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Objective: Cerebral venous oxygenation (Y v ) is a key parameter for the brain's oxygen utilization and has been suggested to be a valuable biomarker in various brain diseases including hypoxic ischemic encephalopathy in neonates and Alzheimer's disease in older adults. T 2 -Relaxation-Under-Spin-Tagging (TRUST) MRI is a widely used technique to measure global Y v level and has been validated against gold-standard PET. However, subject motion during TRUST MRI scan can introduce considerable errors in Y v quantification, especially for noncompliant subjects. The aim of this study was to develop an Automatic Rejection based on Tissue Signal (ARTS) algorithm for automatic detection and exclusion of motion-contaminated images to improve the precision of Y v quantification., Methods: TRUST MRI data were collected from a neonatal cohort (N = 37, 16 females, gestational age = 39.12 ± 1.11 weeks, postnatal age = 1.89 ± 0.74 days) and an older adult cohort (N = 223, 134 females, age = 68.02 ± 9.01 years). Manual identification of motion-corrupted images was conducted for both cohorts to serve as a gold-standard. 9.3% of the images in the neonatal datasets and 0.4% of the images in the older adult datasets were manually identified as motion-contaminated. The ARTS algorithm was trained using the neonatal datasets. TRUST Y v values, as well as the estimation uncertainty (ΔR 2 ) and test-retest coefficient-of-variation (CoV) of Y v , were calculated with and without ARTS motion exclusion. The ARTS algorithm was tested on datasets of older adults: first on the original adult datasets with little motion, and then on simulated adult datasets where the percentage of motion-corrupted images matched that of the neonatal datasets., Results: In the neonatal datasets, the ARTS algorithm exhibited a sensitivity of 0.95 and a specificity of 0.97 in detecting motion-contaminated images. Compared to no motion exclusion, ARTS significantly reduced the ΔR 2 (median = 3.68 Hz vs. 4.89 Hz, P = 0.0002) and CoV (median = 2.57% vs. 6.87%, P = 0.0005) of Y v measurements. In the original older adult datasets, the sensitivity and specificity of ARTS were 0.70 and 1.00, respectively. In the simulated adult datasets, ARTS demonstrated a sensitivity of 0.91 and a specificity of 1.00. Additionally, ARTS significantly reduced the ΔR 2 compared to no motion exclusion (median = 2.15 Hz vs. 3.54 Hz, P < 0.0001)., Conclusion: ARTS can improve the reliability of Y v estimation in noncompliant subjects, which may enhance the utility of Y v as a biomarker for brain diseases., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cerebrovascular reactivity (CVR), an index of brain vessel's dilatory capacity, is typically measured using hypercapnic gas inhalation or breath-holding as a vasoactive challenge. However, these methods require considerable subject cooperation and could be challenging in clinical studies. More recently, there have been attempts to use resting-state BOLD data to map CVR by utilizing spontaneous changes in breathing pattern. However, in subjects who have small fluctuations in their spontaneous breathing pattern, the CVR results could be noisy and unreliable. In this study, we aim to develop a new method for CVR mapping that does not require gas-inhalation yet provides substantially higher sensitivity than resting-state CVR mapping. This new method is largely based on resting-state scan, but introduces intermittent modulation of breathing pattern in the subject to enhance fluctuations in their end-tidal CO2 (EtCO2) level. Here we examined the comfort level, sensitivity, and accuracy of this method in two studies. First, in 8 healthy young subjects, we developed the intermittent breath-modulation method using two different modulation frequencies, 6 ​s per breath and 12 ​s per breath, respectively, and compared the results to three existing CVR methods, specifically hypercapnic gas inhalation, breath-holding, and resting-state. Our results showed that the comfort level of the 6-s breath-modulation method was significantly higher than breath-holding (p ​= ​0.007) and CO2-inhalation (p ​= ​0.015) methods, while not different from the resting-state, i.e. free breathing method (p ​= ​0.52). When comparing the sensitivity of CVR methods, the breath-modulation methods revealed higher Z-statistics compared to the resting-state scan (p ​< ​0.008) and was comparable to breath-holding results. Next, we tested the feasibility of breath-modulation CVR mapping (6 ​s per breath) in 21 cognitively normal elderly participants and compared quantitative CVR values to that obtained with the CO2-inhalation method. Whole-brain CVR was found to be 0.150 ​± ​0.055 and 0.154 ​± ​0.032 %ΔBOLD/mmHg for the breath-modulation and CO2-inhalation method, respectively, with a significant correlation between them (y ​= ​0.97x, p ​= ​0.007). CVR mapping with intermittent breath modulation may be a useful method that combines the advantages of resting-state and CO2-inhalation based approaches., Competing Interests: Declaration of competing interest The authors have no conflicts of interest or financial disclosures to report., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Major depressive disorder (MDD) is a serious, heterogeneous disorder accompanied by brain-related changes, many of which are still to be discovered or refined. Arterial spin labeling (ASL) is a neuroimaging technique used to measure cerebral blood flow (CBF; perfusion) to understand brain function and detect differences among groups. CBF differences have been detected in MDD, and may reveal biosignatures of disease-state. The current work aimed to discover and replicate differences in CBF between MDD participants and healthy controls (HC) as part of the EMBARC study. Participants underwent neuroimaging at baseline, prior to starting study medication, to investigate biosignatures in MDD. Relative CBF (rCBF) was calculated and compared between 106 MDD and 36 HC EMBARC participants (whole-brain Discovery); and 58 MDD EMBARC participants and 58 HC from the DLBS study (region-of-interest Replication). Both analyses revealed reduced rCBF in the right parahippocampus, thalamus, fusiform and middle temporal gyri, as well as the left and right insula, for those with MDD relative to HC. Both samples also revealed increased rCBF in MDD relative to HC in both the left and right inferior parietal lobule, including the supramarginal and angular gyri. Cingulate and prefrontal regions did not fully replicate. Lastly, significant associations were detected between rCBF in replicated regions and clinical measures of MDD chronicity. These results (1) provide reliable evidence for ASL in detecting differences in perfusion for multiple brain regions thought to be important in MDD, and (2) highlight the potential role of using perfusion as a biosignature of MDD.

Cerebral oxygen extraction fraction is an important physiological index of the brain's oxygen consumption and supply and has been suggested to be a potential biomarker for a number of diseases such as stroke, Alzheimer's disease, multiple sclerosis, sickle cell disease, and metabolic disorders. However, in order for oxygen extraction fraction to be a sensitive biomarker for personalized disease diagnosis, inter-subject variations in normal subjects must be minimized or accounted for, which will otherwise obscure its interpretation. Therefore, it is essential to investigate the physiological underpinnings of normal differences in oxygen extraction fraction. This work used two studies, one discovery study and one verification study, to examine the extent to which an individual's end-tidal CO 2 can explain variations in oxygen extraction fraction. It was found that, across normal subjects, oxygen extraction fraction is inversely correlated with end-tidal CO 2 . Approximately 50% of the inter-subject variations in oxygen extraction fraction can be attributed to end-tidal CO 2 differences. In addition, oxygen extraction fraction was found to be positively associated with age and systolic blood pressure. By accounting for end-tidal CO 2 , age, and systolic blood pressure of the subjects, normal variations in oxygen extraction fraction can be reduced by 73%, which is expected to substantially enhance the utility of oxygen extraction fraction as a disease biomarker.

