Does a pharmacologically driven elevation in cerebral blood flow modulate cognition during combined hypoxic and thermal stress?

Cognitive performance is often assumed to be vulnerable to environmental stressors that alter cerebral oxygen delivery. However, evidence that hypoxia or heat – independently or combined – impair cognition remains inconsistent. This variability may reflect differences in how these stressors affect cerebral perfusion, as cerebral blood flow (CBF) is frequently described as a key determinant of cognitive function. If CBF meaningfully contributes to cognitive resilience, then increasing or manipulating CBF may alter cognitive performance under environmental stress. Objective: To determine whether a pharmacologically driven elevation in CBF affects cognitive performance during combined hypoxia and heat stress. Hypothesis: We hypothesized that increasing CBF would improve cognitive performance during simultaneous hypoxic and thermal strain. Methods: Thirteen healthy adults completed a randomized, double-blind, placebo-controlled, crossover protocol in which participants ingested 1,000 mg acetazolamide (ACZ) or a placebo (PLA) 4 hours before testing. Cognitive performance (Go/No-Go and Flanker tasks) was assessed during the final 5 minutes of 10-minute normoxic and poikilocapnic hypoxic trials (FiO 2 ≈ 10%) under two sequential thermal conditions: an initial normothermic condition followed by passive heat–induced hyperthermia using a water-perfused suit targeting a +1.5–2.0°C increase in core temperature. Primary outcomes included global CBF, measured via Doppler ultrasound of the internal carotid artery (ICA) and vertebral artery (VA) (global CBF = (ICA + VA) × 2), and cognitive performance metrics (reaction time and accuracy). Secondary outcomes included end-tidal gases (PetO 2 , PetCO 2 ), arterial oxygen saturation (SpO 2 ), and skin and core temperature. Results: ACZ increased resting global CBF compared with PLA (1271 ± 290 vs. 1070 ± 192 mL/min, +19.8 ± 22.1%, p = 0.009) and remained elevated during all subsequent testing conditions (17–32% above PLA). Passive heat stress duration tended to be longer during the ACZ visit (65.5 ± 18.1 vs. 56.3 ± 11.7 min, p = 0.060) but elicited comparable increases in core temperature (ACZ +1.6 ± 0.5°C vs. PLA +1.7 ± 0.2°C, p = 0.548) and skin temperature. Hypoxia produced similar reductions in PetO 2 , PetCO 2 , and SpO 2 during ACZ and PLA sessions – both alone and when combined with heat (all p > 0.05). Relative to normothermia, heat exposure led to modest and comparable improvements in reaction time in both ACZ (-49.5 ± 61.3, p = 0.012) and PLA (-94.04 ± 121.4, p < 0.001) while accuracy was preserved. However, general cognitive performance (reaction time and accuracy) did not differ between the conditions, despite the substantial elevation in CBF with ACZ. Conclusion: Pharmacologically elevating CBF did not alter cognitive performance during combined hypoxia and heat, suggesting that cerebral perfusion may not be a primary determinant of cognitive resilience under these environmental stressors. Funding: This work was supported by the Health of the Forces" initiative led by the College of Health and Human Sciences (HHS) and the Military Family Research Institute (MFRI), and by the Arthur C. Guyton Award from the American Physiological Society. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.