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Abstract: Background: To determine if global brain hypoperfusion and oxygen hypometabolism occur in patients with amnestic mild cognitive impairment (aMCI). Methods: Thirty-two aMCI and 21 normal subjects participated. Total cerebral blood flow (TCBF), cerebral metabolic rate of oxygen (CMRO2), and brain tissue volume were measured using color-coded duplex ultrasonography (CDUS), near-infrared spectroscopy (NIRS), and MRI. TCBF was normalized by total brain tissue volume (TBV) for group comparisons (nTCBF). Cerebrovascular resistance (CVR) was calculated as mean arterial pressure divided by TCBF. Results: Reductions in nTCBF by 9%, CMRO2 by 11%, and an increase in CVR by 13% were observed in aMCI relative to normal subjects. No group differences in TBV were observed. nTCBF was correlated with CMRO2 in normal controls, but not in aMCI. Conclusions: Global brain hypoperfusion, oxygen hypometabolism, and neurovascular decoupling observed in aMCI suggest that changes in cerebral hemodynamics occur early at a prodromal stage of Alzheimer's disease, which can be assessed using low-cost and bedside-available CDUS and NIRS technology. [Copyright &y& Elsevier]

Subcortical brain regions are absolutely essential for normal human function. These phylogenetically early brain regions play critical roles in human behaviors such as the orientation of attention, arousal, and the modulation of sensory signals to cerebral cortex. Despite the critical health importance of subcortical brain regions, there has been a dearth of research on their neurovascular responses. Blood oxygen level dependent (BOLD) functional MRI (fMRI) experiments can help fill this gap in our understanding. The BOLD hemodynamic response function (HRF) evoked by brief (<4 s) neural activation is crucial for the interpretation of fMRI results because linear analysis between neural activity and the BOLD response relies on the HRF. Moreover, the HRF is a consequence of underlying local blood flow and oxygen metabolism, so characterization of the HRF enables understanding of neurovascular and neurometabolic coupling. We measured the subcortical HRF at 9.4T and 3T with high spatiotemporal resolution using protocols that enabled reliable delineation of HRFs in individual subjects. These results were compared with the HRF in visual cortex. The HRF was faster in subcortical regions than cortical regions at both field strengths. There was no significant undershoot in subcortical areas while there was a significant post-stimulus undershoot that was tightly coupled with its peak amplitude in cortex. The different BOLD temporal dynamics indicate different vascular dynamics and neurometabolic responses between cortex and subcortical nuclei., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Taylor, Himmelbach, Hagberg, Scheffler and Ress.)

Significance: Cerebral metabolic rate of oxygen ( CMRO 2 ) consumption is a key physiological variable that characterizes brain metabolism in a steady state and during functional activation., Aim: We aim to develop a minimally invasive optical technique for real-time measurement of CMRO 2 concurrently with cerebral blood flow (CBF)., Approach: We used a pair of macromolecular phosphorescent probes with nonoverlapping optical spectra, which were localized in the intra- and extravascular compartments of the brain tissue, thus providing a readout of oxygen gradients between these two compartments. In parallel, we measured CBF using laser speckle contrast imaging., Results: The method enables computation and tracking of CMRO 2 during functional activation with high temporal resolution ( ∼ 7    Hz ). In contrast to other approaches, our assessment of CMRO 2 does not require measurements of CBF or hemoglobin oxygen saturation., Conclusions: The independent records of intravascular and extravascular partial pressures of oxygen, CBF, and CMRO 2 provide information about the physiological events that accompany neuronal activation, creating opportunities for dynamic quantification of brain metabolism., (© 2022 The Authors.)

Quantitative BOLD (qBOLD) MRI permits noninvasive evaluation of hemodynamic and metabolic states of the brain by quantifying parametric maps of deoxygenated blood volume (DBV) and hemoglobin oxygen saturation level of venous blood (Y v), and along with a measurement of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO 2). The method, thus should have potential to provide important information on many neurological disorders as well as normal cerebral physiology. One major challenge in qBOLD is to separate deoxyhemoglobin's contribution to R 2 ′ from other sources modulating the voxel signal, for instance, R 2 , R 2 ′ from non-heme iron (R′ 2,nh), and macroscopic magnetic field variations. Further, even with successful separation of the several confounders, it is still challenging to extract DBV and Y v from the heme-originated R 2 ′ because of limited sensitivity of the qBOLD model. These issues, which have not been fully addressed in currently practiced qBOLD methods, have so far precluded 3D whole-brain implementation of qBOLD. Thus, the purpose of this work was to develop a new 3D MRI oximetry technique that enables robust qBOLD parameter mapping across the entire brain. To achieve this goal, we employed a rapid, R 2 ′-sensitive, steady-state 3D pulse sequence (termed 'AUSFIDE') for data acquisition, and implemented a prior-constrained qBOLD processing pipeline that exploits a plurality of preliminary parameters obtained via AUSFIDE, along with additionally measured cerebral venous blood volume. Numerical simulations and in vivo studies at 3 T were performed to evaluate the performance of the proposed, constrained qBOLD mapping in comparison to the parent qBOLD method. Measured parameters (Y v , DBV, R′ 2,nh , nonblood magnetic susceptibility) in ten healthy subjects demonstrate the expected contrast across brain territories, while yielding group-averages of 64.0 ± 2.3 % and 62.2 ± 3.1 % for Y v and 2.8 ± 0.5 % and 1.8 ± 0.4 % for DBV in cortical gray and white matter, respectively. Given the Y v measurements, additionally quantified CBF in seven of the ten study subjects enabled whole-brain 3D CMRO 2 mapping, yielding group averages of 134.2 ± 21.1 and 79.4 ± 12.6 μmol/100 g/min for cortical gray and white matter, in good agreement with literature values. The results suggest feasibility of the proposed method as a practical and reliable means for measuring neurometabolic parameters over an extended brain coverage. [ABSTRACT FROM AUTHOR]

