Key points• The partial pressures of arterial carbon dioxide (P aCO 2 ) and oxygen (P aO 2 ) has a marked influence on brain blood flow.• It is unclear if the larger brain arteries are also sensitive to changing P aCO 2 and P aO 2 and if different areas of the brain possess different sensitivities.• We separately altered P aCO 2 and P aO 2 and measured the diameter and blood flow in the main arteries delivering blood to the cortex and brainstem.• During alterations in P aCO 2 and P aO 2 , the large arteries changed diameter and blood flow to the brainstem changed more than that to the cortex.• These findings change the basis of our understanding of brain blood flow control in humans.Abstract Despite the importance of blood flow on brainstem control of respiratory and autonomic function, little is known about regional cerebral blood flow (CBF) during changes in arterial blood gases. We quantified: (1) anterior and posterior CBF and reactivity through a wide range of steady-state changes in the partial pressures of CO 2 (P aCO 2 ) and O 2 (P aO 2 ) in arterial blood, and (2) determined if the internal carotid artery (ICA) and vertebral artery (VA) change diameter through the same range. We used near-concurrent vascular ultrasound measures of flow through the ICA and VA, and blood velocity in their downstream arteries (the middle (MCA) and posterior (PCA) cerebral arteries). Part A (n = 16) examined iso-oxic changes in P aCO 2 , consisting of three hypocapnic stages (P aCO 2 = ∼15, ∼20 and ∼30 mmHg) and four hypercapnic stages (P aCO 2 = ∼50, ∼55, ∼60 and ∼65 mmHg). In Part B (n = 10), during isocapnia, P aO 2 was decreased to ∼60, ∼44, and ∼35 mmHg and increased to ∼320 mmHg and ∼430 mmHg. Stages lasted ∼15 min. Intra-arterial pressure was measured continuously; arterial blood gases were sampled at the end of each stage. There were three principal findings. (1) Regional reactivity: the VA reactivity to hypocapnia was larger than the ICA, MCA and PCA; hypercapnic reactivity was similar. With profound hypoxia (35 mmHg) the relative increase in VA flow was 50% greater than the other vessels. (2) Neck vessel diameters: changes in diameter (∼25%) of the ICA was positively related to changes in P aCO 2 (R 2 , 0.63 ± 0.26; P < 0.05); VA diameter was unaltered in response to changed P aCO 2 but yielded a diameter increase of +9% with severe hypoxia. blood flow regulation to the brainstem and cortex; (2) cerebrovascular resistance is not solely modulated at the level of the arteriolar pial vessels; and (3) transcranial Doppler ultrasound may underestimate measurements of CBF during extreme hypoxia and/or hypercapnia.

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Key pointsr This study assessed the dynamic response of global cerebral blood flow (CBF) and cerebral fuel utilization during and following incremental supine exercise to exhaustion.r Global CBF increased more during exercise and recovery at high altitude (HA) compared with sea level (SL) such that cerebral oxygen delivery (CD O 2 ) was maintained.r The increase in cerebral metabolic rate of oxygen during maximal exercise at HA was half the increase observed at SL.r Arterial lactate production during exercise at the same absolute intensities was greater at HA compared with SL, but reduced at the same relative intensities.r Cerebral carbohydrate uptake (lactate and glucose) is greater than oxygen uptake at HA compared with SL, indicating a shift towards an increased non-oxidative metabolic utilization.r These results suggest that CBF increases to maintain CD O 2 during exercise at HA while changes in arterial lactate concentration and exercise intensity augment the oxidative and non-oxidative pathways to cerebral metabolism at HA. AbstractWe examined the hypotheses that: (1) during incremental exercise and recovery following 4-6 days at high altitude (HA) global cerebral blood flow (gCBF) increases to preserve cerebral oxygen delivery (CD O 2 ) in excess of that required by an increasing cerebral metabolic rate of oxygen (CMR O 2 ); (2) the trans-cerebral exchange of oxygen vs. carbohydrates (OCI; carbohydrates = glucose + ½lactate) would be similar during exercise and recovery at HA and sea level (SL). Global CBF, intra-cranial arterial blood velocities, extra-cranial blood flows, and arterial-jugular venous substrate differences were measured during progressive steady-state exercise (20, 40, 60, 80, 100% maximum workload (W max )) and through 30 min of recovery. Measurements (n = 8) were made at SL and following partial acclimatization to 5050 m. At HA, absolute W max was reduced by ß50%. During submaximal exercise workloads (20-60% W max ), despite an elevated absolute gCBF (ß20%, P < 0.05) the relative increases in gCBF were not different at HA and SL. In contrast, gCBF was elevated at HA compared with SL during 80 and 100% W max and recovery.

The interindividual variation in ventilatory acclimatization to high altitude is likely reflected in variability in the cerebrovascular responses to high altitude, particularly between brain regions displaying disparate hypoxic sensitivity. We assessed regional differences in cerebral blood flow (CBF) measured with Duplex ultrasound of the left internal carotid and vertebral arteries. End-tidal Pco2, oxyhemoglobin saturation (SpO2), blood pressure, and heart rate were measured during a trekking ascent to, and during the first 2 wk at, 5,050 m. Transcranial color-coded Duplex ultrasound (TCCD) was employed to measure flow and diameter of the middle cerebral artery (MCA). Measures were collected at 344 m (TCCD-baseline), 1,338 m (CBF-baseline), 3,440 m, and 4,371 m. Following arrival to 5,050 m, regional CBF was measured every 12 h during the first 3 days, once at 5-9 days, and once at 12-16 days. Total CBF was calculated as twice the sum of internal carotid and vertebral flow and increased steadily with ascent, reaching a maximum of 842 ± 110 ml/min (+53 ± 7.6% vs. 1,338 m; mean ± SE) at ∼ 60 h after arrival at 5,050 m. These changes returned to +15 ± 12% after 12-16 days at 5,050 m and were related to changes in SpO2 (R(2) = 0.36; P < 0.0001). TCCD-measured MCA flow paralleled the temporal changes in total CBF. Dilation of the MCA was sustained on days 2 (+12.6 ± 4.6%) and 8 (+12.9 ± 2.9%) after arrival at 5,050 m. We observed no significant differences in regional CBF at any time point. In conclusion, the variability in CBF during ascent and acclimatization is related to ventilatory acclimatization, as reflected in changes in SpO2.

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