Thermodynamic limitations on brain oxygen metabolism: physiological implications.

Recent thermodynamic modelling indicates that maintaining the brain tissue ratio of O2 to CO2 (abbreviated tissue O2 /CO2 ) is critical for preserving the entropy increase available from oxidative metabolism of glucose, with a fall of that available entropy leading to a reduction of the phosphorylation potential and impairment of brain energy metabolism. This provides a novel perspective for understanding physiological responses under different conditions in terms of preserving tissue O2 /CO2 . To enable estimation of tissue O2 /CO2 in the human brain, a detailed mathematical model of O2 and CO2 transport was developed, and applied to reported physiological responses to different challenges, asking: how well is tissue O2 /CO2 preserved? Reported experimental results for increased neural activity, hypercapnia and hypoxia due to high altitude are consistent with preserving tissue O2 /CO2 . The results highlight two physiological mechanisms that control tissue O2 /CO2 : cerebral blood flow, which modulates tissue O2 ; and ventilation rate, which modulates tissue CO2 . The hypoxia modelling focused on humans at high altitude, including acclimatized lowlanders and Tibetan and Andean adapted populations, with a primary finding that decreasing CO2 by increasing ventilation rate is more effective for preserving tissue O2 /CO2 than increasing blood haemoglobin content to maintain O2 delivery to tissue. This work focused on the function served by particular physiological responses, and the underlying mechanisms require further investigation. The modelling provides a new framework and perspective for understanding how blood flow and other physiological factors support energy metabolism in the brain under a wide range of conditions. KEY POINTS: Thermodynamic modelling indicates that preserving the O2 /CO2 ratio in brain tissue is critical for preserving the entropy change available from oxidative metabolism of glucose and the phosphorylation potential underlying energy metabolism. A detailed model of O2 and CO2 transport was developed to allow estimation of the tissue O2 /CO2 ratio in the human brain in different physiological states. Reported experimental results during hypoxia, hypercapnia and increased oxygen metabolic rate in response to increased neural activity are consistent with maintaining brain tissue O2 /CO2 ratio. The hypoxia modelling of high-altitude acclimatization and adaptation in humans demonstrates the critical role of reducing CO2 with increased ventilation for preserving tissue O2 /CO2 . Preservation of tissue O2 /CO2 provides a novel perspective for understanding the function of observed physiological responses under different conditions in terms of preserving brain energy metabolism, although the mechanisms underlying these functions are not well understood.

Metabolic energetics underlying attractors in neural models.

Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular-level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as ∼2 × 109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered to exhibit steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The energy cost of limit cycles, with oscillations much faster than the average neuronal firing rate of the population, is tracked more closely with the firing rate than the limit cycle frequency. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. As an example of a simple network in which each node is a WC model, a combination of three nodes can serve as a flexible circuit element that turns on with an oscillating output when input passes a threshold and then persists after the input ends (an "on-switch"), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.NEW & NOTEWORTHY This work bridges two approaches for understanding brain function: cellular-level studies of the metabolic energy costs of different aspects of neural activity and neural population modeling, including the role of neural attractors. The proposed modeling framework connects energetic costs, in ATP consumed per second per neuron, to the more abstract variables used in neural population modeling. In particular, this work anchors potential neural attractors to physiologically plausible bioenergetics requirements.

Sleep-stage-dependent alterations in cerebral oxygen metabolism quantified by magnetic resonance.

A key function of sleep is to provide a regular period of reduced brain metabolism, which is critical for maintenance of healthy brain function. The purpose of this work was to quantify the sleep-stage-dependent changes in brain energetics in terms of cerebral metabolic rate of oxygen (CMRO2 ) as a function of sleep stage using quantitative magnetic resonance imaging (MRI) with concurrent electroencephalography (EEG) during sleep in the scanner. Twenty-two young and older subjects with regular sleep hygiene and Pittsburgh Sleep Quality Index (PSQI) in the normal range were recruited for the study. Cerebral blood flow (CBF) and venous oxygen saturation (SvO2 ) were obtained simultaneously at 3 Tesla field strength and 2.7-s temporal resolution during an 80-min time series using OxFlow, an in-house developed imaging sequence. The method yields whole-brain CMRO2 in absolute physiologic units via Fick's Principle. Nineteen subjects yielded evaluable data free of subject motion artifacts. Among these subjects, 10 achieved slow-wave (N3) sleep, 16 achieved N2 sleep, and 19 achieved N1 sleep while undergoing the MRI protocol during scanning. Mean CMRO2 was 98 ± 7(µmol min-1 )/100 g awake, declining progressively toward deepest sleep stage: 94 ± 10.8 (N1), 91 ± 11.4 (N2), and 76 ± 9.0 µmol min-1 /100 g (N3), with each level differing significantly from the wake state. The technology described is able to quantify cerebral oxygen metabolism in absolute physiologic units along with non-REM sleep stage, indicating brain oxygen consumption to be closely associated with depth of sleep, with deeper sleep stages exhibiting progressively lower CMRO2 levels.