• Oxidative metabolism is investigated in the cuprizone mouse model of demyelination. • Demyelination in gray matter is associated with reduced OEF and metabolic rate. • Cuprizone mitochondria show abnormal redox state and ATP-linked respiration. • Evidence for metabolic hypoxia is found during demyelination in gray matter. • Metabolic rate and mitochondrial status recover post cuprizone during remyelination. Disruptions in oxidative metabolism may occur in multiple sclerosis and other demyelinating neurological diseases. The impact of demyelination on metabolic rate is also not understood. It is possible that mitochondrial damage may be associated with many such neurological disorders. To study oxidative metabolism with one model of demyelination, we implemented a novel multimodal imaging technique combining Near-Infrared Spectroscopy (NIRS) and MRI to cuprizone mouse model. The cuprizone model is used to study demyelination and may be associated with inhibition of mitochondrial function. Cuprizone mice showed reduced oxygen extraction fraction (−39.1%, p ≤ 0.001), increased tissue oxygenation (6.4%, p ≤ 0.001), and reduced cerebral metabolic rate of oxygen in cortical gray matter (−62.1%, p ≤ 0.001). These changes resolved after the cessation of cuprizone exposure and partial remyelination. A decrease in hemoglobin concentration (−34.4%, p ≤ 0.001), but no change in cerebral blood flow were also observed during demyelination. The oxidized state of the mitochondrial enzyme, Cytochrome C Oxidase (CCO) increased (46.3%, p ≤ 0.001) while the reduced state decreased (−34.4%, p ≤ 0.05) significantly in cuprizone mice. The total amount of CCO did not change significantly during cuprizone exposure. Total CCO did decline after recovery both in control (−23.1%, p ≤ 0.01) and cuprizone (−28.8%, p ≤ 0.001) groups which may relate to age. A reduction in the magnetization transfer ratio, indicating demyelination, was found in the cuprizone group in the cerebral cortex (−3.2%, p ≤ 0.01) and corpus callosum (−5.5%, p ≤ 0.001). In summary, we were able to detect evidence of altered CCO metabolism during cuprizone exposure, consistent with a mitochondrial defect. We observed increased oxygenation and reduced metabolic rate associated with reduced myelination in the gray and white matter. The novel multimodal imaging technique applied here shows promise for noninvasively assessing parameters associated with oxidative metabolism in both mouse models of neurological disease and for translation to study oxidative metabolism in the human brain. [ABSTRACT FROM AUTHOR]

The cerebral metabolic rate of oxygen of small animals can be reliably imaged using the in vivo 17O magnetic resonance approach at high field. However, a separate measurement is required for imaging the cerebral blood flow in the same animal. In this study, we demonstrate that the 17O NMR signal of metabolically produced H217O in the rat brain following an 17O2 inhalation can serve as a perfusion tracer and its decay rate can be used to determine the absolute values of cerebral blood flow across a wide range of animal conditions. This finding suggests that the in vivo 17O magnetic resonance approach is capable of imaging both cerebral metabolic rate of oxygen and cerebral blood flow simultaneously and noninvasively; and it provides new utilities for studying the cerebral oxygen metabolism and perfusion commonly associated with brain function and diseases. Magn Reson Med 70:309-314, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Methylene blue USP (MB) at low doses has metabolic-enhancing and antioxidant properties and exhibits experimental neurotherapeutic benefits, but little is known about its in vivo effects on cerebral blood flow (CBF), functional evoked responses, and the associated changes in cerebral metabolic rate of oxygen (CMRO2). This study used magnetic resonance imaging (MRI) to evaluate the in vivo effects of a single intravenous MB therapeutic dose (0.5mg/kg) on basal CBF, blood oxygenation level-dependent (BOLD) and CBF responses to hypercapnic (5% CO2 in air) inhalation, as well as changes in BOLD, CBF, and CMRO2 during forepaw stimulation in the rat brain. MB did not have significant effects on arterial oxygen saturation, heart rate and fMRI responses to hypercapnia. However, MB significantly potentiated forepaw-evoked BOLD and CBF changes under normoxia. To further evaluate in vivo effects of MB under metabolic stress conditions, MRI measurements were also made under mild hypoxia (15% O2). Hypoxia per se increased evoked functional MRI responses. MB under hypoxia further potentiated forepaw-evoked BOLD, CBF and oxygen consumption responses relative to normoxia. These findings provide insights into MB''s effects on cerebral hemodynamics in vivo and could help to optimize treatments in neurological diseases with mitochondrial dysfunction and oxidative stress. [Copyright &y& Elsevier]

Cerebral metabolic rate of oxygen (CMRO2) is an important index of tissue viability and brain function, but this parameter cannot yet be measured routinely on clinical scanners. Recently, a noninvasive technique was proposed which estimates global CMRO2 by concomitantly measuring oxygen-extraction-fraction using T2-relaxation-under-spin-tagging MRI and pulse oximetry, and cerebral-blood-flow using phase-contrast MRI. This study sought to establish a standard acquisition procedure for this technique and to evaluate its test-retest reproducibility in healthy subjects. Each subject was examined in five sessions and each session included two measurements. Intrasession, intersession, and intersubject coefficients of variation for CMRO2 were found to be 3.84 ± 1.44% ( N = 7, mean ± standard deviation), 6.59 ± 1.56%, and 8.80% respectively. These reproducibility values were comparable or slightly superior to 15O positron emission tomography (PET) results reported in the literature. It was also found that oxygen-extraction-fraction and cerebral-blood-flow tended to co-vary across sessions ( P = 0.002) and subjects ( P = 0.01), and their coefficients of variation were greater than that of CMRO2. The simplicity and reliability features may afford this global CMRO2 technique great potential for immediate clinical applications. Magn Reson Med, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The amplitude of the BOLD response to a stimulus is not only determined by changes in cerebral blood flow (CBF) and oxygen metabolism (CMRO2), but also by baseline physiological parameters such as haematocrit, oxygen extraction fraction (OEF) and blood volume. The calibrated BOLD approach aims to account for this physiological variation by performing an additional calibration scan. This calibration typically consists of a hypercapnia or hyperoxia respiratory challenge, although we propose that a measurement of the reversible transverse relaxation rate, R2′, might also be used. A detailed model of the BOLD effect was used to simulate each of the calibration experiments, as well as the activation experiment, whilst varying a number of physiological parameters associated with the baseline state and response to activation. The effectiveness of the different calibration methods was considered by testing whether the BOLD response to activation scaled by the calibration parameter combined with the measured CBF provides sufficient information to reliably distinguish different levels of CMRO2 response despite underlying physiological variability. In addition the effect of inaccuracies in the underlying assumptions of each technique were tested, e.g. isometabolism during hypercapnia. The three primary findings of the study were: 1) The new calibration method based on R2′ worked reasonably well, although not as well as the ideal hypercapnia method; 2) The hyperoxia calibration method was significantly worse because baseline haematocrit and OEF must be assumed, and these physiological parameters have a significant effect on the measurements; and 3) the venous blood volume change with activation is an important confounding variable for all of the methods, with the hypercapnia method being the most robust when this is uncertain. [Copyright &y& Elsevier]