Purpose: To evaluate different T 2 -oxygenation calibrations for estimating venous oxygenation in people with sickle cell anemia (SCA)., Methods: Blood T 2 values were measured at 3 T in the internal jugular veins of 12 healthy volunteers and 11 SCA participants with no history of stroke, recent transfusion, or renal impairment. T 2 -oxygenation relationships of both sickled and normal blood samples were calibrated individually and compared with values generated from published models. After converting venous T 2 values to venous oxygenation, whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen were calculated., Results: Sickle blood samples' oxygenation values calculated from our individual calibrations agreed well with measurements using a blood analyzer, whereas previous T 2 calibrations based on normal blood samples showed 13%-19% underestimation. Meanwhile, oxygenation values calculated from previous grouped T 2 calibration for sickle blood agreed well with experimental measurement on averaged values, but showed up to 20% variation for several individual samples. Using individual T 2 calibrations, the whole-brain oxygen extraction fraction and cerebral metabolic rate of oxygen of SCA participants were 0.38 ± 0.08 and 172 ± 42 µmol/min/100 g, respectively, which were comparable to those values measured on healthy volunteers., Conclusion: Our results confirm that sickle blood T 2 values not only depend on the hematocrit and oxygenation values, but also on other hematological factors. The individual T 2 calibrations minimized the effect of heterogeneity of sickle blood between different SCA populations and improved the accuracy of T 2 -based oximetry. The measured oxygen extraction fraction and cerebral metabolic rate of oxygen of this group of SCA participants were found to not differ significantly from those of healthy individuals., (© 2019 International Society for Magnetic Resonance in Medicine.)

Cerebrovascular reactivity (CVR) mapping using CO 2 -inhalation can provide important insight into vascular health. At present, blood-oxygenation-level-dependent (BOLD) MRI acquisition is the most commonly used CVR method due to its high sensitivity, high spatial resolution, and relatively straightforward processing. However, large variations in CVR across subjects and across different sessions of the same subject are often observed, which can cloud the ability of this promising measure in detecting diseases or monitoring treatment responses. The present work aims to identify the physiological components underlying the observed variability in CVR data. When studying the association between CVR value and the subject's CO 2 levels in a total of N = 253 healthy participants, we found that CVR was lower in individuals with a higher basal end-tidal CO 2 , EtCO 2 (slope = -0.0036 ± 0.0008%/mmHg 2 , p < 0.001), or with a greater EtCO 2 change (ΔEtCO 2 ) with hypercapnic condition (slope = -0.0072 ± 0.0018%/mmHg 2 , p < 0.001). In a within-subject setting, when studying the CVR difference between two repeated scans (with repositioning) in relation to the corresponding differences in basal EtCO 2 and ΔEtCO 2 (n = 11), it was found that CVR values were lower if the basal EtCO 2 or ΔEtCO 2 during that particular scan session was greater. The present work suggests that basal physiological state and the level of hypercapnic stimulus intensity should be considered in application studies of CVR in order to reduce inter-subject and intra-subject variations in the data. Potential approaches to use these findings to reduce noise and augment sensitivity are proposed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: Noninvasive measurement of cerebral venous oxygenation (Y v ) in neonates is important in the assessment of brain oxygen extraction and consumption, and may be useful in characterizing brain development and neonatal brain diseases. This study aims to develop a rapid method for vessel-specific measurement of Y v in neonates., Methods: We developed a pulse sequence, named accelerated T 2 -relaxation-under-phase-contrast (aTRUPC), which consists of velocity-encoding phase-contrast module to isolate pure blood signal, flow-insensitive T 2 -preparation to quantify blood T 2 , and turbo-field-echo (TFE) scheme for rapid image acquisition, which is critical for neonatal MRI. A series of studies were conducted. First, the pulse sequence was optimized in terms of TFE factor, velocity encoding (VENC), and slice thickness for best sensitivity. Second, to account for the influence of TFE acquisition on T 2 quantification, simulation and experiments were conducted to establish the relationship between TFE-T 2 and standard T 2 . Finally, the complete aTRUPC sequence was applied on a group of healthy neonates and normative Y v values were determined., Results: Optimal parameters of aTRUPC in neonates were found to be a TFE factor of 15, VENC of 5 cm/s, and slice thickness of 10 mm. The TFE-T 2 was on average 3.9% lower than standard T 2 . These two measures were strongly correlated (R 2 = 0.86); thus their difference can be accounted for by a correction equation, T 2,standard = 1.2002 × T 2,TFE - 10.6276. Neonatal Y v values in veins draining cortical brain and those draining central brain were 64.8 ± 2.9% and 70.2 ± 3.3%, respectively, with a significant difference (P =.02)., Conclusion: The aTRUPC MRI has the potential to provide vessel-specific quantification of cerebral Y v in neonates., (© 2019 International Society for Magnetic Resonance in Medicine.)

There is increasing interest in applying physiological MRI in neonates, based on the premise that physiological parameters may provide an early biomarker of neonatal brain health and injury. Two commonly used techniques are oxygen extraction fraction (OEF) measurement using T 2 -relaxation-under-spin-tagging (TRUST) MRI and cerebral blood flow measurement using phase-contrast (PC) quantitative flow MRI, which collectively provide an assessment of the brain's oxygen consumption. However, prior research has only demonstrated proof of principle of these methods in neonates, without characterization or benchmarking of the techniques. This is because available time is limited in neonatal subjects, especially when scans are performed as add-ons to clinical scans (typically less than 5 min). The work presented aims to examine the TRUST and PC MRI sequences systematically in normal neonates, through research-dedicated scan sessions. A series of characterization and optimization studies were conducted in a total of 26 radiographically normal neonates on 3 T systems. Our results show that TRUST MRI at the superior sagittal sinus (SSS) provides an OEF measurement equivalent to that at the internal jugular vein (r = 0.80, n = 10), yet with shorter scan time. Lower resolution provided better precision in the TRUST measurement (p = 0.001, n = 9). Therefore, the preferred OEF measurement is to apply TRUST MRI at the SSS using a spatial resolution of 2.5 mm. For PC MRI, our results showed that non-gated PC MRI yielded blood flow measurements comparable to those from the more time-consuming gated approach in neonates (r = 0.89, n = 7). It was also found that blood flow could be overestimated by 18% when imaging resolution is larger than 0.3 mm (n = 7). Therefore, non-gated PC MRI with a spatial resolution of 0.3 mm is recommended for neonatal applications. In conclusion, this study verifies consistency of neonatal brain oxygenation and flow measurements across acquisition schemes and points to optimal strategies in parameter selection when using these sequences., (© 2019 John Wiley & Sons, Ltd.)

Purpose: To demonstrate the feasibility of mapping cerebrovascular reactivity (CVR) using resting-state functional MRI (fMRI) data without gas or other challenges in patients with cerebrovascular diseases and to show that brain regions affected by the diseases have diminished vascular reactivity., Materials and Methods: Two sub-studies were performed on patients with stroke and Moyamoya disease. In Study 1, 20 stroke patients (56.3 ± 9.7 years, 7 females) were enrolled and resting-state blood‑oxygenation-level-dependent (rs-BOLD) fMRI data were collected, from which CVR maps were computed. CVR values were compared across lesion, perilesional and control ROIs defined on anatomic images. Reproducibility of the CVR measurement was tested in 6 patients with follow-up scans. In Study 2, rs-BOLD fMRI and dynamic susceptibility contrast (DSC) MRI scans were collected in 5 patients with Moyamoya disease (32.4 ± 8.2 years, 4 females). Cerebral blood flow (CBF), cerebral blood volume (CBV), and time-to-peak (TTP) maps were obtained from the DSC MRI data. CVR values were compared between stenotic brain regions and control regions perfused by non-stenotic arteries., Results: In stroke patients, lesion CVR (0.250 ± 0.055 relative unit (r.u.)) was lower than control CVR (0.731 ± 0.088 r.u., p = 0.0002). CVR was also lower in the perilesional regions in a graded manner (perilesion 1 CVR = 0.422 ± 0.051 r.u., perilesion 2 CVR = 0.492 ± 0.046 r.u.), relative to that in the control regions (p = 0.005 and 0.036, respectively). In the repeatability analysis, a strong correlation was observed between lesion CVR (r 2  = 0.91, p = 0.006) measured at two time points, as well as between control CVR (r 2  = 0.79, p = 0.036) at two time points. In Moyamoya patients, CVR in the perfusion deficit regions delineated by DSC TTP maps (0.178 ± 0.189 r.u.) was lower than that in the control regions (0.868 ± 0.214 r.u., p = 0.013). Furthermore, the extent of reduction in CVR was significantly correlated with the extent of lengthening in TTP (r 2  = 0.91, p = 0.033)., Conclusion: Our findings suggested that rs-BOLD data can be used to reproducibly evaluate CVR in patients with cerebrovascular diseases without the use of any vasoactive challenges., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: To optimize phase-contrast (PC) MRI for the measurement of global cerebral blood flow (CBF) in the mouse at 11.7T., Methods: We determined proper velocity encoding (VENC) for internal carotid arteries (ICAs) and vertebral arteries (VAs). Next, we optimized spatial resolution of the sequence. To shorten scan time without compromising data quality, we further optimized repetition time and developed a reduced field-of-view (FOV) scheme for ICA and VA PC MRI. Whole-brain volume was determined with T 2 -weighted image to obtain unit-volume CBF., Results: Peak flow velocities were 13.8 ± 1.7, 14.4 ± 0.6, 6.5 ± 1.7, and 6.7 ± 1.3 cm/s for left ICA, right ICA, left VA, and right VA, respectively. Thus, VENC values of 20 and 10 cm/s were chosen for ICA and VA PC MRI, respectively. An in-plane spatial resolution of 50 × 50 μm 2 was found to provide a reasonable trade-off between reducing partial-volume effects and maintaining signal-to-noise ratio. Because of the fact that saturated spins in the imaging slice are rapidly replaced by fresh spins, TR of the sequence can be decreased to as short as 15 ms without reducing signal intensity, thereby substantially lowering scan time. Moreover, reduced FOV along the phase-encoding direction was able to shorten scan time by 33.3% while maintaining measurement accuracy. With these optimizations, it took 96 seconds to evaluate CBF with a test-retest variability of approximately 5% and an inter-rater correlation of >0.95. Global unit-volume CBF was found to be 279.5 ± 11.1 mL of blood/100 ml of tissue/min., Conclusion: We have optimized PC MRI for noninvasive quantification of blood flow in mice at 11.7T., (© 2018 International Society for Magnetic Resonance in Medicine.)

