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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What is the topic of this review? The manuscript collectively combines the experimental observations from >100 publications focusing on the regulation of cerebral blood flow and metabolism during exercise from 1945 to the present day. What advances does it highlight? This article highlights the importance of traditional and historical assessments of cerebral blood flow and metabolism during exercise, as well as traditional and new insights into the complex factors involved in the integrative regulation of brain blood flow and metabolism during exercise. The overarching theme is the importance of quantifying cerebral blood flow and metabolism during exercise using techniques that consider multiple volumetric cerebral haemodynamics (i.e. velocity, diameter, shear and flow). Cerebral function in humans is crucially dependent upon continuous oxygen delivery, metabolic nutrients and active regulation of cerebral blood flow (CBF). As a consequence, cerebrovascular function is precisely titrated by multiple physiological mechanisms, characterized by complex integration, synergism and protective redundancy. At rest, adequate CBF is regulated through reflexive responses in the following order of regulatory importance: fluctuating arterial blood gases (in particularly, partial pressure of carbon dioxide), cerebral metabolism, arterial blood pressure, neurogenic activity and cardiac output. Unfortunately, the magnitude that these integrative and synergistic relationships contribute to governing the CBF during exercise remains unclear. Despite some evidence indicating that CBF regulation during exercise is dependent on the changes of blood pressure, neurogenic activity and cardiac output, their role as a primary governor of the CBF response to exercise remains controversial. In contrast, the balance between the partial pressure of carbon dioxide and cerebral metabolism continues to gain empirical support as the primary contributor to the intensity-dependent changes in CBF observed during submaximal, moderate and maximal exercise. The goal of this review is to summarize the fundamental physiology and mechanisms involved in regulation of CBF and metabolism during exercise. The clinical implications of a better understanding of CBF during exercise and new research directions are also outlined.

The study examined the influence of cerebral (prefrontal cortex) and muscle (vastus lateralis) oxygenation on the ability to perform repeated, cycling sprints. Thirteen team-sport athletes performed ten, 10-s sprints (with 30 s of rest) under normoxic (F(I)O(2) 0.21) and acute hypoxic (F(I)O(2) 0.13) conditions in a randomised, single-blind fashion and crossover design. Mechanical work was calculated and arterial O(2) saturation (S(p)O(2)) was estimated via pulse oximetry for every sprint. Cerebral and muscle oxy-(O(2)Hb), deoxy-(HHb), and total haemoglobin (THb) were monitored continuously by near-infrared spectroscopy. Compared with normoxia, hypoxia induced larger decrements in S(p)O(2) and work (11.6 and 7.6%, respectively; P < 0.05). In the muscle, we observed a fairly constant level of deoxygenation across sprints, with no effect of the condition. In normoxia, regional cerebral oxygenation increased during the first two sprints and slightly fluctuated thereafter. In contrast, this initial cerebral hyper-oxygenation was attenuated in hypoxia. Changes in [O(2)Hb] and [HHb] occurred earlier and were larger in hypoxia compared with normoxia (P < 0.05), while regional blood volume (Delta[THb]) remained unaffected by the condition. Changes in cerebral [HHb] and mechanical work were strongly correlated in normoxia and hypoxia (R(2) = 0.81 and R(2) = 0.85, respectively; P < 0.05), although the slope of this relationship differed (normoxia, -351.3 +/- 183.3 vs. hypoxia, -442.4 +/- 227.2; P < 0.05). The results of this NIRS study show that O(2) availability influences prefrontal cortex, but not muscle, oxygenation during repeated, short sprints. By using a hypoxia paradigm, the study suggests that cerebral oxygenation contributes to the impairment of repeated-sprint ability.

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.