Abstract: Calibrated blood oxygenation level dependent (BOLD) imaging, a technique used to measure changes in cerebral O2 metabolism, depends on an accurate model of how the BOLD signal is affected by the mismatch between changes in cerebral blood flow (CBF) and cerebral metabolic rate of O2 (CMRO2). However, other factors such as the cerebral blood volume (CBV) distribution at rest and with activation also affect the BOLD signal. The Davis model originally proposed for calibrated BOLD studies () is widely used because of its simplicity, but it assumes CBV changes are uniformly distributed across vascular compartments, neglects intravascular signal changes, and ignores blood-tissue signal exchange effects as CBV increases and supplants tissue volume. More recent studies suggest that venous CBV changes are smaller than arterial changes, and that intravascular signal changes and CBV exchange effects can bias estimated CMRO2. In this paper, recent experimental results for the relationship between deoxyhemoglobin and BOLD signal changes are integrated in order to simulate the BOLD signal in detail by expanding a previous model to include a tissue compartment and three blood compartments rather than only the venous blood compartment. The simulated data were then used to test the accuracy of the Davis model of calibrated BOLD, demonstrating that the errors in estimated CMRO2 responses across the typical CBF–CMRO2 coupling range are modest despite the simplicity of the assumptions underlying the original derivation of the model. Nevertheless, the accuracy of the model can be improved by abandoning the original physical meaning of the two parameters α and β and treating them as adjustable parameters that capture several physical effects. For a 3Tesla field and a dominant arterial volume change with activation, the accuracy of the Davis model is improved with new values of α=0.14 and β=0.91. [Copyright &y& Elsevier]

Abstract: Functional magnetic resonance imaging (fMRI) provides an indirect reflection of neural activity change in the working brain through detection of blood oxygenation level dependent (BOLD) signal changes. Although widely used to map patterns of brain activation, fMRI has not yet met its potential for clinical and pharmacological studies due to difficulties in quantitatively interpreting the BOLD signal. This difficulty is due to the BOLD response being strongly modulated by two physiological factors in addition to the level of neural activity: the amount of deoxyhemoglobin present in the baseline state and the coupling ratio, n, of evoked changes in blood flow and oxygen metabolism. In this study, we used a quantitative fMRI approach with dual measurement of blood flow and BOLD responses to overcome these limitations and show that these two sources of modulation work in opposite directions following caffeine administration in healthy human subjects. A strong 27% reduction in baseline blood flow and a 22% increase in baseline oxygen metabolism after caffeine consumption led to a decrease in baseline blood oxygenation and were expected to increase the subsequent BOLD response to the visual stimulus. Opposing this, caffeine reduced n through a strong 61% increase in the evoked oxygen metabolism response to the visual stimulus. The combined effect was that BOLD responses pre- and post-caffeine were similar despite large underlying physiological changes, indicating that the magnitude of the BOLD response alone should not be interpreted as a direct measure of underlying neurophysiological changes. Instead, a quantitative methodology based on dual-echo measurement of blood flow and BOLD responses is a promising tool for applying fMRI to disease and drug studies in which both baseline conditions and the coupling of blood flow and oxygen metabolism responses to a stimulus may be altered. [Copyright &y& Elsevier]

Abstract: BOLD fMRI localizes activated brain areas by measuring decreases of deoxygenated hemoglobin (deoxy-Hb) caused by neurovascular coupling. To date, it is unclear whether intracranial pressure (ICP) modifies deoxy-Hb signaling for brain mapping. In addition, ICP elevation can test whether the BOLD post-stimulus undershoot, a transient hypo-oxygenation following functional activation, is due to vascular compliance rather than elevated cerebral metabolic rate of oxygen (CMRO2). We addressed these questions by studying the effect of ICP elevation on neurovascular coupling. In anesthetized rats, a cranial window was implanted over the somatosensory cortex. Using laser Doppler flowmetry and optical spectroscopy, changes in cerebral blood flow (CBF), cerebral blood volume (CBV) and deoxy-Hb were measured during electrical forepaw stimulation. Neuronal activity was monitored by somatosensory evoked potentials. ICP was elevated by subarachnoideal and intracisternal infusion of artificial cerebrospinal fluid. ICP elevation did not abrogate neurovascular coupling. However, the concomitant deoxy-Hb decrease was reduced (ICP=14mmHg) and reversed (ICP=28mmHg). Therefore, the validity of BOLD fMRI has to be questioned during increased ICP. Moreover, the amplitude of the deoxy-Hb post-stimulus overshoot was reduced with ICP elevation. CMRO2 was not elevated during the post-stimulus response. Therefore, these data provide experimental evidence that the BOLD post-stimulus undershoot is a passive vascular phenomenon. [Copyright &y& Elsevier]

The purpose of this study was to investigate activation-induced hypermetabolism and hyperemia by using a multifrequency (4, 8, and 16 Hz) reversing-checkerboard visual stimulation paradigm. Specifically, we sought to (i) quantify the relative contributions of the oxidative and nonoxidative metabolic pathways in meeting the increased energy demands [i.e., ATP production (JATP)] of task-induced neuronal activation and (ii) determine whether task-induced cerebral blood flow (CBF) augmentation was driven by oxidative or nonoxidative metabolic pathways. Focal increases in CBF, cerebral metabolic rate of oxygen (CMRO2; i.e., index of aerobic metabolism), and lactate production (JLac; i.e., index of anaerobic metabolism) were measured by using physiologically quantitative MRI and spectroscopy methods. Task-induced increases in JATP were small (1 2.2-1 6.7%) at all stimulation frequencies and were generated by aerobic metabolism (approximately 98%), with %ΔJATP being linearly correlated with the percentage change in CMRO2 (r = 1.00, P < 0.001). In contrast, task- induced increases in CBF were large (51.7-65.1%) and negatively correlated with the percentage change in CMRO2 (r= -0.64, P= 0.024), but positively correlated with %ΔJLac (r = 0.91, P < 0.001). These results indicate that (i) the energy demand of task-induced brain activation is small (approximately 15%) relative to the hyperemic response (approximately 60%), (ii) this energy demand is met through oxidative metabolism, and (iii) the CBF response is mediated by factors other than oxygen demand. [ABSTRACT FROM AUTHOR]

Neurovascular coupling provides the basis for many functional neuroimaging techniques. Nitric oxide (NO), adenosine, cyclooxygenase, CYP450 epoxygenase, and potassium are involved in dilating arterioles during neuronal activation. We combined inhibition of NO synthase, cyclooxygenase, adenosine receptors, CYP450 epoxygenase, and inward rectifier potassium (Kir) channels to test whether these pathways could explain the blood flow response to neuronal activation. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) of the somatosensory cortex were measured during forepaw stimulation in 24 rats using a laser Doppler/spectroscopy probe through a cranial window. Combined inhibition reduced CBF responses by two-thirds, somatosensory evoked potentials and activation-induced CMRO2 increases remained unchanged, and deoxy-hemoglobin (deoxy-Hb) response was abrogated. This shows that in the rat somatosensory cortex, one-third of the physiological blood flow increase is sufficient to prevent microcirculatory increase of deoxy-Hb concentration during neuronal activity. The large physiological CBF response is not necessary to support small changes in CMRO2. We speculate that the CBF response safeguards substrate delivery during functional activation with a considerable ‘safety factor’. Reduction of the CBF response in pathological states may abolish the BOLD–fMRI signal, without affecting underlying neuronal activity. [ABSTRACT FROM AUTHOR]