Purpose: To develop a non-contrast-agent MRI technique to quantify cerebral venous T 2 in mice., Methods: We implemented and optimized a T 2 -relaxation-under-spin-tagging (TRUST) sequence on an 11.7 Tesla animal imaging system. A flow-sensitive-alternating-inversion-recovery (FAIR) module was used to generate control and label images, pair-wise subtraction of which yielded blood signals. Then, a T 2 -preparation module was applied to produce T 2 -weighted images, from which blood T 2 was quantified. We conducted a series of technical studies to optimize the imaging slice position, inversion slab thickness, post-labeling delay (PLD), and repetition time. We also performed three physiological studies to examine the venous T 2 dependence on hyperoxia (N = 4), anesthesia (N = 3), and brain aging (N = 5)., Results: Our technical studies suggested that, for efficient data acquisition with minimal bias in estimated T 2 , a preferred TRUST protocol was to place the imaging slice at the confluence of sagittal sinuses with an inversion-slab thickness of 2.5-mm, a PLD of 1000 ms and a repetition time of 3.5 s. Venous T 2 values under normoxia and hyperoxia (inhaling pure oxygen) were 26.9 ± 1.7 and 32.3 ± 2.2 ms, respectively. Moreover, standard isoflurane anesthesia resulted in a higher venous T 2 compared with dexmedetomidine anesthesia (N = 3; P = 0.01) which is more commonly used in animal functional MRI studies to preserve brain function. Venous T 2 exhibited a decrease with age (N = 5; P < 0.001)., Conclusion: We have developed and optimized a noninvasive method to quantify cerebral venous blood T 2 in mouse at 11.7 T. This method may prove useful in studies of brain physiology and pathophysiology in animal models. Magn Reson Med 80:521-528, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Background: With the disappointing outcomes of clinical trials on patients with Alzheimer's disease or mild cognitive impairment (MCI), there is increasing attention to understanding cognitive decline in normal elderly individuals, with the goal of identifying subjects who are most susceptible to imminent cognitive impairment., Purpose/hypothesis: To evaluate the potential of cerebral blood flow (CBF) as a biomarker by investigating the relationship between CBF at baseline and cognition at follow-up., Study Type: Prospective longitudinal study with a 4-year time interval., Population: 309 healthy subjects aged 20-89 years old., Field Strength/sequence: 3T pseudo-continuous-arterial-spin-labeling MRI., Assessment: CBF at baseline and cognitive assessment at both baseline and follow-up., Statistical Tests: Linear regression analyses with age, systolic blood pressure, physical activity, and baseline cognition as covariates., Results: Linear regression analyses revealed that whole-brain CBF at baseline was predictive of general fluid cognition at follow-up. This effect was observed in the older group (age ≥54 years, β = 0.221, P = 0.004), but not in younger or entire sample (β = 0.018, P = 0.867 and β = 0.089, P = 0.098, respectively). Among major brain lobes, frontal CBF had the highest sensitivity in predicting future cognition, with a significant effect observed for fluid cognition (β = 0.244 P = 0.001), episodic memory (β = 0.294, P = 0.001), and reasoning (β = 0.186, P = 0.027). These associations remained significant after accounting for baseline cognition. Voxelwise analysis revealed that medial frontal cortex and anterior cingulate cortex, part of the default mode network (DMN), are among the most important regions in predicting fluid cognition., Data Conclusion: In a healthy aging cohort, CBF can predict general cognitive ability as well as specific domains of cognitive function., Level of Evidence: 1 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2018;48:449-458., (© 2018 International Society for Magnetic Resonance in Medicine.)

Background and purpose Vascular risk factors have been associated with decreased cerebral blood flow (CBF) but this is etiologically nonspecific and may result from vascular insufficiency or a response to decreased brain metabolic activity. We apply new MRI techniques to measure oxygen extraction fraction (OEF) and cerebral metabolic rate of oxygen consumption (CMRO 2 ), hypothesizing that decreased CBF related to these vascular risk factors will be associated with increased OEF, confirming a primary vascular insufficiency. Methods 3T MRI was obtained on 70 community-based participants in this IRB-approved study with informed consent, with previous assessment of systolic blood pressure, hypertension medication, elevated serum triglycerides, low serum HDL, and diabetes mellitus. CBF was measured using phase contrast adjusted for brain volume (ml/100 g/min), OEF (%) was obtained from T2-Relaxation-Under-Spin-Tagging (TRUST), and CMRO 2 (μmol/100 g/min) was derived using the Fick principle. Stepwise linear regression identified optimal predictors of CBF with age, sex, and hematocrit included for adjustment. This predictive model was then evaluated against OEF and CMRO 2 . Results Hypertriglyceridemia was associated with low CBF and high OEF. High systolic blood pressure was associated with high CBF and low OEF, which was primarily attributable to those with pressures above 160 mmHg. Neither risk factor was associated with significant differences in cerebral metabolic rate. Conclusion Low CBF related to hypertriglyceridemia was accompanied by high OEF with no significant difference in CMRO 2 , confirming subclinical vascular insufficiency. High CBF related to high systolic blood pressure likely reflected limitations of autoregulation at higher blood pressures.

Purpose: Cerebral venous oxygenation (Y v ) is an important biomarker for brain diseases. This study aims to develop an R2*-based MR oximetry that can measure cerebral Y v in 3D., Methods: This technique separates blood signal from tissue by velocity-encoding phase contrast and measures the R2* of pure blood by multi-gradient-echo acquisition. The blood R2* was converted to Y v using an R2*-versus-oxygenation (Y) calibration curve, which was obtained by in vitro bovine blood experiments. Reproducibility, sensitivity, validity, and resolution dependence of the technique were evaluated., Results: In vitro R2*-Y calibration plot revealed a strong dependence of blood R2* on oxygenation, with additional dependence on hematocrit. In vivo results demonstrated that the technique can provide a 3D venous oxygenation map that depicts both large sinuses and smaller cortical veins, with venous oxygenation ranging from 57 to 72%. Intrasession coefficient of variation of the measurement was 3.0%. The technique detected an average Y v increase of 10.8% as a result of hyperoxia, which was validated by global oxygenation measurement from T 2 -Relaxation-Under-Spin-Tagging (TRUST) MRI. Two spatial resolutions, one with an isotropic voxel dimension and the other with a nonisotropic dimension, were tested for full brain coverage., Conclusions: This study demonstrated the feasibility of 3D brain oxygenation mapping without using contrast agent. Magn Reson Med 79:1304-1313, 2018. © 2017 International Society for Magnetic Resonance in Medicine., (© 2017 International Society for Magnetic Resonance in Medicine.)

