Neuropathological and Behavioral Effects of Mild Traumatic Brain Injury at High Altitude

Objective: In lowlanders, ascent to and prolonged stay at high altitude (HA) can trigger maladaptive changes in neurovascularization, immune function, and hippocampal-dependent cognitive impairment. Mild traumatic brain injury (mTBI) induces similar neuropathological and behavioral alterations. The primary objective of this study was to characterize the impact of mTBI at HA on behavioral and neuropathological outcomes in controlled murine models. Methods: Baseline magnetic resonance imaging (MRI), diffusion tensor imaging (DTI), and [¹⁸F]fluorodeoxyglucose positron emission tomography (PET) were conducted in male C57BL/6J mice prior to exposure to either sea level (SL) or chronic HA (12 weeks, 5000 m simulated in a hypobaric chamber). Mice were then assigned to mTBI (three repetitive closed head injuries) or Sham groups. The impact of HA-mTBI on novel object recognition and contextual fear memory recall, analogs of human subcategories of memory altered at HA, was evaluated 9–12 days postinjury, followed by imaging. Results: Relative to their post-HA imaging assessment, HA-mTBI cerebral blood flow within the cortex, hippocampus, and thalamus was reduced, as was global brain volume. Moreover, statistical parametric mapping analysis detected clear HA-mTBI interactions in glucose uptake with reductions at the injury site and contralateral increases in the cortex and amygdala. Significant clusters were identified by MRI and DTI in the cortex, caudate, and corpus callosum for T2 values, trace, and radial diffusivity in HA-mTBI animals relative to their post-HA assessments. The principal component analysis and Pearson’s correlations reveal distinct imaging signatures associated with HA exposure and TBI hippocampal integrity and thalamocortical connectivity, which may contribute to deficits in spatial memory and alterations in exploratory behavior. Summary: The combined burden of chronic HA exposure and mTBI induces a complex neuropathological interaction, evidenced by region-dependent white matter vulnerability, gray matter alterations, and impaired cerebral glucose metabolism. Although HA exposure and mTBI independently produced behavioral deficits, a synergistic behavioral effect was not detected, revealing a critical dissociation between structural/metabolic injury and functional outcomes.