The brain is a vital organ that relies on a constant and adequate blood flow to match oxygen and glucose delivery with the local metabolic demands of active neurons. Thus exquisite regulation of ...cerebral blood flow (CBF) is particularly important under hypoxic conditions to prevent a detrimental decrease in the partial pressure of oxygen within the brain tissues. Cerebrovascular sensitivity to hypoxia, assessed as the change in CBF during a hypoxic challenge, represents the capacity of cerebral vessels to respond to, and compensate for, a reduced oxygen supply, and has been shown to be impaired or blunted in a number of conditions. For instance, this is observed with aging, and in clinical conditions such as untreated obstructive sleep apnea (OSA) and in healthy humans exposed to intermittent hypoxia. This review will
) provide a brief overview of cerebral blood flow regulation and results of pharmacological intervention studies which we have performed to better elucidate the basic mechanisms of cerebrovascular regulation in humans; and
) present data from studies in clinical and healthy populations, using a translational physiology approach, to investigate human CBF control during hypoxia. Results from studies in patients with chronic obstructive pulmonary disease and OSA will be presented to identify the effects of the disease processes on cerebrovascular sensitivity to hypoxia. Data emerging from experimental human models of intermittent hypoxia during wakefulness will also be reviewed to highlight the effects of intermittent hypoxia on the brain.
Periodic occlusion of the upper airway in patients with obstructive sleep apnea leads to chronic intermittent hypoxia, which increases the acute hypoxic ventilatory response (AHVR). Animal studies ...suggest that oxidative stress may modulate AHVR by increasing carotid body sensitivity to hypoxia. This has not been shown in humans.
To determine whether 4 days of exposure to chronic intermittent hypoxia increases AHVR and oxidative stress and to determine the strength of the association between oxidative stress and AHVR.
After two normoxic control days (Day -4 and Day 0), 10 young healthy men were exposed awake to 4 days (Days 1-4) of intermittent hypoxia for 6 hours per day.
AHVR, assessed using an isocapnic hypoxia protocol, was determined as the slope of the linear regression between ventilation and oxygen desaturation. Oxidative stress was evaluated by measuring plasma DNA, lipid and protein oxidation, uric acid and antioxidant status by measuring alpha-tocopherol, total vitamin C, and antioxidant enzymatic activities. Between baseline and Day 4, there were significant increases in AHVR, DNA oxidation, uric acid, and vitamin C, whereas antioxidant enzymatic activities and alpha-tocopherol were unchanged. There were strong correlations between the changes in AHVR and DNA oxidation (r = 0.88; P = 0.002).
Chronic intermittent hypoxia increases oxidative stress by increasing production of reactive oxygen species without a compensatory increase in antioxidant activity. This human study shows that reactive oxygen species overproduction modulates increased AHVR. These mechanisms may be responsible for increased AHVR in patients with obstructive sleep apnea.
Neurocognitive functions are affected by high altitude, however the altitude effects of acclimatization and repeated exposures are unclear. We investigated the effects of acute, subacute and repeated ...exposure to 5,050 m on cognition among altitude-naïve participants compared to control subjects tested at low altitude.
Twenty-one altitude-naïve individuals (25.3 ± 3.8 years, 13 females) were exposed to 5,050 m for 1 week (
and re-exposed after a week of rest at sea-level (
). Baseline (BL, 520 m), acute (Day 1, HA1) and acclimatization (Day 6, HA6, 5,050 m) measurements were taken in both cycles. Seventeen control subjects (24.9 ± 2.6 years, 12 females) were tested over a similar period in Calgary, Canada (1,103 m). The Reaction Time (RTI), Attention Switching Task (AST), Rapid Visual Processing (RVP) and One Touch Stockings of Cambridge (OTS) tasks were administered and outcomes were expressed in milliseconds/frequencies. Lake Louise Score (LLS) and blood oxygen saturation (SpO
) were recorded.