Baseline hematocrit fraction (Hct) is a determinant for baseline cerebral blood flow (CBF) and between-subject variation of Hct thus causes variation in task-based BOLD fMRI signal changes. We first verified in healthy volunteers (n = 12) that Hct values can be derived reliably from venous blood T 1 values by comparison with the conventional lab test. Together with CBF measured using phase-contrast MRI, this noninvasive estimation of Hct, instead of using a population-averaged Hct value, enabled more individual determination of oxygen delivery (DO 2 ), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO 2 ). The inverse correlation of CBF and Hct explained about 80% of between-subject variation of CBF in this relatively uniform cohort of subjects, as expected based on the regulation of DO 2 to maintain constant CMRO 2 . Furthermore, we compared the relationships of visual task-evoked BOLD response with Hct and CBF. We showed that Hct and CBF contributed 22%-33% of variance in BOLD signal and removing the positive correlation with Hct and negative correlation with CBF allowed normalization of BOLD signal with 16%-22% lower variability. The results of this study suggest that adjustment for Hct effects is useful for studies of MRI perfusion and BOLD fMRI. Hum Brain Mapp 39:344-353, 2018. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Purpose: Assessment of brain hemodynamics without exogenous contrast agents is of increasing importance in clinical applications. This study aims to develop an MR perfusion technique that can provide noncontrast and multiparametric estimation of hemodynamic markers., Methods: We devised an arterial spin labeling (ASL) method based on the principle of MR fingerprinting (MRF), referred to as MRF-ASL. By taking advantage of the rich information contained in MRF sequence, up to seven hemodynamic parameters can be estimated concomitantly. Feasibility demonstration, flip angle optimization, comparison with Look-Locker ASL, reproducibility test, sensitivity to hypercapnia challenge, and initial clinical application in an intracranial steno-occlusive process, Moyamoya disease, were performed to evaluate this technique., Results: Magnetic resonance fingerprinting ASL provided estimation of up to seven parameters, including B1+, tissue T 1 , cerebral blood flow (CBF), tissue bolus arrival time (BAT), pass-through arterial BAT, pass-through blood volume, and pass-through blood travel time. Coefficients of variation of the estimated parameters ranged from 0.2 to 9.6%. Hypercapnia resulted in an increase in CBF by 57.7%, and a decrease in BAT by 13.7 and 24.8% in tissue and vessels, respectively. Patients with Moyamoya disease showed diminished CBF and lengthened BAT that could not be detected with regular ASL., Conclusion: Magnetic resonance fingerprinting ASL is a promising technique for noncontrast, multiparametric perfusion assessment. Magn Reson Med 78:1812-1823, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

A better understanding of the effect of oxygen on brain electrophysiological activity may provide a more mechanistic insight into clinical studies that use oxygen treatment in pathological conditions, as well as in studies that use oxygen to calibrate functional magnetic resonance imaging (fMRI) signals. This study applied electroencephalography (EEG) in healthy subjects and investigated how high a concentration of oxygen in inhaled air (i.e., normobaric hyperoxia) alters brain activity under resting-state and task-evoked conditions. Study 1 investigated its impact on resting EEG and revealed that hyperoxia suppressed α (8-13Hz) and β (14-35Hz) band power (by 15.6±2.3% and 14.1±3.1%, respectively), but did not change the δ (1-3Hz), θ (4-7Hz), and γ (36-75Hz) bands. Sham control experiments did not result in such changes. Study 2 reproduced these findings, and, furthermore, examined the effect of hyperoxia on visual stimulation event-related potentials (ERP). It was found that the main peaks of visual ERP, specifically N1 and P2, were both delayed during hyperoxia compared to normoxia (P = 0.04 and 0.02, respectively). In contrast, the amplitude of the peaks did not show a change. Our results suggest that hyperoxia has a pronounced effect on brain neural activity, for both resting-state and task-evoked potentials.

The human brain develops rapidly during 32-45 postmenstrual weeks (PMW), a critical stage characterized by dramatic increases of metabolic demand. The increasing metabolic demand can be inferred through measurements of regional cerebral blood flow (CBF), which might be coupled to regional metabolism in preterm brains. Arterial spin labeled (ASL) perfusion MRI is one of the few viable approaches for imaging regional CBF of preterm brains, but must be optimized for the extremely slow blood velocity unique in preterm brains. In this study, we explored the spatiotemporal CBF distribution in newborns scanned at the age of 32-45PMW using a pseudo-continuous ASL (pCASL) protocol adapted to slow blood flow in neonates. A total of 89 neonates were recruited. PCASL MRI was acquired from 34 normal newborns and phase contrast (PC) images from 19 newborns. Diffusion tensor images (DTI) were acquired from all 89 neonates for measuring cortical fractional anisotropy (FA), which characterizes cortical microstructure. Reproducible CBF measurements were obtained with the adjusted pCASL sequence. Global CBF measurement based on PC MRI was found to double its value in the 3rd trimester. Regional CBF increases were heterogeneous across the brain with a significantly higher rate of CBF increase in the frontal lobe and a lower rate of CBF increase in the occipital lobe. A significant correlation was found between frontal cortical CBF and cortical FA measurements (p<0.01). Increasing CBF values observed in the frontal lobe corresponded to lower FA values, suggesting that dendritic arborization and synaptic formation might be associated with an elevated local CBF. These results offer a preliminary account of heterogeneous regional CBF increases in a vital early developmental period and may shed the light on underlying metabolic support for cortical microstructural changes during the developmental period of 32-45PMW. Preterm effects and limitations of pCASL techniques in newborns need to be carefully considered for interpretation these results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Diagnosis and treatment monitoring of cerebrovascular diseases routinely require hemodynamic imaging of the brain. Current methods either only provide part of the desired information or require the injection of multiple exogenous agents. In this study, we developed a multiparametric imaging scheme for the imaging of brain hemodynamics and function using gas-inhalation MRI. The proposed technique uses a single MRI scan to provide simultaneous measurements of baseline venous cerebral blood volume (vCBV), cerebrovascular reactivity (CVR), bolus arrival time (BAT), and resting-state functional connectivity (fcMRI). This was achieved with a novel, concomitant O 2 and CO 2 gas inhalation paradigm, rapid MRI image acquisition with a 9.3min BOLD sequence, and an advanced algorithm to extract multiple hemodynamic information from the same dataset. In healthy subjects, CVR and vCBV values were 0.23±0.03%/mmHg and 0.0056±0.0006%/mmHg, respectively, with a strong correlation (r=0.96 for CVR and r=0.91 for vCBV) with more conventional, separate acquisitions that take twice the scan time. In patients with Moyamoya syndrome, CVR in the stenosis-affected flow territories (typically anterior-cerebral-artery, ACA, and middle-cerebral-artery, MCA, territories) was significantly lower than that in posterior-cerebral-artery (PCA), which typically has minimal stenosis, flow territories (0.12±0.06%/mmHg vs. 0.21±0.05%/mmHg, p<0.001). BAT of the gas bolus was significantly longer (p=0.008) in ACA/MCA territories, compared to PCA, and the maps were consistent with the conventional contrast-enhanced CT perfusion method. FcMRI networks were robustly identified from the gas-inhalation MRI data after factoring out the influence of CO 2 and O 2 on the signal time course. The spatial correspondence between the gas-data-derived fcMRI maps and those using a separate, conventional fcMRI scan was excellent, showing a spatial correlation of 0.58±0.17 and 0.64±0.20 for default mode network and primary visual network, respectively. These findings suggest that advanced gas-inhalation MRI provides reliable measurements of multiple hemodynamic parameters within a clinically acceptable imaging time and is suitable for patient examinations., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Whole-brain cerebral blood flow (CBF) measured by phase-contrast MRI (PC-MRI) provides an important index for brain function. This work aimed to optimize the PC-MRI imaging protocol for accurate CBF measurements., Methods: Two studies were performed on a 3 Tesla system. In Study 1 (N = 12), we optimized in-plane resolution of PC-MRI acquisition for CBF quantification by considering accuracy, precision, and scan duration. In Study 2 (N = 7), we assessed the detrimental effect of nonperpendicular imaging slice orientation on CBF quantification. Both One-way analysis of variance with repeated measurement and Friedman test were used to examine the effects of resolution and angulation on CBF quantification. Additionally, we evaluated the inter-rater reliability in PC-MRI data processing., Results: Our results showed that CBF measurement with 0.7 mm resolution could be overestimated by up to 13.3% when compared with 0.4 mm resolution. Moreover, CBF could also be overestimated by up to 18.8% when the slice orientation is deviated by 30° from the ideal angulation. However, within 10° of the ideal slice orientation, estimated CBF was not significantly different from each other (P = 0.23 and 0.45 for internal carotid artery and vertebral artery, respectively). Inter-rater difference was <3%., Conclusion: For fast and accurate quantification of whole-brain CBF with PC-MRI, we recommend the use of an imaging resolution of 0.5 mm and a slice orientation that is less than 10° from vessel's axial plane., (© 2015 Wiley Periodicals, Inc.)