Neurovascular coupling provides the basis for many functional neuroimaging techniques. Nitric oxide (NO), adenosine, cyclooxygenase, CYP450 epoxygenase, and potassium are involved in dilating arterioles during neuronal activation. We combined inhibition of NO synthase, cyclooxygenase, adenosine receptors, CYP450 epoxygenase, and inward rectifier potassium (Kir) channels to test whether these pathways could explain the blood flow response to neuronal activation. Cerebral blood flow (CBF) and cerebral metabolic rate of oxygen (CMRO2) of the somatosensory cortex were measured during forepaw stimulation in 24 rats using a laser Doppler/spectroscopy probe through a cranial window. Combined inhibition reduced CBF responses by two-thirds, somatosensory evoked potentials and activation-induced CMRO2 increases remained unchanged, and deoxy-hemoglobin (deoxy-Hb) response was abrogated. This shows that in the rat somatosensory cortex, one-third of the physiological blood flow increase is sufficient to prevent microcirculatory increase of deoxy-Hb concentration during neuronal activity. The large physiological CBF response is not necessary to support small changes in CMRO2. We speculate that the CBF response safeguards substrate delivery during functional activation with a considerable ‘safety factor’. Reduction of the CBF response in pathological states may abolish the BOLD–fMRI signal, without affecting underlying neuronal activity. [ABSTRACT FROM AUTHOR]

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 vivo 17O 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 vivo 17O MRS imaging should provide a sensitive neuroimaging modality for mapping CMRO2 and its change induced by brain physiology and/or pathologic alteration.Journal of Cerebral Blood Flow & Metabolism (2009) 29, 10–18; doi:10.1038/jcbfm.2008.97; published online 10 September 2008 [ABSTRACT FROM AUTHOR]

Liposome-encapsulated Hb (LEH) is being developed as an artificially assembled, low-toxicity, and spatially isolated Hb-based oxygen carrier (HBOC). Standard methods of evaluating oxygen carriers are based on surrogate indicators of physiology in animal models of shock. Assessment of actual delivery of oxygen by HBOCs and resultant improvement in oxygen metabolism at the tissue level has been a technical challenge. In this work, we report our findings from 15O-positron emission tomographic (15O-PET) evaluation of LEH in a rat model of 40% hypovolemic shock. In vitro studies showed that PEGylated LEH formulation containing ∼7.5% Hb and consisting of neutral lipids (distearoylphosphatidylcholine:cholesterol:α-tocopherol, 51.4:46.4:2.2) efficiently picks up 15O-labeled oxygen gas. The final preparation of LEH contained 5% human serum albumin to provide oncotic pressure. Cerebral PET images of anesthetized rats inhaling 15O-labeled O2 gas showed efficient oxygen-carrying and delivery capacity of LEH formulation. From the PET images, we determined cerebral metabolic rate of oxygen (CMRO2) as a direct indicator of oxygen-carrying capacity of LEH as well as oxygen delivery and metabolism in rat brain. Compared with control fluids [saline and 5% human serum albumin (HSA)], LEH significantly improved CMRO2 to ∼80% of baseline level. Saline and HSA resuscitation could not improve hypovolemia-induced decrease in CMRO2. On the other hand, resuscitation of shed blood was the most efficient in restoring oxygen metabolism. The results suggest that 15O-PET technology can be successfully employed to evaluate potential oxygen carriers and blood substitutes and that LEH resuscitation in hemorrhage enhances oxygen delivery to the cerebral tissue and improves oxygen metabolism in brain. [ABSTRACT FROM AUTHOR]

Ability to image cerebral metabolic rate of oxygen (CMRO2) is essential for studying the fundamental role of oxidative metabolism in brain function and disease. We have demonstrated recently that three-dimensional (3D) CMRO2 images can be obtained in the rat brain during a 2-min 17O2 inhalation using the 17O MR spectroscopic imaging (MRSI) approach at high field. The feasibility for establishing a completely noninvasive approach for imaging CMRO2 has also been demonstrated. In this study, we further explored the feasibility of 17O MRSI approach for performing repeated CMRO2 measurements within a short period of time and evaluated the reproducibility of the repeated measurements. Subsequently, we applied the 17O MRSI approach to measure CMRO2 and cerebral blood flow (CBF) values at two brain temperatures in the α-chloralose anesthetized rat brain at 9.4 T. Finally, we tested the validity of simplified model for noninvasively determining CMRO2 in normothermic and hypothermic rat brain. The results show (i) an excellent reproducibility among repeated measurements of 3D CMRO2 images under the same physiologic condition; (ii) a 44% decrease of CMRO2 across the rat brain at mild hypothermic (32°C) condition as compared with normothermic (37°C) condition; and (iii) a close correlation between CMRO2 and CBF within a relatively wide physiologic range. This study demonstrates the capability of 17O MRSI approach for noninvasively imaging CMRO2 and its changes caused by physiologic perturbation. This approach, thus, should provide a promising neuroimaging modality for studying oxidative metabolism and bioenergetics associated with brain functions and diseases.Journal of Cerebral Blood Flow & Metabolism (2007) 27, 1225–1234; doi:10.1038/sj.jcbfm.9600421; published online 29 November 2006 [ABSTRACT FROM AUTHOR]

Objective: To evaluate the association between global cerebral blood flow and different cerebral perfusion pressure ranges in severe head injury.Design: A retrospective studySetting: Neurosurgical and trauma patients in an intensive care unit in a regional hospital.Patients and Participants: Out of a series of 237 consecutive patients with severe head injuries (GCSInterventions: None.Measurements and Results: Most (95.6%) of xenon-CT studies were obtained with CPP values within the 50-90 mmHg range. Perfusion data were grouped according to CPP values: (1) below 50 mmHg, (2) 50-60 mmHg, (3) 60-70 mmHg, (4) above 70 mmHg. Global cerebral blood flow did not differ among the groups (p=0.49). No differences in physiological variables were found among the CPP groups, except for intracranial pressure, higher in the group with CPP below 50 mmHg, and mean arterial pressure, higher in the CPP above 70 mmHg group (p<0.0001). No differences were found for cerebral metabolic rate of oxygen and lactate.Conclusions: There was little correlation between CPP values and global cerebral blood flow levels in our selected patients, probably because pressure autoregulation was preserved. Global metabolism measurements were constant within the groups, suggesting that in patients with controlled physiological variables an interplay between cerebral blood flow and metabolism might be more relevant than the relationship between CPP and cerebral blood flow. [ABSTRACT FROM AUTHOR]

