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1
Jain, Varsha, Erin M. Buckley, Daniel J. Licht, Jennifer M. Lynch, Peter J. Schwab, Maryam Y. Naim, Natasha A. Lavin, et al. "Cerebral Oxygen Metabolism in Neonates with Congenital Heart Disease Quantified by MRI and Optics." Journal of Cerebral Blood Flow & Metabolism 34, no. 3 (December 11, 2013): 380–88. http://dx.doi.org/10.1038/jcbfm.2013.214.
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Neonatal congenital heart disease (CHD) is associated with altered cerebral hemodynamics and increased risk of brain injury. Two novel noninvasive techniques, magnetic resonance imaging (MRI) and diffuse optical and correlation spectroscopies (diffuse optical spectroscopy (DOS), diffuse correlation spectroscopy (DCS)), were employed to quantify cerebral blood flow ( CBF) and oxygen metabolism ( CMRO2) of 32 anesthetized CHD neonates at rest and during hypercapnia. Cerebral venous oxygen saturation ( Sv O2) and CBF were measured simultaneously with MRI in the superior sagittal sinus, yielding global oxygen extraction fraction ( OEF) and global CMRO2 in physiologic units. In addition, microvascular tissue oxygenation ( StO2) and indices of microvascular CBF (BFI) and CMRO2 ( CMRO2i) in the frontal cortex were determined by DOS/DCS. Median resting-state MRI-measured OEF, CBF, and CMRO2 were 0.38, 9.7 mL/minute per 100 g and 0.52 mL O2/minute per 100 g, respectively. These CBF and CMRO2 values are lower than literature reports for healthy term neonates (which are sparse and quantified using different methods) and resemble values reported for premature infants. Comparison of MRI measurements of global Sv O2, CBF, and CMRO2 with corresponding local DOS/DCS measurements demonstrated strong linear correlations ( R2=0.69, 0.67, 0.67; P<0.001), permitting calibration of DOS/DCS indices. The results suggest that MRI and optics offer new tools to evaluate cerebral hemodynamics and metabolism in CHD neonates.
2
Klementavicius, Richard, Edwin M. Nemoto, and Howard Yonas. "The Q10 ratio for basal cerebral metabolic rate for oxygen in rats." Journal of Neurosurgery 85, no. 3 (September 1996): 482–87. http://dx.doi.org/10.3171/jns.1996.85.3.0482.
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✓ Previously the authors showed that hypothermia exerts a greater effect on the cerebral metabolic rate for oxygen (CMRO2) that is associated with the maintenance of cellular viability, or “basal” CMRO2, than on electroencephalogram (EEG)-associated CMRO2 or “functional” CMRO2. On the basis of their findings, the authors hypothesized that the ratio of CMRO2 over a 10°C temperature range (Q10) for basal CMRO2 was greater than that for functional and total CMRO2. They tested their hypothesis by determining the Q10 for basal CMRO2 from 38°C to 28°C. They measured whole-brain cerebral blood flow (CBF) and CMRO2 in six rats during progressive hypothermia at a brain temperature of 38°C and, after induction of an isoelectric EEG signal (50 µV/cm) with thiopental sodium, they repeated the measurements at 38°C, 34°C, 30°C, and 28°C. In a control group (five rats), six sequential measurements of CBF and CMRO2 were made while the animals were anesthetized by 0.5% isoflurane/70% N2O/30% O2 at a brain temperature of 38°C over a time span equivalent to the hypothermic group, that is, approximately 3 hours. The Q10 for basal CMRO2 calculated over 38°C to 28°C was 5.2 ± 0.92. However, the decrease in basal CMRO2 between 38°C and 28°C was nonlinear on a log plot, revealing a two-component response: a high temperature sensitivity component between 38°C and 30°C with a Q10 of 12.1, and a lower temperature sensitivity component between 30°C and 28°C with a Q10 of 2.8. The combined overall Q10 for basal CMRO2 between 38° and 28°C was 5.2. The energy-requiring processes associated with these high and low temperature sensitivity components of basal CMRO2 have yet to be identified.
3
Zhu, Xiao-Hong, Nanyin Zhang, Yi Zhang, Kâmil Uğurbil, and Wei Chen. "New Insights into Central Roles of Cerebral Oxygen Metabolism in the Resting and Stimulus-Evoked Brain." Journal of Cerebral Blood Flow & Metabolism 29, no. 1 (September 10, 2008): 10–18. http://dx.doi.org/10.1038/jcbfm.2008.97.
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The possible role of oxygen metabolism in supporting brain activation remains elusive. We have used a newly developed neuroimaging approach based on high-field in vivo17O magnetic resonance spectroscopic (MRS) imaging to noninvasively image cerebral metabolic rate of oxygen (CMRO2) consumption in cats at rest and during visual stimulation. It was found that CMRO2 increases significantly (32.3% ± 10.8%, n = 6) in the activated visual cortical region as depicted in blood oxygenation level dependence functional maps; this increase is also accompanied by a CMRO2 decrease in surrounding cortical regions, resulting a smaller increase (9.7% ± 1.9%) of total CMRO2 change over a larger cortical region displaying either a positive or negative CMRO2 alteration. Moreover, a negative correlation between stimulus-evoked percent CMRO2 increase and resting CMRO2 was observed, indicating an essential impact of resting brain metabolic activity level on stimulus-evoked percent CMRO2 change and neuroimaging signals. These findings provide new insights into the critical roles of oxidative metabolism in supporting brain activation and function. They also suggest that in vivo17O MRS imaging should provide a sensitive neuroimaging modality for mapping CMRO2 and its change induced by brain physiology and/or pathologic alteration.
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Meyer, E., J. L. Tyler, C. J. Thompson, C. Redies, M. Diksic, and A. M. Hakim. "Estimation of Cerebral Oxygen Utilization Rate by Single-Bolus 15O2 Inhalation and Dynamic Positron Emission Tomography." Journal of Cerebral Blood Flow & Metabolism 7, no. 4 (August 1987): 403–14. http://dx.doi.org/10.1038/jcbfm.1987.83.
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This study shows that regional CMRO2 can be estimated by means of nonlinear regression using dynamic positron emission tomographic data acquired during 1 min following single-bolus inhalation of 15O2. The feasibility of simultaneous estimation of CBF, cerebral blood volume (CBV), oxygen extraction ratio (OER), and CMRO2 was assessed by simulations using the model of Mintun et al. Four oxygen metabolic measurements, each consisting of a CBF, CBV, and 15O2 bolus study, were carried out on three volunteers. Regional values for CBF, CBV, OER, and CMRO2 were derived in two ways: from the fits of the time-activity curves of the dynamic 15O2 bolus study alone [CMRO2(fit)] and from the three separate studies [CMRO2 (control)]. For the 56 regions of interest analyzed, using a fit interval of 60 s, CMRO2(fit) was 93.4 ± 7.8% of CMRO2(control) (mean ± SD) with a correlation coefficient of r = 0.95. CMRO2(control) ranged from 87 to 290 μmol/min/100 g. Individual simultaneous estimates of CBF, CBV, and OER were not reliable. Finally, we found that the validity of the model was limited in practice to the first minute after tracer inhalation.
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Thomsen, Kirsten, Henning Piilgaard, Albert Gjedde, Gilles Bonvento, and Martin Lauritzen. "Principal Cell Spiking, Postsynaptic Excitation, and Oxygen Consumption in the Rat Cerebellar Cortex." Journal of Neurophysiology 102, no. 3 (September 2009): 1503–12. http://dx.doi.org/10.1152/jn.00289.2009.
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One contention within the field of neuroimaging concerns the character of the depicted activity: Does it represent neuronal action potential generation (i.e., spiking) or postsynaptic excitation? This question is related to the metabolic costs of different aspects of neurosignaling. The cerebellar cortex is well suited for addressing this problem because synaptic input to and spiking of the principal cell, the Purkinje cell (PC), are spatially segregated. Also, PCs are pacemakers, able to generate spikes endogenously. We examined the contributions to cerebellar cortical oxygen consumption (CMRO2) of postsynaptic excitation and PC spiking during evoked and ongoing neuronal activity in the rat. By inhibiting excitatory synaptic input using ionotropic glutamate receptor blockers, we found that the increase in CMRO2 evoked by parallel fiber (PF) stimulation depended entirely on postsynaptic excitation. In contrast, PC spiking was largely responsible for the increase in CMRO2 when ongoing neuronal activity was increased by γ-aminobutyric acid type A receptor blockade. In this case, CMRO2 increased equally during PC spiking with excitatory synaptic activity as during PC pacemaker spiking without excitatory synaptic input. Subsequent inhibition of action potential propagation and neurotransmission by blocking voltage-gated Na+-channels eliminated the increases in CMRO2 due to PF stimulation and increased PC spiking, but left a large fraction of CMRO2, i.e., basal CMRO2, intact. In conclusion, whereas basal CMRO2 in anesthetized animals did not seem to be related to neurosignaling, increases in CMRO2 could be induced by all aspects of neurosignaling. Our findings imply that CMRO2 responses cannot a priori be assigned to specific neuronal activities.
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Rodgers, Zachary B., John A. Detre, and Felix W. Wehrli. "MRI-based methods for quantification of the cerebral metabolic rate of oxygen." Journal of Cerebral Blood Flow & Metabolism 36, no. 7 (April 18, 2016): 1165–85. http://dx.doi.org/10.1177/0271678x16643090.
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The brain depends almost entirely on oxidative metabolism to meet its significant energy requirements. As such, the cerebral metabolic rate of oxygen (CMRO2) represents a key measure of brain function. Quantification of CMRO2 has helped elucidate brain functional physiology and holds potential as a clinical tool for evaluating neurological disorders including stroke, brain tumors, Alzheimer’s disease, and obstructive sleep apnea. In recent years, a variety of magnetic resonance imaging (MRI)-based CMRO2 quantification methods have emerged. Unlike positron emission tomography – the current “gold standard” for measurement and mapping of CMRO2 – MRI is non-invasive, relatively inexpensive, and ubiquitously available in modern medical centers. All MRI-based CMRO2 methods are based on modeling the effect of paramagnetic deoxyhemoglobin on the magnetic resonance signal. The various methods can be classified in terms of the MRI contrast mechanism used to quantify CMRO2: T2*, T2′, T2, or magnetic susceptibility. This review article provides an overview of MRI-based CMRO2 quantification techniques. After a brief historical discussion motivating the need for improved CMRO2 methodology, current state-of-the-art MRI-based methods are critically appraised in terms of their respective tradeoffs between spatial resolution, temporal resolution, and robustness, all of critical importance given the spatially heterogeneous and temporally dynamic nature of brain energy requirements.
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Vazquez, Alberto L., Mitsuhiro Fukuda, and Seong-Gi Kim. "Evolution of the Dynamic Changes in Functional Cerebral Oxidative Metabolism from Tissue Mitochondria to Blood Oxygen." Journal of Cerebral Blood Flow & Metabolism 32, no. 4 (February 1, 2012): 745–58. http://dx.doi.org/10.1038/jcbfm.2011.198.
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The dynamic properties of the cerebral metabolic rate of oxygen consumption (CMRO2) during changes in brain activity remain unclear. Therefore, the spatial and temporal evolution of functional increases in CMRO2 was investigated in the rat somato-sensory cortex during forelimb stimulation under a suppressed blood flow response condition. Temporally, stimulation elicited a fast increase in tissue mitochondria CMRO2 described by a time constant of ~ 1 second measured using flavoprotein autofluorescence imaging. CMRO2-driven changes in the tissue oxygen tension measured using an oxygen electrode and blood oxygenation measured using optical imaging of intrinsic signal followed; however, these changes were slow with time constants of ~ 5 and ~ 10 seconds, respectively. This slow change in CMRO2-driven blood oxygenation partly explains the commonly observed post-stimulus blood oxygen level-dependent (BOLD) undershoot. Spatially, the changes in mitochondria CMRO2 were similar to the changes in blood oxygenation. Finally, the increases in CMRO2 were well correlated with the evoked multi-unit spiking activity. These findings show that dynamic CMRO2 calculations made using only blood oxygenation data (e.g., BOLD functional magnetic resonance imaging (fMRI)) do not directly reflect the temporal changes in the tissue's mitochondria metabolic rate; however, the findings presented can bridge the gap between the changes in cellular oxidative rate and blood oxygenation.
