Repeated Exposures to Air Travel-Relevant Hypobaria Induce Anxiety-Like Behavior and Alter Functional Connectivity and White Matter Integrity in a Ferret Model of Traumatic Brain Injury

Under-vehicle blast (UVB) caused by landmine detonation induces a distinct traumatic brain injury (TBI) and can be accompanied by head impact. Injured soldiers often undergo multiple flights after injury to access medical care and return to duty. Previous work has shown that low air pressure during air travel (hypobaria [HB]) exacerbates neurological injury, but the effects of one or more HB exposures on chronic brain injury are unknown. We hypothesized that multiple HB exposures after TBI would result in worse outcomes than 0-1 exposures. Sedated male ferrets underwent UVB and controlled cortical impact (CCI) under anesthesia (BCCI), followed by zero (normobaria [BCCI + NB]), one (BCCI + 1HB), or five (BCCI + 5HB) 6-h HB exposure(s) over 6 months post-injury or remained experimentally naïve. Anxiety-like behavior was assessed with the Open Field at 6 months post-injury. Ferrets also underwent T₂-weighted (T2w), resting-state functional magnetic resonance imaging, and diffusion-weighted imaging scans at pre-injury baseline and 6 months post-injury under anesthesia. Relative to naïve, BCCI + 5HB animals expressed significantly more anxiety-like behavior. Region of interest (ROI)-to-ROI functional connectivity (FC) analysis was conducted to evaluate FC changes within the anxiety network. ROI-based diffusion tensor and kurtosis imaging modeling was conducted to evaluate the white matter (WM) integrity of major anxiety-associated WM tracts. Results indicated increased FC between prefrontal cortex, amygdala, and hippocampus and decreased fractional anisotropy and mean kurtosis in cerebral WM, corpus callosum, cingulum, and fornix WM tracts when comparing BCCI + 5HB with all other groups. Together, these suggest that multiple HB exposures after BCCI exacerbate changes in neurological activity in the anxiety regulation brain network, as well as structural damage in the anxiety-associated WM tracts. Our findings demonstrate that air travel after TBI, particularly multiple flights, can have a chronic negative impact on brain structure and function.