Estimates of the global population of humans living at high altitude vary widely, and such data at the country level are unavailable. Herein, we use a geographic information system (GIS)-based ...approach to quantify human population at 500-m elevation intervals for each country. Based on georeferenced data for population (LandScan Global 2019) and elevation (Global Multiresolution Terrain Elevation Data), 500.3 million humans live at ≥1,500 m, 81.6 million at ≥2,500 m, and 14.4 million at ≥3,500 m. Ethiopia has the largest absolute population at ≥1,500 m and ≥2,500 m, while China has the greatest at ≥3,500 m. Lesotho has the greatest percentage of its population above 1,500 m, while Bolivia has the greatest at ≥2,500 m and ≥3,500 m. High altitude presents a myriad of environmental stresses that provoke physiological responses and adaptation, and consequently impact disease prevalence and severity. While the majority of high-altitude physiology research is based upon lowlanders from western, educated, industrialized, rich, and democratic countries ascending to high altitude, the global population distribution of high-altitude residents encourages an increased emphasis on understanding high-altitude physiology, adaptation, epidemiology, and public health in the ∼500 million permanent high-altitude residents.
Hypoxic ischemic brain injury (HIBI) after cardiac arrest (CA) is a leading cause of mortality and long-term neurologic disability in survivors. The pathophysiology of HIBI encompasses a ...heterogeneous cascade that culminates in secondary brain injury and neuronal cell death. This begins with primary injury to the brain caused by the immediate cessation of cerebral blood flow following CA. Thereafter, the secondary injury of HIBI takes place in the hours and days following the initial CA and reperfusion. Among factors that may be implicated in this secondary injury include reperfusion injury, microcirculatory dysfunction, impaired cerebral autoregulation, hypoxemia, hyperoxia, hyperthermia, fluctuations in arterial carbon dioxide, and concomitant anemia.Clarifying the underlying pathophysiology of HIBI is imperative and has been the focus of considerable research to identify therapeutic targets. Most notably, targeted temperature management has been studied rigorously in preventing secondary injury after HIBI and is associated with improved outcome compared with hyperthermia. Recent advances point to important roles of anemia, carbon dioxide perturbations, hypoxemia, hyperoxia, and cerebral edema as contributing to secondary injury after HIBI and adverse outcomes. Furthermore, breakthroughs in the individualization of perfusion targets for patients with HIBI using cerebral autoregulation monitoring represent an attractive area of future work with therapeutic implications.We provide an in-depth review of the pathophysiology of HIBI to critically evaluate current approaches for the early treatment of HIBI secondary to CA. Potential therapeutic targets and future research directions are summarized.
New Findings
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 response of cerebral vasculature to exercise is different from other peripheral vasculature; it has a small vascular bed and is strongly regulated by cerebral autoregulation and the partial ...pressure of arterial carbon dioxide (Pa(CO(2))). In contrast to other organs, the traditional thinking is that total cerebral blood flow (CBF) remains relatively constant and is largely unaffected by a variety of conditions, including those imposed during exercise. Recent research, however, indicates that cerebral neuronal activity and metabolism drive an increase in CBF during exercise. Increases in exercise intensity up to approximately 60% of maximal oxygen uptake produce elevations in CBF, after which CBF decreases toward baseline values because of lower Pa(CO(2)) via hyperventilation-induced cerebral vasoconstriction. This finding indicates that, during heavy exercise, CBF decreases despite the cerebral metabolic demand. In contrast, this reduced CBF during heavy exercise lowers cerebral oxygenation and therefore may act as an independent influence on central fatigue. In this review, we highlight methodological considerations relevant for the assessment of CBF and then summarize the integrative mechanisms underlying the regulation of CBF at rest and during exercise. In addition, we examine how CBF regulation during exercise is altered by exercise training, hypoxia, and aging and suggest avenues for future research.
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.
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.
Cerebral blood flow (CBF) and its distribution are highly sensitive to changes in the partial pressure of arterial CO(2) (Pa(CO(2))). This physiological response, termed cerebrovascular CO(2) ...reactivity, is a vital homeostatic function that helps regulate and maintain central pH and, therefore, affects the respiratory central chemoreceptor stimulus. CBF increases with hypercapnia to wash out CO(2) from brain tissue, thereby attenuating the rise in central Pco(2), whereas hypocapnia causes cerebral vasoconstriction, which reduces CBF and attenuates the fall of brain tissue Pco(2). Cerebrovascular reactivity and ventilatory response to Pa(CO(2)) are therefore tightly linked, so that the regulation of CBF has an important role in stabilizing breathing during fluctuating levels of chemical stimuli. Indeed, recent reports indicate that cerebrovascular responsiveness to CO(2), primarily via its effects at the level of the central chemoreceptors, is an important determinant of eupneic and hypercapnic ventilatory responsiveness in otherwise healthy humans during wakefulness, sleep, and exercise and at high altitude. In particular, reductions in cerebrovascular responsiveness to CO(2) that provoke an increase in the gain of the chemoreflex control of breathing may underpin breathing instability during central sleep apnea in patients with congestive heart failure and on ascent to high altitude. In this review, we summarize the major factors that regulate CBF to emphasize the integrated mechanisms, in addition to Pa(CO(2)), that control CBF. We discuss in detail the assessment and interpretation of cerebrovascular reactivity to CO(2). Next, we provide a detailed update on the integration of the role of cerebrovascular CO(2) reactivity and CBF in regulation of chemoreflex control of breathing in health and disease. Finally, we describe the use of a newly developed steady-state modeling approach to examine the effects of changes in CBF on the chemoreflex control of breathing and suggest avenues for future research.
Neurovascular coupling reflects the close temporal and regional linkage between neural activity and cerebral blood flow. Although providing mechanistic insight, our understanding of neurovascular ...coupling is largely limited to non-physiological ex vivo preparations and non-human models using sedatives/anesthetics with confounding cerebrovascular implications. Herein, with particular focus on humans, we review the present mechanistic understanding of neurovascular coupling and highlight current approaches to assess these responses and the application in health and disease. Moreover, we present new guidelines for standardizing the assessment of neurovascular coupling in humans. To improve the reliability of measurement and related interpretation, the utility of new automated software for neurovascular coupling is demonstrated, which provides the capacity for coalescing repetitive trials and time intervals into single contours and extracting numerous metrics (e.g., conductance and pulsatility, critical closing pressure, etc.) according to patterns of interest (e.g., peak/minimum response, time of response, etc.). This versatile software also permits the normalization of neurovascular coupling metrics to dynamic changes in arterial blood gases, potentially influencing the hyperemic response. It is hoped that these guidelines, combined with the newly developed and openly available software, will help to propel the understanding of neurovascular coupling in humans and also lead to improved clinical management of this critical physiological function.
Abstract Although the human cerebral circulation is richly innervated with sympathetic nerve fibers, the role of sympathetic nerve activity (SNA) on the regulation of cerebral blood flow (CBF) ...remains debated. Several issues may be responsible for the conflicting conclusions reported in the animal vs. human literature in regards to the sympathetic control of the brain circulation. Furthermore, due to the physiological consequences associated with SNA blockade (e.g. changes in blood pressure and cardiac output), and differences in methodology (e.g. assessment of CBF), interpretation of the role of SNA in CBF regulation in humans is challenging. The goals of this brief review are to provide an overview of the role of neural control in the regulation of CBF, with a focus on SNA and discuss the likely reasons behind the controversial influence of SNA on CBF regulation. A final objective of this article is to critically review the various methods available to measure CBF and highlight their strengths and weaknesses to provide insight in SNA regulation of CBF.
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