Anorexia nervosa is a serious psychiatric disorder characterized by restricted eating, a pursuit of thinness, and altered perceptions of body shape and size. Neuroimaging in anorexia nervosa has revealed morphological and functional alterations in the brain. A better understanding of physiological changes in anorexia nervosa could provide a brain-specific health marker relevant to treatment and outcomes. In this study, we applied several advanced magnetic resonance imaging (MRI) techniques to quantify regional and global cerebral blood flow (CBF) in 25 healthy women (HC), 23 patients currently with anorexia (AN-C) and 19 patients in long-term weight recovery following anorexia (AN-WR). Specifically, CBF was measured with pseudo-continuous arterial spin labeling (pCASL) MRI and then verified by a different technique, phase contrast (PC) MRI. Venous T2 values were determined by T2 relaxation under spin tagging (TRUST) MRI, and were used to corroborate the CBF results. These novel techniques were implemented on a standard 3T MRI scanner without any exogenous tracers, and the total scan duration was less than 10min. Voxel-wise comparison revealed that the AN-WR group showed lower CBF in bilateral temporal and frontal lobes than the AN-C group. Compared with the HC group, the AN-C group also showed higher CBF in the right temporal lobe. Whole-brain-averaged CBF was significantly decreased in the AN-WR group compared with the AN-C group, consistent with the PC-MRI results. Venous T2 values were lower in the AN-WR group than in the AN-C group, consistent with the CBF results. A review of prior work examining CBF in anorexia nervosa is included in the discussion. This study identifies several differences in the cerebral physiological alterations in anorexia nervosa, and finds specific differences relevant to the current state of the disorder., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Caffeine, as the most commonly used stimulant drug, improves vigilance and, in some cases, cognition. However, the exact effect of caffeine on brain activity has not been fully elucidated. Because caffeine has a pronounced vascular effect which is independent of any neural effects, many hemodynamics-based methods such as fMRI cannot be readily applied without a proper calibration. The scope of the present work is two-fold. In Study 1, we used a recently developed MRI technique to examine the time-dependent changes in whole-brain cerebral metabolic rate of oxygen (CMRO2) following the ingestion of 200mg caffeine. It was found that, despite a pronounced decrease in CBF (p<0.001), global CMRO2 did not change significantly. Instead, the oxygen extraction fraction (OEF) was significantly elevated (p=0.002) to fully compensate for the reduced blood supply. Using the whole-brain finding as a reference, we aim to investigate whether there are any regional differences in the brain's response to caffeine. Therefore, in Study 2, we examined regional heterogeneities in CBF changes following the same amount of caffeine ingestion. We found that posterior brain regions such as posterior cingulate cortex and superior temporal regions manifested a slower CBF reduction, whereas anterior brain regions including dorsolateral prefrontal cortex and medial frontal cortex showed a faster rate of decline. These findings have a few possible explanations. One is that caffeine may result in a region-dependent increase or decrease in brain activity, resulting in an unaltered average brain metabolic rate. The other is that caffeine's effect on vasculature may be region-specific. Plausibility of these explanations is discussed in the context of spatial distribution of the adenosine receptors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

While it is known that specific nuclei of the brain, for example hypothalamus, contain glucose-sensing neurons thus their activity is affected by blood glucose level, the effect of glucose modulation on whole-brain metabolism is not completely understood. Several recent reports have elucidated the long-term impact of caloric restriction on the brain, showing that animals under caloric restriction had enhanced rate of tricarboxylic acid cycle (TCA) cycle flux accompanied by extended life span. However, acute effect of postprandial blood glucose increase has not been addressed in detail, partly due to a scarcity and complexity of measurement techniques. In this study, using a recently developed noninvasive MR technique, we measured dynamic changes in global cerebral metabolic rate of O2 (CMRO2 ) following a 50 g glucose ingestion (N = 10). A time dependent decrease in CMRO2 was observed, which was accompanied by a reduction in oxygen extraction fraction (OEF) with unaltered cerebral blood flow (CBF). At 40 min post-ingestion, the amount of CMRO2 reduction was 7.8 ± 1.6%. A control study without glucose ingestion was performed (N = 10), which revealed no changes in CMRO2 , CBF, or OEF, suggesting that the observations in the glucose study was not due to subject drowsiness or fatigue after staying inside the scanner. These findings suggest that ingestion of glucose may alter the rate of cerebral metabolism of oxygen in an acute setting., (© 2014 Wiley Periodicals, Inc.)

The brain is a spatially heterogeneous and temporally dynamic organ, with different regions requiring different amount of blood supply at different time. Therefore, the ability of the blood vessels to dilate or constrict, known as Cerebral-Vascular-Reactivity (CVR), represents an important domain of vascular function. An imaging marker representing this dynamic property will provide new information of cerebral vessels under normal and diseased conditions such as stroke, dementia, atherosclerosis, small vessel diseases, brain tumor, traumatic brain injury, and multiple sclerosis. In order to perform this type of measurement in humans, it is necessary to deliver a vasoactive stimulus such as CO2 and/or O2 gas mixture while quantitative brain magnetic resonance images (MRI) are being collected. In this work, we presented a MR compatible gas-delivery system and the associated protocol that allow the delivery of special gas mixtures (e.g., O2, CO2, N2, and their combinations) while the subject is lying inside the MRI scanner. This system is relatively simple, economical, and easy to use, and the experimental protocol allows accurate mapping of CVR in both healthy volunteers and patients with neurological disorders. This approach has the potential to be used in broad clinical applications and in better understanding of brain vascular pathophysiology. In the video, we demonstrate how to set up the system inside an MRI suite and how to perform a complete experiment on a human participant.