In both cycles, no significant changes were found with acute exposure on the AST total score, mean latency and SD. Significant changes were found upon acclimatization solely in the altitude group, with improved AST Mean Latency HA1 (588 ± 92) vs. HA6 (526 ± 91),
< 0.001 and Latency SD HA1 (189 ± 86) vs. HA6 (135 ± 65),
< 0.001 compared to acute exposure, in
. No significant differences were present in the control group. When entering Acute SpO
(HA1-BL), Acclimatization SpO
(HA6-BL) and LLS score as covariates for both cycles, the effects of acclimatization on AST outcomes disappeared indicating that the changes were partially explained by SpO
and LLS. The changes in AST Mean Latency ΔBL (-61.2 ± 70.2) vs. ΔHA6 (-28.0 ± 58),
= 0.005 and the changes in Latency SD ΔBL (-28.4 ± 41.2) vs. ΔHA6 (-0.2235 ± 34.8),
= 0.007 across the two cycles were smaller with acclimatization. However, the percent changes did not differ between cycles. These results indicate independent effects of altitude across repeated exposures.
Selective and sustained attention are impaired at altitude and improves with acclimatization.The observed changes are associated, in part, with AMS score and SpO
. The gains in cognition with acclimatization during a first exposure are not carried over to repeated exposures.
High altitude (HA) hypoxia may affect cognitive performance and sleep quality. Further, vigilance is reduced following sleep deprivation. We investigated the effect on vigilance, actigraphic sleep ...indices, and their relationships with acute mountain sickness (AMS) during very HA exposure, acclimatization, and re-exposure.
A total of 21 healthy altitude-naive individuals (25 ± 4 years; 13 females) completed 2 cycles of altitude exposure separated by 7 days at low altitude (LA, 520 m). Participants slept at 2900 m and spent the day at HA, (5050 m). We report acute altitude exposure on Day 1 (LA vs. HA1) and after 6 days of acclimatization (HA1 vs. HA6). Vigilance was quantified by reaction speed in the 10-min psychomotor vigilance test reaction speed (PVT-RS). AMS was evaluated using the Environmental Symptoms Questionnaire Cerebral Score (AMS-C score). Nocturnal rest/activity was recorded to estimate sleep duration using actigraphy.
In
, PVT-RS was slower at HA1 compared to LA (4.1 ± 0.8 vs. 4.5 ± 0.6 s
, respectively,
= 0.029), but not at HA6 (4.6 ± 0.7;
> 0.05). In
, PVT-RS at HA1 (4.6 ± 0.7) and HA6 (4.8 ± 0.6) were not different from LA (4.8 ± 0.6,
> 0.05) and significantly greater than corresponding values in
. In both cycles, AMS scores were higher at HA1 than at LA and HA6 (
< 0.05). Estimated sleep durations (TST) at LA, 1st and 5th nights were 431.3 ± 28.7, 418.1 ± 48.6, and 379.7 ± 51.4 min, respectively, in
and they were significantly reduced during acclimatization exposures (LA vs. 1st night,
> 0.05; LA vs. 5th night,
= 0.012; and 1st vs. 5th night,
= 0.054). LA, 1st and 5th nights TST in
were 477.5 ± 96.9, 430.9 ± 34, and 341.4 ± 32.2, respectively, and we observed similar deteriorations in TST as in
(LA vs. 1st night,
> 0.05; LA vs. 5th night,
= 0.001; and 1st vs. 5th night,
< 0.0001). At HA1, subjects who reported higher AMS-C scores exhibited slower PVT-RS (
= -0.56;
< 0.01). Subjects with higher AMS-C scores took longer time to react to the stimuli during acute exposure (
= 0.62,
< 0.01) during HA1 of
.
Acute exposure to HA reduces the PVT-RS. Altitude acclimatization over 6 days recovers the reaction speed and prevents impairments during subsequent altitude re-exposure after 1 week spent near sea level. However, acclimatization does not lead to improvement in total sleep time during acute and subacute exposures.
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