We investigated 1) the regional distribution of cerebral blood flow (CBF), 2) the influence of end-tidal Pco2 (PetCO2) on CBF, and 3) the potential for an extracranial blood "steal" from the anterior brain region during passive hyperthermia. Nineteen (13 male) volunteers underwent supine passive heating until a steady-state esophageal temperature of 2°C above resting was established. Measurements were obtained 1) during normothermia (Normo), 2) during poikilocapnic hyperthermia (Hyper), and 3) during hyperthermia with PetCO2 and end-tidal Po2 clamped to Normo levels (Hyper-clamp). Blood flow in the internal carotid (Qica), vertebral (QVA), and external carotid (Qeca) arteries (Duplex ultrasound), blood velocity of the middle cerebral (MCAv) and posterior cerebral (PCAv) arteries (transcranial Doppler), and cutaneous vascular conductance on the cheek (cheek CVC; Doppler velocimetry) were measured at each stage. During Hyper, PetCO2 was lowered by 7.0 ± 5.2 mmHg, resulting in a reduction in Qica (-18 ± 17%), Qva (-31 ± 21%), MCAv (-22 ± 13%), and PCAv (-18 ± 10%) compared with Normo (P < 0.05). The reduction in QVA was greater than that in QICA (P = 0.017), MCAv (P = 0.047), and PCAv (P = 0.034). Blood flow/velocity was completely restored in each intracranial vessel (ICA, VA, MCA, and PCA) during Hyper-clamp. Despite a ∼250% increase in QECA and a subsequent increase in cheek CVC during Hyper compared with Normo, reductions in QICA were unrelated to changes in QECA. These data provide three novel findings: 1) hyperthermia attenuates QVA to a greater extent than QICA, 2) reductions in CBF during hyperthermia are governed primarily by reductions in arterial Pco2, and 3) increased QECA is unlikely to compromise QICA during hyperthermia.

Non-technical summary Heat stress reduces brain blood flow and impairs orthostatic tolerance. Brain blood flow is largely controlled by the partial pressure of arterial P CO 2 . Indeed, hyperthermia-induced over-breathing and related reductions in arterial P CO 2 account for ∼50% of the reduction in brain blood flow. This investigation tested the unique hypothesis that the distribution of cardiac output during heat stress (challenged by thermoregulatory increases in skin blood flow and sweat loss) contributes to the remaining 50%. We show that cardiac output is not related to brain blood flow, but rather arterial P CO 2 plays a much larger role than previously suggested. These findings help us understand the mechanisms relating heat stress with an increased likelihood of fainting, and are also relevant to pathological conditions that are accompanied by elevations in body temperature.Abstract Cerebral blood flow (CBF) is reduced during passive heat stress, with 50% of this reduction associated with hyperventilatory-induced hypocapnia and subsequent cerebral vasoconstriction. It remains unknown, however, what other factors may contribute to the remaining 50%. We tested the hypothesis that the distribution of cardiac output plays an important role in maintaining cerebral perfusion during mild and severe heat stress. Middle cerebral artery and posterior cerebral artery blood flow velocity (MCAv and PCAv; transcranial Doppler) and left ventricular end-diastolic and end-systolic volumes (2-D echocardiography) were measured under conditions of normothermia and mild and severe passive heat stress (core temperature +0.8 ± 0.1• C (Protocol I; n = 10) and 1.8 ± 0.1 • C (Protocol II; n = 8) above baseline). Venous return was manipulated by passive tilt table positioning (30 deg head-down tilt (HDT) and 30 deg head-up tilt (HUT)). Measurements were made under poikilocapnic and isocapnic conditions. Protocol I consisted of mild heat stress which resulted in small reductions in end-tidal CO 2 (−5.6 ± 3.5%), MCAv/PCAv (−7.3 ± 2.3% and −10.3 ± 2.9%, respectively) and stroke volume (−8.5 ± 4.2%); while end-diastolic volume was significantly reduced (−16.9 ± 4.0%) and cardiac output augmented (17.2 ± 7.4%). During mild heat stress, CBF was related to left ventricular end-diastolic volume (MCAv, r 2 = 0.81; PCAv, r 2 = 0.83; P < 0.05) and stroke volume (MCAv, r 2 = 0.38; PCAv, r 2 = 0.43), but not with cardiac output. Protocol II consisted of severe heat stress which resulted in much greater reductions in end-tidal CO 2 (−87.5 ± 31.5%) and CBF (MCAv, −36.4 ± 6.1%; PCAv, −30.1 ± 4.8%; P < 0.01 for all variables), while end-diastolic volume and stroke volume decreased to a similar extent as for mild heat stress. Importantly, isocapnia restored MCAv and PCAv back to normothermic baseline. This investigation therefore produced two novel findings: first, that venous return and stroke volume are related to CBF during mild heat stress; and second, that hyperventilatory hypocapnia has a major influence on CBF during severe passive heat str...