Because oxidative metabolism is the primary form of energy production in the brain, the amount of oxygen consumed by the brain, denoted by a physiological parameter termed cerebral metabolic rate of oxygen (CMRO2), represents a key marker for tissue viability and brain function. Quantitative assessment of cerebral oxygen metabolism in the neonate may provide an important marker in better understanding normal brain development and in making diagnosis and treatment decisions in neonatal brain injuries. Measurement of CMRO2 in humans has been a challenging task, particularly in neonates. Recently, several promising techniques have been proposed to quantify neonatal CMRO2 and the purpose of this article is to provide a technical review of these techniques. Among these, we will focus the review on the NIRS optic based methods and MRI methods which are non-invasive, have been applied in normal and sick newborns and show great potentials. Potential clinical prospects of CMRO2 techniques are discussed in the context of their advantages, challenges and limitations., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Importance: Cerebrovascular reactivity (CVR) is an inherent indicator of the dilatory capacity of cerebral arterioles for a vasomotor stimulus for maintaining a spontaneous and instant increase of cerebral blood flow (CBF) in response to neural activation. The integrity of this mechanism is essential to preserving healthy neurovascular coupling; however, to our knowledge, no studies have investigated whether there are CVR abnormalities in multiple sclerosis (MS)., Objective: To use hypercapnic perfusion magnetic resonance imaging to assess CVR impairment in patients with MS., Design, Setting, and Participants: A total of 19 healthy volunteers and 19 patients with MS underwent perfusion magnetic resonance imaging based on pseudocontinuous arterial spin labeling to measure CBF at normocapnia (ie, breathing room air) and hypercapnia. The hypercapnia condition is achieved by breathing 5% carbon dioxide gas mixture, which is a potent vasodilator causing an increase of CBF., Main Outcomes and Measures: Cerebrovascular reactivity was calculated as the percent increase of normocapnic to hypercapnic CBF normalized by the change in end-tidal carbon dioxide, which was recorded during both conditions. Group analysis was performed for regional and global CVR comparison between patients and controls. Regression analysis was also performed between CVR values, lesion load, and brain atrophy measures in patients with MS., Results: A significant decrease of mean (SD) global gray matter CVR was found in patients with MS (3.56 [0.81]) compared with healthy controls (5.08 [1.56]; P = .001). Voxel-by-voxel analysis showed diffuse reduction of CVR in multiple regions of patients with MS. There was a significant negative correlation between gray matter CVR and lesion volume (R = 0.6, P = .004) and a significant positive correlation between global gray matter CVR and gray matter atrophy index (R = 0.5, P = .03)., Conclusions and Relevance: Our quantitative imaging findings suggest impairment in functional cerebrovascular pathophysiology, by measuring a diffuse decrease in CVR, which may be the underlying cause of neurodegeneration in MS.

Importance: Disorders of brain metabolism are multiform in their mechanisms and manifestations, many of which remain insufficiently understood and are thus similarly treated. Glucose transporter type I deficiency (G1D) is commonly associated with seizures and with electrographic spike-waves. The G1D syndrome has long been attributed to energy (ie, adenosine triphosphate synthetic) failure such as that consequent to tricarboxylic acid (TCA) cycle intermediate depletion. Indeed, glucose and other substrates generate TCAs via anaplerosis. However, TCAs are preserved in murine G1D, rendering energy-failure inferences premature and suggesting a different hypothesis, also grounded on our work, that consumption of alternate TCA precursors is stimulated and may be detrimental. Second, common ketogenic diets lead to a therapeutically counterintuitive reduction in blood glucose available to the G1D brain and prove ineffective in one-third of patients., Objective: To identify the most helpful outcomes for treatment evaluation and to uphold (rather than diminish) blood glucose concentration and stimulate the TCA cycle, including anaplerosis, in G1D using the medium-chain, food-grade triglyceride triheptanoin., Design, Setting, and Participants: Unsponsored, open-label cases series conducted in an academic setting. Fourteen children and adults with G1D who were not receiving a ketogenic diet were selected on a first-come, first-enrolled basis., Intervention: Supplementation of the regular diet with food-grade triheptanoin., Main Outcomes and Measures: First, we show that, regardless of electroencephalographic spike-waves, most seizures are rarely visible, such that perceptions by patients or others are inadequate for treatment evaluation. Thus, we used quantitative electroencephalographic, neuropsychological, blood analytical, and magnetic resonance imaging cerebral metabolic rate measurements., Results: One participant (7%) did not manifest spike-waves; however, spike-waves promptly decreased by 70% (P = .001) in the other participants after consumption of triheptanoin. In addition, the neuropsychological performance and cerebral metabolic rate increased in most patients. Eleven patients (78%) had no adverse effects after prolonged use of triheptanoin. Three patients (21%) experienced gastrointestinal symptoms, and 1 (7%) discontinued the use of triheptanoin., Conclusions and Relevance: Triheptanoin can favorably influence cardinal aspects of neural function in G1D. In addition, our outcome measures constitute an important framework for the evaluation of therapies for encephalopathies associated with impaired intermediary metabolism.

With age, many aspects of the brain structure undergo a pronounced decline, yet individuals generally function well until advanced old age. There appear to be several compensatory mechanisms in brain aging, but their precise nature is not well characterized. Here we provide evidence that the brain of older adults expends more energy when compared to younger adults, as manifested by an age-related increase (P=0.03) in cerebral metabolic rate of oxygen (CMRO2) (N=118, men=56, ages 18 to 74). We further showed that, before the mean menopausal age of 51years old, female and male groups have similar rates of CMRO2 increase (P=0.015) and there was no interaction between age and sex effects (P=0.85). However, when using data from the entire age range, women have a slower rate of CMRO2 change when compared to men (P<0.001 for age×sex interaction term). Thus, menopause and estrogen level may have played a role in this sex difference. Our data also revealed a possible circadian rhythm of CMRO2 in that brain metabolic rate is greater at noon than in the morning (P=0.02). This study reveals a potential neurobiological mechanism for age-related compensation in brain function and also suggests a sex-difference in its temporal pattern., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Long-term cocaine use is known to negatively impact neural and cerebrovascular systems. However, the use of imaging markers to separately assess these parameters remains challenging. The primary reason is that most functional imaging markers, such as cerebral blood flow, functional connectivity, and task-evoked functional MRI, are known to reflect a complex interplay between neural and vascular components, thus the interpretation of the results is not straightforward. The goal of the present study is to examine neural-activity-specific changes in cocaine addiction, using cerebral metabolic rate of oxygen (CMRO2) as a surrogate marker of aggregated neural activity. We applied a recently developed CMRO2 technique in 13 cocaine-addicted subjects and 13 age- and gender-matched control subjects, and examined the impact of long-term cocaine use on CMRO2. Our results showed that CMRO2 in cocaine-addicted subjects (152 ± 16 µmol/100 g/min) is significantly lower (p = 0.031) than that in controls (169 ± 20 µmol/100 g/min). Furthermore, the severity of this decreased metabolism is associated with lifetime cocaine use (p = 0.05). Additionally, the CMRO2 reduction was accompanied by a trend of decrease in cerebral blood flow (p = 0.058), but venous oxygenation was unaffected (p = 0.96), which suggested that the CMRO2 change may be attributed to a vascular deficiency in chronic cocaine users. To our knowledge, this is the first study to measure CMRO2 in cocaine-addicted individuals. Our findings suggest that CMRO2 may be a promising approach for assessing the long-term effects of cocaine use on the brain., (Copyright © 2014 John Wiley & Sons, Ltd.)

Purpose: The calibratable relationship between blood oxygenation (Y) and T(2) allows quantification of cerebral venous oxygenation. We aim to establish a calibration plot between blood T(2) , Y, and hematocrit at 7 T, and using T(2) -relaxation-under-spin-tagging MRI, determine human venous blood oxygenation in vivo., Methods: In vitro experiments were performed at 7 T on bovine blood samples using a Carr-Purcell-Meiboom-Gill-T2 sequence, from which we characterized the relationship among T(2) , Y, and hematocrit. T(2) -relaxation-under-spin-tagging MRI was implemented at 7 T to measure venous blood T2 in vivo, from which oxygenation was estimated using the in vitro calibration plot. Hyperoxia was performed to test the sensitivity of the method to oxygenation changes, and the 7 T results were compared with those at 3 T., Results: In vitro data showed that arterial and venous T(2) at 7 T are 68 and 20 ms, respectively, at a typical hematocrit of 0.42. In vivo measurement showed a cerebral venous oxygenation of 64.7 ± 5.0% and a test-retest coefficient-of-variation of 3.6 ± 2.4%. Hyperoxia increased Yv by 9.0 ± 1.4% (P = 0.001) and the 3 and 7 T results showed a strong correlation (R = 0.95) across individuals., Conclusion: We provided an in vitro calibration plot for conversion of blood T(2) to oxygenation at 7 T and demonstrated its utility in vivo., (Copyright © 2013 Wiley Periodicals, Inc.)