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Vafaee, Manouchehr S., Albert Gjedde, Nasrin Imamirad, Kim Vang, Mallar M. Chakravarty, Jason P. Lerch, and Paul Cumming. "Smoking Normalizes Cerebral Blood Flow and Oxygen Consumption after 12-Hour Abstention." Journal of Cerebral Blood Flow & Metabolism 35, no. 4 (January 21, 2015): 699–705. http://dx.doi.org/10.1038/jcbfm.2014.246.
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Acute nicotine administration stimulates [14C]deoxyglucose trapping in thalamus and other regions of rat brain, but acute effects of nicotine and smoking on energy metabolism have rarely been investigated in human brain by positron emission tomography (PET). We obtained quantitative PET measurements of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) in 12 smokers who had refrained from smoking overnight, and in a historical group of nonsmokers, testing the prediction that overnight abstinence results in widespread, coupled reductions of CBF and CMRO2. At the end of the abstention period, global grey-matter CBF and CMRO2 were both reduced by 17% relative to nonsmokers. At 15 minutes after renewed smoking, global CBF had increased insignificantly, while global CMRO2 had increased by 11%. Regional analysis showed that CMRO2 had increased in the left putamen and thalamus, and in right posterior cortical regions at this time. At 60 and 105 minutes after smoking resumption, CBF had increased by 8% and CMRO2 had increased by 11–12%. Thus, we find substantial and global impairment of CBF/CMRO2 in abstaining smokers, and acute restoration by resumption of smoking. The reduced CBF and CMRO2 during acute abstention may mediate the cognitive changes described in chronic smokers.
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Busija, D. W., C. W. Leffler, and M. Pourcyrous. "Hyperthermia increases cerebral metabolic rate and blood flow in neonatal pigs." American Journal of Physiology-Heart and Circulatory Physiology 255, no. 2 (August 1, 1988): H343—H346. http://dx.doi.org/10.1152/ajpheart.1988.255.2.h343.
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We examined effects of hyperthermia on cerebral metabolic rate for oxygen (CMRO2) and cerebral blood flow (CBF) in anesthetized, newborn pigs (2–5 days old). CBF and CMRO2 were measured during normothermia (38 degrees C) and during hyperthermia induced by body heating (42 degrees C). During normothermia, total CBF was 32 +/- 3 ml.min-1.100 g-1 (n = 9), and CMRO2 was 1.34 +/- 0.08 ml O2.100 g-1.min-1 (n = 7). During hyperthermia, total CBF increased by 97 +/- 23% and CMRO2 by 65 +/- 24%. We also examined whether cerebral resistance vessels were responsive under these conditions. During hyperthermia, total CBF was 63 +/- 6 ml.min-1.100 g-1, and CMRO2 was 2.13 +/- 0.27 ml O2.100 g-1.min-1. During sustained hyperthermia, intravenous injection of 5 mg/kg of indomethacin decreased total CBF by 45 +/- 7% (n = 9), and CMRO2 fell by 55 +/- 10% (n = 5). We conclude that 1) hyperthermia increases CBF and CMRO2, and 2) the dilated cerebrovascular bed during hyperthermia still is responsive to a constrictor stimulus.
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Singh, Narendra C., Patrick M. Kochanek, Joanne K. Schiding, John A. Melick, and Edwin M. Nemoto. "Uncoupled Cerebral Blood Flow and Metabolism after Severe Global Ischemia in Rats." Journal of Cerebral Blood Flow & Metabolism 12, no. 5 (September 1992): 802–8. http://dx.doi.org/10.1038/jcbfm.1992.111.
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In a rat model of complete global brain ischemia (neck tourniquet) lasting either 3 min or 20 min, we monitored global CBF (sagittal sinus H2 clearance) and CMRO2 for 6 h to test the hypothesis that delayed postischemic hyperemia and uncoupling of CBF and CMRO2 occur depending on the severity of the insult. Early postischemic hyperemia occurred in both the 3-min and 20-min groups ( p < 0.05 vs. baseline values) and resolved by 15 min. Hypoperfusion occurred in the 3-min group between 15 and 60 min postischemia (≈23% reduction), and in the 20-min group from 15 to 120 min postischemia (≈50% reduction) ( p < 0.05), and then resolved. CMRO2 was not significantly different from baseline at any time after ischemia in the 3-min group. After 20 min of ischemia, however, CMRO2 was decreased (≈60%) throughout the postischemic period ( p < 0.05). At 5 min after ischemia, CBF/CMRO2 was increased in both groups but returned to baseline from 60 to 120 min postischemia. In the 3-min group, CBF/CMRO2 remained at baseline throughout the rest of the experiment. However, in the 20-min group, CBF/CMRO2 once again increased (≈100%), reaching a significant level at 180 min and remaining so for the rest of the 6-h period ( p < 0.05). These data demonstrate biphasic uncoupling of CBF and CMRO2 after severe (20 min) global ischemia in rats. This relatively early reemergence of CBF/CMRO2 uncoupling after 180 min of reperfusion is similar to that observed after prolonged cardiac arrest and resuscitation in humans.
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Horvath, Ildiko, Norbert T. Sandor, Zoltan Ruttner, and Alan C. McLaughlin. "Role of Nitric Oxide in Regulating Cerebrocortical Oxygen Consumption and Blood Flow during Hypercapnia." Journal of Cerebral Blood Flow & Metabolism 14, no. 3 (May 1994): 503–9. http://dx.doi.org/10.1038/jcbfm.1994.62.
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The effect of the nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) on the response of cerebrocortical oxygen consumption (CMRO2) and blood flow (CBF) to two levels of hypercapnia (Paco2 ∼ 60 mm Hg and Paco2 ∼ 90 mm Hg) was investigated in ketamine-anesthetized rats. CBF was calculated using the Kety–Schmidt approach and CMRO2 was calculated from the product of CBF and the arteriovenous (superior sagittal sinus) difference for oxygen. l-NAME treatment did not have a significant effect on either CMRO2 or CBE under normocapnic conditions but inhibited the hypercapnic increase of CMRO2 and the hypercapnic increase in CBF. These results suggest that NO plays a role in the response of CMRO2 and CBF during hypercapnia and are consistent with the suggestion that at least part of the increase in CBF observed during hypercapnia is coupled to an increase in CMRO2.
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Madsen, Peter Lund, Søren Holm, Margrethe Herning, and Niels A. Lassen. "Average Blood Flow and Oxygen Uptake in the Human Brain during Resting Wakefulness: A Critical Appraisal of the Kety—Schmidt Technique." Journal of Cerebral Blood Flow & Metabolism 13, no. 4 (July 1993): 646–55. http://dx.doi.org/10.1038/jcbfm.1993.83.
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The Kety–Schmidt technique can be regarded as the reference method for measurement of global average cerebral blood flow (average CBF) and global average cerebral metabolic rate of oxygen (average CMRO2). However, in the practical application of the method, diffusion equilibrium for inert gas tracer between the brain and its venous blood is not reached. As a consequence, normal values for CBF and CMRO2 of 54 ml 100 g−1 min−1 and 3.5 ml 100 g−1 min−1 obtained with the Kety–Schmidt technique are an overestimation of the true values. Using the Kety–Schmidt technique we have performed 57 measurements of CBF and CMRO2 during EEG-verified wakeful rest in young normal adults. In order to estimate the equilibrium values for CBF and CMRO2, a simple computer-based simulation model was employed to quantitate the systematic overestimation caused by incomplete tracer equilibrium. When correcting the measured data, we find that the true average values for CBF and CMRO2 in the healthy young adult are ∼46 ml 100 g−1 min−1 and ∼3.0 ml 100 g−1 min−1. Previous studies have suggested that some of the variation in CMRO2 values could be ascribed to differences in cerebral venous anatomy. However in the present study, no correlation between CMRO2 and cerebral venous anatomy as imaged by magnetic resonance angiography could be established. Our data show that the interindividual variation of CMRO2 is 11% (coefficient of variation).
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Parnianfard, Neda, Fatemeh Seifar, Mohammad Aboutalebi, Farid Hajibonabi, and Manouchehr S. Vafaee. "30: CEREBRAL BLOOD FLOW AND CEREBRAL OXYGEN METABOLISM IN NORMAL AGING: A PRECURSOR FOR STUDY OF DEMENTIA AND ALZHEIMER'S DISEASE." BMJ Open 7, Suppl 1 (February 2017): bmjopen—2016–015415.30. http://dx.doi.org/10.1136/bmjopen-2016-015415.30.
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Background and aims:Aging brain has been demonstrated to be the main risk factor for dementia and Alzheimer's disease (AD). Recent findings provide clear evidence that the structural and functional integrity of the brain depends on the delicate balance between substrate delivery through blood flow and energy demands imposed by neural activity. Imaging studies of aging have in general shown reductions of cerebral blood flow (CBF) and the cerebral metabolic rates of oxygen (CMRO2) in healthy elderly adults. Based on the existing evidence, we hypothesized the CBF and CMRO2 in healthy young subjects will be higher than CBF and CMRO2 in elderly adults which itself should be higher than AD patients. Therefore, we designed the present studies specifically to reveal the role of defective cerebral oxygen metabolism and cerebral blood flow in normal aging.Methods:To test the predictions, we acquired PET scans of CBF and CMRO2 at baseline from 12 young and 12 healthy elderly subjects. The subjects underwent 2 sessions of 3-min PET scans of CBF, and CMRO2. During the CBF scans, 500 MBq of 15O-labelled water (15O-H215O) were injected intravenously at the start of each scan while they inhaled 500 MBq of 15O-[O2] in one breathe at the start of each CMRO2 scan. Quantitative CBF and CMRO2 measures were computed as parametric maps. Each subject also underwent MRI scan for structural-functional (MRI-PET) correlation.Results:The resulting global values of CBF and CMRO2 were not significantly different from each other in each age group implying that whole brain cerebral blood flow and oxygen metabolism globally do not differ from each other as one ages. However, ROI (region of interest) analysis of average CBF scans of young versus elderly revealed significant CBF and CMRO2 differences as shown in Figure 1.Conclusion:Aging appears to decrease both CBF and CMRO2, which in turn might lead to impairment in cognitive functions, an important hallmark of dementia and AD. Although it remains a matter of controversy as to whether cerebral perfusion and metabolism declines with healthy aging, however the current study confirms that indeed CBF and CMRO2 decline with age in healthy individuals.
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Valabrègue, Romain, Agnès Aubert, Jacques Burger, Jacques Bittoun, and Robert Costalat. "Relation between Cerebral Blood Flow and Metabolism Explained by a Model of Oxygen Exchange." Journal of Cerebral Blood Flow & Metabolism 23, no. 5 (May 2003): 536–45. http://dx.doi.org/10.1097/01.wcb.0000055178.31872.38.
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The cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) are major determinants of the contrast in functional magnetic resonance imaging and optical imaging. However, the coupling between CBF and CMRO2 during cerebral activation remains controversial. Whereas most of the previous models tend to show a nonlinear coupling, experimental studies have led to conflicting conclusions. A physiologic model was developed of oxygen transport through the blood–brain barrier (BBB) for dynamic and stationary states. Common model simplifications are proposed and their implications for the CBF/CMRO2 relation are studied. The tissue oxygen pool, the BBB permeability, and the hemoglobin dissociation curve are physiologic parameters directly involved in the CBF/CMRO2 relation. We have been shown that the hypothesis of a negligible tissue oxygen pool, which was admitted by most of the previous models, implies a tight coupling between CBF and CMRO2. By relaxing this hypothesis, a real uncoupling was allowed that gives a more coherent view of the CBF/CMRO2 relation, in better agreement with the hypercapnia data and with the variability reported in experimental works for the relative changes of those two variables. This also allows a temporal mismatch between CBF and CMRO2, which influences the temporal shape of oxygenation at the capillary end.
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Donegan, J. H., R. J. Traystman, R. C. Koehler, M. D. Jones, and M. C. Rogers. "Cerebrovascular hypoxic and autoregulatory responses during reduced brain metabolism." American Journal of Physiology-Heart and Circulatory Physiology 249, no. 2 (August 1, 1985): H421—H429. http://dx.doi.org/10.1152/ajpheart.1985.249.2.h421.