The impact of isoflurane anesthesia on brain metabolism in mice: An MRI and electroencephalography study.

Isoflurane is one of the most widely used anesthetic agents in rodent imaging studies. However, the impact of isoflurane on brain metabolism has not been fully characterized to date, primarily due to a scarcity of noninvasive technologies to quantitatively measure the brain's metabolic rate in vivo. In this study, using noncontrast MRI techniques, we dynamically measured cerebral metabolic rate of oxygen (CMRO2) under varying doses of isoflurane anesthesia in mice. Concurrently, systemic parameters of heart and respiration rates were recorded alongside CMRO2. Additionally, electroencephalogram (EEG) recording was used to identify changes in neuronal activities under the same anesthetic regimen employed in the MRI experiments. We found suppression of the CMRO2 by isoflurane in a dose-dependent manner, concomitant with a diminished high-frequency EEG activity. The degree of metabolic suppression by isoflurane was strongly correlated with the respiration rate, which offers a potential approach to calibrate CMRO2 measurements. Furthermore, the metabolic level associated with neural responses of the somatosensory and motor cortices in mice was estimated as 308.2 µmol/100 g/min. These findings may facilitate the integration of metabolic parameters into future studies involving animal disease models and anesthesia usage.

Identification of prognostic imaging biomarkers in H3 K27-altered diffuse midline gliomas in adults: impact of tumor oxygenation imaging biomarkers on survival.

PURPOSE: To investigate prognostic markers for H3 K27-altered diffuse midline gliomas (DMGs) in adults with clinical, qualitative and quantitative imaging phenotypes, including tumor oxygenation characteristics. METHODS: Retrospective chart and imaging reviews were conducted on 32 adults with H3 K27-altered DMGs between 2017 and 2023. Clinical and qualitative imaging characteristics were analyzed. Quantitative imaging assessment was performed from the tumor mask via automatic segmentation to calculate normalized cerebral blood volume (nCBV), capillary transit time heterogeneity (CTH), oxygen extraction fraction (OEF), relative cerebral metabolic rate of oxygen (rCMRO2), and mean ADC values. Leptomeningeal metastases (LM) was diagnosed with imaging. Cox analyses were conducted to determine predictors of overall survival (OS) in entire patients and a subgroup of patients with contrast-enhancing (CE) tumor. RESULTS: The median patient age was 40.5 years (range 19.9-75.7), with an OS of 30.3 months (interquartile range 11.3-32.3). In entire patients, the presence of LM was the only independent predictor of OS (hazard ratio [HR] = 6.01, P = 0.009). In the subgroup of 23 (71.9%) patients with CE tumors, rCMRO2 of CE tumor (HR = 1.08, P = 0.019) and the presence of LM (HR = 5.92, P = 0.043) were independent predictors of OS. CONCLUSION: The presence of LM was independently associated with poor prognosis in adult patients with H3 K27-altered DMG. In patients with CE tumors, higher rCMRO2 of CE tumor, which may reflect higher metabolic activity in the tumor oxygenation microenvironment, may be a useful imaging biomarker to predict poor prognosis.

Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD.

OBJECTIVE: The objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. METHODS: Twenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. RESULTS: Whole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. CONCLUSION: CMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Cerebral oxygen metabolism from MRI susceptibility.

