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.

Herein, we review mechanisms regulating cerebral blood flow (CBF), with specific focus on humans. We revisit important concepts from the older literature and describe the interaction of various mechanisms of cerebrovascular control. We amalgamate this broad scope of information into a brief review, rather than detailing any one mechanism or area of research. The relationship between regulatory mechanisms is emphasized, but the following three broad categories of control are explicated: (1) the effect of blood gases and neuronal metabolism on CBF; (2) buffering of CBF with changes in blood pressure, termed cerebral autoregulation; and (3) the role of the autonomic nervous system in CBF regulation. With respect to these control mechanisms, we provide evidence against several canonized paradigms of CBF control. Specifically, we corroborate the following four key theses: (1) that cerebral autoregulation does not maintain constant perfusion through a mean arterial pressure range of 60-150 mmHg; (2) that there is important stimulatory synergism and regulatory interdependence of arterial blood gases and blood pressure on CBF regulation; (3) that cerebral autoregulation and cerebrovascular sensitivity to changes in arterial blood gases are not modulated solely at the pial arterioles; and (4) that neurogenic control of the cerebral vasculature is an important player in autoregulatory function and, crucially, acts to buffer surges in perfusion pressure. Finally, we summarize the state of our knowledge with respect to these areas, outline important gaps in the literature and suggest avenues for future research. G -monomethyl-L-arginine; MAP, mean arterial pressure; MRI, magnetic resonance imaging; P aCO2 , arterial partial pressure of carbon dioxide; P aO2 , arterial partial pressure of oxygen; PET, positron emission tomography; SNS, sympathetic nervous system; VA, vertebral artery.Christopher Willie discovered physiology as an undergraduate student in the laboratory of Dr. Richard Wilson while working toward his Bachelors of Health Science degree at the University of Calgary. He met Dr Philip Ainslie at the same time and five years later began his PhD under Dr Ainslie's supervision. Mr. Willie's interests are studying human integrative physiology, with focus on cerebrovascular responses to changes in blood gases and blood pressure. To keep balanced, he enjoys rock, ice and alpine climbing around the world. In the future, Mr Willie plans to continue both his scientific and adventurous pursuits. Philip Ainslie is currently a Professor in the School of Health and Exercise Sciences at the University of British Columbia-Okanagan and holds a Canada Research Chair in Cerebrovascular Physiology. His main research focus attempts to examine the fundamental mechanisms that regulate human cerebral blood flow in health and in disease. He has a particular interest in how environmental stress -especially in the context of hypoxia, temperature, pressure and exercise -may impact on cerebral blood flow regulation.

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Abstract-Cerebral autoregulation (CA) is a critical process for the maintenance of cerebral blood flow and oxygenation.Assessment of CA is frequently used for experimental research and in the diagnosis, monitoring, or prognosis of cerebrovascular disease; however, despite the extensive use and reference to static CA, a valid quantification of "normal" CA has not been clearly identified. While controlling for the influence of arterial PCO 2 , we provide the first clear examination of static CA in healthy humans over a wide range of blood pressure. In 11 healthy humans, beat-to-beat blood pressure (radial arterial), middle cerebral artery blood velocity (MCAv; transcranial Doppler ultrasound), end-tidal PCO 2 , and cerebral oxygenation (near infrared spectroscopy) were recorded continuously during pharmacological-induced changes in mean blood pressure. In a randomized order, steady-state decreases and increases in mean blood pressure (8 to 14 levels; range: Ϸ40 to Ϸ125 mm Hg) were achieved using intravenous infusions of sodium nitroprusside or phenylephrine, respectively. MCAv mean was altered by 0.82Ϯ0.35% per millimeter of mercury change in mean blood pressure (R 2 ϭ0.82). Changes in cortical oxygenation index were inversely related to changes in mean blood pressure (slopeϭϪ0.18%/mm Hg; R 2 ϭ0.60) and MCAv mean (slopeϭϪ0.26%/cm ⅐ s Ϫ1; R 2 ϭ0.54). There was a progressive increase in MCAv pulsatility with hypotension. These findings indicate that cerebral blood flow closely follows pharmacological-induced changes in blood pressure in otherwise healthy humans. Thus, a finite slope of the plateau region does not necessarily imply a defective CA. Moreover, with progressive hypotension and hypertension there are differential changes in cerebral oxygenation and MCAv mean . (Hypertension. 2010;55:698-705.)