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The effect of reducing cerebral oxygen consumption (CMRO2) on the cerebral blood flow (CBF) responses to isocapnic hypoxic hypoxia and hypotension was examined in sheep. Newborn and adult animals were studied because of their different base-line CMRO2. Microsphere-measured CBF responses during pentobarbital coma (i.e., electroencephalographic silence) were compared with responses in conscious or lightly sedated animals. Induction of barbiturate coma reduced both CMRO2 and CBF by 50% from the awake value and by 25% from the value obtained in animals sedated with pentobarbital. The CBF response to 30 and 50% reductions in arterial O2 content (CaO2) was attenuated during coma, but only in proportion to the decrease in CMRO2. Whether CMRO2 was normal or reduced, the normoxic cerebral O2 delivery (CaO2 X CBF) was maintained during hypoxia in both newborns and adults. The relative autoregulatory index (fractional change in CBF divided by fractional change in perfusion pressure) was determined during graded hemorrhage. The index was not significantly different from zero (which represents perfect autoregulation) in awake, lightly sedated, or comatose animals. The data demonstrate that both base-line CBF and responses to hypoxia are closely tied to CMRO2 and that 50% reduction of CMRO2 does not impair cerebrovascular autoregulation.
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Madsen, P. L., J. F. Schmidt, G. Wildschiodtz, L. Friberg, S. Holm, S. Vorstrup, and N. A. Lassen. "Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep." Journal of Applied Physiology 70, no. 6 (June 1, 1991): 2597–601. http://dx.doi.org/10.1152/jappl.1991.70.6.2597.
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It could be expected that the various stages of sleep were reflected in variation of the overall level of cerebral activity and thereby in the magnitude of cerebral metabolic rate of oxygen (CMRO2) and cerebral blood flow (CBF). The elusive nature of sleep imposes major methodological restrictions on examination of this question. We have now measured CBF and CMRO2 in young healthy volunteers using the Kety-Schmidt technique with 133Xe as the inert gas. Measurements were performed during wakefulness, deep sleep (stage 3/4), and rapid-eye-movement (REM) sleep as verified by standard polysomnography. Contrary to the only previous study in humans, which reported an insignificant 3% reduction in CMRO2 during sleep, we found a deep-sleep-associated statistically highly significant 25% decrease in CMRO2, a magnitude of depression according with studies of glucose uptake and reaching levels otherwise associated with light anesthesia. During REM sleep (dream sleep) CMRO2 was practically the same as in the awake state. Changes in CBF paralleled changes in CMRO2 during both deep and REM sleep.
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Tichauer, Kenneth M., Derek W. Brown, Jennifer Hadway, Ting-Yim Lee, and Keith St Lawrence. "Near-infrared spectroscopy measurements of cerebral blood flow and oxygen consumption following hypoxia-ischemia in newborn piglets." Journal of Applied Physiology 100, no. 3 (March 2006): 850–57. http://dx.doi.org/10.1152/japplphysiol.00830.2005.
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Impaired oxidative metabolism following hypoxia-ischemia (HI) is believed to be an early indicator of delayed brain injury. The cerebral metabolic rate of oxygen (CMRO2) can be measured by combining near-infrared spectroscopy (NIRS) measurements of cerebral blood flow (CBF) and cerebral deoxy-hemoglobin concentration. The ability of NIRS to measure changes in CMRO2 following HI was investigated in newborn piglets. Nine piglets were subjected to 30 min of HI by occluding both carotid arteries and reducing the fraction of inspired oxygen to 8%. An additional nine piglets served as sham-operated controls. Measurements of CBF, oxygen extraction fraction (OEF), and CMRO2 were obtained at baseline and at 6 h after the HI insult. Of the three parameters, only CMRO2 showed a persistent and significant change after HI. Five minutes after reoxygenation, there was a 28 ± 12% (mean ± SE) decrease in CMRO2, a 72 ± 50% increase in CBF, and a 56 ± 19% decrease in OEF compared with baseline ( P < 0.05). By 30 min postinsult and for the remainder of the study, there were no significant differences in CBF and OEF between control and insult groups, whereas CMRO2 remained depressed throughout the 6-h postinsult period. This study demonstrates that NIRS can measure decreases in CMRO2 caused by HI. The results highlight the potential for NIRS to be used in the neonatal intensive care unit to detect delayed brain damage.
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McPherson, R. W., D. Eimerl, and R. J. Traystman. "Interaction of hypoxia and hypercapnia on cerebral hemodynamics and brain electrical activity in dogs." American Journal of Physiology-Heart and Circulatory Physiology 253, no. 4 (October 1, 1987): H890—H897. http://dx.doi.org/10.1152/ajpheart.1987.253.4.h890.
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The interaction of hypoxic hypoxia, hypercapnia, and mean arterial blood pressure (MABP) was studied in 15 pentobarbital-anesthetized ventilated dogs. In one group of animals (n = 5) hypercapnia [arterial CO2 partial pressure (PaCO2) approximately 50 Torr] was added to both moderate hypoxia and severe hypoxia. Moderate hypoxia [arterial O2 partial pressure (PaO2) = 36 mmHg] increased MABP and cerebral blood flow (CBF) without changes in cerebral O2 uptake (CMRO2). Superimposed hypercapnia increased CBF and MABP further with no change in CMRO2. In another group of animals (n = 5), a MABP increase of approximately 40 mmHg during moderate hypoxia without hypercapnia did not further increase CBF, suggesting intact autoregulation. Thus, during moderate hypoxia, hypercapnia is capable of increasing CBF. Severe hypoxia (PaO2 = 22 mmHg) increased CBF, but MABP and CMRO2 declined. Superimposed hypercapnia further decreased MABP and decreased CBF from its elevated level and further decreased CMRO2. Raising MABP under these circumstances in another animal group (n = 5) increased CBF above the level present during severe hypoxia alone and increased CMRO2. The change in CBF and CMRO2 during severe hypoxia plus hypercapnia with MABP elevation were not different from that severe hypoxia alone. We conclude that, during hypoxia sufficiently severe to impair CMRO2, superimposed hypercapnia has a detrimental influence due to decreased MABP, which causes a decrease in CBF and cerebral O2 delivery.
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Zhang, Yaoyu, Yayan Yin, Huanjie Li, and Jia-Hong Gao. "Measurement of CMRO2 and its relationship with CBF in hypoxia with an extended calibrated BOLD method." Journal of Cerebral Blood Flow & Metabolism 40, no. 10 (October 30, 2019): 2066–80. http://dx.doi.org/10.1177/0271678x19885124.
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Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) are physiological parameters that not only reflect brain health and disease but also jointly contribute to blood oxygen level-dependent (BOLD) signals. Nevertheless, unsolved issues remain concerning the CBF–CMRO2 relationship in the working brain under various oxygen conditions. In particular, the CMRO2 responses to functional tasks in hypoxia are less studied. We extended the calibrated BOLD model to incorporate CMRO2 measurements in hypoxia. The extended model, which was cross-validated with a multicompartment BOLD model, considers the influences of the reduced arterial saturation level and increased baseline cerebral blood volume (CBV) and deoxyhemoglobin concentration on the changes of BOLD signals in hypoxia. By implementing a pulse sequence to simultaneously acquire the CBV-, CBF- and BOLD-weighted signals, we investigated the effects of mild hypoxia on the CBF and CMRO2 responses to graded visual stimuli. Compared with normoxia, mild hypoxia caused significant alterations in both the amplitude and the trend of the CMRO2 responses but did not impact the corresponding CBF responses. Our observations suggested that the flow-metabolism coupling strategies in the brain during mild hypoxia were different from those during normoxia.
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Zhang, Nanyin, Xiao-Hong Zhu, Hao Lei, Kamil Ugurbil, and Wei Chen. "Simplified Methods for Calculating Cerebral Metabolic Rate of Oxygen Based on 17O Magnetic Resonance Spectroscopic Imaging Measurement during a Short 17O2 Inhalation." Journal of Cerebral Blood Flow & Metabolism 24, no. 8 (August 2004): 840–48. http://dx.doi.org/10.1097/01.wcb.0000125885.54676.82.
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It has recently been shown that 17O magnetic resonance (MR) spectroscopic imaging at ultrahigh fields provides a reliable method for measuring CMRO2 during a short period of 17O2 gas inhalation. The mathematical (or complete) model used in the 17O MR method for calculating CMRO2 requires simultaneous measurements of multiple parameters including the concentration of H217O produced in the brain tissue from inhaled 17O2 gas (Cb), CBF, and the input function for the H217O concentration in the feeding artery (Ca). Both invasive and noninvasive measurements are involved in determining all of these parameters. In this article, two simplified methods are proposed and validated for calculating CMRO2 based on 17O MR measurement(s); the first method requires the measurements of Cb and CBF, but not Ca, and the second method only requires a single noninvasive measurement of Cb. The simplified methods were used to calculate CMRO2 in anesthetized rat brain, and the results were compared with those obtained using the complete model. The results from this work show (1) the validity of the simplified methods for quantifying CMRO2, and (2) the feasibility for establishing a completely noninvasive 17O MR approach for imaging CMRO2 in vivo.
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Bush, Adam M., Matthew Borzage, Soyoung Choi, Thomas Coates, and John C. Wood. "Elevated Cerebral Metabolic Oxygen Consumption in Sickle Cell Disease." Blood 124, no. 21 (December 6, 2014): 2706. http://dx.doi.org/10.1182/blood.v124.21.2706.2706.
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Abstract Introduction Stroke occurs when cerebral blood flow (CBF) is inadequate to the metabolic needs of the brain. In sickle cell disease (SCD) stroke is common, however accurate quantification of basal cerebral oxygen consumption (CMRO2) has not been performed. Early PET studies suggested CMRO2 was decreased in SCD patients, but these studies lacked data regarding brain volume and gray-white matter fractions; lower CMRO2 may simply have reflected brain loss from prior stroke. In contrast, NIRS and global resting energy expenditure studies have demonstrated elevated peripheral metabolic rate in SCD patients at baseline, with further increases during painful crisis. In those studies, oxygen consumption was correlated with markers of inflammation, particularly white blood cell count, consistent with metabolic consequences of neutrophil activation. Characterizing CMRO2 in SCD provides insight into better prevention and management of stroke in the SCD population. Accordingly, we measured CBF and cerebral venous saturation (SvO2) via a recently developed magnetic resonance imaging (MRI) technique: T2 Relaxation Under Spin Tagging (TRUST). Using the Fick Principle, this allowed for quantification of oxygen extraction fraction (OEF) and the first quantitative measurements of CMRO2in SCD patients. Methods All patients were recruited with informed consent or assent and this study was approved by the CHLA IRB. Exclusion criteria included pregnancy, previous stroke, acute chest or pain crisis hospitalization within one month. Fifteen patients with SCD and 12 healthy ethnicity matched controls (CTL) were studied. Arterial oxygen saturation (SaO2) was measured via peripheral pulse oximetery. TRUST was used to measured T2 relaxation of blood within the sagittal sinus; T2 relaxation was converted to SvO2 using established calibration curves. OEF represented the difference of SaO2 andSvO2 .Phase Contrast (PC) of the carotid and vertebral arteries was used to measure global CBF. CMRO2 was calculated as the product of CBF and OEF. High resolution, 3D, T1 weighted images were used for grey-white segmentation and brain volume calculations using BrainSuiteñ software. Relative grey matter CMRO2 and white matterCMRO2 were estimated by assuming that (gm) CMRO2 was three-fold higher than (wm) CRMRO2. Complete blood count, cell free hemoglobin, LDH, and hemoglobin electrophoresis were measured at the study visit. Results Table 1 summarizes the results. To compensate for their chronic anemia, SCD patients had 67% greater CBF than control subjects, producing a normal SvO2 and OEF. Oxygen delivery also trended higher than for controls leading to higher total CMRO2 in the SCD patients. CMRO2 increases remained significant even after correction for differences in grey and white matter volumes. We found no correlation between WBC and CMRO2when tested by population. Discussion Our study demonstrates elevated cerebral metabolism in SCD, mirroring increases in global resting energy expenditure and peripheral metabolic rate described by other groups. The etiology of the increased CMRO2 is unknown but could reflect neuroinflammation or energy demands from chronic injury/repair. Regardless, our observation at least partially explains the increase of CBF beyond predicted by anemia alone. By excluding patients with overt stroke and by correcting for differences in brain volume and composition, our results are the first CMRO2 measurements in SCD that are unconfounded by brain volume loss. Given the age differences between our study and control populations, we cannot exclude developmental differences in CMRO2 among patients and controls. However, in general, CMRO2 increases with age, which would tend to lessen rather than increase the CMRO2 differences seen in our study. Table 1 Controls SCD p Age (years) 37.2 + 2.8 20.3 + 2.6 <0.05 Sex 9 F, 3 M 9 F, 6 M ns Hemoglobin (g/dl) 13.5 + 1.2 9.6 + 1.1 <0.05 WBC (103/uL) 6.1 + 2.2 11.0 + 4.2 <0.05 Sa O2 (%) 95.7 + 1.5 94.1 + 4.1 ns Sv O2 (%) 65.6 + 6.7 63.6 + 8.4 ns OEF 30.0 + 7.1 32.3 + 7.4 ns CBF (ml/100g/min) 70.0 + 4.6 116.8 + 19.1 <0.05 Cerebral O2 delivery (umol O2/100g/min) 193.0 + 44.9 239.0 + 35.7 ns Grey Matter Mass (ml) 499.6 + 72.0 528.4 + 58.1 ns White Matter Mass (ml) 444.6 + 58.2 422.9 + 59.5 ns CMRO2 (umol O2/100g/min) 193.1 + 44.9 239.0 + 35.7 <0.05 (gm)CMRO2 250.7 + 58.7 292.7 + 39.7 <0.05 (wm) CMRO2 175.5 + 41.1 204.9 + 27.8 <0.05 Disclosures Coates: Novartis: Honoraria, Speakers Bureau; Apo Pharma: Consultancy, Honoraria; Acceleron: Consultancy, Honoraria; SHire: Consultancy, Honoraria.