This article provides an overview of MRI methods exploiting magnetic susceptibility properties of blood to assess cerebral oxygen metabolism, including the tissue oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2). The first section is devoted to describing blood magnetic susceptibility and its effect on the MRI signal. Blood circulating in the vasculature can have diamagnetic (oxyhemoglobin) or paramagnetic properties (deoxyhemoglobin). The overall balance between oxygenated and deoxygenated hemoglobin determines the induced magnetic field which, in turn, modulates the transverse relaxation decay of the MRI signal via additional phase accumulation. The following sections of this review then illustrate the principles underpinning susceptibility-based techniques for quantifying OEF and CMRO2. Here, it is detailed whether these techniques provide global (OxFlow) or local (Quantitative Susceptibility Mapping - QSM, calibrated BOLD - cBOLD, quantitative BOLD - qBOLD, QSM+qBOLD) measurements of OEF or CMRO2, and what signal components (magnitude or phase) and tissue pools they consider (intravascular or extravascular). Validations studies and potential limitations of each method are also described. The latter include (but are not limited to) challenges in the experimental setup, the accuracy of signal modeling, and assumptions on the measured signal. The last section outlines the clinical uses of these techniques in healthy aging and neurodegenerative diseases and contextualizes these reports relative to results from gold-standard PET.

Venous Blood Oxygenation Measurements Using TRUST and T2-TRIR MRI During Hypoxic and Hypercapnic Gas Challenges.

BACKGROUND: Oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) may serve as biomarkers in several diseases. OEF and CMRO2 can be estimated from venous blood oxygenation (Yv ) levels, which in turn can be calculated from venous blood T2 values (T2b ). T2b can be measured using different MRI sequences, including T2-relaxation-under-spin-tagging (TRUST) and T2-prepared-blood-relaxation-imaging-with-inversion-recovery (T2-TRIR). The latter measures both T2b and T1 (T1b ) but was found previously to overestimate T2b compared to TRUST. It remained unclear, however, if this bias is constant across higher and lower oxygen saturations. PURPOSE: To compare TRUST and T2-TRIR across a range of O2 saturations using hypoxic and hypercapnic gas challenges. STUDY TYPE: Prospective. POPULATION: Twelve healthy volunteers (four female, age 36 ± 10 years). FIELD STRENGTH/SEQUENCE: A 3T; turbo-field echo-planar-imaging (TFEPI), echo-planar-imaging (EPI), and fast-field-echo (FFE). ASSESSMENT: TRUST- and T2-TRIR-derived T2b , Yv , OEF, and CMRO2 were compared across different respiratory challenges. T1b from T2-TRIR was used to estimate Hct (HctTRIR ) and compared with venipuncture (HctVP ). STATISTICAL TESTS: Shapiro-Wilk, one-sample and paired-sample t-test, repeated measures ANOVA, Friedman test, Bland-Altman, and correlation analysis. Bonferroni multiple-comparison correction was performed. Significance level was 0.05. RESULTS: A significant bias was observed between TRUST- and T2-TRIR-derived T2b , Yv , and OEF values (-13 ± 11 msec, -5.3% ± 3.5% and 5.9 ± 4.1%, respectively). For Yv and OEF, this bias was constant across the range of measured values. T1b was significantly lower during severe hypoxia and hypercapnia compared to baseline (1712 ± 86 msec and 1634 ± 79 msec compared to 1757 ± 90 msec). While no significant bias was found between HctVP and HctTRIR (0.02% ± 0.06%, P = 0.20), the correlation between these Hct values was significant but weak (r = 0.19). DATA CONCLUSION: Given the constant bias, TRUST- and T2-TRIR-derived venous T2b values can be used interchangeably to estimate Yv , OEF, and CMRO2 across a broad range of oxygen saturations. Hct from T2-TRIR-derived T1-values only weakly correlated with Hct from venipuncture. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

The effects of mydriatic eye drops on cerebral blood flow and oxygenation in retinopathy of prematurity examinations.

