysfunction. Dynamic OFC–MFG disconnectivity may index vulnerability to cognitive decline and dementia risk in LLD patients.