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Wang, Kang, Zachary M. Smith, Richard B. Buxton, Erik R. Swenson, and David J. Dubowitz. "Acetazolamide during acute hypoxia improves tissue oxygenation in the human brain." Journal of Applied Physiology 119, no. 12 (December 15, 2015): 1494–500. http://dx.doi.org/10.1152/japplphysiol.00117.2015.
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Low doses of the carbonic anhydrase inhibitor acetazolamide provides accelerated acclimatization to high-altitude hypoxia and prevention of cerebral and other symptoms of acute mountain sickness. We previously observed increases in cerebral O2 metabolism (CMRO2) during hypoxia. In this study, we investigate whether low-dose oral acetazolamide (250 mg) reduces this elevated CMRO2 and in turn might improve cerebral tissue oxygenation (PtiO2) during acute hypoxia. Six normal human subjects were exposed to 6 h of normobaric hypoxia with and without acetazolamide prophylaxis. We determined CMRO2 and cerebral PtiO2 from MRI measurements of cerebral blood flow (CBF) and cerebral venous O2 saturation. During normoxia, low-dose acetazolamide resulted in no significant change in CBF, CMRO2, or PtiO2. During hypoxia, we observed increases in CBF [48.5 (SD 12.4) (normoxia) to 65.5 (20.4) ml·100 ml−1·min−1 (hypoxia), P < 0.05] and CMRO2 [1.54 (0.19) to 1.79 (0.25) μmol·ml−1·min−1, P < 0.05] and a dramatic decline in PtiO2 [25.0 to 11.4 (2.7) mmHg, P < 0.05]. Acetazolamide prophylaxis mitigated these rises in CBF [53.7 (20.7) ml·100 ml−1·min−1 (hypoxia + acetazolamide)] and CMRO2 [1.41 (0.09) μmol·ml−1·min−1 (hypoxia + acetazolamide)] associated with acute hypoxia but also reduced O2 delivery [6.92 (1.45) (hypoxia) to 5.60 (1.14) mmol/min (hypoxia + acetazolamide), P < 0.05]. The net effect was improved cerebral tissue PtiO2 during acute hypoxia [11.4 (2.7) (hypoxia) to 16.5 (3.0) mmHg (hypoxia + acetazolamide), P < 0.05]. In addition to its renal effect, low-dose acetazolamide is effective at the capillary endothelium, and we hypothesize that local interruption in cerebral CO2 excretion accounts for the improvements in CMRO2 and ultimately in cerebral tissue oxygenation during hypoxia. This study suggests a potentially pivotal role of cerebral CO2 and pH in modulating CMRO2 and PtiO2 during acute hypoxia.
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Kida, Ikuhiro, Richard P. Kennan, Douglas L. Rothman, Kevin L. Behar, and Fahmeed Hyder. "High-Resolution CMRO2 Mapping in Rat Cortex: A Multiparametric Approach to Calibration of BOLD Image Contrast at 7 Tesla." Journal of Cerebral Blood Flow & Metabolism 20, no. 5 (May 2000): 847–60. http://dx.doi.org/10.1097/00004647-200005000-00012.
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The blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) method, which is sensitive to vascular paramagnetic deoxyhemoglobin, is dependent on regional values of cerebral metabolic rate of oxygen utilization (CMRO2), blood flow (CBF), and volume (CBV). Induced changes in deoxyhemoglobin function as an endogenous contrast agent, which in turn affects the transverse relaxation rates of tissue water that can be measured by gradient-echo and spin-echo sequences in BOLD fMRI. The purpose here was to define the quantitative relation between BOLD signal change and underlying physiologic parameters. To this end, magnetic resonance imaging and spectroscopy methods were used to measure CBF, CMRO2, CBV, and relaxation rates (with gradient-echo and spin-echo sequences) at 7 Tesla in rat sensorimotor cortex, where cerebral activity was altered pharmacologically within the autoregulatory range. The changes in tissue transverse relaxation rates were negatively and linearly correlated with changes in CBF, CMRO2, and CBV. The multiparametric measurements revealed that CBF and CMRO2 are the dominant physiologic parameters that modulate the BOLD fMRI signal, where the ratios of (ΔCMRO2/CMRO2)/(ΔCBF/CBF) and (ΔCBV/CBV)/(ΔCBF/CBF) were 0.86 ± 0.02 and 0.03 ± 0.02, respectively. The calibrated BOLD signals (spatial resolution of 48 μL) from gradient-echo and spin-echo sequences were used to predict changes in CMRO2 using measured changes in CBF, CBV, and transverse relaxation rates. The excellent agreement between measured and predicted values for changes in CMRO2 provides experimental support of the current theory of the BOLD phenomenon. In gradient-echo sequences, BOLD contrast is affected by reversible processes such as static inhomogeneities and slow diffusion, whereas in spin-echo sequences these effects are refocused and are mainly altered by extravascular spin diffusion. This study provides steps by which multiparametric MRI measurements can be used to obtain high-spatial resolution CMRO2 maps.
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Deckers, Pieter T., Alex A. Bhogal, Mathijs BJ Dijsselhof, Carlos C. Faraco, Peiying Liu, Hanzhang Lu, Manus J. Donahue, and Jeroen CW Siero. "Hemodynamic and metabolic changes during hypercapnia with normoxia and hyperoxia using pCASL and TRUST MRI in healthy adults." Journal of Cerebral Blood Flow & Metabolism 42, no. 5 (December 1, 2021): 861–75. http://dx.doi.org/10.1177/0271678x211064572.
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Blood oxygenation level-dependent (BOLD) or arterial spin labeling (ASL) MRI with hypercapnic stimuli allow for measuring cerebrovascular reactivity (CVR). Hypercapnic stimuli are also employed in calibrated BOLD functional MRI for quantifying neuronally-evoked changes in cerebral oxygen metabolism (CMRO2). It is often assumed that hypercapnic stimuli (with or without hyperoxia) are iso-metabolic; increasing arterial CO2 or O2 does not affect CMRO2. We evaluated the null hypothesis that two common hypercapnic stimuli, ‘CO2 in air’ and carbogen, are iso-metabolic. TRUST and ASL MRI were used to measure the cerebral venous oxygenation and cerebral blood flow (CBF), from which the oxygen extraction fraction (OEF) and CMRO2 were calculated for room-air, ‘CO2 in air’ and carbogen. As expected, CBF significantly increased (9.9% ± 9.3% and 12.1% ± 8.8% for ‘CO2 in air’ and carbogen, respectively). CMRO2 decreased for ‘CO2 in air’ (−13.4% ± 13.0%, p < 0.01) compared to room-air, while the CMRO2 during carbogen did not significantly change. Our findings indicate that ‘CO2 in air’ is not iso-metabolic, while carbogen appears to elicit a mixed effect; the CMRO2 reduction during hypercapnia is mitigated when including hyperoxia. These findings can be important for interpreting measurements using hypercapnic or hypercapnic-hyperoxic (carbogen) stimuli.
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Altman, Denis I., Jeffrey M. Perlman, Joseph J. Volpe, and William J. Powers. "Cerebral Oxygen Metabolism in Newborns." Pediatrics 92, no. 1 (July 1, 1993): 99–104. http://dx.doi.org/10.1542/peds.92.1.99.
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Objective. A better understanding of the developmental changes in brain energy metabolism that occur in human neonates is critically important for designing rational treatment strategies that ensure an adequate supply of nutrients to the brain and minimize deleterious side effects of therapeutic interventions in sick newborns. Methods. Cerebral metabolic rate for oxygen (CMRO2) was measured with positron emission tomography in 11 sick newborns of different gestational ages. Results. In five preterm infants, mean hemispheric CMRO2 was 0.06 to 0.54 mL 100 g-1 min-1. Two of these preterm infants with virtually absent CMRO2 (0.06 mL 100 g-1 min-1) had minimal or no evidence of parenchymal brain injury detected in the newborn period. In six term infants, mean hemispheric CMRO2 was 0.0 to 1.3 mL 100 g-1 min-1. Two with no neurological disease had mean hemispheric CMRO2 of 0.4 and 0.7 mL 100 g-1 min-1 and were normal at 6 and 7 months, respectively. Conclusions. CMRO2 in four newborns who had minimal or no detectable brain injury was considerably below the threshold for brain viability in adults of 1.3 mL 100 g-1 min-1. This indicates that energy requirements in fetal and newborn brain are minimal or can be met by nonoxidative metabolism.
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Baligand, Celine, Olivier Barret, Amélie Tourais, Jean-Baptiste Pérot, Didier Thenadey, Fanny Petit, Géraldine Liot, et al. "Zero Echo Time 17O-MRI Reveals Decreased Cerebral Metabolic Rate of Oxygen Consumption in a Murine Model of Amyloidosis." Metabolites 11, no. 5 (April 22, 2021): 263. http://dx.doi.org/10.3390/metabo11050263.
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The cerebral metabolic rate of oxygen consumption (CMRO2) is a key metric to investigate the mechanisms involved in neurodegeneration in animal models and evaluate potential new therapies. CMRO2 can be measured by direct 17O magnetic resonance imaging (17O-MRI) of H217O signal changes during inhalation of 17O-labeled oxygen gas. In this study, we built a simple gas distribution system and used 3D zero echo time (ZTE-)MRI at 11.7 T to measure CMRO2 in the APPswe/PS1dE9 mouse model of amyloidosis. We found that CMRO2 was significantly lower in the APPswe/PS1dE9 brain than in wild-type at 12–14 months. We also estimated cerebral blood flow (CBF) from the post-inhalation washout curve and found no difference between groups. These results suggest that the lower CMRO2 observed in APPswe/PS1dE9 is likely due to metabolism impairment rather than to reduced blood flow. Analysis of the 17O-MRI data using different quantification models (linear and 3-phase model) showed that the choice of the model does not affect group comparison results. However, the simplified linear model significantly underestimated the absolute CMRO2 values compared to a 3-phase model. This may become of importance when combining several metabolic fluxes measurements to study neuro-metabolic coupling.
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Göttler, Jens, Stephan Kaczmarz, Michael Kallmayer, Isabel Wustrow, Hans-Henning Eckstein, Claus Zimmer, Christian Sorg, Christine Preibisch, and Fahmeed Hyder. "Flow-metabolism uncoupling in patients with asymptomatic unilateral carotid artery stenosis assessed by multi-modal magnetic resonance imaging." Journal of Cerebral Blood Flow & Metabolism 39, no. 11 (July 3, 2018): 2132–43. http://dx.doi.org/10.1177/0271678x18783369.