The cerebral metabolic rate of oxygen (CMRO2) is the rate of oxygen consumption by the brain, and is thought to be a direct index of energy homeostasis and brain health. However, in vivo measurement of CMRO2 is challenging, in particular for the neonatal population, in whom conventional radiotracer methods are not applicable because of safety concerns. In this study, we propose a method to quantify global CMRO2 in neonates based on arteriovenous differences in oxygen content, and employ separate measurements of oxygenation and cerebral blood flow (CBF) parameters. Specifically, arterial and venous oxygenation levels were determined with pulse oximetry and the novel T2 relaxation under spin tagging (TRUST) MRI, respectively. Global CBF was measured with phase contrast (PC) flow velocity MRI. The proposed method was implemented on a standard 3-T MRI scanner without the need for any exogenous tracers, and the total scan duration was less than 5 min. We demonstrated the feasibility of this method in 12 healthy neonates within an age range of 35-42 gestational weeks. CMRO2 values were successfully obtained from 10 neonates. It was found that the average CMRO2 in this age range was 38.3 ± 17.7 µmol/100 g/min and was positively correlated with age (p = 0.007; slope, 5.2 µmol/100 g/min per week), although the highest CMRO2 value in this age range was still less than half of the adult level. Test-retest studies showed a coefficient of variation of 5.8 ± 2.2% between repeated CMRO2 measurements. In addition, given the highly variable blood flow velocity within this age range, it is recommended that the TRUST labeling thickness and position should be determined on a subject-by-subject basis, and an automatic algorithm was developed for this purpose. Although this method provides a global CMRO2 measure only, the clinical significance of an energy consumption marker and the convenience of this technique may make it a useful tool in the functional assessment of the neonatal population., (Copyright © 2014 John Wiley & Sons, Ltd.)

BOLD fMRI has provided a wealth of information about the aging brain. A common finding is that posterior regions of the brain manifest an age-related decrease in activation while the anterior regions show an age-related increase. Several neurocognitive models have been proposed to interpret these findings. However, one issue that has not been sufficiently considered to date is that the BOLD signal is based on vascular responses secondary to neural activity. Thus the above findings could be in part due to a vascular change, especially in view of the expected decline of vascular health with age. In the present study, we aim to examine age-related differences in memory-encoding fMRI response in the context of vascular aging. One hundred and thirty healthy subjects ranging from 20 to 89 years old underwent a scene-viewing fMRI task and, in the same session, cerebrovascular reactivity (CVR) was measured in each subject using a CO2-inhalation task. Without accounting for the influence of vascular changes, the task-activated fMRI signal showed the typical age-related decrease in visual cortex and medial temporal lobe (MTL), but manifested an increase in the right inferior frontal gyrus (IFG). In the same individuals, an age-related CVR reduction was observed in all of these regions. We then used a previously proposed normalization approach to calculate a CVR-corrected fMRI signal, which was defined as the uncorrected signal divided by CVR. Based on the CVR-corrected fMRI signal, an age-related increase is now seen in both the left and right sides of IFG; and no brain regions showed a signal decrease with age. We additionally used a model-based approach to examine the fMRI data in the context of CVR, which again suggested an age-related change in the two frontal regions, but not in the visual and MTL regions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

One of the main obstacles in quantitative interpretation of functional magnetic resonance imaging (fMRI) signal is that this signal is influenced by non-neural factors such as vascular properties of the brain, which effectively increases signal variability. One approach to account for non-neural components is to identify and measure these confounding factors and to include them as covariates in data analysis or interpretation. Previously, several research groups have independently identified four potential physiologic modulators of fMRI signals, including baseline venous oxygenation (Yv ), cerebrovascular reactivity (CVR), resting state BOLD fluctuation amplitude (RSFA), and baseline cerebral blood flow (CBF). This study sought to directly compare the modulation effects of these indices in the same fMRI session. The physiologic parameters were measured with techniques comparable with those used in the previous studies except for CBF, which was determined globally with a velocity-based phase-contrast MRI (instead of arterial-spin-labeling MRI). Using an event-related, scene-categorization fMRI task, we showed that the fMRI signal amplitude was positively correlated with CVR (P < 0.0001) and RSFA (P = 0.002), while negatively correlated with baseline Yv (P < 0.0001). The fMRI-CBF correlation did not reach significance, although the (negative) sign of the correlation was consistent with the earlier study. Furthermore, among the physiologic modulators themselves, significant correlations were observed between baseline Yv and baseline CBF (P = 0.01), and between CVR and RSFA (P = 0.05), suggesting that some of the modulators may partly be of similar physiologic origins. These observations as well as findings in recent literature suggest that additional measurement of physiologic modulator(s) in an fMRI session may provide a practical approach to control for inter-subject variations and to improve the ability of fMRI in detecting disease or medication related differences. Hum Brain Mapp 34:2078-2088, 2013. © 2011 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.)

Cerebral metabolic rate of oxygen (CMRO(2)) 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 CMRO(2) by concomitantly measuring oxygen-extraction-fraction using T(2)-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 CMRO(2) 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 (15) O 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 CMRO(2). The simplicity and reliability features may afford this global CMRO(2) technique great potential for immediate clinical applications., (Copyright © 2012 Wiley Periodicals, Inc.)

Characterizing the effect of oxygen (O(2)) modulation on the brain may provide a better understanding of several clinically relevant problems, including acute mountain sickness and hyperoxic therapy in patients with traumatic brain injury or ischemia. Quantifying the O(2) effects on brain metabolism is also critical when using this physiologic maneuver to calibrate functional magnetic resonance imaging (fMRI) signals. Although intuitively crucial, the question of whether the brain's metabolic rate depends on the amount of O(2) available has not been addressed in detail previously. This can be largely attributed to the scarcity and complexity of measurement techniques. Recently, we have developed an MR method that provides a noninvasive (devoid of exogenous agents), rapid (<5 minutes), and reliable (coefficient of variant, CoV <3%) measurement of the global cerebral metabolic rate of O(2) (CMRO(2)). In the present study, we evaluated metabolic and vascular responses to manipulation of the fraction of inspired O(2) (FiO(2)). Hypoxia with 14% FiO(2) was found to increase both CMRO(2) (5.0±2.0%, N=16, P=0.02) and cerebral blood flow (CBF) (9.8±2.3%, P<0.001). However, hyperoxia decreased CMRO(2) by 10.3±1.5% (P<0.001) and 16.9±2.7% (P<0.001) for FiO(2) of 50% and 98%, respectively. The CBF showed minimal changes with hyperoxia. Our results suggest that modulation of inspired O(2) alters brain metabolism in a dose-dependent manner.

A T(2) -relaxation-under-spin-tagging technique was recently developed to estimate cerebral blood oxygenation, providing potentials for noninvasive assessment of the brain's oxygen consumption. A limitation of the current sequence is the need for long repetition time, as shorter repetition time causes an over-estimation in blood R(2). This study proposes a postsaturation T(2)-relaxation-under-spin-tagging by placing a nonselective 90° pulse after the signal acquisition to reset magnetization in the whole brain. This scheme was found to eliminate estimation bias at a slight cost of precision. To improve the precision, echo time of the sequence was optimized and it was found that a modest echo time shortening of 3.4 ms can reduce the estimation error by 49%. We recommend the use of postsaturation T(2)-relaxation-under-spin-tagging sequence with a repetition time of 3000 ms and a echo time of 3.6 ms, which allows the determination of global venous oxygenation with scan duration of 1 min 12 s and an estimation precision of ± 1% (in units of oxygen saturation percentage)., (Copyright © 2011 Wiley Periodicals, Inc.)

Pseudo-continuous arterial spin labeling (PCASL) MRI is a relatively new arterial spin labeling technique and has the potential to extend the cerebral blood flow (CBF) measurement to all tissue types, including white matter. However, the arterial transit time (δ(a)) for white matter is not well established and a limited number of reports using multi-delay methods have yielded inconsistent findings. In this study, we used a different approach and measured white matter δ(a) (mean ± standard deviation, 1541 ± 173  ms) by determining the arrival times of exogenous contrast agent in a bolus tracking experiment. The data also confirmed δ(a) of gray matter to be 912 ± 209  ms. In the second part of this study, we used these parameters in PCASL kinetic models and compared relative CBF (rCBF, with respect to the whole brain) maps with those measured using a single photon emission computed tomography (SPECT) technique. It was found that the use of tissue-specific δ(a) in the PCASL model was helpful in improving the correspondence between the two modalities. On a regional level, the gray/white matter CBF ratios were 2.47 ± 0.39 and 2.44 ± 0.18 for PCASL and SPECT, respectively. On a single-voxel level, the variance between the modalities was still considerable, with an average rCBF difference of 0.27., (Copyright © 2011 John Wiley & Sons, Ltd.)