We examined the between-day reproducibility of active (squat-stand maneuvers)- and passive [oscillatory lower-body negative pressure (OLBNP) maneuvers]-driven oscillations in blood pressure. These relationships were examined in both younger (n = 10; 25 ± 3 yr) and older (n = 9; 66 ± 4 yr) adults. Each testing protocol incorporated rest (5 min), followed by driven maneuvers at 0.05 (5 min) and 0.10 (5 min) Hz to increase blood-pressure variability and improve assessment of the pressure-flow dynamics using linear transfer function analysis. Beat-to-beat blood pressure, middle cerebral artery velocity, and end-tidal partial pressure of CO2 were monitored. The pressure-flow relationship was quantified in the very low (0.02-0.07 Hz) and low (0.07-0.20 Hz) frequencies (LF; spontaneous data) and at 0.05 and 0.10 Hz (driven maneuvers point estimates). Although there were no between-age differences, very few spontaneous and OLBNP transfer function metrics met the criteria for acceptable reproducibility, as reflected in a between-day, within-subject coefficient of variation (CoV) of <20%. Combined CoV data consist of LF coherence (15.1 ± 12.2%), LF gain (15.1 ± 12.2%), and LF normalized gain (18.5 ± 10.9%); OLBNP data consist of 0.05 (12.1 ± 15.%) and 0.10 (4.7 ± 7.8%) Hz coherence. In contrast, the squat-stand maneuvers revealed that all metrics (coherence: 0.6 ± 0.5 and 0.3 ± 0.5%; gain: 17.4 ± 12.3 and 12.7 ± 11.0%; normalized gain: 16.7 ± 10.9 and 15.7 ± 11.0%; and phase: 11.6 ± 10.2 and 17.3 ± 10.8%) at 0.05 and 0.10 Hz, respectively, were considered biologically acceptable for reproducibility. These findings have important implications for the reliable assessment and interpretation of cerebral pressure-flow dynamics in humans.

We assessed the convergent validity of commonly applied metrics of cerebral autoregulation (CA) to determine the extent to which the metrics can be used interchangeably. To examine between-subject relationships among low-frequency (LF; 0.07-0.2 Hz) and very-low-frequency (VLF; 0.02-0.07 Hz) transfer function coherence, phase, gain, and normalized gain, we performed retrospective transfer function analysis on spontaneous blood pressure and middle cerebral artery blood velocity recordings from 105 individuals. We characterized the relationships (n ϭ 29) among spontaneous transfer function metrics and the rate of regulation index and autoregulatory index derived from bilateral thigh-cuff deflation tests. In addition, we analyzed data from subjects (n ϭ 29) who underwent a repeated squat-to-stand protocol to determine the relationships between transfer function metrics during forced blood pressure fluctuations. Finally, data from subjects (n ϭ 16) who underwent step changes in end-tidal PCO 2 (PETCO 2 ) were analyzed to determine whether transfer function metrics could reliably track the modulation of CA within individuals. CA metrics were generally unrelated or showed only weak to moderate correlations. Changes in PET CO 2 were positively related to coherence [LF: ␤ ϭ 0.0065 arbitrary units (AU)/mmHg and VLF: ␤ ϭ 0.011 AU/mmHg, both P Ͻ 0.01] and inversely related to phase (LF: ␤ ϭ Ϫ0.026 rad/mmHg and VLF: ␤ ϭ Ϫ0.018 rad/mmHg, both P Ͻ 0.01) and normalized gain (LF: ␤ ϭ Ϫ0.042%/mmHg 2 and VLF: ␤ ϭ Ϫ0.013%/mmHg 2 , both P Ͻ 0.01). However, PETCO 2 was positively associated with gain (LF: ␤ ϭ 0.0070 cm·s

Cerebral autoregulation (CA) is integral to the delicate process of maintaining stable cerebral perfusion and brain tissue oxygenation against changes in arterial blood pressure. The last four decades has seen dramatic advances in understanding CA physiology, and the role that CA might play in the causation and progression of disease processes that affect the cerebral circulation such as stroke. However, the translation of these basic scientific advances into clinical practice has been limited by the maintenance of old constructs and because there are persistent gaps in our understanding of how this vital vascular mechanism should be quantified. In this review, we re-evaluate relevant studies that challenge established paradigms about how the cerebral perfusion pressure and blood flow are related. In the context of blood pressure being a major haemodynamic challenge to the cerebral circulation, we conclude that: (1) the physiological properties of CA remain inconclusive, (2) many extant methods for CA characterisation are based on simplistic assumptions that can give rise to misleading interpretations, and (3) robust evaluation of CA requires thorough consideration not only of active vasomotor function, but also the unique properties of the intracranial environment.

Abstract-The cerebrovasculature dilates or constricts in response to acute blood pressure changes to stabilize cerebral blood flow across a range of blood pressures. It is unclear, however, whether such dynamic cerebral autoregulation (dCA) is equally effective in responding to falling versus rising blood pressure. In this study we applied a pharmacological approach to evaluate dCA gain to transient hypotension and hypertension and compared this method with 2 established indices of dCA that do not explicitly differentiate between dCA efficacy and falling versus rising blood pressure. Middle cerebral arterial velocity and blood pressure recordings were made in 26 healthy volunteers randomized to 2 protocols. In 10 subjects, dCA gain to transient hypotension induced with intravenous nitroprusside was compared with dCA gain to transient hypertension induced with intravenous phenylephrine.