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Oxygen extraction (OEF), oxidative metabolism (CMRO2), and blood flow (CBF) in the brain, as well as the coupling between CMRO2 and CBF due to cerebral autoregulation are fundamental to brain's health. We used a clinically feasible MRI protocol to assess impairments of these parameters in the perfusion territories of stenosed carotid arteries. Twenty-nine patients with unilateral high-grade carotid stenosis and thirty age-matched healthy controls underwent multi-modal MRI scans. Pseudo-continuous arterial spin labeling (pCASL) yielded absolute CBF, whereas multi-parametric quantitative blood oxygenation level dependent (mqBOLD) modeling allowed imaging of relative OEF and CMRO2. Both CBF and CMRO2 were significantly reduced in the stenosed territory compared to the contralateral side, while OEF was evenly distributed across both hemispheres similarly in patients and controls. The CMRO2-CBF coupling was significantly different between both hemispheres in patients, i.e. significant interhemispheric flow-metabolism uncoupling was observed in patients compared to controls. Given that CBF and CMRO2 are intimately linked to brain function in health and disease, the proposed easily applicable MRI protocol of pCASL and mqBOLD imaging might serve as a valuable tool for early diagnosis of potentially harmful cerebral hemodynamic and metabolic states with the final aim to select clinically asymptomatic patients who would benefit from carotid revascularization therapy.
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Ko, Tiffany S., Constantine D. Mavroudis, Wesley B. Baker, Vincent C. Morano, Kobina Mensah-Brown, Timothy W. Boorady, Alexander L. Schmidt, et al. "Non-invasive optical neuromonitoring of the temperature-dependence of cerebral oxygen metabolism during deep hypothermic cardiopulmonary bypass in neonatal swine." Journal of Cerebral Blood Flow & Metabolism 40, no. 1 (October 30, 2018): 187–203. http://dx.doi.org/10.1177/0271678x18809828.
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Management of deep hypothermic (DH) cardiopulmonary bypass (CPB), a critical neuroprotective strategy, currently relies on non-invasive temperature to guide cerebral metabolic suppression during complex cardiac surgery in neonates. Considerable inter-subject variability in temperature response and residual metabolism may contribute to the persisting risk for postoperative neurological injury. To characterize and mitigate this variability, we assess the sufficiency of conventional nasopharyngeal temperature (NPT) guidance, and in the process, validate combined non-invasive frequency-domain diffuse optical spectroscopy (FD-DOS) and diffuse correlation spectroscopy (DCS) for direct measurement of cerebral metabolic rate of oxygen ( CMRO2). During CPB, n = 8 neonatal swine underwent cooling from normothermia to 18℃, sustained DH perfusion for 40 min, and then rewarming to simulate cardiac surgery. Continuous non-invasive and invasive measurements of intracranial temperature (ICT) and CMRO2 were acquired. Significant hysteresis ( p < 0.001) between cooling and rewarming periods in the NPT versus ICT and NPT versus CMRO2 relationships were found. Resolution of this hysteresis in the ICT versus CMRO2 relationship identified a crucial insufficiency of conventional NPT guidance. Non-invasive CMRO2 temperature coefficients with respect to NPT ( Q10 = 2.0) and ICT ( Q10 = 2.5) are consistent with previous reports and provide further validation of FD-DOS/DCS CMRO2 monitoring during DH CPB to optimize management.
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Tichauer, Kenneth M., Jonathan T. Elliott, Jennifer A. Hadway, Ting-Yim Lee, and Keith St. Lawrence. "Cerebral metabolic rate of oxygen and amplitude-integrated electroencephalography during early reperfusion after hypoxia-ischemia in piglets." Journal of Applied Physiology 106, no. 5 (May 2009): 1506–12. http://dx.doi.org/10.1152/japplphysiol.91156.2008.
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The therapeutic window following perinatal hypoxia-ischemia is brief, and early clinical signs of injury can be subtle. Electroencephalography (EEG) represents the most promising early diagnostic of hypoxia-ischemia; however, some studies have questioned the sensitivity and specificity of EEG. The present study investigated the use of both near-infrared spectroscopy (NIRS) measurements of the cerebral metabolic rate of oxygen (CMRO2) and amplitude-integrated EEG (aEEG) to detect the severity of hypoxia-ischemia after 1 h of reperfusion in newborn piglets (10 insult, 3 control). The CMRO2 was measured before and after 1 h of reperfusion from hypoxia-ischemia, the duration of which was varied from piglet to piglet with a range of 3–24 min, under fentanyl/nitrous oxide anesthesia to mimic awake-like levels of cerebral metabolism. EEG data were collected throughout the study. On average, the CMRO2 and mean aEEG background signals were significantly depressed following the insult ( P < 0.05). Mean CMRO2 and mean aEEG background were 2.61 ± 0.11 ml O2·min−1·100 g−1 and 20.4 ± 2.7 μV before the insult and 1.58 ± 0.09 ml O2·min−1·100 g−1 and 11.8 ± 2.9 μV after 1 h of reperfusion, respectively. Both CMRO2 and aEEG displayed statistically significant correlations with duration of ischemia ( P < 0.05; r = 0.71 and r = 0.89, respectively); however, only CMRO2 was sensitive to milder injuries (<5 min). This study highlights the potential for combining NIRS measures of CMRO2 with EEG in the neonatal intensive care unit to improve early detection of perinatal hypoxia-ischemia.
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Lin, Weili, Hongyu An, Azim Celik, and Yueh Lee. "Quantitative Measurements of Cerebral Metabolic Rate of Oxygen (CMRO2) Using MRI." Stroke 32, suppl_1 (January 2001): 340. http://dx.doi.org/10.1161/str.32.suppl_1.340.
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P10 Recently, we have demonstrated that a quantitative estimate of cerebral blood oxygen saturation can be obtained in vivo via blood oxygen level dependent contrast. With a ROI analysis, a mean cerebral blood oxygen saturation (CBOS) of 58.4% ± 1.8% was obtained from 8 normal healthy volunteers. When converting the MR measured CBOS to the oxygen extraction fraction (OEF) via the Hill equation as well as the oxygen dissociation curve, an MR-OEF of 42.6% was obtained, in excellent agreement with the known OEF under normal physiological conditions via PET. While it is known that the level of OEF is a strong indicator of the functional status of brain tissue, OEF by itself does not uniquely indicate brain ischemia or brain viability. Therefore, CMRO2, which includes both CBF and OEF, has been utilized to better characterize the balance between oxygen supply and demand in brain tissue. In order to obtain a quantitative estimate of MR-CMRO2, a measure of both OEF and CBF is required. In total, 5 normal healthy volunteers were studied. A 2D multiecho gradient/spin echo sequence was employed to acquire images, which were subsequently post-processed to obtain an estimate of MR-OEF. In addition, a dynamic imaging approach was utilized to acquire images before, during and after the injection of a paramagnetic contrast agent and post-processed via the singular value decomposition so that a quantitative estimate of CBF can be obtained. Finally, pixe-by-pixel MR-CMRO2 maps were calculated as the product of MR-OEF and MR-CBF. Four ROIs: one located in the cortical and one in the subcortical regions of each hemisphere, were defined to obtain measurements of MR-CMRO2 in all volunteers. A mean MR-CMRO2 of 27.7±6.2 ml/100gm/min and 10.5±3.2 ml/100gm/min was obtained for the cortical and subcortical regions, respectively. Notice the MR-CMRO2 differs from the conventionally measured CMRO2 via PET. No normalization with respect to the arterial oxygen content of each volunteer was made for the MR-CMRO2. With the non-invasive nature of MRI and the ability to provide quantitative estimates of cerebral oxygen metabolism in vivo, MR-CMRO2 should open a new avenue for the investigation of cerebrovascular disease.
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Lin, Weili, Jin-Moo Lee, Katie D. Vo, Hongyu An, Azim Celik, Yueh Lee, and Chung Y. Hsu. "Clinical Utility of CMRO2 Obtained with MRI in Determining Ischemic Brain Tissue at Risk." Stroke 32, suppl_1 (January 2001): 341–42. http://dx.doi.org/10.1161/str.32.suppl_1.341-d.
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P16 It has been suggested that the relationship between oxygen delivery and oxygen demand defines brain tissue at risk during cerebral ischemia. We have recently demonstrated that a quantitative estimate of cerebral blood oxygen saturation (and thereby oxygen extraction fraction, OEF) can be obtained using MRI in vivo. When combined with MR estimated cerebral blood flow (CBF), a quantitative measure of MR-CMRO2 can be calculated. In this study, we sought to explore the potential clinical utility of MR-CMRO2 in determining brain tissue at risk during cerebral ischemia. Seven patients with acute ischemic strokes were imaged at 4.5±.9 hrs (tp1) and 6 of the patients were imaged 3–5 days after stroke onset (tp2) with diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). In addition, a 2D multiecho gradient/spin echo sequence was employed to acquire images which were subsequently used to estimate MR-OEF. Singular value decomposition was used to obtain a quantitative estimate of CBF to calculate MR-CMRO2 (= MR-OEF x MR-CBF). At tp1, 5/7 patients showed a DWI-PWI mismatch (PWI>DWI) while 2/7 patients exhibited match. At tp2, only 1 patient showed PWI<DWI, and the remaining patients had matched defects. In addition, 4/6 patients had DWI lesion volumes similar to tp1 abnormal PWI volumes, while 2/6 had smaller lesion volumes at tp2. Regional measurements of MR-CMRO2 were obtained in the regions where PWI and DWI abnormalities coincided (“core”), regions where PWI were abnormal (“core+penumbra”), and the corresponding regions on the contralateral hemisphere. In patients who demonstrated mismatched PWI-DWI defects at tp1, CMRO2 in the “core” regions was 35.3±3.4% of the contralateral region. In contrast, CMRO2 in the “core+penumbra” was 48.9±5.4% of the contralateral region, which was significantly different from “core” CMRO2 (p<0.003). Furthermore, the two patients with matched DWI-PWI at tp1 had CMRO2 values 16.6±14.1% of the contralateral regions. Analysis of tp2 images revealed that all “core” regions became infarcted. These results suggest that brain regions with CMRO2 above 35.3% of the contralateral hemisphere may represent salvageable tissue.
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Vaclavu, Lena, Esben Thade Petersen, Ed T. VanBavel, Charles BL Majoie, Aart J. Nederveen, and Bart J. Biemond. "Reduced Cerebral Metabolic Rate of Oxygen in Adults with Sickle Cell Disease." Blood 132, Supplement 1 (November 29, 2018): 11. http://dx.doi.org/10.1182/blood-2018-99-116194.
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Abstract Introduction: Cerebral blood flow (CBF) is increased in sickle cell disease (SCD) to compensate for chronic hemolytic anemia. Since the brain is strongly dependent on adequate oxygen levels, severe anemia may result in ischemia and silent cerebral infarctions (SCIs), which are present in the majority of patients with SCD. Besides CBF, the cerebral metabolic rate of oxygen (CMRO2), representing the cerebral oxygen consumption, can be measured using specialized MRI techniques. CMRO2 is dependent on CBF, OEF oxygen extraction fraction (OEF) and the hematocrit in the cerebral circulation. In order to maintain stable CMRO2 the OEF changes to compensate for fluctuations in CBF. Previous studies found either elevated or reduced rather than stable CMRO2 in SCD. To further explore the regulation of cerebral oxygenation in SCD, we measured CMRO2, OEF and CBF using MRI at rest and upon administration of acetazolamide (ACZ), a non-metabolic vasodilator. In addition, we related the CMRO2 to the prevalence and location of SCIs and to laboratory parameters of hemolysis. Methods: Adult SCD patients (HbSS/HbSβ0) without a history of stroke, and healthy age-, sex, and race-matched controls were recruited for this IRB-approved MRI study with ACZ-induced vasodilation and venous blood sampling. MRI images were acquired at 3T (Philips Healthcare, Best, NL). Sequences included 3D FLAIR with 1mm isotropic resolution for lesion evaluation, longitudinal and transverse relaxation times of blood (T1b and T2b) in the cerebral sagittal sinus using a T2 prepared tissue relaxation with inversion recovery sequence (T2-TRIR), and pseudo-continuous arterial spin labeling (ASL) for whole brain CBF measurements. T1b was used to correct ASL-based CBF values. T2b was converted to venous saturation (Yv) using a recently published SCD-specific model, which was calibrated in sickle blood rather than bovine blood. CBF was measured at baseline and 10 min post acetazolamide (ACZ) (16mg/kg intravenous infusion over 3min). Images were co-registered and quantified using the ExploreASL toolbox. CMRO2 was calculated as follows: CMRO2 = CBF * OEF * Ca, where CBF is the whole brain CBF map from ASL, OEF is the arteriovenous oxygen saturation (Y) difference (Ya-Yv/Ya) derived from T2 measurements, and Ca is the oxygen carrying capacity of blood calculated from hematocrit sampled immediately prior to MRI. Blood markers of hemolysis (reticulocyte count and bilirubin) were correlated to MRI hemodynamic markers using bivariate Spearman's rho (ρ). Group comparisons were tested using Student's t-tests. P values <0.05 were considered statistically significant. Results: As expected, CBF was significantly higher in patients with SCD (69 ± 16 mL/100g/min) compared to healthy controls (42 ± 4 mL/100g/min, P <0.001), whereas oxygen carrying capacity (Ca) was significantly lower in patients with SCD vs healthy controls due to lower hematocrit (485 ± 83 vs 794 ± 66 μmol O2/100ml blood, P=0.001). At baseline, mean CMRO2 was lower in patients with SCD compared to healthy controls (88 ± 20 vs 117 ± 18 μmol/100 g/min, P = 0.002), contrary to our hypothesis, indicating a reduced oxygen metabolism in patients with SCD. After acetazolamide, CMRO2 remained the same due to an increase in CBF (P<0.001) and a compensatory reduction in OEF. The reduction in OEF in patients with SCD and healthy controls (20 ± 7 vs 19 ± 6, respectively P= 0.76) indicates that OEF adjusts appropriately according to the increased flow. By mapping CMRO2 and the locations of SCIs, we found that lesions were most prevalent in the regions with the lowest CMRO2 corresponding to the deep white matter and borderzone regions, supporting an ischemic etiology of lesions. High hemolytic rate was associated with higher CMRO2 most likely due to an increased CBF. Conclusion: We observed reduced CMRO2 in patients with SCD compared to healthy controls due to low OEF. A reduced CMRO2 could pose a risk for ischemia, despite high flow rate delivering oxygen, because of low OEF. This is supported by the fact that the silent cerebral infarcts are located in regions with the lowest CMRO2. We postulate that patients with SCD have a reduced capacity to increase the OEF in regions with inadequate CBF resulting in local ischemia and local infarction. The pathogenesis of the reduced OEF remains unclear but could be related to arteriovenous shunting whereby there is insufficient time for oxygen to dissociate. Figure Figure. Disclosures No relevant conflicts of interest to declare.