Mydriatic eye drops used during retinopathy examination have been associated with cardiovascular, respiratory, and gastrointestinal side effects. The aim of our study was to investigate the effects of the drops used for pupil dilatation on cerebral blood flow and cerebral oxygenation. The study included 62 infants who underwent retinopathy screening exams. Vital signs, heart rate (HR), arterial oxygen saturation (SpO2), and mean arterial pressure (MAP) were recorded. Cerebral oxygenation and middle cerebral artery blood flow velocity were evaluated using near-infrared spectroscopy (NIRS) and Doppler ultrasonography, respectively, and the cerebral metabolic rate of oxygen (CMRO2) was also calculated. The mean gestational age of the infants included was 31.29 ± 1.42 weeks, and the mean birth weight was 1620 ± 265 g. Heart rate was found to be significantly decreased after mydriatic eye drop instillation; however, there were no significant differences regarding blood pressure and oxygen saturation levels (HR: p < 0.001; MAP: p = 0.851; SpO2: p = 0.986, respectively). After instillation while cerebral regional oxygen saturation (rScO2) measurements were significantly decreased at the 60th minute (p = 0.01), no significant difference was found in Vmax and Vmean of MCA before and after mydriatic eye drop instillation (p = 0.755, p = 0.515, respectively). Regarding CMRO2 measurements, we also did not find any statistical difference (p = 0.442).    Conclusion: Our study has shown that although eye drops may affect heart rate and regional cerebral oxygen saturation, they do not alter cerebral blood flow velocities and metabolic rate of oxygen consumption. Current recommendations for mydriatic eye drop use in retinopathy exam appear to be safe. What is Known: • Mydriatic eye drop installation is recommended for pupil dilatation during ROP screening exams. • It's known that mydriatics used in ROP examination have affects on the vital signs, cerebral oxygenation and blood flow. What is New: • This is the first study evaluating the changes in cerebral oxygenation and blood flow velocity after mydriatic drop instillation using NIRS and Doppler US concomitantly. • While the eye drops may affect heart rate and regional cerebral oxygen saturation, they do not alter cerebral blood flow velocities and metabolic rate of oxygen consumption.

Abnormal oxidative metabolism in the cuprizone mouse model of demyelination: An in vivo NIRS-MRI study.

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.

Whole-brain 3D mapping of oxygen metabolism using constrained quantitative BOLD.

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 (Yv), and along with a measurement of cerebral blood flow (CBF), the cerebral metabolic rate of oxygen (CMRO2). 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 R2' from other sources modulating the voxel signal, for instance, R2, R2' 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 Yv from the heme-originated R2' 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, R2'-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 (Yv, 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 Yv and 2.8 ± 0.5 % and 1.8 ± 0.4 % for DBV in cortical gray and white matter, respectively. Given the Yv measurements, additionally quantified CBF in seven of the ten study subjects enabled whole-brain 3D CMRO2 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.

QQ-NET - using deep learning to solve quantitative susceptibility mapping and quantitative blood oxygen level dependent magnitude (QSM+qBOLD or QQ) based oxygen extraction fraction (OEF) mapping.

PURPOSE: To improve accuracy and speed of quantitative susceptibility mapping plus quantitative blood oxygen level-dependent magnitude (QSM+qBOLD or QQ) -based oxygen extraction fraction (OEF) mapping using a deep neural network (QQ-NET). METHODS: The 3D multi-echo gradient echo images were acquired in 34 ischemic stroke patients and 4 healthy subjects. Arterial spin labeling and diffusion weighted imaging (DWI) were also performed in the patients. NET was developed to solve the QQ model inversion problem based on Unet. QQ-based OEF maps were reconstructed with previously introduced temporal clustering, tissue composition, and total variation (CCTV) and NET. The results were compared in simulation, ischemic stroke patients, and healthy subjects using a two-sample Kolmogorov-Smirnov test. RESULTS: In the simulation, QQ-NET provided more accurate and precise OEF maps than QQ-CCTV with 150 times faster reconstruction speed. In the subacute stroke patients, OEF from QQ-NET had greater contrast-to-noise ratio (CNR) between DWI-defined lesions and their unaffected contralateral normal tissue than with QQ-CCTV: 1.9 ± 1.3 vs 6.6 ± 10.7 (p = 0.03). In healthy subjects, both QQ-CCTV and QQ-NET provided uniform OEF maps. CONCLUSION: QQ-NET improves the accuracy of QQ-based OEF with faster reconstruction.

Cerebral oxygen extraction fraction: Comparison of dual-gas challenge calibrated BOLD with CBF and challenge-free gradient echo QSM+qBOLD.