Recently, a T(2) -Relaxation-Under-Spin-Tagging (TRUST) MRI technique was developed to quantitatively estimate blood oxygen saturation fraction (Y) via the measurement of pure blood T(2) . This technique has shown promise for normalization of fMRI signals, for the assessment of oxygen metabolism, and in studies of cognitive aging and multiple sclerosis. However, a human validation study has not been conducted. In addition, the calibration curve used to convert blood T(2) to Y has not accounted for the effects of hematocrit (Hct). In this study, we first conducted experiments on blood samples under physiologic conditions, and the Carr-Purcell-Meiboom-Gill T(2) was determined for a range of Y and Hct values. The data were fitted to a two-compartment exchange model to allow the characterization of a three-dimensional plot that can serve to calibrate the in vivo data. Next, in a validation study in humans, we showed that arterial Y estimated using TRUST MRI was 0.837 ± 0.036 (N=7) during the inhalation of 14% O2, which was in excellent agreement with the gold-standard Y values of 0.840 ± 0.036 based on Pulse-Oximetry. These data suggest that the availability of this calibration plot should enhance the applicability of T(2) -Relaxation-Under-Spin-Tagging MRI for noninvasive assessment of cerebral blood oxygenation., (Copyright © 2011 Wiley-Liss, Inc.)

Cerebral blood volume (CBV) has been shown to be an important biomarker in a number of neurological disorders and in the quantitative interpretation of functional MRI. One approach to determine CBV in humans is vascular-space-occupancy MRI, and this technique has been applied to the studies of brain glioma, Schizophrenia, and Alzheimer's disease. However, validation of this technique with a gold standard method has not been reported. In this study, we compared vascular-space-occupancy MRI with a radiotracer-based positron emission tomography technique in a group of healthy subjects. It was found that regional CBV measured with vascular-space-occupancy MRI was highly correlated with that of the positron emission tomography data (R=0.79±0.10, N=8). Furthermore, absolute CBV values quantified by vascular-space-occupancy were also in excellent agreement with those by positron emission tomography (slope=1.00±0.15). Because of the differences in the labeling principles between the two modalities, systematic CBV differences were observed in large vessel and ventricle regions., (Copyright © 2010 Wiley-Liss, Inc.)

A major difference between arterial-spin-labeling MRI and gold-standard radiotracer blood flow methods is that the compartment localization of the labeled spins in the arterial-spin-labeling image is often ambiguous, which may affect the quantification of cerebral blood flow. In this study, we aim to probe whether the spins are located in the vascular system or tissue by using T2 of the arterial-spin-labeling signal as a marker. We combined two recently developed techniques, pseudo-continuous arterial spin labeling and T2-Relaxation-Under-Spin-Tagging, to determine the T2 of the labeled spins at multiple postlabeling delay times. Our data suggest that the labeled spins first showed the T2 of arterial blood followed by gradually approaching and stabilizing at the tissue T2. The T2 values did not decrease further toward the venous T2. By fitting the experimental data to a two-compartment model, we estimated gray matter cerebral blood flow, arterial transit time, and tissue transit time to be 74.0 ± 10.7 mL/100g/min (mean ± SD, N = 10), 938 ± 156 msec, and 1901 ± 181 msec, respectively. The arterial blood volume was calculated to be 1.18 ± 0.21 mL/100 g. A postlabeling delay time of 2 s is sufficient to allow the spins to completely enter the tissue space for gray matter but not for white matter., (© 2010 Wiley-Liss, Inc.)

BackgroundWith the disappointing outcomes of clinical trials on patients with Alzheimer's disease or mild cognitive impairment (MCI), there is increasing attention to understanding cognitive decline in normal elderly individuals, with the goal of identifying subjects who are most susceptible to imminent cognitive impairment.Purpose/hypothesisTo evaluate the potential of cerebral blood flow (CBF) as a biomarker by investigating the relationship between CBF at baseline and cognition at follow-up.Study typeProspective longitudinal study with a 4-year time interval.Population309 healthy subjects aged 20-89 years old.Field strength/sequence3T pseudo-continuous-arterial-spin-labeling MRI.AssessmentCBF at baseline and cognitive assessment at both baseline and follow-up.Statistical testsLinear regression analyses with age, systolic blood pressure, physical activity, and baseline cognition as covariates.ResultsLinear regression analyses revealed that whole-brain CBF at baseline was predictive of general fluid cognition at follow-up. This effect was observed in the older group (age ≥54 years, β = 0.221, P = 0.004), but not in younger or entire sample (β = 0.018, P = 0.867 and β = 0.089, P = 0.098, respectively). Among major brain lobes, frontal CBF had the highest sensitivity in predicting future cognition, with a significant effect observed for fluid cognition (β = 0.244 P = 0.001), episodic memory (β = 0.294, P = 0.001), and reasoning (β = 0.186, P = 0.027). These associations remained significant after accounting for baseline cognition. Voxelwise analysis revealed that medial frontal cortex and anterior cingulate cortex, part of the default mode network (DMN), are among the most important regions in predicting fluid cognition.Data conclusionIn a healthy aging cohort, CBF can predict general cognitive ability as well as specific domains of cognitive function.Level of evidence1 Technical Efficacy: Stage 3 J. MAGN. RESON. IMAGING 2018;48:449-458.

Most studies examining neurocognitive aging are based on the blood‐oxygen level‐dependent signal obtained during functional magnetic resonance imaging (fMRI). The physiological basis of this signal is neural–vascular coupling, the process by which neurons signal cerebrovasculature to dilate in response to an increase in active neural metabolism due to stimulation. These fMRI studies of aging rely on the hemodynamic equivalence assumption that this process is not disrupted by physiologic deterioration associated with aging. Studies of neural–vascular coupling challenge this assumption and show that neural–vascular coupling is closely related to cognition. In this review, we put forward a theory of processing speed decline in aging and how it is related to age‐related neural–vascular coupling changes based on the results of studies elucidating the relationships between cognition, cerebrovascular dynamics, and aging. Impact Statement: Theories of neurocognitive aging are based on conflicting results of functional magnetic resonance imaging‐blood‐oxygen‐level‐dependent imaging studies that probably reflect age‐differences in complex neural‐vascular signaling processes. In this review, we present evidence that supports a theory centering on the importance of cerebrovascular dynamics in age‐related cognitive decline. [ABSTRACT FROM AUTHOR]

Arterial spin labeling (ASL) has emerged as a technique for assessing mild traumatic brain injury (mTBI), as it can noninvasively evaluate cerebrovascular physiology. To date, there is substantial variability in methodology and findings of ASL studies of mTBI. While both increased and decreased perfusion are reported after mTBI, more consistency is emerging when perfusion is examined with regard to symptomology. We evaluated 15 teenage athletes two and six weeks after sports-related concussion (SRC group) using pseudo-continuous ASL. We acquired comparison data from 15 matched controls from a single time point. At each time point, we completed whole-brain contrasts to evaluate differences between the SRC group and controls in relative cerebral blood flow (rCBF). Cluster-level findings directed region of interest (ROI) analyses to test for group differences in rCBF across the left dorsal anterior cingulate cortex (ACC) and left insula. Finally, we evaluated ROI rCBF and symptomology in the SRC group. At two weeks post-injury, the SRC group had significantly higher rCBF in the left dorsal ACC and left insula than controls; at six weeks post-injury, elevated rCBF persisted in the SRC group in the left dorsal ACC. Perfusion in the left dorsal ACC was higher in athletes reporting physical symptoms six weeks post-injury compared with asymptomatic athletes and controls. Overall, these findings are inconsistent with reports of reduced rCBF after mTBI but coherent with studies that report increased perfusion in persons with greater or persistent mTBI-related symptomology. Future work should continue to assess how CBF perfusion relates to symptomology and recovery after mTBI. [ABSTRACT FROM AUTHOR]