The magnitude of the blood oxygenation level-dependent (BOLD) signal depends on cerebral blood flow (CBF), cerebral blood volume (CBV) and cerebral metabolic rate of oxygen (CMRO2). Thus, it is difficult to separate CMRO2 changes from CBF and CBV changes. To detect the BOLD signal changes induced only by CMRO2 responses without significant evoked CBF and CBV changes, BOLD and CBV functional magnetic resonance imaging (fMRI) responses to visual stimulation were measured under normal and hypotension conditions in isoflurane-anesthetized cats at 4.7 T. When the mean arterial blood pressure (MABP) decreased from 89±10 to 50±1 mm Hg (mean±standard deviation, n=5) by infusion of vasodilator sodium nitroprusside, baseline CBV in the visual cortex increased by 28.4%±8.3%. The neural activity-evoked CBV increase in the visual cortex was 10.8%±3.9% at normal MABP, but was negligible at hypotension. Positive BOLD changes of +1.8%±0.5% (gradient echo time=25 ms) at normal MABP condition became prolonged negative changes of −1.2%±0.3% at hypotension. The negative BOLD response at hypotension starts approximately 1 sec earlier than positive BOLD response, but similar to CBV change at normal MABP condition. Our finding shows that the negative BOLD signals in an absence of CBV changes are indicative of an increase in CMRO2. The vasodilator-induced hypotension model simplifies the physiological source of the BOLD fMRI signals, providing an insight into spatial and temporal CMRO2 changes.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 1043–1051. doi:10.1038/sj.jcbfm.9600251; published online 14 December 2005 [ABSTRACT FROM AUTHOR]

Predicting the onset of secondary energy failure after a hypoxic–ischemic insult in newborns is critical for providing effective treatment. Measuring reductions in the cerebral metabolic rate of oxygen (CMRO2) may be one method for early detection, as hypoxia–ischemia is believed to impair oxidative metabolism. We have developed a near-infrared spectroscopy (NIRS) technique based on the Fick Principle for measuring CMRO2. This technique combines cerebral blood flow (CBF) measurements obtained using the tracer indocyanine green with measurements of the cerebral deoxy-hemoglobin (Hb) concentration. In this study, NIRS measurements of CMRO2 were compared with CMRO2 determined from the product of CBF and the cerebral arteriovenous difference in oxygen measured from blood samples. The blood samples were collected from a peripheral artery and the sagittal sinus. Eight piglets were subjected to five cerebral metabolic states created by varying the plane of anesthesia. No significant difference was found between CMRO2 measurements obtained with the two techniques at any anesthetic level (P>0.5). Furthermore, there was a strong correlation when concomitant CMRO2 values from the two techniques were compared (R2=0.88, P<0.001). This work showed that CMRO2 can be determined accurately by combining NIRS measurements of CBF and Hb. Since NIRS is safe and measurements can be obtained at the bedside, it is believed that this technique could assist in the early diagnosis of cerebral energy dysfunction after hypoxia–ischemia.Journal of Cerebral Blood Flow & Metabolism (2006) 26, 722–730. doi:10.1038/sj.jcbfm.9600230; published online 28 September 2005 [ABSTRACT FROM AUTHOR]

Abstract: Functional magnetic resonance imaging (fMRI) was used to investigate the effects of inspired hypoxic, hyperoxic, and hypercapnic gases on baseline and stimulus-evoked changes in blood oxygenation level-dependent (BOLD) signals, cerebral blood flow (CBF), and the cerebral metabolic rate of oxygen (CMRO2) in spontaneously breathing rats under isoflurane anesthesia. Each animal was subjected to a baseline period of six inspired gas conditions (9% O2, 12% O2, 21% O2, 100% O2, 5% CO2, and 10% CO2) followed by a superimposed period of forepaw stimulation. Significant stimulus-evoked fMRI responses were found in the primary somatosensory cortices. Relative fMRI responses to forepaw stimulation varied across gas conditions and were dependent on baseline physiology, whereas absolute fMRI responses were similar across moderate gas conditions (12% O2, 21% O2 100% O2, and 5% CO2) and were relatively independent of baseline physiology. Consistent with data obtained using well-established techniques, baseline and stimulus-evoked CMRO2 were invariant across moderate physiological perturbations thereby supporting a CMRO2-fMRI technique for non-invasive CMRO2 measurement. However, under 9% O2 and 10% CO2, stimulus-evoked CBF and BOLD were substantially reduced and the CMRO2 formalism appeared invalid, likely due to attenuated neurovascular coupling and/or a failure of the model under extreme physiological perturbations. These findings demonstrate that absolute fMRI measurements help distinguish neural from non-neural contributions to the fMRI signals and may lend a more accurate measure of brain activity during states of altered basal physiology. Moreover, since numerous pharmacologic agents, pathophysiological states, and psychiatric conditions alter baseline physiology independent of neural activity, these results have implications for neuroimaging studies using relative fMRI changes to map brain activity. [Copyright &y& Elsevier]

With recent discussions in the literature regarding prophylactic use of early (within the first 12 h after birth), low-dose indomethacin to reduce the incidence and severity of intraventricular hemorrhage, knowledge pertaining to the cerebral hemodynamic effects of indomethacin in this age group is of significant interest. The cerebral circulation is known to undergo significant changes during the first few days of postnatal life. In the present study, we have investigated the hypothesis that postnatal adaptive changes influence the cerebral hemodynamic response to indomethacin in an age-dependent manner. Near-infrared spectroscopy with indocyanine green was used to measure cerebral hemodynamics, cerebral metabolic rate of oxygen, and cerebral oxygen extraction fraction in 39 newborn piglets. Piglets were grouped by age and received either 0.2 mg/kg indomethacin (14 were <13 h of age and 12 were >13 h of age) or saline (8 were <13 h of age and 5 were >13 h of age) infusions. In a subgroup of indomethacin-treated piglets (9 less than and 7 greater than 13 h of age), Doppler flow ultrasound was used to diagnose and monitor the presence and persistence of patent ductus arteriosus. Age was a significant factor in the cerebral hemodynamic response to indomethacin with piglets < 13 h of age exhibiting delayed increases in cerebral blood flow and cerebral blood volume at 150 rain post-indomethacin infusion. [ABSTRACT FROM AUTHOR]

SummaryIt 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 H2 17O produced in the brain tissue from inhaled 17O2gas (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 CMRO2in vivo.Journal of Cerebral Blood Flow & Metabolism (2004) 24, 840–848; doi:10.1097/01.WCB.0000125885.54676.82 [ABSTRACT FROM AUTHOR]