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Acharya, Deepshikha, Ankita Mukherjea, Jiaming Cao, Alexander Ruesch, Samantha Schmitt, Jason Yang, Matthew A. Smith, and Jana M. Kainerstorfer. "Non-Invasive Spectroscopy for Measuring Cerebral Tissue Oxygenation and Metabolism as a Function of Cerebral Perfusion Pressure." Metabolites 12, no. 7 (July 20, 2022): 667. http://dx.doi.org/10.3390/metabo12070667.
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Near-infrared spectroscopy (NIRS) and diffuse correlation spectroscopy (DCS) measure cerebral hemodynamics, which in turn can be used to assess the cerebral metabolic rate of oxygen (CMRO2) and cerebral autoregulation (CA). However, current mathematical models for CMRO2 estimation make assumptions that break down for cerebral perfusion pressure (CPP)-induced changes in CA. Here, we performed preclinical experiments with controlled changes in CPP while simultaneously measuring NIRS and DCS at rest. We observed changes in arterial oxygen saturation (~10%) and arterial blood volume (~50%) with CPP, two variables often assumed to be constant in CMRO2 estimations. Hence, we propose a general mathematical model that accounts for these variations when estimating CMRO2 and validate its use for CA monitoring on our experimental data. We observed significant changes in the various oxygenation parameters, including the coupling ratio (CMRO2/blood flow) between regions of autoregulation and dysregulation. Our work provides an appropriate model and preliminary experimental evidence for the use of NIRS- and DCS-based tissue oxygenation and metabolism metrics for non-invasive diagnosis of CA health in CPP-altering neuropathologies.
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Powers, William J., Tom O. Videen, Joanne Markham, Vonn Walter, and Joel S. Perlmutter. "Metabolic Control of Resting Hemispheric Cerebral Blood Flow is Oxidative, not Glycolytic." Journal of Cerebral Blood Flow & Metabolism 31, no. 5 (February 9, 2011): 1223–28. http://dx.doi.org/10.1038/jcbfm.2011.5.
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Although the close regional coupling of resting cerebral blood flow (CBF) with both cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) within individuals is well documented, there are few data regarding the coupling between whole brain flow and metabolism among different subjects. To investigate the metabolic control of resting whole brain CBF, we performed multivariate analysis of hemispheric CMRO2, CMRglc, and other covariates as predictors of resting CBF among 23 normal humans. The univariate analysis showed that only CMRO2 was a significant predictor of CBF. The final multivariate model contained two additional terms in addition to CMRO2: arterial oxygen content and oxygen extraction fraction. Notably, arterial plasma glucose concentration and CMRglc were not included in the final model. Our data demonstrate that the metabolic factor controlling hemispheric CBF in the normal resting brain is CMRO2 and that CMRglc does not make a contribution. Our findings provide evidence for compartmentalization of brain metabolism into a basal component in which CBF is coupled to oxygen metabolism and an activation component in which CBF is controlled by another mechanism.
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Stingele, R., B. Wagner, M. V. Kameneva, M. A. Williams, D. A. Wilson, N. V. Thakor, R. J. Traystman, and D. F. Hanley. "Reduction of cytochrome-c oxidase copper precedes failing cerebral O2 utilization in fluorocarbon-perfused cats." American Journal of Physiology-Heart and Circulatory Physiology 271, no. 2 (August 1, 1996): H579—H587. http://dx.doi.org/10.1152/ajpheart.1996.271.2.h579.
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We determined the relationship of the low-potential copper (CuA) redox state of cytochrome-c oxidase to the brain tissue PO2 (PtiO2) and global cerebral O2 consumption (CMRO2) in vivo. The redox state of cytochrome-c oxidase copper was monitored in perfluorocarbon-exchanged cats under normoxic and graded hypoxic conditions with use of near-infrared spectroscopy. Continuous spectra ranging from 730 to 960 nm were acquired, and the change in copper redox state was assessed by the absorption changes at 830 nm. PtiO2 was measured with O2-sensitive electrodes implanted into the cortex, and CMRO2 was determined by sampling arterial and superior sagittal sinus perfusate and by measuring blood flow with radiolabeled microspheres. As PtiO2 decreased with hypoxia, the CuA of cytochrome-c oxidase became progressively reduced, whereas the CMRO2 was unchanged during the initial stages of hypoxia. Only with severe hypoxia, did CMRO2 and the amplitude of somatosensory evoked potentials decrease. We conclude that the CuA site of cytochrome-c oxidase is involved in a regulatory adjustment that helps maintain CMRO2 constant.
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Bain, Anthony R., Philip N. Ainslie, Otto F. Barak, Ryan L. Hoiland, Ivan Drvis, Tanja Mijacika, Damian M. Bailey, et al. "Hypercapnia is essential to reduce the cerebral oxidative metabolism during extreme apnea in humans." Journal of Cerebral Blood Flow & Metabolism 37, no. 9 (January 10, 2017): 3231–42. http://dx.doi.org/10.1177/0271678x16686093.
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The cerebral metabolic rate of oxygen (CMRO2) is reduced during apnea that yields profound hypoxia and hypercapnia. In this study, to dissociate the impact of hypoxia and hypercapnia on the reduction in CMRO2, 11 breath-hold competitors completed three apneas under: (a) normal conditions (NM), yielding severe hypercapnia and hypoxemia, (b) with prior hyperventilation (HV), yielding severe hypoxemia only, and (c) with prior 100% oxygen breathing (HX), yielding the greatest level of hypercapnia, but in the absence of hypoxemia. The CMRO2 was calculated from the product of cerebral blood flow (ultrasound) and the radial artery-jugular venous oxygen content difference (cannulation). Secondary measures included net-cerebral glucose/lactate exchange and nonoxidative metabolism. Reductions in CMRO2 were largest in the HX condition (−44 ± 15%, p < 0.05), with the most severe hypercapnia (PaCO2 = 58 ± 5 mmHg) but maintained oxygen saturation. The CMRO2 was reduced by 24 ± 27% in NM ( p = 0.05), but unchanged in the HV apnea where hypercapnia was absent. A net-cerebral lactate release was observed at the end of apnea in the HV and NM condition, but not in the HX apnea (main effect p < 0.05). These novel data support hypercapnia/pH as a key mechanism mediating reductions in CMRO2 during apnea, and show that severe hypoxemia stimulates lactate release from the brain.
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Hyder, Fahmeed, Richard P. Kennan, Ikuhiro Kida, Graeme F. Mason, Kevin L. Behar, and Douglas Rothman. "Dependence of Oxygen Delivery on Blood Flow in Rat Brain: A 7 Tesla Nuclear Magnetic Resonance Study." Journal of Cerebral Blood Flow & Metabolism 20, no. 3 (March 2000): 485–98. http://dx.doi.org/10.1097/00004647-200003000-00007.
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Magnetic resonance imaging (MRI) and spectroscopy (MRS) were used at a magnetic field strength of 7 T to measure CBF and CMRO2 in the sensorimotor cortex of mature rats at different levels of cortical activity. In rats maintained on morphine anesthesia, transitions to lower activity and higher activity states were produced by administration of pentobarbital and nicotine, respectively. Under basal conditions of morphine sulfate anesthesia, CBF was 0.75 ± 0.09 mL · g−1 · min−1 and CMRO2 was 3.15 ± 0.18 μmol · g−1 · min−1. Administration of sodium pentobarbital reduced CBF and CMRO2 by 66% ± 16% and 61% ± 6%, respectively (i.e., “deactivation”). In contrast, administration of nicotine hydrogen tartrate increased CBF and CMRO2 by 41% ± 5% and 30% ± 3%, respectively (i.e., “activation”). The resting values of CBF and CMRO2 for α-chloralose anesthetized rats were 0.40 ± 0.09 mL · g−1 · min−1 and 1.51 ± 0.06 μmol · g−1 · min−1, respectively. Upon forepaw stimulation, CBF and CMRO2 were focally increased by 34% ± 10% and 26% ± 12%, respectively, above the resting nonanesthetized values (i.e., “activation”). Incremental changes in CBF and CMRO2, when expressed as a percentage change for “deactivation” and “activation” from the respective control conditions, were linear (R2 = 0.997) over the entire range examined with the global and local perturbations. This tight correlation for cerebral oxygen delivery in vivo is supported by a recent model where the consequence of a changing effective diffusivity of the capillary bed for oxygen, D, has been hypothetically shown to be linked to alterations in CMRO2 and CBF. This assumed functional characteristic of the capillary bed can be theoretically assessed by the ratio of fractional changes in D with respect to changes in CBF, signified by Ω. A value 0.81 ± 0.23 was calculated for Ω with the in vivo data presented here, which in turn corresponds to a supposition that the effective oxygen diffusivity of the capillary bed is not constant but presumably varies to meet local requirements in oxygen demand in a similar manner with both “deactivation” and “activation.”
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Vu, Chau, Adam Bush, Thomas Coates, and John C. Wood. "Cerebral Oxygen Delivery and Metabolic Rate in Chronically Anemic Subjects." Blood 134, Supplement_1 (November 13, 2019): 2273. http://dx.doi.org/10.1182/blood-2019-125897.