PURPOSE: To compare cortical gray matter oxygen extraction fraction (OEF) estimated from 2 MRI methods: (1) the quantitative susceptibility mapping (QSM) plus quantitative blood oxygen level dependent imaging (qBOLD) (QSM+qBOLD or QQ), and (2) the dual-gas calibrated-BOLD (DGCB) in healthy subjects; and to investigate the validity of iso-cerebral metabolic rate of oxygen consumption assumption during hypercapnia using QQ. METHODS: In 10 healthy subjects, 3 tesla MRI including a multi-echo gradient echo sequence at baseline and hypercapnia for QQ, as well as an EPI dual-echo pseudo-continuous arterial spin labeling for DGCB, were performed under a hypercapnic and a hyperoxic condition. OEFs from QQ and DGCB were compared using region of interest analysis and paired t test. For QQ, cerebral metabolic rate of oxygen consumption = cerebral blood flow*OEF*arterial oxygen content was generated for both baseline and hypercapnia, which were compared. RESULTS: Average OEF in cortical gray matter across 10 subjects from QQ versus DGCB was 35.5 ± 6.7% versus 38.0 ± 9.1% (P = .49) at baseline and 20.7 ± 4.4% versus 28.4 ± 7.6% (P = .02) in hypercapnia: OEF in cortical gray matter was significantly reduced as measured in QQ (P < .01) and in DGCB (P < .01). Cerebral metabolic rate of oxygen consumption (in µmol O2 /min/100 g) was 168.2 ± 54.1 at baseline from DGCB and was 153.1 ± 33.8 at baseline and 126.4 ± 34.2 (P < .01) in hypercapnia from QQ. CONCLUSION: The differences in OEF obtained from QQ and DGCB are small and nonsignificant at baseline but are statistically significant during hypercapnia. In addition, QQ shows a cerebral metabolic rate of oxygen consumption decrease (17.4%) during hypercapnia.

Quantitative and simultaneous measurement of oxygen consumption rates in rat brain and skeletal muscle using 17 O MRS imaging at 16.4T.

PURPOSE: Oxygen-17 (17 O) MRS imaging, successfully used in the brain, is extended by imaging the oxygen metabolic rate in the resting skeletal muscle and used to determine the total whole-body oxygen metabolic rate in the rat. METHODS: During and after inhalations of 17 O2 gas, dynamic 17 O MRSI was performed in rats (n = 8) ventilated with N2 O or N2 at 16.4 T. Time courses of the H217 O concentration from regions of interest located in brain and muscle tissue were examined and used to fit an animal-adapted 3-phase metabolic model of oxygen consumption. CBF was determined with an independent washout method. Finally, body oxygen metabolic rate was calculated using a global steady-state approach. RESULTS: Cerebral metabolic rate of oxygen consumption was 1.97 ± 0.19 µmol/g/min on average. The resting metabolic rate of oxygen consumption in skeletal muscle was 0.32 ± 0.12 µmol/g/min and >6 times lower than cerebral metabolic rate of oxygen consumption. Global oxygen consumed by the body was 24.2 ± 3.6 mL O2 /kg body weight/min. CBF was estimated to be 0.28 ± 0.02 mL/g/min and 0.34 ± 0.06 mL/g/min for the N2 and N2 O ventilation condition, respectively. CONCLUSION: We have evaluated the feasibility of 17 O MRSI for imaging and quantifying the oxygen consumption rate in low metabolizing organs such as the skeletal muscle at rest. Additionally, we have shown that CBF is slightly increased in the case of ventilation with N2 O. We expect this study to be beneficial to the application of 17 O MRSI to a wider range of organs, although further validation is advised.

Brain metabolism in tau and amyloid mouse models of Alzheimer's disease: An MRI study.

Alzheimer's disease (AD) is the leading cause of cognitive impairment and dementia in elderly individuals. According to the current biomarker framework for "unbiased descriptive classification", biomarkers of neurodegeneration, "N", constitute a critical component in the tri-category "A/T/N" system. Current biomarkers of neurodegeneration suffer from potential drawbacks such as requiring invasive lumbar puncture, involving ionizing radiation, or representing a late, irreversible marker. Recent human studies have suggested that reduced brain oxygen metabolism may be a new functional marker of neurodegeneration in AD, but the heterogeneity and the presence of mixed pathology in human patients did not allow a full understanding of the role of oxygen extraction and metabolism in AD. In this report, global brain oxygen metabolism and related physiological parameters were studied in two AD mouse models with relatively pure pathology, using advanced MRI techniques including T2 -relaxation-under-spin-tagging (TRUST) and phase contrast (PC) MRI. Additionally, regional cerebral blood flow (CBF) was determined with pseudocontinuous arterial spin labeling. Reduced global oxygen extraction fraction (by -18.7%, p = 0.008), unit-mass cerebral metabolic rate of oxygen (CMRO2 ) (by -17.4%, p = 0.04) and total CMRO2 (by -30.8%, p < 0.001) were observed in Tau4RΔK mice-referred to as the tau AD model-which manifested pronounced neurodegeneration, as measured by diminished brain volume (by -15.2%, p < 0.001). Global and regional CBF in these mice were not different from those of wild-type mice (p > 0.05), suggesting normal vascular function. By contrast, in B6;SJL-Tg [APPSWE]2576Kha (APP) mice-referred to as the amyloid AD model-no brain volume reduction, as well as relatively intact brain oxygen extraction and metabolism, were found (p > 0.05). Consistent with the imaging data, behavioral measures of walking distance were impaired in Tau4RΔK mice (p = 0.004), but not in APP mice (p = 0.88). Collectively, these findings support the hypothesis that noninvasive MRI measurement of brain oxygen metabolism may be a promising biomarker of neurodegeneration in AD.