Measurement of cerebral blood flow (CBF), cerebral blood volume (CBV), cerebral oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2) by positron emission tomography (PET) with oxygen-15 labelled carbon dioxide (C15O2) or 15O-labelled water (H215O), 15O-labelled carbon monoxide (C15O) and 15O-labelled oxygen (15O2) is useful for diagnosis and treatment planning in cases of cerebrovascular disease. The measured values theoretically depend on various factors, which may differ between PET centres. This study explored the applicability of a database of 15O-PET by examining between-centre and within-centre variation in values. Eleven PET centres participated in this multicentre study; seven used the steady-state inhalation method, one used build-up inhalation and three used bolus administration of C15O2 (or H215O) and 15O2. All used C15O for measurement of CBV. Subjects comprised 70 healthy volunteers (43 men and 27 women; mean age 51.8±15.1 years). Overall mean±SD values for cerebral cortical regions were: CBF=44.4±6.5 ml 100 ml-1 min-1; CBV=3.8±0.7 ml 100 ml-1; OEF=0.44±0.06; CMRO2=3.3±0.5 ml 100 ml-1 min-1. Significant between-centre variation was observed in CBV, OEF and CMRO2 by one-way analysis of variance. However, the overall inter-individual variation in CBF, CBV, OEF and CMRO2 was acceptably small. Building a database of normal cerebral haemodynamics obtained by the15O-PET methods may be practicable. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is increasingly used to quantify regional hemodynamic and metabolic changes in different animal models. Most of these (multitracer) studies provided important early data on already functionally altered brain tissue, indicating selective vulnerability by a large variability in the functional blood flow threshold of individual neurons. To fill the gap between experimental studies at early time points and rather late clinical studies at well-defined but singular time points, we repeatedly measured cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), oxygen extraction rate and cerebral metabolic rate of glucose (CMRglc) in three cats before and up to 28 h after decompressive hemicraniectomy on normal brain tissue. Decompressive hemicraniectomy in the cat decreased CBF, and to a lesser extent CMRO2 and CMRglc 2 h after surgical intervention in normal brain tissue that last for at least 1 day. CBF significantly decreased (p<0.01) and oxygen extraction fraction (OEF) (p<0.05) significantly increased. CMRO2 and CMRglc decreased only in regions with most severe CBF reduction. These effects remained for at least a day irrespective of corrective sustaining cranioplasty. The method and data analysis is decreased and discussed in detail in the presented protocol. In conclusion, serial positron emission tomography studies are best suited to repeatedly and non-invasively demonstrate circulatory and biochemical changes by surgical interventions in normal brain tissue for at least one day. The transition of normal brain tissue into misery-perfused or non-viable regions can be followed over time. Such state-of-the-art imaging modalities as sequential high-resolution positron emission tomography provide insight into the dynamic of regional pathophysiology and may thus further justify the development of rational therapeutic strategies for decompressive hemicraniectomy, especially for disease with focal disturbances in cerebral blood flow. [Copyright &y& Elsevier]

Acetazolamide, a carbonic anhydrase inhibitor, has an anticonvulsant effect which may result from a decrease in the efficacy of synaptic transmission due to a decrease of pH. Our previous study showed that acetazolamide induced a significant increase in global and regional cerebral blood flow (CBF), but caused no significant change in the cerebral metabolic rate of oxygen (CMRO2). To investigate the effect of acetazolamide on the responses of CBF and CMRO2 during neural stimulation, we used positron emission tomography to measure CBF and CMRO2 in six normal volunteers at the fixation-only baseline visual state and during visual stimulation before and after administration of 1 g of acetazolamide. Visual stimulation induced a significant increase in CBF (33%) in the visual cortex compared with baseline values, but caused no significant change in CMRO2, while no significant change in global CBF or CMRO2 was found. During visual stimulation after acetazolamide administration, both global and visual cortical CBF and CMRO2 showed similar changes compared with the respective baseline values (37 and 65% increases in CBF and 8 and 16% decreases in CMRO2, respectively). When corrected by the global values, the magnitudes of the CBF and CMRO2 responses to visual stimulation after acetazolamide administration were less than those before (20% vs 38% in CBF and −9% vs 3% in CMRO2). Considering our previous observation that the effect of acetazolamide was similar throughout cerebral cortical regions, we suggest that acetazolamide decreases the responses of both CBF and CMRO2 during visual stimulation, which indicates that this drug may affect neuronal excitability. [Copyright &y& Elsevier]

Hemicraniectomy is increasingly used as treatment option in stroke and in head trauma, but little is known on the (patho)physiological regional effects of hemicraniectomy in the normal brain. A standard left-sided craniectomy was performed in three cats. Regional cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2) and cerebral metabolic rate of glucose (CMRglc) were measured from the brain tissue underneath the craniectomy at 2, 20 and 28 h after hemicraniectomy. CBF significantly decreased (P<0.01) and oxygen extraction fraction (OEF) (P<0.05) significantly increased. CMRO2 and CMRglc decreased only in regions with most severe CBF reduction. These effects remained for at least a day irrespective of corrective sustaining cranioplasty. The authors demonstrated for the first time that decompressive hemicraniectomy in the cat decreases CBF, and to a lesser extent CMR02 and CMRglc 2 h after hemicraniectomy in normal brain tissue that last for at least 1 day. Even though the underlying basis of these phenomena are not fully understood, this finding implies that persisting pathophysiological processes are induced by hemicraniectomy and should be taken into consideration for surgical indications. [Copyright &y& Elsevier]

Dynamic changes in the cerebral metabolic rate of oxygen (CMRO2) and oxygen extraction ratio (OER) in an event-related functional MRI (ER-fMRI) were measured in this study. Six subjects participated in this study at a magnetic field of 1.9 T. Cerebral blood flow (CBF) and blood oxygenation level-dependent (BOLD) changes were acquired during the brief visual stimulation, and the corresponding changes in CMRO2 and OER were then determined. The results showed that the maximum relative changes in CMRO2 and OER were about 10.36 ± 0.85 and −6.54 ± 0.55%, respectively, while the maximum changes in CBF and BOLD were approximately 17.35 ± 1.37 and 1.03 ± 0.06%, respectively. The CBF, CMRO2, and OER changes reach their maximum approximately 1 s earlier than the BOLD signal change (4.15 ± 0.21, 4.16 ± 0.21, and 4.17 ± 0.21 s vs 5.12 ± 0.24 s after stimulation, P < 0.05). [Copyright &y& Elsevier]