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Introduction: In subjects with chronic anemia syndromes, such as sickle cell disease and major thalassemia, cerebral blood flow (CBF) has been shown to increase in compensation for the decreased oxygen content. In previous works using pseudo-continuous arterial spin labeling, our laboratory has demonstrated the phenomenon of venous outflow suggestive of physiological arteriovenous shunting in anemic subjects with high CBF and short microvascular transit time (Bush et al., 2018). In this study, we evaluated CBF, oxygen delivery (DO2), oxygen extraction fraction (OEF) and cerebral metabolic rate (CMRO2) in three subject groups: sickle cell disease (SCD), non-sickle anemia (ACTL) and healthy controls (CTL). We hypothesize that even though DO2 is preserved in the presence of chronic anemia, due to physiological shunting, OEF and CMRO2 are impaired in anemic subjects compared to controls. Methods: Three study groups of 50 SCD subjects, 27 ACTL subjects and 44 healthy controls were tested (Table 1). Oxygen content, DO2, OEF and CMRO2 were computed from the hemoglobin level, CBF from phase contrast MRI and venous saturation from TRUST MRI. Results: Table 2 shows the global DO2, OEF and CMRO2. As expected, anemic patients had approximately 50% higher CBF but similar DO2 levels compared to healthy controls. Despite normal delivery, both CMRO2 and OEF are significantly decreased in SCD and ACTL subjects. Resting DO2, whether entered as CBF and O2 content separately or as their product, was the strongest predictor of the brain's metabolic rate, explaining approximately 21% of the variation in baseline CMRO2. Even after controlling for the variations in delivery, our subjects still demonstrated significant differences based on disease state, with the lowest CMRO2 in SCD patients, followed by ACTL and then healthy controls (p<0.01). After correcting for both DO2 and disease state, CMRO2 was independent of transfusion status, age, sex, hemolytic indices, fetal hemoglobin levels and mean corpuscular volume but remained directly proportional to hemoglobin (p=0.01) and platelets (p=0.01) with a combined r2=0.62. Discussion: Using a larger cohort, our results recapitulated the compensatory hyperemic response previously described in anemic subjects. Despite the ability to maintain a normal level of oxygen supply to the brain, these anemic patients had significantly lower cerebral metabolism, consistent with reports from two other laboratories (Vaclavu et al., 2019; Croal et al., 2019). We postulate that poor oxygen utilization is caused by non-nutritive perfusion or physiological arteriovenous shunting. This phenomenon has been previously characterized in SCD and other anemias with high CBF and reduced microvascular transit times. Microvascular oxygen unloading requires sufficient transit time in the capillaries network for efficient oxygen extraction, but transit times had been demonstrated to be significantly shorter in the presence of anemia due to compensatory hyperemia. In chronic anemia syndromes, the elevated CBF that preserves normal DO2 shortens transit times and impairs oxygen unloading, leading to a decrease in OEF and CMRO2 in both SCD and ACTL subjects. The predictors of baseline CMRO2 yielded interesting insights into the physiological impact of chronic anemia on cerebral oxygen availability and utilization. In acute normovolemic anemia, CMRO2 is preserved despite declining O2 carrying capacity. However, in our chronically anemic cohort, CMRO2 was strongly proportional to resting DO2; this result suggests that there is a divergence in physiological responses to acute versus chronic anemia. While DO2 was the strongest predictor of CMRO2, disease state, hemoglobin level and platelets remained in the multivariate model, confirming the roles of anemia, inflammation, and disease-specific factors in the modulating CMRO2. In summary, this report demonstrates impaired cerebral oxygen supply-demand matching in chronically anemic subjects. Cerebral hyperemia appears to simultaneously preserve DO2 while diminishing OEF and CMRO2. This observation may explain why absolute hemoglobin level remains the strongest predictor of poor neurovascular outcome in SCD patients, and raises questions regarding the proper hemoglobin target level for hydroxyurea and chronic transfusion therapy. Disclosures Coates: celgene: Consultancy, Honoraria, Other: steering committee of clinical study; vifor: Consultancy, Honoraria; agios pharma: Consultancy, Honoraria; apo pharma: Consultancy, Honoraria, Speakers Bureau. Wood:National Institutes of Health: Research Funding; Philips Healthcare: Research Funding; BluebirdBio: Consultancy; Celgene: Consultancy; BiomedInformatics: Consultancy; Imago Biosciences: Consultancy; Apopharma: Consultancy; WorldcareClinical: Consultancy.
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Leblanc, Richard, Jane L. Tyler, Gérard Mohr, Ernst Meyer, Mirko Diksic, Lucas Yamamoto, Laughlin Taylor, Serge Gauthier, and Antoine Hakim. "Hemodynamic and metabolic effects of cerebral revascularization." Journal of Neurosurgery 66, no. 4 (April 1987): 529–35. http://dx.doi.org/10.3171/jns.1987.66.4.0529.
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✓ Pre- and postoperative positron emission tomography (PET) was performed in six patients undergoing extracranial to intracranial bypass procedures for the treatment of symptomatic extracranial carotid occlusion. The six patients were all men, aged 52 to 68 years. Their symptoms included transient ischemic attacks (five cases), amaurosis fugax (two cases), and completed stroke with good recovery (one case). Positron emission tomography was performed within 4 weeks prior to surgery and between 3 to 6 months postoperatively, using oxygen-15-labeled CO, O2, and CO2 and fluorine-18-labeled fluorodeoxyglucose. Cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral metabolic rates for oxygen and glucose (CMRO2 and CMRGlu), and the oxygen extraction fraction (OEF) were measured in both hemispheres. Preoperatively, compared to five elderly control subjects, patients had increased CBV, a decreased CBF/CBV ratio, and decreased CMRO2, indicating reduced cerebral perfusion pressure and depressed oxygen metabolism. The CBF was decreased in only one patient who had bilateral carotid occlusions; the OEF, CMRGlu, and CMRO2/CMRGlu and CMRGlu/CBF ratios were not significantly different from control measurements. All bypasses were patent and all patients were asymptomatic following surgery. Postoperative PET revealed decreased CBV and an increased CBF/CBV ratio, indicating improved hemodynamic function. This was associated with increased CMRO2 in two patients in whom the postoperative OEF was also increased. The CMRGlu and CMRGlu/CBF ratio were increased in five patients. Changes in CBF and the CMRO2/CMRGlu ratio were variable. One patient with preoperative progressive mental deterioration, documented by serial neuropsychological testing and decreasing CBF and CMRO2, had improved postoperative CBF, CBV, and CMRO2 concomitant with improved neuropsychological functioning and oxygen hypometabolism. It is concluded that symptomatic carotid occlusion is associated with altered hemodynamic function. Cerebral revascularization results in decreased CBV, indicating improved hemodynamic reserve, but does not consistently improve oxygen metabolism.
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Xu, J., E. Geng, L. Brake, A. Wiemken, B. Keenan, L. Kubin, and R. Schwab. "0424 Effect of Chronic Intermittent Hypoxia on Global Cerebral Metabolic Rate of Oxygen Consumption in Rats." Sleep 43, Supplement_1 (April 2020): A162—A163. http://dx.doi.org/10.1093/sleep/zsaa056.421.
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Abstract Introduction Patients with obstructive sleep apnea (OSA) commonly exhibit grey and white matter loss, which may be related to hypoxic damage in the brain during sleep. Our preliminary data demonstrated lower values of cerebral metabolic rate of oxygen (CMRO2) consumption in apneics versus controls. As such, reduced CMRO2 may be an important contributor to the neurologic consequences of OSA. Here we report a rodent model for chronic intermittent hypoxia (CIH) to quantify effects on CMRO2 consumption. We hypothesized that increased severity of CIH results in decreased CMRO2 levels. Methods Three groups of rats were subject to varying levels of hypoxia: sham (21% oxygen; n = 19), moderate (11% oxygen; n = 14), and severe (6% oxygen; n = 21). To deliver hypoxia, rats were exposed to three-minute cycles of oxygen between 21% and condition-specific nadir O2 for 12 hours daily during their sleep cycle. CMRO2 values were measured with MRI techniques, performed on anesthetized rats before and after 3 months exposure to CIH. Results Rats from the three hypoxia groups did not differ significantly in CMRO2 values at baseline (0 months). After 3 months of exposure to hypoxic conditions, there was a trending difference (p=0.0726) in percent change from baseline between severely hypoxic (-35.3%) and sham (+12.3%) rats. Moderately hypoxic rats demonstrated an intermediate decrease from baseline after 3 months (-19.0%). Conclusion Our findings suggest that increased severity of intermittent hypoxia yields a dose-response decrease in brain oxygen consumption. Our data add to the growing body of evidence on the relationship between obstructive sleep apnea and hypoxic damage in the brain, suggesting that CMRO2 levels may be an indicator of the neurologic consequences of OSA. Support Funded by NIH P01 HL094307
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Gleason, C. A., M. D. Jones, R. J. Traystman, and R. H. Notter. "Fetal cerebral responses to ventilation and oxygenation in utero." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 255, no. 6 (December 1, 1988): R1049—R1054. http://dx.doi.org/10.1152/ajpregu.1988.255.6.r1049.
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Previous studies have shown that cerebral oxygen consumption (CMRO2) increases by nearly 50% at birth. The perinatal factors responsible for this increase are unknown; however, one possibility is that fetal CMRO2 is constrained by the normal intrauterine arterial PO2 (PaO2) of approximately 20 mmHg. We investigated this possibility in seven near-term chronically instrumented fetal sheep (131-138 days gestation) in which we inserted vascular catheters and an endotracheal tube. After 1-3 days recovery, we measured cerebral blood flow (CBF) with radiolabeled microspheres and calculated CMRO2. Measurements were made in utero under three conditions for each fetus: 1) nonventilated control; 2) ventilation with 3% O2-5% CO2-92% N2; and 3) ventilation with an inspired oxygen concentration sufficient to raise fetal PaO2 to normal newborn levels (mean 73 mmHg). A calf lung surfactant extract (CLSE) was instilled into the endotracheal tube of the fetus before ventilation to ensure adequate levels of alveolar surfactant and to maintain stable pH and arterial PCO2. The results showed that increasing fetal arterial PO2 to postnatal levels did not consistently increase CMRO2. CBF decreased as arterial O2 content (CaO2) rose, with an inverse hyperbolic response similar to that previously found to relate CBF to CaO2 during fetal hypoxic hypoxia. This indicates that the normally low intrauterine PaO2 does not intrinsically limit CMRO2 and implies that the rapid increase in CMRO2 at birth reflects the activation of specific cellular and physiological processes at (or near) this unique developmental event.
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Barzilay, Z., A. G. Britten, R. C. Koehler, J. M. Dean, and R. J. Traystman. "Interaction of CO2 and ammonia on cerebral blood flow and O2 consumption in dogs." American Journal of Physiology-Heart and Circulatory Physiology 248, no. 4 (April 1, 1985): H500—H507. http://dx.doi.org/10.1152/ajpheart.1985.248.4.h500.
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Studies of acutely induced hyperammonemia and chronic hyperammonemia associated with liver dysfunction suggest that cerebral blood flow (CBF) and O2 consumption (CMRO2) become uncoupled and that CMRo2 may depend on arterial CO2 tension (PaCO2). We examined CBF (radiolabeled microspheres) and CMRO2 during hypercapnia (PaCO2 congruent to 74 Torr) and hypocapnia (PaCO2 congruent to 21 Torr) both before and during intravenous ammonium acetate infusion in pentobarbital-anesthetized dogs. Continuous infusion over 120 min produced stable increases of arterial ammonia levels (1,400 mumol/l) by 30 min, whereas CBF, CMRO2, and O2 extraction (measured at sagittal sinus) remained unchanged when PaCO2 was held constant (congruent to 35 Torr). Acute hyperammonemia attenuated the increase in CBF during hypercapnia by 44% and abolished the decrease in CBF during hypercapnia. Regional blood flow to pons and midbrain increased under normocapnic conditions, and midbrain blood flow increased further during hypocapnia. Sodium acetate infusion did not affect CBF responses to CO2. Thus we failed to observe an uncoupling of global CBF and CMRO2 during normocapnic hyperammonemia, or an interaction of CO2 and ammonia on CMRO2, although the increased pons and midbrain blood flow may reflect regional effects of ammonia on reticular activating system metabolism. On the basis of the literature, we suggest that the attenuated hypercapnic CBF response may arise from impaired glial regulation of extracellular potassium and bicarbonate concentrations and that lactic acid production, enhanced by combined alkalosis and hyperammonemia, may contribute to the abolition of hypocapnic vasoconstriction.
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Jain, Varsha, Michael C. Langham, and Felix W. Wehrli. "MRI Estimation of Global Brain Oxygen Consumption Rate." Journal of Cerebral Blood Flow & Metabolism 30, no. 9 (April 21, 2010): 1598–607. http://dx.doi.org/10.1038/jcbfm.2010.49.