Multi-Parametric Evaluation of Cerebral Hemodynamics in Neonatal Piglets Using Non-Contrast-Enhanced Magnetic Resonance Imaging Methods.

BACKGROUND: Disruption of brain oxygen delivery and consumption after hypoxic-ischemic injury contributes to neonatal mortality and neurological impairment. Measuring cerebral hemodynamic parameters, including cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2 ), is clinically important. PURPOSE: Phase-contrast (PC), velocity-selective arterial spin labeling (VSASL), and T2 -relaxation-under-phase-contrast (TRUPC) are magnetic resonance imaging (MRI) techniques that have shown promising results in assessing cerebral hemodynamics in humans. We aimed to test their feasibility in quantifying CBF, OEF, and CMRO2 in piglets. STUDY TYPE: Prospective. ANIMAL MODEL: Ten neonatal piglets subacutely recovered from global hypoxia-ischemia (N = 2), excitotoxic brain injury (N = 6), or sham procedure (N = 2). FIELD STRENGTH/SEQUENCE: VSASL, TRUPC, and PC MRI acquired at 3.0 T. ASSESSMENT: Regional CBF was measured by VSASL. Global CBF was quantified by both PC and VSASL. TRUPC assessed OEF at the superior sagittal sinus (SSS) and internal cerebral veins (ICVs). CMRO2 was calculated from global CBF and SSS-derived OEF. End-tidal carbon dioxide (EtCO2 ) levels of the piglets were also measured. Brain damage was assessed in tissue sections postmortem by counting damaged neurons. STATISTICAL TESTS: Spearman correlations were performed to evaluate associations among CBF (by PC or VSASL), OEF, CMRO2 , EtCO2 , and the pathological neuron counts. Paired t-test was used to compare OEF at SSS with OEF at ICV. RESULTS: Global CBF was 32.1 ± 14.9 mL/100 g/minute and 30.9 ± 8.3 mL/100 g/minute for PC and VSASL, respectively, showing a significant correlation (r = 0.82, P < 0.05). OEF was 54.9 ± 8.8% at SSS and 46.1 ± 5.6% at ICV, showing a significant difference (P < 0.05). Global CMRO2 was 79.1 ± 26.2 µmol/100 g/minute and 77.2 ± 12.2 µmol/100 g/minute using PC and VSASL-derived CBF, respectively. EtCO2 correlated positively with PC-based CBF (r = 0.81, P < 0.05) but negatively with OEF at SSS (r = -0.84, P < 0.05). Relative CBF of subcortical brain regions and OEF at ICV did not significantly correlate, respectively, with the ratios of degenerating-to-total neurons (P = 0.30, P = 0.10). DATA CONCLUSION: Non-contrast MRI can quantify cerebral hemodynamic parameters in normal and brain-injured neonatal piglets. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Quantification of brain oxygen extraction and metabolism with [15O]-gas PET: A technical review in the era of PET/MRI.

Oxygen extraction fraction (OEF) and the cerebral metabolic rate of oxygen (CMRO2) are key cerebral physiological parameters to identify at-risk cerebrovascular patients and understand brain health and function. PET imaging with [15O]-oxygen tracers, either through continuous or bolus inhalation, provides non-invasive assessment of OEF and CMRO2. Numerous tracer delivery, PET acquisition, and kinetic modeling approaches have been adopted to map brain oxygenation. The purpose of this technical review is to critically evaluate different methods for [15O]-gas PET and its impact on the accuracy and reproducibility of OEF and CMRO2 measurements. We perform a meta-analysis of brain oxygenation PET studies in healthy volunteers and compare between continuous and bolus inhalation techniques. We also describe OEF metrics that have been used to detect hemodynamic impairment in cerebrovascular disease. For these patients, advanced techniques to accelerate the PET scans and potential synthesis with MRI to avoid arterial blood sampling would facilitate broader use of [15O]-oxygen PET for brain physiological assessment.

