Uchida, Kôji

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

Background Despite improvements in military aircraft safety, many aviation incidents are attributed to hypoxia. The correlation between moderate hypoxia and cognitive function are well studied but results remain controversial. Comparatively, the effects of severe hypoxia are still not well understood. In the present study, we examined the executive cognitive function and physiological indices under both moderate and severe hypoxia conditions. Purpose To examine the relationship between executive function and physiological indices during acute hypoxia exposure. Methods Ten young healthy participants (4M/6F, 29±4 years) completed two different levels of hypoxia: 1) 10 minute moderate hypoxia (MH; F i O 2 = 0.118) and 2) 3 minute severe hypoxia (SH; F i O 2 = 0.077) following 3 minute baseline (BL; F i O 2 =0.209). Reaction time and errors of commission (defined as a response to a non‐target stimulus) were evaluated continuously using a custom Go/No‐go test at baseline and throughout hypoxia exposure. In this Go/No‐go test, participants were required to push a key when upper case “A” or “@” appeared but not when lower case “a” appeared on a computer monitor as quick and as accurately as possible. The stimuli were presented one at a time at any one of nine differing locations across the screen. Cerebral oxygenation (rSO 2 ) was continuously monitored with near‐infrared spectroscopy (NIRS) positioned above the left supraorbital ridge. Finger oxygen saturation (S p O 2 ) was continuously assessed using a pulse oximetry. Data were analyzed in every 30 seconds and are presented as mean±SE. Two‐way ANOVA and Bonferroni test for multiple comparisons was used to evaluate significant differences. Results Both S p O 2 and rSO 2 were reduced with SH (S p O 2 %, BL: 99.3±0.1% vs. SH: 70.7±1.5%, P<0.01; rSO 2 %, BL: 70±4% vs. SH: 58±4%, P<0.01). In SH, correlations of S p O 2 and rSO 2 were significant to the number of errors during the cognitive performance task (S p O 2 ; R= −0.65, rSO 2 ; R= −0.58, Both P<0.01). SH significantly increased errors of commission of the last 30 seconds in 3 minute hypoxic exposure. (BL: 0.6±0.2 errors vs. SH: 1.7±0.5 errors, P<0.01). SH significantly decreased reaction time over hypoxic exposure (BL: 0.43±0.01 sec vs. SH: 0.41±0.01 sec, P<0.01). Comparatively, MH did not elicit an increase in the number of errors of commission nor a decrease in reaction time (Both, P>0.05). Conclusion Executive function deteriorated during severe hypoxia. Oxygenation of the prefrontal lobe which controls inhibition may be related to the increase in commission errors. Devices that monitor physiological indices such as S p O 2 or rSO 2 might be beneficial for a model to predict executive deterioration. Support or Funding Information This project was funded by the Office of Naval Research (ONR), grant number N00014‐18‐D‐7001‐TO1.

Background In humans, exercise tolerance is determined by the balance of diffusive and convective elements of oxygen transport. Mathematical models have suggested that alterations in hemoglobin‐oxygen (Hb‐O 2 ) binding affinity (P 50 ) have minimal effects of on oxygen delivery. However, there is limited experimental data in humans to evaluate these models during exercise in humans. Purpose We sought to investigate skeletal muscle blood flow and vascular conductance (hyperemic response to exercise and hypoxia) during exercise in otherwise healthy participants with chronically high Hb‐O 2 affinity (HAH). We hypothesized that patients with HAH would have a blunted hyperemic response to both handgrip and hypoxia due to the marked polycythemia that is typical in participants with HAH compared to controls. Methods Participants with HAH (n=6, 3 men, age= 37±12 yr, P 50 =15±2 mmHg) and control participants matched for age, sex, and BMI (CTL, n=5, 3 men, age=41±8 yr, and P 50 =26±1 mmHg) completed two intensities (10% and 20% maximal voluntary contraction (MVC)) of rhythmic handgrip exercise with a duty cycle of 1s contraction and 2s relaxation (20 contractions·min −1 ). Each exercise intensity was performed breathing three different gas mixtures: 21%, 15%, and 10% oxygen. Brachial artery mean blood velocity was measured using Doppler ultrasound. Beat‐by‐beat blood pressure was measured via arterial catheterization. Forearm blood flow (FBF) was calculated as the product of mean blood velocity (cm·s −1 ) and brachial artery cross‐sectional area (cm 2 ) and expressed as milliliters per minute (mL·min −1 ), and forearm vascular conductance (FVC) was calculated as (FBF) × (mean arterial pressure) −1 × 100 and expressed as mL·min −1 ·mmHg −1 . Data were analyzed using a three‐way ANOVA (Inspirate [21%, 15%, 10% O 2 ], group [CTL, HAH], handgrip intensity [Rest, 10% and 20% MVC]). Results During normoxia (21% O 2 ), groups were not different in FBF (P>0.05), FVC (P>0.05) or arterial saturation (S a O 2 , P=0.54). Similarly, the moderate hypoxia condition (15% O 2 ), groups were not different in FBF (P>0.05), or FVC (P>0.05) despite a preservation in arterial saturation in HAH (S a O 2 , CTL: 89.0±0.7% vs. HAH: 95.1±1.7%, P<0.001). However, with more severe hypoxic exposure (10% O 2 ), FBF and FVC were higher in HAH than controls during the 20% MVC exercise (P<0.05). HAH also had higher FBF (P<0.05) and trended towards higher FVC in the 10% MVC exercise (P=0.08). Interestingly, arterial saturation was drastically higher for HAH at the end of handgrip exercise (20% MVC) in 10% O 2 (CTL: 69.2±4.5% vs. HAH: 89.1±1.4%, P<0.001). Conclusion As predicted in mathematical models, Hb‐O 2 binding affinity had little effect on skeletal muscle blood flow and forearm vascular conductance during light exercise under normoxic and moderate hypoxic conditions (21% and 15% O 2 ). However, with a greater physiological stress to skeletal muscle O 2 uptake in a more severe hypoxic condition (10% O 2 ), participants with HAH, contrary to our initial hypothesis, had preserved arterial O 2 saturation and a greater hyperemic response than controls. Support or Funding Information This work was supported by the NIH (5T32DK007352‐39 to CCW, R35HL139854 to MJJ) Rest 10% MVC 20% MVC FBF, mL·min − 1 21% O 2 CTL 87 ± 8 327 ± 25 589 ± 26 HAH 142 ± 19 420 ± 29 716 ± 68 15% O 2 CTL 173 ± 61 357 ± 63 707 ± 62 HAH 156 ± 66 539 ± 111 930 ± 143 10% O 2 CTL 154 ± 72 386 ± 81 668 ± 57 HAH 244 ± 133 703 ± 199 * 932 ± 118 * FVC, mL·min − 1 ·mmHg − 1 21% O 2 CTL 94 ± 9 356 ± 27 621 ± 24 HAH 130 ± 19 363 ± 25 617 ± 63 15% O 2 CTL 187 ± 63 384 ± 54 758 ± 53 HAH 137 ± 44 453 ± 79 764 ± 226 10% O 2 CTL 171 ± 71 431 ± 73 708 ± 67 HAH 221 ± 109 718 ± 136 917 ± 172 Abbreviations: FBF, forearm blood flow; FVC, forearm vascular conductance; MVC, maximal voluntary contraction; CTL, control group; HAH, high‐affinity Hb group. Values are presented as mean±SE. * indicates significant difference (P<0.05) from CTL group at same %MVC.