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Measuring the global cerebral metabolic rate of oxygen ( CMRO2) is a valuable tool for assessing brain vitality and function. Measurement of blood oxygen saturation ( HbO2) and flow in the major cerebral outflow and inflow vessels can provide a global estimate of CMRO2. We demonstrate a rapid noninvasive method for quantifying CMRO2 by simultaneously measuring venous oxygen saturation in the superior sagittal sinus with magnetic resonance susceptometry-based oximetry, a technique that exploits the intrinsic susceptibility of deoxygenated hemoglobin, and the average blood inflow rate with phase-contrast magnetic resonance imaging. The average venous HbO2, cerebral blood flow, and global CMRO2 values in eight healthy, normal study subjects were 64%±4%, 45.2±3.2 mL per 100 g per minute, and 127±7 μmol per 100 g per minute, respectively. These values are in good agreement with those reported in literature. The technique described is noninvasive, robust, and reproducible for in vivo applications, making it ideal for use in clinical settings for assessing the pathologies associated with dysregulation of cerebral metabolism. In addition, the short acquisition time (∼30 seconds) makes the technique suitable for studying the temporal variations in CMRO2 in response to physiologic challenges.
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Ances, Beau M., David F. Wilson, Joel H. Greenberg, and John A. Detre. "Dynamic Changes in Cerebral Blood Flow, O2 Tension, and Calculated Cerebral Metabolic Rate of O2 during Functional Activation Using Oxygen Phosphorescence Quenching." Journal of Cerebral Blood Flow & Metabolism 21, no. 5 (May 2001): 511–16. http://dx.doi.org/10.1097/00004647-200105000-00005.
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Changes in cerebral blood flow (CBF) using laser–Doppler and microvascular O2 oxygen tension using oxygen-dependent phosphorescence quenching in the rat somatosensory cortex were obtained during electrical forepaw stimulation. The signal-averaged CBF response resulting from electrical forepaw stimulation consisted of an initial peak (t = 3.1 ± 0.8 seconds after onset of stimulation), followed by a plateau phase that was maintained throughout the length of the stimulus. In contrast, microvascular O2 tension changes were delayed, reached a plateau level (t = 23.5 ± 1.7 seconds after the onset of stimulation) that remained for the length of the stimulus and for several seconds after stimulus termination, and then returned to baseline. Using Fick's equation and these dynamic measurements, changes in the calculated cerebral metabolic rate of oxygen (CMRO2) during functional stimulation were determined. The calculated CMRO2 response initially was comparable with the CBF, but with protracted stimulation, CMRO2 changes were approximately one-third that of CBF changes. These results suggest that a complex relation exists, with comparable changes in CBF and CMRO2 initially occurring after stimulation but excessive changes in CBF compared with CMRO2 arising with protracted stimulation.
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Smith, Zachary M., Erin Krizay, Jia Guo, David D. Shin, Miriam Scadeng, and David J. Dubowitz. "Sustained high-altitude hypoxia increases cerebral oxygen metabolism." Journal of Applied Physiology 114, no. 1 (January 1, 2013): 11–18. http://dx.doi.org/10.1152/japplphysiol.00703.2012.
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Acute mountain sickness (AMS) is a common condition occurring within hours of rapid exposure to high altitude. Despite its frequent occurrence, the pathophysiological mechanisms that underlie the condition remain poorly understood. We investigated the role of cerebral oxygen metabolism (CMRO2) in AMS. The purpose of this study was to test 1) if CMRO2 changes in response to hypoxia, and 2) if there is a difference in how individuals adapt to oxygen metabolic changes that may determine who develops AMS and who does not. Twenty-six normal human subjects were recruited into two groups based on Lake Louise AMS score (LLS): those with no AMS (LLS ≤ 2), and those with unambiguous AMS (LLS ≥ 5). [Subjects with intermediate scores (LLS 3–4) were not included.] CMRO2 was calculated from cerebral blood flow and arterial-venous difference in O2 content. Cerebral blood flow was measured using arterial spin labeling MRI; venous O2 saturation was calculated from the MRI of transverse relaxation in the superior sagittal sinus. Arterial O2 saturation was measured via pulse oximeter. Measurements were made during normoxia and after 2-day high-altitude exposure at 3,800 m. In all subjects, CMRO2 increased with sustained high-altitude hypoxia [1.54 (0.37) to 1.82 (0.49) μmol·g−1·min−1, n = 26, P = 0.045]. There was no significant difference in CMRO2 between AMS and no-AMS groups. End-tidal Pco2 was significantly reduced during hypoxia. Low arterial Pco2 is known to increase neural excitability, and we hypothesize that the low arterial Pco2 resulting from ventilatory acclimatization causes the observed increase in CMRO2.
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Koehler, R. C., J. E. Backofen, R. W. McPherson, M. D. Jones, M. C. Rogers, and R. J. Traystman. "Cerebral blood flow and evoked potentials during Cushing response in sheep." American Journal of Physiology-Heart and Circulatory Physiology 256, no. 3 (March 1, 1989): H779—H788. http://dx.doi.org/10.1152/ajpheart.1989.256.3.h779.
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We determined how alterations in systemic hemodynamics, characteristic of the Cushing response, are related to changes in cerebral blood flow (CBF), cerebral metabolic rate of O2 (CMRO2), and brain electrical conductive function, as assessed by somatosensory-evoked potentials (SEP) and brain stem auditory-evoked responses (BAER). In three groups of eight pentobarbital-anesthetized sheep, intracranial pressure was gradually elevated to within 50, 25, or 0 mmHg of base-line mean arterial pressure and then held constant for 40 min by intraventricular infusion of mock cerebrospinal fluid. Microsphere-determined CBF fell when cerebral perfusion pressure was less than 50 mmHg. CMRO2 fell when CBF fell greater than 30-40%. Mean aortic pressure and cardiac output increased when CBF fell greater than 40%, i.e., at approximately the level at which CMRO2 fell. Furthermore, the magnitude of the increase in arterial pressure and cardiac output correlated with the reduction of CMRO2. SEP latency did not increase unless CBF fell greater than 55-65%, corresponding to a 20-30% reduction of CMRO2. Increased latency of BAER wave V was associated with a fall in midbrain blood flow of greater than 65-70%. Thus increase in SEP and BAER latencies required reductions of flow greater than those required to elicit a systemic response. This demonstrates that there is a range of intracranial pressure over which the increase in arterial pressure preserves sufficient CBF to sustain minimal electrical conductive function. The best predictor of the onset and magnitude of the Cushing response in adult sheep is the decrease in CMRO2.
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Robb, W. Hudson, Omair A. Khan, Humza A. Ahmed, Judy Li, Elizabeth E. Moore, Francis E. Cambronero, Kimberly R. Pechman, et al. "Lower cerebral oxygen utilization is associated with Alzheimer’s disease-related neurodegeneration and poorer cognitive performance among apolipoprotein E ε4 carriers." Journal of Cerebral Blood Flow & Metabolism 42, no. 4 (November 7, 2021): 642–55. http://dx.doi.org/10.1177/0271678x211056393.
Full textAbstract:
Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) are markers of cerebral oxygen homeostasis and metabolism that may offer insights into abnormal changes in brain aging. The present study cross-sectionally related OEF and CMRO2 to cognitive performance and structural neuroimaging variables among older adults (n = 246, 74 ± 7 years, 37% female) and tested whether apolipoprotein E ( APOE)-ε4 status modified these associations. Main effects of OEF and CMRO2 were null (p-values >0.06), and OEF interactions with APOE-ε4 status on cognitive and structural imaging outcomes were null (p-values >0.06). However, CMRO2 interacted with APOE-ε4 status on language (p = 0.002), executive function (p = 0.03), visuospatial (p = 0.005), and episodic memory performances (p = 0.03), and on hippocampal (p = 0.006) and inferior lateral ventricle volumes (p = 0.02). In stratified analyses, lower oxygen metabolism related to worse language (p = 0.02) and episodic memory performance (p = 0.03) among APOE-ε4 carriers only. Associations between CMRO2 and cognitive performance were primarily driven by APOE-ε4 carriers with existing cognitive impairment. Congruence across language and episodic memory results as well as hippocampal and inferior lateral ventricle volume findings suggest that APOE-ε4 may interact with cerebral oxygen metabolism in the pathogenesis of Alzheimer’s disease and related neurodegeneration.
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Hayashi, Takuya, Hiroshi Watabe, Nobuyuki Kudomi, Kyeong Min Kim, Jun-Ichiro Enmi, Kohei Hayashida, and Hidehiro Iida. "A Theoretical Model of Oxygen Delivery and Metabolism for Physiologic Interpretation of Quantitative Cerebral Blood Flow and Metabolic Rate of Oxygen." Journal of Cerebral Blood Flow & Metabolism 23, no. 11 (November 2003): 1314–23. http://dx.doi.org/10.1097/01.wcb.0000090506.76664.00.
Full textAbstract:
The coupling of cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO2) during physiologic and pathophysiologic conditions remains the subject of debate. In the present study, we have developed a theoretical model for oxygen delivery and metabolism, which describes the diffusion of oxygen at the capillary-tissue interface and the nonlinear nature of hemoglobin (Hb) affinity to oxygen, allowing a variation in simple-capillary oxygen diffusibility, termed “effective oxygen diffusibility (EOD).” The model was used to simulate the relationship between CBF and CMRO2, as well as oxygen extraction fraction (OEF), when various pathophysiologic conditions were assumed involving functional activation, ischemia, hypoxia, anemia, or hypo- and hyper-capnic CBF variations. The simulations revealed that, to maintain CMRO2 constant, a variation in CBF and Hb required active change in EOD. In contrast, unless the EOD change took place, the brain allowed small but significant nonlinear change in CMRO2 directly dependent upon oxygen delivery. Application of the present model to quantitative neuroimaging of CBF and CMRO2 enables us to evaluate the biologic response at capillary level other than Hb- and flow-dependent properties of oxygen transport and may give us another insight regarding the physiologic control of oxygen delivery in the human brain.
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Yang, Shih-Ping, and John A. Krasney. "Cerebral Blood Flow and Metabolic Responses to Sustained Hypercapnia in Awake Sheep." Journal of Cerebral Blood Flow & Metabolism 15, no. 1 (January 1995): 115–23. http://dx.doi.org/10.1038/jcbfm.1995.13.
Full textAbstract:
This investigation determined the effects of sustained hypercapnia on cerebral blood flow (CBF; radiolabeled microspheres), cerebral metabolic rates for O2 and glucose (CMRO2 and CMRglc), and brain water content in conscious sheep instrumented with aortic, left ventricular, vena cava, and brain sagittal sinus catheters. PaCO2 was elevated from 38 ± 3 to 53 ± 3 (mean ± SD) mm Hg and PaO2 from 109 ± 7 to 131 ± 4 mm Hg for 96 h in an environmental chamber. Hypercapnia did not alter sheep behavior, food and water intake, arterial pressures, core temperature, or brain lactate release. Total and regional CBF and CBF/CMRO2 reached peak values at 1 h and then readjusted, to stabilize at lower, but still elevated levels at 24 h and thereafter. CMRO2 and CMRglc increased at 6 h and thereafter during hypercapnia. PaCO2, CBF, CMRO2, and CMRglc remained elevated at 3 h after restoration to room air, while CBF/CMRO2 returned to the control value. Frontal and occipital lobe wet-to-dry weight ratios increased modestly but significantly after hypercapnic exposure. It is concluded that sustained hypercapnia induces stable and nonadapting increases in both CBF and brain metabolism that persist for at least 3 h after restoration to room air in association with hypoventilization and modest elevations of brain water.
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Pozzilli, C., M. Itoh, T. Matsuzawa, H. Fukuda, Y. Abe, T. Sato, S. Takeda, and T. Ido. "Positron Emission Tomography in Minor Ischemic Stroke Using Oxygen-15 Steady-State Technique." Journal of Cerebral Blood Flow & Metabolism 7, no. 2 (April 1987): 137–42. http://dx.doi.org/10.1038/jcbfm.1987.36.
Full textAbstract:
A study with positron emission tomography (PET) was performed on 10 patients with ischemic stroke and mild disability. The patients underwent cerebral angiography, x-ray computed tomography (CT) scan and regional cerebral measurements of CBF, CMRO2, oxygen extraction ratio (OER), and cerebral blood volume (CBV). Only minor arterial involvement was detected by angiography. In all patients, PET images of functional defects were more extensive than the corresponding CT hypodensity, and there were statistically significant reductions in CBF, CMRO2, and CBF/CBV ratio as compared with control subjects. Half of the regions analyzed in the affected hemisphere demonstrated a disruption of the normal coupling between CBF and CMRO2 as reflected by OER values significantly higher or lower than those of the corresponding region of the contralateral hemisphere. The pathophysiological pattern of high OER combined with a reduction in CBF proportionally greater than the reduction in CMRO2 was particularly indicative of regional chronic hemodynamic compromise in these patients.