Background: The mechanism behind indomethacin-induced cerebral vasoconstriction is incompletely understood. We tested the hypothesis that the mixed endothelin-1 receptor antagonist bosentan would modify or prevent indomethacin-induced reduction of CBF in the anaesthetized pig. Furthermore, we investigated the effect of bosentan on resting CBF and CMRO2.Methods: Twelve pigs were randomized in two groups of six, and received either bosentan and indomethacin (group 1), or placebo and indomethacin (group 2). Anaesthesia was induced with ketamine and midazolam and maintained with fentanyl, nitrous oxide and pancuronium. Baseline measurements of CBF and CMRO2 were performed before intravenous bolus injection of bosentan (10 mg/kg) or placebo (0.9% NaCl). The second CBF and CMRO2 measurement was performed 30 min after administration of bosentan/placebo. A 40-min infusion of indomethacin (0.05 mg/kg/min) was administered and the third CBF and CMRO2 measurement was performed 80 min after administration of bosentan/placebo. Independently, pharmacokinetic data of bosentan were generated in four pigs.Results: In group 1, baseline CBF was 55 +/- 7 ml/100 cm3/min. Administration of bosentan i.v. did not change CBF significantly. Indomethacin decreased CBF to 41 +/- 5 ml/100 cm3/min (P < 0.002). In group 2, baseline CBF was 54 +/- 10 ml/100 cm3/min. Placebo did not change CBF while indomethacin decreased CBF significantly to 41 +/- 5 ml/100 cm3/min (P < 0.002). No significant changes in CMRO2 were observed. In group 2, a significant increase in MABP was observed after administration of indomethacin. No change in MABP was observed in the bosentan-treated animals. Total plasma concentrations of bosentan at the time of the first and the second PET measurement were 3.9 and 1.4 microg/ml, respectively. The corresponding values for the pharmacologically active metabolite Ro 48-5033 were 1.2 and 0.4 microg/ml.Conclusion: These findings indicate that endothelin receptor stimulation is not involved in indomethacin-induced cerebral vasoconstriction or maintenance of cerebrovascular tone in the anaesthetized pig. However, our results suggest that the increase in MABP is mediated through endothelin receptors. [ABSTRACT FROM AUTHOR]

Background: Effects of propofol on human cerebral blood flow (CBF), cerebral metabolic rate of oxygen (CMRO2), and blood flow-metabolism coupling have not been fully evaluated. We therefore assessed the effects of propofol on total-CBF and CMRO2 in patients without noxious stimuli and neurologic disorders.Methods: General anesthesia was induced with midazolam (0.2 mg/kg) and fentanyl (5 microg/kg) in 10 patients (ASA physical status I) undergoing knee joint endoscopic surgery. Epidural anesthesia was also performed to avoid noxious stimuli during surgery. Cerebral blood flow (CBF) and cerebral arteriovenous oxygen content difference (a-vDO2) was measured using the Kety-Schmidt method with 15% N2O as a tracer before and after propofol infusion (6 mg/kg/h for 40 min), and the CMRO2 was also calculated.Results: CBF decreased following propofol infusion from 34.4 ml/100 g/min (range 28.4-52.0) to 30.0 ml/100 g/min (range 20.2-42.4) (P=0.04). Although there was no significant change in a-vDO2, CMRO2 decreased following propofol infusion from 2.7 ml/100 g/min (range 2.2-4.3) to 2.2 ml/100 g/min (range 1.4-3.0) (P=0.04). There was a strong linear correlation between CBF and CMRO2 (r=0.90).Conclusion: Propofol proportionally decreased CBF and CMRO2 without affecting a-vDO2 in humans, suggesting that normal cerebral circulation and metabolism are maintained. [ABSTRACT FROM AUTHOR]

The ischemic penumbra is defined as the severely hypoperfused, functionally impaired, at-risk but not yet infarcted tissue that will be progressively recruited into the infarct core. Early reperfusion aims to save the ischemic penumbra by preventing infarct core expansion and is the mainstay of acute ischemic stroke therapy. Intravenous thrombolysis and mechanical thrombectomy for selected patients with large vessel occlusion has been shown to improve functional outcome. Given the varying speed of infarct core progression among individuals, a therapeutic window tailored to each patient has recently been proposed. Recent studies have demonstrated that reperfusion therapies are beneficial in patients with a persistent ischemic penumbra, beyond conventional time windows. As a result, mapping the penumbra has become crucial in emergency settings for guiding personalized therapy. The penumbra was first characterized as an area with a reduced cerebral blood flow, increased oxygen extraction fraction and preserved cerebral metabolic rate of oxygen using positron emission tomography (PET) with radiolabeled O 2 . Because this imaging method is not feasible in an acute clinical setting, the magnetic resonance imaging (MRI) mismatch between perfusion-weighted imaging and diffusion-weighted imaging, as well as computed tomography perfusion have been proposed as surrogate markers to identify the penumbra in acute ischemic stroke patients. Transversal studies comparing PET and MRI or using longitudinal assessment of a limited sample of patients have been used to define perfusion thresholds. However, in the era of mechanical thrombectomy, these thresholds are debatable. Using various MRI methods, the original penumbra definition has recently gained a significant interest. The aim of this review is to provide an overview of the evolution of the ischemic penumbra imaging methods, including their respective strengths and limitations, as well as to map the current intellectual structure of the field using bibliometric analysis and explore future directions., Competing Interests: LC, DR, and TB are employees of Olea Medical, a company developing the OleaSphere platform including pipelines for ischemic penumbra. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chalet, Boutelier, Christen, Raguenes, Debatisse, Eker, Becker, Nighoghossian, Cho, Canet-Soulas and Mechtouff.)

A piglet model was developed to study the effect of epidural volume expansion on cerebral perfusion pressure (CPP) by stepwise elevating intracranial pressure (ICP). Mean arterial blood pressure (ABP) was strictly maintained using an extracorporeal ABP controller. Two-week-old piglets (n = 10) were studied by surgically placing an epidural balloon over the right parietal region and gradually increasing the inflation to increase ICP to 25, 35 and 45 mm Hg, maintaining each pressure level for 30 min. Regional cerebral blood flow was measured using the colored microsphere technique, and cerebral oxygen delivery and cerebral metabolic rate of oxygen were calculated at baseline conditions and after reaching ICP levels of 25, 35 and 45 mm Hg. The results showed that this model of epidural volume expansion reproducibly reduces CPP to 70, 50 and 33% of baseline CPP values with elevation of ICP, and that the physiological variables remained stable throughout each increase in ICP. We conclude that the model simulates the effects of an acute intracranial focal mass expansion and is well suited for the evaluation of different therapeutical strategies for increased ICP in newborns and infants. [ABSTRACT FROM AUTHOR]

Secondary brain lesions resulting from cerebral metabolic and hemodynamic reactions can be prevented by neurocritical care management. It must be initiated as soon as possible, ideally in a prehospital setting. Tracheal intubation, controlled ventilation and hemodynamic stabilization are the prerequisites. Beside intracranial and cerebral perfusion pressure, monitoring must evaluate the coupling between cerebral metabolic demand and blood flow. Jugular bulb oximetry is the most reliable approach to global cerebral coupling. Transcranial Doppler evaluates cerebral blood flow indirectly and noninvasively. Technological developments have led to local metabolic evaluation that does not yet have any clinical relevance. Therapeutic developments are more a new approach to the use of old drugs. Controlled hyperventilation, mannitol and, more recently, hypertonic saline solutions, used for restoring cerebral metabolic coupling, are the foundations of treatment. Thiopental, revisited as a vasoconstrictive agent, the ”Lund” vasoconstrictive approach with anti-hypertensive drugs and cerebral vasoconstrictors, must be further evaluated in children, as must therapeutic hypothermia. Finally, what we probably need for the immediate future is a noninvasive and easily reproducible method of monitoring cerebral metabolic coupling that will allow precise therapeutic adaptation of multimodal therapy to the individual needs of the child. [ABSTRACT FROM AUTHOR]