Cluster analysis of time evolution (CAT) for quantitative susceptibility mapping (QSM) and quantitative blood oxygen level-dependent magnitude (qBOLD)-based oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) mapping.

PURPOSE: To improve the accuracy of QSM plus quantitative blood oxygen level-dependent magnitude (QSM + qBOLD or QQ)-based mapping of the oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) using cluster analysis of time evolution (CAT). METHODS: 3D multi-echo gradient echo and arterial spin labeling images were acquired in 11 healthy subjects and 5 ischemic stroke patients. DWI was also carried out on patients. CAT was developed for analyzing signal evolution over TE. QQ-based OEF and CMRO2 were reconstructed with and without CAT, and results were compared using region of interest analysis and a paired t-test. RESULTS: Simulations demonstrated that CAT substantially reduced noise error in QQ-based OEF. In healthy subjects, QQ-based OEF appeared less noisy and more uniform with CAT than without CAT; average OEF with and without CAT in cortical gray matter was 32.7 ± 4.0% and 37.9 ± 4.5%, with corresponding CMRO2 of 148.4 ± 23.8 and 171.4 ± 22.4 µmol/100 g/min, respectively. In patients, regions of low OEF were confined within the ischemic lesions defined on DWI when using CAT, which was not observed without CAT. CONCLUSION: The cluster analysis of time evolution (CAT) significantly improves the robustness of QQ-based OEF against noise.

Acute-stage MRI cerebral oxygen consumption biomarkers predict 24-hour neurological outcome in a rat cardiac arrest model.

Brain injury following cardiac arrest (CA) is thought to be caused by a sudden loss of blood flow resulting in disruption in oxygen delivery, neural function and metabolism. However, temporal trajectories of the brain's physiology in the first few hours following CA have not been fully characterized. Furthermore, the extent to which these early measures can predict future neurological outcomes has not been determined. The present study sought to perform dynamic measurements of cerebral blood flow (CBF), oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen (CMRO2 ) with MRI in the first 3 hours following the return of spontaneous circulation (ROSC) in a rat CA model. It was found that CBF, OEF and CMRO2 all revealed a time-dependent increase during the first 3 hours after the ROSC. Furthermore, the temporal trajectories of CBF and CMRO2 , but not OEF, were different across rats and related to neurologic outcomes at a later time (24 hours after the ROSC) (P < .001). Rats who manifested better outcomes revealed faster increases in CBF and CMRO2 during the acute stage. When investigating physiological parameters measured at a single time point, CBF (ρ = 0.82, P = .004) and CMRO2 (ρ = 0.80, P = .006) measured at ~ 3 hours post-ROSC were positively associated with neurologic outcome scores at 24 hours. These findings shed light on brain physiological changes following CA, and suggest that MRI measures of brain perfusion and metabolism may provide a potential biomarker to guide post-CA management.

Relationship between topological efficiency in white matter structural networks with cerebral oxygen metabolism in young adults.

The relationship between the topological characteristics of the white matter (WM) network have been shown to be related to neural development, intelligence, and various diseases; however, few studies have been conducted to explore the relationship between topological characteristics of the WM network and cerebral metabolism. In a recent study we investigated the relationship between WM network topological and metabolic metrics of the cerebral parenchyma in healthy volunteers using the newly developed T2-relaxation-under-spin-tagging (TRUST) magnetic resonance imaging technique and graph theory approaches. Ninety-six healthy adults (25.5 ±â€¯1.8 years of age) were recruited as volunteers in the current study. The cerebral metabolic rate of oxygen (CMRO2), oxygen extraction fraction, and the global topological metrics of the WM network (global efficiency [Eglob], local efficiency, and small-worldliness) were assessed. A stepwise multiple linear regression model was estimated. CMRO2 was entered as the dependent variable. The topological and demographic parameters (age, gender, FIQ, SBP, gray matter volume, and WM volume) were entered as independent variables in the model. The final performing models were comprised of predictors of Eglob, FIQ, and age (adjusted R2 values were 0.489 [L-AAL] and 0.424 [H-1024]). Our study initially revealed a relationship between Eglob and cerebral oxygen metabolism in healthy young adults.