Dynamic functional connectivity variability may explain hypoxia-induced cognitive impairment at high-altitude.

Long-term exposure to a high-altitude (HA) hypoxic environment induces cognitive impairments, yet the underlying temporal mechanisms remain elusive. This longitudinal study investigated brain functional alterations associated with cognitive changes in 49 college freshmen relocated from sea level to Tibet, with comprehensive cognitive assessments and magnetic resonance imaging (MRI) at baseline and 2- and 4-year follow-ups. Resting-state fMRI quantified changes in regional homogeneity (ReHo), amplitude of low-frequency fluctuations (ALFF)/fractional ALFF (fALFF), static functional connectivity (sFC), and dynamic FC (dFC). Behavioral data confirmed persistent cognitive deficits, while neuroimaging analyses revealed biphasic patterns (initial suppression then partial/full recovery) in ReHo, ALFF/fALFF, and sFC. Notably, dFC variability in the right orbital middle frontal gyrus (ORBmid.R) and Heschl's gyrus (HES.R) increased at 2 years and remained elevated, with this alteration strongly correlated with cognitive changes. Our findings highlight that elevated dFC variability in two brain regions is a key contributor to chronic hypoxia-induced cognitive impairments.