The present study was undertaken in 8 healthy volunteers to examine the effect of a clinically relevant dose of nimodipine (NIM) (15 and 30 microgram/kg/h) on CBF, its CO reactivity, and CMRO. Mean arterial blood pressure (MABP) was measured intra-arterially. Regional CBF was measured by SPECT of inhaled Xenon-133. During the CO reactivity tests changes in CBF were estimated by the arterio-venous-oxygen-difference method. Median CBF was 52 ml/ 100 g/min (48-53) with a normal regional distribution, and median baseline MABP was 96 mmHg (92-99). MABP was slightly reduced, by 8 mmHg (7-9), and 9 mmHg (4-11) after infusion of NIM for 2 and 4 hours, respectively. CBF, however, remained constant, although correction for changes in PaCO, revealed a slight increase after 4 hours (p=0.08). CMRO2 was 3.5 ml/100 g/min (3.2-3.5) and was not changed by the infusion of NIM. At arterial CO tensions ranging from 4.0 to 6.5 Kpa the CO reactivity was 3.0% CBF/ 0.1 kPa (2.6-3.7) and decreased significantly to 2.6% CBF/0.1 kPa (1.8-3.2) after the infusion of NIM for 3 hours (p=0.02). The median slope of the LnCBFsat/PaCO relationship was 1.5 at baseline compared to 1.3 after NIM (p<0.01). No side effects were observed. The present study shows a decreased CO of the cerebral vessels and a maintained coupling of CBF and CMRO during the infusion of nimodipine. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) provides the ability to extract useful quantitative information not available through other radiological techniques. In certain studies, the physiological parameters of interest cannot be determined from the data obtained from a single PET experiment alone. In this case, multiple experiments are required. At present, the methods used to analyse measurements acquired from multiple experiments often involve considering them separately during the modelling procedures. These methods of analysis may cause errors to be propagated through successive modelling procedures and do not fully utilise the information content provided by the PET measurements. A new method is presented, based on linear least squares for the analysis of PET dynamic data acquired from multiple experiments. This method simultaneously considers the complete set of measurements obtained and provides reliable parameter estimates. The efficient use of the information content provided by multiple experiments is considered and the propagation of errors is discussed. To facilitate our discussion, we apply this new method to the estimation of the cerebral metabolic rate of oxygen and the parameters of the oxygen utilisation model as a practical example. The results demonstrate a significant improvement in the reliability and estimation accuracy of the estimates for this new method. Furthermore, this method reduced the likelihood of errors being propagated. Therefore, the proposed method is suitable for the analysis of multiple PET dynamic datasets. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to assess the spatiotemporal evolution of oxygen extraction fraction (OEF) in ischemic stroke with a newly developed cluster analysis of time evolution (CAT) for a combined quantitative susceptibility mapping and quantitative blood oxygen level-dependent model (QSM + qBOLD, QQ)., Method: One hundred and fifteen patients in different ischemic stroke phases were retrospectively collected for measurement of OEF of the infarcted area defined on diffusion-weighted imaging (DWI). Clinical severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Of the 115 patients, 11 underwent two longitudinal MRI scans, namely, three-dimensional (3D) multi-echo gradient recalled echo (mGRE) and 3D pseudo-continuous arterial spin labeling (pCASL), to evaluate the reversal region (RR) of the initial diffusion lesion (IDL) that did not overlap with the final infarct (FI). The temporal evolution of OEF and the cerebral blood flow (CBF) in the IDL, the RR, and the FI were assessed., Results: Compared to the contralateral mirror area, the OEF of the infarcted region was decreased regardless of stroke phases ( p < 0.05) and showed a declining tendency from the acute to the chronic phase ( p = 0.022). Five of the 11 patients with longitudinal scans showed reversal of the IDL. Relative oxygen extraction fraction (rOEF, compared to the contralateral mirror area) of the RR increased from the first to the second MRI ( p = 0.044). CBF was about 1.5-fold higher in the IDL than in the contralateral mirror area in the first MRI. Two patients showed penumbra according to the enlarged FI volume. The rOEF of the penumbra fluctuated around 1.0 at earlier scan times and then decreased, while the CBF decreased continuously., Conclusion: The spatiotemporal evolution of OEF and perfusion in ischemic lesions is heterogeneous, and the CAT-based QQ method is feasible to capture cerebral oxygen metabolic information., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wu, Zhou, Cho, Shen, Li, Qin, Zhang, Yan, Xie, Zhang, Zhu and Wang.)

Quantitative measurements of resting cerebral blood flow (CBF) and metabolic rate of oxygen (CMRO 2 ) show large between-subject and regional variability, but the relationships between CBF and CMRO 2 measurements regionally and globally are not fully established. Here, we investigated the between-subject and regional associations between CBF and CMRO 2 measures with independent and quantitative PET techniques. We included resting CBF and CMRO 2 measurements from 50 healthy volunteers (aged 22-81 yr), and calculated the regional and global values of oxygen delivery (Do 2 ) and oxygen extraction fraction (OEF). Linear mixed-model analysis showed that CBF and CMRO 2 measurements were closely associated regionally, but no significant between-subject association could be demonstrated, even when adjusting for arterial Pco 2 and hemoglobin concentration. The analysis also showed regional differences of OEF, reflecting variable relationship between Do 2 and CMRO 2 , resulting in lower estimates of OEF in thalami, brainstem, and mesial temporal cortices and higher estimates of OEF in occipital cortex. In the present study, we demonstrated no between-subject association of quantitative measurements of CBF and CMRO 2 in healthy subjects. Thus, quantitative measurements of CBF did not reflect the underlying between-subject variability of oxygen metabolism measures, mainly because of large interindividual OEF variability not accounted for by Pco 2 and hemoglobin concentration. NEW & NOTEWORTHY Using quantitative PET-measurements in healthy human subjects, we confirmed a regional association of CBF and CMRO 2 , but did not find an association of these values across subjects. This suggests that subjects have an individual coupling between perfusion and metabolism and shows that absolute perfusion measurements does not serve as a surrogate measure of individual measures of oxygen metabolism. The analysis further showed smaller, but significant regional differences of oxygen extraction fraction at rest.